A total synthesis of the antitumour macrolide rhizoxin D

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A R T I C L E

Ian S. Mitchell, Gerald Pattenden* and Jeffrey Stonehouse

School of Chemistry, The University of Nottingham, Nottingham, UK NG7 2RD

Received 27th May 2005, Accepted 7th October 2005

First published as an Advance Article on the web 15th November 2005

An enantioselective synthesis of rhizoxin D (2), isolated from the plant pathogenic fungus Rhizopus chinensis, is

described. The overall strategy is based on elaboration of the d-lactone-substituted vinyl stannane 7 and the

phosphonate-substituted vinyl iodide 9, followed by their coupling to the core 16-membered macrolide 6 via a

sequential intermolecular Horner–Wadsworth–Emmons oleﬁnation, leading to 50, and by an intramolecular Stille

reaction. The triene oxazole-containing side chain in rhizoxin D is then introduced using the phosphine oxide 8 in an

E-selective Horner–Wittig reaction with the macrolide aldehyde 51b.

the context of contemporaneous studies with rhizoxins by other

researchers.

Introduction

Rhizoxin 1 and rhizoxin D (2), together with a number of con-

geners, e.g. 3, 4 and 5, comprise a family of novel 16-membered

Discussion

macrolides which were ﬁrst isolated in 1984 from the plant

pathogenic fungus Rhizopus chinensis.^1,2Rhizoxin 1 exhibits pro-

Although a variety of tactics are available, any synthesis of

nounced antifungal activity and potent in vitro cytotoxicity and

in vivo antitumour activity.³Indeed, rhizoxin has now undergone

extensive clinical trials as a potential drug candidate for treat-

ment of a number of cancers.⁴Its mechanism of action is similar

to other tubulin polymerisation inhibitors such as maytansine,

vinblastine, vincristine, podophyllotoxin and colchicine.⁵

The structure of rhizoxin 1 is unprecedented, and is based on

a 16-membered macrolide core which accommodates nine stere-

ogenic centres and two epoxides. Two of these stereogenic centres

form part of a ring-fused d-lactone and the structure includes

a triene oxazole-containing side chain having two additional

stereogenic centres. Rhizoxin D (2), i.e. didesepoxyrhizoxin,

is the putative biogenetic precursor of 1.⁶The rhizoxins have

attracted considerable interest within the synthetic chemistry

community and a total synthesis of rhizoxin 1,⁷together

with eight total syntheses of rhizoxin D (2)^8,9have now been

published.¹⁰Our own enantioselestive total synthesis of rhizoxin

D was published in a preliminary communication in 2002.⁹In

this paper we provide full details of our novel synthesis, and in

rhizoxin D (2) has needed to address procedures for, and the

timing of, elaboration of the macrolide core, and the introduc-

tion of the triene oxazole-containing side chain in the structure.

These issues are apart from the general problem of incorporating

the eleven stereogenic centres in the various sub-units used in

any assemblage of the natural product. In seven of the eight

total syntheses of rhizoxin D, the macrolide core has been

elaborated, often at a late stage, using an intramolecular Horner–

Wadsworth–Emmons (HWE) oleﬁnation reaction at C2–C3.

Our own synthesis is distinguished by using an intramolecular

Stille reaction at C10–C11 to close the macrolide, also as a

late step in the overall synthesis (Scheme 1). In the syntheses

described by Leahy^8cand Keck,^8dand their respective co-

workers, the intramolecular HWE oleﬁnation at C2–C3 was

carried out with the triene oxazole-containing side chain intact.

In all other syntheses of rhizoxin D ⁸the side chain was

incorporated following macrocyclisation using combinations

of intermolecular Stille, Horner–Wittig and HWE coupling

reactions. Most of these strategies towards the total synthesis

4 4 1 2

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

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 5

©

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Scheme 1 Overall strategy for the synthesis of rhizoxin D.

of rhizoxin D, including routes to key chiral sub-units, have

been collected together in a useful review published recently by

Hong and White.¹¹

13 in three straightforward steps via the methyl ether 11b and

the primary alcohol 12. Correspondingly, the silyl enol ether

17 was smoothly synthesised in three steps from (E)-3-iodo-2-

methylpropenoic acid 14 ¹⁷following conversion to the Weinreb

amide 15, which was next treated with MeMgBr to provide

the methyl ketone 16. Deprotonation of 16 using LiHMDS

at −78 ^◦C, followed by quenching the resulting enolate with

TMSCl then gave the silyl enol ether 17 as an unstable oil.

Based on some precedent from the work of Evans et al.¹⁸we

ﬁrst carried out the Mukaiyama aldol reaction between 13 and

17 in the presence of BF₃OEt₂at −78 ^◦C. These conditions

gave predominantly one diastereoisomer (76% de) in 82% yield.

Unfortunately, subsequent assignment of the stereochemistry

of the secondary alcohol centre (at C-15) in the product (vide

infra) showed that the BF₃OEt₂-catalysed reaction had given the

diastereoisomer 18a predominantly, with the undesired (Felkin)

selectively. After further experimentation we prepared the p-

methoxybenzyl (PMB) ether 18b corresponding to the methyl

ether 18a. When this ether was treated with DDQ in DCM

at room temperature it was converted into the p-methoxyphenyl

(PMP) acetal 20 in quantitative yield. NOe experiments with the

PMP acetal 20 showed enhancements between all the protons

Our own overall synthetic strategy to rhizoxin D (2) was based

on elaboration of the d-lactone-substituted vinyl stannane 7 and

the phosphonate-substituted vinyl iodide 9 sub-units, and their

coupling to the core 16-membered macrolide via a sequential

intermolecular HWE oleﬁnation followed by an intramolecular

Stille reaction^12,13as key steps, leading to 6. The triene oxazole-

containing side chain in the target would then be introduced,

as a late step, using the phosphine oxide 8 ¹⁴in an E-selective

Horner–Wittig reaction (Scheme 1).

Synthesis of the phosphonate-substituted vinyl iodide 9

The key strategy we used in the synthesis of the sub-unit 9

was a diastereoselective Mukaiyama aldol reaction between

the aldehyde 13 and the silyl enol ether 17. Thus, an Evans

aldol reaction¹⁵between (R)-4-benzyl-3-propionyloxazolidin-2-

one and the known a,b-unsaturated aldehyde 10 ¹⁶ﬁrst gave the

corresponding imide 11a as a single diastereoisomer in 87% yield

(Scheme 2). The imide 11a was then converted into the aldehyde

Scheme 2 Reagents and conditions: (i) (R)-4-benzyl-3-propionyloxazolidin-2-one, Bu₂BOTf, Et₃N, DCM, −78 ^◦C → rt, 3 h, 87%; (ii) MeOTf,

2,6-di-tert-butyl-4-methylpyridine (DTBMP), CHCl₃, reﬂux, 6 h, 89%; (iii) LiBH₄, MeOH, Et₂O, 0 ^◦C, 2 h, 79%; (iv) Dess–Martin, DCM, rt, 30 min,

99%; (v) NHMeOMe·HCl, ⁱPr₂EtN, pentaﬂuorophenyl diphenylphosphinate (FDPP), DCM, 0 ^◦C → rt, 18 h, 74%; (vi) MeMgBr, THF, 0 ^◦C, 2 h,

77%; (vii) LiHMDS, THF, −78 ^◦C, 1 h, then Et₃N, TMSCl, −78 ^◦C → rt, 2 h, 100%.

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 1 3

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(H₁–H₄) on the lower face of the acetal ring, thereby establishing

the ‘undesired’ (b-OH) stereochemistry at C-15 in the BF₃OEt₂-

catalysed Mukaiyama aldol reaction between 13 and 17.

Scheme

3

Reagents and conditions: (i) (Me₄N)BH(OAc)₃,

MeCN–AcOH (2 : 1), −30 ^◦C, 18 h, 83%; (ii) TBSOTf, 2,4,6-collidine,

THF, −78 ^◦C, 15 min, 68%; (iii) diethylphosphonoacetic acid, DCC,

DMAP, DCM, rt, 2 h, 89%; (iv) p-TSA·H₂O, 2,2-dimethoxypropane,

rt, 5 h, 89%.

More recent studies by Evans et al.¹⁹demonstrated the rather

exceptional chelating ability of the Lewis acid dimethylalu-

minium chloride in Mukaiyama aldol reactions. We were pleased

to ﬁnd therefore that when these Evans conditions were applied

to the aldehyde 13 and the silyl enol ether 17, the diastereoiso-

meric aldol 19 with the ‘correct’ stereochemistry for rhizoxin

was secured in 43% yield (85% based on recovered aldehyde

13) and with ꢀ92% de. The stereochemical assignment of 19

followed from comparison of its NMR spectroscopic data with

those of the minor diastereoisomer formed in the corresponding

Mukaiyama aldol reaction between 13 and 17 in the presence of

BF₃OEt₂. Furthermore, reduction of the aldol product 19, using

tetramethylammonium triacetoxyborohydride gave the anti-1,3-

diol (21a, 83%) as a single diastereoisomer (Scheme 3), whose

acetonide 22 had appropriate signals in its ¹³C NMR spectrum

(d_C100.8, 24.8 and 24.2 ppm) consistent with the assigned (anti-)

stereochemistry.²⁰Protection of the C13–OH group in 21a as its

tert-butyldimethylsiloxy (TBS) ether 21b, followed by acylation

of the C15–OH group using diethylphosphonoacetic acid ﬁnally

gave the phosphonate-substituted vinyl iodide sub-unit 9.

Scheme 4 Reagents and conditions: (i) DIBAL-H, THF, −78 ^◦C,

1 h, 93%; (ii) EtOCH CH₂, Hg(O₂CCF₃)₂, rt, 8 h, 78%; (iii) 170 ^◦C,

=

sealed tube, 36 h, 97%; (iv) Bu₂BOTf, Et₃N, (4S,5R)-4-methyl-5-

phenyl-3-propionyloxazolidin-2-one, CH₂Cl₂, −78 → 0 ^◦C, 2 h, 79%.

79%. The diastereoisomers were separated by chromatography

and their stereochemistries were established from analysis of

NMR data recorded for the corresponding d-lactones 30 and

33 produced from them (Scheme 5). Thus, removal of the chiral

auxiliaries in the separated imides 26 and 27, using lithium boro-

hydride, ﬁrst gave the corresponding alcohols 28/31 which were

next converted into their respective PMB ethers 29a and 32a in a

selective manner using p-methoxybenzyl trichloroacetimidate in

the presence of camphorsulfonic acid (CSA) at 0 ^◦C.²²Removal

of the triphenylsilyl (TPS) protection groups, followed by

oxidation of the resulting 1,5-diols 29b/32b using tetrapropy-

lammonium perruthenate (TPAP), then gave the corresponding

diatereoisomeric d-lactones 30 and 33 respectively.

Synthesis of the vinyl stannane sub-unit 7

A number of complementary synthetic approaches were

investigated to synthesise the chiral d-lactone-substituted

vinyl stannane 7. In a simple, yet interesting, approach we

ﬁrst prepared the allyl vinyl ether 24 from the known a,b-

unsaturated ester 23a ²¹via the corresponding primary alcohol

23b. A Claisen rearrangement with 24 then delivered the

racemic c,d-unsaturated aldehyde 25 in 97% yield (Scheme 4).

The introduction of the 1,3-syn arrangement of chiral centres

across the d-lactone unit in 7 was achieved by an Evans

aldol reaction between 25 and (4S,5R)-4-methyl-5-phenyl-3-

propionyloxazolidin-2-one which gave a 1 : 1 mixture of the

diastereoisomeric imides, 26 and 27, in a combined yield of

Examination of coupling constant data between H₂and H₃

in the ¹H NMR spectrum of the d-lactone 30 produced from the

diastereoisomer 26, i.e. J = 11 and 6 Hz, were consistent with

4 4 1 4

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

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◦

=

Scheme 5 Reagents and conditions: (i) LiBH₄, MeOH, Et₂O, 0 C, ca. 70%; (ii) PMBO(N H)CCl₃, CSA, CH₂Cl₂, −20 → 0 C, ca. 60%; (iii) TBAF,

THF, ca. 83%; (iv) TPAP, NMO, CH₂Cl₂, 0 ^◦C, ca. 65%.

an axial–axial interaction and an axial–equatorial interaction

respectively. Likewise, corresponding coupling constant data,

i.e. J = 6 and 7 Hz, recorded for the d-lactone 33 produced

from the diastereoisomer 27 were consistent with an equatorial–

equatorial and axial–equatorial interaction respectively. These

data are captured on Fig. 1 for the two d-lactones 30 and 33, and

demonstrated that the diastereoisomeric 1,3-diol 29b derived

from the imide 26 had the ‘correct’ stereochemistry for rhizoxin.

cleavage met with failure. Instead, therefore, we carried out a

hydroboration–oxidation sequence on the alkene 32a derived

from the imide 27 which proved trouble-free and led to the 1,5-

diol 34 in 91% yield. Oxidation of 34, using silver carbonate

on Celite next gave the d-lactone 35 which, in two high yielding

steps was then converted into the corresponding aldehyde 36

(Scheme 6). The aldehyde 36 was now treated with dimethyl

diazomethylphosphonate, i.e. Seyferth’s reagent,²³which led

to the terminal acetylene 37 in quantitative yield. Treatment

of the acetylene 37 with NBS and AgNO₃then gave the

corresponding bromoacetylene which, on further treatment with

catalytic Pd₂dba₃/PPh₃followed by Bu₃SnH, produced the (E)-

vinyl stannane 38. The E-conﬁguration assigned to the vinyl

stannane 38 ²⁴followed from the magnitude of the vicinal

coupling, i.e. J = 19 Hz, between the oleﬁnic protons in its

¹H NMR spectrum. A small amount of the corresponding Z-

isomer of 38 (<5%) was produced concurrently and was removed

by chromatography. Finally, deprotection of the TPS group in

38 led to the corresponding alcohol which underwent smooth

oxidation in the presence of Dess–Martin periodinane to give the

aldehyde-substituted vinyl stannane 7 in readiness for coupling

to the phosphonate-substituted vinyl iodide 9.

Fig. 1 ¹H NMR coupling data between H₂and H₃in the d-lactones 30

and 33.

We were now in a position to study the conversions of the

diastereoisomeric compounds 29/32 and 30/33 into the key

vinyl stannane intermediate 7 en route to rhizoxin D. Much to

our initial frustration, our attempts to functionalise the alkene

bond in the 1,3-diequatorial lactone 30 by either hydroboration–

oxidation, by radical addition of sulﬁde, or by direct oxidative

Interestingly, the diastereoisomeric imide 26 derived from the

Evans aldol reaction with 25, could also be used to synthesise

the same 1,5-diol intermediate 34, thereby allowing recycling of

this easily available precursor. Thus, following the conversion

of 26 into the PMB ether 29a, interchange of the TPS silyl

Scheme 6 Reagents and conditions: (i) 9-BBN-H, 0 ^◦C → rt, 12 h; (ii) Ag₂CO₃/Celite, PhH, reﬂux, 3 h, 91%; (iii) DDQ, CH₂Cl₂, rt, 2 h, 100%;

(iv) Dess–Martin, CH₂Cl₂, rt, 1 h, 84%; (v) (MeO)₂(O)PCHN₂, KO^tBu, THF, −78 ^◦C, 2 h, 100%; (vi) NBS, AgNO₃, acetone, 1 h, then Pd₂dba₃/PPh₃,

Bu₃SnH, THF, rt, 3 h, 70%; (vii) TBAF, TsOH, THF, rt, 3 h, 70%; (viii) Dess–Martin, Py, CH₂Cl₂, rt, 1 h, 70%.

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 1 5

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ether protecting group for the corresponding TBS ether gave the

alkene 39 (Scheme 7). Hydroboration of 39 next gave the 1,5-

diol 40 which was then protected as the TPS ether 41. Finally,

selective deprotection of the TBS ether in 41, using pyridinium

p-toluenesulfonate (PPTS) in EtOH at 60 ^◦C gave the 1,5-diol 34

whose spectroscopic data were identical with those obtained for

the same compound prepared from the opposite diastereoisomer

27.

the Weinreb amide 44a which was then protected as its TBS ether

44b (Scheme 8). Reduction of the amide 44b, using DIBAL-H at

−78 ^◦C, followed by homologation of the resulting aldehyde 45

using the Seyferth reagent gave the alkyne 46 in excellent overall

yield. The alkyne 46a was next deprotected to 46b, which was

then converted into the bromoalkyne 47, following sequential

bromination, using NBS and silver nitrate, and vicinal

dihydroxylation using catalytic OsO₄–NMO. In this manner the

triol 47 was obtained as a 7 : 1 mixture of syn-diols in 76% overall

yield. Hydrostannylation of 47 next led to the E-vinyl stannane

48 exclusively. Treatment of 48 with NaIO₄on silica followed

by oxidation of the resulting lactol 49 using silver carbonate on

Celite, ﬁnally gave the aldehyde-substituted vinyl stannane 7,

which was identical with the previously synthesised material.

Macrolide formation and end game

With the two sub-units 7 and 9 in hand we were now in a position

to synthesise the macrolide 6 and then complete a total synthesis

of rhizoxin D, according to Scheme 1.

A Horner–Wadsworth–Emmons oleﬁnation reaction between

the phosphonate 9 and the aldeyhyde 7, under Masamune–

Roush conditions (LiCl, DBU, MeCN, 0–25 ^◦C)²⁵led exclusively

to the (E)-a,b-unsaturated ester 50, in 78% yield (see Scheme 9).

When this stannane-iodide 50 was treated with _◦Ph₃As–Pd(0)

dibenzylideneacetone²⁶in degrassed DMF at 70 C for 5 h, it

underwent smooth intramolecular sp²–sp²cross-coupling with

preservation of the E-geometries of the two alkene bonds leading

to the 16-membered macrolide 6 in an acceptable 48% yield.²⁷

The trimethylsilylethoxymethyl (SEM)–PMB ether correspond-

ing to the TBS–TPS ether 6 was synthesised earlier by Williams

et al.^8band the ¹H NMR spectroscopic data for the two

compounds were shown to be remarkably similar. Selective

removal of the primary TPS protecting group in 6, followed

by oxidation of the resulting allylic alcohol 51a with MnO₂next

gave the unsaturated aldehyde 51b. A Horner–Wittig oleﬁnation

reaction between the aldehyde 51b and the oxazole-substituted

Scheme 7 Reagents and conditions: (i) TBAF, THF, rt, 2 h, 99%;

(ii) TBSCl, Imidazole, CH₂Cl₂, rt, 2 h, 82%; (iii) 9-BBN-H, 0 ^◦C →

rt, 12 h, then NaOH, H₂O₂, 0 ^◦C, 4 h, 95%; (iv) TDPSCl, Imidazole,

CH₂Cl₂, rt, 2 h, 96%; (v) PPTS, EtOH, 60 ^◦C, 2 h, 72%.

In an alternative approach to the vinyl stannane sub-unit 7,

which we found more amenable to producing large quantities

of this key intermediate, the cyclopentene aldehyde 42 was ﬁrst

subjected to an Evans aldol reaction¹⁵with (S)-4-benzyl-3-

propionyloxazolidin-2-one which led to the imide 43 as a single

diastereoisomer in 77% yield. Transamidation of the imide using

N,O-dimethylhydroxylamine in the presence of Me₃Al next gave

Scheme 8 Reagents and conditions: (i) (S)-4-benzyl-3-propionyloxazolidin-2-one, Bu₂BOTf, ⁱPr₂EtN, DCM, −5 ^◦C then 42, DCM, −78 ^◦C → rt,

4 h, 77%; (ii) AlMe₃, MeONHMe·HCl, DCM, −10 ^◦C → rt, 2 h, 84%; (iii) TBSOTf, 2,6-lutidine, 0 ^◦C, 45 min, 100%; (iv) DIBAL-H, THF, −78 ^◦C,

2 h, 96%; (v) (MeO)₂(O)PCHN₂, KO^tBu, THF, −78 ^◦C, 2 h, 94%; (vi) HF/Py, THF, rt, 2 d, 100%; (vii) NBS, AgNO₃(cat.), acetone, rt, 1 h, then

OsO₄(cat.), NMO, acetone–H₂O (2 : 1), rt, 90 min, 76% over two steps; (viii) Pd(Ph₃P)₄, Bu₃SnH, THF, rt, 2 h, 100%; (ix) NaIO₄on SiO₂, DCM, rt,

15 min; (x) Ag₂CO₃on Celite, PhMe, reﬂux, 3 h, 61% over two steps.

4 4 1 6

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

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Scheme 9 Reagents and conditions: (i) LiCl, DBU, MeCN, 0 ^◦C → rt, 1 h, 78%; (ii) Pd₂dba₃, AsPh₃, DMF, 70 ^◦C, 5 h, 48%; (iii) TBAF–AcOH

(1 : 1), THF, rt, 8 h, 74%; (iv) MnO₂, CH₂Cl₂, rt, 3 h, 100%; (v) 8, KHMDS, THF; then add 51b, −78 → 0 ^◦C, then Yamaguchi esteriﬁcation, 38%;

(vi) HF/Py, Py, THF, rt, 48 h, 78%.

a,b-unsaturated phosphine oxide 8,¹⁴at −78 ^◦C in the presence

of KHMDS led to the corresponding all-E polyene 52, but

with some concomitant ring-opening of the d-lactone ring in the

product. A similar observation was observed by Williams et al.^8b

in their synthesis of rhizoxin D. Accordingly, the crude Horner–

Wittig oleﬁnation product was treated with 2,4,6-trichloro-

benzoyl chloride–Et₃N–Me₃N–C₅H₄N, under Yamaguchi con-

ditions, which re-instated the d-lactone functionality and gave

the protected rhizoxin 52 in 38% yield over the two-step

sequence. Finally, deprotection of the silyl ether 52 with

HF/pyridine gave (+)-rhizoxin D (2) which showed chiroptical

and spectroscopic data which were indistinguishable from those

recorded for the natural product.

In conclusion, we have achieved a concise enantioselective

total synthesis of rhizoxin D (2), which featured an intramolec-

ular Stille reaction, as the key stratagem, to elaborate the 16-

membered macrolide core in the natural product. The synthesis

was accomplished in a 21-step longest linear sequence, in an

overall yield of 0.45%.

broad band decoupled mode. The multiplicities were obtained

using a DEPT sequence, where the following symbols are used

for the multiplicities in ¹³C NMR spectra: q, primary methyl; t,

secondary methylene; d, tertiary methine; s, quaternary carbon.

Mass spectra were recorded on an AEI MS-902, a VG

Micromass 7070 E, or a VG Autospec instrument using electron-

impact ionisation (EI), fast atom bombardment (FAB), chemical

ionisation (CI), or electrospray (ES) techniques.

Flash column chromatography was performed using Merck

silica gel 60 (230–400 mesh ASTM) as the stationary phase. All

reactions were monitored by thin layer chromotography (TLC)

using Merck silica gel 60 F₂₅₄precoated aluminium plates which

were visualised under ultraviolet light and then developed with

basic potassium permanganate solution, acidic ceric ammonium

molybdate solution, or acidic alcoholic vanillin solution.

All solvents and chemicals were used as provided by the sup-

plier, or were dried and/or puriﬁed following accepted literature

procedures. Syringe needles were dried in an oven at 150 ^◦C and

cooled under a stream of nitrogen before use. All reactions were

conducted at room temperature in oven-dried glassware under

an atmosphere of nitrogen unless otherwise stated. All organic

extracts were dried over anhydrous magnesium sulfate and

ﬁltered under gravity. Solvents were removed from the extracts

on a Bu¨chi rotary evaporator under water pump or oil pressure.

Experimental

General details

All melting points were determined on a Kopﬂer hot-stage

apparatus and are uncorrected. Infrared spectra were recorded

using a Perkin-Elmer FT 1600 spectrometer, as either liquid

ﬁlms or as dilute solutions in spectroscopic grade chloroform or

dichloromethane.

(E)-4-(tert-Butyldiphenylsiloxy)-2-methyl-but-2-enal 10

The aldehyde was prepared as described in the literature¹⁶and

was obtained as a colourless oil; (Found: C, 74.6; H, 7.6. Calc.

for C₂₁H₂₆O₂Si: C, 74.5; H, 7.7%); m_max(CHCl₃, sol.)/cm⁻¹2719,

1731, 1650, 1589; d_H(360 MHz, CDCl₃), 9.40 (1H, s, CHO),

7.68 (4H, m, ArH), 7.44–7.37 (6H, m, ArH), 6.59 (1H, dq, J 1.3

¹H NMR spectra were recorded on a Bru¨ker DPX 360

(360 MHz), a Bru¨ker AV 400 (400 MHz) or a Bru¨ker DRX

500 (500 MHz) instrument as dilute solutions in deuterated

chloroform unless otherwise stated. The chemical shifts are

reported relative to tetramethylsilane or residual chloroform as

an internal standard. The multiplicity of the signals is designated

by the following abbreviations: s, singlet; d, doublet; t, triplet;

q, quartet; quin., quintet; br., broad; m, multiplet. All coupling

constants, J, are reported in Hertz (Hz). ¹³C NMR spectra were

recorded on a Jeol JNM-EX 270 (67.8 MHz), a Bru¨ker DPX

360 (90 MHz) or a Bru¨ker DRX 500 (125 MHz) instrument.

The spectra were recorded as dilute solutions in deuterated

chloroform unless otherwise stated with chemical shifts reported

relative to the residual chloroform as an internal standard on a

=

and 5.4, CH CCH₃), 4.51 (2H, d, J 5.4, CH₂OTPS), 1.56 (3H,

=

d, J 1.3, CH CCH₃), 1.07 [9H, s, OSiC(CH₃)₃]; d_C(67.8 MHz,

CDCl₃), 194.6 (d), 152.5 (d), 137.8 (s), 135.5 (d), 133.0 (s), 129.9

(d), 127.8 (d), 61.2 (t), 26.7 (q), 19.1 (s), 9.3 (q); m/z (FAB)

339.1779 (M + H: C₂₁H₂₇O₂Si requires 339.1780), 339 (100%),

281 (20).

(R)-4-Benzyl-3-[(2R,3R)-(E)-6-(tert-butyldiphenylsiloxy)-

3-hydroxy-2,4-dimethylhex-4-enoyl]-oxazolidin-2-one 11a

A

solution of dibutylboron triﬂate in dichloromethane

(1.00 M, 8.35 mL, 8.35 mmol), and N,N-di-isopropylethylamine

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 1 7

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(1.59 mL, 9.11 mmol) were added sequentially to a stirred

solution of (R)-4-benzyl-3-propionyloxazolidin-2-one (1.77 g,

7.60 mmol) in dichloromethane (80 mL) at −10 ^◦C. The

mixture was stirred at −10 ^◦C for 20 min and then cooled to

added sequentially to a stirred solution of the methyl ether 11b

(260 mg, 0.45 mmol) in diethyl ether (10 mL) at 0 ^◦C. The

mixture was stirred at 0 ^◦C for 2 h and then quenched with

aqueous sodium hydroxide solution (2.00 M, 2.00 mL). The

aqueous phase was separated and then extracted with diethyl

ether (3 × 5 mL). The combined organic extracts were dried

and concentrated in vacuo to leave a colourless oil. This oil

was puriﬁed by ﬂash column chromatography, eluting with

◦

−78 C. A solution of the aldehyde 10 (2.57 g, 7.60 mmol) in

dichloromethane (10 mL) was added over 10 min via cannula.

The mixture was stirred at −78 ^◦C for 2 h, then warmed to 0 ^◦C

over 30 min and stirred at 0 ^◦C for 30 min. The mixture was

quenched at 0 ^◦C by the sequential addition of pH 7 phosphate

buffer (20 mL), methanol (20 mL), and hydrogen peroxide

(20 mL), and then stirred at 0 ^◦C for 1 h. The aqueous layer was

separated and extracted with dichloromethane (3 × 50 mL). The

combined organic extracts were dried and then concentrated in

vacuo to leave an orange oil. The oil was puriﬁed by ﬂash column

chromatography, eluting with diethyl ether–light petroleum

(bp 40–60 ^◦C) (1 : 3) to give the aldol product (3.78 g, 87%)

as a colourless oil. [a]²_D¹−18 (c 1.02 in CHCl₃); (Found: C, 71.5;

H, 7.2; N, 2.5. C₃₄H₄₁NO₅Si requires: C, 71.4; H, 7.2; N, 2.45%);

m_max(sol.)/cm⁻¹2931, 2859, 1780, 1694; d_H(360 MHz, CDCl₃)

7.72–7.69 (4H, m, ArH), 7.44–7.30 (9H, ArH), 7.23–7.21 (2H,

◦

ethyl acetate–light petroleum (bp 40–60 C) (1 : 3) to give the

alcohol (145 mg, 79%) as a colourless oil. [a]²_D¹+21.9 (c 0.63

in CHCl₃); (Found: C, 72.75; H, 8.85. C₂₅H₃₄O₃Si requires: C,

73.1; H, 8.35%); m_max(sol.)/cm⁻¹3488 (br.), 2961, 2859, 1428;

d_H(360 MHz, CDCl₃), 7.69 (4H, m, ArH), 7.43–7.35 (6H, m,

=

ArH), 5.62 (1H, tq, J 0.9 and 6.1, CH CCH₃), 4.29 (2H, d, J

6.1, CH₂OTPS), 3.54–3.44 (2H, m, CH₂OH), 3.39 (1H, d, J 6.9,

CHOCH₃), 3.18 (3H, s, CHOCH₃), 1.98 (1H, br. s, CH₂OH),

=

1.86–1.79 (1H, m, CHCH₃), 1.41 (3H, d, J 0.9, CH CCH₃), 1.05

[9H, s, OSiC(CH₃)₃], 0.95 (3H, d, J 6.9, CHCH₃); d_C(67.8 MHz,

CDCl₃), 135.5 (d), 135.0 (s), 133.8 (s), 129.6 (d), 128.0 (d), 127.7

(d), 89.2 (d), 66.1 (t), 60.5 (t), 56.4 (q), 38.2 (d), 26.7 (q), 19.1

(s), 12.6 (q), 12.2(q); m/z (ES) 435 (100%), 324 (5), 310 (20), 280

(17).

=

ArH), 5.81 (1H, t, J 6.1, CH CCH₃), 4.72–4.65 (1H, m, CHBn),

4.35 (1H, d, J 3.7, CHOH), 4.31 (2H, d, J 6.1, CH₂OTPS), 4.18–

=

4.16 (2H, m, CH₂OC O), 3.97 (1H, dq, J 3.7 and 7.0, CHCH₃),

3.28 (1H, dd, J 3.2 and 13.3, CHHPh), 2.80 (1H, dd, J 9.5 and

(E)-(2R,3R)-6-(tert-Butyldiphenylsiloxy)-3-methoxy-

2,4-dimethylhex-4-enal 13

=

13.3, CHHPh), 1.47 (3H, s, CH CCH₃), 1.19 (3H, d, J 7.0,

CHCH₃), 1.06 [9H, s, OSiC(CH₃)₃]; d_C(90.6 MHz, CDCl₃),

176.7 (s), 153.0 (s), 135.5 (d), 135.1 (s), 135.0 (s), 133.8 (s), 129.6

(d), 129.4 (d), 128.9 (d), 127.6 (d), 127.4 (d), 125.9 (d), 74.9 (d),

66.1 (t), 60.8 (t), 55.3 (d), 40.3 (d), 37.7 (t), 26.8 (q), 19.1 (s),

13.5 (q), 10.4 (q); m/z (ES) 594.2622 (M + Na: C₃₄H₄₁NO₅SiNa

requires 594.2652), 594 (100%).

Dess–Martin periodinane (424 mg, 1.00 mmol) was added in a

single portion to a stirred solution of the alcohol 12 (206 mg,

0.50 mmol) in dichloromethane (5 mL) at room temperature.

The suspension was stirred at room temperature for 30 min

and then a saturated solution of sodium thiosulfate (5 mL)

was added. The biphasic mixture was stirred for 20 min and

then the upper aqueous phase was separated and extracted with

dichloromethane (2 × 5 mL). The combined organic extracts

were washed with a saturated solution of sodium bicarbonate

(2 × 10 mL), dried and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography, eluting with ethyl

acetate–light petroleum (bp 40–60 ^◦C) (1 : 4) to give the aldehyde

(204 mg, 99%) as a colourless oil. [a]²_D¹+4.2 (c 1.05 in CHCl₃);

m_max(sol.)/cm⁻¹2742, 1732, 1111; d_H(360 MHz, CDCl₃), 9.60

(1H, d, J 1.9, CHO), 7.69–7.66 (4H, m, ArH), 7.43–7.36 (6H,

(R)-4-Benzyl-3-[(2R,3R)-(E)-6-(tert-butyldiphenylsiloxy)-

3-methoxy-2,4-dimethylhex-4-enoyl]-oxazolidin-2-one 11b

2,6-Di-tert-butyl-4-methylpyridine (1.08 g, 5.25 mmol) and

methyl triﬂuoromethanesulfonate (300 lL, 2.62 mmol) were

added sequentially to a stirred solution of 11a (100 mg, 0.18

mmol) in chloroform (2 mL) at room temperature. The mixture

was heated at reﬂux for 6 h, then allowed to cool to room

temperature, and quenched by the careful addition of methanol

(1 mL). The mixture was diluted with dichloromethane (30 mL)

and then washed with saturated sodium bicarbonate solution

(2 × 30 mL). The combined aqueous phases were re-extracted

with dichloromethane (2 × 20 mL) and the combined organic

phases were then dried and concentrated in vacuo. The residue

was puriﬁed by ﬂash column chromatography, eluting with

diethyl ether–light petroleum (bp 40–60 ^◦C) (2 : 3) to give

the methyl ether (91 mg, 89%) as a colourless oil. [a]²_D¹−25.4

(c 0.89 in CHCl₃); m_max(sol.)/cm⁻¹2932, 2859, 1779, 1697; d_H

(360 MHz, CDCl₃), 7.73–7.67 (4H, m, ArH), 7.45–7.30 (9H, m,

=

m, ArH), 5.57 (1H, t, J 6.0, CH CCH₃), 4.29 (2H, d, J 6.0,

CH₂OTPS), 3.72 (1H, d, J 6.5, CHOCH₃), 3.20 (3H, s, OCH₃),

=

2.53–2.47 (1H, m, CHCH₃), 1.37 (3H, s, CH CCH₃), 1.06 (3H,

d, J 7.0, CHCH₃), 1.04 [9H, s, OSiC(CH₃)₃]; d_C(90.6 MHz,

CDCl₃), 203.5 (d), 135.5 (d), 133.7 (s), 132.7 (s), 129.6 (d), 129.2

(d), 127.7 (d), 85.7 (d), 60.6 (t), 56.5 (q), 49.4 (d), 26.8 (q), 19.1

(s), 12.3 (q), 9.3 (q); m/z (ES) 433.2178 (M + Na: C₂₅H₃₄O₃SiNa

requires 433.2175), 433 (100%).

(E)-3-Iodo-N-methoxy-2,N-dimethylacrylamide 15

=

ArH), 7.24–7.22 (2H, m, ArH), 5.70 (1H, t, J 6.0, CH CCH₃),

4.55–4.51 (1H, m, CHNC O), 4.34–4.24 (2H, m, CH₂OTPS),

N,N-Di-isopropylethylamine (383 lL, 2.20 mmol) was added

=

dropwise over

5 min to a stirred solution of (E)-3-

4.16 (1H, quin., J 6.8, CHCH₃), 4.07 (1H, dd, J 2.1 and 9.0,

iodo-2-methylacrylic acid 14 (212 mg, 1.00 mmol),¹⁷N,O-

dimethylhydroxylamine hydrochloride (107 mg, 1.10 mmol) and

pentaﬂuorophenyl diphenylphosphinate (384 mg, 1.00 mmol)

in dichloromethane (10 mL) at 0 ^◦C. The mixture was warmed

to room temperature, then stirred overnight and quenched by

the addition of deionised water (1 mL). The separated aqueous

phase was extracted with dichloromethane (3 × 1 mL) and

the combined organic extracts were then washed successively

with dilute hydrochloric acid (2.0 M, 10 mL), saturated sodium

bicarbonate solution (10 mL), and brine (10 mL), then dried and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, eluting with ethyl acetate–light petroleum (bp

=

CHHOC O), 3.95 (1H, t, J 9.0, CHHOC O), 3.79 (1H, d, J

8.3, CHOCH₃), 3.29 (1H, dd, J 2.7 and 13.3, CHHPh), 3.24

(3H, s, CHOCH₃), 2.77 (1H, dd, J 9.7 and 13.3, CHHPh), 1.47

=

(3H, s, CH CCH₃), 1.33 (3H, d, J 6.8, CHCH₃), 1.07 [9H, s,

OSiC(CH₃)₃]; d_C(90.6 MHz, CDCl₃), 174.8 (s), 153.0 (s), 135.5

(d), 135.4 (d), 135.3 (s), 133.9 (s), 133.8 (s), 133.6 (s), 129.6 (d),

129.5 (d), 129.4 (d), 129.2 (d), 128.9 (d), 127.7 (d), 127.6 (d),

127.3 (d), 86.9 (d), 65.9 (t), 60.6 (t), 56.6 (d), 55.5 (q), 40.9 (d),

37.7 (t), 26.8 (q), 19.2 (s), 13.6 (q), 11.6 (q); m/z (ES) 608.2859

(M + Na: C₃₅H₄₃NO₅SiNa requires 608.2808), 608 (100%), 585

(3), 333 (5).

◦

40–60 C) (1 : 1), to give the Weinreb amide (189 mg, 74%) as

(E)-(2S,3R)-6-(tert-Butyldiphenylsiloxy)-3-methoxy-

2,4-dimethylhex-4-en-1-ol 12

a colourless oil. (Found: C, 28.7; H, 3.9; N, 5.3. C₆H₁₀INO₂

requires: C, 28.3; H, 3.9; N, 5.5%); m_max(sol.)/cm⁻¹3058 (br.),

=

A solution of lithium borohydride in tetrahydrofuran (2.00 M,

0.90 mL, 1.78 mmol) and methanol (72.0 lL, 1.78 mmol) was

1654, 1073; d_H(360 MHz, CDCl₃), 6.80 (1H, q, J 1.2, C CHI),

3.64 (3H, s, OCH₃), 3.23 (3H, s, NCH₃), 2.04 (3H, d, J 1.2,

4 4 1 8

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

View Article Online

=

C CCH₃); d_C(90 MHz, CDCl₃), 168.5 (s), 143.0 (s), 86.6

(d), 61.4 (q), 33.3 (q), 22.3 (q); m/z (ESI) 255.9821 (M + H:

(t), 39.9 (d), 26.8 (q), 19.8 (q), 19.1 (s), 12.5 (q), 7.7 (q); m/z

(ES) 643.1760 (M + Na: C₃₀H₄₁IO₄SiNa requires 643.1717), 643

(100%).

C₆H₁₁INO₂requires 255.9834), 256 (100%).

(E)-3-Iodo-3-methylbut-3-en-2-one 16

(1E,8E)-(5R,6S,7R)-6-(tert-Butyldiphenylsiloxy)-5-hydroxy-

1-iodo-7-(4-methoxybenzyloxy)-2,6,8-trimethyldec-1,8-dien-3-

one 18b

A solution of methylmagnesium bromide in diethyl ether (3.0 M,

0.83 mL, 2.50 mmol) was added over 5 min to a solution of

the Weinreb amide 15 (255 mg, 1.00 mmol) in tetrahydrofuran

(10 mL) at 0 ^◦C. The mixture was stirred at 0 ^◦C for 2 h and

then quenched by the addition of dilute hydrochloric acid (2.0 M,

10 mL). The separated aqueous phase was extracted with diethyl

ether (3 × 10 mL), and the combined organic extracts were

washed with brine (20 mL), dried, and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography,

eluting with diethyl ether–light petroleum (bp 40–60 ^◦C) (1 :

1) to give the methyl ketone (162 mg, 77%) as a pale yellow oil;

(Found: C, 28.9; H, 3.2. C₅H₇IO requires: C, 28.6; H, 3.2%);

m_max(ﬁlm)/cm⁻¹1676, 1360; d_H(360 MHz, CDCl₃), 7.78 (1H,

A solution of triﬂuoromethanesulfonic acid (2 drops) in

diethyl ether (1 mL) was added to a stirred solution of the

aldol adduct 11a (1.36 g, 2.34 mmol) and 4-methoxybenzyl

trichloroacetimidate (0.91 mL, 4.76 mmol) in diethyl ether

(50 mL) at room temperature. The mixture was stirred at room

temperature for 5 min and then quenched by the addition of

saturated sodium bicarbonate solution (30 mL). The separated

aqueous phase was extracted with diethyl ether (30 mL)

and the combined organic extracts were washed with dilute

hydrochloric acid (2.0 M, 2 × 30 mL), and brine (30 mL),

then dried and concentrated in vacuo to leave a colourless oil.

The oil was puriﬁed by ﬂash column chromatography, eluting

with diethyl ether–light petroleum (bp 40–60 ^◦C) (1 : 3) to give

(R)-4-benzyl-3-[(2R,3R)-(E)-6-(tert-butyldiphenylsiloxy)-3-(4-

methoxybenzyloxy)-2,4-dimethylhex-4-enoyl]-oxazolidin-2-one

(1.32 g, 81%) as a colourless oil. [a]²_D¹−1.24 (c 0.97 in CHCl₃);

m_max(sol.)/cm⁻¹1778, 1698, 1073; d_H(360 MHz, CDCl₃),

7.79–7.74 (4H, m, ArH), 7.49–7.33 (6H, m, ArH), 7.30 (2H, d, J

=

q, J 0.9, C CHI), 2.36 (3H, s, CH₃C O), 2.01 (3H, d, J 0.9,

C CCH₃); d_C(67.8 MHz, CDCl₃), 192.7 (s), 149.5 (s), 100.8 (d),

=

26.5 (q), 20.1 (q); m/z (ESI) 210.9624 (M + H: C₅H₈IO requires

210.9620), 210 (100%), 209 (62), 73 (27).

[(E)-3-Iodo-2-methyl-1-methyleneallyloxy]-trimethylsilane 17

A solution of lithium hexamethyldisilazane in hexanes (1.0 M,

2.84 mL, 2.84 mmol) was added dropwise over 5 min to a

stirred solution of the methyl ketone 16 (300 mg, 1.42 mmol)

in tetrahydrofuran (14 mL) at −78 ^◦C. The mixture was stirred

at −78 ^◦C for 20 min and then triethylamine (600 lL, 4.26 mmol)

and trimethylsilyl chloride (544 lL, 4.26 mmol) were added. The

mixture was stirred at −78 ^◦C for 30 min, then warmed to room

temperature and stirred for a further 30 min. The mixture was

concentrated in vacuo and the residue was then washed with

pentane (3 × 5 mL). The washings were concentrated in vacuo

to leave the enol silane (400 mg, quantitative) as an unstable

=

8.6, ArH), 7.23 (2H, d, J 8.6, ArH), 5.82 (1H, t, J 6.0, C CH),

4.52 (1H, d, J 11.7, CHHAr), 4.47–4.34 (3H, m, CHN and

CH₂OTPS), 4.24–4.16 (1H, m, CHCH₃), 4.20 (1H, d, J 11.7,

=

CHHAr), 4.06–4.03 (2H, m, CH₂OC O), 3.86–3.80 (1H, m,

CHOPMB), 3.84 (3H, s, OCH₃), 3.29 (1H, dd, J 3.0 and 13.3,

CHHPh), 2.77 (1H, dd, J 9.6 and 13.3, CHHPh), 1.57 (3H, s,

t

=

C CCH₃), 1.34 (3H, d, J 6.7, CHCH₃), 1.13 (9H, s, TPS- Bu);

d_C(90.6 MHz, CDCl₃), 174.4 (s), 159.0 (s), 152.9 (s), 135.5 (d),

135.4 (d), 135.3 (s), 133.8 (s), 133.7 (s), 133.6 (s), 130.4 (s), 129.6

(d), 129.5 (d), 129.3 (d), 128.9 (d), 128.8 (d), 127.7 (d), 127.6

(d), 127.2 (d), 113.6 (d), 83.0 (d), 69.7 (t), 65.7 (t), 60.6 (t), 55.5

(d), 55.1 (q), 40.9 (d), 37.6 (t), 26.7 (q), 19.1 (s), 12.9 (q), 12.0

(q); m/z (ESI) 714.3226 (M + Na: C₄₂H₄₉NNaO₆Si requires

714.3227), 714 (100%), 715 (21).

=

yellow oil; d_H(360 MHz, C₆D₆), 7.18 (1H, q, J 0.4, C CHI),

=

4.56 (1H, d, J 1.7, C CHH), 4.42 (1H, J 1.7, C CHH), 2.02

(3H, d, J 0.4, C CCH₃), 0.19 (9H, s, TMS-Me), which was used

=

without further puriﬁcation.

Methanol (0.31 mL, 7.51 mmol) was added rapidly, followed

by a solution of lithium borohydride in diethyl ether (2.00 M,

3.76 mL, 7.51 mmol) over 5 min, to a stirred solution of the

above oxazolidinone (1.30 g, 1.88 mmol) in diethyl ether (20

mL) at 0 ^◦C. The mixture was warmed to room temperature

over 3 h and then quenched by the addition of sodium hydroxide

solution (2.0 M, 10 mL). The biphasic mixture was stirred for

1 h at room temperature and the separated aqueous phase was

then extracted with diethyl ether (2 × 10 mL). The combined

organic extracts were dried and concentrated in vacuo to leave

a residue which was puriﬁed by ﬂash column chromatogra-

phy, eluting with diethyl ether–light petroleum (bp 40–60 ^◦C)

(1 : 1) to give (E)-(2R,3R)-6-(tert-butyldiphenylsiloxy)-3-(4-

methoxybenzyloxy)-2,4-dimethylhex-4-en-1-ol (905 mg, 93%) as

a colourless oil. [a]²_D¹+44.6 (c 0.63 in CHCl₃); (Found: C, 74.1;

H, 8.25. C₃₂H₄₂O₄Si requires: C, 74.1; H, 8.2%); m_max(sol.)/cm⁻¹

3627, 1613, 1044; d_H(360 MHz, CDCl₃), 8.63–8.61 (4H, m,

ArH), 8.31–8.23 (6H, m, ArH), 8.08 (2H, d, J 8.5, ArH), 7.69

(1E,8E)-(5R,6S,7R)-10-(tert-Butyldiphenylsiloxy)-5-hydroxy-

1-iodo-7-methoxy-2,6,8-trimethyldeca-1,8-dien-3-one 18a

Freshly distilled boron triﬂuoride diethyl etherate (111 lL,

0.880 mmol) was added dropwise over 15 min to a stirred

solution of the aldehyde 13 (242 mg, 0.59 mmol) and the silyl enol

ether 17 (333 mg, 1.18 mmol) in toluene (10 mL) at −78 ^◦C. The

mixture was stirred at −78 ^◦C for 1 h and then left in a freezer

at −85 ^◦C for 72 h. The mixture was allowed to warm to room

temperature and then quenched by the careful addition of a

saturated solution of ammonium chloride (5 mL). The mixture

was extracted with dichloromethane (3 × 10 mL) and the com-

bined organic extracts were dried and concentrated in vacuo

to leave a yellow oil. The oil was puriﬁed by ﬂash column

chromatography, eluting with ethyl acetate–light petroleum (bp

40–60 ^◦C) (1 : 4) to give the aldol product (300 mg, 82%) as

a colourless oil. [a]²_D¹+8.4 (c 1.09 in CHCl₃); (Found: C, 58.6;

H, 6.7. C₃₀H₄₁IO₄Si requires: C, 58.2; H, 6.7%); m_max(sol.)/cm⁻¹

3475 (br.), 2930, 1672, 703; d_H(360 MHz, CDCl₃), 7.84 (1H, s,

=

(2H, d, J 8.5, ArH), 6.35 (1H, tq, J 1.0 and 6.1, C CH), 4.96

(1H, d, J 11.4, CHHAr), 4.86 (2H, d, J 6.1, CH₂OTPS), 4.63

(1H, d, J 11.4, CHHAr), 4.27 (3H, s, OCH₃), 4.03 (1H, d, J

6.8 CHOPMB), 3.93 (1H, dd, J 6.0 and 11.0, CHHOH), 3.84

=

ICH C), 7.72–7.69 (4H, m, ArH), 7.44–7.37 (6H, m, ArH),

5.66 (1H, tq, J 1.1 and 6.0, CH CCH₃), 4.33 (2H, d, J 6.0,

=

CH₂OTPS), 4.17 (1H, ddd, J 2.2, 3.6 and 8.6, CHOH), 3.59

(1H, d, J 6.0, CHOCH₃), 3.22 (3H, s, OCH₃), 2.97 (1H, dd, J 8.6

and 16.7, CHHC O), 2.66 (1H, dd, J 3.6 and 16.7, CHHC O),

2.03 (3H, d, J 1.1, CH CCH₃), 1.62 (1H, ddq, J 2.2, 6.0 and 7.0,

CHCH₃), 1.37 (3H, s, ICH CCH₃), 1.06 [9H, s, OSiC(CH₃)₃],

0.93 (3H, d, J 7.0, CHCH₃); d_C(90.6 MHz, CDCl₃), 196.4 (s),

148.9 (s), 135.5 (d), 133.9 (s), 133.3 (s), 129.6 (d), 127.9 (d),

127.6, (d), 100.6 (d), 89.1 (d), 69.7 (d), 60.7 (t), 56.6 (q), 42.9

(1H, dd, J 4.9 and 11.0, CHHOH), 2.17–2.06 (2H, m, OH and

t

=

CHCH₃), 1.68 (3H, d, J 1.0, C CCH₃), 1.24 (9H, s, TPS- Bu),

=

1.10 (3H, d, J 6.9, CHCH₃); d_C(90.6 MHz, CDCl₃), 159.1 (s),

135.5 (d), 135.2 (s), 133.8 (s), 130.5 (s), 129.6 (d), 129.5 (d),

128.1 (d), 127.7 (d), 113.7 (d), 85.8 (d), 69.8 (t), 65.9 (t), 60.5

(t), 55.2 (q), 38.2 (d), 26.8 (q), 19.1 (s), 12.7 (q), 12.4 (q); m/z

(ESI) 541.2798 (M + Na: C₃₂H₄₂NaO₄Si requires 541.2751), 541

(100%), 519 (4).

=

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 1 9

View Article Online

Dess–Martin periodinane (127 mg, 0.30 mmol) was added

in a single portion to a stirred solution of the above alcohol

(90.0 mg, 0.20 mmol) in dichloromethane (2 mL) at room

temperature. The suspension was stirred at room temperature

for 30 min and then quenched by the addition of saturated

sodium thiosulfate solution (2 mL). The biphasic mixture was

stirred at room temperature for 30 min and the separated

aqueous phase was then extracted with dichloromethane (3 ×

4 mL). The combined organic extracts were washed with

saturated sodium bicarbonate solution (5 mL) and brine (5 mL),

then dried and concentrated in vacuo to leave a residue.

The crude residue was puriﬁed by ﬂash column chromatog-

rap_◦hy, eluting with ethyl acetate–light petroleum (bp 40–

60 C) (1 : 4) to give (E)-(2R,3R)-6-(tert-butyldiphenylsiloxy)-

3-(4-methoxybenzyloxy)-2,4-dimethylhex-4-enal the aldehyde

(83 mg, 93%) as a colourless oil. [a]²_D¹+35.1 (c 1.06 in CHCl₃);

(Found: C, 74.15; H, 7.7. C₃₂H₄₀O₄Si requires: C, 74.4; H, 7.8%);

m_max(sol.)/cm⁻¹2739, 1723, 1613, 1052; d_H(360 MHz, CDCl₃),

9.60 (1H, d, J 2.0, CHO), 7.76–7.73 (4H, m, ArH), 7.47–7.44

(6H, m, ArH), 7.26 (2H, d, J 8.6, ArH), 6.93 (2H, d, J 8.6,

dichloromethane (5 mL) and ﬁltered through a pad of Celite,

washing with dichloromethane (5 mL). The combined washings

were concentrated in vacuo to leave a brown oil which was

puriﬁed by ﬂash column chromatography, eluting with ethyl

acetate–light petroleum (bp 40–60 ^◦C) (1 : 6) to give the acetal

(12 mg, 99%) as a colourless oil. [a]²_D¹−6.4 (c 0.75 in CHCl₃);

m_max(sol.)/cm⁻¹1678, 1033; d_H(360 MHz, CDCl₃), 7.86 (1H, s,

=

C CHI), 7.70–7.68 (4H, m, ArH), 7.42–7.34 (8H, m, ArH), 6.90

(2H, d, J 8.8, ArH), 5.81 (1H, tq, J 1.2 and 6.3, C CH), 5.57

=

(1H, s, CHAr), 4.47 (1H, ddd, J 2.3, 5.3 and 7.4, CHOR), 4.30

(2H, d, J 6.3, CH₂OTPS), 4.25 (1H, br. s, CHOR), 3.82 (3H, s,

OCH₃), 3.15 (1H, dd, J 7.4 and 16.4, CHHC O), 2.69 (1H, dd,

=

J 5.3 and 16.4, CHHC O), 2.03 (3H, d, J 1.2, C CCH₃), 1.79

=

(1H, tq, J 2.3 and 6.9, CHCH₃), 1.43 (3H, s, IC CCH₃), 1.04

(9H, s, TPS-^tBu), 0.87 (3H, d, J 6.9, CHCH₃); d_C(90.6 MHz,

CDCl₃), 194.4 (s), 159.8 (s), 148.9 (s), 135.6 (d), 133.9 (s), 133.5

(s), 131.1 (s), 129.5 (d), 127.5 (d), 124.3 (d), 113.5 (d), 100.9 (2 ×

d), 82.5 (d), 76.9 (d), 60.7 (t), 55.3 (q), 41.4 (t), 33.3 (d), 26.8 (q),

19.9 (q), 19.2 (s), 13.3 (q), 6.3 (q); m/z (ESI) 725.2136 (M + H:

C₃₇H₄₆IO₅Si requires 725.2159), 748 (30%), 725 (100).

=

ArH), 5.76 (1H, tq, J 0.9 and 6.0, C CH), 4.49 (1H, d, J 11.4,

CHHAr), 4.43–4.32 (2H, m, CH₂OTPS), 4.20 (1H, d, J 11.4,

CHHAr), 3.96 (1H, d, J 6.8, CHOPMB), 3.85 (3H, s, OCH₃),

(1E,8E)-(5S,6S,7R)-10-(tert-Butyldiphenylsiloxy)-5-hydroxy-

1-iodo-7-methoxy-2,6,8-trimethyldeca-1,8-dien-3-one 19

2.58 (1H, d quin., J 2.0 and 6.8, CHCH₃), 1.48 (3H, d, J 0.9,

C CCH₃), 1.12 (3H, d, J 6.8, CHCH₃), 1.11 (9H, s, TPS- Bu);

d_C(90.6 MHz, CDCl₃), 203.5 (d), 159.2 (s), 135.5 (d), 133.7 (s),

133.0 (s), 130.1 (s), 129.7 (d), 129.5 (d), 127.7 (d), 113.7 (d), 84.8

(d), 69.7 (t), 60.6 (t), 55.2 (q), 49.3 (d), 26.8 (q), 19.1 (s), 12.3 (q),

9.5 (q); m/z (ESI) 571.2838 (M + Na + MeOH: C₃₃H₄₄NaO₅Si

requires 571.2856), 571 (100%), 539 (5).

Freshly distilled boron triﬂuoride diethyletherate (39.0 lL,

310 lmol) was added over 5 min to a solution of the above

aldehyde (80.0 mg, 155 lmol) and the enol silane 17 (250 mg

crude) in toluene (2 mL) at −78 ^◦C and the mixture was

then placed in a freezer at −85 ^◦C for 14 h. The mixture was

quenched at −78 ^◦C with ammonium hydroxide solution (2.0 M,

2 mL) and then warmed to room temperature. The two layers

were separated and the aqueous phase was then extracted with

dichloromethane (2 × 2 mL). The combined organic extracts

were dried and concentrated in vacuo to leave a colourless oil.

The oil was puriﬁed by ﬂash column chromatography, eluting

with ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 : 6) to give

the aldol product (47 mg, 42%; 56% based on recovered starting

material) as a colourless oil. [a]²_D¹+24.4 (c 0.63 in CHCl₃);

m_max(sol.)/cm⁻¹3494 (br.), 1671, 1054; d_H(360 MHz, CDCl₃),

A solution of dimethylaluminium chloride in hexanes (1.00 M,

2.10 mL, 2.10 mmol) was added over 5 min to a stirred solution

of the aldehyde 13 (340 mg, 0.83 mmol) in dichloromethane

(10 mL) at −78 ^◦C. The mixture was stirred at −78 ^◦C for

5 min and then a solution of the enol silane 17 (650 mg) in

dichloromethane (2 mL) was added. The mixture was stirred

t

=

◦

at −78 C for 2 h and then quenched −78 C by the cautious

addition of ammonium chloride solution (2.0 M, 10 mL). The

biphasic mixture was warmed to room temperature, poured

into deionised water (10 mL) and the separated aqueous phase

was then extracted with dichloromethane (2 × 20 mL). The

combined organic extracts were dried and concentrated in

vacuo to leave an orange oil which was puriﬁed by ﬂash column

chromatography, eluting with ethyl acetate–light petroleum (bp

◦

40–60 C) (1 : 6) to give the aldol product (224 mg, 43%; 85%

based on recovered starting material) as a colourless oil. [a]_D²¹

−12 (c 1.10 in CHCl₃); (Found: C, 58.3; H, 6.5. C₃₀H₄₁IO₄Si

requires: C, 58.2; H, 6.7%); m_max(sol.)/cm⁻¹3462 (br.), 2931,

=

1668, 703; d_H(360 MHz, CDCl₃) 7.84 (1H, s, ICH C), 7.71–

7.68 (4H, m, ArH), 7.45–7.36 (6H, m, ArH), 5.60 (1H, br. t, J

=

6.0, CH CCH₃), 4.31 (2H, d, J 6.0, CH₂OTPS), 4.08–4.02 (1H,

m, CHOH), 3.62 (1H, d, J 4.6, CHOCH₃), 3.36 (1H, d, J 4.2,

=

7.75–7.71 (5H, m, C CHI and ArH), 7.44–7.37 (6H, m, ArH),

=

OH), 3.23 (3H, s, OCH₃), 2.90–2.75 (2H, m, CH₂C O), 2.03

7.24 (2H, d, J 8.7, ArH), 6.88 (2H, d, J 8.7, ArH), 5.74 (1H,

=

(3H, d, J 1.0, CH CCH₃), 1.84–1.76 (1H, m, CHCH₃), 1.38

=

tq, J 1.1 and 6.0, C CH), 4.44 (1H, d, J 11.2, CHHAr), 4.37

=

(3H, s, ICH CCH₃), 1.05 [9H, s, OSiC(CH₃)₃], 0.87 (3H, d, J

(2H, d, J 6.0, CH₂OTPS), 4.15 (1H, d, J 11.2, CHHAr), 4.14–

4.10 (1H, m, CHOH) 3.84 (3H, s, OCH₃), 3.80 (1H, d, J 6.0,

CHOPMB), 2.99 (1H, d, J 2.6, OH), 2.91 (1H, dd, J 8.7 and

7.0, CHCH₃); d_C(90.6 MHz, CDCl₃) 197.0 (s), 148.9 (s), 135.5

(d), 133.8 (s), 133.6 (s), 129.6 (d), 127.6 (d), 126.9 (d), 100.7 (d),

86.1 (d), 69.8 (d), 60.7 (t), 56.8 (q), 41.8 (t), 40.4 (d), 26.7 (q),

19.8 (q), 19.1 (s), 13.1 (q), 10.2 (q); m/z (ES) 643.1706 (M +

Na: C₃₀H₄₁IO₄SiNa requires 643.1717), 643 (100%), 619 (5).

=

16.9, CHHC O), 2.61 (1H, dd, J 3.6 and 16.9, CHHC O),

=

2.01 (3H, d, J 1.1, C CCH₃), 1.70–1.60 (1H, m, CHCH₃), 1.43

t

=

(3H, d, J 0.8, IC CCH₃), 1.08 (9H, s, TPS- Bu), 0.95 (3H, d, J

7.0, CHCH₃); d_C(90.6 MHz, CDCl₃), 196.5 (s), 159.2 (s), 148.8

(s), 135.6 (d), 133.9 (s), 133.6 (s), 130.3 (s), 129.6 (d), 128.2 (d),

127.7 (d), 113.8 (d), 100.7 (d), 85.8 (d), 70.1 (t), 69.4 (d), 60.7 (t),

55.3 (q), 42.3 (t), 39.9 (d), 26.8 (q), 19.8 (q), 19.2 (s), 12.7 (q),

8.1 (q); m/z (ESI) 749.2150 (M + Na: C₃₇H₄₇INaO₅Si requires

749.2135), 749 (100%).

(1E,8E)-(3S,5S,6S,7R)-10-(tert-Butyldiphenylsiloxy)-3,5-

dihydroxy-1-iodo-7-methoxy-2,6,8-trimethyldec-1,8-diene 21a

A solution of the b-hydroxyketone 19 (140 mg, 0.23 mmol)

in acetonitrile (2 mL) was added over 5 min via cannula to a

frozen mixture of tetramethylammonium triacetoxyborohydride

(475 mg, 1.80 mmol) in acetonitrile (8 mL) and glacial acetic acid

(10 mL) at −40 ^◦C. The mixture was left at −30 ^◦C in a freezer

for 18 h, then quenched at −30 ^◦C with saturated Rochelle’s

salt solution (15 mL) and warmed to room temperature. The

emulsion was extracted with dichloromethane (50 mL, then 2 ×

10 mL) and the combined organic extracts were carefully washed

with saturated sodium bicarbonate solution until the aqueous

phase remained basic, then dried and concentrated in vacuo. The

residue was puriﬁed by ﬂash column chromatography, eluting

with ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 : 4) to give

(E)-[(4R,5R,6R)-6-[(E)-3-(tert-Butyldiphenylsiloxy)-

1-methylpropenyl]-2-(4-methoxyphenyl)-5-methyl-[1,3]dioxan-

4-yl]-4-iodo-3-methylbut-3-en-2-one 20

Freshly recrystallised 2,3-dichloro-5,6-dicyano-1,4-benzoqui-

none (5.60 mg, 24.8 lmol) was added in a single portion to a

stirred solution of the aldol adduct 18b (12.0 mg, 16.5 lmol) in

dichloromethane (0.3 mL) at room temperature. The mixture

was stirred at room temperature for 1 h, then diluted with

4 4 2 0

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

View Article Online

the diol (116 mg, 83%) as a pale yellow oil. [a]²_D¹+8.8 (c 0.95

in CHCl₃); m_max(ﬁlm)/cm⁻¹3422 (br.), 1462, 737; d_H(360 MHz,

CDCl₃), 7.72–7.69 (4H, m, ArH), 7.47–7.37 (6H, m, ArH), 6.38

(1H, s, C CHI), 5.61 (1H, br. t, J 6.0, C CH), 4.48 (1H, m,

CHOH), 4.33 (2H, d, J 6.0, CH₂OTPS), 3.81 (1H, m, CHOH),

3.72 (1H, br. s, OH), 3.69 (1H, d, J 4.0, CHOMe), 3.23 (3H, s,

(q), 11.0 (q), −4.9 (q), −5.4 (q); m/z (ESI) 759.2554 (M + Na:

C₃₆H₅₇IO₄Si₂Na requires 759.2539), 760 (20%), 759 (100).

(1E,8E)-(3S,5S,6S,7R)-1-Iodo-10-(tert-butyldiphenylsiloxy)-3-

(tert-butyldimethylsiloxy)-5-(2-diethylphosphonoacetoxy)-7-

methoxy-2,6,8-trimethyldec-1,8-diene 9

=

OCH₃), 1.82 (3H, s, IC CCH₃), 1.79–1.72 (3H, m, CHCH₃and

CH₂CHOH), 1.41 (3H, s, C CCH₃), 1.07 (9H, s, TPS- Bu), 0.87

A solution of diethylphosphonoacetic acid (30.0 lL, 122 lmol)

in dichloromethane (0.3 mL) was added over 5 min, followed

by N,N^ꢀ-dicyclohexylcarbodiimide (38.0 mg, 183 lmol) in a

single portion to a stirred solution of the alcohol 21b (90.0 mg,

122 lmol) and 4-(dimethylamino)pyridine (4.30 mg, 37.0 lmol)

in dichloromethane (6 mL) at room temperature. The mixture

was stirred at room temperature for 90 min and then concen-

trated in vacuo. The residue was puriﬁed by ﬂash column chro-

matography, eluting with ethyl acetate–light petroleum (bp 40–

60 ^◦C) (1 : 3) to give the phosphonate ester (100 mg, 89%) as

a colourless oil. [a]_D²¹−7.2 (c 0.95 in CHCl₃); m_max(sol.)/cm⁻¹

1732, 1052, 703; d_H(360 MHz, CDCl₃), 7.71–7.65 (4H, m, ArH),

t

=

(3H, d, J 7.1, CHCH₃); d_C(90.6 MHz, CDCl₃), 149.6 (s), 135.5

(d), 133.7 (s), 133.0 (s), 129.6 (d), 127.7 (d), 127.6 (d), 87.3 (d),

77.7 (d), 73.9 (d), 71.9 (d), 60.6 (t), 56.6 (q), 40.6 (d), 38.4 (t), 26.7

(q), 21.7 (q), 19.1 (s), 13.3 (q), 11.7 (q); m/z (FAB) 645.1910 (M +

Na: C₃₀H₄₃IO₄SiNa requires 645.1873), 646 (10%), 645 (100).

tert-Butyl-{(4R,5S)-(E)-5-[(4S,6S)-6-(E)-2-iodo-

1-methylvinyl-2,2-dimethyl-[1,3]dioxan-4-yl]-4-methoxy-

3-methylhex-2-enyloxy}-diphenylsilane 22

=

7.44–7.35 (6H, m, ArH), 6.19 (1H, s, C CHI), 5.59 (1H, br. t,

para-Toluenesulfonic acid monohydrate (1 mg) was added to

a stirred solution of the diol 21a (15.0 mg, 24.0 lmol) in

2,2-dimethoxypropane (0.3 mL) at room temperature and the

mixture was stirred at room temperature for 5 h. The mixture

was concentrated in vacuo to leave a crude residue which

was puriﬁed by ﬂash column chromatography, eluting with

diethyl ether–light petroleum (bp 40–60 ^◦C) (1 : 19) to give

the acetonide (14 mg, 89%) as a colourless oil. [a]²_D¹−13 (c

0.45 in CHCl₃); m_max(ﬁlm)/cm⁻¹2958, 1075, 972; d_H(360 MHz,

CDCl₃), 7.71–7.68 (4H, m, ArH), 7.43–7.36 (6H, m, ArH), 6.29

=

J 6.0, C CH), 4.89–4.84 (1H, m, CHOC O), 4.35 (1H, dd,

J 7.0 and 13.0, CHHOTPS), 4.26 (1H, dd, J 5.0 and 13.0,

CHHOTPS), 4.20–4.11 (5H, m, POCH₂and CHOTBS), 3.16

(4H, br. s, CHOMe and OCH₃), 2.94 (1H, dd, J 14.3 and 21.7,

CH₂P), 2.90 (1H, dd, J 14.3 and 21.7, CH₂P), 2.08–1.99 (1H, m,

=

CHCH₃), 1.77 (3H, s, IC CCH₃), 1.67 (2H, m, CH₂CHOTBS),

1.45 (3H, s, C CCH₃), 1.33 (6H, dt, J 1.8 and 7.1, POCH₂CH₃),

=

1.05 (9H, s, TPS-^tBu), 0.93 (3H, d, J 6.9, CHCH₃), 0.82 (9H, s,

TBS-^tBu), −0.03 (3H, s, TBS-Me), −0.07 (3H, s, TBS-Me); d_C

(90.6 MHz, CDCl₃), 164.8 (s), 150.6 (s), 135.5 (d), 133.8 (s),

133.7 (s), 129.5 (d), 128.7 (d), 127.6 (d), 87.8 (d), 78.2 (d), 74.3

(d), 73.8 (d), 62.5 (dt, J 6.1), 60.7 (t), 56.1 (q), 38.3 (d), 35.6

(t), 34.6 (dt, J 133.0), 26.8 (q), 25.7 (q), 19.1 (q), 19.0 (s), 18.0

(s), 16.3 (dq, J 6.1), 11.6 (q), 9.6 (q), −5.0 (q), −5.4 (q); m/z

(ESI) 937.3065 (M + Na: C₄₂H₆₈INaPO₈Si₂requires 937.3133),

938 (12%), 937 (100).

=

(1H, s, C CHI), 5.59 (1H, t, J 6.1, C CH), 4.34–4.26 (3H, m,

CH₂OTPS and CHOR), 3.79 (1H, dt, J 7.9 and 8.1, CHOR),

3.60 (1H, d, J 3.9, CHOMe), 3.20 (3H, s, OCH₃), 1.82 (3H, s,

=

IC CCH₃), 1.71 (2H, dd, J 8.0 and 8.1, CH₂CHOR), 1.67–

1.61 (1H, m, CHCH₃), 1.37 (6H, s, 2 × OCCH₃), 1.35 (3H, s,

t

=

C CCH₃), 1.04 (9H, s, TPS- Bu), 0.74 (3H, d, J 7.0, CHCH₃);

d_C(90.6 MHz, CDCl₃), 147.4 (s), 135.6 (d), 134.0 (s), 133.8 (s),

129.5 (d), 129.4 (d), 125.8 (d), 100.8 (s), 84.2 (d), 77.7 (d), 70.6

(d), 67.1 (d), 60.9 (t), 57.1 (q), 40.8 (d), 35.0 (t), 26.8 (q), 24.8

(q), 24.2 (q), 20.7 (q), 19.2 (s), 13.5 (q), 8.4 (q); m/z (FAB) 663

(45%), 657 (100).

(E)-5-(tert-Butyldiphenylsilanyloxy)-pent-2-enoic acid ethyl

ester 23a

(Carbethoxymethylene)triphenylphosphorane (7.97 g, 22.9

mmol) was added in four equal portions, over 2 min, to a stirred

solution of 1-(tert-butyldiphenylsilyloxy)propanal (6.50 g, 20.8

mmol) in dichloromethane (250 mL) at room temperature. The

solution was stirred at room temperature for 8 h and then

concentrated in vacuo to leave a residue that was extracted into

pentane (300 mL). The solvent was evaporated in vacuo to leave a

colourless oil that was puriﬁed by ﬂash column chromatography

on _◦silica, eluting with ethyl acetate–light petroleum (bp 40–

60 C) (1 : 19) to give the ester (7.3 g, 93%)²¹as a colourless

oil; (Found: C, 72.4; H, 8.0. Calc. for C₂₃H₃₀O₃Si: C 72.2; H,

7.9%); m_max(liquid ﬁlm)/cm⁻¹1720, 1656, 1589; d_H(400 MHz,

CDCl₃) 7.69–7.67 (4H, m, ArH), 7.47–7.38 (6H, m, ArH),

(1E,8E)-(3S,5S,6S,7R)-10-(tert-Butyldiphenylsiloxy)-3-

(tert-butyldimethylsiloxy)-5-hydroxy-1-iodo-7-methoxy-

2,6,8-trimethyldec-1,8-diene 21b

tert-Butyldimethylsilyl triﬂate (33.0 lL, 0.14 mmol) was added

to a stirred solution of the diol 21a (81.0 mg, 0.13 mmol) and

2,4,6-collidine (34.0 lL, 0.26 mmol) in tetrahydrofuran (8 mL)

at −78 ^◦C. The mixture was stirred at −78 ^◦C for 15 min,

then quenched with saturated sodium bicarbonate solution (8

mL), and warmed to room temperature. The aqueous phase

was separated and extracted with dichloromethane (3 × 5 mL)

and the combined organic extracts were then dried and con-

centrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, eluting with ethyl acetate–light petroleum (bp

40–60 ^◦C) (1 : 9) to give the silyl ether (64 mg, 68%) as a colourless

oil. [a]²_D¹−6.0 (c 1.0 in CHCl₃); m_max(ﬁlm)/cm⁻¹3480 (br.), 1463,

1112; d_H(360 MHz, CDCl₃), 7.73–7.70 (4H, m, ArH), 7.44–

=

7.00 (1H, dt, J 15.6 and 7.1, CH CHCO₂Et), 5.88 (1H,

dt, J 15.6 and 1.5, CH CHCO₂Et), 4.21 (2H, q, J 7.1,

=

CO₂CH₂CH₃), 3.79 (2H, t, J 6.5, CH₂OTBDPS), 2.46 (2H,

=

apparent qd, J 6.6 and 1.5, CH₂CH CH), 1.31 (3H, t, J

7.1, CO₂CH₂CH₃), 1.07 [9H, s, OSiC(CH₃)₃]; d_C(67.8 MHz,

=

CDCl₃) 166.4 (s, CO₂Et), 145.8 (d, CH CHCO₂Et), 135.5

(d, Ar), 133.5 (s, Ar), 129.6 (d, Ar), 127.6 (d, Ar), 123.0 (d,

=

7.37 (6H, m, ArH), 6.28 (1H, s, C CHI), 5.59 (1H, t, J 6.0,

C CH), 4.51 (1H, dd, J 2.5 and 7.9, CHOTBS), 4.33 (2H, d,

=

CH CHCO₂Et), 62.2 (t, CH₂OTBDPS), 60.1 (CO₂CH₂CH₃),

=

35.4 (t, CH₂CH₂OTBDPS), 26.7 [q, OSiC(CH₃)₃], 19.1 [s,

J 6.0, CH₂OTPS), 3.71 (1H, apparent quin., J 4.6, CHOH),

3.60 (1H, d, J 4.3, CHOMe), 3.25 (1H, d, J 4.6, OH), 3.22

(3H, s, OCH₃), 1.80 (3H, s, IC CCH₃), 1.72–1.66 (2H, m,

•

OSiC(CH₃)₃], 14.2 (q, CO₂CH₂CH₃); m/z (EI) 325.1291 [M⁺

C(CH₃)₃. C₁₉H₂₁O₃Si requires 325.1260].

−

=

CHCH₃and CHHCHOH), 1.52 (1H, ddd, J 2.9, 10.2 and 13.8,

(E)-5-(tert-Butyldiphenylsilanyloxy)-pent-2-en-1-ol 23b

t

=

CHHCHOH), 1.40 (3H, s, C CCH₃), 1.07 (9H, s, TPS- Bu),

0.90 (9H, s, TBS-^tBu), 0.87 (3H, d, J 7.1, CHCH₃), 0.09 (3H, s,

TBS-Me), 0.02 (3H, s, TBS-Me); d_C(90.6 MHz, CDCl₃), 150.1

(s), 135.5 (d), 133.8 (s), 133.4 (s), 129.6 (d), 127.6 (d), 127.1

(d), 86.8 (d), 77.5 (d), 74.8 (d), 70.3 (d), 60.8 (t), 56.6 (q), 41.0

(d), 40.5 (t), 26.8 (q), 25.7 (q), 20.5 (q), 19.1 (s), 18.1 (s), 13.3

Di-isobutylaluminium hydride (1.5 mol dm⁻³in toluene;

27.6 mL, 41.4 mmol) was added dropwise over 15 min, to

a stirred solution (E)-5-(tert-butyldiphenylsilanyloxy)-pent-2-

enoic acid ethyl ester 23a (7.20 g, 18.8 mmol) in dichloromethane

(150 mL) at −78 ^◦C. The mixture was stirred at −78 ^◦C for

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 2 1

View Article Online

◦

(2^ꢀS,3^ꢀR,4R,5S,5^ꢀS)-3-{5^ꢀ-[2^ꢀꢀ-(tert-Butyldiphenylsilanyloxy)-

1 h, after which it was quenched at −78 C by the addition of

ethyl]-3^ꢀ-hydroxy-2^ꢀ-methylhept-6^ꢀ-enoyl}-4-methyl-5-

phenyloxazolidin-2-one 27 and (2^ꢀS,3^ꢀR,4R,5S,5^ꢀR)-

3-{5^ꢀ-[2^ꢀꢀ-(tert-Butyldiphenylsilanyloxy)-ethyl]-3^ꢀ-hydroxy-2^ꢀ-

methylhept-6^ꢀ-enoyl}-4-methyl-5-phenyloxazolidin-2-one 26

methanol (8 mL), and allowed to warm to room temperature

over 1 h. A saturated aqueous solution of potassium sodium

tartrate (150 mL) was added to the mixture which was the

stirred vigorously at room temperature for 2 h. The mixture

was extracted with dichloromethane (80 mL), washed with

brine (30 mL), dried over anhydrous magnesium sulfate and

concentrated in vacuo to leave a residue that was puriﬁed by ﬂash

column chromatography on silica, eluting with ethyl acetate–

light petroleum (bp 40–60 ^◦C) (1 : 9) to give the alcohol (5.9 g,

93%) as a colourless oil; (Found: C, 74.2; H, 8.6. C₂₁H₂₈O₂Si

requires: C 74.1; H, 8.3%); m_max(liquid ﬁlm)/cm⁻¹3344, 3070,

1589; d_H(400 MHz, CDCl₃) 7.70–7.67 (4H, m, ArH), 7.47–7.38

(6H, m, ArH), 5.70–5.68 (2H, m, CH CHCH₂OH), 4.09–4.07

(2H, m, CH₂OH), 3.73 (2H, t, J 6.7, CH₂OTBDPS), 2.35–

2.30 (2H, m, CH₂CH₂OTBDPS), 1.07 [9H, s, SiC(CH₃)₃]; d_C

(67.8 MHz, CDCl₃) 136.0 (d, Ar), 134.3 (s, Ar), 131.4 (d, CH),

130.0 (d, Ar), 129.9 (d, CH), 128.1 (d, Ar), 64.1 (t, CH₂OH),

A

solution of dibutylboron triﬂuoromethanesulfonate

(1.0 mol dm⁻³in dichloromethane, 7.10 mL, 7.10 mmol)

was added dropwise over 5 min to a stirred solution of (4S,5R)-

N-propionyl-5-methyl-4-phenyloxazolidin-2-one (1.50 g, 6.46

mmol) and di-isopropylethylamine_◦(1.00 g, 1.35 mL, 7.75 mmol)

in dichloromethane (40 mL) at 0 C. The solution was stirred

at 0 ^◦C for 30 min and then at −78 ^◦C for 30 min, after which a

solution of (a)-3-[2-(tert-butyldiphenylsilanyloxy)-ethyl]-pent-

4-enal 25 (2.60 g, 7.10 mmol) in dichloromethane (10 mL)

was added dropwise over 5 min at −78 ^◦C. The reaction was

stirred at −78 ^◦C for 30 min and then at room temperature for a

further 90 min, after which it was cooled to 0 ^◦C and quenched

by the addition of methanol (30 mL), pH 7 phosphate buffer

(15 mL) and hydrogen peroxide (100 vol, 15 mL). The solution

=

63.9 (t, CH₂OTBDPS), 36.0 (t, CH₂CH₂OTBDPS), 27.3 [q,

•

OSiC(CH₃)₃], 19.7 [s, OSiC(CH₃)₃]; m/z (EI) 283.1167 [M⁺

−

◦

was stirred vigorously at 0 C for 2 h and then extracted with

C(CH₃)₃. C₁₇H₁₉O₂Si requires 283.1154].

dichloromethane (150 mL). The extracts were washed with

brine (50 mL), dried over anhydrous magnesium sulfate and

concentrated in vacuo to leave a colourless oil. The oil was

puriﬁed by ﬂash column chromatography on silica, eluting with

ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 : 19) to give the

(2^ꢀS,3^ꢀR,4S,5R,5^ꢀS) isomer 26 (1.5 g, 39%) as a colourless oil.

[a]²_D¹+11.1 (c 1.15 in CHCl₃); (Found: C, 72.2; H, 7.8; N, 2.4.

C₃₂H₃₆NO₅Si requires: C, 72.1; H, 7.6; N, 2.3%;); m_max(liquid

ﬁlm)/cm⁻¹3540, 1788, 1698, 1640; d_H(400 MHz, CDCl₃) 7.70

(4H, d, J 6.9, ArH), 7.48–7.38 (9H, m, ArH), 7.31 (2H, d,

J 6.9, ArH), 5.67 (1H, d, J 7.2, CHPh), 5.48 (1H, apparent

tert-Butyldiphenyl-(5-vinyloxypent-3-enyloxy)-silane 24

Mercury(II) triﬂuoroacetate (750 mg, 1.76 mmol) was

added in one portion to a stirred solution of (E)-5-(tert-

butyldiphenylsilanyloxy)-pent-2-en-1-ol 23b (6.00 g, 17.6 mmol)

in anhydrous ethyl vinyl ether (120 mL) at room temperature.

The solution was stirred at room temperature for 8 h, after which

it was concentrated in vacuo to leave a colourless oil that was

puriﬁed by ﬂash column chromatography on silica, eluting with

diethyl ether–light petroleum (bp 40–60 ^◦C) (1 : 49) to give the

vinyl ether (5.0 g, 78%) as a colourless oil; (Found: C, 75.6; H,

8.4. C₂₃H₃₀O₂Si requires: C 75.4; H, 8.3%); m_max(liquid ﬁlm)/cm⁻¹

1634, 1612; d_H(250 MHz, CDCl₃) 7.70–7.66 (4H, m, ArH), 7.47–

=

dt, J 17 and 10, CH CH₂), 5.08–5.01 (2H, m, CH CH₂),

4.80 (1H, apparent quin., J 6.7, NCHCH₃), 4.01–3.98 (1H, m,

CHOH), 3.77–3.66 (3H, m, CH₂OTBDPS and NCOCHCH₃),

=

2.75 (1H, d, J 2.7, CHOH), 2.58–2.51 (1H, m, CHCH CH₂),

=

7.35 (6H, m, ArH), 6.47 (1H, dd, J 14.3 and 6.8, OCH CH₂),

1.80–1.70 (1H, m, CHHCH₂OTBDPS), 1.68–1.54 (2H, m,

CHHCH₂OTBDPS and CHHCHOH), 1.33–1.21 (4H, m,

NCOCHCH₃and CHHCHOH), 1.08 [9H, s, OSiC(CH₃)₃],

0.90 (3H, d, J 6.7, NCHCH₃); d_C(67.8 MHz, CDCl₃) 177.1 (s,

=

5.82–5.62 (2H, m, CH CHCH₂O and CH CHCH₂O), 4.25–

=

4.16 (3H, m, OCH CHH and CH CHCH₂O), 4.02 (1H, dd,

=

J 6.8 and 2, OCH CHH), 3.72 (2H, t, J 6.7, CH₂OTBDPS),

2.38–2.30 (2H, m, CH₂CH₂OTBDPS), 1.06 [9H, s, OSiC(CH₃)₃];

d_C(67.8 MHz, CDCl₃) 151.4 (d, OCH CH₂), 135.5 (d, Ar),

133.8 (s, Ar), 131.7 (d, CH), 129.6 (d, Ar), 127.6 (d, Ar),

=

NCOCHCH₃), 152.5 (s, NCOO), 141.6 (d, CH CH₂), 135.5

=

(d, Ar), 133.9 (s, Ar), 133.1 (s, Ar), 129.5 (d, Ar), 128.7 (d,

=

Ar), 127.5 (d, Ar), 125.5 (d, Ar), 115.8 (t, CH CH₂), 78.8

=

126.8 (d, CH), 86.9 (t, OCH CH₂), 68.8 (t, CH₂OCH CH₂),

(d, CHPh), 69.0 (d, CHOH), 61.8 (t, CH₂OTBDPS), 54.6

(d, NCHCH₃), 42.8 (d, NCOCHCH₃), 39.2 (t, CH₂), 38.3 (t,

63.3 (t, CH₂OTBDPS), 35.6 (t, CH₂CH₂OTBDPS), 26.8 [q,

•

OSiC(CH₃)₃], 19.2 [s, OSiC(CH₃)₃]; m/z (EI) 309.1322 [M⁺

−

=

CH₂), 37.2 (d, CHCH CH₂), 26.8 [q, OSiC(CH₃)₃], 19.1 [s,

C(CH₃)₃. C₁₉H₂₁O₂Si requires 309.1311].

OSiC(CH₃)₃], 14.3 (q, NCOCHCH₃), 10.7 (q, NCHCH₃); m/z

•

(EI) 542.2405 [M⁺− C(CH₃)₃. C₃₂H₃₆NO₅Si requires 542.2363].

Further elution with ethyl acetate–light petroleum (bp 40–

◦

60 C) (1 : 19) gave the (2^ꢀS,3^ꢀR,4S,5R,5^ꢀR) isomer 27 (1.6 g,

(a)-3-[2-(tert-Butyldiphenylsilanyloxy)-ethyl]-pent-4-enal 25

40%) as a colourless oil. [a]²_D¹+8.7 (c 0.66 in CHCl₃); m_max

(liquid ﬁlm)/cm⁻¹3527, 1783, 1738, 1698, 1640; d_H(400 MHz,

CDCl₃) 7.69 (4H, dd, J 7.5 and 1.6, ArH), 7.46–7.38 (9H,

m, ArH), 7.32 (2H, d, J 6.4, ArH), 5.68 (1H, d, J 7.3,

A solution of tert-butyldiphenyl-(5-vinyloxypent-3-enyloxy)-

silane 24 (3.10 g, 8._◦47 mmol) in toluene (4 mL) was heated in a

sealed tube at 170 C for 36 h. The reaction vessel was cooled

to room temperature over 2 h and the solution was then con-

centrated in vacuo to leave a colourless oil. Puriﬁcation by ﬂash

column chromatography on silica, eluting with ethyl acetate–

=

CHPh), 5.60 (1H, apparent dt, J 17.3 and 9.5, CH CH₂), 5.05–

4.94 (2H, m, CH CH₂), 4.84–4.75 (1H, m, NCHCH₃), 4.10–

=

4.05 (1H, m, CHOH), 3.81 (1H, apparent dq, J 7.1 and 2.7,

NCOCHCH₃), 3.74–3.64 (2H, m, CH₂OTBDPS), 3.02 (1H, s,

CHOH), 2.50–2.40 (1H, m, CH₂CH CH₂), 1.80–1.72 (1H,

m, CHHCH₂OTBDPS), 1.65–1.45 (2H, m, CHHCH₂OTBDPS

and CHHCHOH), 1.27–1.24 (4H, d and m, J 7.1, NCOCHCH₃

and CHHCHOH), 1.07 [9H, s, OSiC(CH₃)₃], 0.90 (3H, d, J

6.6, NCHCH₃); d_C(101 MHz, CDCl₃) 177.4 (s, NCOCHCH₃),

◦

light petroleum (bp 40–60 C) (1 : 9) gave the aldehyde (3.0 g,

97%) as a colourless oil; (Found: C, 75.3; H, 8.4. C₂₃H₃₀O₂Si

requires: C 75.4; H, 8.3%); m_max(liquid ﬁlm)/cm⁻¹2716, 1725,

1688, 1640; d_H(400 MHz, CDCl₃) 9.71 (1H, t, J 2.2, CHO),

7.68 (4H, d, J 7.8, ArH), 7.46–7.38 (6H, m, ArH), 5.69–5.60

=

(1H, m, CH CH₂), 5.07–5.03 (2H, m, CH CH₂), 3.71 (2H, t, J

6.3, CH₂OTBDPS), 2.94–2.89 (1H, m, CHCH CH₂), 2.49–2.37

=

152.5 (s, NCOO), 142.4 (d, CH CH₂), 135.6 (d, Ar), 134.1 (s,

Ar), 133.2 (s, Ar), 129.6 (d, Ar), 128.8 (d, Ar), 127.6 (d, Ar),

(2H, m, CH₂CHO), 1.75–1.57 (2H, m, CH₂CH₂OTBDPS), 1.08

[9H, s, SiC(CH₃)₃]; d_C(67.8 MHz, CDCl₃) 202.3 (d, CHO), 140.3

(d, CH CH₂), 135.5 (d, Ar), 133.7 (s, Ar), 129.6 (d, Ar), 127.6

(d, Ar), 115.7 (t, CH CH₂), 61.2 (t, CH₂OTBDPS), 48.2 (t,

CH₂CHO), 37.2 (t, CH₂CH₂OTBDPS), 34.9 (d, CHCH CH₂),

=

125.6 (d, Ar), 115.0 (t, CH CH₂), 78.9 (d, CHPh), 69.6 (d,

=

CHOH), 61.7 (t, CH₂OTBDPS), 54.7 (d, NCHCH₃), 41.5 (d,

=

NCOCHCH₃), 39.0 (t, CH₂CHOH), 37.4 (d, CHCH CH₂),

=

37.3 (t, CH₂CH₂OTBDPS), 26.9 [q, OSiC(CH₃)₃], 19.2 [s,

OSiC(CH₃)₃], 14.4 (q, NCOCHCH₃), 10.3 (q, NCHCH₃);

26.8 [q, SiC(CH₃)₃], 19.2 [s, SiC(CH₃)₃]; m/z (EI) 309.1286

•

[M⁺− C(CH₃)₃. C₁₉H₂₁O₂Si requires 309.1311].

4 4 2 2

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

View Article Online

m/z (FAB, 3-NBA) 600.3106 (M⁺+ H. C₃₆H₄₆NO₅Si requires

600.3145).

CHCH₃), 1.61–1.49 (3H, m, CH₂CH₂OH and CHHCHOH),

1.25–1.19 (1H, m, CHHCHOH), 0.89 (3H, d, J 7.1, CHCH₃);

=

d_C(67.8 MHz, CDCl₃) 159.1 (s, Ar), 142.3 (d, CH CH₂),

(2R,3R,5S)-5-[2^ꢀ-(tert-Butyldiphenylsilanyloxy)-ethyl]-

2-methylhept-6-ene-1,3-diol 28

=

130.0 (s, Ar), 129.1 (d, Ar), 115.3 (t, CH CH₂), 113.7 (d, Ar),

73.9 (t, CH₂OPMB), 72.8 (t, OCH₂Ar), 71.2 (d, CHOH), 60.4

(t, CH₂OH), 55.1 (q, OCH₃), 38.7 (t, CH₂CHOH), 38.4 (d,

Lithium borohydride (60 mg, 2.75 mmol) was added, cautiously

over 2 min, to a stirred solution of the imide 26 (550 mg,

9.18 mmol) in methanol (88 mg, 110 mm³, 2.75 mmol) and

diethyl ether (10 mL) at 0 ^◦C. The solution was allowed to

warm to room temperature over 30 min, and then stirred at

room temperature for a further 2 h. The mixture was quenched

with aqueous sodium hydroxide (2 mol dm⁻³, 3 mL, 6 mmol)

and extracted into diethyl ether (20 mL). The ether extracts

were dried over anhydrous magnesium sulfate and concentrated

in vacuo to leave a colourless oil that was puriﬁed by ﬂash

column chromatography on silica, eluting with ethyl acetate–

light petroleum (bp 40–60 ^◦C) (3 : 7) to_◦leave the 1,3-diol

(390 mg, 96%) as a colourless oil. [a]²_D¹+10.2 (c 0.92 in CHCl₃);

m_max(liquid ﬁlm)/cm⁻¹3379, 1667, 1640, 1589; d_H(400 MHz,

CDCl₃) 7.69 (4H, d, J 6.2, ArH), 7.44–7.38 (6H, m, ArH), 5.49

=

CHCH₃), 38.3 (t, CH₂CH₂OH), 37.4 (d, CHCH CH₂), 11.2

(q, CHCH₃); m/z (FAB, 3-NBA) 309.2043 (M⁺+ H. C₁₈H₂₉O₄

requires 309.2066).

3-Ethenyl-7-(4-methoxybenzyl)-6-methylheptan-5-olide

(1^ꢀR,4R,6R)-6-[2^ꢀ-(4-methoxybenzyloxy)-1^ꢀ-methylethyl]-

4-vinyltetrahydropyran-2-one 30

Tetrapropylammonium perruthenate(VII) (23 mg, 65 lmol) was

added cautiously to a stirred suspension of the 1,5-diol 29b

(200 mg, 649 lmol), N-methylmorpholine N-oxide (228 mg,

˚

1.95 mmol) and activated 4 A molecular sieves (500 mg) in

dichloromethane (20 mL) at 0 ^◦C under an atmosphere of argon.

The slurry was warmed to room temperature and stirred at

room temperature for 24 h. The mixture was then concentrated

in vacuo to leave a yellow residue that was puriﬁed by ﬂash

column chromatography on silica, eluting with ethyl acetate–

light petroleum (bp 40–60 ^◦C) (1 : 4) to give the lactone (130 mg,

65%) as a colourless oil; d_H(400 MHz, CDCl₃) 7.25 (2H, d, J 8.3,

ArH), 6.88 (2H, d, J 8.5, ArH), 5.73 (1H, ddd, J 17.0, 10.4 and

=

(1H, apparent dt, J 17.8 and 9.1, CH CH₂), 5.04–5.00 (2H, m,

=

CH CH₂), 3.86 (1H, br. d, J 8.7, CHOH), 3.72–3.68 (4H, m,

=

CH₂OH and CH₂OTBDPS), 2.50–2.43 (2H, m, CHCH CH₂

and OH), 2.28 (1H, br. s, OH), 1.79–1.69 (2H, m, CHCH₃and

CHHCH₂OTBDPS), 1.64–1.55 (2H, m, CHHCH₂OTBDPS

and CHHCHOH), 1.33–1.26 (1H, m, CHHCHOH), 1.07 [9H, s,

OSiC(CH₃)₃], 0.90 (3H, d, J 6.9, CHCH₃); d_C(67.8 MHz,

=

6.6, CH CH₂), 5.10–5.05 (2H, m, CH CH₂), 4.53 (1H, dt, J 12

and 3.0, CHOCO), 4.44 (2H, apparent q, J 9.0, OCH₂Ar), 3.81

(3H, s, ArOCH₃), 3.52 (1H, apparent t, J 8.4, CHHOPMB), 3.39

(1H, dd, J 9.2 and 5.3, CHHOPMB), 2.73 (1H, ddd, J 17.5, 5.9

=

CDCl₃) 141.9 (d, CH CH₂), 135.5 (d, Ar), 134 (s, Ar), 129.5

=

(d, Ar), 127.6 (d, Ar), 115.6 (t, CH CH₂), 72.0 (d, CHOH),

=

and 1.6, CHHCO₂), 2.65–2.60 (1H, m, CHCH CH₂), 2.22 (1H,

67.0 (t, CH₂OH), 61.7 (t, CH₂OTBDPS), 39.7 (d, CHCH₃),

dd, J 17.5 and 10.8, CHHCO₂), 2.02–1.95 (1H, m, CHCH₃),

1.98 (1H, br. d, J 12, CHHCHOCO), 1.51 (1H, apparent q, J

12, CHHCHOCO), 0.98 (3H, d, J 6.9, CHCH₃); d_C(67.8 MHz,

CDCl₃) 171.0 (s, C O), 159.1 (s, Ar), 139.8 (d, CH CH₂), 130.3

(s, Ar), 129.3 (d, Ar), 114.7 (t, CH₂CH), 113.7 (d, Ar), 80.1

=

38.9 (t, CH₂), 38.1 (t, CH₂), 37.2 (d, CHCH CH₂), 26.8 [q,

OSiC(CH₃)₃], 19.1 [s, OSiC(CH₃)₃], 10.6 (q, CHCH₃); m/z (EI)

•

351.1766 [M⁺− C(CH₃)₃− H₂O. C₂₂H₂₇O₂Si requires 351.1780].

=

(2R,3R,5S)-5-[2^ꢀ-(tert-Butyldiphenylsilanyloxy)-ethyl]-1-

(4-methoxybenzyloxy)-2-methylhept-6-en-3-ol 29a

(d, CHOCO), 72.9 (t, OCH₂Ar), 71.2 (t, CH₂OPMB), 55.2

(q, ArOCH₃), 38.2 (d, CHCH₃), 35.5 (t, CH₂CO₂), 35.5 (d,

Camphorsulfonic acid (20 mg) was added, in a single portion,

to a solution of the 1,3-diol 28 (b-vinyl) (3.0 g, 7.04 mmol) and

4-methoxybenzyl 2,2,2-trichloroaceti_◦midate (2.2 g, 7.75 mmol)

in dichloromethane (50 mL) at −20 C. The mixture was then

stirred at 0 ^◦C for 72 h. The solution was concentrated in

vacuo to leave an orange oil that was then puriﬁed by ﬂash

column chromatography on silica, eluting with ethyl acetate–

light petroleum (bp 40–60 ^◦C) (1 : 9) to give the ether (2.4 g,

62%) as a colourless oil. [a]²_D¹+9.5^◦(c 1.16 in CHCl₃); (Found:

C, 74.2; H, 8.8. C₃₄H₄₆O₄Si requires: C, 74.7; H, 8.5%); m_max

(liquid ﬁlm)/cm⁻¹3488, 1638, 1612; further elution with ethyl

acetate–light petroleum (bp 40–60 ^◦C) (1 : 4) gave unreacted

starting material (0.7 g, 23%).

=

CHCH CH₂), 32.1 (t, CH₂CHOCO), 11.0 (q, CHCH₃); m/z

•

(EI) 304.1690 (M⁺. C₁₈H₂₄O₄requires 304.1675).

(2R,3R,5R)-5-[2-(tert-Butyldiphenylsilanyloxy)-ethyl]-

2-methylhept-6-ene-1,3-diol 31

Lithium borohydride (153 mg, 7.01 mmol) was added, cautiously

over 2 min, to a stirred solution of the oxazolidinone 27 (1.40 g,

2.34 mmol) in methanol (225 mg, 28.5 mL, 7.01 mmol) and

diethyl ether (30 mL) at 0 ^◦C. The solution was allowed to warm

to room temperature over 30 min and then stirred at room

temperature for a further 30 min. The mixture was quenched

with aqueous sodium hydroxide solution (2 mol dm⁻³, 10 mL,

20 mmol) and extracted into diethyl ether (100 mL). The ether

extracts were dried over anhydrous magnesium sulfate, washed

with brine, and concentrated in vacuo to leave a colourless oil

that was puriﬁed by ﬂash column chromatography on silica,

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (2 :

3) to give the 1,3-diol (700 mg, 70%) as a colourless oil. [a]_D²¹

+5.4 (c 1.14 in CHCl₃); (Found: C, 72.7; H, 9.3. C₂₆H₃₈O₃Si

requires: C 73.2; H, 9.0%); m_max(liquid ﬁlm)/cm⁻¹3374, 3071,

3049, 1640, 1589; d_H(400 MHz, CDCl₃) 7.67 (4H, dd, J 7.8

and 1.5, ArH), 7.45–7.37 (6H, m, ArH), 5.64 (1H, apparent

(3S,5R,6R)-7-(4-Methoxybenzyloxy)-6-methyl-3-

vinylheptane-1,5-diol 29b

Tetrabutylammonium ﬂuoride (635 mg, 2.01 mmol) was added

in a single portion to a stirred solution of the TPS ether

29a (110 mg, 201 lmol) in tetrahydrofuran (2 mL) at room

temperature. The solution was stirred at room temperature for

2 h, and then concentrated in vacuo to leave a coloured residue

that was puriﬁed by ﬂash column chromatography on silica,

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (3 : 1)

to give the 1,5-diol (61 mg, 99%) as a colourless oil. [a]²_D¹+8.4^◦

(c 1.14 in CHCl₃); (Found: C, 69.7; H, 9.5. C₁₈H₂₈O₄requires:

C 70.1; H, 9.2%); m_max(liquid ﬁlm)/cm⁻¹3378, 1639, 1613; d_H

(400 MHz, CDCl₃) 7.24–7.21 (2H, m, ArH), 6.88–6.85 (2H, m,

=

dt, J 17.2 and 9.5, CH CH₂), 5.07–4.99 (2H, m, CH CH₂),

3.97–3.93 (1H, m, CHOH), 3.70–3.64 (4H, m, CH₂OH and

=

CH₂OTBDPS), 2.50–2.36 (3H, m, CHCH CH₂and 2 × OH),

1.78–1.69 (2H, m, CHCH₃and CHHCH₂OTBDPS), 1.55–1.45

(3H, m, CHHCH₂OTBDPS and CH₂CHOH), 1.06 [9H, s,

OSiC(CH₃)₃], 0.93 (3H, d, J 7.1, CHCH₃); d_C(67.8 MHz,

=

ArH), 5.53 (1H, ddd, J 19.1, 10.0 and 9.1, CH CH₂), 5.09–5.01

(2H, m, CH CH₂), 4.41 (2H, apparent d, J 6.8, CH₂OAr), 3.79–

=

CDCl₃) 143.1 (d, CH CH₂), 135.5 (d, Ar), 133.8 (s, Ar), 129.6

(d, Ar), 127.6 (d, Ar), 115.3 (t, CH CH₂), 73.6 (d, CHOH),

67.3 (t, CH₂OH), 61.5 (t, CH₂OTBDPS), 39.5 (t, CH₂CHOH),

38.8 (d, CH), 38.7 (d, CH), 37.6 (t, CH₂CH₂OTBDPS), 26.8 [q,

=

3.74 (4H, m, OCH₃and CHOH), 3.67–3.55 (2H, m, CH₂OH),

3.48–3.43 (2H, m, CH₂OPMB), 2.99 (1H, br. s, OH), 2.77 (1H,

br. s, OH), 2.46–2.41 (1H, m, CHCH CH₂), 1.85–1.79 (1H, m,

=

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 2 3

View Article Online

OSiC(CH₃)₃], 19.2 [s, OSiC(CH₃)₃], 9.9 (q, CHCH₃); m/z (EI)

column chromatography on silica, eluting with ethyl acetate–

light petroleum (bp 40–60 ^◦C) (1 : 4) to give the lactone (24 mg,

57%) as a colourless oil; m_max(CHCl₃)/cm⁻¹1724, 1602; d_H

(400 MHz, CDCl₃) 7.26–7.22 (2H, m, ArH), 6.90–6.87 (2H,

•

351.1771 [M⁺− C(CH₃)₃− H₂O. C₂₂H₂₇O₂Si requires 351.1780].

(2R,3R,5R)-5-[2-(tert-Butyldiphenylsilanyloxy)-ethyl]-1-

(4-methoxybenzyloxy)-2-methylhept-6-en-3-ol 32a

=

m, ArH), 5.84 (1H, ddd, J 16.9, 10.6 and 6.4, CH CH₂), 5.15–

=

5.05 (2H, m, CH CH₂), 4.49 (1H, dt, J 11.4 and 4.0, CHOCO),

Camphorsulfonic acid (10 mg) was added, in a single portion,

to a stirred solution of the 1,3-diol 31 (3.04 g, 7.14 mmol) and

4-methoxybenzyl 2,2,2-trichloroacetimidate (2.20 g, 7.85 mmol)

in dichloromethane (30 mL) at −20 ^◦C. The mixture was stirred

at 0 ^◦C for 72 h and then concentrated in vacuo to leave an orange

oil that was puriﬁed by ﬂash column chromatography on silica,

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 : 9) to

give the ether (2.34 g, 60%) as a colourless oil. [a]²_D¹+6.9 (c 0.96 in

CHCl₃); m_max(liquid ﬁlm)/cm⁻¹3502, 1713, 1612; d_H(400 MHz,

CDCl₃) 7.68 (4H, dd, J 7.8 and 1.6, ArH), 7.45–7.37 (6H, m,

ArH), 7.26 (2H, d, J 8.4, ArH), 6.89 (2H, d, J 8.4, ArH), 5.64–

4.43 (2H, apparent q, J 11.0, OCH₂Ar), 3.81 (3H, s, ArOCH₃),

3.47 (1H, dd, J 9.3 and 7.4, CH₂OPMB), 3.39 (1H, dd, J 9.3

=

and 5.3, CH₂OPMB), 2.79–2.74 (1H, m, CHCH CH₂), 2.57

(1H, dd, J 16.6 and 6.1, CHHCO₂), 2.50 (1H, ddd, J 16.6,

7.4 and 0.6, CHHCO₂), 2.01–1.90 (2H, m, CHHCHOCO and

CHCH₃), 1.69 (1H, dt, J 14.1 and 7.6, CHHCHOCO), 1.01 (3H,

=

d, J 7.0, CHCH₃); d_C(67.8 MHz, CDCl₃) 172.1 (s, C O), 159.2

=

(s, Ar), 139.6 (d, CH CH₂), 130.3 (s, Ar), 129.3 (d, Ar), 115.3 (t,

=

CH₂CH), 113.8 (d, Ar), 77.1 (d, CHOCO), 72.9 (t, OCH₂Ar),

71.4 (t, CH₂OPMB), 55.3 (q, ArOCH₃), 37.9 (d, CHCH₃), 34.1

(t, CH₂CO₂), 32.8 (d, CHCH CH₂), 30.7 (t, CH₂CHOCO),

=

5.56 (1H, m, CH CH₂), 5.00–4.95 (2H, m, CH CH₂), 4.45

(2H, apparent d, J 4.0, OCH₂Ar), 3.90–3.86 (1H, m, CHOH),

3.81 (3H, s, OCH₃), 3.71–3.65 (2H, m, CH₂OTBDPS), 3.51–3.48

(2H, m, CH₂OPMB), 2.37 (1H, br. s, OH), 2.42–2.33 (1H, m,

11.5 (q, CHCH₃).

(3R,5R,6R)-3-[2-(tert-Butyldiphenylsilanyloxy)-ethyl]-7-

(4-methoxybenzyloxy)-6-methylheptane-1,5-diol 34

=

CHCH CH₂), 1.88–1.82 (1H, m, CHHCH₂OTBDPS), 1.77–

(a) From the alkene 32a. A solution of 9-borabicyclo-

[3.3.1]nonane (0.5 mol dm⁻³in tetrahydrofuran, 4.0 mL, 2.02

mmol) was added dropwise over 5 min to a stirred solution of

th_◦e alkene 32a (500 mg, 920 lmol) in tetrahydrofuran (2 mL) at

1.70 (1H, m, CHCH₃), 1.55–1.44 (3H, m, CHHCH₂OTBDPS

and CH₂CHOH), 1.06 [9H, s, OSiC(CH₃)₃], 0.93 (3H, d, J

7.0, CHCH₃); d_C(101 MHz, CDCl₃) 159.3 (s, Ar), 143.1 (d,

CH CH₂), 135.7 (d, Ar), 134.1 (s, Ar), 130.4 (s, Ar), 129.6

(d, Ar), 129.3 (d, Ar), 127.7 (d, Ar), 114.7 (t, CH CH₂),

113.9 (d, Ar), 74.5 (t, CH₂OPMB), 73.1 (t, OCH₂Ar), 71.9 (d,

CHOH), 61.8 (t, CH₂OTBDPS), 55.3 (q, ArOCH₃), 39.6 (t,

CH₂CHOH), 38.0 (d, CHCH₃), 37.6 (t, CH₂CH₂OTBDPS), 37.4

(d, CHCH CH₂), 26.9 [q, OSiC(CH₃)₃], 19.3 [s, OSiC(CH₃)₃],

10.4 (q, CHCH₃); m/z (FAB, 3-NBA) (%) 547 (3), 121 (100).

=

◦

0 C. The solution was stirred at 0 C for 30 min and then at

=

room temperature for 12 h, after which it was cooled to 0 ^◦C. An

aqueous solution of sodium hydroxide (2 mol dm⁻³, 5 mL) was

added in one portion to the solution, followed immediately by

the dropwise addition of hydrogen peroxide (100 vol, 5 mL)

over 5 min. The heterogeneous mixture was stirred vigorously

at 0 ^◦C for 4 h, extracted with diethyl ether (40 mL), washed

with brine (10 mL) and then dried over anhydrous magnesium

sulfate. The solution was concentrated in vacuo to leave a residue

that was puriﬁed by ﬂash column chromatography on silica,

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (3 :

7) to give the alcohol (470 mg, 91%) as a colourless oil. [a]_D²¹

+12.4 (c 0.50 in CHCl₃); m_max(CHCl₃)/cm⁻¹3429, 1612, 1513;

d_H(400 MHz, CDCl₃) 7.68 (4H, dd, J 7.8 and 1.5, ArH), 7.75–

7.37 (6H, m, ArH), 7.24 (2H, apparent d, J 8.6, ArH), 6.88 (2H,

apparent d, J 8.6, ArH), 4.43 (2H, apparent dd, J 18.3 and 11.6,

OCH₂Ar), 3.81–3.78 (4H, m, ArOCH₃and CHOH), 3.73–3.63

(4H, m, CH₂OTBDPS and CH₂CH₂OH), 3.52–3.44 (2H, m,

CH₂OPMB), 3.03 (1H, br. s, OH), 2.49 (1H, br. s, OH), 1.88–

1.75 (2H, m, CHCH₂CH₂OH and CHCH₃), 1.66–1.40 (5H, m,

CH₂CH₂OTBDPS, CH₂CH₂OH and CHHCHOH), 1.27–1.18

(1H, m, CHHCHOH), 1.06 [9H, s, OSiC(CH₃)₃], 0.89 (3H, d, J

7.1, CHCH₃); d_C(101 MHz, CDCl₃) 135.7 (d, Ar), 134.0 (s, Ar),

130.1 (s, Ar), 129.7 (d, Ar), 129.4 (d, Ar), 127.8 (d, Ar), 114.0 (d,

Ar), 74.7 (t, CH₂OPMB), 73.4 (d, CHOH), 73.2 (t, OCH₂Ar),

62.3 (t, CH₂OH), 60.6 (t, CH₂OTBDPS), 55.4 (q, OCH₃),

38.4 (d, CHCH₃), 38.1 (t, CH₂CHOH), 38.1 (t, CH₂CH₂OH),

37.6 (t, CH₂CH₂OTBDPS), 28.9 (d, CHCH₂CH₂OH), 27.0 [q,

OSiC(CH₃)₃], 19.2 [s, OSiC(CH₃)₃], 11.0 (q, CHCH₃).

=

(3R,5R,6R)-7-(4-Methoxybenzyloxy)-6-methyl-

3-vinylheptane-1,5-diol 32b

Tetrabutylammonium ﬂuoride (180 mg, 550 lmol) was added

in one portion to a stirred solution of the alkene 32a (100 mg,

180 lmol) in tetrahydrofuran (5 mL) at room temperature. The

solution was stirred at room temperature for 2 h, and then the

mixture was concentrated in vacuo to leave a coloured residue

that was puriﬁed by ﬂash column chromatography on silica,

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 :

3) to leave the 1,5-diol (47 mg, 83%) as a colourless oil; m_max

(CHCl₃)/cm⁻¹3620, 3482, 1612, 1514; d_H(400 MHz, CDCl₃)

7.24 (2H, d, J 8.6, ArH), 6.88 (2H, d, J 8.6, ArH), 5.73–5.63 (1H,

=

m, CH CH₂), 5.08–5.00 (2H, m, CH CH₂), 4.43 (2H, d, J 5.0,

OCH₂Ar), 3.89–3.86 (1H, m, CHOH), 3.81 (3H, s, ArOCH₃),

3.72–3.60 (2H, m, CH₂OH), 3.49–3.46 (2H, m, CH₂OPMB),

=

2.82 (1H, br. s, OH), 2.37–2.30 (1H, m, CHCH CH₂), 1.95–1.83

(2H, m, OH and CHHCH₂OH), 1.80–1.72 (1H, m, CHCH₃),

1.58–1.39 (3H, m, CHHCH₂OH and CH₂CHOH), 0.92 (3H,

d, J 7.1, CHCH₃); d_C(101 M, CDCl₃) 159.3 (s, Ar), 143.2 (d,

CH CH₂), 130.2 (s, Ar), 129.3 (d, Ar), 114.7 (t, CH CH₂),

113.7 (d, Ar), 74.4 (t, OCH₂Ar), 73.1 (t, CH₂OPMB), 71.6

(d, CHOH), 61.0 (t, CH₂OH), 55.3 (q, ArOCH₃), 39.5 (t,

=

(b) From the TBS ether 41. Pyridinium p-toluenesulfonate

(40 mg, 1.60 lmol) was added to a stirred solution of the

TBS ether 41 (100 mg, 150 lmol) in ethanol (2 mL) at_◦room

temperature. The solution was stirred and heated at 55 C for

2 h and then concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography on silica, eluting with ethyl

acetate–light petroleum (bp 40–60 ^◦C) (3 : 7) to give the alcohol

(60 mg, 72%) as a colourless oil which exhibited identical data

to those presented under section (a) above.

=

CH₂CHOH), 38.2 (d, CHCH₃), 37.6 (d, CHCH CH₂), 37.1

(t, CH₂CH₂OH), 10.7 (q, CHCH₃).

(1^ꢀS,4S,6R)-6-[2^ꢀ-(4-Methoxybenzyloxy)-1^ꢀ-methylethyl]-

4-vinyltetrahydropyran-2-one 33

Tetrapropylammonium perruthenate(VII) (5 mg, 14 lmol) was

added cautiously to a stirred suspension of the 1,5-diol 32b

(43 mg, 140 lmol), N-methylmorpholine N-oxide (50 mg,

˚

420 lmol) and activated 4 A molecular sieves (200 mg) in

(1^ꢀR,4R,6R)-4-[2-(tert-Butyldiphenylsilanyloxy)-ethyl]-6-[2^ꢀ-(4-

dichloromethane (5 mL) at 0 ^◦C under an atmosphere of argon.

The slurry was warmed to room temperature and stirred at

room temperature for 24 h The mixture was then concentrated

in vacuo to leave a yellow residue that was puriﬁed by ﬂash

methoxybenzyloxy)-1^ꢀ-methylethyl]-tetrahydropyran-2-one 35

A freshly prepared precipitate of silver nitrate on Celite (2.2 g)

was added to a stirred solution of the 1,5-diol 34 (130 mg, 230

4 4 2 4

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

View Article Online

lmol), in benzene (20 mL) at room temperature. The slurry

was then stirred and heated at 80 ^◦C for 3 h, after which

it was cooled to room temperature, ﬁltered through a pad of

Celite and concentrated in vacuo to leave a colourless oil. The

oil was puriﬁed by ﬂash column chromatography on silica,

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 :

4) to give the lactone (117 mg, 91%) as a colourless oil. [a]_D²¹

−8.9 (c 0.81 in CHCl₃); m_max(CHCl₃)/cm⁻¹1719, 1612; d_H

(400 MHz, CDCl₃) 7.65 (4H, d, J 7.6, ArH), 7.44–7.38 (6H,

m, ArH), 7.26 (2H, d, J 6.9, ArH), 6.89 (2H, d, J 6.9), 4.49–

4.40 (3H, m, ArCH₂O and CHOCO), 3.81 (3H, s, ArOCH₃),

3.71 (2H, t, J 5.4, CH₂OTBDPS), 3.52 (1H, apparent t, J 8.5,

CHHOPMB), 3.92–3.56 (1H, m, CHHOPMB), 2.67 (1H, dd, J

17.5 and 5.8, CHCHHCO₂), 2.25–2.10 (1H, m, CHCH₂CO₂),

2.04 (1H, dd, J 17.5 and 11.0, CHCHHCO₂), 1.97–1.90 (1H,

m, CHCH₃), 1.76 (1H, br. d, J ≈ 13, CHHCHOCO), 1.55 (2H,

apparent q, J 5.8, CH₂CH₂OTBDPS), 1.30 (1H, apparent q, J

12.3, CHHCHOCO), 1.06 [9H, s, C(CH₃)]₃, 0.95 (3H, d, J 6.9,

(c 0.84 in CHCl₃); m_max(CHCl₃)/cm⁻¹1726, 1685; d_H(360 MHz,

CDCl₃) 9.74 (1H, d, J 0.9 CHO), 7.67–7.64 (4H, m, ArH),

7.47–7.38 (6H, m, ArH), 4.64 (1H, ddd, J 12.1, 4.5 and 2.9,

CHOH), 3.72 (2H, t, J 6.0, CH₂OTBDPS), 2.71 (1H, ddd,

J 17.5, 5.7 and 1.8, CHHCO₂), 2.59–2.53 (1H, m, CHCH₃),

2.27–2.19 (1H, m, CHCH₂CH₂OTBDPS), 2.08 (1H, dd, J 17.5

and 10.9, CHHCO₂), 1.89 (1H, br. d, J 14, CHHCHOCO),

1.56 (2H, apparent q, J 6.2, CH₂CH₂OTBDPS), 1.33–1.23

(1H, m, CHHCHOCO), 1.21 (3H, d, J 7.2, CHCH₃), 1.06

[9H, s, SiC(CH₃)₃]; d_C(67.8 MHz, CDCl₃) 202.0 (d, CHO),

=

170.5 (s, C O), 135.5 (d, Ar), 133.4 (s, Ar), 129.8 (d, Ar),

127.7 (d, Ar), 79.1 (d, CHOCO), 60.6 (t, CH₂OTBDPS), 50.2

(d, CHCH₃), 38.6 (t, CH₂CH₂OTBDPS), 36.2 (t, CH₂CO₂),

32.2 (t, CH₂CHOCO), 28.5 (d, CHCH₂CH₂OTBDPS), 26.8

[q, SiC(CH₃)₃], 19.1 [s, SiC(CH₃)₃], 8.5 (q, CHCH₃); m/z (EI)

•

381.1514 [M⁺− C(CH₃)₃. C₂₂H₂₅O₄Si requires 381.1522].

(1^ꢀR,4R,6R)-4-[2-(tert-Butyldiphenylsilanyloxy)-ethyl]-

=

CHCH₃); d_C(67.8 MHz, CDCl₃) 171.6 (s, C O), 159.2 (s, Ar),

135.5 (d, Ar), 133.5 (s, Ar), 130.4 (s, Ar), 129.7 (d, Ar), 129.3

6-(1^ꢀ-methylprop-2^ꢀ-ynyl)-tetrahydropyran-2-one 37

=

(d, Ar), 127.7 (d, Ar), 113.8 (d, Ar), 80.2 (d, CHOC O), 72.9

A solution of potassium tert-butoxide (11 mg, 96 lmol) in

tetrahydrofuran (1 mL) was added dropwise over 2 min to a

stirred solution of dimethyl diazomethylphosphonate (13 mg,

88 lmol) in tetrahydrofuran (1 mL) at −78 ^◦C. The solution

was stirred at −78 ^◦C for 30 min, after which it was added to a

solution of the aldehyde 36 (35 mg, 80 lmol) in tetrahydrofuran

(0.5 mL) at −78 ^◦C. The mixture was stirred at −78 ^◦C for 2 h

and then quenched by the addition of water (1 mL), allowed

to warm to room temperature and extracted into diethyl ether

(10 mL). The organic extracts were dried over anhydrous mag-

nesium sulfate and concentrated in vacuo to leave a colourless

oil that was puriﬁed by ﬂash column chromatography on silica,

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (2 :

3) to give the acetylene (32 mg, 92%) as a colourless oil.

[a]²_D¹+5.6 (c 1.00 in CHCl₃); m_max(CHCl₃)/cm⁻¹3307, 2990,

2858, 1727; d_H(400 MHz, CDCl₃) 7.67–7.65 (4H, m, ArH),

7.47–7.38 (6H, m, ArH), 4.16–4.10 (1H, m, CHOCO), 3.73

(2H, t, J 5.9, CH₂OTBDPS), 2.77–2.65 (2H, m, CHHCOO

and CHCH₃), 2.25–2.16 (2H, m, CHCH₂CH₂OTBDPS and

CHHCOO), 2.12 (1H, d, J 2.4, C≡CH), 1.65–1.56 (3H,

m, CH₂CH₂OTBDPS and CHHCHOCO), 1.36–1.25 (4H, m,

CHCH₃and CHHCHOCO), 1.06 [9H, s, OSiC(CH₃)₃]; d_C

(t, ArCH₂O), 71.4 (t, CH₂OPMB), 60.8 (t, CH₂OTBDPS), 55.2

(q, ArOCH₃), 38.8 (t, CH₂CH₂OTBDPS), 38.1 (d, CHCH₃),

36.4 (t, CH₂CO₂), 32.4 (t, CH₂CHOCO), 28.5 (d, CHCH₂CO₂),

26.8 [q, C(CH₃)₃], 19.1 [s, C(CH₃)₃], 10.9 (q, CHCH₃); m/z (EI)

•

503.2248 [M⁺− C(CH₃)₃. C₃₀H₃₅O₅Si requires 503.2254].

(2R,4^ꢀR,6^ꢀR)-2-{4^ꢀ-[2-(tert-Butyldiphenylsilanyloxy)-ethyl]-

6^ꢀ-oxo-tetrahydropyran-2^ꢀ-yl}-propionaldehyde 36

2,3-Dichloro-5,6-dicyanobenzoquinone (35 mg, 150 lmol) was

added in a single portion to a stirred solution of the d-lactone

35 (55 mg, 98 lmol) in dichloromethane (2 mL) and water

(0.1 mL) at room temperature. The slurry was stirred at room

temperature for 2 h and then quenched by the addition of

saturated aqueous sodium bicarbonate solution (5 mL). The

mixture was extracted with dichloromethane (50 mL), washed

with brine (10 mL) and dried over anhydrous magnesium

sulfate. The solution was then concentrated in vacuo to leave

a residue that was puriﬁed by ﬂash column chromatography

on silica, eluting with ethyl acetate–light petroleum (bp 40–

60 ^◦C) (3 : 1) to give the corresponding alcohol (43 mg,

100%) as a colourless oil. [a]²_D¹−4.1 (c 1.26 in CHCl₃); m_max

(CHCl₃)/cm⁻¹3446, 1732, 1589; d_H(400 MHz, CDCl₃) 7.66–

7.65 (4H, m, ArH), 7.47–7.38 (6H, m, ArH), 4.49 (1H, dt,

=

(101 MHz, CDCl₃) 170.8 (s, C O), 135.6 (d, Ar), 133.6 (s,

Ar), 129.9 (d, Ar), 127.8 (d, Ar), 84.0 (s, C≡C), 82.3 (d,

CHOCO), 71.4 (s, C≡C), 60.9 (t, CH₂OTBDPS), 38.7 (t,

CH₂CH₂OTBDPS), 36.4 (t, CH₂CO₂), 32.2 (d, CHCH₃), 32.1

(t, CH₂CHOCO), 28.3 (d, CHCH₂CH₂OTBDPS), 27.0 [q,

SiC(CH₃)₃], 19.3 [s, SiC(CH₃)₃], 17.1 (q, CHCH₃).

=

J 12.0 and 3.0, CHOC O), 3.74–3.70 (3H, m, CH₂OTBDPS

and CHHOH), 3.60 (1H, dd, J 10.8 and 5.5, CHHOH), 2.68

(1H, ddd, J 17.5, 5.9 and 1.8, CHHCO₂), 2.34–2.14 (1H,

m, CHCH₂CO₂), 2.06 (1H, dd, J 17.5 and 10.8, CHHCO₂),

1.88–1.78 (2H, m, CHCH₃and CHHCHCH₂CO₂), 1.57 (2H,

apparent q, J 6, CH₂CH₂OTBDPS), 1.34 (1H, apparent q, J

≈ 13, CHHCHCH₂CO₂), 1.06 [9H, s, C(CH₃)₃], 0.95 (3H, d,

(1^ꢀR,2^ꢀE,4R,6R)-4-[2-(tert-Butyldiphenylsilanyloxy)-ethyl]-6-

(1^ꢀ-methyl-3^ꢀ-tributylstannanylallyl)-tetrahydropyran-2-one 38

=

J 7.0, CHCH₃); d_C(101 MHz, CDCl₃) 171.6 (s, C O), 135.6

Silver nitrate (1 mg) was added to a stirred solution of the

acetylene 37 (30 mg, 69 lmol) and N-bromosuccinimide (14 mg,

76 lmol) in acetone (1 mL) at room temperature. The solution

was stirred at room temperature for 3 h, ﬁltered through a plug of

silica and concentrated in vacuo to leave the crude bromoacety-

lene intermediate. A solution of this bromoacetylene (35 mg,

68 lmol) in tetrahydrofuran (2 mL) was added added dropwise

over 5 min to a stirred solution of triphenylphosphine (0.7 mg,

2.7 lmol) and tris(dibenzylideneacetone) dipalladium complex

(0.6 mg, 0.7 lmol) in degassed tetrahydrofuran (1 mL) at room

temperature. The solution was stirred at room temperature for

5 min and then tributyltin hydride (43 mg, 40 mm³, 150 lmol)

was added dropwise over 1 min. The mixture was stirred at

room temperature for 30 min, diluted with potassium ﬂuoride

solution (20% in water, 5 mL) and stirred vigorously for 3 h.

The mixture was extracted into diethyl ether, dried over anhy-

drous magnesium sulfate and concentrated in vacuo to leave a

colourless oil that was puriﬁed by ﬂash column chromatography

(d, Ar), 133.6 (s, Ar), 129.8 (d, Ar), 127.8 (d, Ar), 80.5 (d,

=

CHOC O), 64.4 (t, CH₂OH), 60.9 (t, CH₂OTBDPS), 39.8 (d,

CHCH₃), 38.9 (t, CH₂CH₂OTBDPS), 36.5 (t, CH₂CO₂), 32.4

=

(t, CH₂CHOC O), 28.7 (d, CHCH₂CO₂), 26.9 (q, C(CH₃)₃),

•

19.2 (s, C(CH₃)₃), 10.6 (q, CHCH₃); m/z (EI) 383.1691 [M⁺

−

C(CH₃)₃. C₂₂H₂₇O₄Si requires 383.1679].

Dess–Martin periodinane (73 mg, 170 lmol) was added to

a stirred solution of the above alcohol (50 mg, 114 lmol)

and water (3.1 mg, 3.1 mm³, 170 lmol) in dichloromethane

(2.5 mL) at 0 ^◦C. The slurry was stirred at room temperature

for 1 h and then quenched by the addition of a saturated

aqueous solution of sodium thiosulfate (2 mL), extracted into

dichloromethane (20 mL), dried over anhydrous MgSO₄and

concentrated in vacuo to leave a colourless residue. The residue

was puriﬁed by ﬂash column chromatography on silica, eluting

with ethyl acetate–light petroleum (bp 40–60 ^◦C) (2 : 3) to

give the aldehyde (42 mg, 84%) as a colourless oil. [a]²_D¹+5.7

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 2 5

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on silica, eluting with diethyl ether–light petroleum (bp 40–

60 ^◦C) (1 : 4) to give the vinyl stannane (35 mg, 70%) as a

colourless oil. [a]_D²¹+3.0 (c 0.46 in CHCl₃); m_max(CHCl₃)/cm⁻¹

3072, 2960, 2929, 1721; d_H(400 MHz, CDCl₃) 7.65 (4H, dd,

J 6.8 and 1.1, ArH), 7.47–7.38 (6H, m, ArH), 6.03 (1H, d, J

(7H, m, CHHCHOCO and Bu₃Sn-3 × CH₂), 1.09 (3H, d, J 6.8,

CHCH₃) 0.93–0.81 (15H, m, Bu₃Sn-3 × CH₂and 3 × CH₃);

d_C(90.6 MHz, CDCl₃), 199.4 (d), 170.3 (s), 148.3 (d), 130.3 (d),

83.2 (d), 49.8 (t), 46.3 (d), 35.8 (t), 32.1 (t), 29.0 (t), 27.1 (t), 25.8

(d), 15.4 (q), 13.6 (q), 9.4 (t); m/z (FAB), 427.1427 (M − Bu:

C₁₉H₃₃O₃¹¹⁸Sn requires 427.1446), 429 (100%), 427 (80).

=

19, CH CH), 5.87 (1H, dd, J 19 and 7.0, CH CH), 4.15–4.11

(1H, m, CHOCO), 3.70 (2H, t, J 5.9, CH₂OTBDPS), 2.66 (1H,

dd, J 17.2 and 5.7, CHHCOO), 2.47–2.42 (1H, m, CHCH₃),

2.20–2.11 (1H, m, CHCH₂CH₂OTBDPS), 2.01 (1H, dd, J 17.3

and 11.0, CHHCOO), 1.88 (1H, br. d, J 14, CHHCHOCO),

1.60–1.43 (8H, m, CH₂CH₂OTBDPS and 3 × CH₂CH₂), 1.35–

1.27 (7H, m, CHHCHOCO and 3 × CH₂CH₂), 1.11 (3H, d, J

6.5, CHCH₃), 1.06 [9H, s, OSiC(CH₃)₃], 0.97–0.80 (15H, m, 3 ×

CH₃CH₂CH₂and 3 × CH₂Sn); d_C(101 MHz, CDCl₃) 171.5 (s,

(b) From the triol 48. Silica-supported sodium periodate

(4.00 g, 4.80 mmol) was added in one portion to a stirred solution

of the triol 48 (790 mg, 1.61 mmol) in dichloromethane (10 mL)

at room temperature. The slurry was stirred at room temperature

for 15 min, then ﬁltered and washed with dichloromethane (2 ×

10 mL). The combined ﬁltrates were concentrated in vacuo to

leave an oil which was puriﬁed by ﬂash column chromatography

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 : 1)

to give the corresponding lactol 49 (636 mg, 81%) as a colourless

oil (1 : 1 mixture of anomers).

Silver carbonate on Celite (50 wt%, 7.10 g, 13.0 mmol) was

added in one portion to a stirred solution of the lactol (630 mg,

1.30 mmol) in toluene (40 mL) at room temperature, and the

resulting slurry was heated at reﬂux for 3 h and then cooled

to room temperature. The slurry was ﬁltered, and the residue

was washed with ethyl acetate. The combined ﬁltrates were

concentrated in vacuo to leave an oil which was puriﬁed by

ﬂash column chromatography, eluting with ethyl acetate–light

petroleum (bp 40–60 ^◦C) (1 : 3) to give the lactone (473 mg, 61%

over two steps) as a colourless oil whose spectroscopic data were

identical with those presented under section (a) above.

=

C

O), 148.7 (d, CH CH), 135.6 (d, Ar), 133.6 (s, Ar), 130.0 (d,

=

CH CH), 129.8 (d, Ar), 127.8 (d, Ar), 83.8 (d, CHOCO), 60.8 (t,

CH₂OTBDPS), 46.4 (d, CHCH₃), 39.0 (t, CH₂CH₂OTBDPS),

36.5 (t, CH₂CO₂), 32.5 (t, CH₂CHOCO), 29.2 (t, CH₂CH₂),

28.4 (d, CHCH₂CH₂OTBDPS), 27.3 (t, CH₂CH₂), 26.9 [q,

OSiC(CH₃)₃], 19.2 [s, OSiC(CH₃)₃], 15.5 (q, CHCH₃), 13.8

(CH₃CH₂CH₂), 9.6 (t, CH₂Sn); m/z (FAB, 3-NBA, MeOH)

727.3594 (M⁺+ H. C₃₉H₆₃O₃Si¹²⁰Sn requires 727.3568).

(1^ꢀR,2^ꢀE,2R,4R)-[2-(1^ꢀ-Methyl-3^ꢀ-tributylstannanylallyl)-

6-oxotetrahydropyran-4-yl]-acetaldehyde 7

(a) From the TBS ether 38. Tetrabutylammonium ﬂuoride

(44 mg, 140 lmol) was added to a stirred solution of the TPS

ether 38 (34 mg, 47 lmol) and p-toluenesulfonic acid (10 mg,

52 lmol) in tetrahydrofuran (2 mL) at room temperature.

The solution was stirred at room temperature for 3 h and

then concentrated in vacuo to leave a red residue that was

puriﬁed by ﬂash column chromatography_◦on silica, eluting with

ethyl acetate–light petroleum (bp 40–60 C) (3 : 2) to give the

corresponding alcohol (16 mg, 70%) as a colourless oil. [a]_D²¹

+21.7 (c 0.24 in CHCl₃); m_max(CHCl₃)/cm⁻¹3620, 3442, 1720,

(2R,3R,5S)-5-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-1-

(4-methoxybenzyloxy)-2-methylhept-6-en-3-ol 39

tert-Butylchlorodimethylsilane (690 mg, 4.53 mmol) was added

in a single portion to a stirred solution of the 1,5-diol 29a

(1.28 g, 4.12 mmol) and imidazole (310 mg, 4.53 mmol) in

dichloromethane (40 mL) at room temperature. The white

suspension was stirred at room temperature for 2 h after which it

was concentrated in vacuo to leave a white solid. The residue was

washed with diethyl ether (150 mL), the imidazole hydrochloride

salt removed by ﬁltration and the organic extracts concentrated

in vacuo to leave a colourless oil that was puriﬁed by ﬂash

column chromatography on silica, eluting with ethyl acetate–

light petroleum (bp 40–60 ^◦C) (1 : 9) to give the silyl ether

(1.43 g, 82%) as a colourless oil. [a]²_D¹+5.2 (c 0.54 in CHCl₃);

m_max(CHCl₃)/cm⁻¹3482, 1612; d_H(400 MHz, CDCl₃) 7.24 (2H,

d, J 8.6, ArH), 6.88 (2H, d, J 8.6, ArH), 5.50 (1H, apparent

=

1602; d_H(400 MHz, CDCl₃) 6.04 (1H, d, J 19, CH CH), 5.86

(1H, dd, J 19 and 7.1, CH CH), 4.18–4.13 (1H, m, CHOCO),

=

3.72 (2H, t, J 6.2, CH₂OH), 2.77–2.72 (1H, m, CHHCOO),

2.49–2.43 (1H, m, CHCH₃), 2.19–2.05 (2H, m, CHCH₂CH₂OH

and CHHCOO), 1.99 (1H, br. d, J 15.7, CHHCHOCO),

1.64–1.41 (8H, m, CH₂CH₂OH and 3 × CH₂CH₂), 1.36–1.26

(7H, m, CHHCHOCO and 3 × CH₂CH₂), 1.13 (3H, d, J

6.8, CHCH₃), 0.97–0.84 (15H, m, 3 × CH₃CH₂CH₂and 3 ×

=

CH₂Sn); d_C(67.8 MHz, CDCl₃) 171.4 (s, C O), 148.6 (d,

=

CH CH), 130.1 (d, CH CH), 83.6 (d, CHOCO), 59.7 (t,

CH₂OH), 46.6 (d, CHCH₃), 38.9 (t, CH₂CH₂OH), 36.4 (t,

CH₂CO₂), 32.5 (t, CH₂CHOCO), 29.1 (t, CH₂CH₂), 28.2 (d,

CHCH₂CH₂OH), 27.2 (t, CH₂CH₂), 15.6 (q, CHCH₃), 13.7 (q,

CH₃CH₂CH₂), 9.5 (t, CH₂Sn).

=

dt, J 19.5 and 9.8, CH CH₂), 5.06–5.02 (2H, m, CH CH₂),

4.44 (2H, d, J 7.7, OCH₂Ar), 3.81 (3H, s, ArOCH₃), 3.78–

3.74 (1H, m, CHOH), 3.67–3.55 (2H, m, CH₂OTBDMS), 3.47

(2H, d, J 5.7, CH₂OPMB), 2.51 (1H, d, J 5.2, OH), 2.45–2.36

=

(1H, m, CHCH CH₂), 1.88–1.82 (1H, m, CHCH₃), 1.68–1.59

A solution of the alcohol (4 mg, 8 lmol) in dicloromethane

(0.5 mL) was added to a stirred solution of Dess–Martin

periodinane (7 mg, 16 lmol) and pyridine (1.3 mg, 1.3 mm³,

16 lmol) in dichloromethane (0.5 mL) at room temperature.

The slurry was stirred at room temperature for 1 h and then

quenched by the addition of a saturated solution of sodium

thiosulfate (1 mL), extracted into dichloromethane (10 mL),

dried over anhydrous MgSO₄and concentrated in vacuo to

leave a white residue. The residue was puriﬁed by ﬂash column

chromatography on silica, eluting with ethyl acetate–light

petroleum (bp 40–60 ^◦C) (1 : 4) to give the lactone aldehyde

(2.7 mg, 70%) as a colourless oil. [a]²_D¹+12 (c 1.00 in CHCl₃);

(Found: C, 56.4; H, 8.6. C₂₃H₄₂O₃Sn requires: C, 56.7; H, 8.7%);

m_max(sol.)/cm⁻¹2730 (w), 1731; d_H(360 MHz, CDCl₃), 9.74

(1H, m, CH₂CH₂OTBDMS), 1.56–1.47 (2H, m, CHHCHOH

and CHHCH₂OTBDMS), 1.29–1.22 (1H, m, CHHCHOH),

0.93–0.89 [12H, m, CHCH₃and OSiMe₂C(CH₃)₃], 0.05 [6H, s,

OSi(CH₃)₂C(CH₃)₃]; d_C(67.8 MHz, CDCl₃) 159.2 (s, Ar), 142.2

(d, CH CH₂), 130.2 (s, Ar), 129.2 (d, Ar), 115.4 (t, CH CH₂),

113.8 (d, Ar), 74.1 (t, CH₂OPMB), 72.9 (t, OCH₂Ar), 71.3

(d, CHOH), 61.3 (t, CH₂OTBDMS), 55.2 (q, ArOCH₃),

39.2 (t, CH₂CHOH), 38.5 (t, CH₂CH₂OTBDMS), 38.4 (d,

=

CHCH₃), 37.4 (d, CHCH CH₂), 26.0 [q, OSiC(CH₃)₃], 18.3

[s, OSiC(CH₃)₃], 11.3 (q, CHCH₃), −5.3 [q, OSi(CH₃)₂]; m/z

•

(EI) 365.2127 [M⁺− C(CH₃)₃. C₂₀H₃₃O₄Si requires 365.2148].

(3S,5R,6R)-3-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-7-

(4-methoxybenzyloxy)-6-methylheptane-1,5-diol 40

=

(1H, apparent s, CHO), 6.02 (1H, d, J 19.1, SnCH C), 5.82

(1H, dd, J 7.1 and 19.1, SnCH CH), 4.16 (1H, ddd, J 2.9, 6.6

A solution of 9-borabicyclo[3.3.1]nonane (0.5 mol dm⁻³in

tetrahydrofuran, 14.9 mL, 7.45 mmol) was added dropwise

over 5 min to a stirred solution of the alkene 39 (1.43 g, 3.39

mmol) in tetrahydrofuran (5 mL) at 0 ^◦C. The solution was

stirred at 0 ^◦C for 30 min and then at room temperature for

=

and 11.7, CHOCO), 2.74 (1H, dd, J 5.7 and 17.5, CHHCOO),

2.57–2.40 (4H, m, CHCH₂CHO, CH₂CHO and CHCH₃), 2.07

(1H, dd, J 10.0 and 17.5, CHHCOO), 1.99 (1H, br. d, J 14.7,

CHHCHOCO), 1.52–1.43 (6H, m, Bu₃Sn-3 × CH₂), 1.34–1.22

4 4 2 6

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

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12 h, after which it was cooled to 0 ^◦C. An aqueous solution

of sodium hydroxide (2 mol dm⁻³, 10 mL) was added in one

portion to the solution, followed immediately by the dropwise

addition of hydrogen peroxide (100 vol, 10 mL) over 5 min.

The heterogeneous mixture was stirred vigorously at 0 ^◦C for

4 h, extracted with diethyl ether (100 mL), washed with brine

(10 mL) and then dried over anhydrous magnesium sulfate.

The solution was concentrated in vacuo to leave a residue that

was puriﬁed by ﬂash column chromatography on silica, eluting

with ethyl acetate–light petroleum (bp 40–60 ^◦C) (3 : 7) to

give the alcohol (1.49 g, 95%) as a colourless oil. [a]²_D¹+13.9

(c 0.42 in CHCl₃); m_max(liquid ﬁlm)/cm⁻¹3395, 2929, 1612,

1586; d_H(400 MHz, CDCl₃) 7.27 (2H, d, J 8.7, ArH), 6.89

(2H, d, J 8.7, ArH), 4.44 (2H, apparent d, J 3.3, OCH₂Ar), 3.88

(1H, apparent d, J 8.7, CHOH), 3.82 (3H, s, ArOCH₃), 3.71–

3.66 (4H, m, CH₂OTBDMS and CH₂OH), 3.50 (2H, d, J 5.7,

CH₂OPMB), 2.91 (1H, br. s, OH), 2.07 (1H, br. s, OH), 1.87–

1.79 (2H, m, CHCH₃and CHCH₂CH₂OTBDMS), 1.72–1.51

(5H, m, CHHCHOH, CH₂CH₂OTBDMS and CH₂CH₂OH),

1.33–1.28 (1H, m, CHHCHOH), 0.92 (3H, d, J 7.1, CHCH₃),

0.90 [9H, s, OSiC(CH₃)₃], 0.06 [6H, s, OSi(CH₃)₂]; d_C(67.8 MHz,

CDCl₃) 159.2 (s, Ar), 130.1 (s, Ar), 129.2 (d, Ar), 113.8 (d, Ar),

74.3 (t, CH₂OPMB), 73.0 (t, OCH₂Ar), 71.4 (d, CHOH), 61.5

(t, CH₂OTBDMS), 61.2 (t, CH₂OH), 55.2 (q, ArOCH₃), 38.8

(t, CH₂CHOH), 38.3 (d, CHCH₃), 37.7 (t, CH₂CH₂OTBDMS),

36.4 (t, CH₂CH₂OH), 29.0 (d, CHCH₂CH₂OTBDMS), 25.9 [q,

OSiC(CH₃)₃], 18.3 [s, OSiC(CH₃)₃], 11.0 (q, CHCH₃), −5.4 [q,

OSi(CH₃)₂].

dichloromethane (250 mL) at −78 ^◦C. The mixture was stirred

at −78 ^◦C for 2 h, then quenched at −78 ^◦C by the addition of

acetone (20 mL), before being warmed to room temperature. The

mixture was added to a saturated aqueous solution of Rochelle’s

salt (250 mL), via cannula, and the biphasic mixture was then

stirred at room temperature for 14 h. The separated aqueous

phase was extracted with dichloromethane (3 × 100 mL) and the

combined organic extracts were dried and concentrated in vacuo.

The residue was puriﬁed by ﬂash column chromatography,

eluting with diethyl ether–light petroleum (bp 40–60 ^◦C) (1 :

19) to give the aldehyde (3.28 g, 70%) as a colourless oil.

Bp 71–72 ^◦C/16 mmHg; m_max(ﬁlm)/cm⁻¹2719, 1723, 1350; d_H

(400 MHz, CDCl₃), 9.76 (1H, t, J 1.9, CHO), 5.66 (2H, br. s,

=

2 × C CH), 2.74–2.67 (1H, m, CHCH₂CHO) 2.64–2.56 (2H,

=

m, CH₂CH ), 2.51 (2H, dd, J 1.9 and 7.1, CH₂CHO), 2.03–

1.98 (2H, m, CH₂CH ); d_C(100 MHz, CDCl₃), 202.5 (d), 129.5

=

(d), 50.4 (t), 38.7 (t), 31.3 (d); m/z (EI) 110.0727 (M: C₇H₁₀O

requires 110.0731), 110 (28%), 93 (19), 66 (100).

(S)-4-Benzyl-3-[(2S,3R)-4-cyclopent-3-enyl-3-hydroxy-

2-methylbutanoyl]-oxazolidin-2-one 43

A solution of dibutylboron triﬂate in dichloromethane (1.00 M,

56.0 mL, 56.0 mmol), and triethylamine (8.46 mL, 60.6 mmol)

were added sequentially to a stirred solution of (S)-4-benzyl-

3-propionyloxazolidin-2-one (10.8 g, 46.6 mmol) in dichloro-

methane (250 mL) at −10 ^◦C. The mixture was stirred at −10 ^◦C

for 20 min, then cooled to −78 ^◦C when a solution of the

aldehyde 42 (5.65 g, 51.2 mmol) in dichloromethane (100 mL)

was added via cannula over 10 min. The mixture was stirred

at −78 ^◦C for 1 h, then warmed to 0 ^◦C over 30 min and

stirred at 0 ^◦C for a further 30 min. The mixture was quenched

at 0 ^◦C by the sequential addition of pH 7 phosphate buffer

(100 mL), methanol (200 mL) and hydrogen peroxide (100 mL)

and then stirred at 0 ^◦C for 1 h. The aqueous layer was

separated, extracted with dichloromethane (3 × 250 mL) and

the combined organic extracts were then washed with brine

(250 mL), dried and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography, eluting with diethyl

ether–light petroleum (bp 40–60 ^◦C) (1 : 2) to give the aldol

product (12.3 g, 77%) as a colourless oil. [a]²_D¹+58 (c 1.03 in

CHCl₃); (Found: C, 69.8; H, 7.3; N, 3.8. C₂₀H₂₅NO₄requires:

C, 69.9; H, 7.3; N, 4.1%); m_max(sol.)/cm⁻¹3544 (br.), 2927, 1781,

1682; d_H(500 MHz, CDCl₃), 7.36–7.27 (3H, m, ArH), 7.24–7.20

(2R,3R,5R)-5-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-7-

(tert-butyldiphenylsilanyloxy)-1-(4-methoxybenzyloxy)-2-

methylheptan-3-ol 41

tert-Butylchlorodiphenylsilane (0.96 g, 0.91 mL, 3.50 mmol) was

added in a single portion to a stirred solution of the primary al-

cohol 40 (1.40 g, 3.18 mmol) and imidazole (240 mg, 3.50 mmol)

in dichloromethane (30 mL) at room temperature. The colourless

suspension stirred at room temperature for 2 h after which it

was concentrated in vacuo to leave a white solid. The residue was

washed with diethyl ether (200 mL), the imidazole hydrochloride

salt removed by ﬁltration and the organic extracts concentrated

in vacuo to leave a colourless oil that was puriﬁed by ﬂash

column chromatography on silica, eluting with ethyl acetate–

light petroleum (bp 40–60 ^◦C) (1 : 9) to give the silyl ether (2.07 g,

96%) as a colourless oil. [a]²_D¹+7.7 (c 1.22 in CHCl₃); (Found:

C, 70.7; H, 9.4. C₄₀H₆₂O₅Si₂requires: C, 70.8; H, 9.2%); m_max

(CHCl₃)/cm⁻¹3475, 1612, 1588; d_H(270 MHz, CDCl₃) 7.66–

7.62 (4H, m, ArH), 7.40–7.30 (6H, m, ArH), 7.22–7.18 (2H,

m, ArH), 6.86–6.82 (2H, m, ArH), 4.39 (2H, s, OCH₂Ar),

3.76 (4H, apparent s, ArOCH₃and CHOH), 3.66 (2H, t, J

6.8, CH₂OTBDPS), 3.59 (2H, t, J 6.8, CH₂OTBDMS), 3.47–

3.41 (2H, m, CH₂OPMB), 2.71 (1H, d, J 4.3, OH), 1.78–1.73

(2H, m, CHCH₃and CHCH₂CH₂OTBDMS), 1.60–1.36 (5H,

m, CHHCHOH, CH₂CH₂OTBDMS and CH₂CH₂OTBDPS),

1.28–1.21 (1H, m, CHHCHOH), 1.01 [9H, s, OSiC(CH₃)₃],

0.86–0.84 [12H, m, OSiC(CH₃)₃and CHCH₃], 0.00 [6H, s,

OSi(CH₃)₂]; d_C(67.8 MHz, CDCl₃) 159.5 (s, Ar), 135.9 (d, Ar),

134.3 (s, Ar), 130.6 (s, Ar), 129.9 (d, Ar), 129.5 (d, Ar), 127.9 (d,

Ar), 114.1 (d, Ar), 74.6 (t, CH₂OPMB), 73.3 (t, OCH₂Ar), 72.1

(d, CHOH), 62.5 (t, CH₂OTBDPS), 61.7 (t, CH₂OTBDMS),

55.6 (q, ArOCH₃), 39.0 (t, CH₂CHOH), 38.6 (d, CHCH₃),

37.8 (t, CH₂CH₂OTBDMS), 37.2 (t, CH₂CH₂OTBDPS), 29.1

(d, CHCH₂CH₂OTBDPS), 27.2 [q, OSiC(CH₃)₃], 26.3 [q,

OSiC(CH₃)₃], 19.5 [s, OSiC(CH₃)₃], 18.6 [s, OSiC(CH₃)₃], 11.2

(q, CHCH₃), −5.0 [q, OSi(CH₃)₂].

=

(2H, m, ArH), 5.68–5.65 (2H, m, 2 × CH C), 4.71 (1H, m,

CHN), 4.26 (1H, t, J 9.1, CHHO), 4.19 (1H, dd, J 2.9 and

9.1, CHHO), 4.02 (1H, ddd, J 2.7, 3.2 and 9.2, CHOH), 3.75

(1H, dq, J 3.2 and 7.0, CHCH₃), 3.25 (1H, dd, J 3.3 and 13.4,

CHHPh), 2.92 (1H, d, J 2.9, OH), 2.79 (1H, dd, J 9.5 and 13.4,

=

CHHPh), 2.55–2.44 (3H, m, CHCH₂CH C and CH₂CH C),

2.03–1.99 (2H, m, CH₂CH C), 1.71 (1H, ddd, J 5.3, 9.2 and

=

13.8, CHHCHOH), 1.49–1.43 (1H, m, CHHCHOH), 1.27 (3H,

d, J 7.0, CHCH₃); d_C(90.6 MHz, CDCl₃), 177.4 (s), 153.0 (s),

135.0 (s), 130.0 (d), 129.5 (d), 129.4 (d), 128.9 (d), 127.4 (d), 70.4

(d), 66.1 (t), 55.0 (d), 42.4 (d), 40.5 (t), 39.3 (t), 38.4 (t), 37.7 (t),

34.1 (d), 10.5 (q); m/z (ESI) 366.1682 (M + Na: C₂₀H₂₅NaNO₄

requires 366.1681), 366 (100%).

(2S,3R)-4-Cyclopent-3-enyl-3-hydroxy-N-methoxy-

2,N-dimethylbutyramide 44a

A solution of trimethylaluminium in toluene (2.00 M, 10.6 mL,

21.2 mmol) was added over 5 min to a stirred slurry of N,O-

dimethylhydroxylamine hydrochloride (2.10 g, 21.2 mmol) in

dichloromethane (40 mL) at 0 ^◦C. The mixture was warmed

to room temperature, where it was stirred for 10 min and then

cooled to −10 ^◦C. A solution of the imide 43 (2.42 g, 7.06

mmol) in dichloromethane (30 mL) was added to the mixture

Cyclopent-3-enylacetaldehyde 42

◦

A solution of di-isobutylaluminium hydride in toluene (1.50 M,

42.0 mL, 63.0 mmol) was added over 10 min to a stirred

solution of cyclopent-3-enylacetonitrile (4.50 g, 42.0 mmol) in

at −10 C over 5 min and stirring was continued for 2 h. The

mixture was warmed to room temperature, stirred for a further

90 min, and then poured cautiously into a biphasic mixture of

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 2 7

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oil. [a]²_D¹+61 (c 1.00 in CHCl₃); m_max(sol.)/cm⁻¹2712 (w), 1723;

d_H(360 MHz, CDCl₃), 9.80 (1H, d, J 0.9, CHO), 5.70–5.65 (2H,

dilute hydrochloric acid (2.0 M, 140 mL) and dichloromethane

(70 mL). The biphasic mixture was stirred vigorously for 20 min

and then the aqueous phase was separated and extracted with

dichloromethane (3 × 70 mL). The combined organic extracts

were washed with dilute hydrochloric acid (2.0 M, 70 mL), pH 7

phosphate buffer (70 mL), brine (50 mL) and then dried and

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, eluting with ethyl acetate–light petroleum (bp

40–60 ^◦C) (2 : 3) to give the Weinreb amide (1.31 g, 84%) as

a colourless oil. [a]²_D¹+16 (c 1.25 in CHCl₃); (Found: C, 63.15;

H, 9.45; N, 6.2. C₁₂H₂₁NO₃requires: C, 63.4; H, 9.3; N, 6.2%);

m_max(sol.)/cm⁻¹3472 (br.), 2936, 1633; d_H(360 MHz, CDCl₃),

=

m, 2 × CH C), 4.16 (1H, ddd, J 3.2, 6.3 and 7.2, CHOTBS),

=

2.56–2.44 (3H, m, CH₂CH C and CHCH₃), 2.28 (1H, apparent

=

septet, J 7.4, CHCH₂CH C), 2.03–1.94 (2H, m, CH₂CH C),

1.68–1.53 (2H, m, CH₂CHOTBS), 1.07 (3H, d, J 7.0, CHCH₃),

0.87 (9H, s, TBS-^tBu), 0.08 (3H, s, TBS-Me), 0.05 (3H, s, TBS-

Me); d_C(90.6 MHz, CDCl₃), 205.4 (d), 129.8 (d), 129.6 (d), 71.1

(d), 51.3 (d), 41.2 (t), 39.1 (t), 38.9 (t), 33.9 (d), 25.8 (q), 18.0

(s), 7.6 (q), −4.3 (q), −4.6 (q); m/z (ESI) 305.1885 (M + Na:

C₁₆H₃₀NaO₂Si requires 305.1913), 305 (100%).

tert-Butyl-[(1R,2R)-1-cyclopent-3-enylmethyl-2-methylbut-

3-ynyloxy]-dimethylsilane 46a

=

5.68–5.65 (2H, m, 2 × CH C), 3.93 (1H, ddd, J 2.9, 4.3

and 8.9, CHOH), 3.71 (3H, s, OCH₃), 3.21 (3H, s, NCH₃),

=

2.87 (1H, m, CHCH₃), 2.57–2.41 (3H, m, CHCH₂CH C and

A solution of dimethyl diazomethylphosphonate (Seyforth’s

reagent) (4.70 g, 34.5 mmol) in tetrahydrofuran (50 mL) was

added via cannula over 15 min to a stirred suspension of

potassium tert-butoxide (3.87 g, 34.5 mmol) in tetrahydrofuran

(150 mL) at −78 ^◦C. The mixture was stirred at −78 ^◦C for

30 min and then a solution of the aldehyde 45 (6.50 g, 23.0 mmol)

in tetrahydrofuran (50 mL) was added via cannula over 10 min.

=

CH₂CH C), 2.06–1.96 (2H, m, CH₂CH C), 1.71 (1H, ddd, J

5.7, 8.9 and 13.4, CHHCHOH), 1.41 (1H, ddd, J 4.3, 8.2 and

13.4, CHHCHOH), 1.18 (3H, d, J 7.1, CHCH₃); d_C(90.6 MHz,

CDCl₃), 178.3 (s), 129.9 (d), 129.5 (d), 70.3 (d), 61.5 (q), 40.5 (t),

39.2 (t), 38.9 (d), 38.5 (t), 34.1 (d), 31.8 (q), 10.5 (q); m/z (ESI)

291.1669 (M + MeCN + Na: C₁₄H₂₄NaN₂O₃requires 291.1684),

291 (100%), 250 (20).

◦

The mixture was stirred at −78 C for 2 h and then quenched

by the addition of deionised water (100 mL). The biphasic

mixture was warmed to room temperature and the aqueous

phase was then separated and extracted with diethyl ether (3 ×

100 mL). The combined organic extracts were dried and then

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, eluting with diethyl ether–light petroleum (bp

40–60 ^◦C) (1 : 19) to give the alkyne (6.00 g, 94%) as a colourless

oil. [a]²_D¹+26 (c 0.96 in CHCl₃); m_max(sol.)/cm⁻¹2111 (w), 1068;

(2S,3R)-3-(tert-Butyldimethylsiloxy)-4-cyclopent-3-enyl-

N-methoxy-2,N-dimethylbutyramide 44b

tert-Butyldimethylsilyl triﬂuoromethanesulfonate (8.42 mL,

36.6 mmol) was added dropwise over 10 min to a stirred solution

of the alcohol 44a (5.55 g, 24.4 mmol) and 2,6-lutidine (4.84 mL,

41.5 mmol) in dichloromethane (150 mL) at 0 ^◦C. The mixture

was stirred at 0 ^◦C for 45 min and then quenched at 0 ^◦C by

the addition of a saturated solution of sodium bicarbonate

(100 mL). The aqueous phase was separated and extracted

with dichloromethane (2 × 70 mL) and the combined organic

extracts were then washed with sodium bisulfate solution (1.0 M,

100 mL), brine (100 mL), dried and concentrated in vacuo. The

residue was puriﬁed by ﬂash column chromatography, eluting

with ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 : 4) to give

the silyl ether (8.70 g, 100%) as a colourless oil. [a]²_D¹+8.6 (c

1.00 in CHCl₃); (Found: C, 63.35; H, 10.5; N, 4.1. C₁₈H₃₅NO₃Si

requires: C, 63.3; H, 10.3; N, 4.1%); m_max(sol.)/cm⁻¹2897, 1651;

=

d_H(360 MHz, CDCl₃), 5.71–5.65 (2H, m, 2 × CH C), 3.65

(1H, ddd, J 4.1, 4.9 and 7.5, CHOTBS), 2.62–2.41 (4H, m,

=

CHCH₂CH C, CH₂CH C and CHCH₃), 2.06–1.97 (2H, m,

CH₂CH C), 2.05 (1H, d, J 2.5, C≡CH), 1.78 (1H, ddd, J 5.4,

=

7.5 and 13.2, CHHCHOTBS), 1.60 (1H, ddd, J 4.1, 8.6 and 13.2,

CHHCHOTBS), 1.15 (3H, d, J 7.0, CHCH₃), 0.92 (9H, s, TBS-

^tBu), 0.11 (3H, s, TBS-Me), 0.08 (3H, s, TBS-Me); d_C(90.6 MHz,

CDCl₃), 130.1 (d), 129.6 (d), 87.1 (s), 74.0 (d), 69.5 (d), 40.7 (t),

39.7 (t), 38.8 (t), 33.5 (d), 32.6 (d), 25.9 (q), 18.2 (s), 16.6 (q),

−4.3 (2 × q); m/z (FAB) 221.1365 (M-^tBu: C₁₃H₂₁OSi requires

221.1362), 221 (100%), 147 (54).

=

d_H(360 MHz, CDCl₃), 5.66–5.63 (2H, m, 2 × CH C), 3.97

(1H, dt, J 5.8 and 6.2, CHOTBS), 3.68 (3H, s, OCH₃), 3.17

(3H, s, NCH₃), 2.97–2.84 (1H, m, CHCH₃), 2.51–2.45 (2H, m,

(2R,3R)-1-Cyclopent-3-enyl-3-methylpent-4-yn-1-ol 46b

=

CH₂CH C), 2.31 (1H, apparent septet, J 7.3, CHCH₂CH C),

2.04–1.91 (2H, m, CH₂CH C), 1.59 (2H, dd, J 5.8 and 7.3,

HF/pyridine complex (21.0 mL) was added rapidly to a

stirred solution of the silyl ether 46a (6.00 g, 21.5 mmol) in

tetrahydrofuran (150 mL) at room temperature, and the mixture

was then stirred at room temperature for 2 days. A saturated

solution of sodium bicarbonate (500 mL) was added cautiously

and the mixture was then extracted with dichloromethane (4 ×

250 mL). The combined organic extracts were washed with brine

(500 mL), dried and concentrated in vacuo. The residue was

puriﬁed by ﬂash column chromatography, eluting with diethyl

ether–light petroleum (bp 40–60 ^◦C) (1 : 4) to give the alkyne

(3.63 g, 100%) as a colourless oil. [a]²_D¹+58 (c 1.00 in CHCl₃);

(Found: C, 80.15; H, 10.0. C₁₁H₁₆O requires: C, 80.4; H, 9.8%);

m_max(sol.)/cm⁻¹3526 (br.), 2174 (w), 1022; d_H(400 MHz, CDCl₃),

=

CH₂CHOTBS), 1.13 (3H, d, J 7.1, CHCH₃), 0.89 (9H, s, TBS-

^tBu), 0.05 (3H, s, TBS-Me), 0.03 (3H, s, TBS-Me); d_C(90.6 MHz,

CDCl₃), 176.2 (s), 129.9 (d), 129.7 (d), 72.5 (d), 61.2 (q), 43.1

(t), 41.3 (d), 39.5 (t), 39.2 (t), 33.7 (d), 32.1 (q), 26.0 (q), 18.1 (s),

13.3 (q), −4.0 (q), −4.3 (q); m/z (ESI) 405.2530 (M + MeCN +

Na: C₂₀H₃₈NaN₂O₃Si requires 405.2549), 405 (100%), 364 (29),

342 (30).

(2S,3R)-3-(tert-Butyldimethylsiloxy)-4-cyclopent-3-enyl-

2-methylbutyraldehyde 45

A solution of di-isobutylaluminium hydride in toluene (1.50 M,

24.4 mL, 36.6 mmol) was added dropwise over 20 min to a stirred

solution of the amide 44b (8.70 g, 24.4 mmol) in tetrahydrofuran

(120 mL) at −78 ^◦C. The mixture was stirred at −78 ^◦C for

=

5.69–5.63 (2H, m, 2 × CH C), 3.59 (1H, dq, J 5.3 and 9.5,

=

CHOH), 2.60–2.41 (4H, m, CHCH₂CH C, CH₂CH C and

CHCH₃), 2.11 (1H, d, J 2.4, C≡CH), 2.04–1.93 (3H, m, OH

=

◦

and CH₂CH C), 1.69–1.57 (2H, m, CH₂CHOH), 1.17 (3H, d,

2 h and then quenched at −78 C with acetone (10 mL). The

J 6.9, CHCH₃); d_C(90.6 MHz, CDCl₃), 130.0 (d), 129.5 (d), 86.2

(s), 73.0 (d), 70.3 (d), 40.0 (t), 39.5 (t), 38.3 (t), 34.1 (d), 33.0 (d),

15.6 (q); m/z (FAB), 165 (14%), 147 (30), 57 (100).

mixture was warmed to room temperature over 15 min and then

added via cannula to a saturated aqueous solution of Rochelle’s

salt (100 mL). The biphasic mixture was stirred vigorously for

18 h and the aqueous phase was then separated and extracted

with dichloromethane (3 × 100 mL). The combined organic

extracts were washed with brine (100 mL), dried and then

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, eluting with diethyl ether–light petroleum (bp

40–60 ^◦C) (1 : 9) to give the aldehyde (6.70 g, 96%) as a colourless

4-[(2R,3R)-5-Bromo-2-hydroxy-3-methylpent-4-ynyl]-

cyclopentane-1,2-diol 47

N-Bromosuccinimide (593 mg, 3.35 mmol) was added in one

portion, followed by silver nitrate (5.00 mg), to a stirred solution

of the alkyne 46b (0.50 g, 3.04 mmol) in acetone (15 mL).

4 4 2 8

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

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=

The mixture was stirred at room temperature for 2 h and

then diluted with diethyl ether–light petroleum (1 : 4; 50 mL).

The mixture was washed with deionised water (3 × 20 mL),

dried and concentrated in vacuo to leave the cude bromoalkyne

intermediate as a colourless oil (640 mg, 87%).

C CHI), 6.05 (1H, d, J 19.0, C CHSn), 5.87 (1H, dd, J 7.0

=

and 19.0, CH CHSn), 5.83 (1H, d, J 15.6, C CHCO₂), 5.59

=

(1H, apparent t, J 5.7, C CH), 4.84 (1H, dt, J 3.5 and 9.2,

CHOCO), 4.36 (1H, dd, J 7.2 and 13.0, CHHOTPS), 4.24 (1H,

dd, J 4.2 and 13.0, CHHOTPS), 4.20–4.12 (2H, m, CHOTBS

and CHOCO), 3.15 (4H, br. s, CHOMe and OCH₃), 2.74–2.65

(1H, m, CHHCO₂), 2.47 (1H, apparent q, J 6.9, CHCH₃), 2.26–

2.18 (2H, m, CH₂CH C), 2.15–2.03 (3H, m, CHCH₃, CHHCO₂

and CHCH₂CO₂), 1.96 (1H, br. d, J 14.3, CHHCHOCO), 1.76

(3H, s, IC CCH₃), 1.71–1.63 (2H, m, CH₂CHOTBS), 1.54–

1.44 (6H, m, Bu₃Sn-3 × CH₂), 1.47 (3H, s, C CCH₃), 1.35–1.26

Osmium tetroxide (2.5 wt% in ^tBuOH, 3.82 mL, 0.30 mmol)

was added to a stirred solution of the crude bromoalkyne

(640 mg, 2.64 mmol) and 4-methylmorpholine N-oxide (713 mg,

6.09 mmol) in acetone–water (2 : 1; 80 mL) at room temperature.

The mixture was stirred at room temperature for 90 min and then

quenched by the addition of a saturated solution of sodium

thiosulfate (30 mL). The mixture was stirred vigorously for

20 min and then extracted with ethyl acetate (5 × 30 mL).

The combined organic extracts were dried and concentrated

in vacuo to leave a residue which was puriﬁed by ﬂash column

chromatography, eluting with methanol–ethyl acetate (1 : 19)

to give the triol (640 mg, 76% over two steps) as a colourless

crystalline solid (7 : 1 mixture of cis-diol isomers). Mp 112–

113 ^◦C; (Found: C, 47.6; H, 6.1. C₁₁H₁₇BrO₃requires: C, 47.7; H,

6.2%); m_max(sol.)/cm⁻¹3292 (br.), 1130; d_H(360 MHz, CD₃OD),

4.09–4.06 (2H, m, 2 × CHOH), 3.42 (1H, ddd, J 2.7, 6.9 and 9.5,

CHOH), 2.63–2.54 (1H, m, CHCH₂CHOH), 2.48 (1H, apparent

quin., J 6.9, CHCH₃), 1.98–1.88 (2H, m, CH₂CHOH), 1.67–

1.42 (4H, m, 2 × CH₂CHOH), 1.21 (3H, d, J 6.9, CHCH₃); d_C

(90.6 MHz, CD₃OD), 83.3 (s), 74.8 (2 × d), 74.3 (d), 43.0 (t),

41.0 (s), 39.4 (t), 38.2 (t), 35.8 (d), 32.2 (d), 17.2 (q); m/z (FAB),

259 (M − OH, 100%).

=

(7H, m, CHHCHOCO and Bu₃Sn-3 × CH₂), 1.11 (3H, d, J 6.9,

CHCH₃), 1.05 (9H, s, TPS-^tBu), 0.94–0.87 (18H, m, CHCH₃

and Bu₃Sn-3 × CH₂and 3 × CH₃), 0.81 (9H, s, TBS-^tBu),

−0.08 (3H, s, TBS-Me), −0.10 (3H, s, TBS-Me); d_C(90.6 MHz,

CDCl₃), 170.7 (s), 165.2 (s), 150.5 (s), 148.3 (d), 144.5 (d), 135.5

(d), 133.9 (s), 133.8 (s), 130.3 (d), 129.6 (d), 129.0 (d), 127.7 (d),

124.2 (d), 88.3 (d), 83.3 (d), 78.1 (d), 74.5 (d), 72.2 (d), 60.7 (t),

56.1 (q), 46.1 (d), 38.7 (t), 38.2 (d), 36.0 (t), 35.3 (t), 32.1 (t), 30.9

(d), 29.1 (t), 27.2 (t), 26.8 (q), 25.7 (q), 19.2 (s), 19.0 (s), 18.0 (q),

15.3 (q), 13.7 (q), 11.4 (q), 9.9 (q), 9.5 (t), −5.0 (q), −5.4 (q);

m/z (FAB), 1270 (M + Na) (45%), 1190 (M-^tBu) (100).

Macrocyclic core 6

A 0.001 M stock catalyst solution was prepared by adding

tris(dibenzylideneacetone)dipalladium(0) (4.60 mg, 5.00 lmol)

and triphenylarsine (12.5 mg, 40.0 lmol) to freeze/pump/thaw

(×3) degassed dimethylformamide (10 mL). 1.50 mL (1.50 lmol)

of the stock catalyst solution was added to the macrocylisation

precursor 50 (18.0 mg, 14.4 lmol) under argon at room tem-

perature. The resulting solution was stirred and heated at 70 ^◦C

under argon for 5 h, then cooled and concentrated in vacuo (high

vacuum) to leave a crude oil. The oil was puriﬁed by ﬂash column

chromatography, eluting with ethyl acetate–light petroleum (bp

40–60 ^◦C) (1 : 5) to give the E,E-conjugated diene (5.70 mg, 48%)

as a colourless oil. [a]²_D¹−11 (c 1.30 in CHCl₃); m_max(sol.)/cm⁻¹

1722, 1652; d_H(400 MHz, CDCl₃), 7.74–7.67 (4H, m, ArH),

7.47–7.34 (6H, m, ArH), 6.73 (1H, ddd, J 4.7, 11.0 and 15.7,

CH CHCO₂), 6.23 (1H, dd, J 11.0 and 15.2, C CHCH C),

5.69 [1H, dq, J 1.0 and 11.0, CH C(CH₃)], 5.62 (1H, apparent

t, J 5.7, C CHCH₂OTPS), 5.60 (1H, d, J 15.7, C CHCO₂),

5.06 (1H, dd, J 9.7 and 15.2, C CHCHCH₃), 4.52 (1H, dd, J 3.0

and 10.5, CHOCO), 4.37 (1H, dd, J 7.2 and 12.9, CHHOTPS),

4.27 (1H, dd, J 4.8 and 12.9, CHHOTPS), 3.87 (1H, dd, J

3.1 and 10.7, CHOTBS), 3.69 (1H, ddd, J 2.6, 9.8 and 12.1,

CHOCO), 3.18 (1H, d, J 9.2, CHOMe), 3.16 (3H, s, OCH₃),

2.77 (1H, ddd, J 2.0, 5.2 and 17.8, CHHCO₂), 2.57–2.51 (1H, m,

4-[(2R,3R)-(4E)-2-Hydroxy-3-methyltributylstannylpent-4-

enyl]-cyclopentane-1,2-diol 48

Freshly distilled tributyltin hydride (1.02 mL, 3.81 mmol) was

added over 10 min to a stirred solution of the bromoalkyne 47

(480 mg, 1.73 mmol), tris(dibenzylideneacetone)dipalladium(0)

(79.0 mg, 0.09 mmol) and triphenylphosphine (182 mg, 0.69

mmol) in tetrahydrofuran (20 mL) at room temperature. The

mixture was stirred at room temperature for 2 h, and then

concentrated in vacuo. The residue was puriﬁed by ﬂash column

chromatography, eluting with ethyl acetate–light petroleum

(bp 40–60 ^◦C) (1 : 1) to give the tributylstannane (920 mg,

100%) as a colourless oil (7 : 1 mixture of cis-diol isomers);

m_max(sol.)/cm⁻¹3352 (br.), 1130; d_H(400 MHz, CDCl₃), 5.97

=

(1H, d, J 19.1, SnCH C), 5.85 (1H, dd, J 6.6 and 19.1,

SnCH CH) 4.13–4.10 (2H, m, 2 × CHOH), 3.51–3.44 (1H,

=

m, CHOH), 3.18 (1H, br. s, OH) 2.51 (1H, apparent septet., J

8.9, CHCH₂CHOH), 2.28–2.22 (2H, m, CHCH₃and OH), 2.01

(1H, d, J 5.3, OH), 1.94–1.89 (2H, m, CH₂CHOH), 1.64–1.52

(2H, m, CH₂CHOH), 1.51–1.45 (6H, m, Bu₃Sn-3 × CH₂), 1.44–

1.37 (2H, m, CH₂CHOH), 1.35–1.25 (6H, m, Bu₃Sn-3 × CH₂),

1.01 (3H, d, J 6.9, CHCH₃) 0.92–0.85 (15H, m, Bu₃Sn-3 × CH₂

and 3 × CH₃); d_C(90.6 MHz, CDCl₃), 151.2 (d), 128.9 (d), 73.6

(d), 73.5 (d), 47.4 (d), 41.1 (t), 39.2 (t), 38.4 (t), 31.7 (d), 29.1 (t),

27.2 (t), 14.4 (q), 13.7 (q), 9.5 (t); m/z (EI), 433.1778 (M − Bu:

C₁₉H₃₇O₃¹²⁰Sn requires 433.1764), 433 (100%).

=

CHHCH C), 2.30–2.08 (4H, m, 2 × CHCH₃, CHHCHOTBS

and CHHCO₂), 1.98 (1H, br. dd, J 2.6 and 14.3, CHHCHOCO),

=

1.81–1.67 (2H, m, CHHCH C and CHCH₂CO₂), 1.74 (3H, d, J

=

1.0, C CCH₃), 1.63–1.56 (1H, m, CHHCHOTBS), 1.55 (3H, s,

t

=

C CCH₃), 1.21 (3H, d, J 6.5 CHCH₃), 1.06 (9H, s, TPS- Bu),

0.96 (3H, d, J 6.7, CHCH₃), 0.88 (9H, s, TBS-^tBu), 0.66 (1H,

ddd, J 12.1, 12.1 and 14.3, CHHCHOCO), 0.06 (3H, s, TBS-

Me), −0.03 (3H, s, TBS-Me); d_C(90.6 MHz, CDCl₃), 170.4 (s),

165.5 (s), 145.7 (d), 140.1 (s), 135.5 (d), 135.0 (s), 133.7 (s), 133.2

(d), 130.1 (d), 129.6 (d), 129.3 (d), 127.6 (d), 124.6 (d), 124.4 (d),

89.2 (d), 83.4 (d), 78.9 (d), 74.2 (d), 60.6 (t), 56.0 (q), 45.3 (d),

38.2 (d + t), 36.9 (t), 34.6 (t), 34.1 (t), 29.8 (d), 26.8 (q), 25.7

(q), 19.2 (s), 18.0 (s), 16.6 (q), 11.0 (q), 10.9 (q), 9.8 (q) −4.6 (q),

−4.9 (q); m/z (FAB), 851.4704 (M + Na: C₄₉H₇₂O₇NaSi₂requires

851.4714), 852 (M + Na) (100%), 574 (M − OTPS) (46).

Macrocyclisation precursor 50

1,8-Diazobicyclo[5.4.0]undec-7-ene (18.0 lL, 120 lmol) was

added over 5 min to a stirred solution of the phosphonate 9

(100 mg, 109 lmol) and lithium chloride (23.2 mg, 546 lmol) in

acetonitrile (1 mL) at room temperature, and the mixture was

◦

then stirred for 15 min. The mixture was cooled to 0 C and a

solution of the aldehyde 7 (64.0 mg, 131 lmol) in acetonitrile

(0.5 + 0.1 mL) was added at 0 ^◦C over 5 min. The mixture was

◦

stirred at 0 C for 1 h and then concentrated in vacuo to leave

Allylic alcohol 51a

a residue which was puriﬁed by ﬂash column chromatography,

eluting with ethyl acetate–light petroleum (bp 40–60 ^◦C) (1 : 5)

to give the E-unsaturated ester (106 mg, 78%) as a colourless

oil. [a]²_D¹+1.5 (c 0.78 in CHCl₃); m_max(sol.)/cm⁻¹1722, 1655; d_H

(400 MHz, CDCl₃), 7.72–7.68 (4H, m, ArH), 7.46–7.35 (6H, m,

A solution of TBAF–AcOH in tetrahydrofuran (1 : 1, 1.00 M,

64.0 lL, 64.0 lmol) was added to a stirred solution of the

silyl ether 6 (35.0 mg, 42.3 lmol) in tetrahydrofuran (1 mL)

at room temperature under argon. The mixture was stirred at

room temperature under argon for 12 h, and then quenched

=

ArH), 6.81 (1H, dt, J 7.3 and 15.6, CH CHCO₂), 6.14 (1H, s,

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 2 9

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by the addition of a saturated aqueous solution of ammonium

chloride (0.5 mL). The mixture was diluted with ethyl actetate

(15 mL), washed with brine (10 mL) and the aqueous phase was

then separated and extracted with ethyl acetate (2 × 10 mL).

The combined organic extracts were dried and concentrated in

vacuo to leave a crude oil which was puriﬁed by ﬂash column

chromatography, eluting with ethyl acetate–light petroleum (bp

40–60 ^◦C) (1 : 1) to give the alcohol (18.3 mg, 74%) as a

colourless oil. [a]_D²¹−8.3 (c 0.60 in CHCl₃); m_max(sol.)/cm⁻¹3523

(br.), 1721, 1650; d_H(360 MHz, CDCl₃), 6.74 (1H, ddd, J 4.7,

13-(tert-Butyldimethylsilyl)-rhizoxin D 52

The macrocycle 51b and the phosphine oxide 8 were ﬁrst dried

by azeotroping with benzene (× 3) under vacuum. A solution

of potassium hexamethyldisilazane in toluene (0.50 M, 95.0 lL,

47.5 lmol) was added dropwise over 1 min to a stirred solution

of the phosphine oxide (16.0 mg, 47.5 lmol) in tetrahydrofuran

(1 mL) at −78 ^◦C under argon. The resulting bright orange

mixture was then added to a solution of the aldehyde 51b

(14.0 mg, 23.8 lmol) in tetrahydrofuran (1 mL) at −78 ^◦C over

2 min via cannula. The mixture was stirred at −78 ^◦C for 5 min,

then warmed to 0 ^◦C over 10 min and stirred at 0 ^◦C for a further

20 min under argon. The mixture was quenched at 0 ^◦C by the

addition of a saturated aqueous solution of ammonium chloride

(0.2 mL), and then warmed to room temperature. The mixture

was diluted with diethyl ether (10 mL), washed with brine (5

mL), and the organic extracts were then dried and concentrated

in vacuo.

Triethylamine (13 lL, 95.0 lmol), 2,4,6-trichlorobenzoyl

chloride (7.4 lL, 47.5 lmol) and 4-(dimethylamino)-pyridine

(1 crystal) were added sequentially to a stirred solution of the

residue in tetrahydrofuran (1 mL) at room temperature. The

mixture was stirred for 3 h at room temperature, then diluted

with diethyl ether (10 mL), washed with brine (10 mL), dried,

and concentrated in vacuo. The solid residue was puriﬁed by

ﬂash column chromatography, eluting with ethyl acetate–light

petroleum (bp 40–60 ^◦C) (1 : 3) to give the triene oxazole

(5.0 mg, 30%; 38% based on recovered starting material) as

a pale yellow solid. [a]²_D¹+60 (c 0.10 in CHCl₃); m_max(sol.)/cm⁻¹

1720, 1650, 1601; d_H(500 MHz, CDCl₃), 7.56 (1H, s, oxazoleH),

=

11.0 and 15.7, CH CHCO₂), 6.23 (1H, dd, J 11.0 and 15.1,

=

C CHCH C), 5.72 [1H, d, J 11.0, CH C(CH₃)], 5.61 (1H, d, J

=

15.7, C CHCO₂), 5.58 (1H, dd, J 6.4 and 6.9, C CHCH₂OH),

=

5.13 (1H, dd, J 9.7 and 15.1, C CHCHCH₃), 4.53 (1H, dd, J

3.1 and 10.5, CHOCO), 4.33 (1H, dd, J 6.9 and 12.5, CHHOH),

4.24 (1H, dd, J 6.4 and 12.5, CHHOH), 3.90 (1H, dd, J 2.9 and

10.7, CHOTBS), 3.69 (1H, ddd, J 2.6, 9.9 and 12.0, CHOCO),

3.19 (4H, br. s, CHOMe and OCH₃), 2.77 (1H, dd, J 5.1

=

and 18.0, CHHCO₂), 2.55–2.52 (1H, m, CHHCH C), 2.30–

2.19 (2H, m, 2 × CHCH₃), 2.18–2.05 (2H, m, CHHCHOTBS

and CHHCO₂), 1.99 (1H, dd, J 2.6 and 14.0, CHHCHOCO),

=

1.79–1.71 (2H, m, CHHCH C and CHCH₂CO₂), 1.76 (3H, s,

=

C CCH₃), 1.74 (3H, s, C CCH₃), 1.61 (1H, br. s, OH), 1.56

(1H, dd, J 2.9 and 14.9, CHHCHOTBS), 1.22 (3H, d, J 6.4,

CHCH₃), 0.97 (3H, d, J 6.9, CHCH₃), 0.87 (9H, s, TBS-^tBu),

0.68 (1H, ddd, J 12.0, 12.0 and 14.0, CHHCHOCO), 0.05 (3H, s,

TBS-Me), −0.03 (3H, s, TBS-Me); d_C(90.6 MHz, CDCl₃), 170.4

(s), 165.7 (s), 145.9 (d), 140.0 (s), 137.2 (s), 133.4 (d), 130.0 (d),

128.4 (d), 124.6 (2 × d), 89.3 (d), 83.4 (d), 78.9 (d), 74.1 (d), 58.9

(t), 56.2 (q), 45.3 (d), 38.3 (d), 38.2 (t), 36.9 (t), 34.6 (t), 34.0 (t),

29.8 (d), 25.7 (q), 18.0 (s), 16.6 (q), 11.0 (2 × q), 9.9 (q), −4.6 (q),

−5.0 (q); m/z (ESI), 613.3521 (M + Na: C₃₃H₅₄O₇NaSi requires

613.3537), 613 (M + Na) (100%), 573 (M − OH) (13).

=

6.76 (1H, ddd, J 4.6, 11.0 and 15.5, CH CHCO₂), 6.64 (1H,

=

dd, J 10.9 and 15.2, CH CHCH C(CH₃)), 6.38 [1H, d, J 15.2,

CH CHCH C(CH₃)], 6.25 [1H, s, oxazole-CH C(CH₃)], 6.21

=

(1H, dd, J 11.1 and 15.3, C CHCH C), 6.06 [1H, d, J 10.9,

CH CHCH C(CH₃)], 5.68 [1H, d, J 11.1, CH C(CH₃)], 5.61

(1H, d, J 15.5, C CHCO₂), 5.10 (1H, dd, J 9.7 and 15.2,

C CHCHCH₃), 4.54 (1H, dd, J 3.0 and 10.6, CHOCO),

3.84 (1H, dd, J 2.7 and 10.9, CHOTBS), 3.69–3.67 (1H, m,

CHOCO), 3.23 (1H, d, J 8.9, CHOCH₃), 3.19 (3H, s, OCH₃),

2.77 (1H, ddd, J 2.2, 5.3 and 17.9, CHHCO₂), 2.53 (1H,

=

Aldehyde 51b

=

Manganese dioxide (125 mg, 1.44 mmol) was added in a single

portion to a stirred solution of the allylic alcohol 51a (17.0 mg,

28.8 lmol) in dichloromethane (1 mL) at room temperature.

The suspension was stirred rapidly at room temperature for

2 h, and then ﬁltered through a pad of Celite and washed

with dichloromethane (2 × 5 mL). The combined ﬁltrates

were concentrated in vacuo, and the residue was then puriﬁed

by ﬂash column chromatography, eluting with ethyl acetate–

light petroleum (bp 40–60 ^◦C) (1 : 1) to give the aldehyde

(17.0 mg, 100%) as a colourless oil. [a]²_D¹−10.3 (c 1.55 in

CHCl₃); m_max(sol.)/cm⁻¹2856, 1721, 1673, 1650; d_H(360 MHz,

CDCl₃), 10.3 (1H, d, J 7.9, CHO), 6.76 (1H, ddd, J 4.8,

=

m, CHHCH C), 2.43 (3H, s, oxazoleCH₃), 2.30–2.23 (2H,

=

m, 2 × CHCH₃), 2.15 (3H, s, C CCH₃), 2.18–2.06 (2H,

m, CHHCHOTBS and CHHCO₂), 1.99 (1H, br. d, J 13.5,

=

CHHCHOCO), 1.92 (3H, s, C CCH₃), 1.76–1.68 (3H, m,

CHHCH C, CHCH₂CO₂and CHHCHOTBS), 1.73 (3H, s,

=

C CCH₃), 1.20 (3H, d, J 6.4, CHCH₃), 0.99 (3H, d, J 7.0,

CHCH₃), 0.88 (9H, s, TBS-^tBu), 0.68 (1H, ddd, J 11.9, 11.9

and 13.5, CHHCHOCO), 0.04 (3H, s, TBS-Me), −0.06 (3H, s,

TBS-Me); m/z (ESI), 708.4285 (M + H: C₄₁H₆₂NO₇Si requires

708.4296), 708 (M + H) (100%).

=

11.0 and 15.7, CH CHCO₂), 6.24 (1H, dd, J 10.9 and 15.2,

C CHCH C), 5.96 (1H, d, J 7.9, C CHCHO), 5.71 [1H, d,

=

J 10.9, CH C(CH₃)], 5.62 (1H, d, J 15.7, C CHCO₂), 5.14

(1H, dd, J 9.7 and 15.2, C CHCHCH₃), 4.55 (1H, dd, J 3.0

and 10.3, CHOCO), 3.89 (1H, dd, J 3.1 and 10.5, CHOTBS),

3.71 (1H, ddd, J 2.6, 9.9 and 12.0, CHOCO), 3.42 (1H, d, J

7.0, CHOCH₃), 3.23 (3H, s, OCH₃), 2.78 (1H, ddd, J 2.2, 5.3

Rhizoxin D 2

=

Pyridine (3 drops) and HF/pyridine complex (3 drops) were

added sequentially to a stirred solution of the silyl ether 52

(3.0 mg, 4.2 lmol) in tetrahydrofuran (0.5 mL) in a Teﬂon ﬂask at

room temperature. The mixture was stirred at room temperature

for 48 h, and then quenched by the careful addition of a saturated

aqueous solution of sodium bicarbonate (5 mL). The mixture

was diluted with ethyl acetate (5 mL), and the aqueous phase was

then separated. The separated aqueous phase was extracted with

ethyl acetate (3 × 5 mL), and the combined organic extracts were

washed with dilute sodium bisulfate solution (10 mL), and brine

(10 mL), then dried and concentrated in vacuo. The residue was

puriﬁed by preparative TLC (two elutions with ethyl acetate–

light petroleum; 3 : 2) to give rhizoxin D (2.0 mg, 74%) as a pale

yellow solid. R_f0.28 (ethyl acetate–light petroleum; 3 : 2); [a]_D²¹

+286 (c 0.04 in MeOH); k_max(MeOH)/nm 297 (e/dm³mol⁻¹cm⁻¹

38 700), 309 (49 900), 323 (36 500); m_max(sol.)/cm⁻¹3462, 1715,

1650, 1579; d_H(500 MHz, CDCl₃), 7.55 (1H, s, oxazoleH), 6.76

=

and 17.9, CHHCO₂), 2.56–2.53 (1H, m, CHHCH C), 2.31–

=

2.24 (2H, m, 2 × CHCH₃), 2.23 (3H, s, C CCH₃), 2.20–2.09

(2H, m, CHHCHOTBS and CHHCO₂), 1.98 (1H, dd, J 2.4

=

and 14.1, CHHCHOCO), 1.78–1.72 (2H, m, CHHCH C and

CHCH₂CO₂), 1.74 (3H, s, C CCH₃), 1.65 (1H, dd, J 3.1 and

=

14.8, CHHCHOTBS), 1.22 (3H, d, J 6.4, CHCH₃), 0.95 (3H,

d, J 7.0, CHCH₃), 0.87 (9H, s, TBS-^tBu), 0.69 (1H, ddd, J 11.9,

11.9 and 14.2, CHHCHOCO), 0.05 (3H, s, TBS-Me), −0.03

(3H, s, TBS-Me); d_C(90.6 MHz, CDCl₃), 190.7 (d), 170.3 (s),

165.8 (s), 160.2 (s), 146.2 (d), 139.9 (s), 133.5 (d), 130.0 (d), 128.6

(d), 124.6 (d), 124.4 (d), 88.2 (d), 83.3 (d), 78.8 (d), 74.5 (d), 57.2

(q), 45.3 (d), 38.6 (d), 38.2 (t), 36.9 (t), 34.6 (t), 29.7 (d), 29.6 (t),

25.8 (q), 18.0 (s), 16.6 (q), 12.8 (q), 11.0 (q), 9.0 (q), −4.7 (q),

−5.0 (q); m/z (ESI), 611.3359 (M + Na: C₃₃H₅₂O₇NaSi requires

611.3380), 611 (M + Na) (100%), 457 (M − OTBS) (37).

=

(1H, ddd, J 4.7, 11.0 and 15.5, CH CHCO₂), 6.63 [1H, dd,

4 4 3 0

O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

View Article Online

=

J 10.9 and 15.2, CH CHCH C(CH₃)], 6.41 [1H, d, J 15.2,

CH CHCH C(CH₃)], 6.28 [1H, s, oxazole-CH C(CH₃)], 6.23

N. J. Green, E. B. Hauser, M. A. Holoboski, L. E. Keown, C. S.

Nylund Kolz and B. W. Phillips, J. Org. Chem., 2002, 67, 7750–7760;

(f) Y. Jiang, J. Hong and S. D. Burke, Org. Lett., 2004, 6, 1445–

1448; (g) M.-A. N’Zoutani, N. Lensen, A. Pancrazi and J. Ardisson,

Synlett, 2005, 3, 491–495.

9 I. S. Mitchell, G. Pattenden and J. P. Stonehouse, Tetrahedron Lett.,

2002, 43, 493–497.

=

(1H, dd, J 11.1 and 15.3, C CHCH C), 6.13 [1H, d, J 10.9,

CH CHCH C(CH₃)], 5.82 [1H, d, J 11.1, CH C(CH₃)], 5.61

(1H, d, J 15.4, C CHCO₂), 5.16 (1H, dd, J 9.6 and 15.3,

C CHCHCH₃), 4.58 (1H, dd, J 3.0 and 10.5, CHOCO), 3.91

(1H, dd, J 3.5 and 13.4, CHOH), 3.68 (1H, ddd, J 2.6, 9.6

and 11.9, CHOCO), 3.26 (1H, d, J 9.2, CHOCH₃), 3.18 (3H, s,

OCH₃), 2.77 (1H, dd, 3.3 and 17.7, CHHCO₂), 2.53 (1H, m,

=

10 For synthetic approaches, see: A. V. Rama Rao, G. V. M. Sharma

and M. N. Bhanu, Tetrahedron Lett., 1992, 33, 3907–3110; D. L.

Boger and T. T. Curran, J. Org. Chem., 1992, 57, 2235–2244; G. E.

Keck, M. Park and D. Krishnamurthy, J. Org. Chem., 1993, 58,

3787–3788; A. V. Rama Rao, M. N. Bhanu and G. V. M. Sharma,

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Leahy, Tetrahedron Lett., 1995, 36, 6029–6032; D. P. Provencal, C.

Gardelli, J. A. Lafontaine and J. W. Leahy, Tetrahedron Lett., 1995,

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Cressman, Tetrahedron Lett., 1996, 37, 3291–3294; J. D. White, C. S.

Nylund and N. J. Green, Tetrahedron Lett., 1997, 38, 7329–7332; J. D.

White, M. A. Holoboski and N. J. Green, Tetrahedron Lett., 1997,

38, 7333–7336; S. D. Burke, J. Hong and A. P. Mongin, Tetrahedron

Lett., 1998, 39, 2239–2242; S. D. Burke, J. Hong, J. R. Lennox and

A. P. Mongin, J. Org. Chem., 1998, 63, 6952–6967; R. J. Davenport

and A. C. Regan, Tetrahedron Lett., 2000, 41, 7619–7622.

11 J. Hong and J. D. White, Tetrahedron, 2004, 60, 5653–5681.

12 J. K. Stille, Pure Appl. Chem., 1985, 57, 1771–1780; J. K. Stille, Angew.

Chem., Int. Ed. Engl., 1986, 25, 508–524; T. N. Mitchell, Synthesis,

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13 For a review of the intramolecular Stille reaction, see: M. A. J.

Duncton and G. Pattenden, J. Chem. Soc., Perkin Trans. 1, 1999,

1235–1246; see also ref. 27.

=

CHHCH C), 2.47 (3H, s, oxazoleCH₃), 2.32–2.28 (2H, m, 2 ×

=

CHCH₃), 2.16 (3H, s, C CCH₃), 2.14 (1H, m, CHHCHOH),

2.08 (1H, dd, J 11.3 and 18.1, CHHCO₂), 1.97 (1H, br. d, J 13.9,

CHHCHOCO), 1.90 (3H, s, C CCH₃), 1.80 (3H, s, C CCH₃),

1.74 (2H, m, CHHCH C and CHCH₂CO₂), 1.69 (1H, m,

CHHCHOTBS), 1.20 (3H, d, J 6.4, CHCH₃), 1.00 (3H, d, J 6.7,

CHCH₃), 0.68 (1H, ddd, J 12.1, 12.1 and 13.9, CHHCHOCO);

m/z (ESI), 648.3532 (M + MeOH + Na: C₃₆H₅₁NNaO₈requires

648.3512), 648 (M + MeOH + Na) (100%), 576 (M − OH) (15).

=

Acknowledgements

We thank Merck Sharp and Dohme (studentship to I. S. M.)

and the EPSRC, together with Aventis (studentship to J. P. S.),

for support. We also thank Dr D. A. Entwistle for modelling

the key Stille reaction and Professor David Williams for helpful

correspondence and for provision of NMR spectroscopic data

for his synthetic rhizoxin D.

14 The phosphine oxide 8 was ﬁrst prepared by Ohno et al. and used in

their synthesis of rhizoxin A; see ref. 7. It was kindly made available

to us by G. Rescourio from our laboratory.

15 J. R. Gage and D. A. Evans, Org. Synth., 1989, 68, 77–82; J. R. Gage

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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 4 1 2 – 4 4 3 1

4 4 3 1

Article Doi

A total synthesis of the antitumour macrolide rhizoxin D

DOI: 10.1039/b507570j

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