A total synthesis of the unique tris-oxazole macrolide ulapualide a produced by the marine nudibranch Hexabranchus sanguineus

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A total synthesis of the unique tris-oxazole macrolide ulapualide A

produced by the marine nudibranch Hexabranchus sanguineus

Shital K. Chattopadhyay and Gerald Pattenden*

1

School of Chemistry, The University of Nottingham, University Park, Nottingham,

UK NG7 2RD

Received (in Cambridge, UK) 27th January 2000, Accepted 3rd February 2000

Published on the Web 19th June 2000

A total synthesis of ulapualide A (1), whose relative stereochemistry was assigned on the basis of an earlier molecular

mechanics study of its hypothetical metal chelated complex 9, is described. The synthesis is based on: i, elaboration

of the double functionalised tris-oxazole 11; ii, synthesis and installation of the top side chain 16 (C-26–C-41) via a

stereoselective Wittig reaction, leading to 17; iii, conversion of 17 into 73a and attachment of the C-1–C-9 portion

18; iv, macrocyclisation of 19 by an intramolecular Wadsworth–Emmons oleﬁnation leading to the macrolide 20; v,

incorporation of the C-9 methyl group (to 80) and, ﬁnally vi, manipulation of the side chain functionality in 80 and

introduction of the terminal formyl enamine residue. The synthetic ulapualide A showed NMR spectroscopic data

which were almost identical to those described for the natural product, and did not separate from the natural material

in HPLC analysis. Small diﬀerences in the ¹³C NMR spectroscopic data however lead us to conclude that the

stereochemistry of the synthetic ulapualide diﬀers from that in the natural product at one or more of the stereogenic

centres along the C-28–C-33 portion of the side chain.

Ulapualide A (1)¹together with kabiramide C (2),²were the

ﬁrst members of an extraordinarily unique family of tris-

oxazole based macrolides to be isolated from nature. The

“ulapualides” derive their name from the Hawaiian words

“ula”, meaning red and “pua”, meaning ﬂower, since the

founder member 1 was isolated from the striking rosebud-like

egg masses deposited by the nudibranch Hexabranchus

sanguineus on ledges in underwater caves oﬀ the coast of

Hawaii. Simultaneously in 1986, kabiramide C was isolated

from the egg masses of an unidentiﬁed nudibranch collected at

Kariba Bay in the Ryukyus Islands, closely followed by the

isolation and characterisation of the structurally similar “hali-

chondramides”, e.g. 3, from the sponge Halichondria,³and the

mycalolides, e.g. 4, from a sponge of the genus Mycale.⁴The

molecules 1–4, all show structures based on a 25-membered

macrolide core which incorporates a novel tris-oxazole unit and

to which is attached a lipid-like side chain that terminates in an

unusual formyl enamine residue. The molecules diﬀer from

each other largely according to the oxidation patterns and the

level of alkyl group substitutions found in the aliphatic portions

of their structures. Interestingly however, the halichondramide

imide 5 and the ester 6, containing incomplete tris-oxazole

chromophores, were isolated as co-metabolites of halichon-

dramides from Halichondria.³More recently the structurally

related halishigamides 7 and 8 from the Okinawan marine

sponge Halichondria⁵have been added to this strikingly

unusual family of secondary metabolites.

Members of the ulapualide family of natural products show

a profound range of interesting and unusual biological

activities. For example, all of the metabolites show pronounced

antifungal activity, and they also inhibit cell divisions in the

fertilised sea urchin egg assay. In addition, some members show

ichthyotoxic properties whilst others inhibit leukemia cell pro-

liferation. In earlier publications we have suggested that some

of the unique biological properties of these molecules could

be associated with their capacity to sequester and transport

DOI: 10.1039/b000751j

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

This journal is © The Royal Society of Chemistry 2000

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metal ions, i.e. behave as ionophores, using the several oxazole

nitrogen and side chain oxygen ligand binding sites present in

their structures.⁶The combination of a unique chemical struc-

ture with novel biological properties encouraged us to examine

a total synthesis of the founder member, ulapualide A (1), of this

family of marine metabolites and to examine their ionophore

properties. In the immediately preceding paper⁷we described

concise synthetic routes to the tris-oxazole ring system found in

the natural product, and in this paper we describe the extension

of this work culminating in a total synthesis of ulapualide A,

with the relative stereochemistry shown in structure 1.⁸

In spite of considerable eﬀort over a substantial period of

time, it was not until after we had published our completed

synthetic studies in this area, that anything was known about

the stereochemistries of members of the family of ulapualides

isolated from nudibranchs and sponges.⁹The relative stereo-

chemistry shown in structure 1 for ulapualide A is that pre-

dicted by ourselves based on a molecular mechanics study on a

“dummy” metal chelated ulapualide A, e.g. 9, using varying

combinations of its oxygen and nitrogen atom ligating sites.⁶

Interestingly, this study showed that the stereochemistry of

a major part of the polyol side chain in 1 correlated with

corresponding chiral centres in scytophycin B (10), a related

metabolite whose structure had been established by X-ray

crystallography measurements.^10,11

A successful total synthesis of ulapualide A required atten-

tion to a number of details including: i, a synthetic method for

the synthesis of the unusual tris-oxazole unit making up the

macrolide core; ii, a concise synthesis of the (C-28–C-39) side

chain in 1 containing several oxy and methyl substituted chiral

centres; iii, a method for elaborating the terminal formyl enam-

ine unit associated with the side chain, and iv, the development

of methods for producing the macrolide core in the natural

product.¹²

In the preceding publication⁷we described the full details of

a convenient synthesis of gram quantities of the functionalised

Wittig salt 11. In the same publication we also highlighted the

scope for producing the entire tris-oxazole macrolide 13 by util-

ising a macrolactamisation from the ester 12, followed by oxa-

zoline and oxazole ring formation. In other model studies we

found that the formyl enamine unit in the ulapualides, i.e. 14,

could be produced smoothly from a corresponding aldehyde by

reaction with N-methylformamide in the presence of pyridine–

toluene-p-sulfonic acid (Scheme 1).¹³This procedure led to a

mixture of rotamers of the E-isomer of 14, as found in all the

naturally occurring ulapualides.

At the outset of our studies we considered a range of strat-

egies for elaborating the tris-oxazole based macrolide core in

ulapualide A and some of these are summarised on structure

15. Thus, we considered an obvious macrolactonisation from an

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methyl group, and ﬁnally the terminal N-methyl N-alkenyl-

formamide residue (Scheme 2).

The aforementioned design required the synthesis of the

three principal building blocks 11, 16 and 18. The synthesis of

the tris-oxazole substituted phosphonium salt 11 has already

been presented.⁷We will now describe syntheses of the pro-

tected polyol aldehyde 16 and the ω-carboxy phosphonate 18,

followed by their coupling which leads to 17, and the addition

of 18, producing 19. Macrocyclisation of 19 to 20, followed by

incorporation of the C-9 methyl group and manipulation of the

terminal formyl enamine residue then completes the synthesis

of ulapualide A.

Scheme 1

appropriate ω-hydroxy carboxylic acid precursor, an intra-

molecular oleﬁnation reaction producing the C-25–C-26 alkene

bond, and the utilisation of intramolecular sp²–sp²coupling

(e.g. Stille, Suzuki) reactions involving substituted oxazole ring

precursors.¹⁴As mentioned earlier, we also considered making

one or other of the oxazole rings in the natural product as the

last step utilising a macrolactamisation protocol, viz. 12→13.

An alternative, less obvious, macrolide ring forming strategy

was to eﬀect an intramolecular oleﬁnation reaction producing

the C-8–C-9 bond in the molecule, as a conjugated enone, and

then to later introduce the C-9 α-methyl group stereoselectively

using the conformational bias of the macrolide core.

With model work completed and adequate precedent estab-

lished,⁸the synthetic strategy we actually decided on to prepare

ulapualide A was based on: (i) elaboration of the tris-oxazole

phosphonium salt 11 and the protected polyol aldehyde 16,

followed by (ii) their coupling to the alkene 17, (iii) attachment

of the ω-carboxy substituted keto-phosphonate residue 18

producing 19, (iv) macrocyclisation via an intramolecular

Wadsworth–Emmons oleﬁnation leading to 20, and (v) sequen-

tial functional group manipulation, introduction of the C-9

Synthesis of the C-26–C-41 fragment 16 (R

؍

MOM;

RЈ = TBDMS)

An armoury of modern asymmetric synthesis methods is now

available for elaborating the chiral 1,3-diol and chiral 1-oxy, 2-

methyl substitution patterns in the C-26–C-41 side chain unit in

ulapualide A. The most important decision that needed to be

made before embarking on a synthesis of 16 was simply the

choice of appropriate hydroxy protecting groups at C-30, C-38

and C-41, such that they could be removed in a selective man-

ner as and when required. We therefore made the dimethyl

acetal, MOM, TBDMS, TBDPS derivative 21 our target since

these protecting groups could be removed selectively in the

order CH(OMe)₂>OMOM>OTBDMS using dimethylboryl

bromide.¹⁵We designed a convergent synthesis of the C-26–C-

Scheme 2

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41 unit 21¹⁶based on a Wadsworth–Emmons oleﬁnation reac-

tion between the aldehyde 22 and the phosphonate 23, which

were both synthesised from the same precursor, i.e. (E)-5-

benzyloxypent-2-enol 24 (Scheme 3).¹⁷

product 35 as a 1:1 mixture of Z- and E-isomers in 70% yield

and >95% de.

In readiness for oxidative cleavage of the double bond in 35,

the imide residue was next converted into the C-29 α-methyl

group (cf. 38) following reduction to the methanol 36 using

lithium methoxyborohydride,²¹mesylation (to 37) and further

reduction of 37 using lithium methoxyborohydride. Protection

of the secondary alcohol group in 38 as its tert-

butyldimethylsilyl ether 39, followed by ozonolysis of the

alkene bond in 39 at Ϫ78 ЊC then produced the aldehyde 40 in

80% yield. The addition of Brown’s (ϩ)-allyldiisopinocam-

phenylborane²²((ϩ)-IPCBOMe) to the aldehyde 40 proceeded

in a highly diastereoselective manner (de 89%) and, after

chromatography, gave rise to the α-OH orientated homoallylic

alcohol 41 in 65–70% yield. The stereochemistry of the newly

formed C-28–OH centre in 41 was determined through exten-

sive NMR experiments, i.e. ¹H COSY, C–H correlation,²³

homonuclear decoupling and NOE data, matching of com-

puter predicted coupling constants together with correlation of

¹³C chemical shift data for the acetonide 44 (derived from 41

and its diastereoisomer 42) with those data reported in the

literature for authentic syn- and anti-1,3-diol acetonides.²⁴

These data have been collected on structures 43 (predicted shift

data), 44 (data from 41) and 45, (data from the diastereo-

isomer 42 produced after reaction between the aldehyde 40

and (Ϫ)-allyldiisopinocamphenylborane).

Scheme 3

With the stereochemical integrity of the secondary alcohol

41 containing ﬁve of the eight chiral centres in the C-26–C-41

unit in ulapualide A established, its conversion into the key

aldehyde precursor 22 (for elaboration to 63) was then accom-

plished following: i, methylation to 46; ii, deprotection of the

tert-butyldimethylsilyl ether (to 47) and reprotection as the

MOM ether 48; iii, ozonolysis to 49; iv, dimethylacetal 50

formation; v, deprotection of 50 leading to 51; and ﬁnally

oxidation of 51 to 22 using TPAP–NMO (Scheme 5).

The synthesis of the phosphonate 23 containing the remain-

ing three chiral centres in the ulapualide A side chain was

achieved in twelve steps starting from the E-allylic alcohol 24

and featured the controlled ring opening of the chiral α-epoxy

alcohols 52 and 57 by methyl nucleophiles as key reactions

(Scheme 6).²⁵Thus, treatment of the chiral epoxide 52 derived

from 24 with trimethylaluminium at 0 ЊC produced a 9:1 mix-

ture of regioisomeric diols in favour of 53 which on cleavage

with sodium periodate gave the aldehyde 54 in 84% yield. A

Wittig reaction between 54 and ethoxycarbonylmethylene-

triphenylphosphorane next led to the E-unsaturated ester 55

which on reduction with DIBAL-H accessed the (E)-hex-2-en-

1-ol 56. Epoxidation of 56 to 57 via the Sharpless protocol

using (Ϫ)-diethyl tartrate, followed by chelation controlled

epoxide ring opening with methylmagnesium bromide next led

to the 1,3-diol 58 in 85% yield. Protection of the primary and

secondary hydroxy groups in 58 as the tert-butyldimethylsilyl

ether 59, followed by selective deprotection of the primary

Thus, Sharpless epoxidation¹⁸of (E)-5-benzyloxypent-2-enol

24, followed by chelation controlled addition of methylmagne-

sium bromide to the resulting epoxy alcohol 25¹⁹in the pres-

ence of CuI ﬁrst led to the corresponding 1,3-diol 26 in 66%

yield; a small amount (20%) of the unwanted corresponding

1,2-diol resulting from non-selective ring opening in 25 was

produced in this reaction but it was easily removed following

treatment of the crude product with sodium periodate and

chromatography. The primary alcohol group in 26 was next

protected as its tert-butyldiphenylsilyl ether 27 and this was

followed by protection of the secondary alcohol group as the

corresponding methyl ether, producing 28.

Hydrogenolysis of 28, and oxidation of the resulting primary

alcohol 29 then led to the diﬀerentially protected aldehyde 30

(Scheme 4). Our plan now was to elaborate the extended alde-

hyde 40 from 30, involving an anti-aldol reaction between 30

and the boron enolate derived from the unsaturated imide 34

(Scheme 5).²⁰The imide 34 was smoothly produced from the

mono-benzyl ether of propane-1,3-diol, following: i, oxidation

and a Wittig reaction between the resulting aldehyde and

ethoxycarbonylmethylenetriphenylphosphorane, leading to 31;

ii, saponiﬁcation and conversion into the acid chloride 33, and

ﬁnally iii, treatment of 33 with the anion derived from 4-

phenylmethyl-2-oxazolidone. When the aldehyde 30 was added

to a solution of the boron enolate derived from the imide 34

at Ϫ78 ЊC, work up and chromatography led to the anti-aldol

Scheme 4 Reagents and conditions: i, (Ϫ)-DET, Ti(OⁱPr)₄, t-BuOOH (61%); ii, MeMgBr, CuI, (66%); iii, t-BuPh₂SiCl, (94%); iv, NaH, MeI, (66%);

v, H₂, Pd(OH)₂-C, (92%); vi, (COCl)₂, DMSO, Et₃N, (87%).

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Scheme 5 Reagents and conditions: i, DMSO, (COCl)₂, Et₃N, then EtO₂CCH᎐PPh₃(68%); ii, LiOH, H₂O (95%); iii, (COCl)₂, DMF; iv, BuLi, 4-

᎐

phenylmethyl-2-oxazolidone, Ϫ78 ЊC (80%); v, Bu₂BOTf, Et₃N, Ϫ78 ЊC, then 30 (70%); vi, LiBH₄–MeOH (90%); vii, MeSO₂Cl–iPr₂NEt (90%); viii,

LiBH₄–MeOH (82%); ix, t-BuMeSiSO₂CF₃–CH₂Cl₂(95%); x, O₃, CH₂Cl₂, Ϫ78 ЊC (80%); xi CH₂᎐_᎐CHCH₂MgBr, (ϩ)-IPCBOMe, Ϫ78 ЊC (70%); xii,

MeOTf, 2,6-di-tert-butylpyridine (98%); xiii, PPTS, ethanol (90%); xiv, MOM-Cl, iPr₂NEt (95%); xv, O₃, PPh₃(89%); xvi, TMOF, MeOH, pTSA

(98%); xvii, TBAF (100%); xviii, TPAP, NMO (89%).

alcohol then gave 60 which was smoothly oxidised to the cor-

responding aldehyde 61 using TPAP–NMO. Finally, treatment

of the aldehyde 61 with methyl dimethylphosphonate in the

presence of n-BuLi, followed by oxidation of the resulting

alcohol 62 using pyridinium dichromate (PDC) in DMF then

produced the phosphonate 23.

A Wadsworth–Emmons oleﬁnation reaction between 22 and

23 using barium hydroxide in wet THF as base²⁶next gave the

E-alkene 63 in an excellent 95% yield (Scheme 7). Hydrogen-

ation of 63 in the presence of Pearlmans catalyst²⁷then resulted

in simultaneous reduction of the alkene bond and hydrogenoly-

sis of the benzyl protecting group in 63 producing the alcohol

64 in quantitative yield. Protection of the alcohol 64 as the

corresponding tert-butyldiphenylsilyl ether 21, followed by

treatment of the dimethyl acetal with boron dimethyl bromide¹⁵

then led to the C-26–C-41 side chain fragment 16 in ulapualide

A in readiness for coupling to the tris-oxazole phosphonium salt

11 en route to 17 and then to 19 and the macrolide 20.

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Scheme 6 Reagents and conditions: i, (ϩ)-DET, Ti(OiPr)₄, t-BuOOH (76%); ii, Me₃Al; iii, NaIO₄(84%); iv, Ph₃PCHCO₂Et (94%); v, DIBAL-H

(96%); vi, (Ϫ)-DET, Ti(iPr)₄, t-BuOOH (85%); vii, MeMgBr, CuI, THF; NaIO₄, MeOH–H₂O (89%); viii, TBDMS–OTf, 2,6-lutidine (100%); ix,

PPTS, MeOH, DCM (96%); x, TPAP, NMO (94%); xi, MePO(OMe)₂, n-BuLi (90%); xii, PDC, DMF (92%).

Scheme 7 Reagents and conditions: i, Ba(OH)₂, wet THF (95%); ii, Pd(OH)₂-C, H₂(94%); iii, imidazole, TBDPS-Cl (94%); iv, Me₂BBr, CH₂Cl₂

(95%).

Synthesis of the C-1–C-8 fragment 18

of diastereoisomers of the corresponding β-hydroxy phos-

phonate 70 was produced which was easily oxidised using PDC

in DMF leading to the β-keto phosphonate derivative 71.

Hydrogenolysis of the benzyl ester group in 71 ﬁnally produced

the ω-carboxy phosphonate 18.

Our strategy for the synthesis of the homochiral β-hydroxy

carboxylic acid phosphonate derivative 18 relied on access to

the TBDPS intermediate 67 followed by elaboration of the

alkene residue in 67 to the corresponding β-keto phosphonate

unit. A range of chemical²⁸and biological²⁹methods are now

available for the preparation of homochiral β-hydroxy esters

from reductions of the corresponding β-keto esters. We were

attracted to the use of baker’s yeast for the reduction of 65 to

the (3R)-hydroxy ester 66 since this conversion had already

been described by Hirama et al.²⁹during their studies of the

total synthesis of compactin. Thus, saponiﬁcation of the

known β-keto ester 65,³⁰using 1 M potassium hydroxide, fol-

lowed by reduction of the resulting potassium carboxylate

using actively fermenting baker’s yeast and work-up of the (3R)-

hydroxy carboxylic acid with benzyl bromide ﬁrst produced the

benzyl ester 66 in 35% overall yield from 65 and with >99% ee,

as measured by ¹H NMR analysis (Scheme 8). Protection of the

hydroxy group in 66 next gave the TBDPS derivative 67, which,

after hydroboration (to 68) and further oxidation, gave rise to

the aldehyde 69. When the aldehyde 69 was treated with the

anion derived from dimethyl methylphosphonate,³¹a mixture

Elaboration of the macrolide precursor 73 from the tris-oxazole

11 and the polyol side chain 16

We examined two obvious approaches to the macrolide 20 core

in ulapualide A 1. The ﬁrst involved an intramolecular oleﬁn-

ation reaction from the aldehyde phosphonate 19 (Scheme 9),

and the second used macrolactonisation from the ω-hydroxy

carboxylic acid derivative 79 (Scheme 10). In both of these

strategies we ﬁrst required a synthesis of the unit 17 derived

from the ter-oxazole phosphonium salt 11 and the C-26–C-41

fragment 16, followed by connection of the β-keto phosphonate

residue 18. The unit 17 was readily prepared following an E-

selective Wittig reaction between the aldehyde 16 and the ter-

oxazole phosphonium salt 11 using n-butyllithium as base at

Ϫ78 ЊC. The E-geometry assigned to the newly introduced

disubstituted double bond in 17 followed conclusively from the

magnitude (J 15.5 Hz) of the vicinal couplings associated with

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Scheme 8 Reagents and conditions: i, NaH in THF, then BuLi, CH₂᎐_᎐CHCH₂Br; ii, KOH, EtOH, 0 ЊC; iii, -glucose, baker’s yeast, KH₂PO₄, H₂O; iv,

PhCH₂Br, aliquot 336, NaHCO₃(~15–30% overall); v, TBDPS-Cl, imidazole, DMF, rt (81%); vi, BH₃ؒDMS, H₂O₂, NaOH (78%); vii, PDC, DCM

(78%); vii, MePO(OMe)₂, BuLi (55%); ix, PDC, DMF, (84%); x, Pd-C, H₂, EtOAc (98%).

Scheme 9 Reagents and conditions: i, n-BuLi, THF, Ϫ78 ЊC, 70%; ii, DIBAL-H, 0 ЊC, 75%; iii, Dess–Martin periodinane, DCM, 98%; iv, Me₂BBr,

DCM, Ϫ78 ЊC, 95%; v, 2,4,6-trichlorobenzoyl chloride, Et₃N, rt, 3 h, 42%; vi, K₂CO₃, 18-crown-6, toluene, 10–33%.

1

the oleﬁnic hydrogens in the H NMR spectrum of the alkene.

Treatment of 17 with DIBAL-H next resulted in simultaneous

reduction of the oxazole ester group and the ketone function at

C-36 leading to the diol 72, which was then cleanly oxidised

with Dess–Martin periodinane³²to the keto-aldehyde 73a in

quantitative yield. Inspection and comparison of the NMR

data for 17 and 73a established that the conversion into 73a had

proceeded with preservation of the stereochemical integrity at

the C-37 (α-keto methyl) centre. Deprotection of the MOM

ether group in 73a proceeded selectively using boron dimethyl

bromide in CH₂Cl₂at Ϫ78 ЊC and ﬁnally led to the secondary

alcohol-aldehyde intermediate 73b in readiness for its coupling

to the β-keto phosphonate 18.

Formation of the tris-oxazole macrolide core 20, and elaboration

to ulapualide

The two aforementioned strategies towards the macrolide core

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Scheme 10 Reagents and conditions: i, Ba(OH)₂ؒ8H₂O, wet THF, rt, 3 h, 85%; ii, Me₂CuLi, 0 ЊC, 3 h, 50%; iii, Me₂BBr, Ϫ78 ЊC, 1 h, 50%; iv,

Ba(OH)₂ؒ8H₂O, wet THF, rt, 3.5 h, 88%; v, Pd(PPh₃)₄, morpholine, rt, 2 h, 76%.

20 in ulapualide were now evaluated.³³The most useful

method involved esteriﬁcation of the phosphonate carboxylic

acid 18 with the secondary alcohol 73b, leading to 19, fol-

lowed by an intramolecular Wadsworth–Emmons oleﬁnation,

using K₂CO₃in the presence of 18-crown-6,³⁴which produced

the E-macrolide enone 20 in an unoptimised 30% yield

(Scheme 9). In a second approach to the macrolide 20,

shown in Scheme 10, the tris-oxazole aldehyde 73a was ﬁrst

reacted with the keto phosphonate 74 leading to 75 which

was then treated with Me₂CuLi producing 76 as a mixture of

C-9 Me epimers with concomitant deprotection of the allyl

ester. Deprotection of the MOM ether in 76, using Me₂BBr

then gave rise to the ω-hydroxy acid 77. Similarly, the alde-

hyde 73b reacted with the phosphonate 74 producing enone 78

which was then deprotected with Pd(0) catalysis giving rise to

the hydroxy acid 79. The macrolactonisations of 77 and 79,

under Yamaguchi conditions³³gave disappointing low yields

(5–10%) of the corresponding macrolide, cf. 20, under a

range of conditions (Scheme 10). This outcome was possibly

due to the steric incumberance around the reacting centres in

the substrates, and the overall synthetic approach to 20 was

less convenient than that proceeding via the aldehyde phos-

phonate 19.

lar mechanics modelling data⁶allowed us to assign the

α-(equatorial) methyl epimer, i.e. 80a, as the major product of

the methyl cuprate addition to the enone 20; this outcome is

consistent with the delivery of the cuprate to the least

hindered face of the enone unit in 20, relative to the bulky

β-orientated TBDPS ether at C-3. Deprotection of the

C-38 TBDMS ether group in either of the epimers 80 was

smoothly accomplished using trimethylsilyl triﬂate ³⁵at Ϫ78 ЊC,

and acetylation of the resulting secondary alcohol 81 then pro-

duced the corresponding acetate 82 (Scheme 11). Selective

deprotection of the primary alcohol TBDPS group in 82a

using pyridineؒHF,³⁶and oxidation of the resulting alcohol

83a using Dess–Martin periodinane³²then gave the corre-

sponding aldehyde 84a. The same synthetic methods were also

used to convert 81b into 84b. When a solution of either 84a

or 84b in benzene was heated with N-methylformamide in the

presence of pyridine–toluene-p-sulfonic acid¹³for 10–12 h,

chromatography gave the E-isomers of the corresponding

N-methyl-N-alkenylformamides 85a and 85b respectively in

40% yield. The syntheses of the ulapualide A structure 1 and its

C-9 methyl epimer were then completed following deprotec-

tion of the tert-butyldiphenylsilyl ether group in 85a and 85b

using pyridineؒHF.

Treatment of the tris-oxazole macrolide enone 20 with lith-

ium dimethylcuprate in ether at 0 ЊC led to a 3:2 mixture of

C-9 methyl epimers of 80, which could be separated cleanly

by column chromatography. Comparison of the NMR spec-

troscopic data between the epimers of 80 and those of nat-

ural ulapualide A, together with consideration of our molecu-

Stereochemistry of natural and synthetic ulapualide A

Several years ago we carried out a molecular mechanics study

of ulapualide A and some of its hypothetical metal conjugates,⁶

in order to provide a working stereochemical model on which to

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Scheme 11 Reagents and conditions: i, Me₂CuLi, Et₂O, 0 ЊC, 55%; ii, TMSOTf, Ϫ78 ЊC, 85%; iii, Ac₂O, DMAP, pyridine, 90%; iv, HFؒpyridine, 85%;

v, Dess–Martin periodinane, 90%; vi, NHMeCHO, PPTS, benzene, 40%; vii, HFؒPy, pyridine, THF, 80%.

base the synthetic work described in this paper. Thus, brieﬂy, we

ﬁrst showed that in a ulapualide–metal conjugate only two of

the three oxazole nitrogen centres could complex with the metal

at any time, and the best ﬁt energy minimised arrangement was

that shown in the complex 86. We next added the various side

analysis that were similarly close. Very small diﬀerences

between the compounds were found however on inspection of

their ¹³C NMR spectroscopic data, which are shown in Table 1.

Even within these data the only discernable diﬀerences were

associated with the chemical shifts of C-32 (δ 81.0 ppm

observed and δ 81.8 ppm natural; ∆δ 0.8 ppm), the C-33 methyl

group (δ 14.2 ppm observed against δ 15.5 ppm natural; ∆δ 1.3

ppm) and C-34 (δ 26.6 ppm observed and δ 27.6 ppm natural;

∆δ 1.0 ppm), with other chemical shifts mostly lying within 0.4

ppm of each other. These diﬀerences are shown below on struc-

tures 87 (synthetic) and 88 (natural). The similarities in the ¹³

C

NMR spectra were really quite eerie and disconcerting.

chain substituents in ulapualide to this complex, in sequence,

one at a time, and energy minimised each epimer. Each of the

epimers of higher energy was discarded, and when all the sub-

stituents had been added, each stereocentre was again inverted

and the structure re-minimised as a double check. Interestingly,

deletion of the metal (we used octahedral Co() as a typical

“dummy” metal) from the complex and re-minimisation

showed that the metal–ligand conjugate was only 12 kJ mol^Ϫ1

higher in energy than the ligand alone. Using this procedure we

arrived at the relative stereochemistry shown in 1 (cf. 9) as the

most favourable stereostructure for ulapualide A. In the cases

of the centres C-9, C-33 and C-37, the “energetic penalty” upon

stereocentre inversions was found to be very marginal, i.e. 2.3–

4.2 kJ mol^Ϫ1.

With the stereomodel 1 for ulapualide, and no other inform-

ation to hand, in 1990 we embarked on the ambitious total

synthesis presented here, leading to both the C-9 α- and C-9

β-methyl epimers of the stereostructure. Much to our interest,

and almost disbelief, both the α- and β-methyl epimers of our

synthetic ulapualide showed ¹H NMR spectroscopic data which

were almost superimposable on those of a sample of natural

ulapualide A, and the samples had retention times in HPLC

Furthermore, under normal circumstances and in the

absence of spectroscopic data recorded for the natural product,

at the same time, under similar dilution, in the same solvent, on

the same instrument, one might have been forgiven for saying

that either of the C-9 α- and C-9 β-methyl epimers of the syn-

thetic ulapualide were identical to the natural product. We do

not believe this to be the case however. In the ﬁrst instance our

spectroscopic data do not allow us to distinguish the C-9

α-methyl epimer of synthetic ulapualide from its corresponding

β-methyl epimer. Secondly, the diﬀerences in chemical shift

associated with the C-32 to C-34 carbon centres in the ¹³C

NMR spectra of synthetic and natural ulapualide clearly indi-

cate that one or other of the C-32 and C-33 centres is incorrect,

i.e. most likely syn(cis)-orientated in the natural product.

Apart from these diﬀerences however the remainder of the

stereochemistry of the synthetic and natural ulapualide are, for

all intents and purposes, identical. Based on these data and

analyses, and before the important paper presented by Panek

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

2437

View Article Online

After the preliminary publication of our total synthesis of

ulapualide A (with the relative stereochemistry shown in 1),

Panek and Fusetani and their collaborators, unambiguously

established the stereochemistry of the related mycalolide

Fig. 1 The numbering system used to interpret NMR data is shown in

the structure above, and is based on the system by Scheuer et al. in their

structure determination of the natural product.

Table 1 ¹³C NMR data of ulapualide A and synthetic compounds 85a

and 85b

C atom

Natural

ulapualide

α-Methyl epimer β-Methyl epimer

85a

85b

1

2

3

172.6 (s)

42.95 (t)

68.4 (d)

37.2 (t)

172.6

42.9

68.7

172.7

42.9

68.8

4

37.3

37.1

5

6

20.8 (t)

43.9 (t)

20.6

44.0

20.7

44.0

7

8

210.5 (s)

48.1 (t)

210.4

47.9

210.4

47.9

9

28.2 (d)

146.5 (s)

154.2 (s)

133.5 (d)

131.7 (s)

156.2 (s)

137.4 (d)

130.2 (s)

162.7 (s)

137.8 (s)

117.2 (d)

139.9 (d)

33.7 (t)

80.0 (d)

34.6 (d)

73.0 (d)

32.1 (t)

81.8 (d)

40.4 (d)

27.6 (t)

27.7

10

12

14

15

17

19

20

22

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

146.6

154.3

133.4

131.9

156.2

137.4

130.1

162.8

137.8

117.5

139.6

33.1

79.9

34.1

72.8

32.0

81.0

40.4

26.6

39.9

146.5

154.2

133.5

131.6

156.2

137.4

130.5

162.6

137.8

117.6

139.1

33.1

79.9

34.0

72.8

32.0

81.0

40.6

26.6

39.8

metabolites as shown in structure 90.† At the same time these

authors found that ulapualide B had the same stereochemistry

along its C-28–C-39 backbone as the mycalolides, viz. 91.

It is uncanny therefore that the diﬀerences between our syn-

thetic ulapualide and natural ulapualide A are simply: i, the

diﬀering stereochemistry at C-32, i.e. β-OMe instead of α-OMe,

which is reﬂected in the diﬀerent shift data in their ¹³C NMR

spectra, and ii, the mirror image (enantiomeric) relationship

between the C-28–C-30 centres in the two compounds, which is

not reﬂected in their ¹³C NMR shift data, viz. C-28, δ 79.9 ppm

(natural δ 80.0 ppm), C-29, δ 34.1 ppm (natural δ 34.6 ppm),

C-30, δ 72.8 ppm (natural δ 73.0 ppm), C-29–Me, δ 9.1 ppm

(natural δ 9.1 ppm).

39.8 (t)

211.8 (s)

48.6 (d)

77.3 (d)

37.0 (d)

112.2 (d)

110.5 (d)

129.6 (d)

125.5 (d)

162.2 (d)

161.0 (d)

33.1 (q)

19.5 (q)

170.1 (s)

20.9 (q)

13.4 (q)

15.5 (q)

58.1 (q)

9.1 (q)

211.6

48.6

77.6

211.5

48.7

77.3

36.9

112.2

110.5

129.6

125.2

162.2

161.0

33.1

19.2

170.1

20.9

13.4

14.2

57.8

9.1

112.1

110.5

129.6

125.1

162.2

161.0

33.1

19.8

170.2

20.9

13.4

14.2

57.9

9.1

41

43

Metal binding studies with natural ulapualides

The dearth of natural and synthetic ulapualide A 1 prevented

us from carrying out an evaluation of the metal binding

properties of this particular secondary metabolite. However

in contemporaneous studies, and prompted by our earlier

protestations of the metal binding properties of several marine

metabolies (particularly ulapualides and cyclopeptides), Siegel

and co-workers³⁷examined and compared the metal binding of

dihydrohalichondramide 92 isolated from the sponge Halichon-

dria sp., the tris-oxazole 93 and the diphenyloxazole 94. Using

ﬂuorescence quenching and NMR techniques, these authors

demonstrated that the molecules 92–94 showed similar, but

small, binding constants, i.e. 10²and 10⁴for the metals Ag^ϩ,

and Cu^2ϩ, Fe^2ϩ, Hg^2ϩ, and Pb^2ϩ, providing little evidence of any

signiﬁcant chelate eﬀect. Siegel and co-workers³⁷were led to

44

45

38OAc

46

47

32OMe

48

28OMe

49

57.8 (q)

18.9 (q)

57.6

18.9

57.6

18.9

and Fusetani and their co-workers⁹analysing the stereo-

chemistry of the related mycalolides (cf. 4) was published

during 1999, we would have revised the relative stereochemistry

of natural ulapualide to the C-32-(β)-methoxy epimer i.e. 89,

or the C-33-(α)-methyl epimer of structure 1.

† Note added at proof-stage: After the completion and acceptance of

this paper Liu and Panek published a total synthesis of (Ϫ)-mycalolide

90.³⁸

2438

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

View Article Online

1099; δ_H(400 MHz) 7.36–7.29 (5H, m, Ph), 5.75–5.7 (2H, m,

CH᎐CH), 4.53 (2H, s, PhCH O), 4.05–4.0 (2H, br, CH OH),

᎐

2

3.53 (2H, t, J 6.6 Hz, ᎐CH OCH Ph), 2.40–2.3 (2H, m), 2.22

᎐

2

(1H, br s, OH); δ_C(100 MHz) 138.2 (s), 131.0 (d), 128.8 (d),

128.3 (d), 127.6 (d), 127.5 (d), 72.8 (t), 69.5 (t), 63.3 (t), 32.5 (t);

m/z (EI) 192 (M^ϩ).

[3-(2-Benzyloxyethyl)oxiran-2-yl]methanol 25

Titanium() isopropoxide (2.6 ml), (Ϫ)-diethyl tartrate (1.72

ml) and the allylic alcohol 24 (16.1 g) were added sequentially

over 30 min to a suspension of powdered 4 Å sieves (2.5 g) in

dry dichloromethane (170 ml) at Ϫ20 ЊC under nitrogen. The

mixture was stirred at Ϫ20 ЊC for 30 min, and then tert-butyl

hydroperoxide (3 M in isooctane, 55.7 ml) was added dropwise

over 30 min. The mixture was stirred at Ϫ20 ЊC for 10 h and

then kept in a freezer overnight. The mixture was quenched

with water (100 ml) at 20 ЊC and then allowed to warm to room

temperature. A solution of NaOH (30%) in brine (20 ml) was

added and the mixture was stirred vigorously for 45 min at

room temperature and then diluted with dichloromethane (100

ml). The layers were allowed to separate and the inhomogenous

aqueous layer was extracted with dichloromethane (3 × 150

ml). The combined organic extracts were dried (Na₂SO₄), and

then concentrated in vacuo to leave a pale yellow liquid which

was puriﬁed by ﬂash chromatography on silica, using ether as

eluent to give the epoxide (10.64 g, 61%) as a colourless oil; [α]_D²¹

ϩ32 (c, l.0 in CHCl₃) (Found: C, 68.4; H, 7.9. C₁₂H₁₆O₃requires

C, 69.2, H, 7.7%). ν_max(ﬁlm)/cm^Ϫ13436 (br), 3063, 1496, 1455,

1208, 1100; δ_H(400 MHz) 7.36–7.20 (5H, m, Ph), 4.47 (2H, s,

CH₂Ph), 3.81–3.74 (1H, m), 3.65 (2H, t, J 6.0 Hz, CH₂O), 3.53–

3.43 (1H, m), 3.03 (1H, m), 2.91 (1H, dt, J 4.6 and 6.0 Hz,

CHCH₂O), 1.95–1.71 (2H, m); δ_C(100 MHz) 137.8 (s), 128.0

(d), 127.7 (d), 72.6 (t), 66.5 (t), 61.5 (t), 58.6 (t), 53.4 (d), 31.7 (t);

m/z (EI) (Found: 207.1041, (M^ϩϪ 1). C₁₂H₁₅O₃requires

207.1021).

conclude, therefore, that any antifungal properties of dihydro-

halichondramide 92 and its relatives are probably not associated

with their properties to bind metals in vivo.

Experimental

For general experimental details see ref. 7. Also petrol refers to

the fraction of light petroleum with the distillation range 40–

60 ЊC. [α]_Dhas units of 10^Ϫ1deg cm²g^Ϫ1.

(E)-Ethyl 5-benzyloxypent-2-enoate 31

Dimethyl sulfoxide (22 ml, 0.312 mol) was added dropwise over

20 min to a stirred solution of oxalyl chloride (20 ml, 0.226 mol)

in dry dichloromethane (120 ml) at Ϫ78 ЊC under nitrogen.

After 15 min, a solution of the mono-benzyl ether of propane-

1,3-diol (26 g, 0.175 mm) in dry dichloromethane (40 ml) was

added dropwise over 30 min and the mixture was stirred at

Ϫ78 ЊC for a further 1 h. Triethylamine (68 ml, 0.485 mol)

was added dropwise over 30 min to the stirred mixture which

was then stirred for a further 2 min. A solution of ethoxy-

carbonylmethylenetriphenylphosphorane (64 g, 0.184 mol) in

dry dichloromethane (120 ml) was added in one portion and the

mixture was then allowed to warm to room temperature and

stirred overnight. The mixture was diluted with dichlorometh-

ane (200 ml) and the solution was washed successively with

water (2 × 200 ml), saturated NaHCO₃(200 ml) and brine (100

ml) and then dried (MgSO₄). The dried extracts were concen-

trated in vacuo and the residue was triturated with a mixture of

ether (100 ml) and petroleum ether (200 ml) in an ice-bath for

1 h. The precipitated phosphine oxide was ﬁltered oﬀ and the

ﬁltrate was concentrated in vacuo to leave a pale yellow oil.

Distillation gave the (E)-ester (28 g, 68%) as a colourless liquid,

bp 140 ЊC at 1 mmHg; ν_max(ﬁlm)/cm^Ϫ11718, 1656; δ_H(400 MHz)

5-Benzyloxy-2-methylpentane-1,3-diol 26

A solution of methylmagnesium bromide (2 M in THF, 87 ml,

0.26 mol) was added dropwise over 30 min to a stirred suspen-

sion of cuprous iodide (4.95 g, 26 mmol) in dry THF (180 ml) at

Ϫ20 ЊC under nitrogen. The mixture was stirred at Ϫ20 ЊC for a

further 30 min and then a solution of the epoxy alcohol 25 (18

g, 86.4 mmol) in dry THF (90 ml) was added dropwise over 15

min. The mixture was stirred at Ϫ20 ЊC for 2.5 h, then

quenched with saturated aqueous NH₄Cl (180 ml) and allowed

to warm to room temperature. It was then stirred vigorously for

30 min before extracting with ether (4 × 200 ml). The combined

organic extracts were washed with saturated aqueous NH₄Cl

(2 × 100 ml), and brine (100 ml), then dried (MgSO₄) and con-

centrated in vacuo to leave a pale yellow oil. Analysis of the ¹H

NMR spectrum of the residue indicated that a 4:1 mixture of

1,2- and 1,3-regioisomeric diol products had been formed in

favour of the required 1,3-diol. A solution of the residue in

methanol (360 ml) and water (90 ml), was stirred with NaIO₄

(4.5 g, 21 mmol) for 6 h and then the methanol was removed in

vacuo. The residue was diluted with water (400 ml) and then

extracted with dichloromethane (3 × 200 ml). The combined

organic extracts were dried (MgSO₄) and then concentrated

in vacuo to leave a pale yellow oil. Flash chromatography on

silica using diethyl ether as eluent ﬁrst gave 4-benzyloxy-2-

methylbutanal (2.65 g, 16%) and then the diol (12.8 g, 66%) as a

colourless oil; [α]_D²¹Ϫ2.1 (c, 2.5 in CHCl₃) (Found: C, 69.3; H,

9.3. C₁₃H₂₀O₃requires C, 69.6; H, 9.0%); ν_max(ﬁlm)/cm^Ϫ13392,

3088, 1496; δ_H(400 MHz) 7.32 (5H, m, Ph), 4.53 (2H, s,

CH₂Ph), 3.95 (1H, br s, OH), 3.8–3.6 (5H, m), 3.42 (1H, br s,

OH), 1.73–1.63 (3H, m), 0.86 (3H, d, J 6.9 Hz, Me); δ_C(100

MHz) 137.8 (s, Ar), 128.6 (d), 127.9 (d), 127.7 (d), 77.5 (d), 73.6

(t), 69.5 (t), 67.7 (t), 40.3 (d), 34.5 (t), 13.9 (q); m/z (EI) 206

(M Ϫ H₂O)^ϩ.

7.32 (5H, m, Ar), 6.97 (1H, dt, J 15.7 and 6.9 Hz, ᎐CHCH ),

᎐

2

5.89 (1H, dt, J 15.7 and 1.6 Hz, ᎐CHCO Et), 4.50 (2H, s,

᎐

2

PhCH₂O), 4.18 (2H, q, J 7.1 Hz, CH₂CH₃), 3.57 (2H, t, J 6.5

Hz, CH₂O), 2.49 (2H, apparent qd, J ca. 6.6 and 1.6 Hz,

CH CH᎐), 1.2 (3H, t, J 7.1 Hz, CH CH ); δ (100 MHz) 166.3

᎐

2

3

C

(s), 145.5 (d), 138.0 (s), 128.3 (d), 128.2 (d), 127.6 (d), 127.5 (d),

122.9 (d), 72.9 (t), 68.2 (t), 60.1 (t), 32.7 (t), 14.2 (q); m/z (EI)

(Found: 234.1260. C₁₄H₁₈O₃requires 234.1256).

(E)-5-Benzyloxypent-2-en-1-ol 24

A solution of DIBAL-H (1 M in hexane, 250 ml) was added

dropwise over 1 h to a stirred solution of the ester 31 (28 g,

119.5 mmol) in dry THF (250 ml) at 0 ЊC under nitrogen. The

mixture was stirred at 0 ЊC for 2 h and then quenched with 2 M

HCl (10 ml slowly, then 250 ml after the mixture had set to a

gel). The aqueous phase was extracted with ethyl acetate

(2 × 200 ml) and the combined organic extracts were dried

(MgSO₄), and then concentrated in vacuo to leave a yellow oil.

Distillation gave the alcohol (19.3 g, 84%) as a colourless oil, bp

130 ЊC at 1 mmHg (Found: C, 74.8; H, 8.75. C₁₂H₁₆O₂requires

C, 75.0; H, 8.4%); ν_max(ﬁlm)/cm^Ϫ13393 (br), 3031, 2860, 1497,

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

2439

View Article Online

5-Benzyloxy-1-(tert-butyldiphenylsilanyloxy)-2-methylpentan-3-

ol 27

(d), 31.6 (t), 27.3 (q, t-Bu), 19.7 (s, t-Bu), 11.8 (q, Me); m/z (EI)

297 (M^ϩϪ t-Bu Ϫ MeOH).

Imidazole (6.65 g, 95.5 mmol) and tert-butyldiphenylsilyl

chloride (15 ml, 57.7 mmol) were added sequentially to a solu-

tion of the 1,3-diol 26 (11 g, 49 mmol) in dry DMF (55 ml) at

room temperature under nitrogen. The solution was stirred at

room temperature overnight and then diluted with water (300

ml). The combined organic extracts were washed with water

(2 × 100 ml) and brine (100 ml), then dried (Na₂SO₄) and con-

centrated in vacuo to leave a pale yellow oil. Puriﬁcation by ﬂash

chromatography on silica using 7:1 petrol–ethyl acetate as eluent

gave the silyl ether (21.3 g, 94%) as a colourless oil; [α]_D²¹Ϫ5.4 (c,

1.8 in CHCl₃) (Found: C, 75.3; H, 8.7. C₂₉H₃₈O₃Si requires C,

75.3; H, 8.3%); ν_max(ﬁlm)/cm^Ϫ13502 (br), 3070, 2959, 1472;

δ_H(400 MHz) 7.66–7.60 (4H, m, Ph), 7.41–7.30 (11H, m, ArH),

4.53 (2H, s, PhCH₂O), 3.81 (1H, ddd, J 9.3, 7.0 and 2.7 Hz,

CHOH), 3.6–3.70 (4H, m), 2.0–1.80 (3H, m), 1.05 (9H, s), 0.87

(3H, d, J 6.9 Hz, Me); δ_C(67.8 MHz) 138.7 (s), 136 (d), 133.6 (s),

130.1 (d), 128.8 (d), 128.1 (d), 128.0 (d), 128 (d), 74.0 (d), 73.98

(t), 69.0 (t), 68.8 (t), 40.9 (d), 34.7 (t), 27.3 (q, t-Bu), 19.6 (s,

t-Bu), 13.7 (q, Me); m/z (EI) 327 (M^ϩϪ t-Bu-Ph) (3%).

5-(tert-Butyldiphenylsilanyloxy)-3-methoxy-4-methylpentanal

30

A solution of DMSO (1.44 ml) in dry dichloromethane (5 ml)

was added dropwise over 5 min to a solution of oxalyl chloride

(1.07 ml) in dry dichloromethane (20 ml) at Ϫ78 ЊC under

nitrogen. After 5 min, a solution of the alcohol 29 (3.9 g) in dry

dichloromethane (10 ml) was added dropwise over 15 min and

the mixture was stirred at Ϫ78 ЊC for 1.5 h. Triethylamine (6.42

ml) was added dropwise over 15 min to the mixture which was

then allowed to warm to room temperature. The mixture was

diluted with water (50 ml) and dichloromethane (50 ml), and

the aqueous layer was then separated and extracted with di-

chloromethane (2 × 50 ml). The combined dichloromethane

extracts were washed with water (50 ml) and brine (50 ml) then

dried (Na₂SO₄) and evaporated in vacuo to leave a pale yellow

oil. Puriﬁcation by ﬂash chromatography on silica, using

dichloromethane as eluent gave the aldehyde (3.3 g, 87%) as an

unstable colourless viscous oil; [α]_D²¹ϩ1.4 (c, 1.9 in CHCl₃);

ν_max(ﬁlm)/cm^Ϫ13030, 2930, 2857, 1725, 1471; δ_H(400 MHz) 9.80

(1H, apparent t, J 2 Hz, CHO), 7.7–7.6 (4H, m, ArH), 7.5–7.4

(6H, m, ArH), 3.9 (1H, ddd, J 7.9, 5.3 and 4.6 Hz, CHOMe), 3.60

(1H, dd, J 10.3 and 5.2 Hz, CHHOSi), 3.44 (1H, dd, J 10.3 and

6.7 Hz, CHHOSi), 3.26 (3H, s, OMe), 2.4–2.6 (2H, m,

CH₂CHO), 2.0–2.1 (1H, m, CHMe), 1.05 (9H, s), 0.85 (3H, d,

J 6.9 Hz, Me); δ_C(100 MHz) 201.8 (d, CHO), 135.7 (d, Ar),

135.6 (d, Ar), 133.6 (s, Ar), 133.5 (s, Ar), 129.8 (d, Ar), 129.8

(d, Ar), 127.8 (d, Ar), 77.2 (d, C-3), 65.5 (t, C-5), 57.2 (q,

OCH₃), 44.6 (t), 37.8 (d), 27.0 (q, t-Bu), 19.3 (s, t-Bu), 11.8 (q,

Me); m/z (EI) (Found: M^ϩϩ Na, 407.1975. C₂₃H₃₂O₃SiNa

requires 407.2018).

(5-Benzyloxy-3-methoxy-2-(methyl)pentyloxy)-tert-

butyldiphenylsilane 28

Sodium hydride (60% in oil, 1.6 g, 40 mmol) was added in one

portion to a stirred solution of the alcohol 27 (9.1 g, 19.66

mmol) in dry DMF (25 ml) at 0 ЊC under nitrogen. The mixture

was stirred at 0 ЊC for 5 min and then methyl iodide (6 ml, 96.4

mmol) was added in one portion. The resulting mixture was

stirred at room temperature for 2 h and then quenched with

saturated aqueous NH₄Cl (200 ml), diluted with water (200 ml)

and extracted with ether (3 × 100 ml). The combined ether

extracts were washed with water (2 × 100 ml) and brine (50 ml),

then dried (MgSO₄) and concentrated in vacuo to leave a pale

yellow oil. Puriﬁcation by ﬂash chromatography on silica using

petrol–ethyl acetate 10:1 as eluent gave the methyl ether (7.7 g,

66%) as a colourless oil; [α]_D²¹ϩ4.5 (c, 4.4 in CHCl₃) (Found: C,

75.8; H, 8.7. C₃₀H₄₀O₃Si requires C, 75.6; H, 8.5%); ν_max(ﬁlm)/

cm^Ϫ13070, 2931, 1473; δ_H(400 MHz) 7.70–7.65 (4H, m, Ph),

7.37–7.27 (11H, m, Ph), 4.48 (1H, d, J 7 Hz, CHHPh), 4.52

(1H, d, J 7 Hz, CHHPh), 3.66 (4H, m), 3.58 (1H, ddd, J 8.9, 5.9

and 3.0 Hz, CHOMe), 3.28 (s, 3H, OCH₃), 1.9–2.0 (1H, m),

1.80–1.60 (2H, m), 1.05 (9H, s, t-Bu), 0.88 (3H, d, J 7 Hz, Me);

δ_C(100 MHz) 136.0 (s), 135.6 (d), 133.9 (d), 133.8 (s), 129.65 (d),

128.3 (d), 127.65 (d), 127.5 (d), 79.0 (d), 73.0 (t), 63.75 (t), 65.7

(t), 38.1 (d), 30.4 (t), 26.9 (q, t-Bu), 19.3 (s, t-Bu), 12.1 (q, Me);

m/z (EI) 419 (M Ϫ t-Bu)^ϩ.

5-Benzyloxypent-2-enoic acid 32

A solution of lithium hydroxide monohydrate (2.7 g, 64.9

mmol) in water (100 ml) was added in one portion to a solution

of the ester 31 (7.6 g, 32.4 mmol) in 1,4-dioxane (150 ml) and

the mixture was then stirred at room temperature for 3 h. The

mixture was concentrated in vacuo and the residue was then

diluted with water (100 ml). The aqueous solution was

extracted with ether (2 × 100 ml) and was then acidiﬁed to pH

1.0 with 2 M HCl (50 ml) before extracting with 2 × 150 ml

portions of ethyl acetate. The combined extracts were washed

successively with water (50 ml) and brine (50 ml), and then

dried (MgSO₄). The organic extracts were evaporated under

reduced pressure to leave the acid (6.3 g, 95%) as a liquid;

ν_max(ﬁlm)/cm^Ϫ13300–2500, 1698, 1650, 1454; δ_H(400 MHz) 7.3–

5-(tert-Butyldiphenylsilanyloxy)-3-methoxy-4-methylpentan-1-ol

29

7.2 (5H, m, Ph), 7.03 (1H, dt, J 15.8 and 6.6 Hz, CH CH᎐), 5.83

᎐

2

(1H, dt, J 15.8, 1.6 Hz, ᎐CHCO Et), 4.45 (2H, s, CH Ph), 3.53

᎐

2

(2H, t, J 6.6 Hz, CH₂O), 2.47 (2H, apparent qd, J 6.6 and 1.6

Pearlman’s catalyst [Pd(OH)₂-C, 400 mg] was added to a ﬂask

containing a solution of the benzyl ether 28 (4.0 g, 8.4 mmol) in

methanol (40 ml) at room temperature, and the ﬂask was then

evacuated prior to the introduction of hydrogen gas. The mix-

ture was stirred under one atmosphere of hydrogen for 18 h and

then ﬁltered through Celite. The ﬁlter cake was washed with

ether (2 × 25 ml) and the combined ﬁltrate was concentrated in

vacuo to leave a colourless oil. Puriﬁcation by ﬂash chrom-

atography on silica using 3:1 petrol–ethyl acetate as eluent

gave the alcohol (2.98 g, 92%) as a colourless oil; [α]_D²¹ϩ11.3

(c, 5.6 in CHCl₃) (Found: C, 71.3; H, 9.1. C₂₃H₃₄O₃Si requires

C, 71.5; H, 8.9%); ν_max(ﬁlm)/cm^Ϫ13431 (br), 3071, 2960,

1473; δ_H(400 MHz) 7.7–7.6 (4H, m, Ph), 7.4–7.3 (6H, m, Ph),

3.7 (2H, t, J 5.8 Hz, CH₂O), 3.64 (1H, dd, J 10.2 and 5.9 Hz,

CHHOSi), 3.4–3.6 (1H, m), 3.52 (1H, dd, J 10.2, 6.6 Hz,

CHHOSi), 3.33 (3H, s, OMe), 2.61 (1H, br s, OH), 2.2–2.1

(1H, m), 1.67–1.62 (2H, m), 1.10 (9H, s), 0.84 (3H, d, J 6.9

Hz, Me); δ_C(67.80 MHz) 136.0 (d), 134.1 (s), 133.65 (s), 130.1

(d), 128.1 (d), 82.5 (d), 66.2 (t), 61.9 (t), 57.3 (q, OMe), 37.4

Hz, CH CH᎐) which was used without further puriﬁcation.

᎐

2

4-Benzyl-3-(5-benzyloxypent-2-enoyl)-1,3-oxazolidin-2-one 34

Dimethylformamide (80 µl, 1 mmol) and freshly distilled oxalyl

chloride (2.0 ml, 23 mmol) were added dropwise over 5 min to a

solution of the acid 32 (4.1 g, 20 mmol) in dry dichloromethane

(20 ml) at room temperature under argon. The solution was

stirred at room temperature for 30 min, and then the solvent

was removed in vacuo to leave the corresponding acid chloride

33 as a liquid. In a separate ﬂask, n-BuLi (1.6 M, 9.4 ml, 15

mmol) was added dropwise over 15 min to a solution of the 4-

phenylmethyl-1,3-oxazolid-2-one (2.65 g, 15 mmol) in dry THF

(30 ml) at Ϫ78 ЊC under nitrogen until a pale yellow colour

remained. A solution of the acid chloride (20 mmol maximum)

in dry THF (10 ml) was added dropwise over 10 min to the

stirred anion solution at Ϫ78 ЊC. The mixture was stirred at

Ϫ78 ЊC for 0.5 h and then allowed to warm to room temper-

ature where it was stirred for 0.5 h. Aqueous 1 M potassium

2440

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

View Article Online

carbonate (10 ml) was added and the mixture was then stirred at

room temperature for 1 h. The mixture was diluted with water

(70 ml) and extracted with ethyl acetate (3 × 75 ml). The com-

bined extracts were washed with water (50 ml), dried over

MgSO₄, and then concentrated in vacuo to leave a yellow oil.

Flash chromatography on silica using dichloromethane–diethyl

ether (25:1) as eluent gave the imide (4.3 g, 80%) as a colourless

oil; [α]_D²⁰ϩ50.5 (c, 2.6 in CHCl₃) (Found: C 71.5; H, 6.3.

C₂₂H₂₄NO₄requires C, 72.1; H, 6.5%); ν_max(ﬁlm)/cm^Ϫ13028,

2859, 1778, 1682; δ_H(270 MHz) 7.3–7.1 (12H, m, ArH plus

HC᎐CH), 4.67–4.61 (4H, m), 4.45 (2H, s, PhCH O), 4.13–4.07

g, 3.80 mmol) in dry THF (35 ml) at 0 ЊC under nitrogen and

the resulting mixture was stirred at 0 ЊC for 0.5 h. The mixture

was quenched by slow addition of aqueous NaOH (1 M, 22 ml)

and then allowed to warm to room temperature. Ethyl acetate

(100 ml) was added and the separated aqueous phase was then

extracted with more ethyl acetate (3 × 50 ml). The combined

organic extracts were washed with water (50 ml) and brine (50

ml), then dried over Na₂SO₄and concentrated in vacuo to leave

a colourless viscous oil. Puriﬁcation by ﬂash chromatography

on silica using ethyl acetate–petrol (2:1) as eluent gave the 1,3-

diol (1.96 g, 90%) as a colourless viscous oil; [α]_D²⁰ϩ13.8 (c, 4.0

in CHCl₃) (Found: C, 72.5; H, 8.7. C₃₅H₄₈O₅Si requires C, 72.9;

H, 8.4%); ν_max(ﬁlm)/cm^Ϫ13416 (br), 2930, 1428, 1086; δ_H(400

MHz) 7.7–7.65 (4H, m, Ph), 7.4–7.28 (11H, m, Ph), 5.93–5.70

᎐

2

(2H, apparent ABq, 5-H), 3.55 (2H, t, J 6.3 Hz, CH₂OBz), 3.23

(1H, dd, J 13.5 and 3.1 Hz, PhCHH), 2.70 (1H, dd, J 13.5 and

9.6 Hz, PhCHH), 2.53 (2H, apparent q, J 6.3 Hz, CH CH᎐);

᎐

2

δ_C(100 MHz) 164.7 (s), 153.3 (s), 148.0 (d), 138.0 (s, Ph), 135.3

(s, Ph), 129.4 (d), 128.8 (d), 128.5 (d), 128.3 (d), 127.6 (d), 127.5

(d), 127.3 (d, Ph), 121.7 (d), 72.9 (t, PhCH₂O), 68.2 (t), 66.1 (t),

55.2 (d), 37.8 (t, PhCH₂C), 33.0 (t, C-4); m/z (CI) (Found

M^ϩϩ 1, 366.1687. C₂₂H₂₃NO₄requires 366.1705).

(2H, m, HC᎐CH), 4.5 and 4.52 (2H, both d, J 7 Hz, PhCH O),

᎐

2

4.15–4.09 (1H, m, H-3), 4.06 (2H, apparent t, J 6.4 Hz), 4.03

(2H, d, J 5 Hz, H-3Ј), 3.78–3.73 (3.64–3.59) (2H, m, H-7), 3.71

(3.67) (2H, apparent dd, J 9.9 and 5.1 Hz, H-1), 3.58–3.52 (1H,

m, H-5), 3.32 (3.31) (3H, s, OMe), 2.68–2.55 (2H, br s, 2 × OH),

2.62–2.57 (2.33–2.30) (1H, m, H-2), 2.04–2.00 (1H, m, H-6),

1.80–1.73 (1.49–1.41) (2H, m, H-4), 1.06 (9H, s, t-Bu), 0.88

(0.87) (3H, d, J 6.5 Hz, C-7–Me); δ_C(67.8 MHz) 138.2, 138.0

(q), 133.7, 133.6 (q), 135.6, 135.5, 128.9, 128.3, 127.74, 127.7,

127.6, 127.55, 127.1 (all ArCH), 130.5 (130.3), 129.65 (129.5)

(CH, C7/8), 80.0 (79.9) (CH, C-3), 72.4 (71.9) (PhCH₂O), 70.6

(CH₂, C-5), 69.8 (69.5) (CH₂, C-1), 57.5 (57.4) (OMe), 50.0

(45.6) (CH₂, C-6), 37.6 (37.5) (CH, C-2), 33.1 (CH, C-4), 26.8 (s,

t-Bu), 19.2 (q, t-Bu), 12.7 (12.6) (C-2-Me); m/z (FAB) (Found:

M^ϩϩ 1, 577.3349. C₃₅H₄₈O₅Si requires 577.3336).

4-Benzyl-3-{5-benzyloxy-2-[5-(tert-butyldiphenylsilanyloxy)-1-

hydroxy-3-methoxy-4-methylpentyl]pent-3-enoyl}oxazolidin-2-

one 35

Bu₂BOTf (1.7 ml, 8 mmol) and Et₃N (1.4 ml, 10 mmol) were

added to a solution of the imide 34 (2.6 g, 7.11 mmol) in dry

dichloromethane (50 ml) at Ϫ78 ЊC under nitrogen and the

resulting pale yellow solution was stirred at Ϫ78 ЊC for 1 h and

then at 0 ЊC for 30 min before being re-cooled to Ϫ78 ЊC. A

solution of the aldehyde 30 (3 g, 7.8 mmol) in dry dichloro-

methane (15 ml) was added dropwise over 0.5 h to the mix-

ture which was then further stirred at Ϫ78 ЊC for 1.5 h. The

mixture was allowed to warm to 0 ЊC and held at that temper-

ature for 2 h. It was then quenched by adding a solution of

NaOAc (0.5 g) in methanol and water (10 ml, 10:1). After 20

min, aqueous H₂O₂(3 ml, 27%) was added dropwise and the

mixture was stirred at 0 ЊC for 30 min. It was then diluted with

water (100 ml) and the aqueous phase was extracted with

dichloromethane (3 × 100 ml). The combined organic extracts

were washed with water (50 ml) and dried (Na₂SO₄), then

ﬁltered, and the ﬁltrate was concentrated in vacuo to leave a

yellow oil. Flash chromatography on silica using 50:1

dichloromethane–ether as eluent gave recovered aldehyde (1 g)

(eluted ﬁrst) and then the secondary alcohol (2.90 g, 70% based

on recovered aldehyde) as a colourless oil; [α]_D²⁰ϩ4.4 (c, 5.1 in

CHCl₃) (Found: C, 71.6; H, 7.5; N, 1.5. C₄₅H₅₅NO₇Si requires

C, 72.0; H, 7.3; N, 1.8%); ν_max(ﬁlm)/cm^Ϫ13500 (br), 2930, 1781,

1694; δ_H(400 MHz) 7.7–7.65 (4H, m, Ph), 7.4–7.3 (16H, m, Ph),

Methanesulfonic acid 5-benzyloxy-2-[5-(tert-butyldiphenyl-

silanyloxy)-1-hydroxy-3-methoxy-4-methylpentyl]pent-3-enyl

ester 37

N,N-Diisopropylethylamine (1.28 ml, 7.37 mmol) and methane-

sulfonyl chloride (0.255 ml, 3.3 mmol) were added sequentially

to a stirred solution of the diol 36 (1.9 g, 3.30 mmol) in dry

dichloromethane (38 ml) at 0 ЊC under nitrogen. The resulting

solution was stirred at 0 ЊC for 1 h and then at room temper-

ature for 1 h. Aqueous potassium carbonate (1 M, 38 ml)

was added and the resulting two phase mixture was stirred

vigorously at room temperature for 10 min. The aqueous phase

was extracted with dichloromethane (3 × 50 ml) and the com-

bined organic extracts were then dried (Na₂SO₄) and concen-

trated in vacuo to leave a pale yellow oil. Flash chromatography

on silica using dichloromethane–ether (20:1) as eluent gave the

pure methanesulfonate (1.94 g, 90%), as an oil; [α]_D²⁰ϩ2.0 (c, 3.4

in CHCl₃) (Found: C, 65.9; H, 7.9. C₃₆H₅₀O₇SSi requires C, 66.0;

H, 7.7%); ν_max(ﬁlm)/cm^Ϫ13468, 2959, 2932; δ_H(400 MHz) 7.68–

7.64 (4H, m, Ph), 7.43–7.28 (11H, m, Ph), 5.94–5.60 (2H, m,

6.0–5.95 (2H, m, HC᎐CH), 4.9 (4.57) (1H, dd, J 8.0 and 4.1

᎐

Hz), 4.7–4.65 (1H, m, 4Ј-H), 4.48 and 4.52 (2H, J 7 Hz,

PhCH₂O), 4.30–4.2 (1H, m, 5-H), 4.16–4.09 (2H, m, 1-H), 4.07

(2H, d, J 4.7 Hz, 9-H), 4.22–4.16 (2H, m, 9-H), 3.67–3.55 (1H,

m, 3H/3Ј-H), 3.53 (3.32) (3H, s, OMe), 3.23 (1H, t, J 13.5 Hz,

5Ј-H), 2.70 (1H, dd, J 13.5 and 9.7 Hz), 2.0 (1H, sextet, J 6.5

Hz, 2-H), 1.75–1.69 (m, 1H, 4-H), 1.55–1.48 (1H, m, 4-H), 1.06

(9H, s, t-Bu), 0.90 (0.88) (3H, d, J 6.9 Hz); δ_C(100 MHz) 173.7

(173.34) (s, C-1Ј), 153.0 (152.91) (s, C-2Ј), 138.2, 135.6, 133.8 (s,

Ph), 136.2 (d), 135.6 (d), 135.0 (d), 133.7 (d), 132.8 (132.4) (d,

C-8), 129.6 (d), 129.4 (d), 128.9 (d), 128.3 (d), 127.65 (d), 127.3

(d, Ph), 126.7 (126.4), (d, C-7), 79.3 (d, C-3), 72.7 (71.9)

(t, PhCH₂O), 70.2 (66.6) (t, C-9), 69.4 (67.1) (d, C-5), 65.8 (65.7)

(t, C-3Ј), 57.5 (57.4) (q, OMe), 55.0 (d, C-4Ј), 51.6 (48.0) (d,

C-6), 37.9 (d, C-2), 37.4 (t, C-5Ј), 34.0 (33.8) (t, C-4), 26.9 (q,

t-Bu), 19.2 (s, t-Bu), 12.4 (q, Me); m/z (FAB) (Found M^ϩϩ 1,

750.3710. C₄₅H₅₆NO₇Si requires 750.3826).

HC᎐CH), 4.52 and 4.50 (2H, both d, J 7 Hz, PhCH O), 4.35

᎐

2

(1H, dd, J 15.8 and 7.8 Hz, H-10), 4.20 (1H, dd, J 9.8 and 6.7

Hz), 4.15–4.10 (1H, m, CHOH), 4.07 (4.02) (2H, d, J 6.5 Hz,

CH₂OCH₂Ph), 3.71 (3.60) (2H, dd, J 9.9 and 5.0 Hz, CH₂O-

SiR₃), 3.57–3.52 (1H, m, CHOMe), 3.31 (3.30) (3H, s, OMe),

3.00 (2.97) (3H, s, SMe), 2.80–2.76 (2.55–2.48) (1H, m, CH–

CH᎐CH–), 2.05–2.00 (1H, m, CHMe), 1.78–1.71 (1.42–1.33)

᎐

(2H, m), 1.06 (9H, s, t-Bu), 0.38 (0.36) (3H, d, J 7.3 Hz, C2-Me);

δ_C(67.8 MHz) 138.1, 138.0, 133.9, 133.5 (all s, Ph), 135.5, 135.5,

129.5, 128.3, 127.8, 127.6 (all CH, Ph), 132.1 (131.5) and 127.5

(127.2) (CH, C7/8), 79.9 (79.9) (CH, C-3), 72.4 (71.9) (PhCH₂O),

70.2 (65.4) (CH₂, C-4), 67.9 (69.9) (CH₂, C-10), 66.7 (66.6) (CH,

C-5), 65.4 (CH₂, C-1), 57.4 (57.3) (OMe), 48.1 (43.5) (CH, C-6),

37.4 (37.4) (CH, C-2), 37.1 (37.0) (SMe), 33.3 (33.1) (CH₂, C-4),

26.8 (t-Bu), 19.2 (s, t-Bu), 12.7 (12.6) (CH₃, C2-Me); m/z (FAB)

(Found: M^ϩϩ 1, 655.3085. C₃₆H₅₀O₇SSi requires 655.3125).

2-(3-Benzyloxyprop-1-enyl)-7-(tert-butyldiphenylsilanyloxy)-5-

methoxy-6-methylheptane-1,3-diol 36

1-Benzyloxy-9-(tert-butyldiphenylsilanyloxy)-7-methoxy-4,8-

dimethylnon-2-en-5-ol 38

Dry methanol (0.39 ml, 9.5 mmol) and LiBH₄(4.8 ml, 2.5 M in

THF, 9.6 mmol) were added to a solution of the imide 35 (2.85

Dry methanol (0.38 ml, 9.32 mmol) and lithium borohydride

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

2441

View Article Online

(2 M in THF, 4.66 ml, 9.32 mmol) were added sequentially to a

stirred solution of the methanesulfonate 37 (1.74 g, 2.66 mmol)

in dry diglyme (44 ml) at 0 ЊC under nitrogen. The resulting mix-

ture was stirred at 0 ЊC for 90 min and then quenched by adding

aqueous sodium hydroxide (1 M, 45 ml) dropwise. The mixture

was extracted with dichloromethane (3 × 50 ml) and the com-

bined extracts were dried (Na₂SO₄) and concentrated in vacuo

to leave a pale yellow oil. The oil was puriﬁed by ﬂash chrom-

atography on silica using dichloromethane–ether (50:1) as

eluent to give the reduced product (1.2 g, 82%) as a colourless

viscous oil; [α]_D²⁰ϩ14.3 (c, 6.0 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ13473,

2960, 2930 (Found: C, 74.7; H, 8.8. C₃₅H₄₈O₄Si requires C, 74.9;

H, 8.6%); δ_H(400 MHz) 7.69–7.66 (4H, m, Ph), 7.42–7.30 (11H,

centrated in vacuo to leave a residue which was puriﬁed by

chromatography over silica using petrol–ethyl acetate (6:1) as

eluent to give the aldehyde (0.93 g, 80%) as a colourless oil; [α]_D²⁰

Ϫ3.7 (c, 5.8 in CHCl₃); δ_H(270 MHz) 9.64 (1H, d, J 1.3 Hz,

CHO), 7.6–7.55 (4H, m), 7.36–7.31 (6H, m), 4.15 (1H, dt, J 8

and 3.6 Hz), 3.46–3.38 (3H, m), 3.2 (3H, s), 2.51 (1H, dq, J 6.3

and 1.3 Hz), 2.06–1.95 (m, 1H), 1.42 (1H, ddd, J 14.4, 8.6 and

2.3 Hz), 1.30 (1H, ddd, J 3.6, 10.1 and 14.2 Hz), 1.02 (3H, d, J 7

Hz), 0.98 (9H, s), 0.79 (9H, s), 0.73 (3H, d, J 6.9 Hz), 0.00 (6H,

s); δ_C(67.8 MHz) 203.9 (CHO), 135.6 (CH), 133.7 (C), 129.6

(CH), 127.6 (CH), 78.0 (CH), 69.9 (CH), 66.0 (CH₂), 56.0

(OCH₃), 52.8 (CH), 36.7 (CH), 35.0 (CH₂), 26.9 (C–CH₃), 25.9

(C–CH₃), 19.2 (C), 18.0 (q), 10.9 (CH₃), 9.0 (CH₃), Ϫ4.3 (CH₃),

Ϫ4.4 (CH₃); m/z (FAB) 567 (M^ϩϩ H₂O).

m, Ph), 5.76–5.55 (2H, m, HC᎐CH), 4.52 and 4.5 (2H, d, J 7

᎐

Hz, PhCH₂O), 4.09 (1H, apparent td, J 5.4 and 1.4 Hz, H-5),

4.02 (1H, apparent d, J 5.6 Hz, H-3), 3.75–3.69 (1H, m,

CHOH), 3.72–3.68 (3.66–3.59) (2H, m, H-9), 3.62–3.57 (1H, m,

H-7), 3.34 (3.32) (3H, s, OMe), 2.56 (1H, br s, OH), 2.43 (2.26)

(1H, sextet, J 6.5 Hz, H-4), 2.07–2.00 (1H, m, H-8), 1.62–1.50

(2H, m, H-6), 1.07 (9H, s, t-Bu), 1.05 (1.00) (3H, d, J 6.7 Hz,

CHMe), 0.89 (0.88) (3H, d, J 6.9 Hz, C8–Me); δ_C(100 MHz)

138.3, 138.2, 133.7, 133.6 (all q, Ar), 135.5, 135.5, 129.5, 128.2,

128.0, 127.9, 127.6, 127.5, 127.4 (all CH, Ph), 136.2 (135.9),

127.2 (127.0) (CH, C-7/8), 79.7 (79.6) (CH, C-3), 72.1 (71.8)

(PhCH₂O), 71.8 (71.7) (CH, C-5), 70.7 (65.82) (CH₂, C-9), 65.7

(65.59) (CH₂, C-1), 57.4 (OCH₃), 42.9 (38.7) (CH, C-6), 37.6

(CH, C-2), 33.3 (32.9) (CH₂, C-4), 26.8 (26.6) (t-Bu), 19.2 (q,

t-Bu), 17.05 (16.1) (CH₃, C-6), 12.5 (12.4) (Me, C-2); m/z (FAB)

561 (M ϩ H)^ϩ.

6-(tert-Butyldimethylsilanyloxy)-10-(tert-butyldiphenylsilanyl-

oxy)-8-methoxy-5,9-dimethyldec-1-en-4-ol 41

A solution of allylmagnesium bromide (1.0 M in ether, 1.58 ml)

was added dropwise over 2 min to a stirred solution of (ϩ)-

IPC₂BOMe (0.46 g, 1.55 mmol) in dry ether (1.5 ml) at Ϫ78 ЊC

under argon. The resulting thick white slurry was stirred at

Ϫ78 ЊC for 1 h and then allowed to warm to room temperature.

The mixture was stirred for an additional hour at room tem-

perature, then cooled to Ϫ90 ЊC and a solution of the aldehyde

40 (0.86 g, 1.54 mmol) in dry ether (3 ml) was slowly added via

cannula. The mixture was stirred at Ϫ78 ЊC for 5 h and then

quenched by the slow addition of aqueous sodium hydroxide (3

M, 1.12 ml). The mixture was warmed to room temperature and

aqueous H₂O₂(30%, 0.44 ml) was then added slowly. The mix-

ture was heated under reﬂux for an hour, then cooled to room

temperature and diluted with ether (50 ml). The organic

extracts were washed with water (2 × 20 ml) and brine (25 ml),

then dried (Na₂SO₄) and concentrated in vacuo to leave an oil.

Puriﬁcation by ﬂash chromatography on silica using petrol–

ethyl acetate (9:1) as eluent gave the alcohol (0.65 g, 70%) as a

colourless oil; [α]_D²⁰ϩ10.9 (c, 4.2 in CHCl₃) (Found: C, 70.4; H,

10.2. C₃₅H₅₈O₄Si₂requires C, 70.2; H, 9.8%); δ_H(400 MHz)

7.68–7.65 (4H, m, ArH), 7.46–7.37 (6H, m, ArH), 5.8 (1H, ddt,

1-Benzyloxy-9-(tert-butyldiphenylsilanyloxy)-7-methoxy-4,8-

dimethylnon-2-en-5-yl tert-butyldimethylsilyl ether 39

A solution of tert-butyldimethylsilyl triﬂuoromethanesulfonate

(2.5 ml, 10.54 mmol) in dry dichloromethane (10 ml) was added

dropwise over 10 min to a stirred solution of the alcohol 38

(4.93 g, 8.78 mmol) and 2,6-lutidine (2.5 ml, 21.07 mmol) in dry

dichloromethane (45 ml) at 0 ЊC under nitrogen. The mixture

was stirred at 0 ЊC for 1 h and then allowed to warm to room

temperature where stirring was continued for an additional 1 h.

Methanol (3 ml) was added followed by dichloromethane (50

ml) and the solution was then washed with water (2 × 50 ml)

and brine (25 ml) and ﬁnally dried (Na₂SO₄). The dried ﬁltrate

was concentrated in vacuo to leave a pale yellow oil. Puriﬁcation

by ﬂash chromatography on silica using ether–dichloromethane

(50:1) as eluent gave the bis-silyl ether (5.6 g, 95%) as a colour-

less oil; [α]_D²⁵ϩ17.6 (c, 9 in CHCl₃) (Found: C, 73.3; H, 9.6;

C₄₁H₆₂O₄Si₂requires C, 73.0; H, 9.2%); δ_H(400 MHz) 7.60–7.14

(15H, m), 5.57–5.17 (2H, m), 4.43 (2H, s), 4.40 (2H, s), 3.91–

3.60 (2H, m), 3.45–3.36 (2H, m), 3.18 (3H, s), 3.15 (3H, s), 2.65–

2.35 (1H, m), 2.10–1.95 (1H, m), 1.30–1.27 (2H, m), 1.1 (9H, s),

1.04 and 0.99 (3H, both d, J 7 Hz), 0.91 and 0.85 (two singlets,

9H), 0.86 (3H, d, J 7 Hz), 0.04 (6H, 4 singlets); δ_C(100 MHz)

138.4, 138.3, 136.6, 135.6, 135.4, 133.8, 129.5, 128.3, 128.3,

127.8, 127.7, 127.6, 127.5, 126.6, 126.39, 78.3, 76.5, 76.3, 76.3,

72.45, 72.2, 72.17, 71.6, 70.1, 66.1, 56.2, 56.1, 42.55, 38.4, 37.2,

37.1, 33.98, 34.0, 26.9, 26.0, 19.2, 18.1, 15.5, 13.4, 11.4, 4.4, 4.3,

4.2; m/z (FAB) (Found: M^ϩϩ 1, 675.4265. C₄₁H₆₂O₄Si₂requires

675.4289).

J 17, 14 and 7 Hz, H C᎐CHCH ), 5.15–5.05 (2H, m, ᎐CH ),

᎐

2

4.10 (1H, apparent dt, J 2 and 7 Hz, 4-H), 3.90 (1H, dt, J 2 and

6 Hz), 3.55 (2H, apparent d, J 7 Hz, 10-H) 3.40 (1H, br s, OH),

3.35 (1H, ddd, J 2, 4 and 9 Hz), 3.28 (3H, s, OMe), 2.32 (1H,

quintet, J 7 Hz), 2.15 (1H, quintet, J 7 Hz), 2.08–2.04 (1H, m, 9-

H), 1.76–1.69 (1H, m, 7-H), 1.65 (1H, tq, J 2 and 7 Hz, 5-H),

1.55 (1H, ddd, J 2.6, 6 and 14.5 Hz, 7-H), 1.07 (9H, s), 1.03 (3H,

d, J 7.1 Hz), 0.88 (9H, s), 0.86 (3H, d, J 7 Hz), 0.084 (3H, s),

0.076 (3H, s); δ_C(100 MHz) 135.7 (d), 134.6 (s), 129.8 (d), 127.8

(d), 116.6 (t), 79.2 (d), 70.5 (d), 66.1 (t), 56.45 (OCH₃), 40.1 (d),

39.6 (d), 37.3 (t), 35.6 (t), 27.0 (q, t-Bu), 26.0 (q, t-Bu), 19.4 (s,

t-Bu), 18.0 (s, t-Bu), 11.3 (q, Me), 11.0 (q, Me), Ϫ4.1 (q, Me),

Ϫ4.4(q, Me);m/z(FAB)(Found:M^ϩϩ 1, 599.3962. C₃₅H₅₈O₄Si₂

requires 599.3951).

6-(tert-Butyldimethylsilanyloxy)-10-(tert-butyldiphenylsilanyl-

oxy)-4,8-dimethoxy-5,9-dimethyldec-1-ene 46

2,6-Di-tert-butylpyridine (2.13 g, 10.8 mmol) and methyl tri-

ﬂuoromethanesulfonate (0.612 ml, 5.41 mmol) were added

sequentially to a solution of the alcohol 41 (0.22 g, 0.36 mmol)

in chloroform (7.5 ml) under nitrogen. The mixture was heated

to reﬂux for 70 min and then cooled to room temperature. Con-

centrated NH₄OH (0.78 ml, 10.82 mmol) was added and the

mixture was stirred at room temperature for 2 h and then

diluted with dichloromethane (25 ml). The organic phase was

washed successively with water (20 ml), 2 M HCl (3 × 25 ml),

water (20 ml) and brine (25 ml), then dried (Na₂SO₄) and con-

centrated in vacuo to leave a pale yellow oil. Puriﬁcation by ﬂash

chromatography on silica using dichloromethane–petrol (3:2)

as eluent gave the methyl ether (0.21 g, 95%) as a colourless

oil; [α]_D²⁰ϩ16.2 (c, 3.2 in CHCl₃) (Found: C, 70.8; H, 10.1.

3-(tert-Butyldimethylsilanyloxy)-7-(tert-butyldiphenylsilanyl-

oxy)-5-methoxy-2,6-dimethylheptanal 40

A solution of the alkene 39 (1.4 g, 2.1 mmol) in dry dichloro-

methane (30 ml) was ozonised at Ϫ78 ЊC in the presence of a

small amount of Sudan-Red indicator until the solution turned

blue. Oxygen was then bubbled through the solution for 10 min

to remove any excess of ozone. Triphenylphosphine (0.69 g,

2.59 mmol) was added in one portion under nitrogen and the

solution was then stirred at Ϫ78 ЊC for 15 min before being

allowed to warm to room temperature. The solution was con-

2442

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

View Article Online

C₃₆H₆₀O₄Si₂requires C. 70.5; H, 9.9%); δ_H(360 MHz) 7.40–7.50

(6H, m), 7.65–7.70 (4H, m), 5.85 (1H, ddt, J 17, 14 and 7 Hz,

a small amount of Sudan-Red indicator until a blue colour

persisted and then oxygen was bubbled through the solution for

10 min. Triphenylphosphine (0.49 g, 1.85 mmol) was added,

and the mixture was stirred at Ϫ78 ЊC for 15 min under nitro-

gen, and then allowed to warm to room temperature. The mix-

ture was concentrated in vacuo to leave a pale yellow residue

which was puriﬁed by chromatography on silica using

dichloromethane–ether (12:1) as eluent to give the aldehyde

(0.73 g, 89%) as a labile colourless viscous liquid; [α]_D²⁰ϩ20.0 (c,

1.75 in CHCl₃); δ_H(400 MHz) 9.85 (1H, t, J 1.3 Hz, CHO),

7.80–7.71 (4H, m), 7.5–7.4 (6H, m), 4.6 (1H, d, J 6 Hz,

CHHO), 3.52 (1H, d, J 6 Hz, CHHO), 3.80 (1H, ddd, J 9.3, 4.7

and 2.2 Hz), 3.68 (1H, apparent q, J 5.2 Hz), 3.55 (3H, m), 3.3

(3H, s, OMe), 3.20 (3H, s, OCH₃), 3.11 (3H, s), 2.65 (2H, m),

2.14 (1H, m), 1.88 (1H, m), 1.45 (2H, m), 1.31 (2H, m), 1.00

(9H, s), 0.91 (3H, d, J 6.7 Hz), 0.82 (3H, d, J 6.8 Hz); δ_C(100

MHz) 200.8 (CHO), 135.1 (d), 133.1 (s), 129.0 (d), 127.0 (d),

96.2 (t), 77.6 (d), 77.2 (d), 76.8 (d), 65.4 (t), 57.0 (OCH₃), 56.3

(OCH₃), 55.2 (OCH₃), 45.66 (t), 41.0 (d), 36.6 (d), 31.6 (t), 26.3

(t-Bu), 18.6 (Me), 10.6 (q, Me), 9.1 (q, Me) (Found: M ϩ Na

579.3243. C₃₁H₄₈O₆SiNa requires 579.3302); which was used

immediately in the next step.

H C᎐CHCH ), 5.16–5.06 (2H, m), 4.01 (1H, m), 3.60 (2H, m),

᎐

2

3.48 (1H, m), 3.33 (3H, s), 3.31 (3H, s), 2.95 (1H, m), 2.35 (2H,

m), 2.10 (1H, m), 1.86 (1H, m), 1.35 (3H, m), 1.15 (9H, s), 0.92

(3H, d, J 7 Hz), 0.85 (12H, s, 9H ϩ obscured doublet, 3H);

δ_C(100 MHz) 135.6 (CH), 134.6 (CH), 133.8 (C), 129.5 (CH),

127.6 (CH), 117.2 (CH₂), 82.75 (CH), 78.7 (CH), 69.9 (CH),

66.2 (CH₂), 57.3 (OCH₃), 56.8 (OCH₃), 42.5 (CH), 37.4 (CH),

34.8 (CH₂), 33.0 (CH₂), 29.9 (t-Bu), 26.0 (t-Bu), 19.25 (q), 18.0

(q), 11.45 (CH₃), 8.6 (CH₃), Ϫ4.0 (Me), Ϫ4.6 (Me); m/z (FAB)

614 (M ϩ H)^ϩ.

1-(tert-Butyldiphenylsilanyloxy)-3,7-dimethoxy-2,6-dimethyl-

dec-9-en-5-ol 47

Pyridinium toluene-p-sulfonate (160 mg) was added to a solu-

tion of the bis-silyl ether 46 (1.30 g, 2.1 mmol) in ethanol (17

ml) and the mixture was heated to reﬂux for 9 h, then concen-

trated in vacuo. The residue was puriﬁed by chromatography

over silica using dichloromethane–ether (7:1) as eluent to give

the alcohol (948 mg, 90%) as a colourless oil; [α]_D²⁰ϩ7.6 (c, 2.5 in

CHCl₃) (Found: C, 73.0; H, 9.7. C₃₀H₄₆O₄Si requires C, 72.3; H,

9.2%); δ_H(270 MHz) 7.76 (4H, br m), 7.45–7.35 (6H, m), 5.87

tert-Butyl(3,7,9,9-tetramethoxy-5-methoxymethoxy-2,6-dimethyl-

nonyloxy)diphenylsilane 50

(1H, ddt, J 15, 12 and 7 Hz, CH᎐CH ), 5.12–5.0 (2H, m), 3.75

᎐

2

(1H, m), 3.56 (4H, m), 3.35 (3H, s), 3.32 (3H, s), 2.56 (1H, m),

2.21 (1H, m), 2.05 (1H, m), 1.65 (1H, m), 1.54 (3H, m), 1.12

(9H, s), 0.98 (3H, d, J 7 Hz), 0.96 (3H, d, J 7 Hz); δ_C(100 MHz)

136.4 (d), 136.4 (d), 136.1 (q), 130.3 (d), 128.4 (d), 117.6 (t), 82.7

(d), 80.3 (CH), 71.8 (CH, C-OH), 66.6 (t), 58.3 (OCH₃), 41.2

(s), 38.8 (s), 35.93 (CH₂), 35.8 (t), 27.7 (s), 20.1 (q), 12.9 (s),

11.7 (s, CH₃) (Found: M^ϩϩ 1, 499.3232. C₃₀H₄₆O₄Si requires

499.3243).

Toluene-p-sulfonic acid (12 mg, catalytic) was added in one por-

tion to a solution of the aldehyde 49 (780 mg, 1.4 mmol) in a

mixture of trimethyl orthoformate (32 ml) and dry methanol

(22 ml) at room temperature under nitrogen. The homogeneous

mixture was stirred for 1 h and then quenched with saturated

sodium bicarbonate (5 ml). It was then concentrated in vacuo

and the residue was extracted with dichloromethane (3 × 50

ml). The combined organic extract was washed successively

with water (50 ml) and brine (50 ml), then dried (Na₂SO₄), and

concentrated in vacuo to leave a pale yellow oil. Puriﬁcation by

chromatography on silica using dichloromethane–ether (7:1) as

eluent gave the dimethyl acetal (830 mg, 98%) as a colourless oil;

[α]_D²⁰ϩ17.8 (c, 1.65 in CHCl₃); δ_H(400 MHz) 7.72–7.69 (4H, m),

7.45–7.38 (6H, m), 4.72 (1H, d, J 6.7 Hz, CHHO), 4.64 (1H, d,

J 6.7 Hz, CHHO), 4.56 (1H, t, J 5.6 Hz), 3.86 (1H, m), 3.54

(br d, 1H, J 6.3 Hz), 3.38 (3H, s, OCH₃), 3.37 (3H, s, OCH₃),

3.36 (3H, s, OCH₃), 3.35 (3H, s, OCH₃), 3.34 (3H, s, OCH₃),

3.33–3.27 (2H, m), 2.19–2.12 (1H, m), 1.95–1.91 (1H, m), 1.83

(2H, t, J 5.4 Hz), 1.43 (2H, t, J 5.5 Hz), 1.18 (9H, s, t-Bu), 0.95

(3H, d, J 7.0 Hz), 0.86 (3H, d, J 7.0 Hz); δ_C(100 MHz) 135.8 (d),

135.7 (s), 133.9 (d), 129.6 (d), 127.7 (d), 102.3 (d), 96.7 (t), 79.4

(d), 78.2 (d), 77.5 (d), 66.1 (t), 58.1 (OCH₃), 57.0 (OCH₃), 55.8

(OCH₃), 53.2 (OCH₃), 52.0 (OCH₃), 41.4 (d), 37.4 (d), 35.2 (t),

32.1 (t), 26.9 (q, t-Bu), 19.3 (s), 11.3 (q, CH₃), 9.45 (q, CH₃); m/z

(FAB) (Found: M ϩ Na, 613.3492. C₃₃H₅₄O₇SiNa requires

613.3537).

tert-Butyl(3,7-dimethoxy-5-methoxymethoxy-2,6-dimethyldec-

9-enyloxy)diphenylsilane 48

Methoxymethyl chloride (0.56 ml, 8.3 mmol) was added drop-

wise to a solution of the alcohol 47 (0.83 g, 1.66 mmol) and

diisopropylethylamine (2.8 ml, 16.6 mmol) in dry dichlo-

romethane (50 ml) under nitrogen, and the mixture was then

heated under reﬂux for 1 h. The mixture was cooled to room

temperature, and another portion of methoxymethyl chloride

was added and the mixture was then heated to reﬂux for a

further 1 h. The process was repeated once more by which time

no starting alcohol was left by TLC analysis. The mixture was

diluted with dichloromethane (100 ml) and washed several

times with water (until the yellow colour faded), followed by

brine (50 ml) and then dried (Na₂SO₄). The mixture was con-

centrated in vacuo to leave a pale yellow residue which was

puriﬁed by ﬂash chromatography on silica using dichloro-

methane–ether (25:1) as eluent to give the MOM-ether (0.85 g,

95%) as a colourless viscous oil; [α]_D²⁰ϩ16.6 (c, 2.2 in CHCl₃);

(Found: C, 71.3; H, 9.6. C₃₂H₅₀SiO₂requires C, 70.9; H, 9.2%)

δ_H(400 MHz) 7.72–7.69 (4H, m), 7.45–7.38 (6H, m), 5.82 (1H,

3,7,9,9-Tetramethoxy-5-methoxymethoxy-2,6-dimethylnonan-1-

ol 51

ddt, J 15 11 and 7Hz, CH᎐CH ) 5.20–5.08 (2H, m, ᎐CH ), 4.6

᎐

2

and 4.7 (2H, d, J 6.7 Hz, CH₂O), 3.82–3.75 (1H, m), 3.60–3.50

(3H, m), 3.35 (6H, s, 2 × OMe), 3.33 (3H, s, OMe), 3.20–3.10

(1H, m), 2.40–2.31 (2H, m), 2.19–2.10 (1H, m), 2.00–1.90 (1H,

m), 1.45–1.41 (2H, m), 1.12 (9H, m), 0.90 (3H, d, J 7.2 Hz, Me),

0.85 (3H, d, J 7.0 Hz, Me); δ_C(67.8 MHz) 136.0 (d), 135.7 (d),

134.9 (s), 134.1 (d), 129.9 (d), 127.9 (d), 117.4 (t), 96.7 (t), 82.0

(d), 78.65 (d), 76.9 (d), 66.3 (t), 57.5 (q, OMe), 57.3 (q, OMe),

56.0 (q, OMe), 40.0 (s), 37.8 (s), 35.3 (t), 32.3 (t), 27.1 (q, t-Bu),

19.55 (s, t-Bu), 11.7 (q, Me), 9.4 (q, Me) (Found: M^ϩϩ 1,

543.3505. C₃₂H₅₀SiO₅requires 543.3453).

Tetrabutylammonium ﬂuoride (442 mg, 1.69 mmol) was added

in one portion to a stirred solution of the silyl ether 50 (0.825 g,

1.39 mmol) in dry THF (12.5 ml) at room temperature under

nitrogen and the mixture was stirred at room temperature for

5 h. An additional portion of TBAF (100 mg) was added and

stirring was continued for a further 1 h by which time the start-

ing material was completely consumed. The mixture was con-

centrated in vacuo to leave a residue which was extracted with

dichloromethane (3 × 50 ml). The combined organic extracts

were washed with water (50 ml) and brine (50 ml) then dried

(Na₂SO₄) and concentrated in vacuo to leave a pale yellow oil.

Puriﬁcation by chromatography on silica using ether–

dichloromethane (3:1) as eluent gave the alcohol (484 mg, 98%)

as a colourless, viscous liquid; [α]_D²⁰ϩ43.6 (c, 1.6 in CHCl₃);

δ_H(400 MHz) 4.67 (1H, d, J 7 Hz, CHHO), 4.59 (1H, d, J 7 Hz,

9-(tert-Butyldiphenylsilanyloxy)-3,7-dimethoxy-5-methoxy-

methoxy-4,8-dimethylnonanal 49

A solution of the alkene 48 (0.82 g, 1.51 mmol) in dry dichloro-

methane (40 ml) was ozonised at Ϫ78 ЊC in the presence of

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

2443

View Article Online

CHHO), 4.45 (1H, t, J 5.6 Hz, CH(OMe)₂), 3.69–3.43 (3H, m),

3.38 (6H, s, 2 × OCH₃), 3.33 (3H, s, OCH₃), 3.29 (3H, s, OCH₃),

3.27 (3H, s, OCH₃), 3.28–3.15 (1H, m), 1.92–1.82 (2H, m), 1.74

(2H, t, J 6 Hz), 1.52–1.35 (2H, m), 0.85 (3H, d, J 7 Hz, CHMe),

0.84 (3H, d, J 6.9 Hz, CHMe); δ_C(100 MHz) 102.2 (d), 96.5 (t),

80.8 (d), 79.3 (d), 77.9 (d), 65.6 (t), 58.0 (q, OCH₃), 57.9 (q,

OCH₃), 55.6 (q, OCH₃), 53.2 (q, OCH₃), 52.3 (q, OCH₃), 41.0

(d), 38.0 (d), 35.1 (t), 33.4 (t), 12.5 (q, Me), 9.3 (q, Me); m/z

(FAB) (Found: M^ϩϩ Na 375.2325. C₁₇H₃₆O₇Na requires

375.2579).

room temperature and then stirred for 15 h. After cooling back

to 0 ЊC, dilute HCl (2 M, 150 ml) was added cautiously and

the two layers were allowed to separate. The separated aqueous

layer was further extracted with dichloromethane (2 × 200 ml)

and the combined organic extracts were concentrated in vacuo

1

to leave a colourless oil. Analysis of the H NMR spectrum

of the residue showed the presence of a ca. 9:1 mixture of

regioisomeric products in favour of the required 5-benzyloxy-

3-methylpentane-1,2-diol 53. A solution of the residue in

methanol (450 ml) and water (100 ml), was stirred with sodium

periodate (9.6 g) for 6 h and then the methanol was removed

under vacuum. The residue was diluted with water (200 ml)

and the mixture was then extracted with dichloromethane (3 ×

200 ml). The combined dichloromethane extracts were dried

(MgSO₄) and then concentrated in vacuo to leave a pale yellow

oil. Flash chromatography on silica using ether as eluent gave

the aldehyde (7.8 g, 84%) as an unstable colourless oil; ν_max(ﬁlm)/

cm^Ϫ12932, 2869, 1723, 1453, 1364, 1100, 739, 698; δ_H(270 MHz)

9.63 (1H, d, J 1.7 Hz, CHO), 7.34–7.25 (5H, m, Ph), 4.47 (2H, s,

PhCH₂O), 3.55–3.48 (2H, m, CH₂O), 2.52 (1H, apparent sextet

d, J 6.9 and 1.7 Hz, CHMe), 2.10–1.97 (1H, m, H-3), 1.74–1.62

(1H, m, H-3), 1.09 (3H, d, J 6.9 Hz, Me); δ_C(67.8 MHz) 204.5

(d, C-1), 138.0 (s, Ph), 128.2 (d), 128.1 (d), 127.55 (d), 72.8 (t,

PhCH₂O), 67.2 (t, C-4), 43.5 (d, C-2), 30.6 (t, C-3), 13.0 (q, Me).

3,7,9,9-Tetramethoxy-5-methoxymethoxy-2,6-dimethylnonanal

22

A mixture of the alcohol 51 (127 mg, 0.36 mmol), N-

methylmorpholine N-oxide (88 mg, 0.72 mmol) and powdered 4

Å molecular sieves (0.5 g) in dry dichloromethane (10 ml) was

stirred at room temperature for 10 min under nitrogen and then

solid tetrapropylammonium perruthenate (12 mg, 0.036 mmol)

was added in one portion. The mixture was stirred for an add-

itional 1 h then diluted with ether (100 ml) and ﬁltered through

Celite. The ﬁlter cake was washed with ether (2 × 25 ml) and the

combined ether extracts were concentrated in vacuo to leave

a brown residue. Chromatography on silica using dichloro-

methane–ether (3:1) as eluent gave the aldehyde (112 mg, 89%)

as a colourless oil; [α]_D²⁰ϩ13.1 (c, 1.3 in CHCl₃); δ_H(400 MHz)

9.79 (1H, d, J 1.5 Hz, CHO), 4.64 (1H, d, J 7 Hz, OCHH), 4.59

(1H, d, J 7 Hz, OCHH), 4.55 (1H, t, J 5.7 Hz), 3.84 (1H, m),

3.38 (3H, s, OMe), 3.37 (3H, s, OMe), 3.36 (3H, s, OMe), 3.35

(3H, s, OMe), 3.34 (3H, s, OMe), 3.32 (1H, br m), 2.82 (1H, br

m), 1.80 (1H, m), 1.75 (2H, br m), 1.65 (2H, br m), 1.10 (3H, d,

J 6.9 Hz, CHMe), 0.85 (3H, d, J 6.9 Hz, CHMe); δ_C(100 MHz)

204.1 (d), 102.4 (d), 96.7 (t), 79.3 (d), 77.5 (d), 77.1 (d), 58.0 (q),

57.5 (q), 56.0 (q), 53.3 (q), 52.4 (q), 49.3 (d), 41.0 (d), 35.1 (t),

34.1 (t), 9.3 (q), 8.7 (q).

Ethyl 6-benzyloxy-4-methylhex-2-enoate 55

Ethoxycarbonylmethylenetriphenylphosphorane (14.6 g, 42

mmol) was added in one portion to a solution of the aldehyde

54 (7.50 g, 39 mmol) in dry dichloromethane (200 ml) at room

temperature under nitrogen and the resulting yellow solution

was stirred overnight. The mixture was concentrated in vacuo to

leave a pale yellow viscous liquid which was puriﬁed by ﬂash

chromatography on silica using petrol–ethyl acetate (4:1) as

eluent to give the ester (9.60 g, 94%) as a colourless oil;

ν_max(ﬁlm)/cm^Ϫ12979, 2858, 1723, 1655; δ_H7.28–7.14 (5H, m,

[3-(2-Benzyloxyethyl)oxiran-2-yl]methanol 52

ArH), 6.77 (1H, dd, J 7.9 and 15.8 Hz, EtO C–CH᎐CH), 5.72

᎐

2

(1H, dd, J 1.3 and 15.8 Hz, ᎐CHCO Et), 4.38 (2H, s, OCH Ar),

᎐

2

Titanium() isopropoxide (2.64 ml, 8.9 mmol), (ϩ)-diethyl tar-

trate (1.84 ml, 10.7 mmol) and 5-benzyloxypent-2-en-1-ol 24

(16.0 g) were added sequentially over 30 min to a suspension of

powdered 4 Å molecular sieves (2.8 g) in dry dichloromethane

(200 ml) at Ϫ20 Њ C under nitrogen. The mixture was stirred at

Ϫ20 ЊC for 30 min, and then tert-butyl hydroperoxide (3 M in

isooctane, 55.5 ml, 1656 mmol) was added over 30 min. The

resulting mixture was stirred at Ϫ20 ЊC for 8 h and then kept at

Ϫ18 ЊC for 12 h. The reaction was quenched by the addition of

water (100 ml) and then warmed to room temperature over 30

min. Sodium hydroxide in brine (30%, 20 ml) was added, and

the mixture was then stirred at room temperature for 30 min

before the two phases were separated. The aqueous phase was

extracted with more dichloromethane (3 × 200 ml) and the

combined organic extracts then washed with brine and dried

over sodium sulfate. The solution was concentrated in vacuo to

leave a pale yellow oil which was puriﬁed by ﬂash chroma-

tography on silica using diethyl ether as eluent to give the

epoxide (13.1 g, 76%) as a colourless oil; [α]_D²⁵Ϫ30.0 (c, 3.9 in

CHCl₃) (Found: C, 69.4; H, 7.9. C₁₂H₁₆O₃requires C, 69.2;

H, 7.7%.); ν_max(ﬁlm)/cm^Ϫ13427 (br), 2921, 2863, 1454, 1363,

1101, 1029; δ_H(270 MHz) 7.36–7.20 (5H, m, Ph), 4.47 (2H, s,

PhCH₂O), 3.81–3.74 (1H, m), 3.56 (2H, t, J 6.0 Hz, CH₂O),

3.53–3.43 (1H, m), 3.03 (1H, m), 2.91 (1H, dt, J 4.6 and 2.3 Hz),

4.08 (2H, q, J 6.9 Hz, OCH₂CH₃), 3.41–3.33 (2H, m), 2.45 (1H,

apparent septet, J 7 Hz, CHMe), 1.59 (2H, q, J 7 Hz,

OCH₂CH₂), 1.19 (2H, t, J 6.9 Hz, OCH₂CH₃), 0.97 (3H, d, J 7

Hz, CH₃); δ_C166.6 (s), 153.6 (d, C-3), 138.3 (s, Ar), 128.2 (d,

Ar), 127.5 (d, Ar), 127.5 (d, Ar), 119.9 (d, C2), 72.9 (t, OCH₂),

67.8 (t, OCH₂), 60.0 (t, OCH₂), 35.7 (t, C-5), 33.3 (d, C-4), 19.3

(q, Me), 14.2 (q, Me).

6-Benzyloxy-4-methylhex-2-en-1-ol 56

A solution of DIBAL-H in hexane (1 M, 70 ml, 70 mmol) was

added over 30 min to a stirred solution of the ester 55 (9.0 g, 34

mmol) in dry tetrahydrofuran (100 ml) at 0 ЊC under nitrogen.

The mixture was stirred at 0 ЊC for 2 h, and then quenched with

2 M aqueous HCl (5 ml initially, followed by 50 ml after the

reaction had set to a gel). The aqueous phase was separated and

then extracted with ethyl acetate (3 × 50 ml). The combined

extracts were dried over MgSO₄and then concentrated in vacuo

to leave a yellow oil. Flash chromatography on silica using

dichloromethane–ether (7:1) as eluent gave the alcohol (7.28 g,

96%) as an oil; [α]_D²¹Ϫ31.2 (c, 14.1 in CHCl₃) (Found: C, 76.1; H,

9.5. C₁₄H₂O requires C, 76.3; H, 9.2%); ν_max(ﬁlm)/cm^Ϫ13385,

2924, 2863; δ_H(270 MHz) 7.44–7.36 (5H, m, ArH), 5.73–5.35

(2H, m, HC᎐CH), 4.46 (2H, ABq, J 7 Hz, PhCH O), 4.05 (2H,

᎐

2

1.95–1.71 (2H, m, CH CH᎐); δ (67.8 MHz) 137.8 (s, Ph),

128.03 (d), 127.69 (d), 72.6 (t, PhCH₂O), 66.5 (t, C-5), 61.5 (t,

C-1), 58.6 (d, C-2), 53.4 (d, C-3), 31.7 (t, C-4).

br s, CH₂OH), 3.57 (2H, t, J 6.6 Hz, CH₂OBz), 2.40 (1H, septet,

J 6.6 Hz, CHMe), 2.10 (1H, br s, OH), 1.60 (2H, ddd, J 13.2, 6.8

and 3.3 Hz, CH₂CHMe), 1.00 (3H, d, J 6.6 Hz); δ_C(90.6 MHz)

138.2 (s, Ph), 137.8 (d, C-3), 128.7 (d), 127.8 (d), 127.7 (d), 127.4

(d, C-2), 72.6 (t, PhCH₂O), 68.3 (t, C-6), 63.5 (t, C-1), 36.7 (t,

C-5), 33.9 (d, C-4), 20.5 (q, C-4-Me).

᎐

2

C

4-Benzyloxy-2-methylbutyraldehyde 54

Trimethylaluminium (2 M in hexane, 75 ml, 150 mmol) was

added dropwise over 30 min to a stirred solution of the epoxy

alcohol 52 (10.0 g, 48 mmol) in dry dichloromethane (300 ml) at

0 ЊC under argon. The mixture was allowed to warm slowly to

[3-(3-Benzyloxy-1-methylpropyl)oxiran-2-yl]methanol 57

Titanium() isopropoxide (1.0 ml, 3.4 mmol), (Ϫ)-diethyl tar-

2444

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

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trate (0.7 ml, 4.0 mmol) and the allylic alcohol 56 (7.0 g, 32

mmol) were added sequentially over 20 min to a stirred suspen-

sion of powdered 4 Å sieves (1.2 g) in dry dichloromethane (50

ml) at Ϫ20 ЊC under nitrogen. The mixture was stirred at

Ϫ20 ЊC for 30 min, then tert-butyl hydroperoxide (3 M, in iso-

octane, 21.3 ml, 64 mmol) was added over 30 min and the result-

ing mixture was stirred at Ϫ20 ЊC for 8 h. It was then kept at

Ϫ18 ЊC for 12 h before being quenched by the addition of 40 ml

of water. The mixture was warmed to room temperature over 30

min, and then sodium hydroxide in brine (30%, 8 ml) was

added, and the mixture was stirred at room temperature for 30

min. The separated aqueous phase was extracted with more

dichloromethane (50 ml × 3) and the combined organic extracts

were then washed with brine (50 ml) and dried (Na₂SO₄). The

solution was concentrated in vacuo to leave a pale yellow oil,

which was puriﬁed by ﬂash chromatography on silica using

petrol–ethyl acetate (3:2) as eluent to give the epoxide (6.4 g,

85%) as a colourless oil; [α]_Dϩ14.9 (c, 10.7 in CHCl₃) (Found: C,

71.3; H, 8.8. C₁₄H₂₀O₃requires C, 71.2; H, 8.5%); ν_max(ﬁlm)/

cm^Ϫ13415, 2963, 2876; δ_H(250 MHz) 7.35–7.24 (5H, m, Ar),

4.50 (2H, apparent ABq, J ca. 7 Hz, PhCH₂O), 3.86–3.79 (1H,

m, CHO), 3.58–3.49 (3H, m, CHO and CH₂O), 2.96–2.89 (2H,

m, CHO and OH), 2.77 (1H, dd, J 6.6 and 2.5 Hz, CHO), 1.90–

1.82 (1H, m, CH), 1.66–1.54 (2H, m, CH₂), 0.94 (3H, d, J 6.6

Hz, Me); δ_C(67.8 MHz) 138.4, (s, Ph), 128.2 (d), 127.7 (d), 127.5

(d), 72.8 (t, PhCH₂O), 68.0 (t, C-3), 61.8 (t, C-1), 60.3 (d, C-2),

57.0 (d, C-1), 34.2 (t, C-2), 32.4 (C-1), 15.8 (q, Me).

room temperature and then stirred for one more hour before

being quenched with methanol (100 µl). The mixture was

diluted with dichloromethane (50 ml), and then washed with

water (25 ml) and brine (25 ml) and dried (Na₂SO₄). It was then

ﬁltered, and the ﬁltrate was concentrated in vacuo. The residue

was puriﬁed by chromatography on silica using petrol–

dichloromethane (1:1) as eluent to give the pure bis-silyl ether

(1.92 g, 97.5%) as a colourless oil; [α]_D²¹Ϫ1.4 (c, 2.2 in CHCl₃)

(Found: C, 67.45; H, 11.6. C₂₇H₅₂O₃Si₂requires C, 67.5; H

10.8%); δ_H(400 MHz) 7.36–7.34 (5H, m, Ar), 4.53 (1H, d, J 10

Hz, PhCHHO), 4.51 (1H, d, J 10 Hz, PhCHHO), 3.75 (1H, m,

CHOH), 3.58–3.40 (4H, m, OCH₂and OCH₂), 1.90–1.82 (2H,

m, CH₂), 0.96–0.83 (m, 2 × CH, 2 × Me, 2 × t-Bu), 0.08–0.04

(4 × SiMe); δ_C(100 MHz) 138.8 (s, Ar), 128.7 (d), 127.7 (d),

127.55 (d), 78.5 (d, C-3), 73.0 (t, CH₂), 69.3 (t, OCH₂), 65.7 (t,

OCH₂), 40.0 (d, C-2/C-4), 33.7 (d, C-4/C-2), 31.6 (t, C-5), 26.3

(q, t-Bu), 26.1 (q, t-Bu), 19.5 (s, t-Bu), 16.4 (s, t-Bu), 17.6 (q,

C-2/C-4 Me), 14.9 (q, C-4/C-2-Me), Ϫ3.7 (q, SiMe), Ϫ3.9 (s,

SiMe), Ϫ5.1 (s, SiMe), Ϫ5.2 (s, SiMe); m/z 481 (M ϩ H^ϩ)

(22%), 503 (M ϩ Na^ϩ) (30%).

6-Benzyloxy-3-(tert-butyldimethylsilanyloxy)-2,4-dimethyl-

hexan-1-ol 60

Pyridinium toluene-p-sulfonate (55 mg) was added in one por-

tion to a solution of the bis-silyl ether 59 (0.53 g, 1.1 mmol) in

dichloromethane and methanol (14 ml, 1:1) and the resulting

solution was stirred at room temperature under nitrogen for 8 h.

It was then quenched with a solution of saturated NaHCO₃(5

ml), concentrated in vacuo and then diluted with dichlorometh-

ane (50 ml) and water (50 ml). The aqueous layer was extracted

with dichloromethane (2 × 25 ml) and the combined organic

extracts were dried (Na₂SO₄) and then concentrated in vacuo.

The residue was puriﬁed by chromatography on silica using

dichloromethane as eluent to give the primary alcohol (0.38 g,

96%) as a colourless oil; [α]_D²⁰Ϫ1.6 (c, 9.0 in CHCl₃) (Found: C,

68.6; H, 10.8. C₂₁H₃₈O₃Si requires C, 68.8; H, 10.4%); ν_max(ﬁlm)/

cm^Ϫ13423, 2956, 1461; δ_H(400 MHz) 7.45–7.29 (5H, m, Ar),

4.54 (1H, d, J 11 Hz, PhCHHO), 4.51 (1H, d, J 11 Hz,

PhCHHO), 3.78–3.47 (5H, m, 1-H, 6-H and 3-H), 2.71 (1H, t,

J 6 Hz), 1.96–1.82 (3H, m, 5-H and 4/2-H), 1.49–1.38 (1H, m,

2/4-H), 1.07 (6H, d, J 7 Hz, 2 × Me), 0.98 (9H, s, t-Bu), 0.11

(3H, s, SiMe), 0.10 (3H, s, SiMe); δ_C(67.8 MHz) 138.5 (s, Ar),

128.3 (d), 127.5 (d), 127.5 (d), 81.4 (d, C-3), 72.9 (t, OCH₂),

68.8 (t, OCH₂), 66.2 (t, OCH₂), 36.9 (d, C-2/C-4), 35.5 (d, C-4/

C-2), 32.38 (t, C-5), 26.0 (q, t-Bu), 18.2 (q, t-Bu), 16.5 (q, Me),

16.0 (q, Me), Ϫ4.15 (q, SiMe), Ϫ4.35 (q, SiMe) (Found:

M^ϩϩ H, 367.2668. C₂₁H₃₈O₃Si requires 367.2675).

6-Benzyloxy-2,4-dimethylhexane-1,3-diol 58

Methylmagnesium bromide (3 M in THF, 28.5 ml) was added

over 1 h to a stirred suspension of CuI (1.67 g, 8.8 mmol) in dry

tetrahydrofuran (75 ml) at 0 ЊC under nitrogen. The mixture was

stirred for 30 min at 0 ЊC and then a solution of the epoxy

alcohol 57 (6.5 g) in dry THF (50 ml) was added over 30 min.

The reaction was stirred at <5 ЊC for 15 h and then quenched by

the addition of saturated aqueous ammonium chloride (150

ml). The mixture was stirred vigorously at room temperature

for 30 min and then extracted with ether (150 ml × 3). The

combined organic extracts were washed with brine (150 ml),

and then concentrated in vacuo to leave a pale yellow oil. Analy-

sis of the ¹H NMR spectrum of the residue showed that it was

composed of a 9:1 mixture in favour of the required 1,3-diol. A

solution of the residue in methanol (140 ml) and water (35 ml)

was stirred with sodium periodate (1.5 g) for 7 h and then most

of the methanol was removed under vacuum. The residue was

diluted with water (100 ml) and then extracted with dichlo-

romethane (3 × 100 ml). The combined dichloromethane

extracts were dried over MgSO₄and then concentrated in vacuo

to leave a pale yellow oil. Flash chromatography on silica using

petrol–ethyl acetate (1:1) as eluent gave the 1,3-diol (5.85 g,

84%) as a liquid; [α]_D²⁴ϩ10.8 (c, 10.3 in CHCl₃) (Found: C, 71.1;

H, 9.9. C₁₅H₂₄O₃requires C, 71.4; H, 9.5%); ν_max(ﬁlm)/cm^Ϫ1

3408, 2957, 2857; δ_H(270 MHz) 7.36–7.29 (5H, m, Ph), 4.53

(2H, s, PhCH₂O), 3.76 (2H, br d, J 5.6 Hz, H-1), 3.64–3.47 (3H,

m, H-6, plus OH), 3.34 (1H, br q, J 5.3 Hz, H-3), 3.24 (1H, br t,

J 5.3 Hz, OH), 1.95 (1H, heptet J 6.9 Hz, H-4), 1.85 (1H, d

sextet, J 7.3 and 3.5 Hz, H-2), 1.72 (2H, q, J 5.6 Hz, H-5), 0.96

(3H, d, J 6.9 Hz, Me), 0.89 (3H, d, J 7.3 Hz, Me); δ_C(67.8 MHz)

137.8 (s), 128.3 (d), 128.8 (d), 127.6 (d), 81.3 (d), 72.9 (t), 67.8

(t), 67.4 (t), 36.8 (d), 33.1 (d), 30.0 (t), 16.7 (q, Me), 14.0 (q, Me).

6-Benzyloxy-3-(tert-butyldimethylsilanyloxy)-2,4-dimethyl-

hexanal 61

N-Methylmorpholine N-oxide (0.30 g, 2.5 mmol) was added

in one portion to a suspension of the alcohol 60 (0.46 g,

1.24 mmol) and powdered 4 Å molecular sieves (0.7 g) in dry

dichloromethane and the resulting mixture was stirred at room

temperature under nitrogen for 0.5 h. Tetrapropylammonium

perruthenate (0.02 g, 0.06 mmol) was added and the mixture

was stirred for 45 min. It was then diluted with ether (100 ml)

and ﬁltered through Celite. The ﬁltrate was concentrated in

vacuo to leave a brown residue which was puriﬁed by chrom-

atography on silica using dichloromethane as eluent to give the

aldehyde (0.43 g, 96%) as a labile colourless oil; [α]_D²⁴Ϫ23.3 (c, 8.8

in CHCl₃); ν_max(ﬁlm)/cm^Ϫ12851, 2795, 1754, 1697; δ_H(400

MHz) 9.81 (1H, d, J 2.8 Hz, CHO), 7.39–7.29 (5H, m, Ar), 4.55

(1H, d, J 12 Hz, PhCHHO), 4.49 (1H, d, J 12 Hz, PhCHHO),

3.81 (1H, apparent, t, J 4.2 Hz, 3-H), 3.59–3.47 (2H, m, 6-H),

2.57–2.53 (1H, m, 2-H), 1.9–1.94 (1H, m, 5-H), 1.84–1.79

(1H, m, 5-H), 1.48–1.43 (1H, m, 4-H), 1.10 (3H, d, J 7 Hz, C-2-

Me), 0.94 (3H, d, J 7 Hz, C-4-Me), 0.06 (3H, s, SiMe), 0.04 (3H,

s, SiMe); δ_C(67.8 MHz) 205.2 (d, C-1), 138.4 (s, Ar), 128.3 (d),

[4,6-Bis(tert-butyldimethylsilanyloxy)-3,5-dimethylhexyloxy-

methyl]benzene 59

A solution of tert-butyldimethylsilylmethanesulfonate (1.98 ml,

8.61 mmol) in dry dichloromethane (5 ml) was added dropwise

over 5 min to a stirred solution of the diol 58 (1.05 g, 4.1 mmol)

and 2,6-lutidine (1.98 ml, 17.20 mmol) in dry dichloromethane

(10 ml) at 0 ЊC under nitrogen and the resulting solution was

stirred at 0 ЊC for 1 h. The mixture was allowed to warm to

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

2445

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127.5 (d), 127.5 (d), 78.6 (d, C-3), 72.9 (t, OCH₂), 68.45 (t,

OCH₂), 49.2 (d, C-2), 35.4 (d, C-4), 32.4 (t, C-5), 25.9 (q, t-Bu),

18.15 (s, t-Bu), 15.6 (q, C-2Me), 12.5 (q, C-4Me), Ϫ4.15 (q,

SiMe), Ϫ4.53 (q, SiMe).

temperature for 3.5 h and then diluted with dichloromethane

(50 ml). The organic extract was washed with saturated

NaHCO₃(10 ml) and brine (10 ml) and then dried (Na₂SO₄)

and concentrated in vacuo. The residue was puriﬁed by ﬂash

chromatography on silica using petrol–ethyl acetate (2:1) as

eluent to give the E-alkene (73 mg, 95%) as a colourless oil; [α]_D²⁰

Ϫ9.4 (c, 1.78 in CHCl₃); δ_H(400 MHz) 7.26–7.35 (5H, m), 6.83

(1H, dd, J 15.8 and 6.8 Hz), 6.23 (1H, dd, J 15.8 and 1.5 Hz),

4.61 (1H, d, J 6.8 Hz, OCHHO), 4.53 (1H, d, J 6.8 Hz,

OCHHO), 4.4–4.5 (3H, m), 3.96 (1H, dd, J 8 and 3 Hz), 3.80

(1H, m), 3.60 (1H, m), 3.48 (1H, m), 3.39 (3H, s, OCH₃), 3.38

(3H, s, OCH₃), 3.36 (3H, s, OCH₃), 3.34 (3H, s, OCH₃), 3.32

(3H, s, OCH₃), 3.25 (1H, m), 3.06 (1H, m), 2.76 (1H, m), 1.91–

1.81 (5H, m), 1.68–1.65 (2H, m), 1.55–1.44 (2H, m), 1.40–1.30

(2H, m), 1.06 (3H, d, J 7 Hz), 1.01 (3H, d, J 7 Hz), 0.95 (3H, d,

J 7 Hz), 0.91 (3H, d, J 7 Hz), 0.85 (9H, s); δ_C(67.8 MHz) 203.1

(s), 148.6 (d), 138.6 (d), 130.2 (d), 128.3 (d), 127.6 (d), 127.5 (d),

102.2 (d), 96.6 (t), 80.4 (d), 79.2 (d), 78.3 (d), 77.5 (d), 76.5 (d),

72.9 (t), 68.9 (q, OMe), 57.9 (q, OMe), 57.5 (q, OMe), 55.7 (q,

OMe), 53.2 (q, OMe), 52.1 (q, OMe), 48.4 (d), 41.1 (d), 38.9 (d),

35.1 (t), 33.3 (d), 33.1 (t), 30.8 (t), 26.2 (q), 18.4 (s), 16.8 (q),

14.2 (q), 13.2 (q), 9.2 (q), Ϫ4.1 (q), Ϫ4.3 (q); m/z (FAB) (Found:

M ϩ Na, 733.4652. C₃₉H₇₀O₉SiNa requires 733.4687).

[7-Benzyloxy-4-(tert-butyldimethylsilanyloxy)-2-hydroxy-3,5-

dimethylheptyl]phosphonic acid dimethyl ester 62

A solution of n-butyllithium (1.6 M in hexane, 1.6 ml, 2.5

mmol) was added dropwise over 5 min to a stirred solution of

dimethyl methylphosphonate (0.29 ml, 2.55 mmol) in dry THF

(22 ml) at Ϫ78 ЊC under nitrogen and the resulting solution was

stirred for 0.5 h at Ϫ78 ЊC. A solution of the aldehyde 61 (0.44

g, 1.2 mmol) in dry THF (9 ml) was added dropwise over 20

min and the mixture was stirred for an additional hour. It was

then quenched with aqueous saturated NaHCO₃solution (5.6

ml) and allowed to come to room temperature. The mixture was

extracted with ethyl acetate (3 × 50 ml) and the combined

organic extracts were dried (Na₂SO₄) and then concentrated in

vacuo to leave a pale yellow oil. Flash chromatography on silica

using ethyl acetate as eluent gave a mixture of diastereomers of

the hydroxy phosphonate (0.53 g, 90%) as a colourless oil; [α]_D²³

Ϫ1.7 (c, 4 in CHCl₃) (Found: C, 58.8; H, 9.7. C₂₄H₄₅O₆SiP

requiresC, 59.0;H, 9.2%);δ_H(400MHz)7.31–7.21(5H, m, ArH),

4.49–4.43 (2H, m), 3.72 (3.72) (3H, s), 3.71 (3.69) (3H, s, OMe),

3.7–3.6 (1H, m), 3.59 (1H, br s, OH), 3.58–3.40 (1H, m), 2.01–

1.98 (1H, m), 1.96–1.70 (2H, m), 1.37–1.35 (1H, m), 0.95 (3H,

d, J 6.7 Hz), 0.92 (3H, d, J 7.1 Hz), 0.88 (9H, s), 0.06 (3H, s),

0.045 (3H, s); δ_C(100 MHz) 138.5 (s), 128.2 (d), 127.5 (d),

127.39 (d), 80.7 (79.6) (d, C-4), 72.8 (t, OCH₂), 68.75 (68.1) (t,

OCH₂), 65.6, 52.4 (52.3) (q, OCH₃), 52.1 (52.1) (q, OCH₃), 42.7

(42.5), 39.7 (39.6), 34.7 (34.5).

4-(tert-Butyldimethylsilanyloxy)-1-hydroxy-10,14,16,16-tetra-

methoxy-12-methoxymethoxy-3,5,9,13-tetramethylhexadecan-6-

one 64

A solution of the enone 63 (64 mg, 0.1 mmol) in dry methanol

(5 ml) was hydrogenated overnight in the presence of Pearl-

man’s catalyst (25 mg). The mixture was ﬁltered through Celite

and the ﬁltrate was concentrated in vacuo to leave the product

(52.6 mg, 94%) as a liquid; [α]_D²⁰ϩ5.6 (c, 1.0 in CH₂Cl₂); δ_H(500

MHz) 4.67 (1H, d, J 6.7 Hz, OCHHOMe), 4.61 (1H, d, J 6.7

Hz, OCHHOMe), 4.51 (1H, t, J 5.75 Hz), 3.85 (1H, dd, J 2.6

and 8.3 Hz), 3.73 (2H, m, CH₂OH), 3.68 (1H, m), 3.54 (1H, m),

3.36 (3H, s, OMe), 3.31 (3H, s, OMe), 3.29 (3H, s, OMe), 3.28

(3H, s, OMe), 3.27 (3H, s, OMe), 3.20 (2H, m), 2.82 (1H appar-

ent quintet J 7.3 Hz), 2.48–2.42 (3H, m), 1.86–1.75 (5H, m),

1.67–1.61 (1H, m), 1.57–1.53 (1H, m), 1.52–1.43 (1H, m) 1.38–

1.25 (3H, m), 0.96 (6H, d, J 7 Hz, 2 × Me), 0.90 (3H, d, J 7 Hz,

Me), 0.85 (9H, s, t-Bu), 0.75 (3H, d, J 7 Hz, Me), Ϫ0.1 (6H, s,

2 × Me); δ_C(67.8 MHz) 213.0, 102.1 (d), 96.5 (t), 80.8 (d), 79.2

(d), 78.1 (d), 76.5 (d), 60.2 (t), 58.0 (q), 56.7 (q), 55.7 (q), 53.1

(q), 52.0 (q), 50.0 (d), 42.2 (t), 41.3 (d), 35.1 (t), 33.7 (t), 33.4 (d),

33.1 (d), 31.5 (t), 26.4 (t), 26.1 (q), 18.4 (s), 16.7 (q), 14.0 (q),

13.3 (q), 9.3 (q), Ϫ4.3 (q), Ϫ4.4 (q); m/z (FAB) 645 (M ϩ Na)^ϩ.

[7-Benzyloxy-4-(tert-butyldimethylsilanyloxy)-3,5-dimethyl-2-

oxoheptyl]phosphonic acid dimethyl ester 23

Pyridinium dichromate (2.86 g, 7.60 mmol) was added in one

portion to a solution of the alcohol 62 (0.53 g, 1.1 mmol) in dry

DMF (7 ml) and the resulting solution was then stirred at room

temperature under nitrogen for 24 h. The mixture was diluted

with water (35 ml) and then extracted with ether (3 × 50 ml).

The combined ether extracts were washed with water (3 × 25

ml) and brine (25 ml), then dried (Na₂SO₄) and evaporated to

dryness in vacuo. The residue was puriﬁed by ﬂash chrom-

atography on silica using ethyl acetate as eluent to give the keto-

phosphonate (0.49 g, 92%) as a colourless oil; [α]_D²¹Ϫ79.9 (c, 2.5

in CHCl₃) (Found: C, 59.6; H, 9.2. C₂₄H₄₃SiPO₆requires C,

59.3; H, 8.9%); ν_max(ﬁlm)/cm^Ϫ11715; δ_H(400 MHz) 7.46–7.28

(5H, m, ArH), 4.44 (1H, d, J 12 Hz, PhCHHO), 4.39 (1H, d,

J 12 Hz, PhCHHO), 3.71 (3H, d, J 1 Hz, OCH₃), 3.68 (3H, d,

J 1 Hz, OCH₃), 3.46 –3.37 (2H, m, OCH₂), 3.37 (1H, d, J 18 Hz,

CH), 3.34 (1H, d, J 18 Hz, CH), 3.01–2.89 (1H, m), 1.76–1.75

(1H, m), 1.35–1.33 (1H, m), 0.97 (3H, d, J 6.8 Hz, CHMe), 0.87

(3H, d, J 6.8 Hz, CHMe), 0.78 (9H, s, t-Bu), Ϫ0.04 (3H, s,

SiMe), Ϫ0.12 (3H, s, SiMe); δ_C(67.8 MHz) 205.7 (s), 138.4 (s),

128.2 (d), 127.4 (d), 79.4 (d, C-4), 72.8 (t, OCH₂), 68.4 (t,

OCH₂), 52.9 (q, OMe), 52.8 (OMe), 49.9 (d, C-3), 43.9 (t, C-1),

42.0 (t, C-1), 34.6 (t, C-5), 31.6 (t, C-6), 25.9 (q, t-Bu), 18.1 (s, t-

Bu), 15.6 (C-3-Me), 13.91 (C-4-Me), Ϫ4.51 (q, SiMe), Ϫ4.62 (q,

SiMe).

4-(tert-Butyldimethylsilanyloxy)-1-(tert-butyldiphenylsilanyl-

oxy)-10,14,16,16-tetramethoxy-12-methoxymethoxy-3,5,9,13-

tetramethylhexadecan-6-one 21

Imidazole (51 mg) and TBDPS-Cl (162 µml) were added to a

solution of the alcohol 64 (310 mg, 0.5 mmol) in dry DMF (3

ml) under nitrogen at 0 ЊC, and the mixture was then allowed to

warm to room temperature and stirred for 14 h. The mixture

was diluted with water (15 ml) and extracted with ether (3 × 20

ml). The combined organic extracts were washed with water

(3 × 10 ml) and brine (10 ml), then dried (Na₂SO₄) and con-

centrated in vacuo to leave a pale yellow oil. Puriﬁcation by

chromatography on silica using ether–dichloromethane (3:1) as

eluent gave the corresponding TBDPS ether (405 mg, 94%) as a

colourless oil; [α]_D²⁰ϩ1.8 (c, 1.6 in CHCl₃); δ_H(360 MHz) 7.74–

7.68 (4H, m, ArH), 7.48–7.29 (6H, m, ArH), 4.72 (1H, d, J 6.7

Hz, OCHH–OMe), 4.64 (1H, d, J 6.7 Hz, OCHH–OMe), 4.57

(1H, t, J 5.8 Hz, 16-H), 3.86 (1H, dd, J 8.1 and 2.5 Hz), 3.81

(1H, m), 3.75 (1H, dd, J 6.7 and 4.4 Hz), 3.65 (1H, dt, J 9.5 and

5.6 Hz), 3.64 (3H, s, OMe), 3.63 (3H, s, OMe), 3.54 (3H, s,

OMe), 3.52 (3H, s, OMe), 3.50 (3H, s, OMe), 3.30–3.20 (2H,

m), 2.80 (1H, quintet, J 7 Hz), 2.56 (2H, m), 1.93–1.82 (5H, m),

1.60 (1H, m), 1.41–1.28 (4H, m), 1.08 (9H, s), 0.95 (3H, d, J 7.1

1-Benzyloxy-4-(tert-butyldimethylsilanyloxy)-10,14,16,16-tetra-

methoxy-12-methoxymethoxy-3,5,9,13-tetramethylhexadec-7-

en-6-one 63

A solution of the ketophosphonate 23 (58.4 mg, 0.12 mmol)

in dry THF (2.7 ml) was stirred in the presence of activated

barium hydroxide octahydrate (30.2 mg, 0.095 mmol) at room

temperature for 30 min, and then a solution of the aldehyde 22

(38.2 mg, 0.11 mmol) in 40:1 THF–water (2.6 ml) was added.

The inhomogeneous mixture was stirred vigorously at room

2446

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

View Article Online

Hz), 0.93 (3H, d, J 7 Hz), 0.87 (3H, d, J 6.9 Hz), 0.85 (9H, s,

t-Bu), 0.81 (3H, d, J 7 Hz), 0.07 (3H, s), Ϫ0.04 (3H, s); δ_C(100

MHz) 213.8 (s) 135.6 (d), 134.0 (s), 129.7 (s), 127.7 (d), 102.3

(d), 96.8 (t), 81.0 (d), 79.33 (d), 78.8 (d), 77.5 (d), 62.2 (t), 58.1

(OMe), 58.9 (OMe), 55.8 (OMe), 53.3 (OMe), 52.1 (OMe), 50.0

(d), 42.3 (t), 41.4 (d), 35.2 (t), 33.8 (t), 33.6 (d), 33.1 (d), 31.6 (t),

27.0 (q, t-Bu), 26.6 (t), 26.2 (q, t-Bu), 19.3 (s), 18.4 (s), 16.3

(q, Me), 14.3 (q, Me), 13.4 (q, Me), 9.5 (q, Me), Ϫ4.13 (q,

SiMe), Ϫ4.3 (q, SiMe); m/z (FAB) (Found: M Ϫ 1, 859.5535.

C₄₈H₈₃O₉Si₂requires 859.5576).

added in one portion to a stirred solution of the β-ketoester 65

(12.4 g, 0.008 mol) in ethanol (200 ml) at 0 ЊC. The mixture was

stirred at room temperature for 20 h and then evaporated in

vacuo. The yellow residue was diluted with water (300 ml) and

added in one portion to an actively fermenting mixture of -

glucose (500 g, 2.77 mol), baker’s yeast (435 g), KH₂PO₄(1.05 g,

7.6mmol), MgSO₄(0.52g, 4.35mmol)andwater(1.37l)at25 ЊC.

The broth was stirred at room temperature for 2 days, then silica

(1 kg) and acetone (2.5 l) were added and the mixture was ﬁltered

in vacuo. The ﬁlter cake was washed with acetone (3 × 500 ml),

and the combined organic extracts were then concentrated to

~100 ml in vacuo. Water (400 ml) was added and the mixture

was acidiﬁed to pH 1.0 with concentrated hydrochloric acid and

then saturated with NaCl. The mixture was placed under con-

tinuous extraction with dichloromethane for 2 days. The dried

(MgSO₄) organic liquor was evaporated in vacuo to leave the

corresponding β-hydroxyacid as a viscous brown oil. A solution

of benzyl bromide (6 ml, 50 mmol) and aliquat 336 (5.8 g, 14.2

mmol) in dichloromethane (45 ml) was added to a solution of

the crude β-hydroxyacid (4.1 g) and NaHCO₃(2.5 g) in water

(30 ml), and the two phase mixture was stirred at room tem-

perature for 3 days. The separated aqueous layer was extracted

with dichloromethane (2 × 50 ml) and the combined organic

extracts were then dried (MgSO₄) and concentrated in vacuo.

The residue was puriﬁed by chromatography on silica using

petrol–diethyl ether (3:2) as eluent to give the benzyl ester (3.93

g) as a colourless oil; [α]_DϪ15.8 (c, 1.5 in CHCl₃); δ_H(250 MHz,

CDCl₃) 7.45–7.35 (5H, m, ArH), 5.85 (1H, ddt, J 16.5, 10.3 and

13-(tert-Butyldimethylsilanyloxy)-16-(tert-butyldiphenylsilanyl-

oxy)-3,7-dimethoxy-5-methoxymethoxy-4,8,12,14-tetramethyl-

11-oxohexadecanal 16

A solution of dimethylboryl bromide (260 µl, 0.58 mmol) in

dichloromethane (2.25 M) was added to a solution of the di-

methyl acetal 21 (100 mg, 0.12 mmol) in dry ether (3 ml) at

Ϫ78 ЊC under nitrogen. The mixture was stirred for an hour and

then quenched by pouring into a stirred mixture of THF (3 ml)

and saturated NaHCO₃(3 ml). The separated aqueous phase

was extracted with ether (3 × 20 ml) and the combined ether

extracts were washed with saturated NaHCO₃(10 ml) and brine

(10 ml) and then dried (Na₂SO₄). The ether extracts were con-

centrated in vacuo to leave the pure aldehyde (90 mg, 95%) as a

viscous oil; [α]_D²¹ϩ1.9 (c, 1.05 in CHCl₃); δ_H(500 MHz) 9.87 (1H,

t, J 2 Hz, CHO), 7.71–7.68 (4H, m, ArH), 7.48–7.29 (6H, m,

ArH), 4.72 (1H, d, J 6.5 Hz, OCHH–OMe), 4.66 (1H, d, J 6.5

Hz, OCHH–OMe), 3.86 (1H, dd, J 2.5 and 8.2 Hz), 3.80–3.63

(4H, m), 3.44 (3H, s, OMe), 3.39 (3H, s, OMe), 3.39 (3H, s,

OMe), 3.37–3.35 (1H, m), 2.82–2.80 (1H, m), 2.75 (1H, dd,

J 2.5 and 6.5 Hz), 2.72–2.53 (2H, m), 1.97–1.81 (4H, m), 1.43–

1.29 (5H, m), 1.08 (9H, s, t-Bu), 1.06 (3H, d, J 8.1 Hz), 1.00

(3H, d, J 7.9 Hz), 0.94 (3H, d, J 7.1 Hz), 0.90 (3H, d, J 6.9 Hz),

0.87 (9H, s), 0.08 (3H, s), Ϫ0.04 (3H, s); δ_C(69.89 MHz) 213.6

6.5 Hz, CH᎐CH ), 5.11–4.90 (2H, m, ᎐CH ), 4.10–4.01 (1H, m,

᎐

2

CHOH), 3.15 (1H, br s, OH), 2.60–2.45 (2H, m, CH₂CO), 2.25–

2.05 (2H, s, CH CH᎐CH ), 1.70–1.50 (2H, m, CH ); δ (100

᎐

2

C

MHz, CDCl₃) 172.5 (s, 1-C), 138.0 (d, 6-C), 128.7 (d, Ar), 128.4

(s, Ar), 126.7 (d, Ar), 114.9 (t, 6-C), 67.4 (t, OCH₂Ph), 66.4 (d,

3-C), 41.5 (t, 2-C), 35.6 (t, C-5) and 29.7 (t, 4-C); m/z (EI)

(Found: M Ϫ H₂O, 215.9893. C₁₄H₁₆O₂requires 216.1150).

(s, C᎐O), 201.4 (d, CHO), 135.5 (d), 133.6 (s), 129.5 (d), 127.6

᎐

(d), 96.7 (t), 80.7 (d), 78.5 (d), 77.6 (d), 76.5 (d), 61.99 (t), 57.5

(OMe), 56.7 (OMe), 55.8 (OMe), 49.7 (d), 46.2 (t), 42.1 (t), 41.7

(d), 33.6 (t), 33.0 (d), 33.3 (d), 31.6 (t), 26.8 (q, t-Bu), 26.4 (t),

26.1 (q, t-Bu), 19.1 (s), 18.3 (s, t-Bu), 16.1 (q, Me), 14.0, (q, Me),

13.2 (q, Me), 9.6 (q, Me), Ϫ4.3 (q, Me), Ϫ4.5 (q, Me).

3-(tert-Butyldiphenylsilanyloxy)hept-6-enoic acid benzyl ester 67

A solution of the alcohol 66 (3.3 g, 14 mmol), imidazole (2.1 g,

30.9 mmol) and tert-butylchlorodiphenylsilane (4 ml, 15.4

mmol) in dry DMF (35 ml) was stirred at room temperature for

16 h under a nitrogen atmosphere and then quenched with

water (180 ml), and extracted with ether (3 × 100 ml). The

combined organic extracts were washed with water (2 × 50 ml)

and brine (50 ml), then dried (MgSO₄) and concentrated in

vacuo. The residue was puriﬁed by chromatography over silica

using petrol–diethyl ether (10:1) as eluent to give the silyl ether

(5.4 g, 81%) as a colourless oil; [α]_DϪ11.0 (c, 1.5 in CHCl₃)

(Found: C, 76.2; H, 7.9. C₃₀H₃₆O₃Si requires C, 76.2; H, 7.7%);

ν_max(ﬁlm)/cm^Ϫ13069, 2930, 2892, 1736, 1640; δ_H(360 MHz,

CDCl₃) 7.72–7.67 (4H, m, ArH), 7.48–7.28 (11H, m, ArH), 5.60

3-Oxohept-6-enoic acid methyl ester 65

A solution of methyl acetoacetate (23.2 g, 0.2 mol) in dry THF

(30 ml) was added dropwise over 45 min to a stirred suspension

of NaH (60% in oil, 9.6 g, 0.24 mol) in dry THF (200 ml) at

0 ЊC under nitrogen. The turbid mixture was stirred at 0 ЊC for

10 min and then a solution of n-butyllithium (1.6 M) in hexane

(130 ml, 0.21 mol) was added dropwise over 30 min. The brown

solution was stirred at 0 ЊC for a further 10 min and then a

solution of allyl bromide (26.6 ml, 0.22 mol) in dry THF (50

ml) was added dropwise over 20 min. The mixture was warmed

to room temperature over 30 min and then quenched with

dilute hydrochloric acid (2 M, 200 ml). The separated aqueous

layer was extracted with diethyl ether (2 × 200 ml) and the

combined organic extracts were washed with brine (200 ml)

then dried (MgSO₄) and concentrated in vacuo. The residue was

puriﬁed by distillation to give the β-ketoester (18.5 g, 59%) as a

pale yellow oil, bp 110 ЊC at 40 mmHg (Found: C 61.6; H, 8.0.

C₈H₁₂O₃requires C, 61.5; H, 7.7%); ν_max(ﬁlm)/cm^Ϫ12955, 1751;

δ_H(250 MHz, CDCl₃) 5.79 (1H, ddt, J 16.7, 10.2 and 6.5 Hz,

(1H, ddt, J 16.5, 10.3 and 6.5 Hz, CH᎐CH ), 5.06 (1H, d, J 12.3

᎐

2

Hz, OCHHPh), 4.98 (1H, d, J 12.3Hz, OCHHPh), 4.91–4.85

(2H, m, ᎐CH ), 4.25 (1H, quintet, J 6 Hz, CH–OH), 2.60 (1H,

᎐

2

dd, J 6.6 and 14.8 Hz, CHH–CO), 2.53 (1H, dd, J 6.0 and 14.8

Hz, CHH–CO), 2.05–2.00 (2H, m, CH C᎐CH ), 1.62–1.56 (2H,

᎐

2

m, CH₂), 1.06 (9H, s, t-Bu); δ_C(90 MHz, CDCl₃) 171.1 (s, 1-C),

138.0 (d, 6-C), 135.9 (d), 135.9 (d), 133.9 (s), 133.8 (s), 129.6 (d),

128.4 (d), 128.2 (d), 128.1 (d), 127.5 (d), 114.5 (t, 6-C), 69.9 (d,

3-C), 66.2 (t, OCH₂Ph), 41.9 (t, C-2), 36.1 (t, 5-C), 29.0 (t, 4-C),

26.9 (q, t-Bu), 19.3 (s, t-Bu); m/z (FAB), 473 (M ϩ H)^ϩ, 495

(M ϩ Na)^ϩ, 415 (M^ϩϪ t-Bu).

CH᎐CH ), 5.08–4.97 (2H, m, ᎐CH ), 3.73 (3H, s, CO Me), 3.46

᎐

2

(2H, s, COCH₂CO), 2.65 (2H, t, J 7.4 Hz, CH₂CO), 2.33 (2H,

dt, J 7.4 and 6.5 Hz, CH CH᎐CH ); δ (67.8 MHz, CDCl )

201.6 (s, 3-C), 167.3 (s, 1-C), 136.3 (d, 6-C), 115.2 (t, 7-C), 52.0

(q, CO₂Me), 48.7 (t, 2-C), 41.7 (t, 4-C), 27.1 (t, 5-C).

3-(tert-Butyldiphenylsilanyloxy)-7-hydroxyheptanoic acid benzyl

ester 68

᎐

2

C

3

A solution of the oleﬁn 67 (4.5 g, 9.52 mmol) in dry THF (30

ml) was added to a stirred solution of borane–dimethyl sulﬁde

complex (2 M, 5.5 ml, 11 mmol) in dry THF (40 ml) at 0 ЊC

under nitrogen. The mixture was allowed to warm to room

temperature over 3 h and then evaporated in vacuo. Sodium

3-Hydroxyhept-6-enoic acid benzyl ester 66

A solution of KOH (9.8 g, 0.18 mol) in water (175 ml) was

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

2447

View Article Online

hydroxide solution (3 M, 3.5 ml) and 30% aqueous H₂O₂(1.2

ml) were added successively to a solution of the residue in THF

(30 ml) at 0 ЊC. The turbid solution was warmed to room tem-

perature over 2 h and then quenched with water (100 ml) and

extracted with ether (3 × 100 ml). The ether extracts were dried

(MgSO₄), and then concentrated in vacuo. The residue was

puriﬁed by ﬂash chromatography on silica using diethyl ether–

petrol (1:1) as eluent to give the alcohol (3.57 g, 78%) as an oil;

[α]_D²¹Ϫ11.5 (c, 1.6 in CHCl₃) (Found: C, 73.2; H, 8.1. C₃₀H₃₈O₄Si

requires C, 73.4; H, 7.8%); ν_max(ﬁlm)/cm^Ϫ13396, 3068, 1735;

δ_H(360 MHz, CDCl₃) 7.72–7.67 (4H, m, ArH), 7.47–7.29 (11H,

m, ArH), 5.1 (1H, d, J 11.6 Hz, OCHHPh), 5.03 (1H, d, J 11.6

Hz, OCHHPh), 4.27–4.22 (1H, m, CHO), 3.47 (2H, t, J 6 Hz,

CH₂OH), 2.62 (1H, dd, J 6.1 and 12 Hz, CHHCO₂CH₂Ph), 2.55

(1H, dd, J 6.1 and 12 Hz, CHHCO₂Ph), 1.52–1.42 (6H, m,

3 × CH₂), 1.06 (9H, s, t-Bu); δ_C(100 MHz, CDCl₃) 171.3 (s, 1-

C), 135.9 (d, Ar), 134.0 (s, Ar), 128.8 (d), 128.5 (d), 128.3 (d),

128.2 (d), 127.5 (d), 70.3 (d, 3-C), 66.2 (t, OCH₂Ph), 62.4

(t, 7-C), 42.0 (t, 2-C), 36.6 (t, 6-C), 32.3 (t, 5-C), 27.0 (q, t-Bu),

20.8 (t, 4-C), 19.3 (s, t-Bu); m/z (FAB) 513 (M ϩ Na)^ϩ, 491

(M ϩ H)^ϩ(Found: M^ϩϩ 1, 491.2706. C₃₀H₃₈O₄Si requires

491.2617).

OCHHPh), 4.96 (1H, d, J 12.5 Hz, OCHHPh), 4.20 (1H, m,

CHOTBDPS), 3.77 (3H, s, OCH₃), 3.76 (3H, s, OCH₃), 3.75

(3H, s, OCH₃), 3.74 (3H, s, OCH₃), 3.39 (1H, br s, OH), 2.55

(1H, dd, J 6.7 and 14.5 Hz), 2.46 (1H, dd, J 6.5 and 14.5.Hz),

1.81–1.77 (2H, m, CH₂PO), 1.51–1.48 (2H, m, CH₂), 1.45–1.24

(4H, m, 2 × CH₂), 1.02 (9H, s, t-Bu); δ_C(100 MHz, CDCl₃)

171.2 (s, 1-C), 135.9 (d, Ar), 134.0 (s), 133.9 (s), 132.1 (s), 132.0

(s), 129.6 (d), 128.5 (d), 128.2 (d), 126.2 (d), 127.5 (d), 70.3

(70.2) (d, 3-C or 7-C), 66.2 (66.1) (t, OCH₂Ph), 52.4 (q, OCH₃),

42.0 (38.0) (t, 2-C), 37.6 (36.8) (t, 6-C), 33.1 (CH₂, d, J_P-C137

Hz), 26.9 (q, t-Bu), 20.6 (t, C-4), 19.3 (s, t-Bu), 20.6 (t, C-4),

19.3 (s, t-Bu); (Found: M^ϩϩ 613.2611. C₃₃H₄₅O₇PSi requires

613.2750).

3-(tert-Butyldiphenylsilanyloxy)-8-(dimethoxyphosphoryl)-7-

oxooctanoic acid benzyl ester 71

Pyridinium dichromate (4 g, 11.5 mmol) was added in one por-

tion to a stirred solution of the β-hydroxyphosphonate 70

(1.3 g, 2.1 mmol) in dry DMF (10 ml) under nitrogen at room

temperature. The dark orange solution was stirred at room

temperature for 36 h and then diluted with water (100 ml). The

mixture was extracted with ether (3 × 50 ml) and the combined

organic extracts were washed with water (2 × 50 ml) and brine

(25 ml), and then dried (MgSO₄). The ﬁltrate was concen-

trated in vacuo to leave a brown oil which was puriﬁed by ﬂash

chromatography on silica using ethyl acetate as eluent to give

the β-keto phosphonate (1.09 g, 84%) as a colourless oil; [α]_D²¹

Ϫ14.2 (c, 2.0 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ13070, 2999, 1732, 1599;

δ_H(360 MHz, CDCl₃) 7.71–7.66 (4H, m, ArH), 7.48–7.31 (9H,

m, ArH), 7.29 –7.27 (2H, m, ArH), 5.0 (1H, d, J 12.4 Hz,

OCHHPh), 4.92 (1H, d, J 12.4 Hz, OCHHPh), 4.21 (1H,

quintet, J 6 Hz, CHOTBDPS), 3.79 (3H, d, J_P-C0.88 Hz,

OCH₃), 3.77 ( 3H, d, J_P-C0.9 Hz, OCH₃), 2.97 (2H, d, J_P-C22.67

Hz, CH₂O), 2.62 (1H, dd, J 6.65 and 14.9 Hz, CHH-

CO₂CH₂Ph), 2.56 (1H, dd, J 5.9 and 14.9 Hz, CHHCO₂-

CH₂Ph), 2.35 (2H, dt, J 1.4 and 6.4 Hz), 1.57–1.43 (4H, m,

3-(tert-Butyldiphenylsilanyloxy)-7-oxoheptanoic acid benzyl

ester 69

Pyridinium dichromate (3.2 g, 9.2 mmol) was added in one

portion to a stirred solution of the alcohol 68 (2.66 g, 5.42

mmol) in dry dichloromethane (50 ml) under a nitrogen atmos-

phere at room temperature. The solution was stirred for 23 h at

room temperature, ﬁltered through Celite and the ﬁltrate was

then evaporated in vacuo. The residue was puriﬁed by ﬂash

chromatography over silica using petrol–diethyl ether (3:1) as

eluent to give the aldehyde (2.06 g, 78%) as a colourless oil; [α]_D²¹

Ϫ10.3 (c, 2.7 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ13069, 2931, 1734;

δ_H(250 MHz, CDCl₃) 9.71 (1H, br s, CHO), 7.68–7.63 (4H, m,

ArH), 7.46–7.25 (11H, m, ArH), 5.05 (1H, d, J 12.5 Hz,

OCHHPh), 4.97 (1H, d, J, 12.5 Hz, OCHHPh), 4.20 (1H,

apparent quintet, J 6 Hz, CHODBDPS), 2.60 (1H, dd, J 6.5

and 14.8 Hz, CHHCO₂CH₂Ph), 2.52 (1H, dd, J 6 and 14.8 Hz,

CHHCO₂CH₂Ph), 2.05–2.00 (2H, m, CH₂CHO), 1.62–1.56

(4H, m, 2 × CH₂), 1.06 (9H, s, t-Bu); δ_C(67.8 MHz, CDCl₃)

202.1 (d, 7-C), 171.0 (s, 1-C), 135.8 (d), 135.7 (d), 133.7 (s),

133.6 (s), 129.6 (d), 128.4 (d), 128.2 (d), 128.1 (d), 127.5 (d),

69.7 (d, 3-C), 66.2 (t, OCH₂Ph), 43.3 (t, 2-C), 41.8 (t, 6-C),

36.1 (t, 5-C), 26.9 (q, t-Bu), 19.2 (t, 4-C), 17.1 (s, t-Bu); m/z (EI)

431 (M Ϫ t-Bu)^ϩ5.2%.

2 × CH ), 1.05 (9H, s, t-Bu); δ (67.8 MHz, CDCl ) 201.0 (C᎐O,

᎐

2

C

3

d, J_P-CO6 Hz), 170.9 (s, 1-C), 135.8 (d), 135.7 (d), 133.7 (s),

133.6 (s), 132.0 (d), 131. 8 (d), 131.7 (d, Ar), 129.5 (d, Ar), 128.4,

128.3, 128.2, 128.1, 128.0, 127.7, 127.4, (all d, Ar), 69.7 (d, 3-C),

66.1 (t, CH₂Ph), 52.8 (q, OCH₃), 52.8 (q, OCH₃), 43.5 (t, 2-C),

41.9 (t, C-6), 41.7 (CH₂, 8-C, J_P-C128 Hz), 36.3 (t, 5-C), 26.8 (q,

t-Bu), 19.1 (t, 4-C), 18.3 (s, t-Bu); m/z (FAB) 553 (M Ϫ t-Bu)^ϩ

(13%) (Found: M^ϩϪ 57, 553.1791. C₃₃H₄₄O₇PSi requires

553.1780).

3-(tert-Butyldiphenylsilanyloxy)-8-(dimethoxyphosphoryl)-7-

oxooctanoic acid 18

3-(tert-Butyldiphenylsilanyloxy)-8-(dimethoxyphosphoryl)-7-

hydroxyoctanoic acid benzyl ester 70

A solution of the benzyl ester 71 (1.0 g, 1.70 mmol) in ethyl

acetate (50 ml) was hydrogenated in the presence of palladium

on charcoal (10%, 500 mg) for 24 h. The solution was ﬁltered

through Celite and the ﬁlter cake was then washed with ethyl

acetate (3 × 25 ml). The ﬁltrate was concentrated in vacuo to

leave the acid (0.86 g, 98%) as a colourless foam; [α]_D²¹Ϫ13.7 (c,

2.9 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ11714, 1588; δ_H(360 MHz, CDCl₃)

7.72–7.67 (4H, m ArH), 7.49–7.29 (6H, m, ArH), 4.16–4.14

(1H, m, CHOTBDPS), 3.8 (3H, s, OMe), 3.0 (2H, d, J 22.7 Hz,

CH₂PO), 2.5 (2H, apparent d, J 6 Hz, CH₂CO₂Ph), 2.4 (2H, m,

CH₂), 1.53–1.50 (4H, m, 2 × CH₂), 1.07 (9H, s); δ_C(100 MHz,

CDCl₃) 201.2 (s, 7-C), 174.5 (s, 1-C), 135.9 (s, Ar), 133.9 (d),

133.8 (d), 129.8 (d), 127.6 (d), 69.8 (d, 3-C), 53.2 (q, OCH₃),

43.7 (t, 2-C), 41.6 (t, 6-C), 40.4 (d, J_P-C112 Hz, CH₂PO),

35.9 (5-C), 27.0 (q, t-Bu), 19.3 (s, t-Bu), 18.6 (t, 4-C); m/z

(FAB) (Found: (M ϩ H)^ϩ, 521.2132. C₂₆H₃₈O₇SiP requires

521.2124).

A solution of n-butyllithium (1.6 M in hexane, 2.8 ml, 4.5

mmol) was added dropwise over 15 min to a stirred solution of

the dimethyl methylphosphonate (0.49 ml, 4.5 mmol) in dry

THF (65 ml) at Ϫ78 ЊC under a nitrogen atmosphere. The

colourless solution was stirred at Ϫ78 ЊC for 30 min and then

added via cannula over 20 min to a stirred solution of the alde-

hyde 69 (1.7 g, 3.48 mmol) in dry THF (60 ml) at Ϫ78 ЊC under

an atmosphere of nitrogen. The mixture was stirred at Ϫ78 ЊC

for 2 h, then quenched with saturated NaHCO₃solution (8 ml)

and allowed to cool to room temperature. The mixture was

extracted with EtOAc (100 ml) and the separated aqueous layer

was re-extracted with EtOAc (2 × 220 ml). The combined

organic phases were then washed with saturated brine (20 ml)

and dried (MgSO₄). The ﬁltrate was concentrated in vacuo to

leave a pale yellow oil which was puriﬁed by ﬂash chroma-

tography on silica using ethyl acetate as eluent to give a mixture

of diastereoisomers of the β-hydroxyphosphonate (1.2 g, 55%)

as a colourless oil; [α]_D²¹Ϫ13.4 (c, 5.0 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ1

3388, 2953, 1732; δ_H(400 MHz, CDCl₃) 7.68–7.64 (4H, m,

ArH), 7.41–7.25 (11H, m, ArH), 5.02 (1H, d, J 12.5 Hz,

The ter-oxazole alkene ester 17

A solution of n-butyllithium (1.6 M) in hexane (112 µl, 0.2

2448

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

View Article Online

mmol) was added dropwise over 5 min to a stirred suspension

of the phosphonium salt 11 (114 mg, 0.19 mmol) in dry THF

(6 ml) under a nitrogen atmosphere at Ϫ30 ЊC. The deep red

solution was stirred at room temperature for 1.5 h and then

re-cooled to Ϫ78 ЊC. A solution of the aldehyde 55 (150 mg,

0.19 mmol) in dry THF (8 ml) was added dropwise over 15 min

and the yellow solution was then warmed to room temperature

over 2 h. The mixture was quenched with saturated ammonium

chloride solution (5 ml) and then diluted with dichloro-

methane (20 ml). The separated aqueous layer was extracted

with dichloromethane (2 × 10 ml) and the combined organic

phases were washed with saturated brine (20 ml), then dried

(Na₂SO₄) and evaporated in vacuo. The residue was puriﬁed by

chromatography on silica using petrol–ethyl acetate (1:1) as

eluent to give unreacted aldehyde (29 mg) and then the oleﬁn

(109 mg, 70% based on recovered aldehyde) as a colourless

foam; [α]_D²⁵ϩ2.71 (c, 0.7 in CHCl₃); δ_H(500 MHz) 8.46 (1H, s),

8.36 (1H, s), 8.29 (1H, s), 7.71–7.68 (4H, m), 7.48–7.36 (6H, m),

6.95 (1H, dt, J 7.5 and 15.5 Hz), 6.48 (1H, d, J 16.1 Hz), 4.7 (d,

J 6.7 Hz, OCHH–OMe), 4.62 (d, J 6.7 Hz, OCHHOMe), 3.99

(3H, s, CO₂Me), 3.86 (1H, dd, J 2.4 and 7.8 Hz), 3.8–3.7 (2H,

m), 3.7–3.6 (1H, m), 3.45 (3H, s, OMe), 3.4 (3H, s, OMe), 3.35

(3H, s, OMe), 2.8 (1H, quintet, J 7 Hz), 2.6–2.5 (4H, m), 1.9–1.4

(6H, m), 1.4–1.3 (4H, m), 1.1 (9H, s, t-Bu), 1.0 (3H, d, J 8.6 Hz),

0.98 (3H, d, J 6 Hz), 0.9 (3H, d, J 6 Hz), 0.88 (9H, s, SiBu),

Ϫ0.04 (3H, s, SiMe), Ϫ0.06 (3H, s, SiMe); δ_C(100 MHz) 213.8

(s), 162.2 (s), 161.4 (s), 156.5 (s), 155.6 (s), 144.0 (s), 139.4 (s),

138.9 (s), 135.7 (d), 134.1 (s), 131.0 (s), 129.7 (d), 127.7 (d),

117.9 (d), 96.8 (t), 81.5 (d), 81.1 (d), 78.7 (d), 77.4 (d), 62.2 (t),

57.7 (q, OMe), 57.1 (q, OMe), 55.9 (q, OMe), 52.5 (q, OMe),

50.1 (d), 42.3 (t), 40.7 (d), 34.6 (t), 33.9 (t), 33.6 (d), 33.2 (d),

31.6 (t), 29.8 (t), 27.0 (q, t-Bu), 26.6 (t), 26.2 (q, t-Bu), 19.3 (s, t-

Bu), 18.5 (s, t-Bu), 16.3 (q, Me), 14.2 (q, Me), 13.4 (q, Me), 9.4

(q, Me), Ϫ4.1 (q, SiMe), Ϫ4.3 (q, SiMe); m/z (FAB) 1095

(M ϩ Na)^ϩ.

(q, Me), 15.6 (15.5) (q, Me), 14.0 (13.2) (q, Me), 13.2 (13.1) (q,

Me), 9.4 (9.3) (q, Me), Ϫ4.1 (Ϫ4.0) (q, SiMe), Ϫ4.3 (-4.2) (q,

SiMe); m/z (FAB) 1067 (M ϩ Na)^ϩ.

The ter-oxazole aldehyde 73a

A solution of Dess–Martin periodinane (535 mg, 1.25 mmol)

and pyridine (0.6 ml) in dichloromethane (12 ml) was added to

a stirred solution of the diol 72 (0.25 g, 0.24 mmol) in dichloro-

methane (12 ml) under nitrogen at room temperature and the

mixture was stirred for 1 h. It was then diluted with diethyl

ether (100 ml) and stirred at room temperature with a mixture

of saturated aqueous sodium bicarbonate (20 ml) and saturated

sodium thiosulfate (20 ml) for twenty minutes. The organic

phase was separated, and then dried (Na₂SO₄) and evaporated

in vacuo. The residue was puriﬁed by chromatography on silica

using ethyl acetate–petrol (2:1) as eluent to give the keto alde-

hyde (246 mg, 98%) as colourless foam; [α]_D²⁵ϩ2.3 (c, 3.0 in

CHCl ); δ (500 MHz) 10.1 (1H, s, CHO), 8.4 (1H, s, ᎐CH), 8.45

᎐

3

H

(1H, s, ᎐CH), 8.3 (1H, s, ᎐CH), 7.7 (4H, br s, Ar-H), 7.5–7.3

᎐

(6H, m, Ar-H), 6.9 (1H, dt, J 7.5 and 16 Hz, CH᎐CH–CH ), 6.5

᎐

2

(1H, d, J 16 Hz, CH–CH᎐CH ), 4.72 (1H, d, J 6.7 Hz, OCH-

᎐

2

HOMe), 4.64 (1H, d, J 6.7 Hz, OCHHOMe), 3.9 (1H, dd, J 2.4

and 8 Hz), 3.8–3.42 (3H, m), 3.42 (3H, s, OMe), 3.41 (3H, s,

OMe), 3.40 (3H, s, OMe), 3.4–3.3 (1H, m), 2.8 (1H, m), 2.6–2.5

(4H, m), 1.9–1.4 (6H, m), 1.4–1.31 (4H, m), 1.1 (9H, s, t-Bu),

1.0 (3H, d, J 7 Hz), 0.9 (3H, d, J 7 Hz), 0.91 (3H, d, J 7 Hz),

0.88 (3H, d, J 7 Hz), 0.88 (9H, s, t-Bu), 0.07 (3H, s, SiMe),

Ϫ0.04 (3H, s, SiMe); δ_C(90 MHz) 213.8 (s, 36-C), 184.2 (d,

CHO), 162.2 (s, Ox-C), 156.7 (s, Ox-C), 156.1 (s, Ox-C), 143.7

(d, Ox-C), 141.7 (s, Ox-C), 139.4 (d, 26-C), 138.9 (d, Ox-C),

135.6 (d, Ar), 134.0 (s, Ar), 130.7 (s, Ox-C), 130.4 (s, Ox-C),

129.6 (d, Ar), 127.7 (d, Ar), 117.8 (d, 25-C), 96.7 (t,

OCH₂OCH₃), 81.4 (d, OCH), 81.05 (d, OCH), 78.6 (d, OCH),

62.2 (t, C-41), 57.6 (q, OMe), 56.9 (q, OMe), 55.8 (q, OMe),

50.0 (d, 37-C), 42.3 (t, 35-C), 40.7 (d, 38-C), 34.5 (t, 27-C), 33.8

(t, 31-C), 33.5 (d), 33.1 (d), 31.5 (t), 30.4 (d, CH-Me), 29.8 (t),

26.9 (q, t-Bu), 26.5 (t, 40-C), 26.2 (q, t-Bu), 19.3 (s, t-Bu), 18.4

(s, t-Bu), 16.2 (q, Me), 14.1 (q, Me), 13.3 (q, Me), 9.5 (q, Me);

m/z 1065 (M ϩ Na)^ϩ.

The ter-oxazole alcohol 72

A solution of DIBAL-H (1.5 M) in toluene (233 µl, 3.5 mmol)

was added dropwise over 5 min to a stirred solution of the keto-

ester 18 in dry THF (4 ml) under a nitrogen atmosphere at 0 ЊC.

The mixture was stirred at 0 ЊC for 45 min and then warmed to

room temperature over 2 h. It was then cooled back to 0 ЊC

where it was quenched with aqueous sodium hydroxide (1 M,

1 ml). The mixture was diluted with ethyl acetate (25 ml) and

water (10 ml) and the separated aqueous phase was then

extracted with ethyl acetate (2 × 25 ml). The combined organic

phases were washed with saturated brine (25 ml), then dried

(Na₂SO₄) and evaporated in vacuo. The residue was puriﬁed by

chromatography on silica using ethyl acetate as eluent to give a

mixture of diastereomers of the diol (77 mg, 75%) as a colour-

less foam; [α]_D²⁵ϩ6.8 (c, 3.1 in CHCl₃); ν_max(ﬁlm)/cm^Ϫ13583,

3016, 2991, 2858; δ_H(500 MHz) 8.39 (8.33) (1H, s), 8.32 (8.31)

(1H, s), 7.70–7.68 (4H, m), 7.47–7.29 (6H, m), 6.95 (1H, dt,

J 7.5 and 15.8 Hz), 6.48 (1H, d, J 16 Hz), 4.71 (2H, s, CH₂OH),

4.67 (d, J 6.7 Hz, OCHHOME), 4.60 (d, J 6.7 Hz, OCH-

HOMe), 3.86 (1H, dd, J 8 and 2.5 Hz), 3.79–3.43 (4H, m), 3.41

(3.40) (3H, s, OMe), 3.39 (3.38) (3H, s, OMe), 3.37 (3.36) (3H, s,

OMe), 3.35–3.27 (1H, m), 2.80 (1H, quintet, J 7.7 Hz), 2.61–

2.53 (3H, m), 2.07–1.87 (4H, m), 1.42–1.31 (6H, m), 1.08 (1.07)

(9H, s, t-Bu), 0.98 (3H, d, J 7 Hz), 0.97 (3H, d, J 7 Hz), 0.90

(3H, d, J 7 Hz), 0.85 (3H, d, J 7 Hz), 0.87 (9H, s), 0.07 (0.14)

(3H, s), Ϫ0.04 (0.12) (3H, s); δ_C(67.8 MHz) 162.0 (s), 156.2 (s),

155.2 (s), 141.6 (s), 138.1 (d), 138.7 (d), 135.5 (d), 135.1 (d),

133.9 (s), 133.8 (s), 131.4 (s), 130.4 (s), 129.5 (d), 127.6 (d), 117.8

(d), 96.6 (d), 82.7 (84.3) (d), 81.3 (80.9) (d), 77.5 (d), 73.3 (d),

71.4 (d), 61.9 (t), 57.5 (q, OMe), 56.8 (OMe), 56.7 (55.7) (OMe),

49.9 (d), 41.1 (t), 40.6 (d), 40.5 (d), 35.9 (d), 35.3 (d), 34.7 (t),

34.6 (t), 33.9 (d), 33.7 (t), 33.6 (t), 33.4 (t), 33.0 (t), 26.8

(q, t-Bu), 19.1 (18.3) (s, t-Bu), 18.2 (18.1) (s, t-Bu), 16.5 (16.1)

The ter-oxazole (C-30) hydroxy aldehyde 73b

A solution of dimethylboryl bromide (2.67 M) in dichloro-

methane (111 µl, 0.3 mmol) was added to a stirred solution of

the MOM-ether 73a (62 mg, 0.06 mmol) in dichloromethane (5

ml) at Ϫ78 ЊC under nitrogen and the mixture was then stirred

at Ϫ78 ЊC for 45 min. It was then quenched by addition into a

stirred solution of saturated sodium bicarbonate (2 ml) and

THF (2 ml) at room temperature. The mixture was diluted with

dichloromethane (25 ml) and the organic layer was washed with

brine (10 ml), then dried (Na₂SO₄) and evaporated in vacuo. The

residue was puriﬁed by chromatography over silica using ethyl

acetate as eluent to give the alcohol (61 mg, 99%) as a colourless

foam; [α]_D²⁵Ϫ7.7 (c, 1.1 in CHCl₃); δ_H(500 MHz) 10.0 (1H, s,

CHO), 8.4 (1H, s, Ox-H), 8.4 (1H, s, Ox-H), 8.3 (1H, s, Ox-H),

7.7–7.4 (4H, m, Ar-H), 7.4–7.3 (6H, m, Ar-H), 6.9 (1H, dt, J 7.4

and 15.7 Hz, 26-H), 6.5 (1H, d, J 16 Hz, 25-H), 3.8 (1H, t, J 8

Hz, ϪCHOMe), 3.8–3.6 (5H, m), 3.45 (3H, s, OMe), 3.4 (3H, s,

OMe), 2.8–2.75 (1H, quintet, J 7.4 Hz), 2.7 (1H, m), 2.6–2.4

(3H, m), 1.9–1.6 (7H, m), 1.5–1.1 (3H, m), 1.1 (9H, s, t-Bu), 1.0

(3H, d, J 7 Hz), 0.95 (3H, d, J 7 Hz), 0.9 (3H, d, J 7 Hz), 0.85

(9H, s, t-Bu), 0.1 (3H, s, SiMe), 0.05 (3H, s, SiMe); δ_C(90 MHz)

213.7 (s, C-6), 184.0 (d, CHO), 162.0 (s, Ox-C), 156.4 (s, Ox-C),

155.8 (s, Ox-C), 143.6 (d, Ox- C), 141.5 (s, Ox-C), 139.3 (d, Ox-

C), 139.2 (d, Ox-C), 138.7 (d, 16-C), 135.5 (d, Ar), 133.8 (s, Ar),

130.6 (s, Ox-C), 130.3 (s, Ox-C), 129.5 (d, Ar), 127.5 (d, Ar),

117.4 (d), 81.9 (d), 81.8 (d), 78.5 (d), 70.7 (d), 62.0 (t, 41-C), 57.8

(q, OMe), 57.3 (q, OMe), 49.9 (d, 37-C), 42.2 (t, 34-C), 40.7 (d),

34.3 (t), 34.2 (t), 33.9 (d), 33.6 (t), 32.9 (d), 30.2 (d), 29.6 (t), 26.8

(s, t-Bu), 26.2 (t), 26.1 (s, t-Bu), 19.1 (s, t-Bu), 18.2 (s, t-Bu), 16.1

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

2449

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(q, Me), 14.0 (q, Me), 13.9 (q, Me), 11.2 (q, Me), Ϫ4.3 (q,

SiMe), Ϫ4.5 (q, SiMe).

24-C), 137.3 (d, 19-C), 137.0 (s, Ar), 136.0 (d, Ar), 135.9 (d, Ar),

135.6 (d, Ar), 134.3 (s, Ar), 134.1 (s, Ar), 130.9 (s, 20-C), 130.2

(s, 15-C), 129.6 (d, Ar), 128.3 (d, Ar), 127.6 (d, Ar), 126.8 (d, 8-

C), 81.4 (d, 32-C), 79.7 (d, 32-C), 78.5 (d, 38-C), 73.1 (d, 30-C),

69.5 (d, 3-C), 62.1 (t, 41-C), 57.8 (q, OMe), 50.0 (d, 37-C), 44.8

(t, 6-C), 42.4 (t, 2-C), 40.9 (t, 35-C), 39.5 (d, 33-C), 36.8 (t, 4-C),

34.4 (d, 29-C), 33.7 (t, 27-C), 33.3 (d, 39-C), 32.4 (t, 31-C), 30.4

(t, 40-C), 29.7 (t, 34-C), 27.3 (q, t-Bu), 26.9 (q, t-Bu), 26.2

(q, t-Bu), 20.1 (t, 5-C), 19.4 (s, t-Bu), 19.2 (s, t-Bu), 18.4 (s,

t-Bu), 16.2 (q, Me), 14.2 (q, Me), 13.7 (q, Me), 8.2 (q, Me), Ϫ4.1

(s, SiMe), Ϫ4.4 (s, SiMe); m/z (FAB) 1398 (M ϩNa)^ϩ.

The ter-oxazole phosphonate aldehyde 19

Triethylamine (38 µl, 0.27 mmol) and 2,4,6-trichlorobenzoyl

chloride (38 µl, 0.24 mmol) were added sequentially to a stirred

solution of the acid 18 (128 mg, 0. 245 mmol) in toluene (0.5

ml) at room temperature under nitrogen and the resulting solu-

tion was stirred at room temperature for 3 h. A solution of the

alcohol 73b (99 mg, 0.1 mmol) and DMAP (31 mg, 0.254

mmol) in toluene (1 ml) was added and the mixture was stirred

at room temperature under nitrogen for 90 min, and then

quenched with saturated ammonium chloride solution (2 ml).

The mixture was diluted with ethyl acetate (25 ml), washed with

brine (10 ml), and then dried (Na₂SO₄) and concentrated in

vacuo. The residue was puriﬁed by chromatography on silica

using ethyl acetate as eluent to give the ester (90 mg, 60%) as a

colourless foam; [α]_D²⁵ϩ6.2 (c, 0.6 in CHCl₃); δ_H(500 MHz) 10.1

(1H, s, CHO), 8.4 (1H, s, Ox-H), 8.4 (1H, s, Ox-H), 8.3 (1H, s,

Ox-H), 7.7–7.5 (4H, m, Ar), 7.4–7.3 (6H, m, Ar), 6.9 (1H, dt,

J 7.4 and 15.4 Hz), 6.5 (1H, d, J 15.9 Hz), 5.2–5.15 (1H, m),

4.25–4.21 (1H, m), 3.9–3.8 (1H, m), 3.8 (3H, s, OMe), 3.75 (3H,

s, OMe), 3.7–3.6 (3H, m), 3.3 (3H, s, OMe), 3.25 (3H, s, OMe),

C-9 ꢀ- and ꢁ- Methyl epimeric macrolide 80

A solution of methyllithium (1.4 M) in ether (61 µl, 0.22 mmol)

was added dropwise to a stirred suspension of CuI (22 mg, 0.11

mmol) in dry ether (2.4 ml) at Ϫ5 ЊC under argon and the

resulting solution was stirred at Ϫ5 ЊC for 30 min. A solution of

the enone 20 (22 mg, 0.016 mmol) in dry ether (3 ml) was added

dropwise over 15 min and the resulting yellow solution was then

stirred at 0 ЊC for 3.5 h before being quenched with a 1:1 mix-

ture of saturated ammonium chloride (3 ml) and concentrated

ammonia (3 ml). The mixture was extracted with ether (2 × 20

ml) and the combined organic phases were washed with brine (10

ml), then dried (Na₂SO₄) and evaporated in vacuo. The residue

was puriﬁed by chromatography over silica using petrol-ethyl

acetate (6:4) as eluent to give the 3-methyl ketone (12 mg) as a

3:2 mixture of two diastereomers. Further chromatography

gave: (i) the “9β-methyl” diastereoisomer 80b, as an oil; [α]_D

Ϫ13.0 (c, 1.0 in CHCl₃); δ_H(500 MHz) 8.15 (1H, s), 8.1 (1H, s),

7.8–7.7 (8H, m, Ar), 7.5–7.4 (12H, m), 7.15–7.1 (1H, m, 26-H),

6.5 (1H, d, J 16.1 Hz), 5.2 (1H, ddd, J 1, 6 and 8 Hz, 30-H),

4.35–4.3 (1H, m, 3-H), 3.9 (1H, dd, J 2.4 and 8.1 Hz), 3.85–3.8

(1H, m, 41-H), 3.7–3.65 (1H, m, 41-H), 3.5–3.45 (1H, m), 3.4

(3H, s, OMe), 3.35 (3H, s, OMe), 3.2 (1H, dd, J 8.8 and 16 Hz,

8-H), 3.0 (1H, dd, J 3.5 and 9.6 Hz), 2.85–2.80 (1H, quintet,

J 7.7 Hz), 2.7 (1H, dd, J 16 and 5 Hz, 8-H), 2.65–2.5 (6H, m),

2.45–2.4 (1H, m), 2.3–2.25 (1H, m), 1.9–1.85 (2H, m), 1.85–1.8

(2H, m), 1.7–1.6 (2H, m), 1.6–1.5 (2H, m), 1.4–1.35 (1H, m), 1.1

(9H, s, t-Bu), 1.05 (9H, s, t-Bu), 1.0 (3H, d, J 7 Hz), 0.9 (3H, d,

J 7 Hz), 0.85 (3H, d, J 7 Hz), 0.8 (3H, d, J 6.8 Hz), 0.04 (3H,

s, SiMe), Ϫ0.2 (3H, s, SiMe); δ_C(125 MHz) 213.7 (s, 36-C),

210.5 (s, 7-C), 170.6 (s, 1-C), 162.4 (s, 22-C), 156.5 (s, 17-C),

154.1 (s, 12-C), 146.6 (s, 10-C), 138.4 (d, 26-C), 137.4 (d, 24-C),

137.1 (d, 19-C), 136.0 (d, Ar), 135.9 (d, Ar), 135.6 (d, Ar), 134.4

(d, 14-C), 134.2 (s, Ar), 134.0 (d, Ar), 133.4 (s, Ar), 131.9 (s, 15-

C), 130.7 (s, 20-C), 129.6 (d, Ar), 129.5 (d, Ar), 127.7 (d, Ar),

127.6 (d, Ar), 127.5 (d, Ar), 117.6 (d, 25-C), 81.3 (d, 33-C), 80.6

(d, 28-C), 78.5 (d, 38-C), 72.7 (d, 30-C), 70.2 (d, 3-C), 62.2 (t,

41-C), 58.0 (q, OMe), 57.6 (q, OMe), 50.1 (d, 37-C), 47.7 (t, 8-

C), 44.3 (t, 6-C), 42.5 (t, 2-C), 41.0 (t, 35-C), 39.5 (d, 33-C), 36.2

(t, 4-C), 34.5 (d, 29-C), 33.8 (d, 39-C), 33.1 (t, 27-C), 31.3 (t,

31-C), 29.8 (t, 40-C), 27.2 (d, 9-C), 27.2 (q, t-Bu), 26.9 (q, t-Bu),

26.2 (q, t-Bu), 26.1 (t, 34-C), 20.0 (q, 49-C), 19.8 (t, 5-C), 19.5 (s,

t-Bu), 19.3 (s, t-Bu), 18.4 (s, t-Bu), 16.2 (q, 47-C), 14.2 (q, 45-C),

13.8 (q, 46-C), 8.8 (q, 48-C), Ϫ4.3 (q, SiMe), Ϫ4.2 (q, SiMe);

m/z 1413 (M ϩ Na)^ϩ. (ii) The “9α-methyl” diastereoisomer 80a,

as an oil; δ_H(500 MHz) 8.12 (2H, s, 2 × Ox-H), 7.80–7.73 (8H,

m, ArH), 7.50–7.34 (13H, m, ArH and Ox-H), 7.20–7.14 (1H, m,

26-H), 6.42 (1H, d, J 15.8 Hz), 5.19–5.16 (1H, m, 30-H), 4.36–

4.30 (1H, m, 3-H), 3.91–3.89 (1H, dd, J 2.5 and 8.2 Hz, 41-H),

3.81–3.75 (1H, m, 41-H), 3.72–3.67 (1H, m, 38-H), 3.47–3.43

(1H, m), 3.38 (3H, s, OMe), 3.34 (3H, s, OMe), 3.29–3.27 (1H,

m), 3.22 (1H, dd, J 7.8 and 16.7 Hz), 3.00–2.99 (1H, m), 2.83–

2.80 (1H, m), 2.72–2.71 (1H, m), 2.65 (1H, dd, J 5 and 15.6 Hz),

2.61–2.51 (5H, m), 2.45–2.41 (2H, m), 2.33–2.26 (1H, m), 1.96–

1.93 (2H, m), 1.80–1.68 (6H, m), 1.63–1.47 (5H, m), 1.12 (9H, s,

t-Bu), 1.10 (9H, s, t-Bu), 0.99 (3H, d, J 6.9 Hz); δ_C(125 MHz)

213.6 (s, 36-C), 210.6 (s, 7-C), 170.5 (s, 1-C), 162.5 (s, 22-C),

156.5 (s, 17-C), 154.2 (s, 12-C), 146.6 (s, 10-C), 138.9 (d, 26-C),

3.2–3.15 (1H, m), 3.0 (2H, d, J_P-CH22.6 Hz), 2.95–2.9 (1H, m),

2

2.8–2.75 (1H, m), 1.9–1.7 (5H, m), 1.6–1.4 (10H, m), 1.4–1.3

(3H, m), 1.05 (18H, s, 2 × t-Bu), 1.0 (3H, d, J 7.1 Hz), 0.9 (3H,

d, J 7.2 Hz), 0.85 (9H, s, t-Bu), 0.80 (3H, d, J 6.7 Hz), 0.07 (3H,

s, SiMe), Ϫ0.04 (3H, s, SiMe); δ_C(90 MHz) 213.9 (s), 201.3 (d,

J_P-CO6 Hz, 7-C), 170.85 (d), 170.8 (s), 162.2 (s), 156.7 (s), 156.1

(s), 143.8 (d), 141.7 (s), 139.5 (d), 139.0 (d), 138.9 (d), 136.0 (d),

135.9 (d), 135.7 (d), 134.0 (s), 133.9 (s), 132.5 (s), 130.7 (d),

130.3 (d), 129.8 (d), 129.7 (d), 128.1 (d), 127.7 (d), 117.9 (d),

81.5 (d), 81.0 (d), 78.6 (d), 76.8 (d), 69.6 (d), 62.2 (t), 57.9 (q,

OMe), 57.8 (q, OMe), 53.3 (q, OMe), 53.2 (q, OMe), 50.1 (d),

43.9 (t), 42.5 (t), 41.8 (t), 40.4 (d), 35.8 (t), 35.1 (t), 34.0 (d), 33.8

(t), 33.0 (d), 31.0 (t), 29.7 (t), 27.0 (q, t-Bu), 26.9 (q, t-Bu), 26.2

(q, t-Bu), 19.4 (s, t-Bu), 19.2 (s, t-Bu), 18.6 (t), 18.4 (s, t-Bu),

16.2 (q, Me), 14.2 (q, Me), 13.4 (q, Me), 9.4 (q, Me); No M^ϩ

could be observed.

The ter-oxazole macrolide 20

A solution of the aldehyde phosphonate 19 (21 mg, 0.14 mmol)

in dry toluene (8 ml) was added dropwise over 8 h to a stirred

solution of powdered potassium carbonate (3.9 mg, 0.03 mmol)

and 18-crown-6 (14.8 mg, 0.06 mmol) in dry toluene (16 ml) at

room temperature under argon. The solution was stirred at

room temperature for 12 h and then quenched with saturated

ammonium chloride solution (3 ml). The aqueous phase was

separated and extracted with ether (2 × 25 ml). The combined

organic extract was washed with saturated potassium chloride

(3 × 50 ml), then dried (Na₂SO₄) and evaporated in vacuo. The

residue was puriﬁed by chromatography on silica using diethyl

ether–petrol (3:1) as eluent to give the macrolactone (6 mg,

31%) as a colourless foam; [α]_D²⁵ϩ10.8 (c, 0.5 in CHCl₃); δ_H(500

MHz) 8.2 (1H, s, Ox-H), 8.15 (1H, s, Ox-H), 7.90 (1H, s, Ox-H),

7.85–7.8 (4H, m, Ar-H), 7.75–7.7 (6H, m, Ar-H), 7.7 (1H, d,

J 15 Hz, 9-H), 7.5–7.4 (11H, m, Ar-H and 8-H), 7.25–7.2 (1H,

m, 26-H), 6.4 (1H, d, J 15.8 Hz, 25-H), 5.2 (1H, dt, J 1 and 7.6

Hz, 30-H), 4.55–4.50 (1H, m, 3-H), 3.89 (1H, dd, J 2.5 and 8.2

Hz), 3.8–3.75 (1H, m), 3.7–3.65 (1H, m), 3.45–3.4 (1H, m), 3.35

(3H, s, OMe), 3.3 (3H, s, OMe), 3.1 (1H, dd, J 4.3 and 9.1 Hz),

2.8–2.75 (3H, m), 2.6 (1H, dd, J 16.5 and 5.4 Hz), 2.55–2.5 (3H,

m), 2.45–2.4 (1H, m), 2.3 (1H, dt, J 4.8 and 14.2 Hz), 2.2 (1H,

dt, J 4.2 and 12.0 Hz), 2.0–1.7 (7H, m), 1.6–1.55 (2H, m), 1.2

(9H, s, t-Bu), 1.1 (9H, s, t-Bu), 1.0 (3H, d, J 7.1 Hz), 0.95 (3H, d,

J 7 Hz), 0.9 (3H, d, J 6.9 Hz), 0.85 (9H, s, t-Bu), 0.8 (3H, d, J 6.8

Hz), 0.04 (3H, s, SiMe), Ϫ0.05 (3H, s, SiMe); δ_C(125 MHz) 213.5

(s, 36-C), 200.3 (s, 7-C), 170.7 (s, 1-C), 162.6 (s, 22-C), 156.9 (17-

C), 155.2 (s, 12-C), 140.0 (d, 9-C), 139.2 (d, 26-C), 138.3 (d,

2450

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138.4 (d, 24-C), 137.3 (d, 19-C), 136.0 (d, Ar), 135.9 (d, Ar),

135.6 (d, Ar), 134.3 (d, 14-C), 134.2 (s, Ar), 134.0 (d, Ar), 133.5

(s, Ar), 131.9 (s, 15-C), 130.9 (s, 20-C), 129.6 (d, Ar), 130.1 (d,

Ar), 127.7 (d, Ar), 127.6 (d, Ar), 127.5 (d, Ar), 117.3 (d, 25-C),

81.4 (d, 32-C), 80.6 (d, 28-C), 78.5 (d, 38-C), 72.7 (d, 30-C), 69.7

(d, 3-C), 62.2 (t, 41-C), 57.9 (q, OMe), 57.5 (q, OMe), 50.1 (d,

37-C), 47.6 (t, 8-C), 44.1 (t, 6-C), 42.5 (t, 2-C), 41.5 (t, 35-C),

39.2 (d, 33-C), 36.3 (t, 4-C), 34.4 (d, 29-C), 33.8 (d, 39-C), 33.1

(t, 27-C), 32.0 (t, 31-C), 29.5 (t, 40-C), 27.1 (d, 9-C), 27.2 (q, t-

Bu), 26.9 (q, t-Bu), 26.2 (q, t-Bu), 19.8 (s, t-Bu), 19.6 (t, 5-C),

19.4 (s, t-Bu), 19.3 (q, 49-C), 18.4 (s, t-Bu), 16.2 (q, 47-C), 14.2

(q, 45-C), 13.7 (q, 46-C), 8.7 (q, 48-C), Ϫ4.3 (q, SiMe), Ϫ4.2 (q,

SiMe); m/z 1413 (M ϩ Na)^ϩ.

133.5 (d, 14-C), 131.9 (s, 15-C), 130.6 (s, 20-C), 129.7 (d, Ar),

129.6 (d, Ar), 127.7 (d, Ar), 127.6 (d, Ar), 117.3 (d, 25-C), 81.2

(d, 33-C), 80.0 (d, 28-C), 78.1 (d, 38-C), 72.91 (d, 30-C), 69.7 (d,

3-C), 61.8 (t, 41-C), 57.9 (q, OMe), 57.6 (q, OMe), 48.8 (d,

37-C), 47.6 (t, 8-C), 44.1 (t, 6-C), 41.5 (t, 2-C), 41.0 (t, 35-C),

39.3 (d, 32-C), 36.3 (t, 4-C), 34.4 (d, 29-C), 33.6 (t, 40-C), 32.8

(d, 39-C), 32.1 (t, 34-C), 32.0 (t, 31-C), 27.1 (d, 9-C), 27.0 (q,

t-Bu), 26.9 (q, t-Bu), 26.3 (t, 34-C), 19.7 (s, t-Bu), 19.6 (t, 5-C),

19.4 (s, t-Bu), 19.2 (q, 49-C), 16.7 (q, 47-C), 14.3 (q, 46-C), 13.7

(q, 45-C), 8.7 (q, 48-C).

C-9 ꢀ- and ꢁ-Methyl epimers of the macrolide C-38 acetate 82

Acetic anhydride (0.2 ml) was added to a solution of the sec-

ondary alcohol 81 (16.5 mg, 0.013 mmol) and DMAP (1 mg) in

a mixture of dichloromethane (0.5 ml) and dry pyridine (0.5 ml)

at room temperature under nitrogen and the resulting solution

was stirred at room temperature for 12 h. The mixture was

diluted with dichloromethane (20 ml) and water (5 ml) and the

organic extract was washed successively with water (2 × 10 ml),

copper sulfate (2 × 5 ml) and brine (5 ml), then dried (Na₂SO₄)

and concentrated in vacuo. The residue was puriﬁed by chroma-

tography over silica using ethyl acetate–petrol (2:1) as eluent to

give the acetate (15.5 mg, 91%) as a colourless foam; δ_H(500

MHz) 8.15 (1H, s), 8.1 (1H, s), 7.8–7.7 (8H, m, Ar-H), 7.5–7.4

(12H, m, ArH), 7.15–7.1 (1H, m, 26-H), 6.47 (1H, d, J 16 Hz,

25-H), 5.25–5.2 (1H, m, 30-H), 5.15 (1H, dd, J 3.4 and 9.1 Hz,

38-H), 4.35–4.3 (1H, m, 3-H), 3.85–3.8 (1H, m, 41-H), 3.7–3.65

(1H, m, 41-H), 3.45–3.4 (1H, m), 3.4 (3H, s, OMe), 3.35 (3H, s,

OMe), 3.2 (1H, dd, J 8.7 and 16.4 Hz, 8-H), 3.0 (1H, dd, J 4.1

and 9.8 Hz), 2.95–2.9 (1H, m), 2.7–2.5 (6H, m), 2.4–2.35 (2H,

m), 2.3–2.2 (2H, m), 2.0 (3H, COMe), 1.9–1.85 (2H, m), 1.85–

1.8 (2H, m), 1.8–1.75 (2H, m), 1.7–1.6 (2H, m), 1.6–1.5 (2H, m),

1.1 (9H, s, t-Bu), 1.05 (9H, s, t-Bu), 1.05 (3H, d, J 7 Hz), 0.9

(3H, d, J 7 Hz), 0.86 (3H, d, J 6.9 Hz), 0.85 (3H, d, J 7 Hz),

0.84 (3H, d, J 6.8 Hz); δ_C(125 MHz) 211.7 (s, 36-C), 210.5 (s,

7-C), 170.6 (s, 1-C), 170.2 (s, COMe), 162.4 (s, 22-C), 156.5

(s, 17-C), 154.2 (s, 12-C), 146.6 (s, 10-C), 138.4 (d, 26-C), 137.4

(d, 24-C), 137.1 (d, 19-C), 136.0 (d, Ar), 135.9 (d, Ar), 135.5 (d,

Ar), 134.4 (d, 14-C), 134.2 (s, Ar), 133.8 (d, Ar), 133.4 (s, Ar),

131.9 (s, 15-C), 130.7 (s, 20-C), 129.7 (d, Ar), 129.6 (d, Ar),

129.5 (d, Ar), 127.7 (d, Ar), 127.6 (d, Ar), 127.5 (d, Ar), 117.5

(d, 25-C), 81.2 (d, 32-C), 80.5 (d, 28-C), 78.5 (d, 38-C), 72.7 (d,

30-C), 70.2 (d, 3-C), 61.5 (t, 41-C), 58.0 (t, OMe), 57.6 (OMe),

48.2 (d, 37-C), 47.8 (t, 8-C), 44.3 (t, 6-C), 41.1 (t, 2-C), 40.0 (t,

35-C), 39.5 (d, 33-C), 36.2 (t, 4-C), 34.5 (d, 29-C), 32.8 (t, 27-C),

32.0 (t, 40-C), 31.6 (t, 31-C), 30.5 (d, 39-C), 27.2 (d, 9-C), 27.1

(q, t-Bu), 26.9 (q, t-Bu), 26.4 (t, 34-C), 20.9 (q, COMe), 19.9 (q,

49-C), 19.7 (t, 5-C), 19.4 (s, t-Bu), 19.2 (s, t-Bu), 16.6 (q, C-47),

13.8 (q, C-46), 13.4 (q, 45-C), 8.8 (q, 48-C). The corresponding

9α-methyl diastereoisomer 82b was prepared using an identical

procedure and showed δ_H(500 MHz) 8.12 (1H, s, Ox-H), 8.11

(1H, s, Ox-H), 7.74–7.72 (8H, m, Ar-H), 7.50–7.39 (13H, m,

12-ArH and 1-Ox-H), 6.42 (1H, d, J 15.8 Hz), 7.19 (1H, ddd,

J 6.2, 9.3 and 15.7 Hz, 26-H), 5.19–5.15 (1H, m, 38-H), 4.36–

4.32 (1H, m, 3-H), 3.83–3.79 (1H, m, 41-H), 3.72–3.67 (1H, m,

41-H¹) 3.48–3.42 (1H, m), 3.38 (3H, s, OMe), 3.33 (3H, s,

OMe), 3.30–3.26 (1H, m), 3.21 (1H, dd, J 8.9 and 13.6 Hz),

3.00–2.97 (1H, m), 2.94–2.88 (1H, m), 2.73–2.65 (2H, m), 2.64

(1H, dd, J 5.1 and 10.9 Hz), 2.59 (1H, dd, J 6.7 and 15.9 Hz),

2.54–2.50 (3H, m), 2.48–2.40 (3H, m), 2.33–2.28 (1H, m), 2.08–

2.06 (1H, m), 2.02 (3H, s, COMe), 1.96–1.92 (1H, m), 1.88–1.70

(6H, m), 1.63–1.54 (3H, m), 1.48–1.45 (2H, m), 1.34 (3H, d, J 7

Hz), 1.12 (9H, s, t-Bu), 1.10 (9H, s, t-Bu), 0.89 (3H, d, J 6.9 Hz),

0.88 (3H, d, J 6.8), 0.86 (3H, d, J 6.9 Hz); δ_C(125 MHz) 211.7

(s, 36-C), 210.6 (s, 7-C), 170.6 (s, 1-C), 170.1 (s, COMe), 162.4

(s, 22-C), 156.5 (s, 17-C), 146.6 (s, 10-C), 138.9 (d, 26-C), 137.3

(d, 24-C), 137.0 (d, 19-C), 136.1 (d, Ar), 135.9 (d, Ar), 135.6 (d,

Ar), 134.3 (s, Ar), 134.2 (s, Ar), 133.8 (s, Ar), 133.5 (d, 14-C),

131.9 (s, 15-C), 130.7 (s, 20-C), 129.7 (d, Ar), 129.6 (d, Ar),

C-9 ꢀ-and ꢁ- methyl epimers of the macrolide C-38 alcohol 81

Trimethylsilyl triﬂuoromethanesulfonate (2.3 µl, 0.015 mmol)

was added in one portion to a solution of the TBDMS-ether

80b (7 mg, 0.005 mmol) in dry dichloromethane (1.5 ml) at

Ϫ78 ЊC under nitrogen and the resulting solution was stirred at

Ϫ78 ЊC for 1 h. The mixture was quenched by addition into a

stirred solution of THF (1 ml) and saturated sodium bicarbon-

ate (1 ml) and then diluted with dichloromethane (20 ml). The

separated organic layer was dried (Na₂SO₄) and concentrated in

vacuo. The residue was puriﬁed by chromatography on silica gel

using a mixture of petrol and ethyl acetate as eluent to give the

alcohol (5.8 mg, 85%) as a colourless foam; δ_H(500 MHz) 8.13

(1H, s, Ox-H), 8.12 (1H, s, Ox-H), 7.8–7.7 (8H, m, ArH), 7.5–

7.4 (13H, m, ArH and Ox-H), 7.1–7.0 (1H, m, 26-H), 6.5 (1H,

d, J 16 Hz, 25-H), 5.3–5.2 (1H, m, 30-H), 4.35–4.3 (1H, m, 3-

H), 3.85–3.8 (1H, m, 41-H), 3.75–3.7 (1H, m, 41-H), 3.6–3.5

(1H, m, 39-H), 3.41 (3H, s, OMe), 3.5–3.4 (1H, m), 3.41

(1H, m), 3.35 (3H, s, OMe), 3.2 (1H, dd, J 8.6 and 16.3 Hz, 8-

H), 3.0 (1H, dd, J 4 and 14 Hz), 2.9–2.8 (1H, m), 2.7–2.65 (2H,

m), 2.65–2.6 (4H, m), 2.5 (1H, dd, J 7.6 and 15.5 Hz), 2.4 (1H,

dd, J 5.1 and 11.2 Hz), 2.3–2.2 (1H, m), 1.9–1.7 (7H, m), 1.6–1.55

(4H, m), 1.4 (3H, d, J 7.1 Hz), 1.1 (9H, s, t-Bu), 1.0 (9H, s,

t-Bu), 0.95 (3H, d, J 6.8 Hz), 0.9 (3H, d, J 6.8 Hz), 0.85 (3H, d,

J 6.8 Hz); δ_C(125 MHz) 215.8 (s, 36-C), 210.7 (s, 7-C), 170.4 (s,

1-C), 162.4 (s, 22-C), 156.50 (s, 17-C), 154.2 (s, 12-C), 146.6 (s,

10-C), 138.5 (d, 26-C), 137.4 (d, 24-C), 137.1 (d, 19-C), 136.0 (d,

Ar), 135.9 (d, Ar), 135.6 (d, Ar), 134.4 (d, 14-C), 134.1 (s, Ar),

134.0 (d, Ar), 133.4 (s, Ar), 131.9 (s, 15-C), 130.7 (s, 20-C), 129.7

(d, Ar), 129.6 (d, Ar), 129.5 (d, Ar), 127.7 (d, Ar), 127.6 (d, Ar),

127.5 (d, Ar), 117.4 (d, 25-C), 81.1 (d, 32-C), 80.2 (d, 28-C),

78.0 (d, 38-C), 72.8 (d, 30-C), 70.2 (d, 3-C), 61.9 (t, 41-C), 57.8

(q, OMe), 57.6 (q, OMe), 48.8 (d, 37-C), 47.8 (t, 8-C), 44.4 (t,

6-C), 41.2 (t, 2-C), 41.0 (t, 35-C), 39.7 (d, 33-C), 36.1 (t, 4-C),

34.2 (d, 29-C), 33.0 (t, 40-C), 32.7 (d, 39-C), 32.0 (t, 34-C), 31.7

(t, 31-C), 27.4 (d, 9-C), 27.2 (q, t-Bu), 26.9 (q, t-Bu), 26.4 (t,

34-C), 19.7 (q, 49-C), 19.6 (t, 5-C), 19.4 (s, t-Bu), 19.2 (s, t-Bu),

16.9 (47-C), 14.2 (q, 46-C), 13.7 (q, 45-C), 8.8 (q, 48-C). The

corresponding 9α-methyl diastereoisomer 80a was prepared

using an identical procedure and showed δ_H(500 MHz) 8.11

(2H, s, 2 × Ox-H), 7.79–7.73 (8H, m, ArH), 7.50–7.38 (13H,

12 × ArH and 1 × Ox-H), 7.18–7.12 (1H, m, 26-H), 6.42 (1H,

d, J 16 Hz), 5.19–5.16 (1H, m, 30-H), 4.36–4.34 (1H, m, 3-H),

3.83–3.81 (1H, m, 41-H), 3.74–3.69 (1H, m, 41-H), 3.63–3.61

(1H, m, 38-H), 3.47–3.44 (1H, m), 3.38 (3H, s, OMe), 3.33 (3H,

s, OMe), 3.29–3.26 (1H, m), 3.20 (1H, dd, J 7.8 and 16.6 Hz,

8-H), 3.00 (1H, dd, J 2.5 and 10 Hz), 2.85–2.79 (1H, m), 2.73–

2.67 (2H, m), 2.65–2.62 (2H, m), 2.60–2.57 (3H, m), 2.47–2.36

(2H, m), 2.12–2.07 (1H, m), 1.97–1.91 (3H, m), 1.87–1.77 (4H,

m), 1.71–1.66 (2H, m), 1.63–1.58 (2H, m), 1.54–1.45 (2H, m),

1.12 (9H, s, t-Bu), 1.09 (9H, s, t-Bu), 0.98 (3H, d, J 6.7 Hz), 0.95

(3H, d, J 6.9 Hz), 0.89 (3H, d, J 7 Hz), 0.87 (3H, d, J 6.8 Hz);

δ_C(125 MHz) 215.7 (s, 36-C), 210.6 (s, 7-C), 170.6 (s, 1-C), 162.5

(s, 22-C), 156.5 (s, 17-C), 154.2 (s, 12-C), 146.5 (s, 10-C), 138.9

(d, 26-C), 137.3 (d, 24-C), 137.0 (d, 19-C), 136.1 (d, Ar), 135.9

(d, Ar), 135.7 (d, Ar), 134.3 (s, Ar), 134.2 (s, Ar), 134.0 (s, Ar),

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

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127.7 (d, Ar), 127.6 (d, Ar), 117.3 (d, 25-C), 81.3 (d, 32-C), 80.6

(d, 28-C), 78.5 (d, 38-C), 72.7 (d, 30-C), 69.7 (d, 3-C), 61.5 (t,

41-C), 58.0 (q, OMe), 57.5 (q, OMe), 48.2 (d, 37-C), 47.6 (t, 8-

C), 44.1 (t, 6-C), 41.5 (t, 2-C), 40.0 (t, 35-C), 39.2 (d, 33-C), 36.3

(t, 4-C), 34.5 (d, 29-C), 33.2 (t, 27-C), 32.8 (t, 31-C), 31.5 (t, 40-

C), 30.5 (d, 39-C), 27.1 (d, 9-C), 27.1 (q, t-Bu), 26.9 (q, t-Bu),

26.4 (t, 34-C), 20.9 (q, COMe), 19.7 (s, t-Bu), 19.6 (s, t-Bu), 19.4

(t, 5-C), 19.3 (q, 49-C), 16.6 (q, 47-C), 13.7 (q, 46-C), 13.4 (q,

45-C), 8.7 (q, 48-C).

41.5 (t, 4-C), 40.1 (t, 35-C), 39.4 (d, 33-C), 36.3 (t, 4-C), 34.3 (d,

29-C), 33.5 (t, 27-C), 33.3 (t, 32-C), 31.6 (t, 40-C), 31.0

(d, 39-C), 27.2 (d, 9-C), 27.1 (q, t-Bu), 26.5 (t, 34-C), 21.0 (q,

COMe), 19.6 (s, t-Bu), 19.5 (q, 49-C), 19.4 (t, 5-C), 16.5 (q,

47-C), 14.2 (q, 46-C), 13.5 (q, 45-C), 8.7 (q, 48-C).

The macrolide C-41 aldehyde 84

Dess–Martin periodinane (3 mg, 0.0069 mmol) was added in

one portion to a solution of the alcohol 83 (5 mg, 0.005 mmol)

in dry dichloromethane (1 ml) at room temperature under

nitrogen and the resulting solution was stirred at room tem-

perature for 1 h. The mixture was diluted with ether (5 ml) and

then stirred with a mixture of saturated aqueous sodium

bicarbonate (2 ml) and saturated aqueous sodium thiosulfate

(2 ml) for 20 min. The separated organic phase was washed

with brine (2 ml), then dried (Na₂SO₄) and evaporated in

vacuo. The residue was puriﬁed by chromatography over silica

using ethyl acetate as eluent to give the aldehyde (4.5 mg, 90%)

as a colourless foam; δ_H(500 MHz) 9.85 (1H, t, J 1.2 Hz, 42-H),

8.15 (1H, s, Ox-H), 8.14 (1H, s, Ox-H), 7.82–7.74 (4H, m,

Ar-H), 7.49–7.41 (7H, m, ArH and Ox-H), 7.13–7.06 (1H, m,

26-H), 6.50 (1H, d, J 16.1 Hz), 5.26–5.23 (1H, m, 30-H), 5.16

(1H, dd, J 4.7 and 7.8 Hz, 38-H) 4.36–4.32 (1H, m, 3-H), 3.48–

3.43 (1H, m), 3.41 (3H, s, OMe), 3.37 (3H, s, OMe), 3.15 (1H,

dd, J 8.7 and 16.2 Hz, 8-H), 3.04–3.00 (1H, m), 2.89–2.85 (1H,

m), 2.75–2.67 (2H, m), 2.62–2.48 (8H, m), 2.41–2.33 (2H, m),

2.27–2.20 (1H, m), 2.06 (3H, s, OCOMe), 1.95–1.73 (4H, m),

1.63–1.48 (3H, m), 1.35 (3H, d, J 7 Hz), 1.16 (3H, d, J 7 Hz),

1.08 (9H, s, t-Bu), 1.05 (3H, d, J 6.9 Hz), 0.90 (3H, d, J 7 Hz),

0.87 (3H, d, J 6.8 Hz); δ_C(125 MHz) 210.9 (s, 36-C), 210.5 (s,

7-C), 201.3 (d, 42-C), 170.6 (s, 1-C), 170.0 (s, COMe), 162.9 (s,

22-C), 156.5 (s, 17-C), 154.2 (s, 12-C), 146.7 (s, 10-C), 138.4 (d,

26-C), 137.5 (d, 24-C), 137.1 (d, 19-C), 136.0 (d, Ar), 135.9 (d,

Ar), 134.5 (s, Ar), 134.1 (s, Ar), 133.3 (d, 14-C), 131.9 (s, 15-C),

130.8 (s, 20-C), 129.6 (d, Ar), 129.5 (d, Ar), 127.6 (d, Ar),

127.5 (d, Ar), 117.5 (d, 25-C), 81.1 (d, 32-C), 80.2 (d, 28-C),

77.6 (d, 38-C), 72.8 (d, 30-C), 70.2 (d, 3-C), 57.9 (q, OMe),

57.6 (q, OMe), 48.4 (d, 37-C), 47.9 (t, 8-C), 46.0 (t, 40-C), 44.4

(t, 6-C), 41.1 (t, 2-C), 39.9 (t, 35-C), 39.7 (d, 33-C), 36.2 (t, 4-

C), 34.4 (d, 29-C), 33.1 (t, 27-C), 31.8 (t, 31-C), 29.5 (d, 39-C),

27.4 (d, 9-C), 27.1 (q, t-Bu), 26.5 (t, 34-C), 20.9 (q, COMe),

19.8 (s, t-Bu), 19.7 (q, 49-C), 19.5 (t, 5-C), 16.5 (q, 47-C), 13.9

(q, 46-C), 13.3 (q, 45-C), 8.8 (q, 48-C); m/z (FAB) 1101

(M ϩ Na)^ϩ. The corresponding 9α-methyl diastereoisomer 84a

was prepared using an identical procedure and showed δ_H(500

MHz) 9.85 (1H, t, J 1.5 Hz), 8.12 (2H, s, Ox-H), 7.80–7.72 (4H,

m, Ar-H), 7.49–7.39 (7H, m, Ar-H and Ox-H), 7.18–7.12 (1H,

ddd, J 2.8, 6.8 and 16 Hz), 6.42 (1H, d, J 15.9 Hz), 5.21–5.15

(2H, m, 30-H and 39-H), 4.37–4.33 (1H, m, 3-H), 3.48–3.42

(1H, m), 3.38 (3H, s, OMe), 3.33 (3H, s, OMe), 3.31–3.28 (1H,

m), 3.20 (1H, dd, J 7.7 and 16.4 Hz, 8-H), 3.01–2.98 (1H, m),

2.89–2.84 (1H, m), 2.73–2.71 (1H, m), 2.66 (1H, dd, J 4.4 and

16 Hz), 2.61 (1H, dd, J 5.3 and 16 Hz), 2.57–2.55 (1H, m), 2.54–

2.51 (5H, m), 2.45 (1H, dd, J 5.8 and 16.6 Hz), 2.41 (1H, dd,

J 7.4 and 15.5 Hz), 2.38–2.36 (2H, m), 2.06 (3H, s, OCOCH₃),

1.94–1.93 (2H, m), 1.82–1.77 (4H, m), 1.73–1.68 (2H, m), 1.66-

1.58 (3H, m), 1.30 (3H, d, J 6.9 Hz), 1.15 (3H, d, J 7.2), 1.05

(3H, d, J 7 Hz), 0.89 (3H, d, J 7 Hz), 0.87 (3H, d, J 6.8 Hz), 1.10

(9H, s, t-Bu); δ_C(125 MHz) 210.9 (s, 36-C), 210.5 (s, 7-C), 201.2

(d, 41-C), 170.6 (s, 1-C), 170.0 (s, COMe), 162.4 (s, 22-C), 156.5

(s, 17-C), 154.3 (s, 12-C), 146.6 (s, 10-C), 138.9 (d, 26-C), 137.3

(d, 24-C), 137.0 (d, 19-C), 136.1 (d, Ar), 135.9 (d, Ar), 134.3

(s, Ar), 134.2 (s, Ar), 133.5 (d, 14-C), 131.9 (s, 15-C), 130.9 (s,

20-C), 129.6 (d, Ar), 127.6 (d, Ar), 125.6 (d, Ar), 117.3 (d,

25-C), 81.2 (d, 32-C), 80.5 (d, 28-C), 77.6 (d, 38-C), 72.8 (d,

30-C), 69.7 (d, 3-C), 57.9 (q, OMe), 57.5 (q, OMe), 48.5

(d, 37-C), 47.6 (t, 8-C), 45.9 (t, 40-C), 44.1 (t, 6-C), 41.5 (t, 2-C),

39.9 (t, 35-C), 39.3 (d, 32-C), 36.3 (t, 4-C), 34.5 (d, 29-C), 33.2

(t, 27-C), 32.1 (t, 31-C), 29.5 (d, 39-C), 27.2 (d, 9-C), 27.1 (q,

C-9 ꢀ- and ꢁ-Methyl epimers of the macrolide C-41 alcohol 83

PyridineؒHF (0.1 ml) was added to a solution of the silyl ether

82 (11 mg, 0.008 mmol) in dry THF (0.5 ml) and pyridine (0.5

ml) at room temperature under nitrogen and the resulting solu-

tion was stirred at room temperature for 1.5 h then diluted with

ethyl acetate (5 ml) and quenched with saturated aqueous

sodium bicarbonate (2 ml). The organic extract was washed

successively with water (2 × 10 ml), copper sulfate (2 × 5 ml)

and brine (5 ml), then dried (Na₂SO₄) and evaporated in vacuo.

The residue was puriﬁed by chromatography over silica gel

using ethyl acetate as eluent to give the alcohol (7.4 mg, 84%) as

a colourless foam; δ_H(500 MHz) 8.14 (1H, s, Ox-H), 8.13 (1H, s,

Ox-H), 7.81–7.74 (4H, m, Ar-H), 7.48–7.40 (7H, m, ArH and

Ox-H), 7.13–7.06 (1H, m, 26-H), 6.49 (1H, d, J 15.9 Hz, 25-H),

5.27–5.24 (1H, m, 30-H), 5.17 (1H, dd, J 3.9 and 8.6 Hz, 39-H),

4.37–4.33 (1H, m, 3-H), 3.83–3.81 (1H, m, 41-H), 3.69–3.67

(1H, m, 41-H), 3.46–3.43 (1H, m), 3.41 (3H, s, OMe), 3.36 (3H,

s, OMe), 3.16 (1H, dd, J 8.7 and 15.8 Hz, 8-H), 3.03–2.96 (2H,

m), 2.78–2.67 (4H, m), 2.62 (1H, dd, J 5 and 16 Hz), 2.54–2.47

(4H, m), 2.37 (1H, dd, J 5.1 and 16.4 Hz), 2.30–2.24 (1H, m),

2.05 (3H, s, COMe), 1.89–1.85 (3H, m), 2.03–2.00 (2H, m),

1.81–1.77 (4H, m), 1.13 (3H, d, J 7.2 Hz), 1.08 (9H, s, t-Bu),

0.99 (3H, d, J 6.1Hz), 0.91–0.87 (9H, 2 × d, J 7 Hz); δ_C(125

MHz) 211.7 (s, 36-C), 210.9 (s, 7-C), 170.7 (s, 1-C), 170.2 (s,

COMe), 162.4 (s, 22-C), 156.5 (s, 17-C), 154.2 (s, 12-C), 146.6 (s,

10-C), 138.4 (d, 26-C), 137.5 (d, 24-C), 137.1 (d, 19-C), 136.0 (d,

Ar), 135.9 (d, Ar), 134.5 (s, Ar), 133.4 (d, 14-C), 131.8 (s, 15-C),

130.0 (s, 20-C), 129.6 (d, Ar), 129.5 (d, Ar), 127.6 (d, Ar), 127.5

(d, Ar), 117.5 (d, 25-C), 80.8 (d, 32-C), 80.1 (d, 28-C), 78.3 (d,

38-C), 72.8 (d, 30-C), 70.2 (d, 3-C), 60.4 (t, 41-C), 57.8 (q,

OMe), 57.7 (q, OMe), 48.0 (d, 37-C), 47.9 (t, 8-C), 44.4 (t, 6-C),

41.1 (t, 2-C), 40.1 (t, 35-C), 39.4 (d, 33-C), 36.2 (t, 4-C), 34.2 (d,

29-C), 33.5 (t, 27-C), 33.0 (t, 40-C), 30.9 (d, 39-C), 29.8 (t,

31-C), 27.5 (d, 9-C), 27.1 (q, t-Bu), 26.5 (t, 34-C), 20.9 (q,

COMe), 19.8 (q, 49-C), 19.6 (s, t-Bu), 19.4 (t, 5-C), 16.5

(q, 47-C), 13.8 (q, 46-C), 13.5 (q, 45-C), 8.8 (q, 48-C). The

corresponding 9α-methyl diastereoisomer 83a was prepared

using an identical procedure and showed δ_H(500 MHz) 8.12

(2H, s, Ox-H), 7.80–7.75 (4H, m, Ar-H), 7.55–7.39 (7H, m, 6

Ar-H and 1 Ox-H), 7.15 (1H, ddd, J 2.9, 7 and 15.6 Hz), 6.42

(1H, d, J 15.8 Hz, 25-H), 5.20–5.16 (1H, m, 30-H), 4.38–4.34

(1H, m, 3-H), 3.86–3.81 (1H, m. 41-H), 3.71–3.67 (1H, m, 41-

H), 3.48–3.42 (1H, m), 3.38 (3H, s, OMe), 3.33 (3H, s, OMe),

3.31–3.28 (1H, m), 3.18 (1H, dd, J 7.7 and 16.4 Hz), 3.01–2.94

(2H, m), 2.73–2.70 (1H, m), 2.67 (1H, dd, J 5.4 and 16 Hz), 2.60

(1H, dd, J 6.6 and 16.1 Hz), 2.55–2.52 (3H, m), 2.46 (1H, dd,

J 6 and 16.5 Hz), 2.40–2.33 (2H, m), 2.06 (3H, s, OCOMe),

1.94–1.92 (1H, m), 1.83–1.74 (5H, m), 1.69–1.68 (1H, m), 1.64–

1.54 (4H, m), 1.48–1.42 (2H, m), 1.35 (3H, d, J 6.9 Hz, 49-Me),

1.13 (3H, d, J 7.1 Hz, Me), 1.10 (9H, s, t-Bu), 0.99 (3H, d, J 7.0

Hz, Me), 0.89 (3H, d, J 7 Hz, Me), 0.87 (3H, d, J 6.8 Hz, Me);

δ_C(125 MHz) 211.5 (s, 36-C), 210.6 (s, 7-C), 170.6 (s, 1-C), 170.2

(s, COMe), 162.4 (s, 22-C), 156.5 (s, 17-C), 154.3 (s, 12-C), 146.6

(s, 10-C), 138.9 (d, 26-C), 137.3 (d, 24-C), 137.0 (d, 19-C), 136.1

(d, Ar), 135.9 (d, Ar), 134.3 (s, Ar), 134.1 (s, Ar), 133.5 (d,

14-C), 131.9 (s, 15-C), 130.6 (s, 20-C), 129.6 (d, Ar), 127.6

(d, Ar), 117.3 (d, 25-C), 81.1 (d, 32-C), 80.5 (d, 28-C), 78.2 (d,

38-C), 72.8 (d, 30-C), 69.7 (d, 3-C), 60.5 (t, 41-C), 57.9 (q,

OMe), 57.5 (q, OMe), 48.0 (d, 37-C), 47.7 (t, 8-C), 44.1 (t, 6-C),

2452

J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

View Article Online

t-Bu), 26.5 (t, 34-C), 20.9 (q, COMe), 19.7 (s, t-Bu), 19.5 (q,

49-C), 19.3 (t, 5-C), 17.8 (q, Me, 47-C), 14.2 (q, Me, 46-C), 13.8

(q, 45-C), 8.7 (q, 48-C); m/z (FAB) 1101 (M ϩ Na)^ϩ.

dry pyridine (0.1 ml) at room temperature under nitrogen and

the resulting solution was stirred at room temperature for 24 h.

A further amount of pyridineؒHF (0.1 ml) was added and the

mixture was stirred for an additional 12 hours. The mixture was

diluted with dichloromethane (5 ml) and then quenched with

saturated aqueous sodium bicarbonate (1 ml). The separated

organic extract was dried and then concentrated in vacuo to leave

a residue which was puriﬁed by chromatography over silica

using ethyl acetate as eluent to give ulapualide A (0.6 mg, 80%)

as a colourless oil; [α]²¹Ϫ43.3 (c, 0.3 in MeOH); δ_H(500 MHz)

8.36 (1H, s, CHO), 8.13 (2H, s, Ox-H), 7.47 (1H, Ox-H), 7.06–

7.05 (1H, m, 26-H), 6.56 (7.22) (1H, d, J 13.4 Hz, 41-H), 6.48

(1H, d, J 16 Hz), 5.45–5.35 (1H, m, 30-H), 5.21–5.19 (1H, m,

38-H), 5.05 (1H, dd, J 9.6 and 13.6 Hz, 40-H), 4.35–4.30 (1H,

m, 3-H), 3.51–3.48 (1H, m), 3.45 (3H, s, OMe), 3.36 (3H, s,

OMe), 3.10 (3.15) (3H, s, NMe), 3.03–3.00 (1H, m), 2.86–2.82

(1H, m), 2.75–2.70 (2H, m), 2.60–2.59 (1H, m), 2.58–2.47 (6H,

m), 2.07 (3H, s, COMe), 1.94–1.87 (3H, m), 1.86–1.84 (4H, m),

1.58–1.55 (4H, m), 1.39 (3H, d, J 7 Hz, C-9Me), 1.13 (3H, d, J 7

Hz), 1.11 (3H, d, J 7 Hz), 0.97 (3H, d, J 7 Hz), 0.89 (3H, d, J 2

Hz); δ_C(125 MHz) 211.5 (s, 36-C), 210.4 (s, 7-C), 172.6 (s, 1-C),

170.1 (s, COMe), 162.7 (s, 22-C), 162.2 (161.0) (d, 43-C), 156.4

(s, 17-C), 154.3 (s, 12-C), 146.6 (s, 10-C), 139.6 (d, 26-C), 137.8

(d, 24-C), 137.4 (d, 19-C), 133.4 (d, 14-C), 131.9 (s, 15-C), 130.1

(125.2) (d, 41-C), 117.5 (d, 25-C), 110.5 (112.2) (d, 40-C), 81.0

(d, 32-C), 79.9 (d, 28-C), 77.6 (d, 38-C), 72.8 (d, 30-C), 68.7 (d,

3-C), 57.8 (q, OMe), 57.6 (q, OMe), 48.6 (d, 37-C), 44.0 (t, 6-C),

42.9 (t, 2-C), 40.3 (d, 33-C), 39.9 (t, 35-C), 37.3 (t, 39-C), 36.9

(37.0) (d, 39-C), 34.1 (d, 29-C), 33.1 (t, 27-C), 32.8 (27.3)

(44-C), 32.0 (t, 31-C), 27.7 (d, 9-C), 26.6 (t, 34-C), 20.9 (q,

COMe), 20.6 (t, 5-C), 19.2 (q, 45-C), 18.9 (q, 49-C), 14.2 (q,

47-C), 13.4 (13.6) (q, 46-C), 9.1 (q, 48-C). The corresponding

C-9 β-methyldiastereoisomer was prepared using an identical

procedure and showed δ_H(500 MHz) 8.36 (1H, s, CHO), 8.13

(2H, s, 2 × Ox-H), 7.48 (1H, s, Ox-H), 7.05–7.02 (1H, m, 26-H),

6.57 (7.23) (1H, d, J 14.1 Hz, 41-H), 6.52 (1H, d, J 16.2 Hz,

25-H), 5.43–5.38 (1H, m, 30-H), 5.21–4.19 (1H, m, 38-H), 5.05

(1H, dd, J 9 and 14.1 Hz, 40-H), 4.34–4.29 (1H, m, 3-H), 3.54–

3.48 (1H, m), 3.46 (3H, s, OMe), 3.38 (3H, s, OMe), 3.23–3.17

(1H, m), 3.11 (3.15) (3H, s, NMe), 2.87–2.84 (1H, m), 2.73–2.69

(1H, m), 2.63–2.46 (6H, m), 2.08 (3H, s, COMe), 1.95–1.86 (3H,

m), 1.85–1.81 (4H, m), 1.59–1.56 (4H, m), 1.37 (3H, d, J 7 Hz,

C-9-Me), 1.14 (3H, d, J 7 Hz), 1.11 (3H, d, J 6.9 Hz), 0.96 (3H,

d, J 6.8 Hz), 0.90 (0.92) (3H, d, J 6.9 Hz); δ_C(125 MHz) 211.5 (s,

36-C), 210.4 (s, 7-C), 172.7 (s, 1-C), 170.2 (s, COMe), 162.6 (s,

22-C), 162.2 (161.0) (d, 43-C), 156.4 (s, 17-C), 154.6 (s, 12-C),

146.5 (s, 10-C), 139.1 (d, 26-C), 137.8 (d, 24-C), 137.3 (d, 19-C),

133.5 (d, 14-C), 130.5 (s, 20-C), 129.6 (125.1) (d, 41-C), 117.6

(d, 25-C), 110.5 (112.1) (d, 40-C), 81.0 (d, 32-C), 79.9 (d, 28-C),

78.9 (d, 38-C), 72.7 (d, 30-C), 68.8 (d, 3-C), 57.8 (q, OMe), 57.6

(q, OMe), 48.7 (d, 37-C), 47.9 (t, 8-C), 44.0 (t, 6-C), 42.8 (t,

2-C), 40.6 (d, 33-C), 39.8 (t, 35-C), 37.0 (t, 4-C), 36.9 (d, 39-C),

34.0 (d, 29-C), 33.1 (t, 27-C), 32.0 (t, 31-C), 27.7 (d, 9-C), 26.3

(t, 34-C), 20.9 (q, COMe), 20.7 (t, 5C), 19.8 (q, 45-C), 18.9 (q,

49-C), 14.2 (q, 47-C), 13.4 (13.6) (q, 46-C), 9.1 (q, 48-C); m/z

903.4358. (M ϩ Na)^ϩrequires 903.4368.

The macrolide N-methyl-N-alkenylformamide 85

N-Methylformamide (0.4 µl, 0.007 mmol) was added to a solu-

tion of the aldehyde 84b (5 mg, 0.005 mmol) and pyridinium

toluene-p-sulfonate (0.29 mg, 0.001 mmol) in dry benzene (1.5

ml) and the mixture was heated under reﬂux for 3 h. An addi-

tional portion of N-methylformamide (1 drop) was added and

the reﬂuxing was continued for 6 h. The mixture was puriﬁed by

chromatography over silica using ethyl acetate–petrol (3:1) as

eluent to give a mixture of rotamers of the E-alkenylformamide

(2.25 mg, 40%) as a colourless foam; δ_H(500 MHz) 8.4 (1H, s,

CHO), 8.15 (8.14) (1H, s, Ox-H), 8.13 (8.12) (1H, s, Ox-H),

7.80–7.74 (m, 4H, ArH), 7.48–7.40 (m, 7H, 6 × ArH and

Ox-H), 7.13–7.06 (m, 1H, 26-H), 6.56 (7.22) (d, 1H, J 14 Hz,

41-H), 6.49 (6.48) (1H, d, J 16 Hz, 25-H), 5.26–5.22 (1H, m,

30-H), 5.20 (1H, dd, J 4 and 9 Hz, 38-H), 5.1 (5.0) (1H, dd, J 9.4

and 14 Hz, 40-H), 4.35–4.32 (1H, m, 3-H), 3.47–3.45 (1H, m),

3.42 (3H, s, OMe), 3.36 (3H, s, OMe), 3.10 (3.13) (3H, s, NMe),

3.04–3.00 (1H, m), 2.86–2.80 (1H, m), 2.76–2.72 (3H, m), 2.65–

2.59 (2H, m), 2.57–2.49 (2H, m), 2.41–2.36 (2H, m), 2.07 (2.06)

(3H, s, COMe), 1.90–1.76 (3H, m), 1.52–1.48 (4H, m), 1.35 (3H,

d, J 7 Hz, 49-C), 1.13 (1.12) (3H, d, J 7.1 Hz), 1.10 (3H, d, J 7.2

Hz), 1.08 (s, 9H, t-Bu), 0.90 (0.89) (3H, d, J 7 Hz), 0.87 (0.86)

(3H, d, J 7 Hz); δ_C(125 MHz) 211.3 (s, 36-C), 210.5 (s, 7-C),

170.1 (s, 1-C), 170.0 (s, COMe), 162.4 (162.2) (d, CHO), 161.0

(s, 22-C), 156.5 (s, 17-C), 154.2 (s, 12-C), 146.7 (s, 10-C), 138.5

(d, 26-C), 137.5 (d, 24-C), 137.1 (d, 19-C), 136.0 (d, Ar), 135.9

(d, Ar), 134.4 (s, Ar), 134.1 (s, Ar), 133.4 (d, 14-C), 130.0 (s,

15-C), 130.8 (s, 20-C), 129.6 (d, Ar), 129.5 (d, Ar), 127.6 (d, Ar),

127.5 (d, Ar), 117.5 (d, 25-C), 110.6 (112.2) (d, 40-C), 72.8 (d,

30-C), 70.2 (d, 3-C), 57.9 (q, OMe), 57.6 (q, OMe), 48.6 (48.4)

(d, 37-C), 47.8 (t, 8-C), 44.4 (t, 6-C), 41.1 (t, 2-C), 39.9 (t, 35-C),

39.7 (d, 32-C), 36.9 (d, 39-C), 36.2 (t, 4-C), 34.5 (d, 29-C), 33.1

(t, 27-C), 31.9 (t, 31-C), 27.6 (d, 9-C), 27.1 (q, t-Bu), 26.3 (t, 34-

C), 20.9 (q, COMe), 20.7 (t, 5-C), 19.8 (s, t-Bu), 19.6 (19.7) (q,

45-C), 19.5 (q, 49-C), 13.9 (q, 47-C), 13.5 (13.4) (q, 46-C), 8.8

(q, 48-C). The corresponding 9α-methyl diastereoisomer 85a

was prepared using an identical procedure and showed δ_H(500

MHz) 8.35 (1H, s, CHO), 8.14 (2H, s, Ox-H), 7.79–7.71 (4H, m,

ArH), 7.51–7.36 (7H, m, 6 × ArH and Ox-H), 7.14–7.12 (1H,

m, 26-H), 6.55 (7.23) (1H, d, J 13.9 Hz, 41-H), 6.42 (1H, d,

J 15.5 Hz, 25-H), 5.41–5.29 (1H, m), 5.24–5.19 (1H, m, 38-H),

5.06–5.00 (1H, m, 40-H), 4.38–4.26 (1H, m, 3-H), 3.48–3.46

(1H, m), 3.38 (3H, m, OMe), 3.33 (3H, s, OMe), 3.10 (3.14)

(3H, s, NMe), 3.00–2.99 (1H, m), 2.86–2.83 (1H, m), 2.73–2.70

(2H, m), 2.65–2.60 (2H, m), 2.57–2.48 (2H, m), 2.46–2.39 (2H,

m), 2.07 (2.06) (3H, s, COCH₃), 1.89–1.76 (3H, m), 1.53–1.47

(4H, m), 1.36 (3H, d, J 7Hz, 49-C), 1.12 (3H, d, J 7Hz), 1.09

(9H, s, t-Bu), 0.97–0.87 (9H, m, 3 × Me); δ_C(125 MHz) 211.5 (s,

36-C), 210.4 (s, 7-C), 172.7 (s, 1-C), 170.5 (s, COMe), 162.6 (s,

22-C), 162.2 (161.0) (d, CHO), 156.4 (s, 17-C), 154.3 (s, 12-C),

146.5 (s, 10-C), 138.9 (d, 26-C), 137.4 (d, 24-C), 137.0 (d, 19-C),

136.0 (d, Ar), 135.9 (d, Ar), 134.1 (s, Ar), 133.5 (d, 14-C), 130.7

(s, 20-C), 130.02 (124.4) (d, 41-C), 129.6 (d, Ar), 127.6 (d, Ar),

117.3 (d, 25-C), 110.6 (d, 40-C), 81.3 (d, 32-C), 80.5 (d, 28-C),

77.3 (d, 38-C), 72.8 (d, 30-C), 69.7 (d, 3-C), 58.0 (q, OMe), 57.5

(q, OMe), 48.6 (d, 37-C), 47.6 (t, 8-C), 44.1 (t, 6-C), 41.5 (t,

2-C), 39.9 (t, 35-C), 39.8 (d, 33-C), 36.9 (37.0) (d, 39-C), 34.02

(d, 29-C), 33.1 (t, 27-C), 32.2 (t, 31-C), 27.6 (q, NMe), 27.5 (d,

9-C), 27.1 (q, t-Bu), 20.9 (q, COMe), 20.7 (t, 5-C), 19.8 (18.9)

(q, 45-C), 14.2 (q, 47-C), 13.7 (13.4) (46-C), 9.1 (q, 48-C); m/z

(FAB) 1142 (M ϩ Na)^ϩ.

Acknowledgements

We thank the EPSRC for a Research Fellowship (to S. K. C.),

and Milton Kiefel, John Maddock, Michael Reader and David

Waite for their contributions to the early part of these synthetic

studies. We also thank Professor P. J. Sheuer for a sample of

naturally derived ulapualide A.

References

Ulapualide A with relative stereochemistry shown in structure 1

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J. Chem. Soc., Perkin Trans. 1, 2000, 2429–2454

Article Doi

A total synthesis of the unique tris-oxazole macrolide ulapualide a produced by the marine nudibranch Hexabranchus sanguineus

DOI: 10.1039/b000751j

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