Total synthesis of (+)-phorboxazole A, a potent cytostatic agent from the sponge Phorbas sp.

Article abstract of DOI:10.1039/b308305e

A convergent total synthesis of phorboxazole A (1a), from the C(3-19), C(20-27) and C(33-46) fragments 5, 4 and 91, respectively, concentrating on stereocontrolled formation of the bonds at C(2-3), C(19-20) and C(27-28), is described. Although a coupling reaction between a macrolide ketone and the side chain substituted sulfone, at C(27-28) was not successful, a Wadsworth-Emmons olefination involving the oxane methyl ketone 4 and an oxazole produced the oxane 90 which was next coupled to 91 leading to the C(20-46) unit 100. A further coupling of 100 to 71c at C(19-20) then led to 105, ultimately, and the synthesis was completed by a macrocyclisation reaction from 105, at the C(2-3) alkene bond, followed by deprotection of 106.

Full text of DOI:10.1039/b308305e

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Total synthesis of (؉)-phorboxazole A, a potent cytostatic agent
from the sponge Phorbas sp.
Gerald Pattenden,* Miguel A. González, Paul B. Little, David S. Millan, Alleyn T. Plowright,
James A. Tornos and Tao Ye
School of Chemistry, The University of Nottingham, University Park, Nottingham,
UK NG7 2RD. E-mail: gp@nottingham.ac.uk; Fax: ϩ44(0)115 951 3535;
Tel: ϩ44(0)115 951 3530
Received 22nd July 2003, Accepted 29th August 2003
First published as an Advance Article on the web 16th October 2003
A convergent total synthesis of phorboxazole A (1a), from the C(3–19), C(20–27) and C(33–46) fragments 5, 4
and 91, respectively, concentrating on stereocontrolled formation of the bonds at C(2–3), C(19–20) and C(27–28),
is described. Although a coupling reaction between a macrolide ketone and the side chain substituted sulfone, at
C(27–28) was not successful, a Wadsworth–Emmons olefination involving the oxane methyl ketone 4 and an oxazole
produced the oxane 90 which was next coupled to 91 leading to the C(20–46) unit 100. A further coupling of 100 to
71c at C(19–20) then led to 105, ultimately, and the synthesis was completed by a macrocyclisation reaction from 105,
at the C(2–3) alkene bond, followed by deprotection of 106.
Introduction
Synthetic strategy
Phorboxazole A (1) and its C-13 epimer phorboxazole B(2) are
unique oxane–oxazole-based macrolides isolated from a species
of Indian Ocean sponge of the genus Phorbas sp.1 The
compounds exhibit extraordinary cytotoxic activity (GI50 <8 ×
10Ϫ10 M) against the entire panel of human tumour cell lines
held at the National Cancer Institute. Together with the
spongiastatins2 the phorboxazoles are therefore the most
potent naturally occurring cytotoxic agents yet discovered.
Although their mechanism of action remains to be established,
phorboxazole A has been shown to arrest the cell cycle in the
S phase, whilst not inhibiting tubulin polymerisation or inter-
fering with the integrity of microtubules, thereby suggesting a
possibly unique mechanism.1b Their novel structure and potent
biological activity have combined to make the scarcely available
phorboxazoles attractive synthetic targets within the chemistry
community.3 Forsyth et al.4 published the first total synthesis
of phorboxazole A (1) in 1998, and this was followed by a
description of a synthesis of phorboxazole B (2) by Evans et al.
in 2000.5 During 2001 Smith and his collaborators6 described a
second synthesis of phorboxazole A, and two new syntheses of
this compound were reported contemporaneously in 2003 by
Williams et al.7 and from our own laboratory.8 Several other
research groups have described synthetic approaches to the
natural phorboxazoles,3 and a number of structure–activity
studies have been carried out.9 We now provide a full account of
our own total synthesis of (ϩ)-phorboxazole A (1).
The structure of phorboxazole A (1) is based on a 21-membered
macrolactone core, which accommodates a trans-fused oxane,
two cis-fused oxanes and an oxazole linked by one E- and one
Z-alkene bonds. A side chain is attached to the most substituted
cis-oxane in the macrolactone by an E-trisubstituted alkene
linked to a second oxazole, an oxane hemiacetal, an E,E-1,3-
diene unit, and terminating in an E-vinyl bromide. With the
three alkene bonds at C(2–3), C(19–20) and C(27–28) separat-
ing three structural units of comparable complexity, it was clear
from the outset of our studies that the ordered, stereocontrolled
formation of these alkenes would play a crucial role in any
successful total synthesis of phorboxazole A (1). In our
synthetic design we planned to synthesise the key units 3,10 411
and 5,12 and then to examine the coupling between 4 and 5 at
C(19–20) using an E-selective Wittig reaction, followed by an
intramolecular Z-selective Wadsworth–Emmons olefination
reaction at C(2–3) leading to the macrolactone core in phor-
boxazole A. We then felt we would be able to complete a
synthesis of phorboxazole using a Julia olefination with 3 (R =
SO2Ar) producing the C(27–28) E-alkene bond in the target.
We recognised, of course, that having the key units 3, 4 and 5,
and their synthetic precursors, available in quantity would
provide us with the necessary flexibility to assemble them in a
number of ways in order to achieve our objective. We therefore
first describe syntheses of the key units 3, 4, and 5, and then
summarise strategies for their assembly, leading ultimately to
phorboxazole A (1).
The C(28–46) polyene oxane–hemiacetal oxazole side chain 3
Our synthetic approach to the C(28–46) side chain portion 3
in phorboxazole A was based on using an E-selective Julia
benzothiazole sulfone olefination reaction13 between the sulfone
6 and the α,β-unsaturated aldehyde 7, as a key step.10 We then
planned to elaborate the substituted 1,3-diene product 8, from 6
and 7 to the C(31–46) fragment 9 as a prelude to conversion
into the substituted oxazole target 3.14 Both the sulfone 6 and
the α,β-unsaturated aldehyde 7 were easily synthesised from the
chiral pool compounds -malic acid and -xylose respectively,
as summarised in Schemes 1 and 2.
Thus, -malic acid was first converted into the PMB ether 11
via the known dioxolaneethanol 10,15 and then into the differen-
tially protected triol 13a using three straightforward synthetic
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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the corresponding aldehyde 22b, which on treatment with
camphorsulfonic acid in methanol led directly to the dimethyl
acetal 23. Oxidation of 23, using Dess–Martin periodinane,20
followed by a Wittig reaction between the resulting aldehyde
24 and (carbethoxyethylidene)triphenylphosphorane then led
exclusively to the E-unsaturated ester 25a. Finally, reduction
of 25a using DIBAL, and oxidation of the alcohol product
25b with Dess–Martin periodinane gave the E-αβ-unsaturated
aldehyde 7.
Deprotonation of the sulfone 6 using NaHMDS in THF at
Ϫ78 ЊC in the presence of the unsaturated aldehyde 7 led
smoothly to the E,E-1,3-diene 26 in 74% yield (<6% of the
corresponding Z-olefination product was produced concur-
rently) (Scheme 3). Deprotection of the dimethyl acetal group in
26, followed by treatment of the resulting aldehyde 27 with
ethyl diazoacetate, in the presence of Sn()Cl2,21 next led to the
β-keto ester 28. Removal of the PMB protecting group in 28,
using DDQ,22 resulted in spontaneous cyclisation of the inter-
mediate δ-hydroxy ketone producing a single diastereoisomer
of the cyclic hemiacetal 29a in 90% yield. Protection of 29a as
its methyl ether 29b, and deprotection of the terminal acetylene
steps. Deprotection of the PMB ether group in 13a, followed by
oxidation of the resulting alcohol 13b and treatment of the
corresponding aldehyde 14 with Seyferth’s reagent16 next led to
the terminal acetylene 15a (Scheme 1). The acetylene 15a
was then elaborated to the alcohol 16, which, on treatment with
2-mercaptobenzothiazole17 gave the sulfide 17. Oxidation of
17 using MCPBA then gave the benzothiazole sulfone inter-
mediate 6 as a stable crystalline solid.
The α,β-unsaturated aldehyde 7 required for a Julia olefin-
ation reaction with the sulfone 6 was prepared from -xylose
as outlined in Scheme 2. Thus, using literature precedent,18
-xylose was first converted into the known dithioacetal 18a
in four straightforward steps. Protection of the alcohol group in
18a as its PMB ether, followed by hydrolysis of the dithioacetal
next gave the aldehyde 19. Allylboration of 19, using allyl diiso-
pinocamphenylborane,19 followed by oxidation with H2O2–
NaOH led to the homoallylic alcohol 20a which, on methyl-
ation and deprotection of the acetonide was then converted
into the 1,2-diol 21. After protection of the 1,2-diol functional-
ity in 21, oxidative cleavage of the terminal double bond gave
Scheme 1 Reagents and conditions: i, BH3ؒSMe2, B(OEt)3; ii, Me2CO, pTSA, Cu()SO4, 77% (2 steps); iii, PMBCl, KOtBu, NBu4I; iv, pTSA,
MeOH, 69% (2 steps); v, TBDPSCl, Et3N, DMAP, 94%; vi, NaH, MeI, 87%; vii, DDQ, 95%; viii, (COCl)2, DMSO, Et3N, 90%; ix, (MeO)2PCHN2,
KOtBu, 75%; x, TBAF, 96%; xi, TMSCl, BuLi, 70%; xii, 2-mercaptobenzothiazole, PPh3, DEAD, 94%; xiii, MCPBA, NaHCO3, 85%.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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Scheme 2 Reagents and conditions: i, EtSH, HCl; ii, Me2CO, H2SO4; iii, KOBut, DMSO, 35%, three steps; iv, LiAlH4, 90%; v, KOBut, PMBBr, 98%;
vi Hg(ClO4)2, CaCO3, 91%; vii, a) (Ϫ)-β-allyl diisopinocampheylborane, b), H2O2, NaOH, 82%; viii, KBuOt, MeI, 97%; ix, pTSA, MeOH, 88%;
x, TBSOTf, Et3N, 98%; xi, OsO4, NMO, NaIO4, 94% (two steps); xii, CSA, MeOH–DCM, 89%; xiii, Dess–Martin periodinane, 95%;
xiv, CH3C(PPh3)CO2Et, 94%; xv, DIBALH, Ϫ78 ЊC, 89%; xvi, Dess–Martin periodinane, 94%.
unit next led to 30, which on hydrostannylation and treatment
of the resulting vinylstannane with NBS23 in CH3CN at 0 ЊC
then gave the C(31–46) side chain portion 31 in the phorboxa-
zoles.10 The methyl ester corresponding to 31 was synthesised
contemporaneously, but using a different route, by Ahmed and
Forsyth.24 Saponification of the ester group in 31, followed
by coupling the resulting carboxylic acid with serine in the
presence of EDC–HOBT next led to the amide 32 which, by
stepwise cyclodehydration, to 33, and oxidation led to the
substituted oxazole ester 34.25 The synthesis of the sulfone 36
was then completed following reduction of the ester 34 to the
corresponding alcohol 35a, mesylation to 35b, displacement of
the mesylate using the sodium salt of 2-mercaptobenzothiazole
and, finally, oxidation of the resulting sulfide with H2O2 in the
presence of ammonium molybdate (Scheme 3).
of the resulting epoxy-alcohol 48 with titanium tetraiso-
propoxide in refluxing benzene,32 gave the 2,6-cis oxane 49 with
the absolute stereochemistry shown.33
The vicinal diol unit in 49 was next converted into the corre-
sponding terminal epoxide 50, which was then elaborated to
the protected secondary alcohol 51b in two steps. Oxidative
cleavage of the alkene bond in 51b, followed by protection of
the resulting aldehyde 52 as its dimethyl acetal and deprotection
of the silyl ether group led to 53 which on oxidation using
Dess–Martin periodinane finally gave the methyl ketone 4.
The C(3–19) bis-oxane oxazole unit 5
A number of alternative, but complementary, methods for
the synthesis of the cis,trans bis-oxane portion and the corre-
sponding C(3–19) bis-oxane oxazole unit 5 in phorboxazole A,
have been published over the period 1997–2003.34 These
strategies have been based largely on use of the Williamson
ether synthesis and the hetero Diels–Alder reaction,3 but also
some interesting catalytic asymmetric aldol methodology5 and
exploitation of the Petasis–Ferrier rearrangement.6 Our own
synthesis of the bis-oxane oxazole unit 5 was based on an
oxy-anion intramolecular Michael reaction35 of 60 leading to
the cis-oxane intermediate 61, followed by conversion of the
oxazolidine unit in 61 to the corresponding oxazole 63, and
completed by an intramolecular (Williamson) cyclisation of 69
to give the trans-oxane ring in 70 (Scheme 5).12
The C(20–26) pentasubstituted oxane unit 4
The 2,6-cis oxane unit 4 in the phorboxazoles contains five of
the fifteen asymmetric centres in the natural products. Several
solutions to the synthesis of this oxane have now been
developed.26 Our own synthesis, which is summarised in
Scheme 4, started with the chiral pool ester 37, and proceeded
via the protected 1,3,5-triol 42 and the epoxide 48 as key inter-
mediates.11 Thus, following the conversion of methyl (S)-3-
hydroxy-2-methylpropionate 3727 into the known aldehyde 38,28
a crotylboration reaction using (Ϫ)-methoxydiisopinocamphey-
borane and E-2-butene29 next led to the substituted secondary
alcohol 39 with 98% diastereoselectivity and in 76% yield.
The protecting groups in 39 were then interchanged and the
resulting alkene 40b was cleaved oxidatively producing the
corresponding aldehyde 41. Allylation of 41 in a substrate-
controlled manner, using allyltributyltin and BF3ؒOEt2
catalysis30 next gave rise to the homoallylic alcohol 42 in 94%
yield and with 96% diastereoselectivity. A series of functional
group manipulations was then used to convert the secondary
alcohol 42 into the primary alcohol 43b and then to the
aldehyde 44. A Wadsworth–Emmons olefination with 44 next
produced the E-αβ-unsaturated ester 45 which on reduction
using DIBAL at Ϫ78 ЊC led to the allylic alcohol 46. Epoxid-
ation of 46 under Sharpless conditions31 using (ϩ)-diethyl
tartrate then gave rise to the key epoxide intermediate 47 in
excellent yield and with excellent diastereoselectivity. Depro-
tection of the silyl ether group in 47, followed by treatment
Thus, allylboration of Garner’s aldehyde 5436 first gave the
homoallylic alcohol 55a in 80% yield and with 92% dia-
stereoselectivity. Ozonolysis of the protected alcohol 55b,
followed by a second allylboration19 of the resulting aldehyde
56 next gave the corresponding homoallylic alcohol 57a which
was protected as its TIPS ether 57b. Oxidative cleavage of the
double bond in 57, by ozonolysis, then gave the aldehyde 58,
which was converted into the E-unsaturated ester 59 using a
Wittig reaction with (carboethoxymethylene)triphenylphos-
phorane. Deprotection of the TES group in 59 then revealed the
7-hydroxy unsaturated ester 60 which underwent a smooth and
selective intramolecular oxy anion Michael reaction35 in the
presence of NaHMDS at Ϫ78 ЊC leading to the cis-oxane 61 in
88% yield. A small amount (<10%) of the corresponding trans-
oxane was produced concurrently and was easily separated by
routine chromatography. The oxazole ring in the next key
intermediate en route to 5 was elaborated from the oxazolidine
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Scheme 3 Reagents and conditions: i, NaHMDS, Ϫ78 ЊC, then 7, 74%; ii, Me2BBr, Ϫ78 ЊC, 95%; iii, EtO2CCHN2, SnCl2, 74%; iv, DDQ, 96%;
v, PPTS, MeOH, 59%; vi, AgNO3, KCN, 75%; vii, a) Bu3SnH, AIBN, PhH, ∆, b) NBS, 60%, two steps; viii, a) LiOH, MeOH, b) Et3N, serine, EDC,
HOBT, 91%; ix, DAST, Ϫ78 ЊC, 98%; x, BrCCl3, DBU, 66%; xi, DIBAL-H, Ϫ78 ЊC, 98%; xii, Et3N, MsCl, xiii, a) NaHMDS, 2-
mercaptobenzothiazole, 38%; b), (NH4)6Mo7O24, 30% H2O2, MeOH, 60%.
61, following deprotection and conversion of the resulting
β-hydroxyamine to the amide 62a, oxidation to the corre-
sponding aldehyde 62b and cyclisation to 63 using literature
conditions.37 NOE studies with the oxazole cis-oxane 63
confirmed the geometry of this intermediate.
An alternative synthesis of the oxazole cis-oxane 63 was
developed later, which was more amenable to producing
multigram quantities of this key intermediate. In this
sequence the oxazole aldehyde 72 was first prepared starting
from ethyl bromopyruvate and cinnamamide.38 When the alde-
hyde 72 was next treated with Corey’s allylborane39 derived
from 1,2-diphenylethane-1,2-diamine in methylene chloride at
Ϫ78 ЊC an excellent yield of the corresponding alcohol 73 was
produced in >95% ee. Using the same sequence of reactions we
had used in converting the homoallylic alcohol 55a to 61, the
alcohol 73 was then elaborated to 63 in nine straightforward
steps.
In our preliminary publication,12 we showed that the second,
trans-oxane ring in 5 could be introduced via the epoxide 66
derived from 63, following sequential conversion to the alde-
hyde 64a, the alkene 64b, the vicinal diol 6540 and cyclisation of
the tosylate derived from 65. Unfortunately, we observed no
diastereoselectivity during the conversion of 64b into 66. Not
withstanding this disappointment, we decided to press on with
our synthesis of the penultimate precursor 69 to the bis-oxane
70, and examine the reaction of the epoxide 66 with the cuprate
intermediate derived from the vinyl iodide 67. The iodide 67
was produced from ()-malic acid 74 as shown in Scheme 6.
Thus, exhaustive reduction of 74 first led to the corresponding
1,2,4-triol which was then protected as the pivaloyl acetonide
75. Deprotection of the acetonide unit in 75 next gave the 1,2-
diol 76 which was then converted into the epoxide 77, using
a three-step sequence developed by Kolb and Sharpless.41
Treatment of 77 with the anion derived from trimethyl-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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n
Scheme 4 Reagents and conditions: i, BuLi, KOtBu, trans-2-butene, (Ϫ)-methoxydiisopinocampheylborane, Ϫ78 ЊC, BF3ؒEt2O, then 38, NaOH,
30% H2O2, 76%; ii, a) CF3SO3H, 4-methoxybenzyl 2,2,2-trichloroacetimidate; b) TBAF, 54%; iii, BzCl, pyridine, DMAP, 91%; iv, a) OsO4, NMO;
b) NaIO4, pH = 7 buffer, 87%; v, BF3ؒEt2O, Bu3SnCH2CH᎐CH2, Ϫ78 ЊC, 94%; vi, 2,6-lutidine, TESOTf, Ϫ50 ЊC; vii, DIBAL-H, Ϫ78 ЊC, 82% (two
᎐
steps); viii, (COCl)2, DMSO, < Ϫ60 ЊC, then 43b, Et3N; ix, NaHMDS, EtO2CCH2P(O)(OEt)2, Ϫ78 ЊC, 63% (two steps); x, DIBAL-H, Ϫ78 ЊC, 89%;
xi, -(+)-diethyl tartrate, Ti(iOPr)4, tBuOOH, 4 Å sieves, Ϫ25 ЊC, 98%; xii, TBAF, 0 ЊC, 86%; xiii, Ti(OiPr)4, PhH, 76%; xiv, Ts-imidazole, NaH, Et2O,
Ϫ78 ЊC to 0 ЊC, 60%; xv, LiAlH4, Et2O, 75%; xvi, TBSOTf, 2,6-lutidine, DCM, Ϫ78 ЊC to rt, 95%; xvii, a) OsO4, NMO, acetone–water; b) NaIO4 on
silica, DCM, 88%; xviii, CSA, MeOH–DCM; xix, Dess–Martin periodinane, 2,6-lutidine, DCM, 72% (two steps).
silylacetylene gave the secondary alcohol 78a which was then
elaborated to the monosubstituted acetylene 79, via 78b.
Hydroiodination of 79, using 9-iodo-9-borabicyclo[3.3.1]-
nonane, under the conditions of Suzuki et al.,42 next led to the
vinyl iodide 80a which was then deprotected to 81, via 80b, and
finally elaborated to the vinyl iodide 67. When the epoxide 66
was treated with the cuprate intermediate derived from the vinyl
iodide 67, a mixture of epimeric alcohols 68 was produced. The
alcohol was converted into the mesylate diol 69 which then
underwent oxane ring formation in the presence of Et3N
producing a 1:1 mixture of trans- 70a and cis oxanes in 78%
yield. The diastereoisomeric oxanes were separated cleanly by
chromatography to afford the required oxazole bis-oxane 70a in
a 37% yield. The same oxazole bis-oxane unit 70, but with
different protecting groups, was synthesised independently by
Forsyth, Evans, Smith and Williams and their respective
collaborators during the course of our studies.4–7 Indeed, we
found that the strategy developed by Williams et al.43 for the
synthesis of the pivaloate 70b from the aldehyde 64a produced
from the ester 63 was superior to our own route for producing
gram quantities of the oxazole bis-oxane 71. In this sequence,
asymmetric allylation of the aldehyde 64a using the reagent
derived from the allylstannane 82 and (S,S)-1,2-diamino-1,2-
diphenylethane bis-sulfonamide–BBr3 leads first to the differ-
entially protected polyol 83. Mesylation of 83, followed by
deprotection of the TBS ether and cyclisation of the resulting
alcohol then gave rise to the pivaloyl ester 84. Protection of 84
as its TIPS ether 70b,43 and saponification of the resulting
pivaloate finally gave the oxazole bis-oxane 70a, which
was identical with the same material we had synthesised
earlier.
The C(1–27) macrolide 89
With the three sub-units 3, 4 and 5 in phorboxazole A now
synthesised, we examined their assembly to the natural product
focusing on the stereocontrolled formation of the alkene bonds
at C(2–3), C(19–20) and C(27–28). Our first strategy was to link
the units 4 and 5 at C(19–20), and then to elaborate the macro-
lide 89 using an intramolecular Wadsworth–Emmons reaction
at C(2–3) which had been highlighted in the first synthesis of
phorboxazole A by Forsyth et al.4 We then planned to complete
the synthesis of 1a by linking 89 to 3 (R᎐SO Ar) using a stereo-
᎐
2
selective Julia reaction.13
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Scheme 5 Reagents and conditions: i, a) (+)-α-allyl diisopinocampheylborane, b) Et3N, H2O2, 80%; ii, TESCl, Et3N, DMAP, 90%; iii, a) O3,
NaHCO3, b) PPh3, 92%; iv, (+)-α-allyl diisopinocampheylborane, b) Et3N, H2O2, 76%; v, TIPSOTf, 2,6-lutidine, 92%; vi, a) O3, NaHCO3, b) PPh3,
95%; vii, Ph3PCHCO2Et, 87%; viii, PPTS, 84%; ix, NaHMDS, Ϫ78 ЊC, 88%; x, 4 M HCl, dioxane; xi, PMBOCH2CO2H, EDC, HOBt, Et3N, 75%
(2 steps); xii, Dess–Martin periodinane; xiii, a) 2,6-di-tbutylpyridine, PPh3, C2Br2Cl4, b) DBU, 73% (2 steps); xiv, DIBALH, 87%; xv, Ph3PCH3Br,
nBuLi, 60%; xvi, (DHQD)2PYR, K2OsO2(OH)4, K3Fe(CN)6, K2CO3, 95% (based on recovered SM); xvii, NaH, N-tosylimidazole, 76%; xviii, tBuLi,
2-Th-CuCNLi, 60% (based on recovered SM); xix, MsCl, Et3N; xx, CSA, MeOH, 60% (2 steps); xxi, Et3N, MeCN, heat, 78%; xxii, TBSOTf, Et3N,
DCM, 0 ЊC, 90%; xxiii, DDQ, 50 : 1 DCM–H2O, 0 ЊC–rt, 66%; xxiv, MsCl, iPr2NEt, DCM, Ϫ5 ЊC, 76%.
secondary alcohol 87a, which was then converted into the
bis-(2,2,2-trifluoroethyl)phosphonate ester 87b.4 Finally, depro-
tection of the two TBS groups in 87b, using camphorsulfonic
acid, and oxidation of the resulting diol using Dess–Martin
periodinane20 gave the aldehyde phosphonate intermediate 88.
Treatment of 88 under the conditions of Still and Gennari45
In pursuit of this goal, an E-selective Wittig reaction between
the oxane–aldehyde 52 and the phosphonium salt derived
from 70b via the oxazole bis-oxane mesylate 85, in the presence
of DBU44 first gave the oxazole tris-oxane 86a (Scheme 7).
Manipulation of the protecting groups in 86a next gave the
(K2CO3 in the presence of 18-crown-6) then gave the α,β-
unsaturated macrolide 89, but as a disappointing 3 : 2 mixture
of Z- and E- isomers.
In spite of model studies,46 whereby we showed that the
oxane methyl ketone 4 and oxazole methyl sulfones underwent
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Scheme 6 Reagents and conditions: i, BH3ؒSMe2, B(OEt)3, THF; ii, Me2CO, pTSA, Cu()SO4, 74% (2 steps); iii, PivCl, Et3N, DMAP, CH2Cl2, 96%;
iv, pTSA, MeOH, 83%; v, a) MeC(OMe)3, PPTS, CH2Cl2; b) CH3COBr, CH2Cl2; c) K2CO3, MeOH, 75%; vi,CH3SiCCH, BuLi, BF3OEt2, THF, 99%;
vii, TBAF, THF, 93%; viii, TBSOTf, 2,6-lutidine, CH2Cl2, 99%; ix, a) B-I-9BBN, pentane, b) AcOH, c) H2O2, NaOH; x, DIBALH, PhCH3, 91%;
xi, HFؒpy, THF, 96%; xii, CSA, 2,2-dimethoxypropane, 84%.
Julia olefination in the presence of NaHMDS at Ϫ78 ЊC,
leading to the corresponding E-alkenes, much to our chagrin
we were not able to realise a similar coupling reaction between
the macrolide methyl ketone 89 and the side-chain substituted
sulfone 36, and complete a synthesis of phorboxazole A using
this strategy.
Side chain attachment to C(20–27) oxane 4
Following the disappointing outcome of our attempts to
directly link the macrolide portion 89 to the side chain residue
36 in phorboxazole, we decided to follow a new strategy to the
natural product. This strategy was based on first attaching
the oxane methyl ketone 4 to the side chain oxazole at C(27–28)
leading to the oxane–oxazole 90. Encouraged by precedent
established by Evans et al.5b and others,47 we next planned to
couple the side chain lactone 91 to the methyloxazole 90 using
metallation chemistry, leading to the cyclic hemiacetal 92.
Manipulation of the functionality in 92 followed by addition of
the oxazole bis-oxane 5, at C(19–20), was then expected to lead
to a precursor, viz 93, for macrolide formation at C(2–3) and
phorboxazole A itself (Scheme 8).
Scheme 7 Reagents and conditions: i, Bu3P–DMF, then 52, DBU; 99% ii, LiOH, THF–MeOH–H2O; 96% iii, DDQ, DCM, pH = 7 buffer; 86%
iv, TBSCl, imid., DMF; 73% v, (CF3CH2O)2P(O)CH2CO2Me, PhCH3; 60% vi, CSA, MeOH–DCM; 93% vii, Dess–Martin periodinane, DCM; 92%
viii, K2CO3, 18-crown-6, PhCH3; 3 : 2 mixture of Z/E-somers; 77%.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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Scheme 8
Scheme 9 Reagents and conditions: i, TBAF, 92%; ii, a) Cp2Zr(H)Cl, DCM, b) NBS, 88% (2 steps); iii, (NH4)6Mo7O24, 30% H2O2, THF–MeOH,
95%; iv, NaHMDS, then 7, THF, Ϫ78 ЊC to rt, 93%; v, Me2BBr, Et2O, Ϫ78 ЊC, 98%; vi, DDQ, 10 : 1 DCM–H2O, 0 ЊC, 85%; vii, TPAP, NMO,
powdered 4 Å sieves, DCM, 82%.
With this end-game in focus, the δ-lactone 91 was first
prepared starting from the previously prepared aldehyde 7, and
the vinyl bromide sulfone 96 which was elaborated in three
straightforward steps via 94 and 95 from the acetylene
precursor 17 (Scheme 9). A Julia reaction13 between 7 and 96
in the presence of NaHMDS at Ϫ78 ЊC gave the all-E triene
97 exclusively and in 93% yield. Sequential deprotection of
the dimethylacetal and PMB groups in 97, using dimethyl-
boron bromide48 and DDQ respectively, next gave the cyclic
hemiacetal 98 which, on oxidation with TPAP–NMO, then led
to the δ-lactone 91.
introduction of the oxazole bis-oxane unit 5, leading to an
intermediate whose functionality could be manipulated to the
penultimate precursor 93 for macrolide construction and
the natural product itself. In the total syntheses of the phor-
boxazoles described by Evans, Smith and Williams, and
their respective collaborators, the oxazole bis-oxane unit 5 was
attached to the pentasubstituted oxane residue 4 using an
E-selective Wittig reaction at C(19–20) involving the phos-
phonium salt derived from 71c and an appropriately sub-
stituted oxane aldehyde. We also used this strategy. Thus,
selective cleavage of the dimethylacetal unit in 100b, using
dimethylboron bromide, first gave the corresponding oxane
aldehyde 101 in excellent yield. Treatment of the mesylate
71c with tributylphosphine led to the corresponding phos-
phonium salt which, in situ, was treated with the aldehyde 101,
followed by DBU, leading to the E-alkene 102 in 87% overall
yield.
A
Wadsworth–Emmons reaction between the oxazole
phosphonate ester 99 and the oxane methyl ketone 4, under
optimized conditions, in the presence of LDA at Ϫ78 ЊC gave
exclusively the E-alkene 90. When the substituted 2-methyl-
oxazole 90 was deprotonated with LDA, generated in situ, at
Ϫ78 ЊC and then treated with the lactone 91 the desired cyclic
hemiketal 100a was obtained next in high yield and was
immediately protected as its corresponding triethylsilylketal
100b in 66% overall yield (Scheme 10).
Completion of phorboxazole A (1)
With the three key units 3, 4, and 5 linked together in the shape
of 102 we were now poised to construct the macrolide portion
in phorboxazole A and complete its total synthesis. Accord-
ingly, selective cleavage of the primary TBS ether in 102, with
Introduction of the oxazole bis-oxane unit 5
The next major step towards phorboxazole A required
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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Scheme 10 Reagents and conditions: i, LDA, Ϫ78 ЊC, 30 min, then 4, 89% (49% conversion); ii, Et2NH, nBuLi,THF, Ϫ78 ЊC, then 91; iv, TESOTf, py,
10 : 1 MeCN–Et2O, Ϫ47 ЊC, 36 h, 74% (66% conversion, two steps); v, Me2BBr, Et2O, Ϫ78 ЊC, 85%; vi, 71c, Bu3P, DMF, then 101 and DBU, rt to 0 ЊC,
87%; vii, HFؒpyr, pyr, THF, 0 ЊC to rt, 65–70%; viii, Dess–Martin periodinane, py, DCM, 94%.
HFؒpyridine5a at 0 ЊC proceeded smoothly to give the alcohol
Experimental
General details
103a, which was then oxidised to the corresponding aldehyde
103b using Dess–Martin periodinane.20 Removal of the PMB
protecting group in 103b with DDQ in CH2Cl2 at room temper-
ature next led to the secondary alcohol 104 (Scheme 11), which
was converted into the corresponding fluorophosphonate 105
by acylation with bis(2,2,2-trifluoroethyl)phosphonoacetic acid
in the presence of EDC and HOBT.4 Finally, intramolecular
cyclisation of the aldehyde-phosphonate 105, under the con-
ditions of Still and Gennari,45 gave the Z-αβ-unsaturated
macrolide 106, which was found to contain 20–25% of the
corresponding E-isomer. The proportion of the E-isomer in
the mixture followed from examination of the absorptions
associated with the E-(δ 6.90 and 5.85 ppm) and Z-(δ 5.92 ppm)
olefinic H-atoms in the 1H NMR spectrum of mixtures; similar
Z : E-ratios were observed by Forsyth et al.,4 Smith et al.6 and
by Williams et al.7 during their contemporaneous studies of this
macrocyclisation approach to phorboxazole A. Removal of the
three silyl ether protecting groups in 106 with tetrabutyl-
ammonium fluoride in THF at 0 ЊC followed by purification by
reversed phase HPLC then gave phorboxazole A (1a) whose 1H
and 13C NMR spectra, together with HRMS and optical
rotation data corresponded to those reported for the natural
product.1a
Melting points were determined on a Kofler hot-stage appar-
atus and are uncorrected. Optical rotations were recorded in
spectroscopic grade chloroform or dichloromethane on a Jasco
DIP-370 polarimeter at ambient temperature. [α]D values are
recorded in units of 10Ϫ1 deg cm2 gϪ1. Infrared spectra were
obtained using a Perkin-Elmer 1600 series FT-IR instrument or
a Nicolet Magna 550 instrument either as liquid films or as
dilute solutions in spectroscopic grade chloroform. Proton (1H)
NMR spectra were recorded on either a Bruker WM 250
(250 MHz), a Bruker DPX 360 (360 MHz), a Bruker AM
400 (400 MHz), a Bruker DRX 500 (500 MHz), a Varian Unity
300 (300 MHz), a Varian Inova 400 (400 MHz) or a Jeol EX 270
(270 MHz) spectrometer as dilute solutions in deuterochloro-
form, unless otherwise stated. The chemical shifts are quoted in
parts per million (ppm) relative to residual chloroform as
internal standard (δ 7.27) and the multiplicity of each signal is
designated by the following abbreviations: s, singlet; d, doublet;
t, triplet; q, quartet; qu, quintet; b, broad; m, multiplet; app,
apparent. The axial and equatorial protons that are found in
six-membered rings are abbreviated as: ax, axial; eq, equatorial.
All coupling constants are quoted in hertz. Carbon-13 (13C)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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Scheme 11 Reagents and conditions: i, DDQ, DCM–pH = 7 buffer, 85%; ii, EDClؒMeI, HOBT, HO2CCH2PO(OCH2CF3)2, DCM, >80%;
iii, K2CO3, 18-crown-6, PhCH3, rt, 3 : 1 mixture of Z/E-isomers, 82%; iv, TBAF, THF, 0 ЊC–rt, 75%; RP-HPLC purification.
NMR spectra were recorded on either a Bruker DPX 360
(at 90.6 MHz), a Bruker DRX 500 (at 125.8 MHz) or a Jeol
EX-270 (at 67.8 MHz) instrument as dilute solutions in
deuterochloroform, unless otherwise stated. Chemical shifts are
reported relative to internal chloroform standard (δ 77.0) on a
broad band decoupled mode, and the multiplicities determined
(4R)-2Ј-(2,2-Dimethyl-[1,3]-dioxolan-4-yl)-ethanol
(10).
Borane–methyl sulfide complex (26 ml, 0.27 mol) was added
dropwise over 50 min to a stirred solution of ()-(ϩ)-malic acid
(12 g, 89 mmol) and trimethyl borate (41 g, 0.39 mol) in THF
(120 ml) at 0 ЊC under a nitrogen atmosphere. The mixture was
warmed to room temperature, then stirred at this temperature
for 44 h before it was quenched, at 0 ЊC, by the slow dropwise
addition of methanol (100 ml). The mixture was stirred at room
temperature for 30 min and then concentrated in vacuo.
Methanol (2 × 100 ml) was added to the residue and then
removed in vacuo to leave 1,3-dihydroxybutanol as an opaque
oil which was used without further purification.
Anhydrous copper() sulfate (11.2 g, 45 mmol) and para-
toluenesulfonic acid monohydrate (0.34 g, 1.8 mmol) were
added separately, each in one portion, to a stirred solution of
the crude dihydroxybutanol in acetone (300 ml) at room tem-
perature under a nitrogen atmosphere. The mixture was stirred
at room temperature for 48 h, then solid sodium hydrogen-
carbonate (0.8 g) was added in one portion and the mixture was
stirred for 20 min. The mixture was filtered and the filtrate was
concentrated in vacuo to leave a light blue oil. Purification by
flash chromatography, using 40% ethyl acetate–petroleum ether
(bp 40–60 ЊC) as eluent, gave the acetonide15 (10.1 g, 77%) as a
colourless oil; [α]2D1 ϩ3.1 (c 0.9 in CHCl3); νmax (soln: CHCl3)/
cmϪ1 3534, 2946, 1372, 1152, 981; 1H NMR (360 MHz, CDCl3)
δ 4.22–4.32 (1H, m, H-4), 4.09 (1H, dd, J 8.1, 6.0, H-5), 3.79
(2H, dd, J 10.8, 5.5, H-1Ј), 3.59 (1H, dd, J 8.1, 7.4, H-5), 2.36
(1H, bt, J 4.9, OH ), 1.84–1.79 (2H, m, H-2Ј), 1.42 (3H, s,
CCH3), 1.36 (3H, s, CCH3); 13C NMR (67.8 MHz, CDCl3)
δ 109.3 (s), 75.1 (d), 69.7 (t), 60.5 (t), 36.0 (t), 27.1 (q), 25.9 (q);
m/z (EI) Found 131.0706 ([M Ϫ CH3]ϩ C6H11O3 requires
131.0708).
1
using a DEPT sequence. Where required, H–1H COSY and
NOE spectra were recorded on a Bruker DPX 360 (360 MHz)
or a Bruker DRX 500 (500 MHz) instrument using standard
Bruker software with no modifications. Mass spectra were
recorded on a VG Autospec, a MM-701CF, a VG Micromass
7070E or a Micromass LCT spectrometer using electron ionis-
ation (EI), fast atom bombardment (FAB), chemical ionisation
(CI) or electrospray ionisation (ESI) techniques. Microanalyt-
ical data were obtained on a Perkin-Elmer 240B elemental
analyser.
Flash chromatography was performed on Merck silica gel
60 as the stationary phase and the solvents employed were
either of analytical grade or were distilled before use. All
reactions were monitored by thin layer chromatography
(TLC) using Merck silica gel 60 F254 precoated aluminium
backed plates which were visualised with ultraviolet light
and then with either acidic alcoholic vanillin solution, basic
potassium permanganate solution, or acidic anisaldehyde
solution.
Routinely, dry organic solvents were stored under nitrogen
and/or over sodium wire. Other organic solvents were dried by
distillation from the following: THF and benzene (potassium
benzophenone ketyl), dichloromethane (calcium hydride) and
methanol (magnesium methoxide). Other organic solvents and
reagents were purified by the accepted literature procedures.
Dess–Martin periodinane was prepared according to the
modified procedure of Ireland and Liu.49 Dimethyl α-diazo-
methylphosphonate was prepared by the procedure of
Seyferth.16 All organic extracts were dried as stated. Solvent
was removed on a Büchi rotary evaporator. Where necessary,
reactions requiring anhydrous conditions were performed in a
flame or oven dried apparatus under a nitrogen or argon
atmosphere as stated.
(4R)-4-[2Ј-(4-Methoxybenzyloxy)-ethyl]-2,2-dimethyl-[1,3]-
dioxolane (11). Potassium tert-butoxide (11.6 g, 104 mmol) was
added in three portions over 10 min to a stirred solution of the
alcohol (10) (10.1 g, 69.1 mmol) in THF (250 ml) at 0 ЊC under
a nitrogen atmosphere. The yellow solution was stirred at 0 ЊC
for 15 min and then 4-methoxybenzyl chloride (13.0 g, 10.5 ml,
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76.0 mmol) was added dropwise over 20 min followed by
tetrabutylammonium iodide (2.55 g, 6.91 mmol) in one portion.
The mixture was stirred at room temperature for 12 h and then
quenched by addition of a saturated aqueous solution of
sodium hydrogencarbonate (80 ml). The separated aqueous
layer was extracted with ethyl acetate (3 × 200 ml) and the
combined organic extracts were then dried (MgSO4) and con-
centrated in vacuo to leave a yellow oil. Purification by flash
chromatography, using 12% ethyl acetate–petroleum ether (bp
40–60 ЊC) as eluent, gave the benzyloxy derivative (15.1 g, 82%)
as a light yellow oil; [α]2D1 Ϫ1.0 (c 1.6 in CHCl3) (Found: C, 67.2;
H, 8.4. C15H22O4 requires C, 67.6; H, 8.3%); νmax (soln: CHCl3)/
cmϪ1 2838, 1613, 1099; 1H NMR (360 MHz, CDCl3) δ 7.25 (2H,
d, J 8.7, CH, Ar), 6.88 (2H, d, J 8.7, CH, Ar), 4.45 (2H, s,
CH2Ar), 4.16–4.26 (1H, m, H-4), 4.06 (1H, dd, J 8.0, 5.9, H-5),
3.82 (3H, s, OCH3), 3.59–3.53 (3H, m, H-5, H-1Ј), 1.95–1.89
(1H, m, H-2Ј), 1.87–1.81 (1H, m, H-2Ј), 1.41 (3H, s, CCH3),
1.36 (3H, s, CCH3); 13C NMR (67.8 MHz, CDCl3) δ 159.1 (s),
130.4 (s), 129.2 (d), 113.7 (d), 108.5 (s), 73.9 (d), 72.7 (t), 69.6
(t), 66.7 (t), 55.2 (q), 33.8 (t), 26.9 (q), 25.7 (q); m/z (EI) Found
266.1510 (Mϩ C15H22O4 requires 266.1518).
3.68–3.56 (4H, m, H-1, H-4), 2.88 (1H, d, J 3.5, OH ), 1.7–1.83
(2H, m, H-3), 1.08 (9H, s, C(CH3)3); 13C NMR (67.8 MHz,
CDCl3) δ 159.1 (s), 135.5 (d), 133.2 (s), 130.2 (s), 129.7 (d),
129.2 (d), 127.7 (d), 113.7 (d), 72.8 (t), 70.4 (d), 67.7 (t), 67.5 (t),
55.2 (q), 32.9 (t), 26.8 (q), 19.2 (s); m/z (FAB) Found 463.2312
([M Ϫ H]ϩ C28H35O4Si requires 463.2305).
(2R)-tert-Butyl-[2-methoxy-4-(4-methoxybenzyloxy)-butoxy]-
diphenylsilane (13a). A solution of the alcohol (12b) (21.3 g,
45.9 mmol) in THF (80 ml) was added dropwise over 30 min
to a stirred suspension of sodium hydride (60% dispersion in
mineral oil, 5.5 g, 138 mmol) in THF (320 ml) at 0 ЊC under a
nitrogen atmosphere. The mixture was stirred at 0 ЊC for 45 min
and then methyl iodide (32.5 g, 14.3 ml, 229 mmol) was added
dropwise over 30 min. The mixture was warmed to room
temperature and stirred at this temperature for 15 h before it
was quenched with a saturated aqueous solution of ammonium
chloride (100 ml). The mixture was concentrated in vacuo to
leave an aqueous residue, which was taken up in ethyl acetate
(200 ml). The separated aqueous layer was extracted with ethyl
acetate (3 × 200 ml), and the combined organic extracts were
then dried (MgSO4) and concentrated in vacuo to leave a yellow
oil. Purification by flash chromatography, using 8% ethyl
acetate–petroleum ether (bp 40–60 ЊC) as eluent, gave the
methyl ether (19.0 g, 87%) as a colourless oil; [α]2D0 ϩ14.1 (c 1.1
in CHCl3) (Found: C, 72.5; H, 8.1. C29H38O4Si requires C, 72.8;
(2R)-4-(4-Methoxybenzyloxy)-butane-1,2-diol (12a). para-
Toluenesulfonic acid (2.6 g, 13.6 mmol) was added in one
portion to a stirred solution of the acetonide (11) (18.1 g, 68.0
mmol) in methanol (360 ml) at 0 ЊC under a nitrogen atmos-
phere. The mixture was warmed to room temperature and
stirred at this temperature for 12 h before it was quenched with
a saturated aqueous solution of sodium hydrogencarbonate
(120 ml). The methanol was removed in vacuo and the remain-
ing aqueous layer was then extracted with ethyl acetate (3 ×
250 ml, 1 × 100 ml). The combined organic extracts was dried
(Na2SO4) and concentrated in vacuo to leave a yellow oil. Purifi-
cation by flash chromatography, using 80% ethyl acetate–
petroleum ether (bp 40–60 ЊC), increasing to ethyl acetate as
eluent, gave the diol (12.6 g, 84%) as a light yellow oil; [α]2D1 Ϫ7.7
(c 1.0 in CHCl3) (Found: C, 63.9; H, 8.7. C12H18O4 requires C,
63.7; H, 8.0%); νmax (soln: CHCl3)/cmϪ1 3478, 2864, 1613, 1097;
1H NMR (360 MHz, CDCl3) δ 7.25 (2H, d, J 8.7, CH, Ar), 6.88
(2H, d, J 8.7, CH, Ar), 4.46 (2H, s, CH2Ar), 3.91–3.87 (1H, m,
H-2), 3.81 (3H, s, OCH3), 3.68–3.58 (3H, m, H-1, H-4), 3.50
(1H, dd, J 11.3, 5.3, H-1), 3.26 (1H, d, J 3.5, OH ), 2.54 (1H, t,
J 6.2, OH ), 1.84–1.77 (1H, m, H-3), 1.76–1.69 (1H, m, H-3);
13C NMR (67.8 MHz, CDCl3) δ 159.2 (s), 129.8 (s), 129.3 (d),
113.8 (d), 72.9 (t), 71.2 (d), 67.7 (t), 66.5 (t), 55.2 (q), 32.7 (t);
m/z (FAB) Found 227.1278 ([MH]ϩ C12H19O4 requires
227.1283).
1
H, 8.0%); νmax (soln: CHCl3)/cmϪ1 2859, 1613, 1090; H NMR
(360 MHz, CDCl3) δ 7.71–7.68 (4H, m, CH, SiAr), 7.46–7.37
(6H, m, CH, SiAr), 7.26 (2H, d, J 8.7, CH, Ar), 6.88 (2H, d,
J 8.7, CH, Ar), 4.43 (2H, d, J 2.7, CH2Ar), 3.82 (3H, s,
ArOCH3), 3.67 (2H, d, J 4.9, H-1), 3.58–3.52 (2H, m, H-4),
3.43–3.47 (1H, m, H-2), 3.38 (3H, s, OCH3), 1.89–1.85 (1H, m,
H-3), 1.79–1.75 (1H, m, H-3), 1.07 (9H, s, C(CH3)3); 13C NMR
(67.8 MHz, CDCl3) δ 159.0 (s), 135.6 (d), 133.5 (s), 130.6 (s),
129.6 (d), 129.2 (d), 127.6 (d), 113.7 (d), 78.9 (d), 72.5 (t), 66.5
(t), 65.6 (t), 58.1 (q), 55.2 (q), 31.8 (t), 26.8 (q), 19.2 (s); m/z
(FAB) Found 421.1832 ([M Ϫ C4H9]ϩ C25H29O4Si requires
421.1835).
(3R)-4-(tert-Butyldiphenylsilanyloxy)-3-methoxy-butan-1-ol
(13b). 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (2.8 g, 12.6
mmol) was added in one portion to a stirred solution of the
differentially protected triol (13a) (4.0 g, 8.4 mmol) in di-
chloromethane (80 ml) and water (4 ml) at room temperature.
The mixture was stirred at room temperature for 3 h, before it
was quenched with a saturated aqueous solution of sodium
hydrogencarbonate (20 ml). The mixture was filtered through
celite and the filtrate was concentrated in vacuo to leave a red
oil. Purification by flash chromatography, using 20% ethyl
acetate–petroleum ether (bp 40–60 ЊC) as eluent, gave the
alcohol (2.8 g, 95%) as a colourless oil; [α]2D1 ϩ14.8 (c 0.5 in
CHCl3) (Found: C, 69.9; H, 8.7. C21H30O3Si requires C, 70.3; H,
8.4%); νmax (soln: CHCl3)/cmϪ1 3494, 2931, 1112; 1H NMR (360
MHz, CDCl3) δ 7.72–7.67 (4H, m, CH, SiAr), 7.48–7.38 (6H,
m, CH, SiAr), 3.78 (2H, app t, J ∼5.6, H-1), 3.75 (1H, dd,
J 10.8, 5.0, H-4), 3.66 (1H, dd, J 10.8, 5.2, H-4), 3.49 (1H, dddd,
J 7.5, 5.2, 5.0, 5.0, H-3), 3.38 (3H, s, OCH3), 2.63 (1H, b s, OH ),
1.88–1.76 (2H, m, H-2), 1.08 (9H, s, C(CH3)3); 13C NMR (67.8
MHz, CDCl3) δ 135.6 (d), 133.3 (s), 133.2(s), 129.7 (d), 127.7
(d), 81.4 (d), 65.1 (t), 60.7 (t), 57.9 (q), 33.9 (t), 26.8 (q), 19.2 (s);
m/z (FAB) Found 359.2061 ([MH]ϩ C21H31O3Si requires
359.2042).
(2R)-1-(tert-Butyldiphenylsilanyloxy)-4-(4-methoxybenzyl-
oxy)-butan-2-ol (12b). tert-Butylchlorodiphenylsilane (12.4 g,
11.8 ml, 45 mmol) and 4-(dimethylamino)-pyridine (540 mg, 4.6
mmol) were added separately, each in one portion, to a stirred
solution of the diol (12a) (10.0 g, 44 mmol) in dichloromethane
(300 ml) at 0 ЊC under a nitrogen atmosphere. The mixture was
stirred at 0 ЊC for 15 min and then triethylamine (12.3 ml,
88 mmol) was added dropwise over 5 min. The mixture was
warmed to room temperature and stirred at this temperature for
12 h before it was quenched with a saturated aqueous solution
of ammonium chloride (300 ml). The separated aqueous layer
was extracted with dichloromethane (2 × 300 ml) and the
combined organic extracts were then dried (MgSO4) and con-
centrated in vacuo to leave an opaque residue. Purification by
flash chromatography, using 15% ethyl acetate–petroleum ether
(bp 40–60 ЊC) as eluent, gave the silyl ether (19.2 g, 94%) as a
colourless oil; [α]2D1 Ϫ1.9 (c 1.5 in CHCl3) (Found: C, 72.6; H,
8.0. C28H36O4Si requires C, 72.4; H, 7.8%); νmax (soln: CHCl3)/
cmϪ1 3572, 2860, 1613, 1089; 1H NMR (360 MHz, CDCl3)
δ 7.69–7.66 (4H, m, CH, SiAr), 7.47–7.37 (6H, m, CH, SiAr),
7.23 (2H, d, J 8.7, CH, Ar), 6.87 (2H, d, J 8.7, CH, Ar), 4.43
(2H, s, CH2Ar), 3.94–3.91 (1H, m, H-2), 3.81 (3H, s, OCH3),
(3R)-4-(tert-Butyldiphenylsilanyloxy)-3-methoxy-butyralde-
hyde (14). A solution of dimethyl sulfoxide (1.5 g, 1.38 ml, 19.4
mmol) in dichloromethane (16 ml) was added dropwise, via
cannula, over 10 min to a stirred solution of oxalyl chloride
(1.64 g, 1.13 ml, 12.9 mmol) in dichloromethane (30 ml) at
Ϫ78 ЊC under a nitrogen atmosphere. The mixture was stirred
at Ϫ78 ЊC for 15 min and then a solution of the alcohol (13b)
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(2.32 g, 6.47 mmol) in dichloromethane (24 ml) was added
dropwise, via cannula, over 10 min. The mixture was stirred at
Ϫ78 ЊC for 1 h and then diisopropylethylamine (3.34 g, 4.51 ml,
25.9 mmol) was added dropwise over 8 min. The mixture was
warmed to Ϫ10 ЊC over 3.5 h, then quenched with a saturated
aqueous solution of potassium hydrogensulfate (60 ml) and
warmed to room temperature. The separated aqueous layer was
extracted with dichloromethane (2 × 60 ml), and the combined
organic extracts was dried (Na2SO4) and concentrated in vacuo
to leave a yellow oil. Purification by flash chromatography,
using 10% ethyl acetate–petroleum ether (bp 40–60 ЊC) as
eluent, gave the aldehyde (2.1 g, 90%) as a colourless oil; [α]2D1
ϩ16.1 (c 1.1 in CHCl3); νmax (soln: CHCl3)/cmϪ1 2931, 2858,
(2R)-2-Methoxy-5-(trimethylsilanyl)-pent-4-yn-1-ol
(16).
n-Butyllithium (1.6 M in hexanes, 16.2 ml, 25.8 mmol) was
added dropwise over 10 min to a stirred solution of the alkyne
(15b) (1.41 g, 12.3 mmol) in THF (120 ml) at Ϫ78 ЊC under a
nitrogen atmosphere. The solution was stirred at Ϫ78 ЊC for 1 h
and then chlorotrimethylsilane (3.45 ml, 27.2 mmol) was added
dropwise over 10 min. The mixture was stirred at Ϫ78 ЊC for
30 min and then warmed to room temperature and stirred at
this temperature for a further 1 h 30 min. The mixture was
quenched with a saturated aqueous solution of ammonium
chloride (120 ml) and then concentrated in vacuo to leave an
aqueous residue. The residue was extracted with diethyl ether
(2 × 120 ml) and the combined extracts were stirred with 1 M
hydrochloric acid (120 ml) for 45 min. The separated aqueous
layer was extracted with diethyl ether (1 × 180 ml) and the
combined organic extracts were then dried (MgSO4) and con-
centrated in vacuo to leave a yellow oil. Purification by flash
chromatography, using 30% ethyl acetate–petroleum ether (bp
40–60 ЊC) as eluent, gave the silyl alkyne (1.62 g, 70%) as a
colourless oil; [α]2D1 Ϫ36.3 (c 1.8 in CHCl3) (Found: C, 58.1; H,
10.2. C9H18O2Si requires C, 58.0; H, 9.8%); νmax (soln: CHCl3)/
1
1715, 1112; H NMR (360 MHz, CDCl3) δ 9.83 (1H, t, J 2.0,
H-1), 7.69–7.66 (4H, m, CH, SiAr), 7.46–7.38 (6H, m, CH,
SiAr), 3.80–3.72 (2H, m, H-3, H-4), 3.66 (1H, dd, J 10.5, 5.4,
H-4), 3.34 (3H, s, OCH3), 2.70–2.67 (2H, m, H-2), 1.07 (9H, s,
C(CH3)3); 13C NMR (90 MHz, CDCl3) δ 201.1 (d), 135.5 (d),
133.0 (s), 129.8 (d), 127.7 (d), 76.8 (d), 64.5 (t), 57.7 (q), 46.0 (t),
26.7 (q), 19.1 (s); m/z (EI) Found 299.1109 ([M Ϫ C4H9]ϩ
C17H19O3Si requires 299.1104).
1
cmϪ1 3589, 2934, 2174, 1265, 1112, 863; H NMR (360 MHz,
(2R)-tert-Butyl-(2-methoxy-pent-4-ynyloxy)-diphenylsilane
(15a). A solution of potassium tert-butoxide (1 M in THF,
0.86 g, 7.7 ml, 7.7 mmol) in THF (10 ml) was added dropwise
over 8 min to a stirred solution of dimethyl α-diazomethyl-
phosphonate (1.24 g, 8.2 mmol) in THF (30 ml) at Ϫ78 ЊC
under a nitrogen atmosphere. The solution was stirred at Ϫ78 ЊC
for 25 min and then a solution of the aldehyde (14) (2.08 g, 5.9
mmol) in THF (15 ml) at Ϫ78 ЊC was added dropwise, via
cannula, over 10 min. The mixture was stirred at Ϫ78 ЊC for 1 h
20 min, then quenched with water (40 ml) and allowed to warm
to room temperature. The separated aqueous layer was
extracted with ethyl acetate (3 × 50 ml) and the combined
organic extracts were then dried (MgSO4) and concentrated
in vacuo to leave a yellow oil. Purification by flash chromato-
graphy, using 8% ethyl acetate–petroleum ether (bp 40–60 ЊC)
as eluent, gave the alkyne (1.53 g, 75%) as a colourless oil; [α]2D1
ϩ 5.9 (c 1.5 in CHCl3) (Found: C, 75.1; H, 8.2. C22H28O2Si
requires C, 75.0; H, 8.0%); νmax (soln: CHCl3)/cmϪ1 3307, 2931,
CDCl3) δ 3.80 (1H, dd, J 11.6, 3.4, H-1), 3.62 (1H, dd, J 11.6,
6.1, H-1), 3.48–3.42 (4H, m, H-2, OCH3), 2.55 (1H, dd, J 16.9,
5.0, H-3), 2.38 (1H, dd, J 16.9, 7.9, H-3), 2.05 (1H, b s, OH ),
0.15 (9H, s, Si(CH3)3); 13C NMR (67.8 MHz, CDCl3) δ 102.7 (s),
87.0 (s), 80.0 (d), 63.8 (t), 57.6 (q), 21.5 (t), 0.0 (q); m/z (CI)
Found 187.1175 ([MH]ϩ C9H19O2Si requires 187.1154).
(2R)-2Ј-[2-Methoxy-5-(trimethylsilanyl)-pent-4-ynylsulfanyl]-
benzothiazole (17). A solution of the alcohol (16) (500 mg,
2.7 mmol) in THF (20 ml) was added dropwise over 2 min to a
stirred solution of 2-mercaptobenzothiazole (0.9 g, 5.4 mmol)
and triphenylphosphine (1.1 g, 4.0 mmol) in THF (20 ml) at
0 ЊC under a nitrogen atmosphere. Diethyl azodicarboxylate
(0.8 ml, 5.1 mmol) was added dropwise over 2 min and the
mixture was stirred for 1 h 30 min whilst it warmed to room
temperature. The mixture was diluted with diethyl ether (40 ml),
then water (40 ml) and brine (40 ml) were added. The separated
aqueous layer was extracted with ethyl acetate (2 × 10 ml), and
the combined organic extracts were dried (MgSO4) and concen-
trated in vacuo to leave a white solid. Purification by flash
chromatography, using 10% ethyl acetate–petroleum ether
(bp 40–60 ЊC) as eluent, gave the thioether (850 mg, 94%) as a
colourless oil; [α]2D1 Ϫ8.4 (c 2.3 in CHCl3) (Found: C, 57.5; H,
6.5; N, 4.1; S, 19.1. C16H21ONS2Si requires C, 57.3; H, 6.3; N,
4.2; S, 19.1%); νmax (soln: CHCl3)/cmϪ1 2959, 2175, 1457, 1103,
1
1112, 1078; H NMR (360 MHz, CDCl3) δ 7.72–7.68 (4H, m,
CH, SiAr), 7.44–7.37 (6H, m, CH, SiAr), 3.76 (2H, d, J 5.3,
H-1), 3.4–3.5 (1H, m, H-2), 3.41 (3H, s, OCH3), 2.59 (1H, ddd,
J 17.1, 5.6, 2.7, H-3), 2.48 (1H, ddd, J 17.1, 5.6, 2.7, H-3), 1.97
(1H, t, J 2.7, H-5), 1.07 (9H, s, C(CH3)3); 13C NMR (90 MHz,
CDCl3) δ 135.6 (d), 133.4 (s), 129.7 (d), 127.7 (d), 81.0 (d), 79.9
(d), 69.6 (s), 64.0 (t), 57.8 (q), 26.8 (q), 20.9 (t), 19.2 (s); m/z
(FAB) Found 295.1179 ([M Ϫ C4H9]ϩ C18H19O2Si requires
295.1154).
1
996; H NMR (360 MHz, CDCl3) δ 7.86 (1H, ddd, J 8.4, 1.0,
0.5, CH, Ar), 7.76 (1H, ddd, J 8.1, 1.2, 0.5, CH, Ar), 7.42 (1H,
ddd, J 8.4, 7.2, 1.2, CH, Ar), 7.30 (1H, ddd, J 8.1, 7.2, 1.0, CH,
Ar), 3.78–3.73 (1H, m, H-2), 3.73 (1H, dd, J 16.5, 4.8, H-1),
3.61–3.54 (1H, m, H-1), 3.49 (3H, s, OCH3), 2.68 (1H, dd,
J 16.9, 5.4, H-3), 2.60 (1H, dd, J 16.9, 6.2, H-3), 0.18 (9H, s,
Si(CH3)3); 13C NMR (67.8 MHz, CDCl3) δ 167.5 (s), 153.1 (s),
135.0 (s), 126.0 (d), 124.2 (d), 121.5 (d), 120.9 (d), 102.3 (s), 88.0
(s), 78.2 (d), 58.0 (q), 36.7 (t), 24.5 (t), 0.0 (q); m/z (EI) Found
335.0849 (Mϩ C16H21ONS2Si requires 335.0854).
(2R)-2-Methoxy-pent-4-yn-1-ol (15b). Tetrabutylammonium
fluoride (1 M in THF, 23.2 ml, 23.2 mmol) was added dropwise
over 2 min to a stirred solution of the alkyne (15a) (6.8 g,
19.2 mmol) in THF (200 ml) at 0 ЊC under a nitrogen atmos-
phere. The mixture was stirred at room temperature for 2 h 45
min and then quenched with a saturated aqueous solution of
ammonium chloride (200 ml). The separated aqueous layer was
extracted with ethyl acetate (3 × 200 ml) and the combined
organic extracts were then dried (MgSO4) and concentrated
in vacuo to leave a red oil. Purification by flash chromatography,
using 20% ethyl acetate–petroleum ether (bp 40–60 ЊC) as
eluent, gave the alkyne (2.1 g, 96%) as a volatile colourless oil;
[α]2D1 Ϫ38.9 (c 0.6 in CHCl3); νmax (soln: CHCl3)/cmϪ1 3589,
(2R)-2Ј-[2-Methoxy-5-(trimethylsilanyl)-pent-4-yn-1-ylsulf-
onyl]-benzothiazole (6). A solution of meta-chloroperbenzoic
acid (0.44 g, 2.6 mmol) in dichloromethane (10 ml) was added
dropwise over 2 min to a stirred solution of the thioether (13)
(368 mg, 1.08 mmol) and sodium hydrogencarbonate (0.48 g,
5.48 mmol) in dichloromethane (10 ml) at room temperature
under a nitrogen atmosphere. The mixture was stirred at room
temperature for 15 h and then was quenched with a saturated
aqueous solution of sodium thiosulfate (10 ml). The separated
aqueous layer was extracted with dichloromethane (2 × 40 ml)
and the combined organic extracts were dried (MgSO4) and
concentrated in vacuo to leave a white solid. Purification by
1
3307, 2934, 2121, 1111; H NMR (360 MHz, CDCl3) δ 3.78
(1H, dd, J 11.7, 3.6, H-1), 3.64 (1H, dd, J 11.7, 6.0, H-1), 3.48–
3.42 (4H, m, H-2, OCH3), 2.48 (1H, ddd, J 16.9, 5.2, 2.7, H-3),
2.41 (1H, ddd, J 16.9, 7.1, 2.7, H-3), 2.13 (1H, b s, OH ), 2.01
(1H, t, J 2.7, H-5); 13C NMR (67.8 MHz, CDCl3) δ 80.2 (d),
79.6 (d), 70.3 (s), 63.3 (t), 57.4 (q), 19.9 (t); m/z (ESI) Found
137.0584 ([M ϩ Na]ϩ C6H10O2Na requires 137.0578).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4184

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flash chromatography, using 10% ethyl acetate–petroleum ether
(bp 40–60 ЊC) as eluent, gave the sulfone (344 mg, 85%) which
crystallized from petroleum ether as colourless crystals, mp
101–103 ЊC; [α]2D1 Ϫ35.7 (c 1.9 in CHCl3) (Found: C, 52.3; H, 5.7;
N, 3.6; S, 17.4. C16H21O3NS2Si requires C, 52.3; H, 5.8; N, 3.8;
S, 17.5%); νmax (soln: CHCl3)/cmϪ1 2959, 2176, 1327, 1144,
SCH2CH3), 1.20 (3H, t, J 7.4, SCH2CH3); 13C NMR (90 MHz,
CDCl3) δ 135.8 (s), 132.6 (d), 109.6 (s), 78.7 (d), 70.5 (d), 65.6
(t), 27.4 (t), 26.8 (t), 26.5 (q), 25.2 (q), 14.9 (q), 13.7 (q); m/z
(EI) Found: 260.0908 ([M Ϫ H2O]ϩ C12H20O2S2 requires
260.0905).
A solution of the ketene dithioacetal (32.0 g, 0.115 mol) in
THF (300 ml) was added dropwise over 2 h to a suspension of
lithium aluminium hydride (10.0 g, 0.264 mol) in THF (800 ml)
at room temperature, under a nitrogen atmosphere, and the
mixture was then stirred for 3 h. The residual lithium
aluminium hydride was quenched by dropwise sequential
addition of water (10 ml), 2 M sodium hydroxide (10 ml) and
water (20 ml) over a 1 h period. The resulting mixture was
filtered through Celite, and the residual solid was washed with
diethyl ether (500 ml). The filtrate was washed with brine (500
ml), then dried (Na2SO4) and concentrated in vacuo to leave the
alcohol (29.1 g, 90%) as a colourless oil; [α]2D0 ϩ 26.3 (c 3.9 in
CHCl3) [lit.18 ϩ25.6 (c 5.0 in CHCl3)] (Found: C, 51.4; H, 8.9; S,
23.0%, Calc. for C12H24O3S2: C, 51.4; H, 8.6; S, 22.8%); νmax
(soln: CHCl3)/cmϪ1 3471(br), 1372, 1067; 1H NMR (360 MHz,
CDCl3) δ 4.05 (1H, dd, J 10.4, 4.2, H-1), 4.01–3.95 (2H, m, H-4,
H-5), 3.87 (1H, ddd, J 10.0, 4.5, 2.5, H-3), 3.73 (1H, dd, J 10.9,
9.5, H-5), 3.07 (1H, b s, OH ), 2.72–2.51 (4H, m, S(CH2CH3)2),
1.98 (1H, ddd, J 14.2, 7.8, 4.2, H-2), 1.67 (1H, ddd, J 14.2, 10.4,
2.5, H-2), 1.40 (3H, s, CCH3), 1.33 (3H, s, CCH3), 1.23 (6H, t,
J 7.4, S(CH2CH3)2); 13C NMR (90 MHz, CDCl3) δ 109.4 (s),
78.5 (d), 69.5 (d), 65.8 (t), 47.5 (d), 40.1 (t), 26.4 (q), 25.1 (q),
24.2 (t), 23.9 (t), 14.4 (q), 14.3 (q); m/z (EI) Found: 280.1160
([M]ϩ C12H24O3S2 requires 280.1167).
1
1108; H NMR (360 MHz, CDCl3) δ 8.24–8.21 (1H, m, CH,
Ar), 8.03–8.00 (1H, m, CH, Ar), 7.66–7.57 (2H, m, CH, Ar),
4.07–4.02 (1H, m, H-2), 3.94 (1H, dd, J 14.8, 8.9, H-1), 3.81
(1H, dd, J 14.8, 3.0, H-1), 3.25 (3H, s, OCH3), 2.66 (1H, dd,
J 17.0, 4.6, H-3), 2.46 (1H, dd, J 17.0, 7.4, H-3), 0.15 (9H, s,
Si(CH3)3); 13C NMR (67.8 MHz, CDCl3) δ 166.8 (s), 152.6 (s),
136.8 (s), 127.9 (d), 127.5 (d), 125.5 (d), 122.2 (d), 100.6 (s), 88.7
(s), 74.5 (d), 58.7 (t), 57.5 (q), 24.1 (t), Ϫ0.1 (q); m/z (FAB)
Found 368.0798 ([MH]ϩ C16H22O3NS2Si requires 368.0810).
2-Deoxy-4,5-O-isopropylidene-D-threo-pentose diethyl dithio-
acetal (18a). Ethanethiol (50.0 ml, 0.676 mol) was added drop-
wise over 10 min to a stirred solution of ()-xylose (50.0 g,
0.333mol) in 6 M hydrochloric acid (400 ml) at room temper-
ature. The mixture was stirred at room temperature for 2 h and
then neutralised with calcium carbonate (120 g) until pH 7
was attained. The precipitated inorganic residue was removed
by filtration and washed with toluene (500 ml). The biphasic
filtrate was concentrated in vacuo to leave a residue which was
taken up in acetone (1 L), cooled to 0 ЊC and then treated with
concentrated sulfuric acid (15 ml). The resulting solution was
stirred for 16 h and then neutralised by the addition of calcium
hydroxide (50 g). The precipitated solid was removed by
filtration and washed with acetone (500 ml). The filtrate was
concentrated in vacuo to leave a brown oil which was taken up
in diethyl ether and washed with a saturated solution of sodium
bicarbonate (600 ml), and then a saturated solution of brine
(600 ml). The organic extract was dried and then evaporated
in vacuo to leave the crude product (∼70 g) as a yellow oil. An
analytical sample was purified by chromatography on silica,
eluting with 10% ethyl acetate in petroleum ether (bp 40–60 ЊC),
to give 2,3:4,5-di-O-isopropylidene--xylose diethyl dithio-
acetal as a pale yellow oil; [α]2D1 Ϫ70.1 (c 2.6 in acetone) [lit.50
Ϫ67.0 (c 2.8 in acetone)]; νmax (soln: CHCl3)/cmϪ1 2982, 2931,
3-O-(4Ј-Methoxy-benzyl)-2-deoxy-4,5-O-isopropylidene-D-
threo-pentose diethyl dithioacetal (18b). Potassium tert-butoxide
(2.21 g, 19.7 mmol) was added in one portion to a stirred
solution of the alcohol (18a) (4.60 g, 16.4 mmol) in THF
(100 ml) at Ϫ20 ЊC, under a nitrogen atmosphere. The solution
was stirred at Ϫ20 ЊC for 1 h, and then tetrabutylammonium
iodide (0.61 g, 1.6 mmol) followed by a solution of 4-methoxy-
benzyl bromide (4.62 g, 23.0 mmol) in THF (20 ml) were added.
The suspension was allowed to warm to room temperature and
stirring was continued for 15 h. Saturated ammonium chloride
solution (50 ml) was added and the solvent was removed
in vacuo. The residue was extracted with ethyl acetate (3 ×
75 ml), the combined extracts were then dried and concentrated
in vacuo to leave a yellow oil. The oil was purified by chromato-
graphy on silica, eluting with 10% ethyl acetate in petroleum
ether (bp 40–60 ЊC), to give the 4-methoxybenzyl ether (6.41 g,
98%) as a colourless oil; [α]2D1 ϩ 34.0 (c 2.4 in CHCl3); νmax (film)/
cmϪ1 1612, 854, 822; 1H NMR (360 MHz, CDCl3) δ 7.29 (2H, d,
J 8.8, Ar), 6.89 (2H, d, J 8.8, Ar), 4.75 (1H, d, J 11.2,
OCHHAr), 4.69 (1H, d, J 11.2, OCHHAr), 4.25 (1H, dd,
J 13.2, 6.6, H-4), 4.00 (1H, dd, J 8.3, 6.6, H-5), 3.94 (1H, dd,
J 10.6, 4.1, H-1), 3.94–3.88 (1H, m, H-3), 3.82 (3H, s, ArOCH3),
3.74 (1H, dd, J 8.3, 7.1, H-5), 2.71–2.52 (4H, m, S(CH2CH3)2),
2.00 (1H, ddd, J 14.2, 9.6, 4.1, H-2), 1.75 (1H, ddd, J 14.2, 10.6,
1.9, H-2), 1.47 (3H, s, CCH3), 1.38 (3H, s, CCH3) 1.24 (6H, t,
J 7.4, S(CH2CH3)2); 13C NMR (90 MHz, CDCl3) δ 159.2 (s),
130.7 (s), 129.5 (d), 113.7 (d), 109.4 (s), 77.7 (d), 76.9 (d), 72.9
(t), 65.6 (t), 55.2 (q), 47.5 (d), 37.3 (t), 26.4 (q), 25.1 (q), 24.3 (t),
23.4 (t), 14.4 (q), 14.3 (q); m/z (EI) Found: 400.1751 (Mϩ
C20H32O4S2 requires 400.1742).
1
1381, 1372, 1070; H NMR (360 MHz, CDCl3) δ 4.34 (2H, m,
H-2, H-3), 4.12 (1H, dd, J 7.4, 3.1, H-4), 4.04 (1H, dd, J 8.1, 6.7,
H-5), 3.92 (1H, t, J 7.6, H-5), 3.89 (1H, d, J 5.2, H-1), 2.79–2.68
(4H, m, S(CH2CH3)2), 1.45 (3H, s, CCH3), 1.41 (6H, s,
2 × CCH3), 1.36 (3H, s, CCH3), 1.26 (3H, t, J 7.4, SCH2CH3),
1.25 (3H, t, J 7.4, SCH2CH3); 13C NMR (90 MHz, CDCl3)
δ 110.0 (s), 109.4 (s), 80.0 (d), 78.6 (d), 75.2 (d), 65.8 (t), 53.0 (d),
27.3 (q), 27.1 (q), 26.1 (q), 25.5 (q), 25.3 (t), 24.9 (t), 14.3 (q),
14.2 (q); m/z (EI) Found: 336.1445 ([M]ϩ C15H28O4S2 requires
336.1429).
A solution of the acetonide (70 g, 0.21 mol) in THF (300 ml)
was added dropwise over 1 h to a solution of potassium
tert-butoxide (30.4 g, 0.271mol) in THF (750 ml) and dimethyl
sulfoxide (300 ml) at room temperature, under a nitrogen
atmosphere. The mixture was stirred at room temperature for
1 h and then poured onto ice (500 g). The mixture was extracted
with dichloromethane (3 × 400 ml) and the combined organic
extracts were washed with water (500 ml) and dried (Na2SO4).
The solution was concentrated in vacuo to leave a brown oil,
which was purified by chromatography on silica, eluting with
20% ethyl acetate in petroleum ether (bp 40–60 ЊC), to give
2-deoxy-4,5-O-isopropylidene--threo-pent-1-enose
diethyl
(3R,4ЈR)-3-(2Ј,2Ј-Dimethyl-[1Ј,3Ј]-dioxolan-4Ј-yl)-3-(4Љ-
methoxy-benzyloxy)-propionaldehyde (19). Calcium carbonate
(4.2 g, 42.8 mmol) and a solution of mercury() perchlorate
hydrate (11.4 g, 28.5 mmol) in water (60 ml) were added succes-
sively to a solution of the dithioacetal (18b) (5.7 g, 14.2 mmol)
in THF (375 ml). The mixture was stirred at room temperature
for 3 h, then diethyl ether (600 ml) was added and the resulting
suspension stirred for 15 min. The suspension was filtered
through a short pad of silica and the filtrate was then dried
dithioacetal (32.8 g, 35%, 3 steps) as a pale yellow oil; [α]2D1
Ϫ54.4 (c 2.4 in CHCl3) [lit.18 Ϫ48.5 (c 2.4 in CHCl3)] (Found: C,
52.0; H, 8.1%, Calc. for C12H22O3S2: C, 51.8; H, 8.0%);
1
νmax(soln: CHCl3)/cmϪ1 3566 (br), 1374, 1065; H NMR (360
MHz, CDCl3) δ 5.85 (1H, d, J 8.6, H-2), 4.75–4.70 (1H, m,
H-3), 4.03 (1H, app q, J 6.4, H-4), 3.91 (1H, dd, J 8.4, 6.4, H-5),
3.73 (1H, dd, J 8.4, 6.4, H-5), 2.86–2.66 (5H, m, S(CH2CH3)2,
OH ), 1.42 (3H, s, CCH3), 1.32 (3H, s, CCH3), 1.21 (3H, t, J 7.4,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4185

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(Na2SO4) and evaporated in vacuo to leave a colourless oil. The
residue was purified by chromatography on silica eluting with
50% ethyl acetate in petroleum ether (bp 40–60 ЊC), to give the
aldehyde (3.75 g, 91%) as a colourless oil; [α]2D1 ϩ 28.5 (c 3.7 in
CHCl3); νmax (film)/cmϪ1 2729, 1725; 1H NMR (360 MHz,
CDCl3) δ 9.73 (t, J 1.7, 1H, H-1), 7.24 (d, J 8.7, 2H, Ar), 6.88
(d, J 8.7, 2H, Ar), 4.59 (app q, J 11.3, 2H, CH2Ar), 4.32–4.27
(m, 1H, H-5Ј), 4.14–4.09 (m, 1H, H-3), 4.00 (dd, J 8.6, 6.8, 1H,
H-4Ј), 3.83–3.79 (m, 1H, H-5Ј), 3.80 (s, 3H, ArOCH3), 2.61
(ddd, J 7.0, 1.7, 1.7, 2H, H-2), 1.44 (s, 3H, CCH3), 1.36 (s, 3H,
CCH3); 13C NMR (90 MHz, CDCl3) δ 200.7 (d), 159.3 (s), 129.9
(s), 129.6 (d), 113.8 (d), 109.7 (s), 76.3 (d), 73.6 (d), 72.4 (t), 65.2
(t), 55.2 (q), 44.4 (t), 26.2 (q), 24.9 (q); m/z (EI) Found: 294.1460
([M]ϩ C16H22O5 requires 294.1467).
(1H, m, H-3), 3.26 (3H, s, OCH3), 2.30–2.26 (2H, m, H-4),
1.58–1.50 (1H, m, H-2), 1.46 (3H, s, CCH3), 1.44–1.34 (1H, m,
H-2), 1.38 (3H, s, CCH3); 13C NMR (90 MHz, CDCl3) δ 159.1
(s), 134.1 (d), 130.9 (s), 129.6 (d), 117.3 (t), 113.7 (d), 109.2 (s),
78.8 (d), 76.2 (d), 76.1 (d), 72.8 (t), 65.9 (t), 56.3 (q), 55.1 (q),
37.5 (t), 36.1 (t), 26.5 (q), 25.3 (q); m/z (EI) Found 350.2084
([M]ϩ C20H30O5 requires 350.2093).
(2R,3R,5S )-5-Methoxy-3-(4Ј-methoxy-benzyloxy)-oct-7-ene-
1,2-diol (21). 10-Camphorsulfonic acid (12.5 g, 53.9 mmol) was
added to a solution of the acetonide (20b) (8.9 g, 25.4 mmol) in
methanol (160 ml) at 0 ЊC, and the mixture was stirred for 6 h,
whilst allowing it to warm to room temperature. Sodium
bicarbonate (5 g) in water (10 ml) was added and the solvent
was removed in vacuo. The aqueous residue was extracted with
ethyl acetate (3 × 100 ml), and the combined organic extracts
were dried (Na2SO4) and then concentrated in vacuo to leave an
orange oil. The oil was purified by chromatography on silica
eluting with ethyl acetate to give the diol (6.93 g, 88%) as a
colourless oil; [α]2D1 ϩ 3.7 (c 1.4 in CHCl3); νmax (film)/cmϪ1 3574
(2ЈR,3R,5S )-1-(2Ј,2Ј-Dimethyl-[1Ј,3Ј]-dioxolan-4Ј-yl)-1-(4Љ-
methoxy-benzyloxy)-hex-5-en-3-ol
(20a).
Allylmagnesium
bromide (20.5 ml, 1.0 M in Et2O, 20.5 mmol) was added drop-
wise over 15 min to a stirred solution of (Ϫ)-β-methoxydiiso-
pinocampheylborane (7.0 g, 22.2 mmol)19 in anhydrous diethyl
ether (250 ml) at Ϫ78 ЊC under an argon atmosphere. The mix-
ture was warmed to room temperature, stirred for 1 h and then
recooled to Ϫ78 ЊC. A solution of the aldehyde (19) (5.1 g, 17.1
mmol) in diethyl ether (60 ml) was added dropwise over 15 min,
and the suspension was stirred at Ϫ78 ЊC for 3 h before being
quenched with methanol (4 ml). A solution of 2 M aqueous
sodium hydroxide (100 ml) and then hydrogen peroxide (100
ml) were added, and the biphasic mixture was heated under
reflux for 2 h. The mixture was then cooled and the organic
layer was separated. The aqueous layer was extracted with ethyl
acetate (3 × 100 ml) and the combined organic extracts were
dried and concentrated in vacuo to leave a colourless oil. The oil
was purified by chromatography on silica, eluting with 20%
ethyl acetate in petroleum ether (bp 40–60 ЊC), to give the
alcohol (4.69 g, 82%) as a colourless oil; νmax (film)/cmϪ1 3474
1
(br), 1613; H NMR (360 MHz, CDCl3) δ 7.29 (2H, d, J 8.7,
ArH ), 6.91 (2H, d, J 8.7, ArH ), 5.84–5.74 (1H, m, H-7), 5.14–
5.10 (2H, m, H-8), 4.55 (2H, app q, J 11.1, OCH2Ar), 3.82 (3H,
s, ArOCH3), 3.72–3.62 (4H, m, H-1, H-2, H-3), 3.46–3.39 (1H,
m, H-5), 3.35 (3H, s, OCH3), 3.05 (1H, d, J 3.9, CHOH ), 2.77
(1H, b s, CH2OH ), 2.36–2.29 (2H, m, H-6), 1.75–1.71 (2H, m,
H-4); 13C NMR (90 MHz, CDCl3) δ 159.3 (s), 133.8 (d), 130.2
(s), 129.5 (d), 117.6 (t), 113.8 (d), 76.9 (d), 76.6 (d), 73.7 (d), 72.7
(t), 63.8 (t), 56.0 (q), 55.2 (q), 37.3 (t), 35.9 (t); m/z (EI) Found:
310.1780 (Mϩ C17H26O5 requires 310.1780).
(4S,6R,7R)-7,8-Bis-(tert-butyl-dimethyl-silanyloxy)-4-
methoxy-6-(4Ј-methoxy-benzyloxy)-oct-1-ene (22a). Triethyl-
amine (10.9 ml, 77.4 mmol) was added in one portion to a
solution of the diol (21) (6.0 g, 19.2 mmol) in dichloromethane
(120 ml) at 0 ЊC, under a nitrogen atmosphere, and the solution
was stirred at 0 ЊC for 5 min. tert-Butyldimethylsilyl triflate
(10.7 ml, 46.4 mmol) was added dropwise over 1 min and the
mixture was stirred for a further 1 h whilst allowing to warm
to room temperature. Saturated ammonium chloride solution
(240 ml) was added and the organic layer was separated. The
aqueous phase was extracted with dichloromethane (3 × 300
ml) and the combined organic extracts were dried and then
concentrated in vacuo to leave a yellow oil. The oil was purified
by chromatography on silica eluting with 10% ethyl acetate in
petroleum ether (bp 40–60 ЊC), to give the silyl ether (10.3 g,
98%) as a colourless oil; [α]2D0 ϩ 33.8 (c 3.0 in CHCl3) (Found: C,
64.9; H, 10.3%, C29H54O5Si2 requires C, 64.6; H, 10.1%); νmax
1
(br), 1612; H NMR (360 MHz, CDCl3) δ 7.30 (2H, d, J 8.6,
Ar), 6.90 (2H, d, J 8.6, Ar), 5.85–5.73 (1H, m, H-5), 5.13–5.08
(2H, m, H-6), 4.76 (1H, d, J 11.3, OCHHAr), 4.61 (1H, d,
J 11.3, OCHHAr), 4.26 (1H, ddd, J 7.2, 6.6, 6.6, H-4Ј), 4.07–
3.97 (2H, m, H-5Ј), 3.93–3.86 (1H, m, H-3), 3.82 (3H, s,
ArOCH3), 3.67 (1H, dd, J 8.1, 7.6, H-1), 2.23–2.19 (2H, m,
H-4), 1.65–1.45 (2H, m, H-2) 1.46 (3H, s, CCH3), 1.40 (3H, s,
CCH3); 13C NMR (90 MHz, CDCl3) δ 159.3 (s), 134.4 (d), 130.3
(s), 129.8 (d), 118.0 (t), 113.9 (d), 109.6 (s), 78.4 (d), 76.5 (d),
72.8 (t), 68.0 (d), 65.9 (t), 55.3 (q), 42.0 (t), 37.0 (t), 26.5 (q),
25.4 (q); m/z (EI) Found: 336.1931 (Mϩ C19H28O5 requires
336.1937).
1
(2ЈR,3R,5S )-1-(2Ј,2Ј-Dimethyl-[1Ј,3Ј]-dioxolan-4Ј-yl)-1-(4Љ-
methoxy-benzyloxy)-3-methoxy-5-hexene (20b). Potassium tert-
butoxide (2.27 g, 20.2 mmol) was added in one portion to a
stirred solution of the alcohol (20a) (3.40 g, 10.1 mmol) in THF
(100 ml) at Ϫ20 ЊC, under a nitrogen atmosphere. The solution
was stirred at Ϫ20 ЊC for 30 min and then methyl iodide (6.30
ml, 10.1 mmol) was added dropwise over 10 min. The mixture
was allowed to warm to room temperature and then stirred for
6 h. Saturated ammonium chloride solution (50 ml) was added
and the solvent was removed in vacuo. The residue was
extracted with ethyl acetate (4 × 100 ml), and the combined
organic extracts were dried and concentrated in vacuo to leave a
yellow oil. The residue was purified by chromatography on
silica, eluting with 20% ethyl acetate in petroleum ether (bp 40–
60 ЊC), to give the methyl ether (3.43 g, 97%) as a colourless oil;
[α]2D0 ϩ 63.7 (c 2.3 in CHCl3) (Found: C, 68.7; H, 8.8%, C20H30O5
(soln: CHCl3)/cmϪ1 1612, 1086; H NMR (360 MHz, CDCl3)
δ 7.28 (2H, d, J 8.7, ArH ), 6.89 (2H, d, J 8.7, ArH ), 5.86–5.74
(1H, m, H-2), 5.10–5.02 (2H, m, H-1), 4.61 (1H, d, J 11.3,
OCHHAr), 4.48 (1H, d, J 11.3, OCHHAr), 3.84–3.77 (2H, m,
H-7, H-8), 3.81 (3H, s, ArOCH3), 3.69 (1H, ddd, J 10.5, 3.8, 2.2,
H-6), 3.52 (1H, dd, J 11.1, 7.9, H-8), 3.42–3.35 (1H, m, H-4),
3.26 (3H, s, OCH3), 2.30–2.23 (2H, m, H-3), 1.72 (1H, ddd,
J 14.4, 9.8, 2.2, H-5), 1.49 (1H, ddd, J 14.4, 10.5, 3.0, H-5), 0.91
(9H, s, SiC(CH3)3), 0.90 (9H, s, SiC(CH3)3), 0.08 (3H, s, SiCH3),
0.06 (9H, 3 × s, SiCH3); 13C NMR (90 MHz, CDCl3) δ 159.1 (s),
134.7 (d), 131.1 (s), 129.5 (d), 116.9 (t), 113.7 (d), 76.9 (d), 76.8
(d), 74.6 (d), 72.3 (t), 64.4 (t), 56.0 (q), 55.3 (q), 38.0 (t), 34.7 (t),
26.0 (q), 25.9 (q), 18.4 (s), 18.1 (s), Ϫ4.3 (q), Ϫ4.8 (q), Ϫ5.3 (q),
t
Ϫ5.4 (q); m/z (EI) Found: 481.2794 ([M Ϫ Bu]ϩ; C25H45O5Si2
requires 481.2816.
1
requires C, 68.6; H, 8.6%); νmax (soln: CHCl3)/cmϪ1 1612; H
(3R,5R,6R)-6,7-Bis-(tert-butyl-dimethyl-silanyloxy)-3-
NMR (360 MHz, CDCl3) δ 7.30 (2H, d, J 8.6, ArH ), 6.88 (2H,
d, J 8.6, ArH ), 5.82–5.70 (1H, m, H-5), 5.11–5.05 (2H, m, H-6),
4.76 (1H, d, J 11.1, OCH2Ar), 4.55 (1H, d, J 11.1, OCH2Ar),
4.19 (1H, dd, J 13.9, 6.7, H-5Ј), 3.98 (1H, dd, J 8.2, 6.7, H-4Ј),
3.81 (3H, s, ArOCH3), 3.73–3.66 (2H, m, H-5Ј, H-1), 3.48–3.42
methoxy-5-(4Ј-methoxy-benzyloxy)-heptanal (22b). 4-Methyl-
morpholine N-oxide (4.28 g, 36.6 mmol), and osmium tetroxide
(110 mg, 0.43 mmol) were added sequentially to a solution of
the silyl ether (22a) (6.6 g, 12.2 mmol) in acetone (88 ml) and
water (4.4 ml). The mixture was stirred at room temperature for
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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12 h and then a saturated solution of sodium thiosulfate (30 ml)
was added. The solvent was removed in vacuo and the aqueous
residue was extracted with ethyl acetate (3 × 160 ml). The
combined organic extracts were dried (Na2SO4) and evaporated
in vacuo to leave a colourless oil, which was used immediately
without purification. The crude diol in dichloromethane (30 ml)
was added dropwise over 2 min to an aqueous solution of
0.65 M sodium periodate (30 ml, 19.5 mmol,) and a stirred
suspension of silica (35 g) in dichloromethane (160 ml) and
the mixture was stirred at room temperature for 3 h. The
suspension was filtered and the residue was washed with
dichloromethane (500 ml). The combined organic extracts were
evaporated to leave a colourless oil which was purified by
chromatography on silica, eluting with 20% ethyl acetate in
petroleum ether (bp 40–60 ЊC), to give the aldehyde (6.2 g, 94%)
as a colourless oil; [α]2D1 ϩ37.7 (c 2.5 in CHCl3); νmax (soln:
sodium bicarbonate (1 : 1, 220 ml) and stirred vigorously for
30 min. The organic layer was separated and the aqueous
phase was extracted with ethyl acetate (3 × 200 ml). The
combined organic extracts were dried (Na2SO4) and then
evaporated in vacuo to leave a colourless oil, which was purified
by chromatography on silica eluting with 20% ethyl acetate in
petroleum ether (bp 40–60 ЊC), to give the aldehyde (3.3 g, 95%)
as a colourless oil; [α]2D1 ϩ 35.0 (c 2.4 in CHCl3); νmax (soln:
CHCl3)/cmϪ1 1732; 1H NMR (360 MHz, CDCl3) δ 9.71 (1H, d,
J 1.3, H-1), 7.26 (2H, d, J 8.7, Ar), 6.88 (2H, d, J 8.7, Ar),
4.59–4.46 (3H, m, OCH2Ar, H-7), 4.10 (1H, dd, J 4.6, 1.3, H-2),
3.93–3.86 (1H, m, H-3), 3.81 (3H, s, ArOCH3), 3.50–3.45 (1H,
m, H-5), 3.31 (6H, 2 × s, OCH3), 3.26 (3H, s, OCH3), 1.90–1.60
(4H, m, H-4, H-6), 0.92 (9H, s, SiC(CH3)3), 0.07 (3H, s, SiCH3),
0.04 (3H, s, SiCH3); 13C NMR (90 MHz, CDCl3) δ 202.9 (d),
159.3 (s), 130.3 (s), 129.5 (d), 113.8 (d), 102.0 (d), 79.0 (d), 76.8
(d), 74.1 (d), 72.3 (t), 56.2 (q), 55.2 (q), 52.8 (q), 52.7 (q), 37.1
(t), 35.8 (t), 25.7 (q), 18.2 (s), Ϫ4.7 (q), Ϫ5.2 (q); m/z (EI)
1
CHCl3)/cmϪ1 2737, 1723; H NMR (360 MHz, CDCl3) δ 9.77
(1H, t, J 2.4, H-1), 7.26 (2H, d, J 8.6, Ar), 6.88 (2H, d, J 8.6,
Ar), 4.61 (1H, d, J 11.2, OCHHAr), 4.44 (1H, d, J 11.2,
OCHHAr), 3.88–3.84 (1H, m, H-3), 3.81 (3H, s, ArOCH3),
3.82–3.77 (2H, m, H-6, H-7), 3.63 (1H, ddd, J 10.4, 4.2, 1.8,
H-5), 3.51 (1H, dd, J 10.3, 7.1, H-7), 3.25 (3H, s, OCH3), 2.58
(2H, dd, J 5.7, 2.4, H-2), 1.97 (1H, ddd, J 14.4, 8.7, 1.8, H-4),
1.46 (1H, ddd, J 14.4, 10.4, 4.2, H-4), 0.91 (9H, s, SiC(CH3)3),
0.90 (9H, s, SiC(CH3)3), 0.09 (3H, s, SiCH3), 0.07 (3H, s,
SiCH3), 0.06 (6H, 2 × s, SiCH3); 13C NMR (90 MHz, CDCl3)
δ 201.4 (d), 159.2 (s), 130.6 (s), 129.5 (d), 113.8 (d), 77.0 (d), 73.8
(d), 73.7 (d), 72.1 (t), 64.2 (t), 56.4 (q), 55.2 (q), 48.4 (t), 34.7 (t),
26.0 (q), 25.8 (q), 18.3 (s), 18.1 (s), Ϫ4.3 (q), Ϫ4.9 (q), Ϫ5.3 (q),
Ϫ5.4 (q); m/z (CI, NH3): Found 539.3219 ([M Ϫ H] C28H51O6Si2
requires 539.3224).
t
Found: 381.1740 ([M Ϫ Bu Ϫ MeOH]ϩ C19H29O6Si requires
381.1733).
(4R,5R,7R)-4-(tert-Butyl-dimethyl-silanyloxy)-7,9,9-trimeth-
oxy-5-(4Ј-methoxy-benzyloxy)-2-methyl-non-(2E )-enoic
acid
ethyl ester (25a). (Carbethoxyethylidene)triphenylphosphorane
(94%, 9.35 g, 24.24 mmol) was added in one portion to a solu-
tion of the aldehyde (24) (3.8 g, 8.08 mmol) in dry benzene
(115 ml) under a nitrogen atmosphere. The solution was heated
at reflux for 2 days, then allowed to cool and concentrated
in vacuo. The residue was purified by chromatography on silica
eluting with 20% ethyl acetate in petroleum ether (bp 40–60 ЊC),
to give the ester (4.21 g, 94%) as a colourless oil; [α]2D1 ϩ 45.0
(c 3.3 in CHCl3); Found: C, 62.8; H, 9.4%, C29H50O8Si requires
C, 62.8; H, 9.1%; νmax (soln: CHCl3)/cmϪ1 1704, 1613; 1H NMR
(360 MHz, CDCl3) δ 7.26 (2H, d, J 8.7, Ar), 6.86 (2H, d, J 8.7,
Ar), 6.65 (1H, d b q, J 9.1, 1.4, H-3), 4.70 (1H, d, J 11.0,
OCHHAr), 4.56–4.45 (3H, m, OCHHAr, H-4, H-9), 4.23–4.13
(2H, m, CH3CH2OCO), 3.78 (3H, s, ArOCH3), 3.65 (1H, ddd,
J 10.2, 5.4, 2.2, H-5), 3.50–3.44 (1H, m, H-7), 3.29 (6H, 2 × s,
(2R,3R,5R)-2-(tert-Butyl-dimethyl-silanyloxy)-5,7,7-trimeth-
oxy-3-(4Ј-methoxy-benzyloxy)-heptan-1-ol (23). 10-Camphor-
sulfonic acid (1.15 g, 5 mmol) was added in one portion to a
stirred solution of the aldehyde (22b) (5.5 g, 10.2 mmol) in
methanol (160 ml) and dichloromethane (160 ml) under a
nitrogen atmosphere, and the mixture was stirred at room tem-
perature for 1 h. Saturated sodium bicarbonate solution (15 ml)
was added and the solvent was removed in vacuo. The aqueous
residue was extracted with ethyl acetate (3 × 300 ml), and the
combined organic extracts were dried (Na2SO4) and evaporated
in vacuo to leave a colourless oil. The oil was purified by
chromatography on silica eluting with 30% ethyl acetate in
petroleum ether (bp 40–60 ЊC), to give the alcohol (4.3 g, 89%)
as a colourless oil; [α]2D1 ϩ 26.0 (c 2.1 in CHCl3); Found: C, 61.0;
H, 9.7%, C24H44O7Si requires C, 61.0; H, 9.4%; νmax (soln:
CHCl3)/cmϪ1 3494, 2930, 1612, 1082; 1H NMR (500 MHz,
CDCl3) δ 7.23 (2H, d, J 8.6, Ar), 6.89 (2H, d, J 8.6, Ar), 4.60–
4.49 (3H, m, OCH2Ar, H-7), 3.94 (1H, ddd, J 5.5, 5.5, 4.9, H-2),
3.81 (3H, s, ArOCH3), 3.79–3.68 (2H, m, H-1, H-3), 3.60–3.55
(1H, m, H-1), 3.49–3.45 (1H, m, H-5), 3.33 (3H, s, OCH3), 3.32
(3H, s, OCH3), 3.25 (3H, s, OCH3), 2.25 (1H, t, J 6.2, OH ),
1.89–1.82 (2H, m, H-4, H-6), 1.77–1.71 (1H, m, H-6), 1.55 (1H,
ddd, J 14.1, 10.3, 3.5, H-4), 0.90 (9H, s, SiC(CH3)3), 0.08 (6H,
2x s, SiCH3); 13C NMR (125 MHz, CDCl3) δ 159.3 (s), 130.5 (s),
129.6 (d), 113.8 (d), 102.1 (d), 77.8 (d), 74.6 (d), 72.3 (t), 71.2
(d), 63.5 (t), 59.2 (q), 55.3 (q), 52.8 (2x q), 37.5 (t), 34.3 (t), 25.8
(q), 18.0 (s), Ϫ4.7 (q), Ϫ4.8 (q); m/z (EI) Found: 351.1615
([M Ϫ tBu Ϫ 2MeOH]ϩ C18H27O5Si requires 351.1628).
OCH ), 3.22 (3H, s, OCH ), 1.85 (3H, d, J 1.4, CH C᎐CH),
᎐
3
3
3
1.85–1.80 (1H, m, H-8), 1.76–1.66 (2H, m, H-6, H-8), 1.51 (1H,
ddd, J 13.8, 10.2, 3.3, H-6), 1.28 (3H, t, J 7.1, CH3CH2OCO),
0.88 (9H, s, SiC(CH3)3), 0.04 (3H, s, SiCH3), 0.00 (3H, s,
SiCH3); 13C NMR (90 MHz, CDCl3) δ 167.6 (s), 159.1 (s), 140.8
(d), 130.7 (s), 129.5 (d), 128.6 (s), 113.7 (d), 101.9 (d), 79.2 (d),
74.2 (d), 73.1 (t), 71.5 (d), 60.6 (t), 55.9 (q), 55.1 (q), 52.7 (q),
52.5 (q), 37.1 (t), 35.5 (t), 25.7 (q), 18.0 (s), 14.1 (q), 13.3 (q),
t
Ϫ4.6 (q), Ϫ4.9 (q); m/z (EI) Found: 433.2029 ([M Ϫ Bu Ϫ
2MeOH]ϩ C23H33O6Si requires 433.2046).
(4R,5R,7R)-4-(tert-Butyl-dimethyl-silanyloxy)-7,9,9-trimeth-
oxy-5-(4Ј-methoxy-benzyloxy)-2-methyl-non-(2E )-en-1-ol (25b).
A solution of diisobutylaluminium hydride (11.3 ml, 1 M in
hexane, 11.3 mmol) was added dropwise over 5 min to a stirred
solution of the ester (25a) (2.5 g, 4.51 mmol) in dichloro-
methane (25 ml) at Ϫ78 ЊC, under a nitrogen atmosphere. The
mixture was stirred at Ϫ78 ЊC for 1 h, then allowed to warm to
room temperature and stirred for a further 2 h. The mixture was
quenched by the dropwise addition of methanol (1.5 ml), then
poured into an aqueous solution of saturated potassium
sodium tartrate (40 ml) and diluted with dichloromethane (100
ml), and stirred vigorously for 2 h. The separated aqueous layer
was extracted with ethyl acetate (3 × 50 ml) and the combined
organic extracts were then dried (Na2SO4), and evaporated
in vacuo to leave a colourless oil. The oil was purified by
chromatography on silica eluting first with 30% ethyl acetate in
petrol ether and then with ethyl acetate to give the alcohol (2.05
g, 89%) as a colourless oil; [α]2D1 ϩ 33.5 (c 1.9 in CHCl3); νmax
(soln: CHCl3)/cmϪ1 3613, 3455(br); 1H NMR (360 MHz,
CDCl3) δ 7.31 (2H, d, J 8.5, Ar), 6.89 (2H, d, J 8.5, Ar), 5.44
(1H, d b q, J 9.2, 1.2, H-3), 4.76 (1H, d, J 11.0, OCHHAr),
(2S,3R,5R)-2-(tert-Butyl-dimethyl-silanyloxy)-5,7,7-trimeth-
oxy-3-(4Ј-methoxy-benzyloxy)-heptanal
(24).
2,6-Di-tert-
butylpyridine (5.0 ml, 21 mmol) and Dess–Martin periodinane
(3.77 g, 8.89 mmol)20 were added sequentially to a solution
of the alcohol (23) (3.5 g, 7.41 mmol) in dichloromethane
(30 ml) at room temperature, under a nitrogen atmosphere. The
mixture was stirred at room temperature for 2 h, then diethyl
ether (220 ml) was added and the resulting suspension was
poured into a saturated solution of sodium thiosulfate and
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4187

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4.55–4.48 (3H, m, OCHHAr, H-4, H-9), 4.00 (2H, s, H-1), 3.82
(3H, s, ArOCH3), 3.59 (1H, ddd, J 9.7, 5.7, 1.9, H-5), 3.53–3.46
(1H, m, H-7), 3.33 (3H, s, OCH3), 3.32 (3H, s, OCH3), 3.25 (3H,
s, OCH3), 1.97 (1H, b s, OH ), 1.89–1.82 (1H, m, H-8), 1.76–
1.69 (2H, m, H-6, H-8), 1.72 (3H, d, J 1.0, CH C᎐CH), 1.51
(1H, ddd, J 13.6, 10.0, 3.3, H-6), 0.91 (9H, s, SiC(CH3)3), 0.08
(3H, s, SiCH3), 0.04 (3H, s, SiCH3); 13C NMR (90 MHz,
CDCl3) δ 159.1 (s), 136.9 (s), 131.0 (s), 129.5 (d), 125.7 (d),
113.7 (d), 101.9 (d), 79.6 (d), 74.5 (d), 73.0 (t), 71.3 (d), 68.2 (t),
56.1 (q), 55.2 (q), 52.7 (q), 52.5 (q), 37.2 (t), 35.7 (t), 25.8 (q),
18.1 (s), 14.5 (q), Ϫ4.3 (q), Ϫ4.7 (q); m/z (EI) Found: 391.1946
([M Ϫ Bu Ϫ 2MeOH]ϩ C21H31O5Si requires 391.1941).
2 × OCH3), 3.29 (3H, s, OCH3), 3.23 (3H, s, OCH3), 2.59 (1H,
dd, J 16.7, 5.6, H-3), 2.46 (1H, dd, J 16.7, 7.1, H-3), 1.87–1.68
(3H, m, H-11, H-13), 1.79 (3H, s, CH C᎐), 1.48 (1H, ddd,
᎐
3
J 14.0, 10.0, 3.3, H-11), 0.89 (9H, s, C(CH3)3), 0.14 (9H, s,
Si(CH3)3), 0.05 (3H, s, SiCH3), 0.00 (3H, s, SiCH3); 13C NMR
(90 MHz, CDCl3) δ 159.1 (s), 137.6 (d), 133.9 (s), 133.0 (d),
131.1 (s), 129.5 (d), 127.5 (d), 113.7 (d), 103.3 (s), 102.0 (d), 86.5
(s), 80.8 (d), 79.8 (d), 74.4 (d), 73.2 (t), 71.7 (d), 56.6 (q), 56.1
(q), 55.3 (q), 52.9 (q), 52.5 (q), 37.3 (t), 35.8 (t), 27.1 (t), 25.9 (q),
18.1 (s), 13.4 (q), 0.1 (q), Ϫ4.3 (q), Ϫ4.7 (q); m/z (FAB) Found
685.3972 ([MNa]ϩ C36H62O7NaSi2 requires 685.3932).
᎐
3
(3R,5R,6R,11R)-6-(tert-Butyldimethylsilanyloxy)-3,11-di-
methoxy-5-(4-methoxy-benzyloxy)-8-methyl-14-(trimethyl-
silanyl)-tetradeca-7,9-di-(7E,9E )-en-13-ynal (27). A solution of
dimethylboron bromide48 in dichloromethane (2.1 M, 0.92 ml,
1.9 mmol) was added in one portion to a stirred solution of the
dimethyl acetal (26) (160 mg, 0.24 mmol) in diethyl ether (8 ml)
at Ϫ78 ЊC under a nitrogen atmosphere. The solution was
stirred at Ϫ78 ЊC for 2.5 h and then transferred, via cannula, to
a vigorously stirred suspension of THF (8 ml) and a saturated
aqueous solution of sodium hydrogencarbonate (8 ml). The
separated aqueous layer was extracted with diethyl ether (3 ×
10 ml), and the combined organic extracts were then dried
(Na2SO4) and concentrated in vacuo to leave a colourless oil.
Purification by flash chromatography, using 40% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the aldehyde (142
mg, 95%) as a colourless oil; [α]2D0 ϩ 50.4 (c 0.9 in CHCl3); νmax
(4R,5R,7R)-4-(tert-Butyl-dimethyl-silanyloxy)-7,9,9-trimeth-
oxy-5-(4Ј-methoxy-benzyloxy)-2-methyl-non-(2i)-enal (7). 2,6-
Lutidine (0.16 ml, 1.4 mmol) and Dess–Martin periodinane
(2 g, 4.7 mmol)20 were added sequentially to a solution of the
alcohol (25b) (800 mg, 1.6 mmol) in dichloromethane (50 ml) at
room temperature, under a nitrogen atmosphere, and the
mixture was then stirred for 1 h. Diethyl ether (200 ml) was
added and the resulting suspension was poured into a saturated
solution of sodium thiosulfate and sodium bicarbonate (1 : 1,
200 ml) and stirred vigorously for 30 min. The organic layer was
separated and the aqueous phase was extracted with ethyl
acetate (3 × 50 ml). The combined organic extracts were dried
(Na2SO4), and evaporated in vacuo to leave a colourless oil,
which was purified by chromatography on silica eluting with
20% ethyl acetate in petroleum ether (bp 40–60 ЊC), to give the
aldehyde (750 mg, 94%) as a colourless oil; [α]2D1 ϩ 60.7 (c 1.3 in
CHCl3); λmax (EtOH) 203 (ε 8500), 217 (10100), 226 (9000), 232
(9000) nm; νmax (soln: CHCl3)/cmϪ1 1688; 1H NMR (360 MHz,
CDCl3) δ 9.42 (1H, s, H-1), 7.26 (2H, d, J 8.7, Ar), 6.87 (2H, d,
J 8.7, Ar), 6.38 (1H, d b q, J 8.6, 2.3, H-3), 4.71 (1H, dd, J 8.6,
5.2, H-4), 4.67 (1H, d, J 11.1, OCHHAr), 4.53 (1H, d, J 11.1,
OCHHAr), 4.48 (1H, t, J 5.6, H-9), 3.80 (3H, s, ArOCH3), 3.72
(1H, ddd, J 10.2, 5.2, 2.2, H-5), 3.51–3.45 (1H, m, H-7), 3.31
(3H, s, OCH3), 3.30 (3H, s, OCH3), 3.24 (3H, s, OCH3), 1.86
(1H, ddd, J 14.2, 6.1, 5.6, H-8), 1.76–1.68 (2H, m, H-6, H-8),
1
(soln: CHCl3)/cmϪ1 2930, 2175, 1725, 1602, 1089; H NMR
(360 MHz, CDCl3) δ 9.75 (1H, t, J 2.4, H-1), 7.27 (2H, d, J 8.6,
CH, Ar), 6.89 (2H, d, J 8.6, CH, Ar), 6.25 (1H, d, J 15.7, H-9),
5.55 (1H, dd, J 15.7, 7.8, H-10), 5.44 (1H, d, J 9.2, H-7), 4.76
(1H, d, J 11.1, CH2Ar), 4.62 (1H, dd, J 9.2, 5.6, H-6), 4.48 (1H,
d, J 11.1, CH2Ar), 3.86–3.75 (2H, m, H-3, H-11), 3.81 (3H, s,
ArOCH3), 3.63 (1H, ddd, J 10.4, 5.6, 2.0, H-5), 3.31 (3H, s,
OCH3), 3.23 (3H, s, OCH3), 2.63–2.55 (3H, m, H-2, H-12), 2.44
(1H, dd, J 16.7, 7.2, H-12), 1.90–1.80 (1H, m, H-4), 1.80 (3H, s,
CH C᎐), 1.47 (1H, ddd, J 14.4, 10.4, 3.8, H-4), 0.89 (9H, s,
᎐
3
1.77 (3H, d, J 2.3, CH C᎐CH), 1.54 (1H, ddd, J 13.6, 10.2, 3.2,
C(CH3)3), 0.14 (9H, s, Si(CH3)3), 0.06 (3H, s, SiCH3), 0.01 (3H,
s, SiCH3); 13C NMR (90 MHz, CDCl3) δ 201.4 (d), 159.3 (s),
137.4 (d), 134.3 (s), 132.4 (d), 130.6 (s), 129.6 (d), 127.7 (d),
113.8 (d), 103.3 (s), 86.5 (s), 80.7 (d), 79.5 (d), 73.2 (d), 73.1 (t),
70.9 (d), 56.7 (s), 56.3 (q), 55.3 (q), 48.3 (t), 35.6 (t), 27.1 (t),
25.8 (q), 18.1 (s), 13.4 (q), 0.1 (q), Ϫ4.3 (q), Ϫ4.8 (q).
᎐
3
H-6), 0.90 (9H, s, SiC(CH3)3), 0.07 (3H, s, SiCH3), 0.00 (3H, s,
SiCH3); 13C NMR (90 MHz, CDCl3) δ 195.1 (d), 159.3 (s), 152.5
(d), 139.2 (s), 130.5 (s), 129.6 (d), 113.8 (d), 101.9 (d), 79.0 (d),
74.2 (d), 73.1 (t), 71.0 (d), 56.1 (q), 55.3 (q), 52.8 (q), 52.6 (q),
37.1 (t), 35.6 (t), 25.8 (q), 18.1 (s), 10.1 (q), Ϫ4.6 (q), Ϫ4.8 (q);
m/z (FAB) Found: 533.2911 ([M ϩ Na]ϩ C27H46O7NaSi requires
533.2911).
(5R,7R,8R,13R)-8-(tert-Butyldimethylsilanyloxy)-5,13-di-
methoxy-7-(4-methoxy-benzyloxy)-10-methyl-3-oxo-16-tri-
methylsilanyl)-hexadeca-di-(9E,11E )-en-15-ynoic acid ethyl
ester (28). Ethyl diazoacetate (28 mg, 26 µl, 250 µmol) was
added in one portion to a stirred suspension of tin() chloride
(4 mg, 20 µmol) in dichloromethane (10 ml) at room temper-
ature under a nitrogen atmosphere. A solution of the aldehyde
(27) (140 mg, 23 µmol) in dichloromethane (10 ml) was added
dropwise, via cannula, over 2 min, and the reaction mixture was
stirred for 2 h before being concentrated in vacuo to leave a
yellow residue. Purification by flash chromatography, using 20%
ethyl acetate–petroleum ether (bp 40–60 ЊC) as eluent, gave the
β-keto ester (120 mg, 74%) as a colourless oil; [α]2D0 ϩ 39.5 (c 1.2
in CHCl3); νmax (soln: CHCl3)/cmϪ1 2930, 2175, 1740, 1716,
(4R,9R,10R,12R)-9-(tert-Butyldimethylsilanyloxy)-
4,12,14,14-tetramethoxy-10-(4-methoxybenzyloxy)-7-methyl-1-
(trimethylsilanyl)-tetradeca-di-(5E,7E )-en-1-yne (26). Sodium
bis(trimethylsilyl)amide (1 M in THF, 780 µl, 800 µmol) was
added dropwise over 5 min to a stirred solution of the sulfone
(6) (250 mg, 700 µmol) and the aldehyde (7) (250 mg, 500 µmol)
in THF at Ϫ78 ЊC under a nitrogen atmosphere. The solution
was stirred at Ϫ78 ЊC for 3 h and then warmed to room temper-
ature over 1 h. The mixture was quenched with a saturated
aqueous solution of ammonium chloride (50 ml) and the separ-
ated aqueous layer was extracted with ethyl acetate (4 × 50 ml).
The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to leave a yellow oil. Purification by flash
chromatography, using 10% ethyl acetate–petroleum ether (bp
40–60 ЊC) as eluent, gave the 1,3-diene (240 mg, 74%) as a
colourless oil; [α]2D0 ϩ 41.3 (c 1.2 in CHCl3); νmax (soln: CHCl3)/
cmϪ1 2931, 2176, 1613, 1088; 1H NMR (360 MHz, CDCl3)
δ 7.29 (2H, d, J 8.6, CH, Ar), 6.88 (2H, d, J 8.6, CH, Ar), 6.25
(1H, d, J 15.7, H-6), 5.54 (1H, dd, J 15.7, 7.8, H-5), 5.46 (1H, d,
J 9.2, H-8), 4.76 (1H, d, J 11.0, CH2Ar), 4.57 (1H, dd, J 9.2, 5.8,
H-9), 4.51 (1H, d, J 11.0, CH2Ar), 4.48 (1H, t, J 5.6, H-14), 3.81
(3H, s, ArOCH3), 3.81–3.74 (1H, m, H-4), 3.60 (1H, ddd,
J 10.0, 5.8, 1.9, H-10), 3.50–3.47 (1H, m, H-12), 3.30 (6H, s,
1
1088; H NMR (360 MHz, CDCl3) δ 7.27 (2H, d, J 8.6, CH,
Ar), 6.88 (2H, d, J 8.6, CH, Ar), 6.25 (1H, d, J 15.7, H-11), 5.54
(1H, dd, J 15.7, 7.8, H-12), 5.43 (1H, d, J 9.2, H-9), 4.75 (1H, d,
J 11.0, CH2Ar), 4.60 (1H, dd, J 9.2, 5.6, H-8), 4.48 (1H, d,
J 11.0, CH2Ar), 4.18 (2H, q, J 7.1, CO2CH2), 3.86–3.74 (2H, m,
H-5, H-13), 3.81 (3H, s, ArOCH3), 3.58 (1H, ddd, J 10.2, 5.6,
1.8, H-7), 3.42 (2H, s, H-2), 3.31 (3H, s, OCH3), 3.21 (3H, s,
OCH3), 2.74 (1H, dd, J 16.1, 7.1, H-4), 2.63 (1H, dd, J 16.1, 4.7,
H-4), 2.59 (1H, dd, J 16.7, 5.6, H-14), 2.44 (1H, dd, J 16.7, 7.1,
H-14), 1.81–1.73 (1H, m, H-6), 1.79 (3H, d, J 1.0, CH C᎐),
᎐
3
1.44 (1H, ddd, J 14.5, 10.2, 4.3, H-6), 1.27 (3H, t, J 7.1,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4188

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CO2CH2CH3), 0.88 (9H, s, C(CH3)3), 0.14 (9H, s, Si(CH3)3),
0.05 (3H, s, SiCH3), 0.00 (3H, s, SiCH3); 13C NMR (90 MHz,
CDCl3) δ 201.4 (s), 167.0 (s), 159.2 (s), 137.5 (d), 134.2 (s), 132.5
(d), 130.7 (s), 129.6 (d), 127.6 (d), 113.8 (d), 103.3 (s), 86.5 (s),
80.7 (d), 79.8 (d), 74.2 (d), 72.9 (t), 71.0 (d), 61.3 (t), 56.6 (2 ×
q), 55.3 (q), 50.0 (t), 48.1 (t), 35.3 (t), 27.1 (t), 25.8 (q), 18.1 (s),
14.9 (q), 13.4 (q), 0.1 (q), Ϫ4.3 (q), Ϫ4.8 (q); m/z (FAB) Found
725.3815 ([MNa]ϩ C38H62O8NaSi2 requires 725.3881).
(9H, s, C(CH3)3), 0.14 (9H, s, Si(CH3)3), 0.07 (3H, s, SiCH3),
0.01 (3H, s, SiCH3); 13C NMR (90 MHz, CDCl3) δ 169.1 (s),
137.3 (d), 134.2 (s), 132.2 (d), 127.8 (d), 103.2 (s), 99.4 (s), 86.6
(s), 80.7 (d), 73.4 (2xd), 72.1 (d), 60.5 (t), 56.6 (q), 55.6 (q), 47.9
(q), 42.0 (t), 39.3 (t), 32.6 (t), 27.0 (t), 25.8 (q), 18.2 (s), 14.2 (q),
13.4 (q), 0.1 (q), Ϫ4.6 (q), Ϫ4.7 (q); m/z (FAB) Found 595.3467
([M Ϫ H]ϩ C31H55O7Si2 requires 595.3486).
(2R,4R,6R,1ЈR,6ЈR)-{6-[1Ј-(tert-Butyldimethylsilanyloxy)-
6Ј-methoxy-3Ј-methyl-nona-di-(2ЈE,4ЈE )-en-8Ј-ynyl]-2,4-di-
methoxy-tetrahydropyran-2-yl}-acetic acid ethyl ester (30).
A solution of silver nitrate (43 mg, 250 µmol) in a 1 : 1 mixture
of ethanol and water (350 µl of each) was added dropwise over
1 min to a stirred solution of the trimethylsilyl acetylene (29b)
(38 mg, 64 µmol) in THF (1.0 ml) and ethanol (600 µl) at room
temperature under a nitrogen atmosphere. The mixture was
stirred at room temperature for 20 min, then a solution of
potassium cyanide (30 mg, 450 µmol) in water (500 µl) was
added dropwise over 1 min. The mixture was stirred at room
temperature for a further 2 h, and then diluted with ethyl
acetate (50 ml) and water (20 ml). The separated aqueous layer
was extracted with ethyl acetate (2 × 50 ml), and the combined
organic extracts was dried (Na2SO4) and concentrated in vacuo
to leave an opaque oil. Purification by flash chromatography,
using 12% ethyl acetate–petroleum ether (bp 40–60 ЊC) as
(2R,4R,6R,1ЈR,6ЈR)-{6-[1Ј-(tert-Butyldimethylsilanyloxy)-
6Ј-methoxy-3Ј-methyl-9Ј-(trimethylsilanyl)-nona-di-(2ЈE,4ЈE )-
en-8Ј-ynyl]-2-hydroxy-4-methoxy-tetrahydro-pyran-2-yl}-acetic
acid ethyl ester (29a). 2,3-Dichloro-5,6-dicyano-1,4-benzo-
quinone (40 mg, 170 µmol) was added in one portion to a
stirred solution of the β-keto ester (28) (80 mg, 110 µmol) in
dichloromethane (4 ml) and water (4 drops) at room temper-
ature. The mixture was stirred at room temperature for 1 h, then
diluted with dichloromethane (10 ml) and quenched with a
saturated aqueous solution of sodium hydrogencarbonate
(4 ml). The suspension was filtered through celite and washed
with dichloromethane (100 ml), and the filtrate was then
concentrated in vacuo to leave a red oil. Purification by flash
chromatography, using 20% ethyl acetate–petroleum ether (bp
40–60 ЊC) as eluent, gave the cyclic hemiketal (64 mg, 96%) as a
colourless oil; [α]2D0 ϩ 3.4 (c 0.6 in CHCl3); νmax (soln: CHCl3)/
cmϪ1 3466, 2930, 2175, 1714, 1086; 1H NMR (360 MHz,
CDCl3) δ 6.26 (1H, d, J 15.7, H-4Ј), 5.54 (1H, dd, J 15.7, 7.8,
H-5Ј), 5.40 (1H, d, J 9.0, H-2Ј), 5.10 (1H, d, J 2.4, OH ), 4.45
(1H, dd, J 9.0, 6.0, H-1Ј), 4.24–4.15 (2H, m, CO2CH2), 3.89
(1H, ddd, J 12.0, 6.0, 2.0, H-6), 3.81–3.76 (1H, m, H-6Ј), 3.72–
3.67 (1H, m, H-4), 3.35 (3H, s, OCH3), 3.33 (3H, s, OCH3),
2.65–2.56 (3H, m, CH2CO2Et, H-7Ј), 2.45 (1H, dd, J 16.8, 7.2,
H-7Ј), 2.20 (1H, m, H-3eq), 2.03 (1H, m, H-5eq), 1.75 (3H, d,
1
eluent, gave the alkyne (25 mg, 75%) as a colourless oil; H
NMR (360 MHz, CDCl3) δ 6.26 (1H, d, J 15.7, H-4Ј), 5.59 (1H,
dd, J 15.7, 7.8, H-5Ј), 5.40 (1H, d, J 9.3, H-2Ј), 4.42 (1H, dd,
J 9.3, 7.0, H-1Ј), 4.19–4.12 (2H, m, CO2CH2), 3.80 (1H, app q,
J ∼6.5, H-6Ј), 3.60 (1H, dddd, J 11.5, 11.5, 4.5, 4.5, H-4), 3.46
(1H, ddd, J 11.5, 7.0, 1.9, H-6), 3.33 (6H, s, 2xOCH3), 3.26 (3H,
s, OCH3), 2.83 (1H, d, J 14.0, CH2CO2Et), 2.57 (1H, d, J 14.0,
CH2CO2Et), 2.50 (2H, ddd, J 6.0, 6.0, 2.6, H-7Ј), 2.46–2.40 (1H,
m, H-3eq), 2.02 (1H, t, J 2.6, H-9π), 1.92–1.88 (1H, m, H-5eq),
J 1.0, CH C᎐), 1.29 (3H, t, J 7.1, CO CH CH ), 1.16 (1H, ddd,
᎐
3
2
2
3
J 16.9, 11.9, 2.4, H-3ax), 1.05 (1H, app q, J ∼12.0, H-5ax), 0.85
(9H, s, C(CH3)3), 0.14 (9H, s, Si(CH3)3), 0.02 (3H, s, SiCH3),
Ϫ0.01 (3H, s, SiCH3); 13C NMR (90 MHz, CDCl3) δ 172.1 (s),
137.6 (d), 134.1 (s), 132.6 (d), 127.3 (d), 103.3 (s), 96.5 (s), 86.5
(s), 80.5 (d), 73.2 (d), 73.1 (d), 71.4 (d), 60.8 (t), 56.6 (q), 55.6
(q), 44.5 (t), 40.7 (t), 32.1 (t), 26.9 (t), 25.8 (q), 18.2 (s), 14.0 (q),
13.3 (q), 0.1 (q), Ϫ4.5 (q), Ϫ4.8 (q); m/z (FAB) Found 605.3347
([MNa]ϩ C30H54O7NaSi2 requires 605.3330).
1.80 (3H, d, J 1.0, CH C᎐), 1.44 (1H, dd, J 12.6, 11.5, H-3ax),
᎐
3
1.28 (3H, td, J 7.1, 1.1, CO2CH2CH3), 1.05 (1H, ddd, J 11.5,
11.5, 11.5, H-5ax), 0.87 (9H, s, C(CH3)3), 0.06 (3H, s, SiCH3),
0.01 (3H, s, SiCH3); 13C NMR (125 MHz, CDCl3) δ 169.1 (s),
137.5 (d), 134.1 (s), 132.5 (d), 127.4 (d), 99.4 (s), 80.6 (d), 80.3
(d), 73.4 (d), 73.3 (d), 72.1 (d), 69.9 (s), 60.5 (t), 56.6 (q), 55.6
(q), 47.9 (q), 42.0 (t), 39.3 (t), 32.5 (t), 25.8 (t), 25.8 (q), 18.2 (s),
14.2 (q), 13.4 (q), Ϫ4.7 (q), Ϫ4.7 (q); m/z (ESI) Found 547.3104
([MNa]ϩ C28H48O7SiNa requires 547.3067).
(2R,4R,6R,1ЈR,6ЈR)-{6-[1Ј-(tert-Butyldimethylsilanyloxy)-
6Ј-methoxy-3Ј-methyl-9Ј-(trimethylsilanyl)-nona-di-(2ЈE,4ЈE )-
(2R,4R,6R,1ЈR,6ЈR)-{6-[9Ј-Bromo-1Ј-(tert-butyldimethyl-
silanyloxy)-6Ј-methoxy-3Ј-methyl-nona-tri-(2ЈE,4ЈE,8ЈE )-enyl]-
2,4-dimethoxy-tetrahydropyran-2-yl}-acetic acid ethyl ester (31).
Tributyltin hydride (21 mg, 71 µmol) and azo bis(isobutyro-
nitrile) (catalytic) were added separately, each in one portion, to
a stirred solution of the alkyne (30) (25 mg, 48 µmol) in benzene
(2 ml) at room temperature under a nitrogen atmosphere. The
mixture was heated at reflux for 1 h 30 min and then con-
centrated in vacuo to leave the crude vinyl stannane as an
opaque residue.
en-8Ј-ynyl]-2,4-dimethoxy-tetrahydropyran-2-yl}-acetic
acid
ethyl ester (29b). Pyridinium para-toluenesulfonate (35 mg, 136
µmol) was added in one portion to a stirred solution of the
cyclic hemi-ketal (29a) (80 mg, 136 µmol) in methanol (8 ml)
and dichloromethane (5.5 ml) at room temperature under a
nitrogen atmosphere. The solution was stirred at room temper-
ature for 66 h and then quenched with a saturated aqueous
solution of sodium hydrogencarbonate (15 ml). The mixture
was extracted with ethyl acetate (3 × 10 ml), and the combined
organic extracts were then dried (Na2SO4) and concentrated
in vacuo to leave a colourless oil. Purification by flash chrom-
atography, using 10% ethyl acetate–petroleum ether (bp 40–
60 ЊC) as eluent, gave the methyl ketal (48 mg, 59%) as a colour-
less oil; [α]2D0 Ϫ30.6 (c 0.2 in CHCl3); νmax (soln: CHCl3)/cmϪ1
N-Bromosuccinimide (15 mg, 71 µmol) was added in one
portion to a stirred solution of the vinyl stannane in acetonitrile
(2 ml) at 0 ЊC under a nitrogen atmosphere. The solution was
stirred at 0 ЊC for 15 min and then concentrated in vacuo to
leave an opaque residue. Purification by flash chromatography,
using 15% ethyl acetate–petroleum ether (bp 40–60 ЊC) as
eluent, gave the vinyl bromide (17 mg, 60% over two steps) as
1
2931, 2176, 1729, 1089; H NMR (360 MHz, CDCl3) δ 6.25
(1H, d, J 15.7, H-4Ј), 5.56 (1H, dd, J 15.7, 7.6, H-5Ј), 5.39 (1H,
d, J 9.2, H-2Ј), 4.42 (1H, dd, J 9.2, 7.0, H-1Ј), 4.20–4.12 (2H, m,
CO2CH2), 3.78 (1H, app q, J ∼7.6, H-6Ј), 3.59 (1H, dddd,
J 11.0, 11.0, 4.5, 4.5, H-4), 3.47 (1H, ddd, J 12.0, 7.0, 1.9, H-6),
3.33 (3H, s, OCH3), 3.32 (3H, s, OCH3), 3.27 (3H, s, OCH3),
2.83 (1H, d, J 14.0, CH2CO2Et), 2.60 (1H, dd, J 17.0, 5.6, H-7Ј),
2.57 (1H, d, J 14.0, CH2CO2Et), 2.44 (1H, dd, J 17.0, 7.3, H-7Ј),
2.45–2.42 (1H, m, H-3eq), 1.93–1.88 (1H, m, H-5eq), 1.80 (3H,
1
a colourless oil; H NMR (500 MHz, CDCl3) δ 6.19 (1H, d,
J 15.7, H-4Ј), 6.21–6.17 (1H, m, H-8Ј), 6.10 (1H, d, J 13.6,
H-9Ј), 5.45 (1H, dd, J 15.7, 7.9, H-5Ј), 5.39 (1H, d, J 9.2, H-2Ј),
4.42 (1H, dd, J 9.2, 7.0, H-1Ј), 4.18–4.13 (2H, m, CO2CH2),
3.67–3.56 (2H, m, H-4, H-6Ј), 3.48 (1H, ddd, J 12.0, 7.0, 1.7,
H-6), 3.33 (3H, s, OCH3), 3.27 (3H, s, OCH3), 3.27 (3H, s,
OCH3), 2.83 (1H, d, J 14.0, CH2CO2Et), 2.57 (1H, d, J 14.0,
CH2CO2Et), 2.45–2.41 (1H, m, H-3eq), 2.37–2.23 (2H, m,
d, J 1.1, CH C᎐), 1.44 (1H, dd, J 15.7, 11.0, H-3ax), 1.28 (3H, t,
᎐
3
J 7.1, CO2CH2CH3), 1.04 (1H, app q, J ∼12.0, H-5ax), 0.87
H-7Ј), 1.92–1.89 (1H, m, H-5eq), 1.78 (3H, s, CH C᎐), 1.44 (1H,
᎐
3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4189

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dd, J 12.7, 11.1, H-3ax), 1.28 (3H, t, J 7.2, CH2CH3), 1.05 (1H,
ddd, J 12.0, 12.0, 12.0, H-5ax), 0.88 (9H, s, C(CH3)3), 0.07 (3H,
s, SiCH3), 0.02 (3H, s, SiCH3); m/z (ESI) Found 627.2308
([MNa]ϩ C28H49O7SiBrNa requires 627.2329).
mixture was then stirred overnight at room temperature.
Analysis by TLC showed the presence of remaining starting
material, and so further portions of bromotrichloromethane
and DBU were added and the mixture was again stirred for 24
h. The mixture was evaporated in vacuo and the residue was
purified by chromtography on silica, eluting with 50% ethyl
acetate–petrol, to give the oxazole (9.9 mg; 66%) as a pale
Tetrahydropyranyl amide alcohol (32). Aqueous lithium
hydroxide (257 µl; 0.26 mmol) was added to a solution of the
ester (31) (15.5 mg; 0.03 mmol) in methanol (0.5 ml) and THF
(0.5 ml), and the mixture was stirred at room temperature for
22 h. The mixture was neutralized at 0 ЊC with 10% citric acid
solution, and then extracted with ethyl acetate (3 × 5 ml). The
separated organic layer was washed with brine (2 ml), dried
(Na2SO4) and the solvent was then evaporated to leave a pale
orange oil. The oil was purified by eluting through a short plug
of silica with ethyl acetate to afford the corresponding
carboxylic acid as a pale yellow oil (15 mg) which was used
without further purification. Triethylamine (15 µl; 0.11 mmol)
was added to a solution of serine (5 mg; 0.03 mmol) in THF
(1 ml), at 0 ЊC, and the mixture was stirred at 0 ЊC for 15 min. A
solution of the crude carboxylic acid (15 mg; 0.03 mmol) in
THF (1.5 ml) was added via cannula, followed by EDC (6.2 mg;
0.03 mmol), and HOBT (4 mg; 0.03 mmol), and the mixture
was allowed to warm to room temperature overnight. The
mixture was quenched with saturated ammonium chloride solu-
tion (1 ml), diluted with water (1 ml) and extracted with ethyl
acetate (4 × 5 ml). The separated organic extracts were dried
(Na2SO4) and the solvent was then evaporated to leave a pale
yellow oil. The oil was purified by chromatography on silica,
eluting with ethyl acetate, to give the amide (15.8 mg; 91%) as a
colourless oil; 1HNMR (360 MHz, CDCl3) δ 6.50–6.06 (3H, m,
H-4Ј, H-8Ј, H-9Ј), 5.50 (1H, dd, J 15.7, 7.5, H-5Ј), 5.44 (1H, d,
J 8.4, H-2Ј), 4.70–4.55 (2H, m, CHCO2Me, CH2OH), 4.0–3.88
(1H, m, CH2OH), 3.78 (3H, s, CO2Me, 3.70–3.53 (H, m, H-4,
H-6Ј), 3.52–3.43 (1H, m, H-6), 3.32 (3H, s, OCH3), 3.28 (3H, s,
OCH3), 3.25 (3H, s, OCH3), 2.83 (1H, d, J 14.8, CH2OX),
2.54 (1H, d, J 14.8, CH2OX), 2.40–2.23 (3H, m, H-3eq, H-7Ј),
1
yellow oil; H NMR (360 MHz, CDCl3) δ 6.26–6.15 (2H, m,
H-4Ј, H-8Ј), 6.10 (1H, d, J 13.6, H-9Ј), 5.45 (1H, dd, J 15.7, 7.8,
H-5Ј), 5.38 (1H, d, J 9.2, H-2Ј), 4.42 (1H, dd, J 9.1, 6.8, H-1Ј),
3.91 (3H, s, CO2CH3), 3.69–3.60 (1H, m, H-6Ј), 3.59–3.42 (2H,
m, H-4, H-6), CH2OX not observed (under OCH3 resonances),
3.33 (3H, s, OCH3), 3.29 (3H, s, OCH3), 3.27 (3H, s, OCH3),
3.09 (1H, d, J 14.7, CH2OX), 2.39–2.20 (3H, m, H-3eq, H-7Ј),
1.92–18.5 (1H, m, H-5 ), 1.78 (3H, d, J 11.1, CH C᎐), 1.41–
᎐
3
eq
1.36 (1H, m, H-3ax), 1.03 (1H, dd, J 23.6, 11.7, H-5ax), 0.87 (9H,
s, C(CH3)3), 0.06 (3H, s, CH3), 0.01 (3H, s, CH3); m/z (ESI)
Found 680.2191 ([M ϩ Na]ϩ C30H48O8NSi79BrNa requires
680.2230).
Tetrahydropyranyl oxazole methylsulfone (36). Diisobutyl-
aluminium hydride (1.5 M solution; 36 µl; 0.04 mmol) was
added over 5 min to a stirred solution of the ester (34) (9.5 mg;
0.014 mmol) in dichloromethane (0.5 ml) at Ϫ78 ЊC and the
mixture was allowed to warm to 0Њ over 2 h. The mixture
was quenched with saturated ammonium chloride solution
(2 drops), stirred for 15 min, and then eluted through a short
column of silica with ethyl acetate to give the corresponding
alcohol (35a) (8.9 mg; 98%) as a pale yellow oil; 1H NMR (360
MHz, CDCl3) δ 7.52 (1H, s, CH), 6.26–6.16 (2H, m, H-4Ј,
H-8Ј), 6.1 (1H, d, J 13.1, H-9Ј), 5.45 (1H, dd, J 15.6, 7.7Hz,
H-5Ј), 5.39 (1H, d, J 9.9, H-2Ј), 4.58 (2H, s, CH2), 4.4 3(1H, dd,
J 9.11, 6.8, H-1Ј), 3.58–3.42 (3H, m, H-6Ј, H-4, H-6), 3.33 (3H,
s, OCH3), 3.30 (3H, s, OCH3), 3.27 (3H, s, OCH), CH2OX not
observed (under methyl resonances), 3.00 (1H, d, J 15.0,
CH2OX, 2.37–2.23 (3H, m, H-3eq, H-7Ј), 1.95–1.87 (1H, m,
1.95–1.83 (1H, m, H-5 ), 1.81 (3H, s, CH C᎐, H-5 ϩ H-3ax
H-5 ), 1.78 (3H, s, CH C᎐), 1.41–1.35 (1H, m, H-3 ), 1.04 (1H,
᎐
eq 3 ax
᎐
eq
3
ax
not observed (hidden under impurities), 0.90 (9H, s, C(CH3)3),
0.08 (3H, s, CH3), 0.03 (3H, s, CH3); m/z (ESI) Found 700.2547
([M ϩ Na]ϩ C30H52O9NSi79BrNa requires 700.2492).
dd, J 23.6, 12.0, H-5ax), 0.88 (9H, s, C(CH3)3), 0.07 (3H, s, CH3),
0.01 (3H, s, CH3); m/z (ESI) Found 652.2291 ([M ϩ Na]ϩ
C29H48O7NSi79BrNa requires 652.2281).
Triethylamine (13 µl; 0.09 mmol), followed by methane-
sulfonyl chloride (3.6 µl; 0.05 mmol) were added to a solution
of the obtained alcohol (8.9 mg; 0.0137 mmol) in dichloro-
methane (0.5 ml) at room temperature and the mixture was
stirred at room temperature for 1 h. The mixture was quenched
with saturated sodium bicarbonate solution (2 drops) and the
solvents were then evaporated to dryness. The residue was
eluted through a short column of silica with ethyl acetate to
give the mesylate (35b) (10 mg) as a pale yellow oil.
Tetrahydropyranyl oxazolidine (33). DAST (4.3 µl; 0.03
mmol) was added to a solution of the amide alcohol (32)
(15.8 mg; 0.02 mmol) in dichloromethane (0.5 ml) at Ϫ78 ЊC
and the mixture was stirred at Ϫ78 ЊC for 1 h, then quenched
with saturated sodium bicarbonate solution (1 ml) and allowed
to warm to room temperature. The mixture was diluted with
water (2 ml) and extracted with ethyl acetate (4 × 5 ml). The
combined organic extracts were dried (Na2SO4) and evaporated
to leave a pale yellow oil. The oil was eluted through a short
plug of silica with ethyl acetate to give the oxazoline (15 mg;
98%) as a pale yellow oil, which was used without further
A solution of 1 M NaHMDS (28 µl; 0.03 mmol) was added
to a solution of 2-mercaptobenzothiazole (4.7 mg; 0.03 mmol)
in THF (0.1 ml) and the solution was stirred at room temper-
ature for 10 min and then added via cannula to a solution of the
crude mesylate (10 mg; 0.02 mmol) in THF (0.2 ml) at 0 ЊC. The
mixture was stirred at room temperature for 2 h, and then
evaporated in vacuo. The residue was purified by chromato-
graphy on silica, eluting with 10% ethyl acetate–petrol to give
1
purification; HNMR (360 MHz, CDCl3) δ 6.25–6.15 (2H, m,
H-4Ј, H-8Ј), 6.09 (1H, d, J 13.6, H-9Ј), 5.44 (1H, dd, J 15.7, 7.8,
H-5Ј), 5.38 (1H, d, J 8.8, H-2Ј), 4.75 (1H, dd, J 10.4, 8.0,
CH2OH), 4.50 (1H, t, J 8.3, CHCO2Me), 4.46–4.38 (2H, m,
H-1Ј, CH2OH), 3.78 (3H, s, CO2Me), 3.68–3.52 (2H, m, H-4,
H-6Ј), 3.51–3.45 (1H, m, H-6), 3.32 (3H, s, OCH3), 3.28 (3H, s,
OCH3), 3.26 (3H, s, OCH3), 3.02 (1H, d, J 14.4Hz, CH2OX),
2.53 (1H, d, J 14.4Hz, CH2OX), 2.47–2.39 (1H, m, H-3eq), 2.36–
2.24 (2H, m, H-7Ј), 1.92–1.85 (1H, m, H-5eq), 1.77 (3H, d,
1
the sulfide (4.2 mg; 38%) as a colourless oil; H NMR (360
MHz, CDCl3) δ 7.89 (1H, d, J 8.1, ArH, 7.75 (1H, d, J 8.1,
ArH), 7.47–7.36 (1H, m, ArH), 7.34–7.23 (1H, m, ArH), 6.23–
6.15 (2H, m, H-4Ј, H-8Ј), 6.09 (1H, d, J 13.5, H-9Ј), 5.38 (1H,
dd, J 15.5, 7.9, H-5Ј), 5.38 (1H, d, J 8.4, H-2Ј), 4.48 (2H, d,
J 3.5, CH2S), 4.42 (1H, dd, J 9.3, 7.0, H-1Ј), 3.69–3.61 (1H, m,
H-6), 3.60–3.41 (2H, m, H-6Ј, H-4, 3.32 (3H, s, OCH3), 3.29
(3H, s, OCH3), 3.26 (3H, s, OCH3), 2.97 (1H, d, J 14.9,
CH2OX), 2.40–2.20 (3H, m, H-3eq, H-7Ј), 1.98–1.83 (1H, m,
J 1HZ, CH C᎐), 1.46 (1H, dd, J 12.7, H-3 ), 1.03 (1H, dd,
᎐
3
ax
J 23.5, 11.9Hz, H-5ax), 0.86 (9H, s, C(CH3)3), 0.05 (3H, s, CH3),
0.01 (3H, s, CH3); m/z (ESI) Found 682. 2416 ([MϩNa]ϩ
C30H50O8NSi79BrNa requires 682.2387).
Tetrahydropyranyl oxazole ester (34). Bromotrichloro-
methane (9 µl; 0.09 mmol), followed by DBU (14 µl; 0.09
mmol), were added to a solution of the oxazoline (33) (15 mg;
0.022 mmol) in dichloromethane (0.5 ml) at 0 ЊC and the
H-5 ), 1.77 (3H, s, CH C᎐), 1.38 (1H, dd, J 12.8, 11.7, H-3 ),
᎐
eq 3 ax
1.03 (1H, dd, J 23.7, 12.2, H-5ax), 0.87 (9H, s, C(CH3)3), 0.07
(3H, s, CH3), 0.01 (3H, s, CH3); m/z (ESI) Found 801.1987
([M ϩ Na]ϩ C36H5179BrN2O6S2SiNa requires 801.2039).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4190

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Ammonium molybdate (3.6 mg; 2.9 µmol), followed by 30%
hydrogen peroxide solution (65 µl; 57.8 µmol) were added
successively to a solution of the sulfide (4.5 mg; 5.2 µmol) in
methanol (0.5 ml) at room temperature, and the mixture was
then stirred at room temperature for 3 days. The solvent was
evaporated and the residue was purified by chromatography on
silica eluting with 20% ethyl acetate–petrol to give the sulfone
(2.6 mg; 60%) as a colourless oil; 1H NMR (360 MHz, CDCl3)
δ 8.25 (1H, d, J 8.3, ArH), 7.99 (1H, d, J 8.3, ArH), 7.67–7.57
(2H, m, ArH), 7.65 (1H, s, CH), 6.26–6.15 (2H, m, H-4Ј, H-8Ј),
6.09 (1H, d, J 13.6, H-9), 5.61–5.41 (1H, m, H-5Ј), 5.37–5.35
(1H, m, H-2Ј), 4.75 (2H, s, CH2SO2Ar), 4.39 (1H, dd, J 8.7, 7.4,
H-1Ј), 3.82–3.62 (1H, m, H-6), 3.54–3.38 (2H, m, H-6Ј, H-4),
3.27 (3H, s, OCH3), 3.26 (3H, s, OCH3), 3.17 (3H, s, OCH3),
2.88 (1H, d, J 14.9, CH2OX), 2.51–2.45 (1H, m, H-3eq),
2.37–2.24 (1H, m, H-7Ј), 2.1–2.07 (1H, m, H-7Ј), 1.90–1.82 (1H,
ated aqueous layer was extracted with ethyl acetate (3 × 30 ml),
and the combined organic extracts were washed with brine
(50 ml), dried over anhydrous Na2SO4 and evaporated to dry-
ness. The residue was purified by chromatography on silica gel
(20–30% ethyl acetate–petrol as eluant) to give the primary
alcohol (371 mg, 54%) as a colourless oil; [α]2D2 ϩ6.5 (c 1.7 in
CHCl3); νmax(CHCl3)/cmϪ1 3517, 2930, 2854, 1612, 1588, 1463,
1112; 1H NMR (500 MHz, CDCl3) δ 7.28 (2H, d, J 7.0, ArH),
6.88 (2H, d, J 7.0, ArH), 5.8–5.9 (1H, m, CH᎐CH ), 5.11 (1H,
᎐
2
d, J 17.2, CH᎐CH ), 5.05 (1H, d, J 10.0, CH᎐CH ), 4.58 (1H, d,
᎐
᎐
2
2
J 10.6, ArCH2O), 4.45 (1H, d, J 10.6, ArCH2O), 3.81 (3H, s,
CH3O), 3.6–3.65 (1H, m, CH2O), 3.35–3.4 (1H, m, CHOH),
3.5–3.55 (1H, m, CH3CH ), 1.90 (1H, b s, OH), 1.04 (3H, d,
J 6.1, CH3) and 0.95 (3H, d, J CH3); 13C NMR (125 MHz,
CDCl3) δ 159.1 (s), 141.8 (d), 130.8 (s), 129.4 (d), 114.4 (t), 113.7
(d), 83.8 (d), 73.7(t), 66.1 (t), 55.2 (q), 40.8 (d), 17.4 (q), 11.2 (q);
m/z (FAB) Found 263.1640 ([M Ϫ H]ϩ C16H23O3 requires
263.1647).
m, H-5 ), 1.77 (3H, d, J 4.6, CH C᎐), 1.22 (1H, dd, J 14.1, 11.5,
᎐
eq
3
H-3ax), 0.99 (1H, dd, J 23.4, 12.3, H-5ax), 0.85 (9H, s, C(CH3)3),
0.04 (3H, s, CH3), Ϫ0.1 (3H, s, CH3); m/z (ESI) Found 833.1938
([M ϩ Na]ϩ C36H5179Br N2O8S2SiNa requires 833.1937).
Benzoic acid 3-(4-methoxy-benzyloxy)-2,4-dimethyl-hex-5-
enyl ester (40b). Benzoyl chloride (2.1 g, 15 mmol) was added
dropwise over 10 min to a stirred mixture of the alcohol (40a)
(2.64 g, 10 mmol) in pyridine (10 ml), and DMAP (5 mg) at
0 ЊC. The mixture was stirred at 25 ЊC for 3 h and then poured
into aqueous 0.5 M HCl (50 ml) at 0 ЊC, and extracted with
ethyl acetate (3 × 70 ml). The combined organic extracts were
washed with water (50 ml) and brine (50 ml), then dried over
anhydrous Na2SO4 and evaporated to dryness. The residue was
purified by flash chromatography on silica gel eluting with 10%
ether–petrol to give the ester (3.4 g, 91% yield), as a colourless
oil; [α]2D2 ϩ33.0 (c 0.2 in CHCl3); νmax(NaCl)/cmϪ1 2926, 1719,
1-(tert-Butyl-diphenyl-silanyloxy)-2,4-dimethyl-hex-5-en-3-ol
(39). n-Butyllithium in THF (1.6 M, 25 mmol) was added over
10 min, to a stirred mixture of potassium tert-butoxide (2.8 g,
25 mmol, dried at 80 ЊC/0.5 mm for 8 h), THF (7 ml), and trans-
2-butene (4.5 ml, 50 mmol), at Ϫ78 ЊC. The mixture was stirred
at Ϫ45 ЊC for 10 min, recooled to Ϫ78 ЊC, and then treated drop-
wise over 10 min with a solution of (Ϫ)-methoxydiisopino-
campheylborane in ether (1 M, 30 mmol). The mixture was
stirred at Ϫ78 ЊC for 30 min, and then boron trifluoride etherate
(4 ml, 33.5 mmol) was added dropwise over 10.5 min, followed
by (S)-3-(tert-butyldiphenylsilanyloxy-2-methylpropanal (38)28
(8.2 g, 25 mmol) over 30 min at Ϫ78 ЊC. The mixture was stirred
at Ϫ78 ЊC for 3 h, then treated with 3 M NaOH (18 ml) and 30%
H2O2 (7.5 ml), and stirred overnight. The separated organic
layer was washed with water (30 ml) and brine (30 ml), then
dried over anhydrous MgSO4 and evaporated to dryness. The
residue was purified by flash chromatography on silica gel
eluting with 10–30% ether–petrol to give the homoallylic alcohol
(7.3 g, 76% yield, 92% de by NMR analysis), as a colourless oil;
[α]2D2 ϩ15.2 (c 0.4 in CHCl3); νmax(NaCl)/cmϪ1 3550–3300, 3068,
2955, 2927, 2851, 1590, 1471, 1427, 1261, 1112; 1H NMR (360
MHz, CDCl3) δ 7.6–7.7 (4H, m, Ph), 7.2–7.4 (6H, m, Ph), 5.82–
5.9 (1H, m, CH᎐CH ), 5.10 (1H, d, J 6.9, CH᎐CH ), 5.08 ( 1H,
1
1612, 1513, 1452, 1273, 1111; H NMR (360 MHz, CDCl3)
δ 8.05 (2H, d, J 7.0, ArH), 7.55 (1H, d, J 7.4, ArH), 7.45 (2H, dd,
J 7.0, 7.4, ArH), 7.26 (2H, d, J 8.6, ArH), 6.87 (2H, d, J 8.6,
ArH), 5.8–5.9 (1H, m, CH᎐CH ), 5.10 (1H, d, J 16.2,
᎐
2
CH᎐CH ), 5.07 (1H, d, J 11.7, CH᎐CH ), 4.57 (1H, d, J 10.6,
᎐
᎐
2
2
CH2O), 4.44 (1H, d, J 10.6, CH2O), 4.2–4.3 (2H, m, OCH2),
3.80 (3H, s, CH3O), 3.37 (1H, dd, J 4.0, 6.7, OCH), 2.5–2.6 (1H,
m, CH3CH), 2.18–2.26 (1H, m, CH3CH), 1.07 (3H, d, J 6.9,
CH3) and 1.06 (3H, d, J 6.9, CH3); 13C NMR (90 MHz, CDCl3)
δ 166.6(s), 159.1(s), 141.5(d), 132.8(d), 130.9(s), 130.5(s),
129.5(d), 129.5(d), 129.3(d), 128.3(d), 114.6(s), 113.7(d),
82.7(d), 74.1(t), 67.1(t), 55.2(q), 40.9(d), 35.1(d), 17.1(q) and
11.4(q); m/z (ESI) Found 391.2036 ([M ϩ Na]ϩ C23H28O4Na
requires 391.1885).
᎐
᎐
2
2
s, CH᎐CH ), 3.70 (2H, d, J 5.2, CH O), 3.58 (1H, d, J 8.5,
᎐
2
2
CHOH), 2.40 (1H, b s, OH), 2.2–2.3 (1H, m, CH), 1.8–1.85
(1H, m, CH), 1.06 (9H, s, But), 0.94 (3H, d, J 6.8, CH3) and 0.93
(3H, d, J 6.4, CH3); 13C NMR (90 MHz, CDCl3) δ 141.9(d),
135.6(d), 133.3(s), 129.7(d), 127.7(d), 115.3(t), 76.1(d), 68.4(t),
41.7(d), 36.7(d), 26.7(q), 19.2(s), 16.7(q), 9.6(q); m/z (FAB)
Found 383.2408 ([M ϩ H]ϩ C24H34O2Si requires 383.2406).
Benzoic acid 3-(4-methoxy-benzyloxy)-2,4-dimethyl-5-oxo-
pentyl ester (41). Osmium tetroxide (20 mg) was added to a
stirred mixture of the alkene (40b) (3.2 g, 8.7 mmol) and NMO
(1.5 g, 13.1 mmol) in acetone–water (9 : 1) (50 ml) at 0 ЊC. The
mixture was stirred at room temperature for 12 h, and then
aqueous Na2S2O3 (1 M, 20 mol) was added. The mixture was
evaporated to leave an aqueous layer, which was extracted with
ethyl acetate (3 × 50 ml). The combined organic extracts were
washed with sodium bicarbonate and brine, dried (Na2SO4),
and then evaporated. The residue was filtered through a pad
of silica gel with 30–50% ethyl acetate–petrol to give the
corresponding 1,2-diol as a colourless oil.
3-(4-Methoxy-benzyloxy)-2,4-dimethyl-hex-5-en-1-ol (40a).
Trifluoromethanesulfonic acid (12 ml, 0.13 mmol) was added
to a stirred mixture of the alcohol (39) (1.0 g, 2.6 mmol) and
4-methoxybenzyl 2,2,2-trichloroacetimidate (1.5 g, 5.2 mmol)
in ether (26 ml) at 0 ЊC. The mixture was stirred at 0 ЊC for
10 min, then allowed to warm to room temperature and treated
with saturated NaHCO3 solution (30 ml). The organic layer was
separated and the aqeous layer was extracted with ether (3 ×
50 ml). The combined organic extracts were washed with water
(50 ml) and brine (50 ml), then dried over anhydrous Na2SO4
and evaporated to dryness. The residue was purified by chrom-
atography on silica gel (5–10% ether-petrol as eluant) to give the
corresponding PMB ether as a colourless oil, which was used in
the next step.
Sodium periodate (2.8 g, 13.1 mmol) was added to a stirred
solution of the 1,2-diol in THF–pH7 buffer (3 : 1, 50 ml) at
0 ЊC. The reaction was monitored by TLC until the starting
material was consumed. The mixture was evaporated to leave
an aqueous layer which was extracted with ethyl acetate (3 ×
50 ml). The combined organic extracts were washed with water
and brine, dried (Na2SO4), and then evaporated. The residue
was purified by flash chromatography on silica gel eluting with
10–20% ether–petrol to give the aldehyde (3.2 g, 87% over two
TBAF (1 M solution, 3.9 ml) was added dropwise over 5 mins
to a stirred solution of the PMB ether in THF (20 ml) at 0 ЊC.
The mixture was stirred at room temperature for 1 hour and
then poured into aqueous NH4Cl solution (50 ml). The separ-
1
steps), as a colourless oil; H NMR (360 MHz, CDCl3) δ 9.80
(1H, d, J 2.3, CHO), 8.02–8.05 (2H, m, ArH), 7.50–7.56 (1H,
m, ArH), 7.38–7.45 (2H, m, ArH), 7.21 (2H, d, J 8.7, ArH),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4191

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6.82 (2H, d, J 8.7, ArH), 4.50 (2H, dd, J 10.8, 13.3, CH2O), 4.28
(2H, d, J 7.1, CH2O), 3.83 (1H, dd, J 3.1, 7.8, CHOCH2), 3.71
(3H, s, CH3O), 2.7–2.8 (1H, m, CH3CH), 2.18–2.27 (1H, m,
CH3CH), 1.06 (3H, d, J 7.0, CH3) and 1.05 (3H, d, J 6.9, CH3);
13C NMR (90 MHz, CDCl3) δ 203.9 (d), 158.9 (s), 132.8 (d),
129.7 (s), 129.2 (d), 129.2 (d), 128.2 (d), 113.5 (d), 79.3 (d), 73.7
(t), 66.5 (t), 54.8 (q), 48.9 (d), 35.0 (d), 11.0 (q), 10.5 (q).
(3H, s, CH3O), 3.64 (1H, dd, J 2.0, 9.3, OCH), 3.51–3.61 (2H,
m, OCH2), 2.3–2.4 (2H, m, OCHCH2), 2.27 (1H, br. s, OH),
1.86–1.93 (1H, m, CHCH3), 1.78–1.85 (1H, m, CHCH3), 0.97
(9H, t, J 7.8, 3 × SiCH2CH3), 0.87 (3H, d, J 6.9, CH3), 0.82 (3H,
d, J 7.0, CH3) and 0.63 (6H, q, J 7.8, 3 × SiCH2CH3); 13C NMR
(90 MHz, CDCl3) δ 158.8(s), 134.8(d), 131.1(s), 128.7(d),
116.7(t), 113.6(d), 80.0(d), 73.4(t), 71.3(d), 66.4(t), 55.0(q),
40.2(t), 39.0(d), 37.4(d), 10.0(q), 9.1(q), 7.00(q), 5.7(t); m/z
(ESI) Found 445.2902 ([M ϩ Na]ϩ C24H42O4SiNa requires
445.2750).
Benzoic acid 5-hydroxy-3-(4-methoxy-benzyloxy)-2,4-di-
methyl-oct-7-enyl ester (42). Boron trifluoride dietherate
(123 ml, 1 mmol) was added dropwise over 5 min to a stirred
solution of allyltributyltin (341 ml, 1.1 mmol) and the aldehyde
(41) (370 mg, 1 mmol) in CH2Cl2 (10 ml) at Ϫ78 ЊC, and the
mixture was stirred at Ϫ78 ЊC for 2 h, then quenched with
saturated aqueous NaHCO3 (10 ml) and warmed to ambient
temperature. The mixture was diluted with CH2Cl2 (50 ml) and
washed with saturated aqueous NaHCO3 (50 ml). The aqueous
layer was extracted with CH2Cl2 (30 ml) and the combined
organic extracts were dried over anhydrous Na2SO4 and evap-
orated to dryness in vacuo. The residue was purified by flash
chromatograpy on silica gel eluting with 10% ethyl acetate–
petrol to give the homoallylic alcohol (388 mg, 94% yield, 96%
de), as a colourless oil; [α]2D2 ϩ7.1 (c 0.2 in CHCl3); νmax(NaCl)/
5-(4-Methoxy-benzyloxy)-4,6-dimethyl-7-(triethyl-silanyoxy)-
deca-2,9-dienoic acid ethyl ester (45). A solution of dry DMSO
(157 ml, 2.2 mmol) in dichloromethane (2 ml) was added
dropwise over 30 min, at a rate sufficient to maintain the
internal temperature < Ϫ60 ЊC, to a stirred solution of freshly
distilled oxalyl chloride (96 ml, 1.1 mmol) in dichloromethane
(10 ml) under a nitrogen atmosphere. The mixture was stirred
at Ϫ70 ЊC for 10 min, and then a solution of the alcohol (43b)
(423 mg, 1 mmol) in dichloromethane (2 ml) was added drop-
wise over 15 min. Triethylamine (307 ml, 2.2 mmol) was added
to the mixture at Ϫ70 ЊC, and it was then allowed to warm to
Ϫ30 ЊC over 1.5 h. The mixture was poured into iced 1 M HCl
(2.5 ml) and then saturated with NaCl. The separated organic
layer was washed with sodium bicarbonate and brine, dried
(Na2SO4), and then evaporated to dryness. The residue was
purified by flash chromatography on silica gel eluting with
5–10% ether–petrol to give the corresponding aldehyde (44) as a
colourless oil.
NaHMDS (1 M solution, 2 ml) was added over 10 min to a
stirred solution of triethyl phosphonoacetate (595 ml, 3 mmol)
in THF (10 ml) at 0 ЊC under an argon atmosphere and the
mixture was stirred at 0 ЊC for 10 min, and then cooled at
Ϫ78 ЊC. A solution of the aldehyde in THF (2 ml) was added
dropwise at Ϫ78 ЊC, and after 1 h at Ϫ78 ЊC, the mixture was
allowed to warm gradually to 0 ЊC, where it was quenched with
saturated aqueous ammonium chloride solution (1 ml). The
mixture was evaporated and the aqueous residue was extracted
with ethyl acetate (3 × 50 ml). The combined organic extracts
were washed with water and brine, then dried (Na2SO4), and
evaporated to dryness. The residue was purified by flash
chromatography on silica gel eluting with 10–20% ether-petrol
to give the α,β-unsaturated ester (309 mg, 63% over two steps),
as a colourless oil; [α]2D2 ϩ29.1 (c 0.7 in CHCl3); νmax(NaCl)/cmϪ1
2921, 1718, 1593, 1510, 1248, 1115, 1038; 1H NMR (360 MHz,
CDCl3) δ 7.22 (2H, d, J 8.6, ArH), 7.15 (1H, dd, J 15.8, 7.0,
1
cmϪ1 3600–3350, 2922, 1718, 1605, 1513, 1454, 1273, 1112; H
NMR (360 MHz, CDCl3) δ 8.0–8.1 (2H, m, Ph), 7.49–7.57 (1H,
m, Ph), 7.36–7.46 (2H, m, ArH), 7.26 (2H, d, J 8.7, ArH), 6.84
(2H, d, J 8.7, ArH), 5.72–5.9 (1H, m, CH᎐CH ), 5.10 (1H, d,
᎐
2
J 15.3, CH᎐CH ), 5.06 (1H, d, J 10.0, CH᎐CH ) 4.58 (2H, s,
᎐
᎐
2
2
CHOCH2), 4.22–4.32 (2H, m), 4.03–4.9 (1H, m, CHOH), 3.78
(3H, s, CH3O), 3.64 (1H, dd, J 4.3, 8.0, CHOCH2), 2.73 (1H, br.
s, OH), 2.2–2.38 (2H, m, CH2CHOH), 2.1–2.2 (1H, m,
CHCH3), 1.75–1.83 (1H, m, CHCH3), 1.07 (3H, d, J 6.9, CH3)
and 0.96 (3H, d, J 7.0, CH3); 13C NMR (90 MHz, CDCl3)
δ 166.2(s), 159.0(s), 135.2(d), 132.8(d), 130.1 (s), 129.9(s),
129.3(d), 129.2(d), 128.2(d), 117.1(t), 113.6(d), 82.5(d), 74.9(t),
69.5(d), 67.3(t), 54.9(q), 39.5(d), 38.8(d), 35.2(d), 11.5(q),
10.3(q); m/z (FAB) Found 413.2349 ([M ϩ H]ϩ C25H33O5
requires 413.2328).
3-(4-Methoxy-benzyloxy)-2,4-dimethyl-5-(triethyl-silanyl-
oxy)-oct-7-en-1-ol (43b). 2,6-Lutidine (140.0 ml 1.1 mmol) was
added dropwise over 15 min to a stirred mixture of the ester
(42) (412.5 mg, 1 mmol) and TESOTf (162.0 ml, 1.1 mmol) in
CH2Cl2 (10 ml) at Ϫ50 ЊC. The reaction was monitored by TLC
until the starting material was consumed. The mixture was
diluted with CH2Cl2 (50 ml) and the separated organic extract
was washed with saturated aqeous NaHCO3 (50 ml). The
aqueous extract was extracted with CH2Cl2 (30 ml) and the
combined organic extracts were then washed with water and
brine, dried (Na2SO4), and evaporated. The residue was purified
by flash chromatography on silica gel eluting with 10% ether–
petrol to give the corresponding silyl ether (43a) as a colourless
oil.
DIBALH (1.67 ml of a 1.5 M solution in toluene, 2.5 mmol)
was added dropwise over 15 min to a stirred solution of the silyl
ether in hexane (50 ml) at Ϫ78 ЊC under an argon atmosphere
and the mixture was stirred for 2 h and then quenched with
saturated aqueous ammonium chloride solution (1 ml) and
allowed to warm to room temperature. The suspension was
diluted with ether (50 ml), dried over Na2SO4 and the solid
inorganic materials were then removed by filtration through
Florisil. The filtrate was evaporated to dryness and the residue
was purified by chromatography on silica gel (30% ethyl
acetate–petrol) to give the alcohol (347 mg, 82% over two steps),
as a colourless oil; [α]2D2 ϩ6.7 (c 0.7 in CHCl3); νmax(NaCl)/cmϪ1
3550–3300, 2955, 2872, 1611, 1514, 1458, 1248, 1036; 1H NMR
(360 MHz, CDCl3) δ 7.50 (2H, d, J 8.6, ArH), 6.86 (2H, d, J 8.6,
OCCH᎐CH ), 6.86 (2H, d, J, ArH), 5.86 (1H, d, J 15.8, OCCH᎐
᎐
᎐
CH), 5.6–5.8 (1H, m, CH᎐CH ), 5.06 (1H, d, J 17.9, CH᎐CH ),
᎐
᎐
2
2
5.02 (1H, d, J 10.2, CH᎐CH ), 4.42 (2H, dd, J 16.4, 10.6,
᎐
2
CH2O), 4.20 (2H, q, J 7.0, CH2O), 4.1–4.2 (1H, m, OCH), 3.80
(3H, s, CH3O), 3.45 (1H, dd, J 2.7, 8.9, OCH), 2.55–2.65 (1H,
m, CH3CH ), 2.2–2.4 (2H, m, CH2CHO), 1.7–1.8 (1H, m,
CHCH3), 1.30 (3H, t, J 7.0, CH3CH2O), 1.06 (3H, d, J 6.8,
CH3), 0.96 (9H, t, J 7.9, 3 × CH3CH2Si), 0.83 (3H, d, J 6.9,
CH3) and 0.59 (6H, q, J 7.9, 3 × CH3CH2Si); 13C NMR (90
MHz, CDCl3) δ 166.8(s), 159.0(s), 153.6(d), 134.8(d), 130.9(s),
129.0(d), 120.1(d), 116.9(t), 113.6(d), 83.0(d), 78.7(t), 71.0(d),
60.2(t), 55.2(q), 40.3(t), 39.7(d), 38.5(d), 14.2(q), 12.0(q), 9.1(q),
7.1(q), 5.7(t); m/z (ESI) Found 513.3120 ([M
ϩ
Na]ϩ
C28H46O5SiNa requires 513.3012).
5-(4-Methoxy-benzyloxy)-4,6-dimethyl-7-(triethyl-silanyloxy)-
deca-2,9,-dien-1-ol (46). A solution of diisobutylaluminium
hydride (1.5 M) in toluene (0.73 ml, 1.1 mmol) was added
dropwise over 10 min to a solution of the ester (45) (246 mg,
0.5 mmol) in hexane (5 ml) at Ϫ78 ЊC under an argon atmos-
phere. The mixture was stirred at Ϫ78 ЊC for 2 h, then quenched
with saturated aqueous ammonium chloride solution (2 ml)
and allowed to warm to room temperature. The suspension was
diluted with ether (20 ml) and dried over Na2SO4. The solid
ArH), 5.60–5.80 (1H, m, CH᎐CH ), 5.07 (1H, d, J 17.4,
᎐
2
CH᎐CH , 5.02 (1H, d, J 8.2, CH᎐CH ), 4.60 (1H, d, J 11.0,
᎐
᎐
2)
2
OCH2), 4.49 (1H, d, J 11.0, OCH2), 4.1–4.2 (1H, m, OCH), 3.77
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4192

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inorganic materials were removed by filtration through Florisil
and the filtrate was evaporated to dryness. The residue was
purified by flash chromatography of the residue on silica gel
(20–30% ether–petrol) gave the alcohol (200 mg, 89%), as a
colourless oil, [α]2D1 ϩ12.7 (c 0.85 in CHCl3); νmax (film)/cmϪ1
4600–3300, 2955, 1514, 1248, 1037; 1H NMR (360 MHz,
CDCl3) δ 7.23 (2H, d, J 8.6, ArH), 6.85 (2H, d, J 8.6, ArH), 5.78
(1H, dd, J 7.1, 15.8, CH᎐CHCH(CH )), 5.7–5.8 (1H, m,
ArH), 5.84–5.73 (1H, m, CH᎐CH ), 5.14–5.06 (2H, m,
᎐
2
CH᎐CH ), 4.55 (2H, dd, J 10.5, 10.5, CHCH OAr), 4.04–4.00
᎐
2
2
(1H, m, CHOPMB) 3.87–3.84 (1H, m, CH2OH), 3.79 (3H, s,
OCH3), 3.62–3.59 (1H, m, CH2OH), 3.45 (1H, t, J 5.5, OCH ),
3.02–2.99 (1H, m, CHOH), 2.93 (1H, d, J 2.3, OH ), 2.88 (1H,
dd, J 7.7, 2.2, CHO), 2.36–2.26 (2H, m, OH, CH CH᎐CH ),
᎐
2
2
2.17–2.10 (1H, m, CH CH᎐CH ), 1.80–1.68 (2H, m, 2 ×
᎐
2
2
CHCH3), 1.12 (3H, d, J 6.8, CH3), 0.97 (3H, d, J 7.1, CH3); 13
C
᎐
3
CH᎐CH ), 5.64 (1H, dt. J 5.8, 15.6, CH᎐CHCH(CH )), 5.06
NMR (90 MHz, CDCl3) δ 159.3(s), 135.2(d), 129.9(s), 129.5(d),
117.35(t), 113.9(d), 85.8(d), 75.0(t), 69.8(d), 61.2(t), 58.6(d),
55.2(q), 39.4(t), 38.6(d), 38.25(d), 12.4(q), 10.9(q); m/z (FAB)
Found 351.2162 ([M ϩ H]ϩ C20H31O5 requires 351.2171).
᎐
᎐
2
3
(1H, d, J 17.1, CH᎐CH ), 5.02 (1H, d, J 9.3, CH᎐CH ) 4.48
᎐
᎐
2
2
(2H, dd, J 10.5, 10.5, CH2O), 4.12–4.18 (1H, m, OCH), 4.05
(2H, d, J 5.7, OCH2), 3.78 (3H, s, CH3O, 3.37 (1H, dd, J 2.9,
9.7, OCH), 2.4–2.5 (1H, m, CH3CH ), 2.24–2.37 (2H, m,
CH2CHO), 1.69–1.78 (1H, m, CHCH3), 1.01 (3H, d, J 6.9,
CH3), 0.97 (9H, t, J 8.0, 3 × CH3CH2Si), 0.83 (3H, d, J 6.9,
CH3) and 0.61 (6H, q, J 8.0, 3 × CH3CH2Si); 13C NMR (90
MHz, CDCl3) δ 158.9(s), 137.4(d), 135.0(d), 131.4(s), 128.8(d),
127.7(d), 116.7(t), 113.6(d), 83.8(d), 73.6(t), 71.2(d), 63.7(t),
55.2(q), 40.4(t), 39.7(d), 38.2(d), 13.1(q), 9.4(q), 7.0(q), and
5.7(t); m/z (FAB) Found 449.3062 ([M ϩ H]ϩ C26H46O4Si
requires 449.3087).
1-[6-Allyl-4-(4-methoxy-benzyl)-3,5-dimethyl-tetrahydroyran-
2-yl]-ethane-1,2-diol (49). Titanium tetraisopropoxide (60 ml,
1.1 mmol) was added to a solution of the epoxy-alcohol (48)
(350 mg, 1.0 mmol) in dry benzene (20 ml), at room temper-
ature under an argon atmosphere. The mixture was heated
under reflux for 2 h, then cooled to room temperature and
quenched with saturated NH4Cl solution (50 ml). The mixture
was diluted with ethyl acetate (200 ml) and the separated
aqueous layer was extracted with ethyl acetate (100 ml). The
combined organic extracts were washed with brine (200 ml),
dried, and evaporated to dryness. The residue was purified by
chromatography on silica gel (30–50% ethyl acetate–petrol as
eluant) to give the pyran (270 mg, 76%) as a colourless oil, [α]2D1
ϩ 48.0 (c 0.5 in CHCl3); νmax (film)/cmϪ1 3418, 2973, 1514, 1248,
1072; 1H NMR (500 MHz, CDCl3) δ 7.27 (2H, d, J 8.4, ArH),
(2S,3S,4R,5R,6S,7R)-5-(4-Methoxybenzyloxy)-4,6-dimethyl-
2,3-epoxy-7-triethylsilanyloxy-9-decene-1-ol (47). A solution of
-(ϩ)-diethyl tartrate (115 µl, 0.67 mmol), titanium tetraiso-
propoxide (167 µl, 0.60 mmol, and 5 M tert-butylhydroperoxide
in decane (448 µl, 2.24 mmol) was added to a stirred mixture
containing 4 Å molecular sieves (500 mg) under dichloro-
methane (10 ml) at Ϫ25 ЊC. The solution was stirred at Ϫ25 ЊC
for 15 min, and then a solution of the allyl alcohol (46) (501 mg;
1.12 mmol) in dichloromethane (5 ml) was added dropwise over
0.5 h via cannula. The solution was stirred at Ϫ25 ЊC for 30 min
and then stored at Ϫ20 ЊC for 14 h. The mixture was quenched
with 0.5 M tartaric acid solution (1.5 ml), then stirred for
10 min, and extracted with ethyl acetate (3 × 15 ml). The separ-
ated organic extracts were washed with brine (10 ml), dried and
evaporated to leave a colourless oil. The oil was purified by
chromatography, on silica, eluting with 20% ethyl acetate–
petrol, to give the epoxide (507 mg; 98%) as a colourless oil; [α]2D1
ϩ 3.7 (c 0.98 in CHCl3); νmax (film)/cmϪ1 3441, 2954, 1514, 1248,
6.88 (2H, d, J 8.4, ArH), 5.68–5.88 (1H, m, CH᎐CH ), 5.10
᎐
2
(1H, d, J 10.7, CH᎐CH ), 5.07 (1H, d, J 11.0, CH᎐CH ), 4.56
᎐
᎐
2
2
(1H, d, J 11.0, CH2O), 4.27 (1H, d, J 11.0, CH2O), 3.78–3.85
(1H, m, OCH), 3.80 (3H, s, CH3O), 3.70–3.76 (1H, m, OCH2),
3.61–3.70 (1H, m, OCH2), 3.35–3.40 (1H, m, OCH), 3.28–3.36
(1H, m, OCH), 3.1–3.18 (1H, m, OCH), 2.86 (1H, b s, OH),
2.58 (1H, b d, J 8.0, OH), 2.3–2.44 (1H, m, OCHCH2), 2.18–2.2
(1H, m, OCHCH2), 2.1–2.15 (1H, m, CH3CH), 1.6–1.68 (1H,
m, CH3CH), 0.94 (3H, d, J 6.4, CH3) and 0.89 (3H, d, J 6.4,
CH3); 13C NMR (125 MHz, CDCl3) δ 159.2(s), 134.3(d),
130.3(s), 129.3(d), 117.2(d), 113.8(d), 85.0(d), 82.8(d), 78.4(d),
70.3(d), 69.7(t), 62.4(t), 55.2(q), 37.2(t), 33.6(d), 32.7(d), 12.7(q)
and 5.6(q); m/z (FAB) Found: 351.2163 ([M ϩ H]ϩ C20H31O5
requires 351.2171).
1
1087, 1036, 742; H NMR (360 MHz, CDCl3) δ 7.26 (2H, d,
J 8.5, ArH), 6.87 (2H, d, J 8.6, ArH), 5.77–5.66 (1H, m,
CH᎐CH ), 5.08–5.01 (2H, m, CH᎐CH ), 4.51 (2H, dd, J 10.7,
The corresponding acetonide derivative (DMP, PPTSA,
92%) showed 1HNMR (500 MHz, CDCl3) δ 7.26 (2H, d, J 8.2),
6.87 (2H, d, J 8.2), 5.75–5.83 (1H, m), 5.09 (1H, d, J 17.2), 5.04
(1H, d, J 9.8), 4.56 (1H, d, J 11.0), 4.26 (1H, d, J 11.0), 4.17
(1H, m), 3.99 (2H, app d, J 7.0), 3.80 (3H, s), 3.35–3.38 (1H, m),
3.15(1H, dd, J 10.4, 4.3), 3.12 (1H, dd, J 8.8, 4.6), 2.37–2.42
(1H, m), 2.13–2.16 (1H, m), 2.08–2.12 (1H, m), 1.48–1.53(1H,
m), 1.40(3H, s), 1.36 (3H, s), 1.01 (3H, d, J 6.3), 0.88 (3H, d,
J 6.8); 13C NMR (125 MHz, CDCl3) δ 159.19(s), 135.0(d),
130.58(s), 129.31(d), 116.69(t), 113.80(d), 109.20(s), 83.20(d),
80.99(d), 77.77(d), 77.30(d), 69.68(t), 65.51(t), 55.27(s),
37.26(t), 34.54(d), 33.48(d), 26.23(q), 25.97(q), 13.38(q),
5.71(q).
᎐
᎐
2
2
10.7, CH2Ar), 4.20–4.15 (1H, m, CHOPMB), 3.90–3.86 (1H, m,
CHO), 3.80 (3H, s, OCH3), 3.63–3.57 (1H, m, CHO), 3.48 (1H,
dd, J 9.2, 1.7, CHOTES), 3.03–2.99 (2H, m, CH2OH), 2.38–
2.25 (2H, m, CH CH᎐CH ), 1.94 (1H, t, J 6.1, OH), 1.78–1.73
᎐
2
2
(1H, m, CHCH3), 1.56–1.52 (1H, m, CHCH3), 1.05 (3H, d,
J 6.9, CH3), 0.97 (9H, t, J 7.9, 3 × SiCH2CH3), 0.77 (3H, d,
J 6.9, CH3), 0.62 (6H, q, J 7.7, 3 × SiCH2CH3); 13C NMR (90
MHz, CDCl3) δ 159.0(s), 134.7(d), 130.9(s), 128.9(d), 116.9 (t),
113.7 (d), 81.9(d), 73.5(t), 71.0(d), 61.6(t), 60.05(d), 58.0(d),
55.2(q), 40.3(t), 39.2(d), 38.4(d), 10.4(q), 9.1 (q), 7.1(q), 5.8(t);
m/z (FAB) Found 465.3005 ([M ϩ H]ϩ C26H45O5Si requires
465.3036).
(2S,3S,4R,5R,6S,7R)-5-(4-Methoxybenzyloxy)-4,6-dimethyl-
(2R,3R,4R,5R,6S )-2-Allyl-6-((S )-oxiranyl)-4-(4-methoxy-
benzyloxy)-3,5-dimethyltetrahydropyran (50). 60% Sodium
hydride (110 mg; 2.73 mmol) was added to a solution of the
vicinal diol (49) (319 mg; 0.91 mmol) in THF (5 ml) at Ϫ78 ЊC
and the mixture was stirred at Ϫ78 ЊC for 20 min. N-Tosyl-
imidazole (223 mg; 1.00 mmol) was added and the mixture
was allowed to warm to room temperature over 4 h. The mix-
ture was quenched with saturated ammonium chloride solution
and then extracted with ethyl acetate. The separated organic
extract was washed with brine (2 × 5 ml), dried, and evaporated
to leave a pale orange oil. The oil was purified by chromato-
graphy on silica, eluting with 30% ethyl acetate-petrol, to give
2,3-epoxy-9-decene-1,7-diol
(48).
n-Tetrabutylammonium
fluoride (241 mg; 0.76 mmol) was added portionwise over 2 min
to a stirred solution of the silyl ether (47) (236 mg; 0.51 mmol)
in THF (5 ml) at 0 ЊC. The solution was stirred at 0 ЊC for
90 min and then quenched with saturated ammonium chloride
solution (5 ml). The mixture was extracted with ethyl acetate
(3 × 10 ml), and the separated organic extracts were washed
with brine (10 ml), dried (Na2SO4) and evaporated to leave a
colourless oil. The oil was purified by chromatography on silica,
eluting with 50% ethyl acetate–petrol, to give the 1,7-diol (153
mg; 86%) as a colourless oil; [α]2D1 Ϫ14.2 (c 0.36 in CHCl3);
νmax(film)/cmϪ1 3427, 2974, 1514, 1249, 1082, 1035; H NMR
the epoxide (181 mg; 60%; d.e. 86%) as a colourless oil; [α]2D1
ϩ
1
(360 MHz, CDCl3) δ 7.26 (2H, d, J 9.9, ArH), 6.87 (2H, d, J 8.7,
88.0 (c 0.6 in CHCl3); νmax (film)/cmϪ1 3073, 2976, 1642, 1613,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4193

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1
1513, 1249, 1106; H NMR (360 MHz, CDCl3) δ 7.28 (2H, d,
55.3(q), 37.2(t), 33.4(d), 32.9(d), 25.9(q), 18.2(s), 17.6(q),
13.4(q), 5.6(q), 1.0(q), Ϫ4.5(q); m/z (ESI) Found 471.2905
([M ϩ Na]ϩ C26H44O4SiNa requires 471.2907).
J 8.7, ArH), 6.88 (2H, d, J 8.7, ArH), 5.83–5.72 (1H, m,
CH᎐CH ), 5.14–5.04 (2H, m, CH᎐CH ), 4.57 (1H, d, J 11.1,
᎐
᎐
2
2
CH2Ar), 4.28 (1H, d, J 11.1, CH2Ar), 3.80 (3H, s, OCH3), 3.35
(1H, ddd, J 1.9, 7.1, 7.1, CHOCH2), 3.14 (1H, dd, J 10.4, 4.7,
(2R,3R,4R,5R,6S )-2-(2-Oxoethyl)-6-((S )-1-tert-butyldimeth-
ylsilanyloxyethyl)-4-(4-methoxybenzyloxy)-3,5-dimethyltetra-
hydropyran (52). Osmium tetroxide (2.5 wt% in tBuOH, 500 µl)
and N-methylmorpholine N-oxide (94 mg, 0.8 mmol) were
added to a solution of the alkene (51b) (113 mg, 0.27 mmol) in
acetone (26 ml) and water (2 ml). The mixture was stirred at
room temperature for 24 h and then saturated aqueous sodium
thiosulfate (2 ml) was added. The acetone was evaporated off
in vacuo and the residue was filtered through a short column of
silica, eluting with ethyl acetate. The filtrate was evaporated to
leave a colourless oil which was taken up in dichloromethane
and treated with sodium periodate–silica (0.7 g). The mixture
was stirred for 1.5 h, then the solvent was removed in vacuo, and
the residue was purified by chromatography on silica, using
10% ethyl acetate in petrol as eluant to give the aldehyde (90 mg,
88%) as a colourless oil;1H NMR (360 MHz, CDCl3) δ 9.80
(1H, t, J 1.91, CHO), 7.28 (2H, d, J 8.7, ArH), 6.89 (2H, d,
J 8.7, ArH), 4.57 (1H, d, J 11.0, OCH2Ar), 4.29 (1H, d, J 11.0,
OCH2Ar), 3.95 (1H, dq, J 6.4, 2.1), 3.87 (1H, ddd, J 9.2, 4.2,
2.0), 3.82 (3H, s, OMe), 3.18 (1H, dd, J 10.4, 4.7), 3.05(1H, dd,
J 10.4, 2.1), 2.78 (1H, ddd, J 16.4, 9.2, 1.8), 2.36 (1H, ddd,
J 16.4, 3.9, 2.4), 2.05–2.15 (1H, m), 1.57–1.68 (1H, m), 1.15
(3H, d, J 6.5, Me), 0.94 (3H, d, J 6.4, Me), 0.91 (3H, d, J 6.9),
0.88 (9H, s, Me3), 0.04 (6H, s, 2 × Me); 13C NMR (90 MHz,
CDCl3) δ 201.7(d), 159.2(s), 130.4(s), 129.3(d), 2 × 113.8(d),
86.0(d), 82.8(d), 73.3(d), 69.7(t), 68.8(d), 55.2(q), 46.8(t),
34.1(d), 32.6(d), 3 × 25.8(q), 18.1(s), 17.5(q), 13.2(q), 6.0(q),
Ϫ4.6(q), Ϫ4.7(q); m/z (ESI) Found 473.2725 ([M ϩ Na]ϩ
C26H44O4SiNa requires 473.2700).
epox-CHO), 2.97–2.94 (1H, m, CHCH CH᎐CH ), 2.75 (1H,
᎐
2
2
dd, J 5.3, 4.0, CHOPMB), 2.71–2.64 (2H, m, CHOCH2),
2.44–2.36 (1H, m, CH CH᎐CH ), 2.21–2.06 (2H, m, CH -
᎐
2
2
2
CH᎐CH , CHCH ), 1.85–1.76 (1H, m, CHCH ), 1.06 (3H, d,
᎐
2
3
3
13
J 6.5Hz, CH3), 0.92 (3H, d, J 6.9, CH3); C NMR (90 MHz,
CDCl3) 159.1(s), 134.5(d), 130.5(s), 129.2(d), 116.8(t),
δ
113.8(d), 82.7(d), 82.4(d), 78.1(d), 69.6(t), 55.2(q), 53.1(d),
44.3(t), 37.0(t), 35.8(d), 33.2(d), 12.8(q), 5.5(q); m/z
(ESI) Found 355.1919 ([M ϩ Na]ϩ C20H28O4Na requires
355.1885).
(2R,3R,4R,5R,6S )-2-Allyl-6-((S )-1-hydroxyethyl)-4-(4-meth-
oxybenzyloxy)-3,5-dimethyltetrahydropyran (51a). A solution
of the epoxide (50) (175 mg; 0.53 mmol) in ether (2.5 ml) was
added dropwise over 15 min to a slurry of lithium aluminium
hydride (22 mg; 0.58 mmol) in ether (2.5 ml), and the mixture
was stirred at room temperature for 1 h, and then heated under
reflux for 1 h. The mixture was quenched with saturated
ammonium chloride (0.2 ml) and filtered through a pad of
celite. The filtrate was evaporated to leave a colourless oil,
which was purified by chromatography on silica, eluting with
20% ethyl acetate–petrol, to give the alcohol (132 mg; 75%) as a
colourless oil; [α]2D1 ϩ 81.1 (c 0.75 in CHCl3); νmax (film)/cmϪ1
1
3450, 3075, 2972, 1514, 1463; H NMR (360 MHz, CDCl3)
δ 7.27 (2H, d, J 8.7, ArH), 6.88 (2H, d, J 8.7, ArH), 5.85–5.73
(1H, m, CH᎐CH ), 5.14–5.04 (2H, m, CH᎐CH ), 4.57 (1H, d,
᎐
᎐
2
2
J 11.0, CH2Ar), 4.27 (1H, d, J 11.0, CH2Ar), 3.87–3.81 (1H, m,
CHOH), 3.81 (3H, s, OCH3), 3.42–3.37 (1H, m, CHOPMB),
3.17–3.12 (2H, m), 2.45 (1H, d, J 10.7, CHCHOH), 2.42–2.36
(1H, m, CH CH᎐CH ), 2.21–2.09 (2H, m, CH CH᎐CH ,
(2R,3R,4R,5R,6R)-2-(2-Dimethoxyethylacetal)-6-(1-oxo-
ethyl)-4-(4-methoxybenzyloxy)-3,5-dimethyltetrahydropyran (4).
10-Camphorsulfonic acid (11 mg, 0.047 mmol) was added to a
solution of the aldehyde (52) (135 mg, 0.3 mmol) in dichloro-
methane (4 ml) and methanol (4 ml), and the mixture was
stirred at room temperature for 3 h. The mixture was filtered
through a short column of silica using ethyl acetate as eluant to
give the dimethyl acetal secondary alcohol intermediate (53)
(138 mg) as a colourless oil; 1H NMR (360 MHz, CDCl3)
δ 7.27(2H, d, J 8.5, ArH), 6.88 (2H, d, J 8.5, ArH), 4.56 (1H, d,
J 11.0, CH2Ar), 4.51 (1H, dd, J 7.6, 4.0, H-20), 4.28 (2H, d,
J 11, CH2), 3.83 (1H, m), 3.81 (3H, s, OMe), 3.51 (1H, ddd,
J 9.3, 2.3, 2.3), 3.36 (3H, s, OMe), 3.34 (3H, s, OMe), 3.20–3.11
(2H, m), 2.0–2.8 (1H, m), 1.9–1.98 (1H, m), 1.6–1.7 (1H, m),
1.57–1.63(1H, m), 1.15 (3H, d, J 6.5), 0.91 (3H, d, J 6.9), 0.84
(3H, d, J 6.3); 13C NMR (90 MHz, CDCl3) δ 159.2(s), 130.4(s),
129.4 × 2 (d), 113.8 × 2 (d), 102.5(d), 84.0(d), 82.9(d), 74.8(d),
69.8(t), 67.3(d), 55.3(q), 53.9(q), 52.5(), 36.5(t), 34.8(d), 32.7(d),
16.2(q), 12.4(q), 5.9(q). The crude product was used in the next
step without further purification.
Dess–Martin periodinane (254 mg, 0.6 mmol) was added to a
stirred solution of the secondary alcohol (53) in dichloro-
methane (2 ml) and 2,6-lutidine (200 µl, 1.7 mmol) at 0 ЊC, and
the mixture was stirred and allowed to warm to room temper-
ature over 18 h. The mixture was diluted with diethyl ether, then
quenched with saturated Na2S2O3 solution (2 ml) and saturated
NaHCO3 solution (2 ml), and diluted with ethyl acetate.
The separated organic extract was washed with brine and
saturated NaHCO3 solution, then dried, and evaporated to
dryness. The residue was purified by careful chromatography on
silica eluting with 10% ethyl acetate–petroleum ether to give the
methyl ketone (89 mg, 78%; two steps) as a colourless oil; [α]21
ϩ 112.0 (c 1.4 in CHCl3); νmax (NaCl)/cmϪ1 2967, 2935, 1717,
1613, 1514, 1248, 820; 1H NMR (500 MHz, CDCl3) δ 7.26 (2H,
d, J 8.6, ArH), 6.88 (2H, d, J 8.6, ArH), 4.56 (1H, d, J 11.1,
OCH2Ar), 4.52 (1H, dd, J 8.2, 3.3, (MeO)2 CH), 4.29 (1H, d,
᎐
᎐
2
2
2
2
CHCH3), 1.62–1.55 (1H, m, CHCH3), 1.15 (3H, d, J 6.5, CH3),
0.90 (3H, d, J 6.8, CH3), 0.88 (3H, d, J 6.2, CH3); 13C NMR
(90 MHz, CDCl3) δ 159.2(s), 134.8(d), 130.5(s), 129.35(d),
116.9(t), 113.8(d), 83.95(d), 83.15(d), 77.75(d), 69.7(t), 67.3(d),
55.3(q), 37.2(t), 33.8(d), 32.7(d), 16.2(q), 12.4(q), 5.6(q); m/z
(ESI) Found 357.2034 ([M ϩ Na]ϩ C20H30O4Na requires
357.2042).
(2R,3R,4R,5R,6S )-2-Allyl-6-((S )-1-tert-butyldimethylsilanyl-
oxyethyl)-4-(4-methoxybenzyloxy)-3,5-dimethyltetrahydropyran
(51b). 2,6-Lutidine (136 µl; 1.17 mmol) was added to a stirred
solution of the alcohol (51a) (130 mg; 0.389 mmol) in di-
chloromethane (5 ml) at Ϫ78 ЊC, followed by tert-butyl-
dimethylsilyl triflate (136 µl; 1.17 mmol) and the mixture was
then allowed to warm to room temperature over 6 h. The
mixture was quenched with saturated ammonium chloride
solution (1 ml) and extracted with ether (3 × 10 ml). The separ-
ated ether extracts were washed with brine (2 × 2 ml), dried, and
then evaporated to leave a colourless oil. The oil was purified by
chromatography on silica, eluting with 20% ethyl acetate–
petrol, to give the silyl ether (165 mg; 95%) as a colourless oil;
[α]2D1 ϩ 68.0 (c 0.6 in CHCl3); νmax (film)/cmϪ1 3075, 2931, 1643,
1
1614, 1587, 1514, 1463, 1248, 1089, 834; H NMR (360 MHz,
CDCl3) δ 7.29 (2H, d, J 9.0, ArH), 6.89 (2H, d, J 9.0, ArH),
5.90–5.79 (1H, m, CH᎐CH ), 5.14–5.03 (2H, m, CH᎐CH ), 4.58
᎐
᎐
2
2
(1H, d, J 11.1, CH2Ar), 4.27 (1H, d, J 11.1, CH2Ar), 4.02–3.95
(1H, m, CHOH), 3.82 (3H, s, OCH3), 3.31 (1H, ddd, J 1.7, 7.1,
7.1m, CHCH CH᎐CH ), 3.11 (1H, dd, J 10.4, 4.7, CHOPMB),
᎐
2
2
2.98 (1H, dd, J 10.4, 2.3, CHCHOTBS), 2.48–2.41 (1H, m,
CH CH᎐CH ), 2.21–2.13 (1H, m, CH CH᎐CH ), 2.10–2.06
᎐
᎐
2
2
2
2
(1H, m, CHCH3), 1.64–1.58 (1H, m, CHCH3), 1.16 (3H, d,
J 6.5, CH3), 0.94 (3H, d, J 6.4, CH3), 0.90 (3H, d, J 6.9, CH3),
0.89 (9H, s, But), 0.08 (3H, s, CH3), 0.06 (3H, s, CH3); 13C NMR
(90 MHz, CDCl3) δ 159.1(s), 135.4(d), 130.7(s), 129.4(d),
116.3(t) 113.8(d), 85.8(d), 83.5(d), 77.8(d), 69.5(t), 69.2(d),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4194

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J 11.1, OCH2 Ar), 3.80 (3H, s, OMe), 3.53 (1H, ddd, J 9.6,
3.0, 2.0), 3.37 (1H, d, J 10.8), 3.35 (3H, s, OMe), 3.33 (3H, s,
OMe), 3.29 (1H, dd, J 10.4, 4.7), 2.16 (3H, s, Me), 2.06 (1H,
m), 1.93 (1H, m), 1.77 (1H, m), 1.66 (1H, m), 0.97 (3H, d,
J 6.9, Me), 0.89 (3H, d, J 6.4, Me); 13C NMR (125 MHz,
CDCl3) δ 207.21(s), 159.2(s), 130.3(s), 2 × 129.3(d), 2 × 113.8(d),
102.2(d), 87.7(d), 82.7(d), 74.7(d), 69.7(t), 55.3(q), 53.9(q),
52.8(q), 36.6(t), 34.5(d), 32.3(d), 25.3(q), 12.8(q), 6.0(q);
m/z (ESI) Found 403.2128 ([M ϩ Na]ϩ C21H32O6 requires
403.2096).
J 7.9, Si(CH2CH3)3), 0.65 (6H, q, J 7.9, Si(CH2CH3)3); 13C
NMR (90 MHz, C6D6, T = 340 K) δ 153.0 (s), 135.3 (d), 117.2
(t), 94.6 (s), 79.7 (s), 71.5 (d), 63.5 (t), 61.6 (d), 40.7 (t), 28.7 (q),
27.2 (q), 25.2 (q), 7.3 (q), 6.0 (t); m/z (EI) Found 385.2646 ([M]ϩ
C20H39O4NSi requires 385.2648).
(4S,1ЈR)-2,2-Dimethyl-4-[3Ј-oxo-1Ј-(triethylsilanyloxy)-
propyl]-oxazolidine-3-carboxylic acid tert-butyl ester (56).
Ozone was bubbled through a stirred solution of the alkene
(55b) (4.00 g, 10.4 mmol) and sodium hydrogencarbonate
(1.74 g, 20.8 mmol) in dichloromethane (110 ml) at Ϫ78 ЊC. The
solution was stirred at Ϫ78 ЊC for 1 h, at which time the
solution became blue, and then oxygen was bubbled through
the solution until it became colourless. Triphenylphosphine
(2.72 g, 10.4 mmol) was then added to the stirred solution at
Ϫ78 ЊC and then it was allowed to warm to room temperature
over 14 h under a nitrogen atmosphere. The solution was
filtered and concentrated in vacuo to leave a yellow oil. Purifi-
cation by flash chromatography, using 7% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the aldehyde
(3.68 g, 92%) as a colourless oil; [α]2D1 Ϫ23.4 (c 1.6 in CHCl3)
(Found: C, 59.2; H, 9.8; N, 3.6. C19H37O5NSi requires C, 58.9;
H, 9.6; N, 3.6%); νmax (soln: CHCl3)/cmϪ1 2878, 2733, 1722,
1692, 1368; 1H NMR (360 MHz, C6D6, T = 340 K) δ 9.68 (1H, b
s, H-3Ј), 4.46 (1H, app q, J ∼5.9, H-1Ј), 3.99 (1H, dd, J 8.8, 2.0,
H-5), 3.89 (1H, b s, H-4), 3.61 (1H, dd, J 8.8, 6.0, H-5), 2.58–
2.49 (1H, m, H-2Ј), 2.44 (1H, ddd, J 16.5, 5.0, 1.6, H-2Ј), 1.59
(3H, s, CCH3), 1.45 (3H, s, CCH3), 1.38 (9H, s, C(CH3)3), 0.93
(9H, t, J 7.9, Si(CH2CH3)3), 0.58 (6H, q, J 7.9, Si(CH2CH3)3);
13C NMR (90 MHz, C6D6, T = 340 K) δ 199.1 (d), 153.1 (s), 94.7
(s), 80.3 (s), 68.7 (d), 64.6 (t), 62.2 (d), 49.5 (t), 28.5 (q), 27.6 (q),
24.5 (q), 7.0 (q), 5.7 (t); m/z (FAB) Found 388.2543 ([M ϩ H]ϩ
C19H38O5NSi requires 388.2519).
(4S,1ЈR)-4-(1Ј-Hydroxybut-3Ј-enyl)-2,2-dimethyloxazolidine-
3-carboxylic acid tert-butyl ester (55a).29. A solution of
allylmagnesium bromide (1 M) in diethyl ether (35 ml, 350
mmol) was added dropwise over 5 min to a stirred solution of
(ϩ)-β-methoxydiisopinocampheylborane (12.1 g, 38.2 mmol)
in diethyl ether (200 ml) at Ϫ78 ЊC under a nitrogen atmos-
phere. The mixture was stirred at Ϫ78 ЊC for 30 min and then
it was warmed to room temperature and stirred for 1 h. The
mixture was cooled to Ϫ78 ЊC and the Garner’s aldehyde (54)36
(7.3 g, 31.2 mmol) in diethyl ether (120 ml) was added dropwise,
via cannula, over 5 min under a nitrogen atmosphere. The
mixture was stirred at Ϫ78 ЊC for 2 h before it was quenched by
the dropwise addition of methanol (120 ml). Triethylamine
(9 ml) and hydrogen peroxide (30 ml) were then added succes-
sively, each in one portion, and the mixture was allowed to
warm to room temperature and stirred for 12 h. A saturated
aqueous solution of sodium thiosulfate (30 ml) was added to
the mixture and then it was concentrated in vacuo to leave an
opaque residue. The residue was diluted with water (20 ml) and
then extracted with ethyl acetate (3 × 50 ml). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo
to leave a light yellow oil. Purification by flash chromatography,
using 20% ethyl acetate–petroleum ether (bp 40–60 ЊC) as
eluent, gave the alcohol (6.9 g, 80%) as a colourless oil; [α]2D0
Ϫ17.6 (c 3.4 in CHCl3); νmax (soln: CHCl3)/cmϪ1 3368, 2934,
1692, 1455; 1H NMR (360 MHz, C6D6, T = 340 K) δ 5.93–5.86
(1H, m, H-3Ј), 5.07–4.98 (2H, m, H-4Ј), 3.90–3.84 (3H, bm,
H-4, H-5, H-1Ј), 3.62 (1H, dd, J 9.0, 6.8, H-5), 2.19 (2H, app t,
J ∼6.4, H-2Ј), 1.59 (3H, s, CCH3), 1.44 (3H, s, CCH3), 1.36 (9H,
s, C(CH3)3); 13C NMR (90 MHz, C6D6, T = 340 K) δ 153.4 (s),
135.9 (d), 117.1 (t), 94.5 (s), 80.2 (s), 72.2 (d), 64.6 (t), 62.2 (d),
38.9 (t), 28.5 (q), 27.1 (q), 24.3 (q); m/z (EI) Found 256.1544
([M Ϫ CH3]ϩ C13H22O4N requires 256.1549).
(4S,1ЈR,3ЈR)-4-[3Ј-Hydroxy-1Ј-(triethylsilanyloxy)-hex-5Ј-
enyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester
(57a). Allylmagnesium bromide (1 M in diethyl ether, 11.8 ml,
11.8 mmol) was added dropwise over 15 min to a stirred
solution of (ϩ)-β-methoxydiisopinocampheylborane (4.08 g,
12.9 mmol) in diethyl ether (75 ml) at Ϫ78 ЊC under a nitrogen
atmosphere. The mixture was stirred at Ϫ78 ЊC for 30 min and
then it was warmed to room temperature and stirred for 1 h.
The mixture was cooled to Ϫ78 ЊC and the aldehyde (56)
(4.16 g, 10.7 mmol) in diethyl ether (30 ml) was added dropwise,
via cannula, over 10 min under a nitrogen atmosphere. The
mixture was stirred at Ϫ78 ЊC for 2 h 15 min and then it was
quenched by the dropwise addition of methanol (15 ml). Tri-
ethylamine (3 ml) and hydrogen peroxide (12 ml) were then
added successively, each in one portion, and the mixture was
allowed to warm to room temperature and stirred for 12 h. A
saturated aqueous solution of sodium thiosulfate (80 ml) was
added to the mixture, which was then concentrated in vacuo to
leave an opaque residue. The residue was diluted with water
(20 ml) and extracted with ethyl acetate (3 × 100 ml). The com-
bined organic extracts were dried (MgSO4) and concentrated in
vacuo to leave a yellow oil. Purification by flash chromato-
graphy, using 10% ethyl acetate–petroleum ether (bp 40–60 ЊC)
as eluent, gave the alcohol (3.51 g, 76%) as a colourless oil; [α]2D1
Ϫ50.0 (c 2.6 in CHCl3) (Found: C, 61.3; H, 10.1; N, 3.2.
C22H43O5NSi requires C, 61.5; H, 10.1; N, 3.3%); νmax (soln:
CHCl3)/cmϪ1 3400, 2877, 1668, 1394; 1H NMR (360 MHz,
C6D6, T = 340 K) δ 5.87 (1H, b s, H-5Ј), 5.07–5.01 (2H, m,
H-6Ј), 4.46 (1H, ddd, J 7.6, 3.8, 3.8, H-1Ј), 4.18 (1H, dd, J 8.5,
3.1, H-5), 4.12 (1H, b s, H-3Ј), 3.84 (1H, b s, H-4), 3.68 (1H, app
t, J ∼7.7, H-5), 2.21 (2H, b s, H-4Ј), 1.74 (1H, ddd, J 14.0, 9.7,
3.8, H-2Ј), 1.65 (3H, s, CCHЈ), 1.57 (1H, ddd, J 14.0, 8.8, 3.8,
H-2Ј), 1.47 (3H, s, CCH3), 1.39 (9H, s, C(CH3)3), 1.03 (9H, t,
J 7.9, Si(CH2CH3)3), 0.69 (6H, q, J 7.9, Si(CH2CH3)3); 13C
NMR (90 MHz, C6D6, T = 340 K) δ 153.5 (s), 135.2 (d), 117.0
(4S,1ЈR)-2,2-Dimethyl-4-[1Ј-(triethylsilanyloxy)-but-3Ј-enyl]-
oxazolidine-3-carboxylic acid tert-butyl ester (55b). Chloro-
triethylsilane (2.67 g, 2.97 ml, 17.7 mmol) and 4-(dimethyl-
amino)pyridine (1.47 mmol, 0.18 g) were added separately, each
in one portion, to a solution of the alcohol (55a) (4.00 g, 14.7
mmol) in dichloromethane (150 ml) at 0 ЊC under a nitrogen
atmosphere. The solution was stirred at 0 ЊC for 15 min and
then triethylamine (2.98 g, 4.11 ml, 29.5 mmol) was added
dropwise over 5 min. The mixture was warmed to room
temperature and stirred for 12 h before it was quenched with a
saturated aqueous solution of ammonium chloride (100 ml).
The two layers were separated and the aqueous layer was
extracted with dichloromethane (2 × 100 ml). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo
to leave an opaque residue. Purification by flash chromato-
graphy, using 5% ethyl acetate–petroleum ether (bp 40–60 ЊC)
as eluent, gave the protected alkene (5.10 g, 90%) as a colourless
oil; [α]2D0 Ϫ42.9 (c 2.5 in CHCl3) (Found: C, 62.3; H, 10.4; N, 3.4.
C20H39O4NSi requires C, 62.3; H, 10.2; N, 3.6%); νmax (soln:
CHCl3)/cmϪ1 2877, 1682, 1456; 1H NMR (360 MHz, C6D6,
T = 340 K) δ 5.86 (1H, dddd, J 17.2, 10.1, 7.1, 7.1, H-3Ј), 5.05–
4.95 (2H, m, H-4Ј), 4.42 (1H, b s, H-1Ј), 4.11 (1H, dd, J 8.4, 3.9,
H-5), 3.91 (1H, b s, H-4), 3.72 (1H, dd, J 8.4, 7.1, H-5), 2.35–
2.27 (1H, m, H-2Ј), 2.20–2.12 (1H, m, H-2Ј), 1.67 (3H, s,
CCH3), 1.52 (3H, s, CCH3), 1.42 (9H, s, C(CH3)3), 1.01 (9H, t,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4195

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(t), 93.8 (s), 80.7 (s), 69.0 (d), 67.1 (d), 63.4 (t), 60.1 (d), 43.0 (t),
40.4 (t), 28.3 (q), 27.1 (q), 24.6 (q), 6.9 (q), 5.0 (t); m/z (EI)
Found 414.2689 ([M Ϫ CH3]ϩ C21H40O5NSi requires 414.2676).
nitrogen atmosphere. The solution was warmed to room
temperature and stirred for 14 h, and then it was concentrated
in vacuo to leave a white solid. Purification by flash chromato-
graphy, using 2% ethyl acetate–petroleum ether (bp 40–60 ЊC)
to 8% ethyl acetate–petroleum ether (bp 40–60 ЊC) as eluent,
gave the α,β-unsaturated ester (4.20 g, 87%) as a colourless oil;
[α]2D1 Ϫ24.5 (c 2.6 in CHCl3); νmax (soln: CHCl3)/cmϪ1 2868,
1689, 1367; 1H NMR (360 MHz, C6D6, T = 340 K) δ 7.20 (1H,
ddd, J 15.7, 7.3, 7.3, H-5Ј), 6.10 (1H, d, J 15.7, H-6Ј), 4.49 (1H,
b s, H-1Ј), 4.21–4.14 (1H, m, H-3Ј), 4.16 (1H, dd, J 8.5, 3.8,
H-5), 4.08–4.00 (1H, b s, H-4), 4.05 (2H, q, J 7.1, CO2CH2),
3.85 (1H, app t, J ∼7.7, H-5), 2.78–2.70 (1H, m, H-4Ј),
2.45–2.38 (1H, m, H-4Ј), 1.89 (1H, ddd, J 11.6, 7.2, 4.5, H-2Ј),
1.77–1.70 (1H, m, H-2Ј), 1.68 (3H, s, CCH3), 1.49 (3H, s, CCH3),
1.43 (9H, s, C(CH3)3), 1.12–1.00 (33H, m, CO2CH2CH3,
Si(CH2CH3)3, Si(CH(CH3)2)3), 0.71 (6H, q, J 7.9, Si(CH2-
CH3)3); 13C NMR (90 MHz, C6D6, T = 340 K) δ 165.9 (s), 153.5
(s), 144.6 (d), 128.9 (d), 125.1 (d), 94.7 (s), 79.9 (s), 69.7 (d), 63.6
(t), 62.5 (d), 60.1 (t), 43.3 (t), 39.5 (t), 28.7 (q), 27.4 (q), 25.0 (q),
18.6 (q), 14.5 (q), 13.2 (d), 7.4 (q), 6.3 (t); m/z (ESI) Found
680.4327 ([M ϩ Na]ϩ C34H67O7NSi2Na requires 680.4354).
(4S,1ЈR,3ЈR)-2,2-Dimethyl-4-[1Ј-(triethylsilanyloxy)-3Ј-(tri-
isopropylsilanyloxy)-hex-5Ј-enyl]-oxazolidine-3-carboxylic acid
tert-butyl ester (57b). 2,6-Lutidine (1.2 g, 1.3 ml, 11.2 mmol)
and triisopropylsilyl trifluoromethane-sulfonate (1.7 g, 0.15 ml,
5.6 mmol) were added separately, each in one portion, to a
stirred solution of the alcohol (57a) (2.0 g, 4.7 mmol) in
dichloromethane (50 ml) at Ϫ78 ЊC under a nitrogen atmos-
phere. The solution was stirred at Ϫ78 ЊC for 1 h 15 min and
then it was quenched with a saturated aqueous solution of
ammonium chloride (40 ml). The layers were separated and
the aqueous layer was extracted with dichloromethane (2 × 100
ml). The combined organic layer was dried (MgSO4) and
concentrated in vacuo to leave a colourless oil. Purification by
flash chromatography, using 5% ethyl acetate–petroleum ether
(bp 40–60 ЊC) as eluent, gave the protected olefin (2.5 g, 92%) as
a colourless oil; [α]2D1 Ϫ32.2 (c 2.8 in CHCl3); νmax (soln: CHCl3)/
cmϪ1 2868, 1688, 1640, 1090; 1H NMR (360 MHz, C6D6,
T = 340 K) δ 5.93 (1H, dddd, J 17.2, 10.2, 7.0, 7.0, H-5Ј), 5.18
(1H, dd, J 17.2, 1.4, H-6Ј), 5.08 (1H, dd, J 10.2, 1.4, H-6Ј), 4.52
(1H, b s, H-1Ј), 4.18–4.11 (2H, m, H-5, H-3Ј), 4.06 (1H, b s,
H-4), 3.84 (1H, app t, J ∼7.7, H-5), 2.67–2.59 (1H, m, H-4Ј),
2.42–2.35 (1H, m, H-4Ј), 1.87 (1H, ddd, J 13.8, 7.0, 4.8, H-2Ј),
1.76 (1H, ddd, J 13.8, 6.7, 6.7, H-2Ј), 1.68 (3H, s, CCH3),
1.50 (3H, s, CCH3), 1.43 (9H, s, OC(CH3)3), 1.13 (21H, s,
Si(CH(CH3)2)3), 1.05 (9H, t, J 7.9, Si(CH2CH3)3), 0.72 (6H, q,
J 7.9, Si(CH2CH3)3); 13C NMR (90 MHz, C6D6, T = 340 K)
δ 153.4 (s), 135.0 (s), 117.8 (t), 94.7 (s), 79.8 (s), 70.2 (d), 69.1
(d), 63.7 (t), 62.5 (d), 43.0 (t), 41.4 (t), 28.7 (q), 27.3 (q), 25.3 (q),
18.7 (q), 13.4 (d), 7.4 (q), 6.3 (t); m/z (ESI) Found 608.4172 ([M
ϩ Na]ϩ C31H63O5NSi2 requires 608.4143).
(4S,1ЈR,3ЈR)-4-[6Ј-Ethoxycarbonyl-1Ј-hydroxy-3Ј-(triisopro-
pylsilanyloxy)-hex-(5ЈE )-enyl]-2,2-dimethyloxazolidine-3-carb-
oxylic acid tert-butyl ester (60). Pyridinium para-toluene-
sulfonate (2.1 g, 8 mmol) was added in one portion to a stirred
solution of the alkene (59) (5 g, 7.6 mmol) in dichloromethane
(80 ml) at room temperature under a nitrogen atmosphere. The
solution was stirred for 4 h and then it was quenched with
a saturated aqueous solution of sodium hydrogencarbonate
(400 ml). The mixture was diluted with ethyl acetate (500 ml)
and the layers were separated. The aqueous layer was extracted
with ethyl acetate (2 × 200 ml) and the combined organic
extracts were dried (Na2SO4) and concentrated in vacuo to leave
an opaque oil. Purification by flash chromatography, using 20%
ethyl acetate–petroleum ether (bp 40–60 ЊC) as eluent, gave the
alcohol (3.5 g, 84%) as a colourless oil; [α]2D1 Ϫ22.7 (c 6.9 in
CHCl3); νmax (soln: CHCl3)/cmϪ1 3366, 2867, 1704, 1657, 1368;
1H NMR (360 MHz, C6D6, T = 340 K) δ 7.24 (1H, ddd, J 15.7,
7.3, 7.3, H-5Ј), 5.97 (1H, d, J 15.7, H-6Ј), 4.38 (1H, dddd, J 9.2,
4.9, 4.9, 4.9, H-3Ј), 4.03 (2H, q, J 7.1, CO2CH2CH3), 3.86 (1H, b
s, H-1Ј), 3.73 (1H, b s, H-5), 3.65 (2H, bm, H-4, H-5), 2.59–2.52
(1H, m, H-4Ј), 2.38–2.31 (1H, m, H-4Ј), 1.77 (1H, m, H-2Ј),
1.70–1.63 (1H, m, H-2Ј), 1.56 (3H, s, CCH3), 1.38 (12H, s,
CCH3, C(CH3)3), 1.09 (21H, s, Si(CH(CH3)2)3), 1.02 (3H, t,
J 7.1, CO2CH2CH3); 13C NMR (90 MHz, C6D6, T = 340 K)
δ 166.0 (s), 154.3 (s), 145.4 (d), 124.7 (d), 94.9 (s), 80.8 (s), 70.7
(d), 70.2 (d), 65.4 (t), 63.4 (d), 60.1 (t), 40.7 (t), 39.6 (t), 28.6 (q),
26.9 (q), 24.3 (q), 18.6 (q), 14.5 (q), 13.2 (d); m/z (ESI) Found
566.3522 ([M ϩ Na]ϩ C28H53O7NSiNa requires 566.3489).
(4S,1ЈR,3ЈS )-2,2-Dimethyl-4-[5Ј-oxo-1Ј-(triethylsilanyloxy)-
3Ј-(triisopropylsilanyl-oxy)-pentyl]-oxazolidine-3-carboxylic
acid tert-butyl ester (58). Ozone was bubbled through a stirred
solution of the alkene (57b) (4.50 g, 7.68 mmol) and sodium
hydrogencarbonate (1.29 g, 15.4 mmol) in dichloromethane
(70 ml) at Ϫ78 ЊC. The solution was stirred at Ϫ78 ЊC for
30 min, at which time the solution had become blue, and then
oxygen was bubbled through the solution until it became
colourless. Triphenylphosphine (2.12 g, 8.06 mmol) was added
to the stirred solution at Ϫ78 ЊC and then it was stirred at room
temperature for 14 h under a nitrogen atmosphere. The solution
was filtered and concentrated in vacuo to leave a yellow oil.
Purification by flash chromatography, using 10% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the aldehyde
(4.30 g, 95%) as a colourless oil; [α]2D1 Ϫ21.9 (c 3.1 in CHCl3);
νmax (soln: CHCl3)/cmϪ1 2864, 2730, 1721, 1688; 1H NMR (360
MHz, C6D6, T = 340 K) δ 9.71 (1H, b s, H-5Ј), 4.50 (1H, app qu,
J ∼5.8, H-3Ј), 4.37 (1H, b s, H-1Ј), 4.11 (1H, dd, J 8.4, 3.6, H-5),
4.04 (1H, b s, H-4), 3.83 (1H, app t, J ∼7.6, H-5), 2.76 (1H, app
dd, J ∼16.2, 5.5, H-4Ј), 2.47 (1H, ddd, J 16.2, 5.1, 2.2, H-4Ј),
2.03–1.96 (1H, m, H-2Ј), 1.74 (1H, ddd, J 14.0, 6.9, 6.9, H-2Ј),
1.65 (3H, s, CCH3), 1.46 (3H, s, CCH3), 1.41 (9H, s, OC(CH3)3),
1.06 (21H, s, Si(CH(CH3)2)3), 1.01 (9H, t, J 7.9, Si(CH2CH3)3),
0.68 (6H, q, J 7.9, Si(CH2CH3)3); 13C NMR (90 MHz, C6D6,
T = 340 K) δ 199.9 (d), 153.5 (s), 94.7 (s), 79.9 (s), 69.3 (d), 67.0
(d), 63.7 (t), 62.5 (d), 50.6 (t), 43.9 (t), 28.7 (q), 27.4 (q), 25.0 (q),
18.6 (q), 13.2 (d), 7.4 (q), 6.2 (t); m/z (ESI) Found 610.3981 ([M
ϩ Na]ϩ C30H61O6NSi2 requires 610.3935).
(4S,2ЈR,4ЈR,6ЈS )-4-[6Ј-Ethoxycarbonylmethyl-4Ј-(triisopro-
pylsilanyloxy)-tetrahydropyran-2Ј-yl]-2,2-dimethyloxazolidine-
3-carboxylic acid tert-butyl ester (61). A solution of sodium
bis(trimethylsilyl)amide (1 M) in THF (3.26 ml, 3.26 mmol) was
added dropwise over 2 min to a stirred solution of the alcohol
(60) (1.61 g, 2.96 mmol) in THF (30 ml) at Ϫ78 ЊC under a
nitrogen atmosphere. The solution was stirred at Ϫ78 ЊC for 1 h
and then it was quenched with a saturated aqueous solution
of ammonium chloride (30 ml). The mixture was warmed to
room temperature and then concentrated in vacuo to leave the
aqueous residue. The aqueous residue was extracted with ethyl
acetate (3 × 50 ml) and the combined organic layer was dried
(Na2SO4) and concentrated in vacuo to leave a colourless oil.
Purification by flash chromatography, using 20% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the tetrahydro-
pyran (1.40 g, 87%) as a colourless oil; νmax (soln: CHCl3)/cmϪ1
2867, 1729, 1688, 1367; 1H NMR (360 MHz, C6D6, T = 340 K)
δ 4.47–4.39 (1H, m, H-6Ј), 4.24 (1H, b d, J ∼8.5, H-5), 4.19 (1H,
b s, H-4Ј), 4.13 (1H, ddd, J 10.8, 8.3, 2.0, H-2Ј), 4.02–3.93 (1H,
(4S,1ЈR,3ЈR)-4-[6Ј-Ethoxycarbonyl-1Ј-(triethylsilanyloxy)-3Ј-
(triisopropylsilanyl-oxy)-hex-(5ЈE )-enyl]-2,2-dimethyloxazol-
idine-3-carboxylic acid tert-butyl ester (59). (Carboethoxy-
methylene)triphenylphosphorane (2.68 g, 7.68 mmol) was
added in one portion to a stirred solution of the aldehyde (58)
(4.30 g, 7.31 mmol) in dichloromethane (70 ml) at 0 ЊC under a
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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m, H-4), 3.98 (2H, q, J 7.1, CO2CH2CH3), 3.68 (1H, dd, J 8.6,
5.5, H-5), 2.51 (1H, dd, J 15.0, 7.3, H-1Љ), 2.25 (1H, dd, J 15.0,
6.1, H-1Љ), 1.90–1.84 (1H, m, H-3Јeq), 1.75–1.68 (4H, m, CCH3,
H-5Јeq), 1.61–1.53 (4H, m, H-3Јax, CCH3), 1.44 (9H, s,
OC(CH3)3), 1.30 (1H, ddd, J 13.6, 11.6, 2.5, H-5Јax), 1.17–1.03
provide the crude aldehyde (62b) as a pink oil, which was used
without further purification.
Triphenylphosphine (2.42 g, 9.23 mmol), 2,6-di-tert-butyl-
pyridine (3.53 g, 4.13 ml, 18.5 mmol) and dibromotetrachloro-
ethane (3.00 g, 9.23 mmol) were added successively, each in
one portion, to a stirred solution of the crude aldehyde (1.10 g,
1.85 mmol) in dichloromethane (18 ml) at 0 ЊC under a nitrogen
atmosphere. The reaction mixture was stirred at room temper-
ature for 3 h and then 1,8-diazabicyclo[5.4.0]undec-7-ene
(7.03 g, 6.90 ml, 46.2 mmol) in acetonitrile (10 ml) was added
dropwise, via cannula, over 10 min. The mixture was stirred at
room temperature for 1 h and then it was concentrated in vacuo
to leave a black residue. Purification by flash chromatography,
using 20% ethyl acetate–petroleum ether (bp 40–60 ЊC) as
eluent, gave the oxazole (0.65 g, 73% over 2 steps) as a colour-
(21H, m, Si(CH(CH3)2)3), 1.00 (3H, t, J 7.1, CO2CH2CH3); 13
C
NMR (90 MHz, C6D6, T = 340 K) δ 170.5 (s), 152.9 (s), 94.4 (s),
79.6 (s), 73.2 (d), 69.6 (d), 65.8 (d), 65.4 (t), 61.4 (d), 60.2 (t),
42.0 (t), 39.7 (t), 37.5 (t), 28.7 (q), 27.9 (q), 24.6 (q), 18.5 (q),
14.4 (q), 12.9 (d); m/z (FAB) Found 544.3668 ([M ϩ H]ϩ
C28H54O7NSi requires 544.3670).
(1S,2ЈS,4ЈR,6ЈR)-[6Ј-{2-Hydroxy-1-[2-(4-methoxybenzyl-
oxy)-acetylamino]-ethyl}-4Ј-(triisopropylsilanyloxy)-tetrahydro-
pyran-2Ј-yl]-acetic acid ethyl ester (62a).
A solution of
1
hydrochloric acid (4 M) in dioxane (30 ml) was added in one
portion to the tetrahydropyran (61) (1.60 g, 29.4 mmol) at room
temperature under a nitrogen atmosphere. The solution was
stirred for 1 h 20 min and then toluene (50 ml) was added and
the solution was concentrated in vacuo. Two subsequent
additions of toluene (2 × 30 ml) followed by concentration
in vacuo left the crude hydrochloride salt of the amino-alcohol
less oil; νmax (soln: CHCl3)/cmϪ1 2944, 1729, 1100; H NMR
(360 MHz, CDCl3) δ 7.56 (1H, s, CH, ox), 7.29 (2H, d, J 8.4,
CH, Ar), 6.88 (2H, d, J 8.4, CH, Ar), 4.97 (1H, dd, J 11.5, 2.0,
H-6Ј), 4.56 (2H, s, ArCH2), 4.55 (2H, s, PMBOCH2), 4.47 (1H,
dddd, J 13.4, 6.7, 6.7, 1.8, H-2Ј), 4.42–4.40 (1H, m, H-4Ј), 4.17–
4.11 (2H, m, CO2CH2CH3), 3.81 (3H, s, ArOCH3), 2.67 (1H,
dd, J 14.9, 6.7, H-1Љ), 2.42 (1H, dd, J 14.9, 6.7, H-1Љ), 1.98–1.95
(1H, m, H-5Јeq), 1.91–1.86 (1H, m, H-5Јax), 1.84–1.81 (1H,
m, H-3Јeq), 1.60–1.54 (1H, m, H-3Јax), 1.25 (3H, t, J 7.1,
CO2CH2CH3), 1.14–1.06 (21H, m, Si(CH(CH3)2)3); 13C NMR
(90 MHz, CDCl3) δ 171.0 (s), 160.9 (s), 159.5 (s), 142.1 (s), 135.8
(d), 129.8 (d), 129.3 (s), 113.9 (d), 72.7 (t), 69.1 (d), 67.4 (d), 64.7
(d), 63.7 (t), 60.4 (t), 55.3 (q), 41.6 (t), 38.8 (t), 38.1 (t), 18.1 (q),
14.2 (q), 12.2 (d); m/z (ESI) Found 584.2977 ([M ϩ Na]ϩ
C30H47O7NSiNa requires 584.3020).
as
a yellow residue, which was used without further
purification.
Triethylamine (1.20 g, 1.66 ml, 11.9 mmol) was added in one
portion to a stirred solution of the crude amino-alcohol in
THF (30 ml) at 0 ЊC under a nitrogen atmosphere. The solution
was stirred at 0 ЊC for 15 min and then (4-methoxybenzyloxy)-
acetic acid (0.82 g, 4.16 mmol), 1-(3-dimethylaminopropyl)-
3-ethyl-carbodiimide hydrochloride (0.80 g, 4.16 mmol) and
1-hydroxybenzotriazole (0.52 g, 3.87 mmol) were added separ-
ately, each in one portion. The mixture was stirred at 0 ЊC for
45 min and then at room temperature for 20 h before it was
quenched with a saturated aqueous solution of ammonium
chloride (40 ml). The mixture was extracted with ethyl acetate
(3 × 50 ml) and the combined organic layer was dried (Na2SO4)
and concentrated in vacuo to leave a brown oil. Purification by
flash chromatography, using 50% ethyl acetate–petroleum ether
(bp 40–60 ЊC) as eluent, gave the hydroxy-amide (1.34 g, 75%
over 2 steps) as a colourless oil; νmax (soln: CHCl3)/cmϪ1 3506,
(2ЈR,4ЈR,6ЈR)-4-(6Ј-Allyl-4Ј-triisopropylsilanyloxy-tetra-
hydropyran-2Ј-yl)-2-(4-methoxybenzyloxymethyl)-oxazole (64b).
A solution of diisobutylaluminium hydride (1.5 M) in toluene
(0.75 ml, 1.1 mmol) was added dropwise over 5 min to a stirred
solution of the ester (63) (0.60 g, 1.1 mmol) in toluene (9 ml) at
Ϫ78 ЊC under a nitrogen atmosphere. The solution was stirred
at Ϫ78 ЊC for 2 h 30 min and then it was quenched by the
dropwise addition of methanol (1.5 ml) and warmed to room
temperature. The mixture was added, via cannula, to a satur-
ated aqueous solution of potassium sodium tartrate (30 ml)
and stirred vigorously for 3 h. The layers were separated and the
aqueous layer was extracted with ethyl acetate (4 × 50 ml). The
combined organic layer was dried (Na2SO4) and concentrated
in vacuo to leave a yellow oil. Purification by flash chromato-
graphy, using 25% ethyl acetate–petroleum ether (bp 40–60 ЊC)
as eluent, gave (2ЈS,4ЈR,6ЈR)-[6Ј-{2-(4-methoxybenzyloxy-
methyl)-oxazol-4-yl}-4Ј-(triisopropyl-silanyloxy)-tetrahydro-
pyran-2Ј-yl]-acetaldehyde (64a) (0.48 g, 87%) as a colourless oil;
νmax (soln: CHCl3)/cmϪ1 2866, 1725, 1103; 1H NMR (360 MHz,
CDCl3) δ 9.81 (1H, app t, J 2.3, H-2Љ), 7.55 (1H, d, J 0.5, CH,
ox), 7.28 (2H, d, J 8.6, CH, Ar), 6.88 (2H, d, J 8.6, CH, Ar),
4.98 (1H, dd, J 11.2, 2.6, H-6Ј), 4.61–4.56 (1H, m, H-2Ј), 4.55
(2H, s, ArCH2), 4.54 (2H, s, PMBOCH2), 4.43–4.40 (1H, m,
H-4Ј), 3.80 (3H, s, ArOCH3), 2.66 (1H, ddd, J 16.3, 7.8, 2.3,
H-1Љ), 2.49 (1H, ddd, J 16.3, 5.0, 2.3, H-1Љ), 1.98 (1H, ddd,
J 13.5, 5.0, 2.6, H-5Јeq), 1.90 (1H, ddd, J 13.5, 11.2, 2.4,
H-5Јax), 1.80–1.73 (1H, m, H-3Јeq), 1.60 (1H, ddd, J 13.5, 11.6,
2.2, H-3Јax), 1.11–1.05 (21H, m, Si(CH(CH3)2)3); 13C NMR
(90 MHz, CDCl3) δ 201.2 (d), 160.9 (s), 159.4 (s), 141.8 (s),
135.7 (d), 129.7 (d), 129.1 (s), 113.8 (d), 72.6 (t), 67.8 (d), 67.3
(d), 64.5 (d), 63.5 (t), 55.2 (q), 49.5 (t), 38.9 (t), 37.8 (t), 18.0 (q),
12.1 (d); m/z (FAB) Found 518.2986 ([M ϩ H]ϩ C28H44O6NSi
requires 518.2938).
1
3407, 2866, 1730, 1667; H NMR (360 MHz, CDCl3) δ 7.27
(2H, d, J 8.6, CH, Ar), 6.90 (2H, d, J 8.6, CH, Ar), 4.52 (2H, s,
ArCH2), 4.35 (1H, app qu, J ∼2.6, H-4Ј), 4.30–4.22 (1H, m, H-
2Ј), 4.13 (2H, q, J 7.1, CO2CH2CH3), 4.04 (1H, ddd, J 11.5, 5.4,
1.8, H-6Ј), 3.95 (2H, s, PMBOCH2), 3.97–3.88 (2H, m, H-1),
3.82 (3H, s, ArOCH3), 3.60 (1H, b d, J ∼12.2, H-2), 3.02 (1H, b
s, OH ), 2.47 (1H, dd, J 15.2, 8.0, H-1Љ), 2.41 (1H, dd, J 15.2,
5.1, H-1Љ), 1.74–1.67 (2H, m, H-3Јeq, H-5Јeq), 1.59 (1H, ddd,
J 13.2, 11.5, 2.6, H-3Јax), 1.49 (1H, ddd, J 13.7, 11.5, 2.6,
H-5Јax), 1.25 (3H, t, J 7.1, CO2CH2CH3), 1.09–1.01 (21H, m,
Si(CH(CH3)2)3); 13C NMR (90 MHz, CDCl3) δ 171.1 (s), 169.6
(s), 159.6 (s), 129.6 (d), 128.9 (s), 113.9 (d), 73.9 (d), 73.2 (t),
69.4 (d), 69.0 (t), 64.5 (d), 62.5 (t), 60.6 (t), 55.3 (q), 52.8 (d),
40.9 (t), 38.7 (t), 36.1 (t), 18.1 (q), 14.1 (q), 12.1 (d); m/z (ESI)
Found 604.3289 ([M
604.3282).
ϩ
Na]ϩ C30H51O8NSiNa requires
(2ЈS,4ЈR,6ЈR)-[6Ј-{2-(4-Methoxybenzyloxymethyl)-oxazol-4-
yl}-4Ј-(triisopropyl-silanyloxy)-tetrahydropyran-2Ј-yl]-acetic
acid ethyl ester (63). Dess–Martin periodinane (2.35 g, 5.52
mmol) was added in one portion to a stirred solution of the
alcohol (62a) (1.10 g, 1.84 mmol) in dichloromethane (18 ml) at
room temperature under a nitrogen atmosphere. The solution
was stirred for 2 h and then it was diluted with dichloromethane
(10 ml). The solution was poured onto a stirred solution
of saturated aqueous sodium hydrogencarbonate (15 ml) and
saturated aqueous sodium thiosulfate (15 ml) and stirred for 30
min. The layers were separated and the aqueous layer was
extracted with dichloromethane (2 × 50 ml). The combined
organic layer was dried (Na2SO4) and concentrated in vacuo to
n-Butyllithium (2.5 M in hexane, 0.42 ml, 1.1 mmol) was
added dropwise over 2 min to a stirred solution of methyl-
triphenylphosphonium bromide (0.39 g, 1.1 mmol) in THF
(3 ml) at 0 ЊC under a nitrogen atmosphere. The solution was
stirred at 0 ЊC for 1 h and then it was cooled to Ϫ78 ЊC. The
above aldehyde (0.45 g, 0.90 mmol) in THF (4.5 ml) was added
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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dropwise, via cannula, over 5 min and the solution was warmed
to room temperature over 16 h. The solution was quenched
with ammonium chloride (15 ml) and extracted with ethyl
acetate (3 × 25 ml). The combined organic layer was dried
(Na2SO4) and concentrated in vacuo to leave a yellow oil. Purifi-
cation by flash chromatography, using 10% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the terminal olefin
(270 mg, 59%) as a colourless oil and as a single diastereo-
isomer; [α]2D1 ϩ 3.3 (c 0.9 in CHCl3); νmax (soln: CHCl3)/cmϪ1
the diol (65) (45 mg, 71 µmol) in THF (1 ml) at 0 ЊC under a
nitrogen atmosphere. The solution was warmed to room tem-
perature and stirred for 1 h and then it was cooled to 0 ЊC and
N-tosylimidazole (15.9 mg, 71 µmol) was added in one portion.
The stirred solution was warmed to room temperature over 3 h
and then it was quenched with saturated aqueous ammonium
chloride (3 ml). Ethyl acetate (10 ml) was added and the layers
were separated and the aqueous layer was extracted with ethyl
acetate (2 × 10 ml). The combined organic layer was dried
(Na2SO4) and concentrated in vacuo to leave a yellow oil. Purifi-
cation by flash chromatography, using 20% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the epoxide
(30 mg, 76%) as a colourless oil; νmax (soln: CHCl3)/cmϪ1 2944,
1101; 1H NMR (360 MHz, CDCl3) major isomer δ 7.56 (1H, d,
J 0.7, CH, ox), 7.29 (2H, d, J 8.7, CH, Ar), 6.88 (2H, d, J 8.7,
CH, Ar), 4.94 (1H, dd, J 15.2, 2.8, H-2Ј), 4.56 (2H, s, ArCH2),
4.55 (2H, s, PMBOCH2), 4.43–4.40 (1H, m, H-4Ј), 4.30–4.16
(1H, m, H-6Ј), 3.80 (3H, s, ArOCH3), 3.13–3.07 (1H, m, H-2Љ),
2.77 (1H, app t, J ∼4.9, H-3Љ), 2.48 (1H, app dd, J ∼4.9, ∼2.8,
H-3Љ), 1.99–1.83 (3H, m), 1.81–1.65 (2H, m), 1.62–1.46 (1H, m),
1.14–1.05 (21H, s, Si(CH(CH3)2)3); 1H NMR (360 MHz,
CDCl3) minor isomer δ 7.57 (1H, d, J 0.8, CH, ox), 7.29 (2H, d,
J 8.7, CH, Ar), 6.88 (2H, d, J 8.7, CH, Ar), 4.97 (1H, dd, J 14.9,
2.7, H-2Ј), 4.56 (2H, s, ArCH2), 4.55 (2H, s, PMBOCH2), 4.43–
4.40 (1H, m, H-4Ј), 4.30–4.16 (1H, m, H-6Ј), 3.80 (3H, s,
ArOCH3), 3.13–3.07 (1H, m, H-2Љ), 2.76 (1H, app t, J ∼4.6,
H-3Љ), 2.50 (1H, app dd, J ∼4.6, ∼2.8, H-3Љ), 1.99–1.83 (3H, m),
1.81–1.65 (2H, m), 1.62–1.46 (1H, m), 1.14–1.05 (21H, s,
Si(CH(CH3)2)3); 13C NMR (90 MHz, CDCl3) major isomer
δ 160.9 (s), 159.4 (s), 142.2 (s), 135.7 (d), 129.7 (d), 129.2 (s),
113.8 (d), 72.6 (t), 70.1 (d), 67.1 (d), 64.7 (d), 63.6 (t), 55.2 (q),
1
2944, 2866, 1045; H NMR (360 MHz, CDCl3) δ 7.57 (1H, d,
J 0.7, CH, ox), 7.28 (2H, d, J 8.6, CH, Ar), 6.88 (2H, d, J 8.6,
CH, Ar), 5.84 (1H, dddd, J 17.1, 10.2, 7.1, 7.1, H-2Љ), 5.11–5.03
(2H, m, H-3Љ), 4.94 (1H, dd, J 11.4, 2.4, H-2Ј), 4.56 (2H, s,
ArCH2), 4.54 (2H, s, PMBOCH2), 4.41–4.39 (1H, m, H-4Ј),
4.10–4.02 (1H, m, H-6Ј), 3.81 (3H, s, ArOCH3), 2.44–2.37 (1H,
m, H-1Љ), 2.25–2.17 (1H, m, H-1Љ), 1.96 (1H, ddd, J 13.4, 5.0,
2.4, H-3Јeq), 1.87 (1H, ddd, J 13.4, 11.4, 2.5, H-3Јax), 1.78–1.73
(1H, m, H-5Јeq), 1.49 (1H, ddd, J 13.6, 11.4, 2.4, H-5Јax), 1.07
(21H, s, Si(CH(CH3)2)3); 13C NMR (90 MHz, CDCl3) δ 160.8
(s), 159.4 (s), 142.3 (s), 135.7 (d), 134.7 (d), 129.7 (d), 129.2 (s),
116.7 (t), 113.8 (d), 72.6 (t), 71.7 (d), 67.2 (d), 64.8 (d), 63.6 (t),
55.2 (q), 40.5 (t), 38.5 (t), 38.1 (t), 18.1 (q), 12.2 (d); m/z (FAB)
Found 516.3144 ([M ϩ H]ϩ C29H45O5NSi requires 516.3145).
(2ЈR,4R,6ЈR)-3Љ-{6Ј-[2-(4-Methoxybenzyloxymethyl)-oxazol-
4-yl]-4Ј-triisopropyl-silanyloxy-tetrahydropyran-2Ј-yl}-propane-
1Љ,2Љ-diol (65). A solution of the terminal alkene (64b) (56 mg,
0.11 mmol) in tert-butanol (0.3 ml) was added dropwise over
2 min to a vigorously stirred solution of commercial AD-mix
β (0.15 g, 1.4 g per mmol) in tert-butanol (0.2 ml) and water
(0.5 ml) at 0 ЊC and the solution was stirred at 0 ЊC for 18 h.
Thin layer chromatography showed that starting material was
still present, therefore methanesulfonamide (10 mg, 0.11 mmol)
was added in one portion and the solution was stirred for a
further 48 h. Sodium sulfite (0.14 g, 0.87 mmol) was added in
one portion and the mixture was stirred for 30 min before it was
diluted with water (2 ml). The mixture was extracted with ethyl
acetate (4 × 5 ml) and the combined organic layer was dried
(Na2SO4) and concentrated in vacuo to leave a yellow oil. Purifi-
cation by flash chromatography, using 65% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the diol (30 mg,
50%) as a colourless oil (along with the olefin starting material
49.6 (d), 47.0 (t), 39.4 (t), 38.7 (t), 38.1 (t), 18.1 (q), 12.2 (d); 13
C
NMR (90 MHz, CDCl3) minor isomer δ 160.9 (s), 159.4 (s),
142.2 (s), 135.7 (d), 129.7 (d), 129.2 (s), 113.8 (d), 72.6 (t), 69.7
(d), 67.2 (d), 64.7 (d), 63.6 (t), 55.2 (q), 49.3 (d), 46.7 (t), 39.4 (t),
38.9 (t), 38.0 (t), 18.1 (q), 12.2 (d); m/z (ESI) Found 554.2968
([M ϩ Na]ϩ C29H45O6NSiNa requires 554.2914).
4S )-2Љ,2Љ-Dimethyl-propionic acid 2-(2,2-dimethyl-[1,3]-
dioxolan-4-yl)-ethyl ester (75). Trimethylacetyl chloride (0.54 g,
0.55 ml, 4.45 mmol) and 4-(dimethylamino)pyridine (42 mg,
0.34 mmol) were added, each in one portion, to a stirred
solution of the enantiomer of (10) (0.50 g, 3.42 mmol) in di-
chloromethane (20 ml) at 0 ЊC under a nitrogen atmosphere.
The solution was stirred at 0 ЊC for 20 min and then triethyl-
amine (0.87 g, 1.19 ml, 8.55 mmol) was added in one portion.
The solution was warmed to room temperature over 12 h and
then quenched with saturated aqueous ammonium chloride
(10 ml). The separated aqueous layer was extracted with di-
chloromethane (2 × 20 ml) and the combined organic extracts
were dried (MgSO4) and concentrated in vacuo to leave an
opaque residue. Purification by flash chromatography, using
10% ethyl acetate–petroleum ether (bp 40–60 ЊC) as eluent, gave
the pivaloate (0.75 g, 95%) as a colourless oil; [α]2D1 Ϫ4.8 (c 1.9 in
1
(28 mg, 50%)); νmax (soln: CHCl3)/cmϪ1 3464, 2867, 1047; H
NMR (360 MHz, CDCl3) major isomer δ 7.55 (1H, s, CH, ox),
7.29 (2H, d, J 8.6, CH, Ar), 6.88 (2H, d, J 8.6, CH, Ar), 4.99
(1H, dd, J 10.9, 2.7, H-6Ј), 4.55 (2H, s, ArCH2), 4.54 (2H, s,
PMBOCH2), 4.42–4.31 (2H, m, H-4Ј, H-2Љ), 4.03–3.98 (1H, m,
H-2Ј), 3.81 (3H, s, ArOCH3), 3.63 (1H, dd, J 11.2, 3.8, H-1Љ),
3.48 (1H, dd, J 11.2, 5.5, H-1Љ), 1.98–1.85 (2H, m), 1.82–1.55
1
(4H, m), 1.14–1.07 (21H, m, Si(CH(CH3)2)3); H NMR (360
MHz, CDCl3) minor isomer δ 7.55 (1H, s, CH, ox), 7.29 (2H, d,
J 8.6, CH, Ar), 6.88 (2H, d, J 8.6, CH, Ar), 4.93 (1H, dd, J 11.2,
2.3, H-6Ј), 4.55 (2H, s, ArCH2), 4.54 (2H, s, PMBOCH2), 4.42–
4.31 (2H, m, H-4Ј, H-2Љ), 4.03–3.98 (1H, m, H-2Ј), 3.81 (3H, s,
ArOCH3), 3.62 (1H, dd, J 11.2, 3.8, H-1Љ), 3.52 (1H, dd, J 11.2,
6.7, H-1Љ), 1.98–1.85 (2H, m), 1.82–1.55 (4H, m), 1.14–1.07
(21H, m, Si(CH(CH3)2)3); 13C NMR (90 MHz, CDCl3) major
isomer δ 161.1 (s), 159.4 (s), 141.8 (s), 135.4 (d), 129.7 (d), 129.2
(s), 113.9 (d), 72.6 (t), 72.0 (d), 69.3 (d), 67.2 (d), 66.6 (t), 64.4
(d), 63.5 (t), 55.3 (q), 39.6 (t), 38.7 (t), 37.7 (t), 18.1 (q), 12.2 (d);
13C NMR (90 MHz, CDCl3) minor isomer δ 161.1 (s), 159.4 (s),
141.9 (s), 135.5 (d), 129.7 (d), 129.2 (s), 113.9 (d), 73.0 (d), 72.6
(t), 69.9 (d), 67.2 (d), 66.8 (t), 64.7 (d), 63.5 (t), 55.3 (q), 39.0 (t),
38.6 (t), 37.8 (t), 18.1 (q), 12.2 (d); m/z (ESI) Found 572.3048
([M ϩ Na]ϩ C29H47O7NSiNa requires 572.3020).
1
CHCl3); νmax (soln: CHCl3)/cmϪ1 2975, 1722, 1060; H NMR
(360 MHz, CDCl3) δ 4.25–4.10 (3H, m, H-1Ј, H-4), 4.08 (1H,
dd, J 7.9, 5.9, H-5), 3.58 (1H, dd, J 7.9, 7.2, H-5), 2.00–1.82
(2H, m, H-2Ј), 1.41 (3H, s, CCH3), 1.35 (3H, s, CCH3), 1.20
(9H, s, C(CH3)3); 13C NMR (90 MHz, CDCl3) δ 178.4 (s), 108.8
(s), 73.4 (d), 69.4 (t), 61.3 (t), 38.7 (s), 32.8 (t), 27.1 (q), 26.9 (q),
25.7 (q); m/z (EI) Found 215.1288 ([M Ϫ CH3]ϩ C11H19O4
requires 215.1283).
(3S )-2Ј,2Ј-Dimethyl-propionic acid 3,4-dihydroxy-butyl ester
(76). para-Toluenesulfonic acid (0.48 g, 2.54 mmol) was added
in one portion to a stirred solution of the acetonide (75) (1.17 g,
5.01 mmol) in methanol (30 ml) at 0 ЊC under a nitrogen
atmosphere. The mixture was warmed to room temperature and
stirred at this temperature for 12 h before it was quenched with
a saturated aqueous solution of sodium hydrogencarbonate
(2ЈR,4ЈR,6ЈR)-2-(4-Methoxybenzyloxymethyl)-4-(6Ј-oxiranyl-
methyl-4Ј-triiso-propylsilanyloxy-tetrahydropyran-2Ј-yl)-oxazole
(66). Sodium hydride (60% dispersion in mineral oil, 7.1 mg,
0.18 mmol) was added in one portion to a stirred solution of
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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(30 ml). The mixture was concentrated in vacuo to leave the
aqueous layer which was extracted with ethyl acetate (3 × 40
ml). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to leave a yellow oil. Purification by flash
chromatography, using 70% ethyl acetate–petroleum ether (bp
40–60 ЊC) as eluent, gave the diol (0.80 g, 83%) as a colourless
oil; [α]2D2 Ϫ8.8 (c 2.3 in CHCl3); νmax (soln: CHCl3)/cmϪ1 3617,
2969, 1721, 1054; 1H NMR (360 MHz, CDCl3) δ 4.36 (1H, ddd,
J 11.2, 8.5, 5.3, H-1), 4.15 (1H, ddd, J 11.2, 5.5, 5.5, H-1),
3.80–3.73 (1H, m, H-3), 3.66 (1H, dd, J 11.2, 3.2, H-4), 3.49
(1H, dd, J 11.2, 7.3, H-4), 2.59 (2H, b s, 2 × OH ), 1.82–1.73
(2H, m, H-2), 1.20 (9H, s, C(CH3)3); 13C NMR (90 MHz,
CDCl3) δ 179.1 (s), 69.0 (d), 66.4 (t), 61.1 (t), 38.7 (s), 32.2 (t),
27.1 (q); m/z (ES) Found 191.1330 ([MH]ϩ C9H19O4 requires
191.1283).
ddd, J 11.2, 5.5, 5.5, H-1), 3.85–3.78 (1H, m, H-3), 2.51–2.39
(2H, m, H-4), 1.97–1.88 (1H, m, H-2), 1.83–1.73 (2H, m, H-2),
1.20 (9H, s, C(CH3)3), 0.15 (9H, s, Si(CH3)3); 13C NMR (67.8
MHz, CDCl3) δ 178.7 (s), 102.6 (s), 87.8 (s), 67.0 (d), 61.2 (t),
38.7 (s), 35.2 (t), 28.8 (t), 27.2 (q), 0.00 (q); m/z (FAB) Found
271.1730 ([MH]ϩ C14H27O3Si requires 271.1729).
(3R)-2Ј,2Ј-Dimethyl-propionic acid 3-hydroxy-hex-5-ynyl
ester (78b). Tetrabutylammonium fluoride trihydrate (1.25 g,
3.98 mmol) was added in one portion to a stirred solution of
the alcohol (78a) (0.90 g, 3.31 mmol) in THF (40 ml) at 0 ЊC
under a nitrogen atmosphere. The solution was warmed to
room temperature, then stirred at this temperature for 1 h
15 min, and quenched with saturated aqueous ammonium
chloride (20 ml). The mixture was concentrated in vacuo to leave
an aqueous residue which was extracted with ethyl acetate (3 ×
40 ml). The combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to leave a residue which was purified by
flash chromatography, using 15% ethyl acetate–petroleum ether
(bp 40–60 ЊC) as eluent, to give the monosubstituted alkyne
(0.66 g, 93%) as a colourless oil; [α]2D1 Ϫ9.9 (c 1.3 in CHCl3); νmax
(3S )-2Ј,2Ј-Dimethyl-propionic acid 2-oxiranyl-ethyl ester (77).
Trimethyl orthoacetate (0.15 g, 0.16 ml, 1.26 mmol) was added
in one portion to a stirred solution of the diol (76) (0.20 g, 1.05
mmol) and pyridinium para-toluenesulfonate (2.0 mg, 11 µmol)
in dichloromethane (8 ml) at room temperature under a
nitrogen atmosphere. The mixture was stirred for 30 min and
then concentrated in vacuo to leave the crude cyclic orthoester
as a colourless oil, which was used without further purification.
Acetyl bromide (0.16 g, 0.10 ml, 1.26 mmol) was added
dropwise over 2 min to a stirred solution of the cyclic ortho-
ester in dichloromethane (8 ml) at room temperature under
a nitrogen atmosphere. The mixture was stirred at room tem-
perature for 45 min and then concentrated in vacuo to leave
the crude acetoxy bromide as a colourless oil, which was used
without further purification.
1
(soln: CHCl3)/cmϪ1 3592, 3307, 2971, 2120, 1721; H NMR
(360 MHz, CDCl3) δ 4.27 (1H, ddd, J 11.2, 8.5, 5.3, H-1), 4.15
(1H, ddd, J 11.2, 5.3, 5.3, H-1), 3.86–3.79 (1H, m, H-3), 2.63
(1H, b s, OH ), 2.43 (1H, ddd, J 16.7, 5.6, 2.6, H-4), 2.36 (1H,
ddd, J 16.7, 6.1, 2.6, H-4), 2.05 (1H, t, J 2.6, H-6), 1.91 (1H,
dddd, J 14.3, 8.5, 5.3, 3.7, H-2), 1.79 (1H, dddd, J 14.3, 9.0, 5.3,
5.3, H-2), 1.17 (9H, s, C(CH3)3); 13C NMR (67.8 MHz, CDCl3)
δ 178.8 (s), 80.4 (d), 70.9 (s), 66.8 (d), 61.2 (t), 38.7 (s), 35.1 (t),
27.2 (t), 27.1 (q); m/z (EI) Found 180.1157 ([M Ϫ H2O]ϩ
C11H16O2 requires 180.1150).
Potassium carbonate (0.20 g, 1.47 mmol) was added in one
portion to a stirred solution of the acetoxy bromide in meth-
anol (8 ml) at room temperature under a nitrogen atmosphere.
The mixture was stirred at room temperature for 2 h 30 min,
then quenched with saturated aqueous ammonium chloride
(20 ml) and extracted with dichloromethane (3 × 20 ml). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo to leave a residue which was purified by flash
chromatography, using 20% ethyl acetate–petroleum ether (bp
40–60 ЊC) as eluent, to give the epoxide (0.14 g, 75%) as a
colourless oil; [α]2D1 Ϫ12.5 (c 0.9 in CHCl3); (Found: C, 62.7; H,
9.4. C9H16O3 requires C, 62.8; H, 9.4%); νmax (soln: CHCl3)/
cmϪ1 2972, 1722, 1288, 900; 1H NMR (360 MHz, CDCl3) δ 4.20
(2H, app t, J ∼6.3, H-1), 3.02–2.97 (1H, m, H-3), 2.78 (1H, dd,
J 5.0, 4.3, H-4), 2.50 (1H, dd, J 5.0, 2.7, H-4), 1.93–1.76 (2H, m,
H-2), 1.19 (9H, s, C(CH3)3); 13C NMR (90 MHz, CDCl3)
δ 178.3 (s), 61.2 (t), 49.5 (d), 46.8 (t), 38.6 (s), 31.9 (t), 27.1 (q).
(3R)-2Ј,2Ј-Dimethyl-propionic acid 3-(tert-butyldimethyl-
silanyloxy)-hex-5-ynyl ester (79). 2,6-Lutidine (0.47 g, 0.51 ml,
4.34 mmol) and tert-butyldimethylsilyl trifluoromethane-
sulfonate (0.57 g, 0.50 ml, 2.17 mmol) were added, each in
one portion, to a stirred solution of the alcohol (78b) (0.29 g,
1.45 mmol) in dichloromethane (14 ml) at 0 ЊC under a nitrogen
atmosphere. The solution was stirred at 0 ЊC for 1 h and then
quenched with a saturated aqueous solution of ammonium
chloride (10 ml). The separated aqueous layer was extracted
with dichloromethane (2 × 20 ml), and the combined organic
extracts were then dried (Na2SO4) and concentrated in vacuo to
leave a yellow oil. Purification by flash chromatography, using
5% ethyl acetate–petroleum ether (bp 40–60 ЊC) as eluent, gave
the TBS ether (0.45 g, 100%) as a colourless oil; [α]2D2 Ϫ32.6
(c 1.4 in CHCl3); νmax (soln: CHCl3)/cmϪ1 3308, 2931, 2120,
1
1721, 1101; H NMR (360 MHz, CDCl3) δ 4.23 (1H, ddd, J
11.0, 5.3, 5.3, H-1), 4.08 (1H, ddd, J 11.0, 8.5, 5.3, H-1), 3.97–
3.90 (1H, m, H-3), 2.39 (1H, ddd, J 16.6, 5.2, 2.7, H-4), 2.33
(1H, ddd, J 16.6, 7.0, 2.7, H-4), 1.99 (1H, t, J 2.7, H-6), 2.04–
1.95 (1H, m, H-2), 1.80 (1H, dddd, J 13.4, 8.0, 5.3, 5.3, H-2),
1.20 (9H, s, C(CH3)3), 0.89 (9H, s, SiC(CH3)3), 0.09 (3H, s,
SiCH3), 0.07 (3H, s, SiCH3); 13C NMR (90 MHz, CDCl3)
δ 178.4 (s), 80.9 (d), 70.4 (s), 67.7 (d), 60.9 (t), 38.7 (s), 35.4 (t),
27.7 (t), 27.2 (q), 25.7 (q), 18.0 (s), Ϫ4.5 (q), Ϫ4.9 (q); m/z (EI)
Found 255.1415 ([M Ϫ C4H9]ϩ C13H23O3Si requires 255.1417).
(3R)-2Ј,2Ј-Dimethyl-propionic acid 3-hydroxy-6-trimethyl-
silanyl-hex-5-ynyl ester (78a). n-Butyllithium (2.5 M in hexanes,
2.10 ml, 5.23 mmol) was added dropwise over 5 min to a stirred
solution of trimethylsilylacetylene (0.51 g, 0.74 ml, 5.23 mmol)
in THF (25 ml) at Ϫ78 ЊC under a nitrogen atmosphere. The
solution was stirred at Ϫ78 ЊC for 10 min, then boron trifluoride
diethyl etherate (0.46 ml, 3.74 mmol) was added dropwise over
2 min and the mixture was stirred at Ϫ78 ЊC for 10 min. A
solution of the epoxide (77) (0.60 g, 3.48 mmol) in THF (10 ml)
was added dropwise over 5 min and the mixture was stirred at
Ϫ78 ЊC for 30 min, then quenched with a saturated aqueous
solution of ammonium chloride (20 ml) and allowed to warm
to room temperature. The mixture was concentrated in vacuo
to leave the aqueous residue which was extracted with ethyl
acetate (4 × 20 ml). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to leave a residue which
was purified by flash chromatography, using 20% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, to give the alcohol
(0.93 g, 99%) as a colourless oil; [α]2D1 Ϫ4.0 (c 2.1 in CHCl3); νmax
(soln: CHCl3)/cmϪ1 3591, 2960, 2173, 1721; 1H NMR (360
MHz, CDCl3) δ 4.29 (1H, ddd, J 11.2, 8.6, 4.9, H-1), 4.17 (1H,
(3S )-2Ј,2Ј-Dimethyl-propionicacid3-(tert-butyldimethylsilanyl-
oxy)-5-iodo-hex-5-enyl ester (80a). A solution of the alkyne (79)
(0.45 g, 1.44 mmol) in pentane (6 ml) was added dropwise,
via cannula, over 5 min to a stirred solution of 9-iodo-9-
borabicyclo[3.3.1]nonane (1 M in hexane, 1.58 ml, 1.58 mmol)
in pentane (10 ml) at Ϫ20 ЊC under a nitrogen atmosphere. The
mixture was stirred at Ϫ20 ЊC for 1 h 30 min, then glacial acetic
acid (0.9 ml) was added in one portion and the solution was
stirred at Ϫ20 ЊC for 1 h. An aqueous solution of sodium
hydroxide (3 M, 11 ml) and hydrogen peroxide (1.8 ml) were
added, each in one portion, and the mixture was stirred at room
temperature for 1 h 30 min. The mixture was diluted with ethyl
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acetate (10 ml) and water (5 ml) and the separated aqueous
layer was extracted with ethyl acetate (2 × 30 ml). The
combined organic extracts were dried (Na2SO4) and concen-
trated in vacuo to leave a residue which was purified by flash
chromatography, using petroleum ether (bp 40–60 ЊC) and
increasing to 3% ethyl acetate–petroleum ether (bp 40–60 ЊC) as
eluent, to give the vinyl iodide (0.60 g, 95%) as an orange oil;
[α]2D1 Ϫ12.6 (c 2.3 in CHCl3); νmax (soln: CHCl3)/cmϪ1 2930,
in 2,2-dimethoxypropane (3 ml) at room temperature under a
nitrogen atmosphere. The mixture was stirred at room temper-
ature for 6.5 h, then diluted with ethyl acetate (10 ml) and
quenched with a saturated aqueous solution of sodium
hydrogencarbonate (3 ml). The separated aqueous layer was
extracted with ethyl acetate (2 × 10 ml) and the combined
organic extracts were dried (Na2SO4) and concentrated in vacuo
to leave a yellow oil. Purification by flash chromatography,
using 10% ethyl acetate–petroleum ether (bp 40–60 ЊC) as
eluent, gave the vinyl iodide (93 mg, 84%) as a colourless oil;
[α]2D1 ϩ9.1 (c3.2 in CHCl3); νmax (soln: CHCl3)/cmϪ1 2951, 1620,
1098; 1H NMR (360 MHz, CDCl3) δ 6.12 (1H, q, J 1.3, H-3Ј),
5.79 (1H, d, J 1.3, H-3Ј), 4.18–4.10 (1H, m, H-4), 4.00 (1H,
ddd, J 11.9, 11.9, 3.1, H-6), 3.84 (1H, ddd, J 11.9, 5.4, 1.7, H-6),
2.60 (1H, dd, J 14.3, 6.9, H-1Ј), 2.42 (1H, dd, J 14.3, 5.8, H-1Ј),
1.57 (1H, dddd, J 11.9, 11.9, 11.9, 5.4, H-5), 1.50 (3H, s,
CH3), 1.47–1.44 (1H, m, H-5), 1.38 (3H, s, CH3); 13C NMR
(90 MHz, CDCl3) δ 128.0 (t), 106.0 (s), 98.5 (s), 67.6 (d), 59.8
(t), 51.3 (t), 30.1 (t), 29.8 (q), 19.2 (q); m/z (EI) Found 266.9880
([M Ϫ CH3]ϩ C8H12O2I requires 266.9882).
1
1720, 1618, 901; H NMR (360 MHz, CDCl3) δ 6.09 (1H, d,
J 1.1, H-6), 5.75 (1H, d, J 1.1, H-6), 4.22 (1H, ddd, J 11.2, 5.6,
5.6, H-1), 4.11–4.04 (2H, m, H-1, H-3), 2.61 (1H, app dd,
J ∼13.9, ∼5.5, H-4), 2.47 (1H, ddd, J 13.9, 6.7, 0.7, H-4), 1.86
(1H, dddd, J 14.2, 9.9, 5.6, 4.2, H-2), 1.69–1.61 (1H, m, H-2),
1.22 (9H, s, C(CH3)3), 0.89 (9H, s, SiC(CH3)3), 0.11 (3H, s,
SiCH3), 0.10 (3H, s, SiCH3); 13C NMR (90 MHz, CDCl3)
δ 178.4 (s), 128.2 (t), 107.4 (s), 67.8 (d), 60.7 (t), 53.1 (t), 38.7 (s),
35.2 (t), 27.3 (q), 25.8 (q), 18.0 (s), Ϫ4.1 (q), Ϫ4.7 (q); m/z (ES)
Found 463.1152 ([MNa]ϩ C17H33O3SiINa requires 463.1141).
(3S )-3-(tert-Butyldimethylsilanyloxy)-5-iodo-hex-5-en-1-ol
(80b). Diisobutylaluminium hydride (1.5 M in toluene, 1.82 ml,
2.72 mmol) was added dropwise over 5 min to a stirred solution
of the ester (80a) (0.48 g, 1.09 mmol) in toluene (11 ml) at
Ϫ78 ЊC under a nitrogen atmosphere. The solution was stirred
at Ϫ78 ЊC for 1 h and then quenched by the dropwise addition
of methanol (3 ml). The mixture was added, via cannula, to
a saturated aqueous solution of potassium sodium tartrate
(25 ml) and the resulting mixture was then stirred vigorously for
3 h. The separated aqueous layer was extracted with ethyl
acetate (3 × 50 ml), and the combined extracts were then dried
(Na2SO4) and concentrated in vacuo to leave a yellow oil. Purifi-
cation by flash chromatography, using 10% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the alcohol
(0.35 g, 91%) as a colourless oil; [α]2D1 Ϫ2.0 (c 1.9 in CHCl3); νmax
(soln: CHCl3)/cmϪ1 3517, 2930, 1618, 1060; 1H NMR (360
MHz, CDCl3) δ 6.09 (1H, d, J 1.1, H-6), 5.75 (1H, d,
J 1.1, H-6), 4.19–4.12 (1H, m, H-3), 3.81 (1H, ddd, J 11.0, 8.2,
4.5, H-1), 3.73 (1H, ddd, J 11.0, 5.6, 5.6, H-1), 2.64 (1H, app dd,
J ∼14.0, ∼5.7, H-4), 2.53 (1H, app dd, J ∼14.0, ∼7.2, H-4), 2.46
(1H, b s, OH ), 1.87 (1H, dddd, J 14.3, 8.2, 5.6, 4.5, H-2), 1.62
(1H, app dq, J ∼14.3, ∼5.6, H-2), 0.88 (9H, s, SiC(CH3)3), 0.13
(3H, s, SiCH3), 0.12 (3H, s, SiCH3); 13C NMR (90 MHz,
CDCl3) δ 128.2 (t), 107.0 (s), 70.2 (d), 59.7 (t), 52.3 (t), 37.2 (t),
25.8 (q), 17.9 (s), Ϫ4.3 (q), Ϫ4.7 (q); m/z (EI) Found 298.9964
([M Ϫ C4H9]ϩ C8H16O2SiI requires 298.9964).
(2ЈR,4ЈR,6ЈR,4ЉR)-4-(2Љ,2Љ-Dimethyl-[1Љ,3Љ]-dioxan-4Љ-
ylmethyl)-1-{6Ј-[2-(4-methoxybenzyloxymethyl)-oxazol-4-yl]-
4Ј-triisopropylsilanyloxy-tetrahydro-pyran-2Ј-yl}-pent-4-en-2-ol
(68). tert-Butyllithium (1.5 M in pentane, 0.24 ml, 0.40 mmol)
was added dropwise over 2 min to a stirred solution of the vinyl
iodide (67) (56 mg, 200 µmol) in THF (0.8 ml) at Ϫ78 ЊC under
an argon atmosphere. The solution was stirred at Ϫ78 ЊC for
30 min and then a freshly prepared solution of lithium
2-thienylcyanocuprate (0.3 M in THF, 0.66 ml, 200 µmol) was
added dropwise over 2 min. The mixture was stirred at Ϫ40 ЊC
for 1 h and then cooled to Ϫ78 ЊC. A solution of the epoxide
(13) (50 mg, 0.30 mmol) in THF (1.2 ml) was added dropwise,
via cannula, over 2 min and the resulting solution was warmed
to 0 ЊC over 1 h. The solution was stirred at 0 ЊC for 23 h and
then it was quenched with a mixture of saturated aqueous
ammonium chloride and concentrated ammonium hydroxide
(10 : 1 v/v, 4 ml). The mixture was poured onto water (4 ml) and
extracted with ethyl acetate (3 × 20 ml). The combined organic
layer was washed with brine (20 ml), dried (Na2SO4) and
concentrated in vacuo to leave a brown oil. Purification by flash
chromatography, using 20% ethyl acetate–petroleum ether (bp
40–60 ЊC) as eluent, gave the alcohol (16 mg, 20%) and the
starting epoxide (26 mg, 41%), both as colourless oils; 1H NMR
(360 MHz, CDCl3) major isomer δ 7.55 (1H, s, CH, ox), 7.29
(2H, d, J 8.6, CH, Ar), 6.89 (2H, d, J 8.6, CH, Ar), 4.97 (1H,
app dd, J ∼11.5, ∼1.8, H-6Ј), 4.91 (1H, s, H-5), 4.90 (1H, s, H-5),
4.54 (2H, s, CH2Ar), 4.53 (2H, s, CH2Ar), 4.39–4.37 (1H, m,
H-4Ј), 4.30–4.25 (1H, m, H-2), 4.10–4.02 (2H, m, H-2Ј, H-4Љ),
3.96 (1H, ddd, J 12.1, 12.1, 2.9, H-6Љ), 3.85–3.83 (1H, m, H-6Љ),
3.81 (3H, s, OCH3), 2.32–2.13 (4H, m, H-3, H-1Љ), 1.95–1.93
(1H, m), 1.91–1.85 (1H, m), 1.72–1.52 (6H, m), 1.46 (3H, s,
CH3), 1.38 (3H, s, CH3), 1.12–1.04 (21H, m, Si(CH(CH3)2)3);
m/z (ESI) Found 710.4082 ([M ϩ Na]ϩ C38H61O8NSiNa
requires 710.4064).
(3S )-5-Iodo-hex-5-ene-1,3-diol (81). Hydrogen fluoride–
pyridine (0.4 ml) was added in one portion to a stirred solution
of the alcohol (80b) (0.15 g, 0.41 mmol) in THF (4 ml) at room
temperature under a nitrogen atmosphere. The solution was
stirred at room temperature for 3 h, then a second portion of
hydrogen fluoride–pyridine (0.4 ml) was added and the mixture
was stirred for a further 2 h. The mixture was quenched by the
dropwise addition of sodium hydrogencarbonate (5 ml) and
then it was stirred for 30 min. Ethyl acetate (10 ml) was added
and the separated aqueous layer was extracted with ethyl
acetate (2 × 10 ml). The combined organic extracts were dried
(Na2SO4) and concentrated in vacuo to leave a residue which
was purified by flash chromatography, using 70% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent to give the diol (95 mg,
96%) as a colourless oil; [α]2D1 ϩ4.9 (c2.9 in CHCl3); νmax (soln:
CHCl3)/cmϪ1 3626, 3511, 1617, 1068; 1H NMR (360 MHz,
CDCl3) δ 6.17 (1H, d, J 1.2, H-6), 5.83 (1H, d, J 1.2, H-6),
4.16–4.09 (1H, m, H-3), 3.91–3.80 (2H, m, H-1), 3.13 (2H, b s,
(2ЈS,4ЈR,6ЈR,5R)-Methanesulfonic acid 5,7-dihydroxy-1-{6Ј2-
(4-methoxy-benzyloxymethyl)-oxazol-4-yl]-4Јtriisopropylsilany-
loxy-tetrahydropyran-2Јyl-methyl}-3-methyleneheptyl ester (69).
Triethylamine (59 mg, 81 µl, 580 µmol) and methanesulfonyl
chloride (33 mg, 22 µl, 290 µmol) were added, each in one
portion, to a stirred solution of the alcohol (68) (40 mg, 58
µmol) in dichloromethane (2 ml) at 0 ЊC under a nitrogen
atmosphere. The solution was stirred at 0 ЊC for 45 min and
then it was quenched with a saturated aqueous solution of
sodium hydrogencarbonate (30 ml). The mixture was extracted
with dichloromethane (3 × 50 ml) and the combined organic
layer was dried (Na2SO4). Concentration in vacuo left the
mesylate as a light yellow oil, which was used without further
purification.
2 × OH ), 2.60–2.49 (2H, m, H-4), 1.78–1.67 (2H, m, H-2); 13
C
NMR (90 MHz, CDCl3) δ 128.6 (t), 107.0 (s), 69.8 (d), 61.2 (t),
52.8 (t), 37.1 (t).
(4S )-4-(2Ј-Iodo-allyl)-2,2-dimethyl-[1,3]-dioxane (67). 10-
Camphorsulfonic acid (18 mg, 78 µmol) was added in one
portion to a stirred solution of the diol (81) (95 mg, 0.39 mmol)
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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10-Camphorsulfonic acid (6 mg, 24 µmol) was added in
one portion to a stirred solution of the mesylate (45 mg,
59 µmol) in methanol (2 ml) at room temperature under a
nitrogen atmosphere. The mixture was stirred at room temper-
ature for 1 h 30 min and then it was quenched with a saturated
aqueous solution of sodium hydrogencarbonate (30 ml). The
mixture was extracted with ethyl acetate (3 × 50 ml) and then
the combined organic layer was dried (Na2SO4) and concen-
trated in vacuo to leave a yellow oil. Purification by flash
chromatography, using 60% ethyl acetate–petroleum ether
(bp 40–60 ЊC) and increasing to ethyl acetate as eluent, gave the
diol (25 mg, 60% over 2 steps) as a colourless oil; 1H NMR (360
MHz, CDCl3) major isomer δ 7.57 (1H, s, CH, ox), 7.30 (2H, d,
J 8.5, CH, Ar), 6.90 (2H, d, J 8.5, CH, Ar), 5.13–5.04 (1H, m,
triethylamine (23 µl, 0.21 mmol) and dichloromethane (1.2 ml)
at 0 ЊC, and the mixture was stirred for 30 min at 0 ЊC and then
quenched with saturated aqueous ammonium chloride and
diluted with diethyl ether. The separated ether extract was
washed with brine, then dried (Na2SO4) and evaporated to
dryness in vacuo. The residue was purified by chromatography,
eluting with 30% ethyl acetate in petrol ether to give the silyl
ether (70.0 mg, 90%) as a yellow oil; [α]2D5 Ϫ11.1 (c 2.8 in
CHCl3); 1H NMR (360 MHz) δ 7.56 (1H, s, oxCH ); 7.29 (2H,
d, J 8.6, ArH ), 6.88 (2H, d, J 8.6, ArH ), 4.90 (1H, b d, J 9.6),
4.75 (1H, b s, ᎐CH ), 4.72 (1H, b s, ᎐CH ), 4.55 (2H, s,
᎐
᎐
2
2
PMBOCH2), 4.54 (2H, s, PMBOCH2), 4.40 (1H, b s, CHOSi-
(CH(CH3)2)3), 4.10–4.00 (2H, m), 3.91 (1H, m), 3.81 (3H, s,
OCH3), 3.66 (2H, t, J 6.5, CH2OTBS), 2.36 (2H, m), 2.06–
1.50 (10H, m), 1.15–1.05 (21H, m, Si(CH(CH3)2)3), 0.89 (9H, s,
SiC(CH3)3), 0.05 (6H, s, Si(CH3)2); 13C NMR (90 MHz)
δ 160.7(s), 159.4(s), 142.5(s), 142.3(s), 135.6(s), 2 × 129.7(d),
129.3(s), 2 × 113.8(d), 110.1(t), 72.6(t), 69.1(d), 69.0(d), 68.9(d),
67.3(d), 64.9(d), 63.6(t), 59.8(t), 55.3(q), 39.9(t), 39.3(t), 39.3(t),
39.1(t), 38.4(t), 37.0(t), 3 × 26.0(q), 3 × 18.2(q), 18.1(s),
6 × 12.3(d), 2 × Ϫ5.2(q); m/z (FAB) Found: 744.4734
([M ϩ Na]ϩ C41H70NO7Si2 requires 744.4691).
H-1), 5.02 (1H, s, C᎐CH ), 4.98 (1H, s, C᎐CH ), 4.84 (1H, app
᎐
᎐
dd, J ∼10.9, ∼2.4, H-6Ј), 4.57 (2H, s, CH2Ar), 4.56 (2H, s,
CH2Ar), 4.43–4.40 (1H, m, H-4Ј4.21–4.00 (2H, m, H-5,
H-2Ј3.85–3.73 (2H, m, H-7), 3.82 (3H, s, OCH3), 2.94 (3H, s,
SO2CH3), 2.76 (1H, app dd, J ∼14.4, ∼3.9, H-2), 2.44 (1H, dd,
J 14.4, 8.4, H-2), 2.43–2.38 (1H, m), 2.32–2.17 (2H, m),
2.13–2.05 (1H, m), 1.95–1.80 (4H, m), 1.77–1.51 (2H, m),
1.14–1.05 (21H, m, Si(CH(CH3)2)3); m/z (ESI) Found 748.3510
([M ϩ Na]ϩ C36H59O10NSSiNa requires 748.3527).
Oxazole bis-oxane methanol (71b). Dichlorodicyanoquinone
(36.0 mg, 0.16 mmol) was added to a stirred solution of the
PMB-ether (71a) (56.0 mg, 0.078 mmol) in methylene chloride
(0.8 ml) and water (80 µl) at room temperature, and the mixture
was stirred vigorously for 2 h, and then saturated aqueous
sodium bicarbonate (0.2 ml) was added. The mixture was added
to a short column of silica, and eluted with 30% ethyl acetate in
petrol ether. The solvents were removed in vacuo to leave the
alcohol (43.0 mg, 90%) as a pale orange oil; [α]2D2 Ϫ10.0 (c 2.2
(2ЈR,4ЈR,6ЈR,2R,6R)-2Љ-{6Ј2-(4-Methoxybenzyloxymethyl)-
oxazol-4-yl]-4Јtri-isopropylsilanyloxy-tetrahydropyran-2Јyl-
methyl}-4-methylene-tetrahydro-pyran-2-yl)-ethanol
(70a).
Triethylamine (150 mg, 210 µl, 1.5 mmol) was added in one
portion to a stirred solution of the diol (69) (25 mg, 34 µmol) in
acetonitrile (3 ml) at room temperature under a nitrogen
atmosphere. The solution was heated at reflux for 44 h and
then it was cooled to room temperature and diluted with ethyl
acetate (30 ml), brine (15 ml) and water (15 ml). The layers were
separated and the aqueous layer was extracted with ethyl
acetate (2 × 50 ml). The combined organic layer was dried
(Na2SO4) and concentrated in vacuo to leave a yellow oil. Purifi-
cation by flash chromatography, using 25% ethyl acetate–
petroleum ether (bp 40–60 ЊC) as eluent, gave the required
trans-pyran (8 mg, 37%) and the cis-pyran (9 mg, 41%), both as
1
in CHCl3); H NMR (360 MHz) δ 7.54 (1H, d, J 0.7, oxCH ),
4.89 (1H, dd, J 8.6, 2.4), 4.75 (1H, b s, ᎐CH ), 4.72 (1H, b s,
᎐
2
᎐CH ), 4.70 (2H, s, CH OH), 4.40 (1H, b s, CHOSi-
᎐
2
2
(CH(CH3)2)3), 4.10–3.95 (2H, m), 3.90 (1H, m), 3.66 (2H, t,
J 6.5, CH2OTBS), 2.36 (2H, m), 2.08–1.50 (10H, m), 1.15–1.05
(21H, m, Si(CH(CH3)2)3) 0.89 (9H, s, SiC(CH3)3), 0.05 (6H, s,
Si(CH3)2); 13C NMR (90 MHz) δ 163.0(s), 142.3(s), 135.4(d),
135.4(s), 110.2(t), 69.3(d), 69.1(d), 69.0(d), 67.2(d), 64.9(d),
59.9(t), 57.6(t), 39.9(t), 39.3(t), 39.3(t), 39.2(t), 38.4(t), 37.0(t),
3 × 26.0(q), 6 × 18.3(q), 18.1 (s), 3 × 12.0(d), 2 × Ϫ5.3(q); m/z
(FAB) Found: 624.4114 ([M ϩ H]ϩ C33H62NO6Si2 requires
624.4116).
colourless oils; trans-pyran: [α]2D4 Ϫ78.8 (c 2.8 in CHCl3); H
1
NMR (360 MHz, CDCl3) δ 7.57 (1H, d, J 0.8, CH, ox), 7.27
(2H, d, J 8.7, CH, Ar), 6.89 (2H, d, J 8.7, CH, Ar), 4.91 (1H,
dd, J 11.2, 3.2, H-6Ј), 4.77 (1H, s, C᎐CH ), 4.72 (1H, s, C᎐CH ),
᎐
᎐
4.56 (2H, s, CH2Ar), 4.55 (2H, s, CH2Ar), 4.41–4.39 (1H, m,
H-4Ј), 4.18–4.04 (2H, m, H-2, H-2Ј), 4.01–3.95 (1H, m, H-6),
3.81 (3H, s, OCH3), 3.74–3.71 (2H, m, H-1Љ), 2.76 (1H, b s,
OH ), 2.41 (1H, dd, J 13.2, 4.8), 2.28 (1H, dd, J 13.2, 3.7), 2.08
(1H, b d, J ∼14.0), 2.06 (1H, b d, J ∼13.2), 1.98–1.80 (4H, m),
1.74–1.70 (2H, m), 1.66–1.60 (2H, m), 1.17–1.04 (21H, m,
Si(CH(CH3)2)3); 13C NMR (90 MHz, CDCl3) δ 161.0 (s), 159.8
(s), 142.2 (s), 141.8 (s), 135.9 (d), 129.8 (d), 129.3 (s), 113.9 (d),
110.5 (t), 72.7 (t), 71.0 (d), 70.0 (d), 69.8 (d), 67.2 (d), 65.0 (d),
63.7 (t), 60.7 (t), 55.4 (q), 40.2 (t), 39.5 (t), 39.0 (t), 38.6 (t), 38.2
Oxazole bis-oxane mesylate (71c). N,N-Diisopropylethyl-
amine (30 µl, 0.176 mmol) and methanesulfonyl chloride (8 µl,
0.105 mmol) were added to a stirred solution of the alcohol
(71b) (55.0 mg, 0.088 mmol) in methylene chloride (1 ml) at
Ϫ5 ЊC. The mixture was stirred at room temperature for 30 min,
then loaded onto a short column of silica, which was eluted
with 20% ethyl acetate in petrol ether. The solvents were
removed in vacuo to leave the mesylate (47 mg, 76%) as a
colourless oil; [α]2D3 Ϫ11.5 (c 1.6 in CHCl3); 1H NMR (360 MHz)
δ 7.62 (1H, d, J 0.8, oxCH ), 5.27 (2H, s, CH3SO2OCH2), 4.90
1
(t), 37.1 (t), 18.2 (d), 12.3 (q); cis-pyran: H NMR (360 MHz,
CDCl3) δ 7.57 (1H, d, J 0.7, CH, ox), 7.27 (2H, d, J 8.7, CH,
Ar), 6.88 (2H, d, J 8.7, CH, Ar), 4.90 (1H, dd, J 11.1, 2.7, H-6Ј),
(1H, b d, J 10.1), 4.75 (1H, b s, ᎐CH ), 4.73 (1H, b s, ᎐CH ),
᎐
᎐
2
2
4.71–4.69 (2H, m, C᎐CH ), 4.56 (2H, s, CH Ar), 4.54 (2H, s,
4.40 (1H, b s, CHOSi(CH(CH3)2)3), 4.15–3.95 (2H, m),
3.90(1H, m), 3.66 (2H, t, J 6.4, CH2OTBS), 3.11 (3H, s,
CH3SO2), 2.36 (2H, m), 2.06–1.87 (4H, m), 1.83–1.74 (2H, m),
1.68–1.48 (4H, m), 1.15–1.00 (21H, m, Si(CH(CH3)2)3), 0.89
(9H, s, SiC(CH3)3), 0.05 (6H, s, Si(CH3)2); 13C NMR (90 MHz)
δ 156.5(s), 143.7(s), 142.3(s), 136.8(d), 110.2(t), 69.3(d), 69.1(d),
68.9(d), 67.3(d), 64.8(d), 62.1(t), 59.9(t), 39.8(t), 39.4(t), 39.3(t),
39.2(t), 38.6(t), 38.5(q), 37.0(t), 3 × 26.0(q), 6 × 18.2(q), 17.8(s),
3 × 12.3(d), 2 × Ϫ5.3(q); m/z (FAB) Nominal mass Found: 725
([M ϩ H ϩ Na]ϩ C34H64NO8Si2S requires 725).
᎐
2
2
CH2Ar), 4.43–4.41 (1H, m, H-4Ј), 4.30–4.24 (1H, m, H-2Ј),
3.94–3.88 (1H, m), 3.81 (3H, s, OCH3), 3.76–3.70 (1H, m),
3.60–3.54 (2H, m, H-1Љ), 2.36 (2H, app t, J ∼7.3), 2.23–2.17
(2H, m), 2.08–1.85 (4H, m), 1.80–1.63 (4H, m), 1.14–1.06 (21H,
m, Si(CH(CH3)2)3); m/z (ESI) Found 652.3633 ([M ϩ Na]ϩ
C35H55O7NSiNa requires 652.3646).
The same oxazole cis, trans bis-pyran (70a) was obtained by
saponification of the corresponding pivaloate (70b) prepared by
the procedure described by Williams et al.43
Oxazole bis-oxane PMB ether (71a). tert-Butyldimethylsilyl
chloride (30 µl, 0.126 mmol) was added dropwise over 10 min to
a solution of the alcohol (70a) (66.0 mg, 0.105 mmol) and
Oxazole tris-oxane alcohol 87a. Tributylphosphine (10 µl,
36 µmol) was added to a stirred solution of the mesylate (85)
(6 mg, 9 µmol) in dimethylformamide (2 ml) and the mixture
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
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was stirred at room temperature for 24 h. A solution of the
aldehyde (52) (4.1 mg, 9 µmol) in dimethylformamide (1 ml)
was added via canula followed by DBU (3.3 µl, 21 µmol), and
the mixture was stirred at room temperature for 30 min. The
solvents were removed in vacuo [0.2mm Hg, 30 ЊC] and the
residue was purified by chromatography on silica using ethyl
acetate in petrol (3 : 7) as eluant to give the E-olefin (86a) (9 mg,
99%) as a colourless oil; HNMR (500 MHz) δ 7.45 (1H, s,
oxCH ), 7.28 (2H, d, J 8.7, ArH ), 6.88 (2H, d, J 8.7, ArH ), 6.70
(1H, ddd, J 16.0, 8.7, 6.0, H-20), 6.35 (1H, d, J 16.0, H-19), 4.89
2.99 (1H, dd, J 16.1, 4.1, H-21), 2.61–2.54 (1H, m, H-21), 2.41–
2.28 (3H, m), 2.06–1.74 (8H, m), 1.68–1.48 (4H, m), 1.27 (3H,
d, J 7.1, CH3), 1.19 (21H, s, OTIPS), 1.01 (3H, d, J 5.5, CH3),
0.89 (18H, s, 2 × Bu(Me)2Si), 0.06 (12H, s, 2 × Bu(Me)2Si);
m/z (ESI) Found 920.6312; C50H94NO8Si3 requires 920.6287.
t
t
Oxazole tris-oxane phosphonate 87b. Bis-(2,2,2-trifluoro-
ethyl) [methoxy carbonylmethyl] phosphonate (3.8 µl, 20 µmol)
and N,N-dimethylaminopyridine (2.4 mg, 20 µmol) were added
to a solution of the alcohol (87a) (10 mg, 11 µmol) in toluene
(1 ml), and the mixture was then heated to 120 ЊC for 30 h. The
cooled solution was evaporated and the residue was purified by
chromatography on a short column of silica, eluting with ethyl
acetate to give the phosphonate ester (8 mg, 60%) as a colourless
1
(1H, b d, J 8.9, H-15), 4.77 (1H, s, ᎐CH ), 4.73 (1H, s, ᎐CH ),
᎐
᎐
2
2
4.56 (1H, d, J 11.0, OCH2Ar), 4.40 (1H, b app s, H-13),
4.30–4.28 (1H, m, H-5), 4.25 (1H, d, J 11.0, OCH2Ar), 4.18–
4.05 (5H, m, CH2OPiv, H-11, H-22), 3.96 (1H, dq, J 6.4, 2.0,
CHOTBS), 3.92–3.85 (1H, m, H-9), 3.81 (3H, s, OMe), 3.39–
3.36 (1H, m, H-26), 3.11 (1H, dd, J 10.4, 5.7, H-24), 2.94–3.0
(1H, m), 2.61–2.58 (1H, m), 2.28–2.45 (2H, m), 1.5–2.1 (6H, m),
1.05–1.15 (21H, m, OTIPS), 0.85 (9H, s, SiCMe3).
Lithium hydroxide (13 mg, 540 µmol) was added to a stirred
solution of the ester (86a) (18 mg, 18 µmol) in methanol
(0.5 ml), tetrahydrofuran (0.5 ml) and water (0.05 ml) and the
mixture was stirred at room temperature for 16 h. Water (5 ml)
and ethyl acetate (5 ml) were added and the separated aqueous
layer was then extracted with ethyl acetate (5 × 5 ml). The
combined organic extracts were dried and evaporated to leave
the alcohol (86b) (16 mg, 96%) as a colourless oil; 1HNMR (500
MHz) δ 7.46 (1H, s, oxCH ), 7.29 (2H, d, J 8.0, ArH ), 6.89 (2H,
d, J 8.0, ArH ), 6.71 (1H, ddd, J 16.0, 8.6, 5.9, H-20), 6.35 (1H,
d, J 16.0, H-19), 4.89 (1H, dd, J 7.8, 6.1, H-15), 4.76 (1H, s,
1
oil; HNMR (500 MHz) δ 7.43 (1H, s, oxCH ), 6.64 (1H, ddd,
J 16.1, 8.4, 6.3, H-20), 6.33 (1H, d, J 16.1, H-19), 4.88 (1H, d,
J 9.0, H-15), 4.75 (1H, s, ᎐CH ), 4.72 (1H, s, ᎐CH ), 4.52–4.44
᎐
᎐
2
2
(4H, m, 2 × CF3, CH2O), 4.39 (1H, b app s, H-13), 4.08–3.97
(2H, m, H-11 and H-5), 3.91–3.88 (1H, m, H-9), 3.66 (2H, dd,
J 6.6, 6.4, CH2OTBS), 3.49 (1H, dd, J 6.1, 6.0, H-22), 3.23 (1H,
s, CH2P), 3.17 (1H, s, CH2P), 3.03 (1H, dd, J 10.3, 1.9, H-26),
2.59–2.51 (1H, m), 2.41–2.18 (3H, m), 2.06–1.74 (10H, m),
1.18 (3H, d, J 6.5, CH3), 1.09–0.97 (24H, m, OTIPS and CH3),
t
0.92–0.87 (21H, m, 2 × Bu(Me)2 Si and CH3), 0.06 (12H,
2 × tBu(Me)2Si); m/z (ESI) Found 1206.616 (M ϩ H)ϩ;
C56H99NO12Si3F6P requires 1206.612.
Macrolide 89. 10-Camphorsulfonic acid (5 mg, 22 µmol) was
added to a solution of the phosphonate (87b) (8 mg, 6.6. µmol)
in methanol (0.1 ml) and dichloromethane (0.5 ml). The
solution was stirred at room temperature for 1 h and then added
to a short column of silica, which was eluted with ethyl acetate
in petrol (3 : 7) to give the corresponding C-3, C-27 diol (6 mg,
᎐CH ), 4.72 (1H, s, ᎐CH ), 4.56 (1H, d, J 10.9, OCH Ar), 4.40
᎐
᎐
2
2
2
(1H, b app s, H-13), 4.25 (1H, d, J 10.9, OCH2Ar), 4.18–3.92
(5H, m), 3.82 (3H, s, OMe), 3.75 (2H, t, J 5.6, CH2OH), 3.38
(1H, dd, J 7.6, 5.9, H-24), 3.13 (1H, dd, J 9.5, 4.8, H-26), 2.98
(1H, dd, J 10.4, 2.2, H-21), 2.34–2.56 (1H, m, H-21), 2.41–2.27
(2H, m), 2.07–1.54 (12H, m), 1.15 (3H, d, J 6.5, CH3), 1.10
(21H, s, OTIPS), 0.93 (3H, d, J 6.5, CH3), 0.91 (3H, d, J 5.4,
CH3), 0.87 (9H, s, tBu(Me)2Si), 0.04 (6H, s, tBu(Me)2Si).
1
93%) as a colourless oil; HNMR (500 MHz) δ 7.45 (1H, s,
oxCH ), 6.67 (1H, ddd, J 16.0, 6.8, 5.5, H-20), 6.33 (1H, d,
J 16.0, H-19), 4.87 (1H, dd, J 9.3, 7.5, H-15), 4.75 (1H, s,
᎐CH ), 4.72 (1H, s, ᎐CH ), 4.51–4.42 (4H, m, 2 × CF CH O),
᎐
᎐
2
2
3
2
Dichlorodicyanoquinone (10 mg, 43 µmol) was added to a
solution of the alcohol (86b) (16 mg, 17.2 µmol) in dichloro-
methane (0.5 ml) and water (0.05 ml) and the solution was
stirred at room temperature for 15 h, and then saturated
aqueous sodium bicarbonate (0.1 ml) was added. The mixture
was added to a short pad of celite and eluted with dichloro-
methane (50 ml). The filtrate was evaporated to dryness in vacuo
[0.2 mmHg, 48 h], to leave the corresponding C3, C24 diol
(12 mg, 86%) as a orange oil; 1HNMR (500 MHz) δ 7.44 (1H, s,
oxCH ), 6.67 (1H, ddd, J 16.0, 7.5, 6.1, H-20), 6.34 (1H, d,
J 16.0, H-19), 4.88 (1H, dd, J 8.5, 5.1, H-15), 4.77 (1H, s,
4.40 (1H, b app s, H-13), 4.16–3.97 (3H, m, H-11, H-5 and
H-24), 3.89–3.86 (1H, m, H-9), 3.76 (1H, dd, J 5.9, 5.6,
CH2OH), 3.61–3.52 (1H, m, H-22), 3.26 (1H, dd, J 10.3, 2.4,
H-26), 3.23 (1H, s, CH2P), 3.17 (1H, s, CH2P), 2.62–2.52 (1H,
m), 2.38–2.33 (3H, m), 2.18–1.51 (10H, m), 1.19 (3H, d, J 6.4,
CH3), 1.08 (21H, s, OTIPS), 0.92 (3H, d, J 6.9, CH3), 0.83 (3H,
d, J 6.5, H50); m/z (ESI) Found 978.4387. (M ϩ H)ϩ;
C44H71NO12SiPF6 requires 978.4390.
A solution of Dess–Martin periodinane (15% wt/vol) in
dichloromethane (1 ml) was added to a solution of the C-3,
C-27 diol (6 mg, 6 µmol) in dichloromethane (0.1 ml) contain-
ing tert-butanol (15 ml) and sodium bicarbonate (20 mg). The
mixture was stirred at room temperature for 1 h and then added
to a short column of silica, which was eluted with ethyl acetate
in petrol (3:7) to give the aldehyde (88) (5.5 mg, 92%) as a oil;
1HNMR (500 MHz) δ 9.75 (1H, t, J 1.2, CHO), 7.47 (1H, s,
oxCH ), 6.59 (1H, ddd, J 16.0, 8.1, 7.8, H-20), 6.35 (1H, d,
J 16.0, H-19), 4.88 (1H, dd, 10.5, 3.6, H-15), 4.80 (1H, s, ᎐CH ),
᎐CH ), 4.72 (1H, s, ᎐CH ), 4.40 (1H, b app s, H-13), 4.37–4.23
᎐
᎐
2
2
(2H, m, H-11 and H-5), 4.16–4.10 (1H, m, H-9), 4.10–3.93 (1H,
m, H-26), 3.75 (2H, dd, J 5.9, 5.7, CH2OH), 3.46–3.38 (1H, m,
H-24), 2.98 (1H, dd, J 10.2, 2.1, H-21), 2.62–2.52 (1H, m,
H-21), 2.46–2.18 (2H, m), 2.15–1.48 (10H, m), 1.17 (3H, d,
J 6.5, CH3), 1.08 (21H, s, OTIPS), 0.98 (3H, d, J 6.1, CH3),
0.88 (9H, s, tBu(Me)2Si), 0.06 (6H, s, tBu(Me)2Si).
᎐
2
Chloro-tert-butyldimethylsilane (30 mg, 20 µmol) and imid-
azole (2.7 mg, 40 µmol) were added to a solution of the afore-
mentioned diol (12 mg, 14.9 µmol) in dimethylformamide
(0.1 ml), and the mixture was then stirred at room temperature
for 30 min. Water (1 ml), followed by ethyl acetate (5 ml), were
added and the separated aqueous phase was then extracted with
ethyl acetate (5 × 5 ml). The combined organic extracts were
dried and evaporated, and the residue was then purified by
chromatography using ethyl acetate in petrol (3 : 7) as eluent
4.77 (1H, s, ᎐CH ), 4.76 (1H, m), 4.51–4.42 (4H, m, 2 ×
᎐
2
CF3CH2O), 4.40 (1H, b app s, H-13), 4.37–4.28 (1H, m, H-24),
4.08–4.05 (2H, m, H-11 and H-5), 3.64–3.59 (1H, m, H-22),
3.48 (1H, d, J 10.7, H-26), 3.23 (1H, s, CH2P), 3.17 (1H,
s, CH2P), 2.67–2.46 (3H, m), 2.44–2.28 (3H, m), 2.23 (3H, s,
CH3), 2.18–2.13 (1H, m), 2.08–1.84 (7H, m), 1.08 (21H, s,
OTIPS), 1.01 (3H, d, J 6.8, CH3), 0.86 (3H, d, J 6.4, CH3).
Anhydrous potassium carbonate (3.25 mg, 23 µmol) was
added to a stirred solution of 18-crown-6 (12.5 mg, 47 µmol) in
toluene (2 ml) at room temperature. The mixture was stirred for
3 h, then cooled to Ϫ40 ЊC and a solution of the aldehyde (88)
(5.5 mg, 5.6 µmol) in toluene (1 ml) was then added via cannula.
The mixture was allowed to warm to room temperature
overnight and was then purified by chromatography on a short
column of silica, eluting with ethyl acetate in petrol (3 : 7) to
1
to give the alcohol (10 mg, 73%) as a colourless oil; HNMR
(500 MHz) δ 7.43 (1H, s, oxCH ), 6.68 (1H, ddd, J 16.2, 8.4, 6.1,
H-20), 6.34 (1H, d, J 16.2, H-19), 4.88 (1H, d, J 9.4, H-15), 4.75
(1H, s, ᎐CH ), 4.72 (1H, s, ᎐CH ), 4.42–4.39 (1H, b app s,
᎐
᎐
2
2
H-13), 4.08–3.98 (2H, m, H-11and H-5), 3.96–3.85 (1H, m,
H-5), 3.66 (2H, dd, J 6.5, 6.4, CH2OTBS), 3.45–3.41 (2H,m),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 7 3 – 4 2 0 8
4202