Total synthesis of milbemycin E: Synthesis of the C(11)-C(25) fragment

Article abstract of DOI:10.1039/a605892b

Treatment of 2-methylpropanal with the (E)-but-2-enyl(diisopinocampheyl)borane 9 prepared from (+)-α-pinene gives the anti- and syn-products 10 and 11, ratio 88:12, from which the major anti-isomer 10 is separated by preparative GLC. Hydroboration-oxidation of its tert-butyldimethylsilyl ether 14 gives the primary alcohol 15 which has been converted into the bromide 16 and iodide 17. The propenyl(diisopinocampheyl)borane 23 prepared from (-)-α-pinene reacts with the aldehyde 22 prepared from (S)-malic acid to give the anti- and syn-1,3-diol derivatives 24 and 25, ratio 86:14, and the anti-product 24 has been taken through to the epoxide 31. Sequential alkylation of 1,3-dithiane with the iodide 17 and the epoxide 31 gives the 2,2-dialkyl-1,3-dithiane 33 which is converted into the spiroacetal 4 by treatment with dilute aqueous hydrogen fluoride. After protection, ozonolysis gives the aldehyde 43 which has been condensed with the ylide 34 to give the α,β-unsaturated ester 44. This has been reduced and converted into the iodide 46 which has been used to alkylate the chiral oxazolidinone 39 to give the required C(11)-C(25) fragment 48 of milbemycin E 1 after reductive removal of the chiral auxiliary. This has been converted into the phosphonium salt 2 ready for Wittig coupling with the hydroxybutenolide 3 for the assembly of the milbemycin nucleus.

Full text of DOI:10.1039/a605892b

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Total synthesis of milbemycin E: synthesis of the C(11)–C(25)
fragment
Patrick G. Steel and Eric J. Thomas*,†
The Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, UK
Treatment of 2-methylpropanal with the (E)-but-2-enyl(diisopinocampheyl)borane 9 prepared from
(+)-á-pinene gives the anti- and syn-products 10 and 11, ratio 88 :12, from which the major anti-isomer 10 is
separated by preparative G LC. H ydroboration–oxidation of its tert-butyldimethylsilyl ether 14 gives the
primary alcohol 15 which has been converted into the bromide 16 and iodide 17. The propenyl(diisopino-
campheyl)borane 23 prepared from (Ϫ)-á-pinene reacts with the aldehyde 22 prepared from (S)-malic acid
to give the anti- and syn-1,3-diol derivatives 24 and 25, ratio 86 :14, and the anti-product 24 has been taken
through to the epoxide 31. Sequential alkylation of 1,3-dithiane with the iodide 17 and the epoxide 31
gives the 2,2-dialkyl-1,3-dithiane 33 which is converted into the spiroacetal 4 by treatment with dilute
aqueous hydrogen fluoride. After protection, ozonolysis gives the aldehyde 43 which has been condensed
with the ylide 34 to give the á,â-unsaturated ester 44. This has been reduced and converted into the iodide
46 which has been used to alkylate the chiral oxazolidinone 39 to give the required C(11)–C(25) fragment
48 of milbemycin E 1 after reductive removal of the chiral auxiliary. This has been converted into the
phosphonium salt 2 ready for Wittig coupling with the hydroxybutenolide 3 for the assembly of the
milbemycin nucleus.
The milbemycins and avermectins are an important group of
macrolides with potent and useful biological activities.1 We are
developing a convergent approach to these compounds based
on the use of a Wittig reaction between a phosphorane corre-
sponding to the C(11)–C(25) fragment and an aldehyde corre-
sponding to the C(1)–C(10) fragment as the key convergent
step.2 As applied to a synthesis of milbemycin E 1, this would
involve the Wittig reaction between the spiroacetal-containing
phosphonium salt 2 and the hydroxybutenolide 3.3 We previ-
ously described a synthesis of milbemycin spiroacetals from
methyl α--glucopyranoside.4 We now report an alternative
synthesis of these spiroacetals using chiral allylboranes and
aldehydes to prepare homoallylic alcohols as developed by
H. C. Brown,5 and the completion of a synthesis of the phos-
phonium salt 2.6 The accompanying papers describe a syn-
thesis of the hydroxybutenolide 3 and the completion of a
synthesis of milbemycin E 1.
separated by preparative GLC, and shown to correspond to an
enantiomeric excess of >80% by treatment with Mosher’s (S)-
acid chloride9 which gave the two diastereoisomers 12 and 13
which could be distinguished by 1H NMR spectroscopy.
Protection of the anti-alcohol 10 using tert-butyldimethylsilyl
trifluoromethanesulfonate10 gave the silyl ether 14 which was
hydroborated using borane–tetrahydrofuran to give the pri-
mary alcohol 15 after oxidation. The alcohol was converted
into the bromide 16 and iodide 17 using carbon tetrabromide11
and triphenylphosphine, and iodine, imidazole and triphenyl-
phosphine, in good yield.12
Dimethyl (S)-malate 18 was reduced to methyl (S)-3,4-
dihydroxybutanoate 19 following the literature procedure,13
and the diol protected as its acetonide 20 (Scheme 2). Further
reduction gave the alcohol 21 which was oxidized to the alde-
hyde 22. Reactions of this aldehyde with achiral Grignard
reagents were not stereoselective and so it was necessary to
use a chiral reagent to control the stereoselectivity of add-
ition to the aldehyde group. This was achieved using the
The present approach to spiroacetals is based on the alkyl-
ation of 1,3-dithiane with an alkyl halide 7 and an epoxide 6
to give the protected triol 5.7 The use of other acyl carbanion
equivalents was briefly investigated but was not successful.
Deprotection of the dialkylated dithiane 5 gave the spiroacetal
4 which was taken through to the phosphonium salt 2.
prop-2-enyl(diisopinocampheyl)borane 23 prepared
as
described by Brown from (Ϫ)-α-pinene.14 Reaction of the
borane 23 with the aldehyde 22 gave, after oxidative removal
of the auxiliary, a mixture of the 1,3-anti- and 1,3-syn-
products 24 and 25, ratio 86:14, whose spectroscopic and
optical rotation data agreed with those reported in the liter-
ature.15 This mixture of alcohols was not separated on a pre-
parative scale, rather the mixture was protected using (2-
trimethylsilylethoxy)methyl chloride (SEM chloride) to give
the (2-trimethylsilylethoxy)methyl ether 26 containing ca.
10% of its syn-diastereoisomer.16 Ozonolysis gave the alde-
hyde 27, but attempts to generate a Grignard reagent from
the bromide 16 and add it to the aldehyde 27 were not suc-
cessful, in that complex mixtures of products were obtained.
As an alternative procedure for the coupling of the aldehyde
27 and alkyl halides 16 or 17, the aldehyde was converted
into its trimethylsilylated cyanohydrin 28. However, attempts
to deprotonate this cyanohydrin and alkylate it using either
the bromide 16 or iodide 17 were not successful.
Results and discussion
Methoxy(diisopinocampheyl)borane 8 was prepared by hydro-
boration of (+)-α-pinene, equilibration with an excess of (+)-α-
pinene to optimize its optical purity, followed by methanolysis
of the diisopinocampheylborane so obtained.8 Treatment of
the methoxyborane 8 with the organometallic reagent gener-
ated by treatment of (E)-but-2-ene with butyllithium and
potassium tert-butoxide gave (E)-but-2-enyl(diisopinocam-
pheyl)borane 9 which was reacted in situ with 2-methylpropanal
followed by oxidative cleavage of the chiral auxiliary to give
anti- and syn-2,4-dimethylhex-5-en-3-ol 10 and 11, yield 80%,
ratio 88:12 (Scheme 1).5 The major diastereoisomer 10 was
At this point it was decided to develop the chemistry of the
acetal-containing end of the (2-trimethylsilylethoxy)methyl
ether 26. Selective hydrolysis of the acetonide gave the diol 29
† Present address: Department of Chemistry, University of Manches-
ter, Manchester M13 9PL, UK.
J. Chem. Soc., Perkin Trans. 1, 1997
371

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Scheme 1 Reagents: i, (E)-but-2-ene, butyllithium, potassium tert-
butoxide, then boron trifluoride–diethyl ether; ii, 2-methylpropanal,
then sodium hydroxide, hydrogen peroxide (80%; 10:11 = 88:12); iii,
(S)-2-methoxy-2-trifluoromethyl-2-phenylacetyl chloride, pyridine
(67%); iv, tert-butyldimethylsilyl trifluoromethanesulfonate, 2,6-lutidine
(95%); v, borane in tetrahydrofuran, then sodium hydroxide, hydrogen
peroxide (85%); vi, triphenylphosphine, carbon tetrabromide (83%); vii,
triphenylphosphine, imidazole, iodine 99%)
prepared earlier from methyl α--glucopyranoside,4 although,
in our hands, the convergent synthesis reported here is more
amenable to scale-up than that reported earlier from the glu-
cose derivative, and has since been applied to synthesise more
complex spiroacetals and the intact C(11)–C(25) fragments of
avermectins.18
It remained to develop the chemistry of the spiroacetal side-
chain to complete a synthesis of the required phosphonium salt
2. The sequence devised by Baker in his synthesis of milbe-
mycin β3, which uses the stereoselective alkylation of a chiral
oxazolidinone to introduce the remaining chiral centre, was
selected as the most appropriate at this stage.19 To get a feel for
the reactions involved, the aldehyde 27 was condensed with the
stabilized phosphorane 34 to give the (E)-alkene 35 which was
reduced using diisobutylaluminium hydride to the alcohol 36
(Scheme 4). This was converted into the bromide 37 and iodide
38, and the latter was found to react effectively with the lithium
enolate of oxazolidinone 3920 to give the alkylated oxazolidi-
none 40. This appeared to be a single diastereoisomer, its
structure being assigned by analogy with the stereoselectivity
expected for alkylation of the (Z)-enolate of the oxazol-
idinone 39. Reduction using lithium aluminium hydride then
which was converted into the toluene-p-sulfonate 30. Treatment
with potassium carbonate in methanol then gave the epoxide 31
which was also obtained directly from the diol 29 using diethyl
diazodicarboxylate and triphenylphosphine in anhydrous N,N-
dimethylformamide.17 The next phase of the work involved
alkylation of 1,3-dithiane with the alkyl iodide 16 and then with
the epoxide 31.
Alkylation of 1,3-dithiane using the iodide 17 was achieved
using butyllithium as base to give the 2-alkyldithiane 32 in a
yield of 87% (Scheme 3). For the second alkylation using
epoxide 31, tert-butyllithium was found to be a suitable base,
and the 2,2-dialkyldithiane 33 was isolated in an excellent yield
(97%). It was intended at this stage to deprotect the hydroxy
groups of the intermediate 33, and then to investigate
hydrolysis of the dithiane and spiroacetal formation. However,
it was found that all these transformations can be accomplished
in a single step, since treatment of 33 with dilute aqueous
hydrogen fluoride in acetonitrile gave the spiroacetal 4 directly
(87%). This spiroacetal was identified on the basis of spectro-
scopic data, and was identical with a sample which had been
1
gave the alcohol 41 which, by H and 13C NMR spectroscopy,
appeared to be essentially a single diastereoisomer.
This sequence was used to convert the spiroacetal 4 into the
phosphonium salt 2 (Scheme 5). The spiroacetal was protected
as its tert-butyldimethylsilyl ether 42 which was converted into
the aldehyde 43 by ozonolysis followed by a reductive work-up.
Wittig condensation with the phosphorane 34 gave the α,β-
unsaturated ester 44 which was reduced to the alcohol 45 using
diisobutylaluminium hydride. This alcohol was converted into
the iodide 46 as before, and the iodide used to alkylate the
enolate of the chiral oxazolidinone 39.20 The product from this
reaction appeared by NMR spectroscopy to be essentially a
single diastereoisomer, and was assigned the structure 47 by
372
J. Chem. Soc., Perkin Trans. 1, 1997

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Scheme 3 Reagents: i, 1,3-dithiane, butyllithium (87%); ii, tert-butyl-
lithium, 31 (97%); iii, hydrogen fluoride, aqueous acetonitrile (87%)
Scheme 2 Reagents: i, sodium borohydride, borane–dimethyl sulfide
complex; ii, dimethoxypropane, toluene-p-sulfonic acid; iii, lithium
aluminium hydride (94%); iv, oxalyl chloride, dimethyl sulfoxide (96%);
v, 23, then hydrogen peroxide, sodium hydroxide (24, 61%; 25, 11%); vi,
(2-trimethylsilylethoxy)methyl chloride, N,N-diisopropylethylamine
(100%); vii, ozone, methanol, Ϫ78 ЊC, then dimethyl sulfide (82%); viii,
sodium metabisulfite, sodium cyanide, then trimethylsilyl chloride, tri-
ethylamine (64%); ix, aqueous hydrogen chloride (84%); x, toluene-p-
sulfonyl chloride, triethylamine, 4-dimethylaminopyridine (64%); xi,
diethyl azodicarboxylate, triphenylphosphine, N,N-dimethylformamide
(77% from 29); xii, anhydrous potassium carbonate, methanol (92%
from 30)
Scheme 4 Reagents: i, ozone, dimethyl sulfide, then 34 (90%); ii,
diisobutylaluminium hydride (99%); iii, triphenylphosphine, carbon
tetrabromide (79%); iv, iodine, triphenylphosphine, imidazole; v, lith-
ium enolate of 39 (70% from 36); vi, lithium aluminium hydride (67%)
analogy with the literature. Reduction gave the alcohol 48
which was converted into the phosphonium salt 2 by way of the
iodide 49.
The structures of the later intermediates in this synthesis
were assigned by analogy with the literature and were consistent
with their spectroscopic data. The incorporation of the phos-
phonium salt 2 into a synthesis of milbemycin E 1, which was
found to be identical with the natural product, confirmed the
stereochemical assignments.3
This work provides a convergent synthesis of the spiroacetal
4 and procedures for the conversion of this spiroacetal into the
phosphonium salt 2 corresponding to the C(11)–C(25) frag-
ment of milbemycin E 1. The accompanying papers describe a
synthesis of the C(1)–C(10) fragment of non-aromatic β-mil-
bemycins and a total synthesis of milbemycin E 1.
Experimental
For general experimental details see the first paper in this ser-
ies.2 Dimethyl (S)-malate 18 (30 g, 0.181 mol) was reduced using
borane–dimethyl sulfide and sodium borohydride as reported in
the literature13 and the crude product converted into methyl
(S)-3,4-isopropylidenedioxybutanoate 20 (25.5 g, 79%), bp 54–
56 ЊC/0.5 mmHg, using 2,2-dimethoxypropane and toluene-p-
sulfonic acid. Reduction using lithium aluminium hydride gave
(S)-3,4-isopropylidenedioxybutanol 21 (17.3 g, 94%), bp 101–
102 ЊC/15 mmHg (lit.,21 55–56 ЊC/0.05 mmHg); [α]D Ϫ1.07 (c
J. Chem. Soc., Perkin Trans. 1, 1997
373

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for 10 min. The solution was cooled to Ϫ78 ЊC and methoxy-
(diisopinocampheyl)borane 8 in ether [1 ; 0.15 mol; from (+)-
α-pinene] was added dropwise. After stirring the mixture for 30
min at Ϫ78 ЊC, boron trifluoride–diethyl ether (20 cm3, 0.167
mol) was added dropwise followed by a solution of 2-methyl-
propanal (16.1 cm3, 0.175 mol) in ether (50 cm3). The mixture
was stirred at Ϫ78 ЊC for 3 h, aqueous sodium hydroxide (3 ;
91.2 cm3, 0.275 mol) and aqueous hydrogen peroxide (30%; 37.5
cm3) were added and the reaction was heated under reflux for 1
h. After cooling, the aqueous layer was separated and extracted
with ether (150 cm3) and the combined organic layers washed
with water (150 cm3) and brine (150 cm3), dried (MgSO4) and
concentrated under reduced pressure. The residue was distilled
and the fraction boiling from 50–75 ЊC/25 mmHg was collected.
Chromatography, using light petroleum–ethyl acetate 15:1 as
eluent, gave the anti- and syn-alcohols 10 and 11 (12 g, 80%),
ratio 88:12, as a mixture of diastereoisomers. Preparative GLC
using a 15% polyethylene glycol adipate (PEGA) on Chromo-
sorb A (60–85 mesh) column, 15 ft × 0.375 in, 110 ЊC, afforded
the title compound 10 (60–70%), [α]D Ϫ17.96 (c 1.7, CHCl3)
(Found: M+ + NH4, 146.1546. C8H20NO requires M, 146.1545);
νmax/cmϪ1 3700–3100, 3070, 1639, 1460, 1384, 1368, 1085, 995
and 912; δH 5.79 (1 H, m, 5-H), 5.12 (2 H, m, 6-H2), 3.10 (1 H,
ddd, J 5, 5.5, 4.5, 3-H), 2.34 (1 H, m, 4-H), 1.76 (1 H, m, 2-H),
1.47 (1 H, d, J 4.5, OH), 1.01 (3 H, d, J 6.6, 4-CH3) and 0.97 and
0.93 (each 3 H, d, J 6.8, CH3); δC 140.5 (d), 115.8 (t), 79.5 (d),
41.4 (d), 30.5 (d), 19.8 (q), 17.0 (q) and 16.4 (q); m/z (CI) 146
(M+ + NH4, 100%), 128 (M+, 18) and 111 (41). In addition, a
small amount of (3R,4R)-2,4-dimethylhex-5-en-3-ol 11 (10%)
was obtained, [α]D Ϫ6.72 (c 1.4, CHCl3); νmax/cmϪ1 3700–3120,
3070, 1644, 1460, 1383, 1368, 998, 981, 967 and 912; δH 5.80 (1
H, m, 5-H), 5.12 (2 H, m, 6-H2), 3.19 (1 H, m, 3-H), 2.40 (1 H,
m, 4-H), 1.76 (1 H, m, 2-H), 1.40 (1 H, br s, OH), 1.03 (3 H, d, J
6.5, 4-CH3), 0.96 and 0.94 (each 3 H, d, J 6, CH3); δC 142.2 (d),
114.6 (t), 79.5 (d), 40.6 (d), 30.4 (d), 19.5 (q), 16.8 (q) and 13.6
(q); m/z (CI) 146 (M+ + NH4, 100%), 128 (M+, 35) and 111 (45).
(S)-(Ϫ)-2-Methoxy-2-trifluoromethyl-2-phenylacetyl chlor-
ide (51 µl, 0.3 mmol) was added to a solution of the alcohol 10
(35 mg, 0.27 mmol) in carbon tetrachloride–pyridine (20 drops
of a 1:1 mixture). The mixture was stirred at room temperature
for 12 h and water (1 cm3) was added. The mixture was diluted
with ether (20 cm3), washed with aqueous hydrogen chloride
(0.1 ; 5 cm3), saturated aqueous sodium hydrogen carbonate (5
cm3), water (5 cm3) and brine (5 cm3), dried (MgSO4) and con-
centrated under reduced pressure. Chromatography of the resi-
due afforded the ester 12 (63 mg, 67%); νmax/cmϪ1 3080, 1750,
1640, 1450, 1260, 1170, 1120, 1080, 1015, 995 and 720; δH 7.59
(2 H, m, ArH), 7.41 (3 H, m, ArH), 5.65 (1 H, m, 5-H), 5.01–
4.89 (3 H, m, 3-H and 6-H2), 3.53 (3 H, s, OCH3), 2.53 (1 H, m,
4-H), 1.97 (1 H, m, 2-H), 0.97 (3 H, d, J 7, CH3) and 0.92 and
0.88 (each 3 H, d, J 6.7, CH3); m/z (CI) 362 (M+ + NH4, 67%),
189 (88) and 128 (36).
Scheme
5
Reagents: i, tert-butyldimethylsilyl chloride, imidazole
(3S,4R)-4-tert-Butyldimethylsilyloxy-3,5-dimethylhex-1-ene 14
tert-Butyldimethylsilyl trifluoromethanesulfonate (36.6 cm3,
158 mmol) was added dropwise to a solution of the alcohol 10
(13.5 g, 105 mmol) and 2,6-lutidine (2,6-dimethylpyridine) (39.4
cm3, 264 mmol) in dichloromethane (40 cm3) at 0 ЊC. The mix-
ture was stirred at room temperature for 2 h before being
diluted with ether (80 cm3) and washed with aqueous hydrogen
chloride (30 cm3), water (30 cm3) and brine (30 cm3). After
drying (MgSO4) the mixture was concentrated under reduced
pressure. Distillation of the residue gave the title compound 14
(24.1 g, 95%), bp 103–105 ЊC/20 mmHg, [α]D 0 (c 0.95, CHCl3)
(Found: M+ + H, 243.2154. C14H31OSi requires M, 243.2144);
νmax/cmϪ1 3070, 1640, 1460, 1385, 1360, 1255, 1095, 1050, 1000,
910, 860, 835 and 770; δH 5.91 (1 H, m, 2-H), 4.97 (2 H, m,
1-H2), 3.28 (1 H, dd, J 4.0, 6.5, 4-H), 2.37 (1 H, m, 3-H),
1.75 (1 H, m, 5-H), 1.01 (3 H, d, J 7, CH3), 0.92 [9 H, s,
SiC(CH3)3], 0.88 and 0.87 (each 3 H, d, J 7, CH3) and 0.03 [6
(91%); ii, ozone, dimethyl sulfide; iii, 34 (69% from 42); iv, diisobutyl-
aluminium hydride (99%); v, iodine, triphenylphosphine, imidazole; vi,
lithium enolate of 39 (87% from 45); vii, lithium aluminium hydride
(99%); viii, iodine, triphenylphosphine, imidazole (89%); ix, triphenyl-
phosphine, acetonitrile (84%)
2.54, MeOH) [lit.,21 Ϫ1.29 (c 4.6, MeOH)]. Oxidation using
oxalyl chloride and dimethyl sulfoxide gave the aldehyde 2213
(16.4 g, 96%) which was used directly in the reaction with the
propenylborane 23.
(3R,4S)-2,4-Dimethylhex-5-en-3-ol 10
Butyllithium in tetrahydrofuran (2 ; 62.5 cm3, 0.125 mol) was
added to a stirred solution of potassium tert-butoxide (14.0 g,
0.125 mol) and (E)-but-2-ene (22.5 cm3, 0.25 mol) in tetra-
hydrofuran (35 cm3) at Ϫ78 ЊC and the mixture stirred at Ϫ45 ЊC
374
J. Chem. Soc., Perkin Trans. 1, 1997

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H, s, Si(CH3)2]; m/z (CI) 243 (M+ + H, 18%), 187 (30), 128
(27) and 111 (100).
(3S)-3,4-Isopropylidenedioxybutanal 22
A solution of dimethyl sulfoxide (20.4 cm3, 238 mmol) in
dichloromethane (45 cm3) was added dropwise to a cooled solu-
tion of oxalyl chloride (15.5 cm3, 178 mmol) in dichlorometh-
ane (225 cm3) at Ϫ78 ЊC. After 5 min, a solution of the alcohol
21 (17.3 g, 119 mmol) in dichloromethane (120 cm3) was added
dropwise followed, after 15 min, by triethylamine (83 cm3, 595
mmol) and the resultant mixture was stirred at Ϫ78 ЊC for 15
min, before being allowed to warm to room temperature. After
stirring at this temperature for 20 min the mixture was par-
titioned between benzene, ether and water (4:1:1; 600 cm3).
The aqueous layer was extracted with ether (100 cm3) and the
organic fractions washed with brine (50 cm3), dried (MgSO4–
K2CO3) and concentrated under reduced pressure to afford the
title compound 22 (16.4 g, 96%) which was used without further
purification; δH 9.80 (1 H, t, J 2, 1-H), 4.54 (1 H, quintet, J 6,
3-H), 4.20 (1 H, dd, J 6, 7, 4-H), 3.59 (1 H, dd, J 6, 7, 4-HЈ), 2.76
(2 H, m, 2-H2) and 1.43 and 1.39 (each 3 H, s, CH3).
(3S,4R)-4-tert-Butyldimethylsilyloxy-3,5-dimethylhexanol 15
Borane in tetrahydrofuran (1.0 ; 108 cm3, 108 mmol) was
added dropwise to a stirred solution of the alkene 14 (23.7 g, 98
mmol) in tetrahydrofuran (50 cm3) at 0 ЊC and the mixture
stirred at room temperature until all the alkene had been con-
sumed (TLC). The mixture was cooled to 0 ЊC and aqueous
sodium hydroxide (3 ; 36 cm3, 108 mmol) and aqueous hydro-
gen peroxide (30%; 48 cm3, 360 mmol) were added dropwise
such that the reaction temperature did not exceed 35 ЊC. On
completion of the addition the reaction was heated under reflux
for 1 h, cooled to room temperature and the aqueous layer
extracted with ether (2 × 50 cm3). The organic extracts were
washed with brine (50 cm3), dried (MgSO4) and concentrated
under reduced pressure. Distillation of the residue gave the title
compound 15 (22 g, 85%), bp 95–96 ЊC/0.65 mmHg, [α]D 0 (c
1.13, CHCl3) (Found: M+ + H, 261.2241. C14H33O2Si requires
M, 261.2250); νmax/cmϪ1 3600–3100, 1460, 1265, 1095, 1051,
1005, 835 and 770; δH 3.72 and 3.63 (each 1 H, m, 1-H), 3.25 (1
H, dd, J 4, 6, 4-H), 2.0 (1 H, br s, OH), 1.76 (3 H, m, 2-H2 and
3-H), 1.53 (1 H, m, 5-H), 0.96 (3 H, d, J 7, CH3), 0.93 [9 H, s,
SiC(CH3)3], 0.91 and 0.87 (each 3 H, d, J 7, CH3) and 0.08 [6 H,
s, Si(CH3)2]; m/z (CI) 261 (M+ + H, 100%).
(4R,6S)-4-Hydroxy-6,7-isopropylidenedioxyhept-1-ene 24
Prop-2-enylmagnesium bromide (1.52  in ether; 85.5 cm3, 130
mmol) was added dropwise to a solution of methoxydiisopino-
campheylborane [1  in ether; 150 mmol; from (S)-(Ϫ)-α-
pinene] at Ϫ78 ЊC. The reaction mixture was stirred at Ϫ78 ЊC
for 20 min and allowed to warm to room temperature. The
resulting suspension was cooled to Ϫ78 ЊC and the aldehyde 22
(15.8 g, 110 mmol) in ether (75 cm3) was added dropwise. After
1 h at Ϫ78 ЊC, the reaction was allowed to attain ambient tem-
perature, aqueous sodium hydroxide (3 ; 116 cm3, 350 mmol)
and aqueous hydrogen peroxide (30%; 45 cm3, 400 mmol) were
added and the mixture heated under reflux for 1 h. After cool-
ing, the aqueous layer was extracted with ether (150 cm3) and
the organic extracts were washed with water (100 cm3) and
brine (100 cm3), dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using gradi-
ent elution (light petroleum, ethyl acetate, benzene) gave the less
polar (4S)-diastereoisomer 25 (1.3 g, 11%), [α]D +11.5 (c 1.12,
CHCl3); δH 5.79 (1 H, m, 2-H), 5.09 (2 H, m, 1-H2), 4.23 (1 H,
m, 6-H), 4.06 (1 H, dd, J 8, 6, 7-H), 3.82 (1 H, m, 4-H), 3.54 (1
H, dd, J 8, 7, 7-HЈ), 3.1 (1 H, s, OH), 2.23 (2 H, m, 3-H2), 1.66 (2
H, m, 5-H2) and 1.39 and 1.33 (each 3 H, s, CH3); δC 134.7 (d),
117.8 (t), 109.4 (s), 75.5 (d), 70.0 (d), 69.6 (t), 41.7 (t), 39.5 (t),
26.7 (q) and 25.6 (q); followed by the title compound 24 (7.4 g,
61%), [α]D Ϫ8.0 (c 0.26, CHCl3) [lit., Ϫ8.5 (c 2.6, CHCl3)]
(Found: M+ + H, 187.1334. C10H19O3 requires M, 187.1334);
νmax/cmϪ1 3610–3200, 3080, 1640, 1380, 1370, 1245, 1215,
1158, 1055, 915, 877 and 826; δH 5.83 (1 H, m, 2-H), 5.14 (2 H, m,
1-H2), 4.34 (1 H, m, 6-H), 4.10 (1 H, dd, J 9, 6.5, 7-H), 3.91 (1
H, m, 4-H), 3.59 (1 H, dd, J 9, 7.5, 7-HЈ), 2.29 (2 H, m, 3-H2),
1.73 (2 H, m, 5-H2) and 1.43 and 1.38 (each 3 H, s, CH3); δC
134.6 (d), 118.3 (t), 108.8 (s), 73.6 (d), 69.5 (t), 67.8 (d), 42.2 (t),
39.4 (t), 26.8 (q) and 25.5 (q); m/z (CI) 204 (M+ + NH4, 13%)
and 187 (M+ + H, 100).
(3S,4R)-1-Bromo-4-tert-butyldimethylsilyloxy-3,5-dimethyl-
hexane 16
Triphenylphosphine (5.24 g, 20 mmol) in dichloromethane (27
cm3) was added to a cooled solution of the alcohol 15 (5.13 g,
19.7 mmol) and carbon tetrabromide (6.63 g, 20.0 mmol) in
dichloromethane (85 cm3) at a rate such that the temperature
did not exceed 0 ЊC. The mixture was stirred at 0 ЊC until all
starting material had been consumed (TLC). Silica gel was
added and the slurry concentrated under reduced pressure.
Chromatography of the residue, using light petroleum as elu-
ent, gave the bromide 16 (5.27 g, 83%). A small sample was
distilled using a Kugelrohr to give the title compound 16, bp 89–
90 ЊC/1 mmHg, [α]D Ϫ14.77 (c 1.04, CHCl3) (Found: M+ Ϫ
C4H9, 265.0623. C10H1279BrOSi requires M, 265.0624); νmax
/
cmϪ1 1470, 1465, 1387, 1361, 1260, 1050, 1008, 840, 775 and
670; δH 3.55 and 3.39 (each 1 H, m, 1-H), 3.24 (1 H, dd, J 5, 6,
4-H), 2.07 (1 H, m), 1.75 (3 H, m), 0.92 [9 H, s, SiC(CH3)3], 0.91
(9 H, overlapping d, 3 × CH3) and 0.08 [6 H, s, Si(CH3)2]; m/z
(EI) 281 (14%), 279 (14), 211 (22), 209 (22) and 185 (64).
(3S,4R)-4-tert-Butyldimethylsilyloxy-1-iodo-3,5-dimethylhexane
17
A solution of the alcohol 15 (2.25 g, 8.65 mmol), triphenyl-
phosphine (9.12 g, 34.7 mmol), imidazole (2.36 g, 34.7 mmol)
and iodine (6.59 g, 26.0 mmol) in benzene (400 cm3) was heated
at 80 ЊC for 45 min. After cooling, saturated aqueous sodium
hydrogen carbonate (400 cm3) was added, and the resulting
solution stirred for 10 min. Iodine was added until the organic
layer remained coloured on prolonged stirring. The excess of
the iodine was removed by the addition of saturated aqueous
sodium thiosulfate. After extraction of the aqueous layer with
ether (2 × 50 cm3), the organic extracts were washed with water
(75 cm3) and brine (75 cm3), dried (MgSO4) and concentrated
under reduced pressure to give a mixture of the iodide 17 and
triphenylphosphine oxide. The latter was removed by filtration
through a short column of silica gel eluting with petrol. Con-
centration of the filtrate afforded the title compound 17 (3.2 g,
99%) (Found: M+ Ϫ C4H9, 313.0485. C10H22IOSi requires M,
313.0486); νmax/cmϪ1 1470, 1460, 1387, 1360, 1250, 1185, 1045,
1005, 835 and 775; δH 3.38 (1 H, m, 1-H), 3.26 (1 H, br t, J 5,
4-H), 3.24 (1 H, m, 1-HЈ), 2.09 (1 H, m), 1.76 (2 H, m), 1.61 (1
H, m), 0.91 [12 H, m, CH3 and SiC(CH3)3], 0.9 and 0.88 (each 3
H, d, J 5, CH3) and 0.07 [6 H, s, Si(CH3)2]; m/z (EI) 327 (32%),
313 (17) and 257 (64).
(4R,6S)-6,7-Isopropylidenedioxy-4-(2-trimethylsilylethoxy-
methoxy)hept-1-ene 26
(2-Trimethylsilylethoxy)methyl chloride (10.6 cm3, 59.7 mmol)
was added dropwise to the alcohol 24 (7.4 g, 39.4 mmol) and
N,N-diisopropylethylamine (17.3 cm3, 99.5 mmol) in dichloro-
methane (60 cm3) at 0 ЊC, and the mixture stirred at room
temperature for 16 h. The reaction was diluted with ether (100
cm3) and quenched with water (30 cm3). The aqueous layer was
extracted with ether (2 × 50 cm3) and the organic extracts
washed with water (30 cm3) and brine (30 cm3), dried (MgSO4)
and concentrated under reduced pressure. Chromatography
using light petroleum–ether as eluent gave the title compound 26
(12.6 g, 100%), [α]D Ϫ13.8 (c 0.4, CHCl3) (Found: M+ + NH4,
334.2409. C16H36NO4Si requires M, 334.2414); νmax/cmϪ1 3080,
1640, 1378, 1368, 1250, 1214, 1160, 1153, 1105, 1055, 1030, 995,
937, 917, 860 and 835; δH 5.71 (1 H, m, 2-H), 5.00 (2 H, m,
J. Chem. Soc., Perkin Trans. 1, 1997
375

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1-H2), 4.77 and 4.75 (each 1 H, d, J 7, OHCHO), 4.12 (1 H, m,
6-H), 3.96 (1 H, dd, J 6, 8, 7-H), 3.75 (1 H, m, 4-H), 3.53 [2 H,
m, CH2CH2Si(CH3)3], 3.43 (1 H, t, J 7.5, 7-HЈ), 2.24 (2 H, m,
3-H2), 1.68 and 1.56 (each 1 H, m, 5-H), 1.30 and 1.25 (each 3
H, s, CH3), 0.86 [2 H, m, CH2Si(CH3)3] and Ϫ0.07 [9 H, s,
Si(CH3)3]; m/z (CI) 334 (M+ + NH4, 1%).
H, m, 1-H and OCH2CH2Si(CH3)3], 3.45 (1 H, dd, J 6.5, 10.5,
1-HЈ), 2.93 (2 H, br s, 2 × OH), 2.33 (2 H, m, 5-H2), 1.58 (2 H,
m, 3-H2), 0.95 [2 H, m, CH2Si(CH3)3] and 0.03 [9 H, s,
Si(CH3)3]; m/z (CI) 294 (M+ + NH4, 34%), 277 (M+ + H, 97),
247 (25), 231 (61) and 213 (100).
(2S,4R)-2-Hydroxy-4-(2-trimethylsilylethoxymethoxy)hept-6-en-
1-yl toluene-p-sulfonate 30
(3S,5S)-5,6-Isopropylidenedioxy-3-(2-trimethylsilylethoxy-
methoxy)hexanal 27
Toluene-p-sulfonyl chloride (3.8 g, 19.9 mmol) in dichloro-
methane (20 cm3) was added to the diol 29 (5 g, 18.1 mmol),
triethylamine (12.6 cm3, 90 mmol) and 4-dimethylamino-
pyridine (220 mg, 1.8 mmol) in dichloromethane (55 cm3) at
0 ЊC. The mixture was stirred at 0 ЊC for 12 h then diluted with
ether (100 cm3) and quenched with water (10 cm3). The aqueous
layer was separated, extracted with ether (3 × 50 cm3) and the
organic extracts washed with brine (40 cm3), dried (MgSO4) and
concentrated under reduced pressure. Chromatography of the
residue using light petroleum–ethyl acetate (4:1) as eluent gave
the title compound 30 (5.0 g, 64%); νmax/cmϪ1 3580–3220, 3070,
1640, 1600, 1364, 1248, 1189, 1175, 1095, 1055, 1026, 973, 860,
834 and 665; δH 7.80 and 7.35 (each 2 H, d, J 9.5, ArH), 5.75
(1 H, m, 6-H), 5.08 (2 H, m, 7-H2), 4.69 (2 H, s, OCH2O), 4.09
(1 H, m, 2-H), 3.98 (2 H, m, 1-H2), 3.86 (1 H, m, 4-H), 3.60
[2 H, m, OCH2CH2Si(CH3)3], 2.47 (3 H, s, ArCH3), 2.23 (2 H,
m, 5-H2), 1.82 (1 H, br s, OH), 1.54 (2 H, m, 3-H2), 0.95 [2 H, m,
CH2Si(CH3)3] and 0.03 [9 H, s, Si(CH3)3]; m/z (CI) 330 (100%)
and 313 (22).
Ozone was bubbled through a solution of the alkene 26 (3.24 g,
10.3 mmol) in methanol (100 cm3) at Ϫ78 ЊC until a blue colour
persisted. The reaction vessel was flushed with oxygen, dimethyl
sulfide (10.54 cm3, 144 mmol) was added and the reaction was
allowed to warm slowly to room temperature. After 1 h, the
solution was concentrated under reduced pressure, and the
residue dissolved in ether (100 cm3), washed with water (30 cm3)
and brine (30 cm3), dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue gave the title
compound 27 (2.65 g, 82%), [α]D +8.33 (c 1.37, CHCl3); νmax
/
cmϪ1 1725, 1478, 1469, 1247, 1215, 1155, 1096, 1054, 1028, 937,
920, 860 and 835; δH 10.01 (1 H, t, J 2.7, 1-H), 4.97 (2 H, s,
OCH2O), 4.46 (2 H, m, 3-H and 5-H), 4.29 (1 H, dd, J 5, 7,
6-H), 3.83 [3 H, m, 6-HЈ and OCH2CH2Si(CH3)3], 2.90 (2 H, m,
2-H2), 2.03 (2 H, m, 4-H2), 1.63 and 1.58 (each 3 H, s, CH3),
0.86 [2 H, m, CH2Si(CH3)3] and 0.25 [9 H, s, Si(CH3)3]; m/z (CI)
336 (M+ + NH4, 5%), 318 (M+, 3) and 289 (100).
(4S,6S)-2-Trimethylsilyloxy-6,7-isopropylidenedioxy-4-(2-tri-
methylsilylethoxymethoxy)heptanenitrile 28
(4R,6S)-6,7-Epoxy-4-(2-trimethylsilylethoxymethoxy)hept-1-
ene 31
Sodium metabisulfite (300 mg, 3.2 mmol) in water (4 cm3) was
added to the aldehyde 27 (1.0 g, 3.14 mmol) and the resultant
suspension shaken for 20 min. After stirring at room tempera-
ture for 1 h, the mixture was cooled to 0 ЊC and sodium cyanide
(154 mg, 3.14 mmol) in water (3 cm3) was added at such a rate
that the temperature did not exceed 35 ЊC. The mixture was
extracted with benzene (4 × 10 cm3) and the organic fractions
were washed with aqueous sodium hydrogen sulfite, dried
(MgSO4) and concentrated under reduced pressure to yield the
cyanohydrin (1.06 g, 98%). This was dissolved in tetrahydro-
furan (10 cm3) and trimethylsilyl chloride (0.80 cm3, 6.3 mmol)
and triethylamine (1.10 cm3, 7.0 mmol) were added. The
resulting suspension was stirred at room temperature for 16 h
then filtered and the filter cake washed with anhydrous benzene.
Concentration of the filtrate under reduced pressure gave the
product (830 mg, 64%) which was purified by Kugelrohr distil-
lation, bp 150 ЊC/0.1 mmHg, to give the title compound 28 as a
mixture of epimers at C(1); νmax/cmϪ1 1380, 1370, 1250, 1102,
1054, 1028 and 843; δH 4.58 (3 H, m), 4.09 (1 H, m), 3.97 (1 H,
m, 7-H), 3.86 and 3.77 (each 0.5 H, m), 3.54 [2 H, m, CH2-
CH2Si(CH3)3], 3.41 (1 H, m, 7-HЈ), 1.97 (2 H, m, 3-H2), 1.68 (2
H, m, 5-H2), 1.31 and 1.25 (each 3 H, s, CH3), 0.88 [2 H, m,
CH2Si(CH3)3], 0.14 and 0.13 [each 4.5 H, s, Si(CH3)3] and
Ϫ0.06 [9 H, s, Si(CH3)3].
Diethyl diazodicarboxylate (7.44 cm3, 47.3 mmol) was added
dropwise to the diol 29 (8.7 g, 31.5 mmol) and triphenylphos-
phine (12.4 g, 47.3 mmol) in dimethylformamide (160 cm3) and
the solution heated at 80 ЊC for 60 h. After cooling to room
temperature, the reaction mixture was partitioned between
ether (250 cm3) and water (250 cm3). The aqueous layer was
extracted with ether (2 × 100 cm3) and the organic extracts
washed with water (50 cm3) and brine (50 cm3), dried (MgSO4)
and concentrated under reduced pressure. Trituration in ether–
light petroleum removed triphenylphosphine oxide and diethyl
hydrazinodicarboxylate. Concentration of the mother liquor
under reduced pressure and chromatography of the residue
gave the title compound 31 (6.3 g, 77%), [α]D Ϫ25.4 (c 1.16,
CHCl3) (Found: C, 60.8; H, 10.4. C13H26O3Si requires C, 60.4;
H, 10.15%. Found: M+ + NH4, 276.1999. C13H30NO3Si requires
M, 276.1995); νmax/cmϪ1 3070, 3040, 1639, 1248, 1098, 1054,
1030, 860 and 835; δH 5.80 (1 H, m, 2-H), 5.10 (2 H, m, 1-H2),
4.76 and 4.74 (each 1 H, d, J 7, OHCHO), 3.89 (1 H, m, 4-H),
3.65 [2 H, m, OCH2CH2Si(CH3)3], 3.04 (1 H, m, 6-H), 2.80 (1
H, t, J 5, 7-H), 2.50 (1 H, dd, J 5, 2.5, 7-HЈ), 2.37 (2 H, m,
3-H2), 1.68 (2 H, m, 5-H2), 0.95 [2 H, m, CH2Si(CH3)3] and 0.02
[9 H, s, Si(CH3)3]; δC 134.3 (d), 117.4 (t), 93.7 (t), 74.5 (d), 65.2
(t), 49.5 (d), 47.3 (t), 39.4 (t), 37.7 (t), 18.1 (t) and Ϫ1.5 (q); m/z
(CI) 275 (M+ + NH4, 2%).
(2S,4R)-4-(2-Trimethylsilylethoxymethoxy)hept-6-ene-1,2-diol
29
Alternatively, anhydrous potassium carbonate (3.3 g, 23.7
mmol) was added to a solution of the toluene-p-sulfonate 30
(4.95 g, 11.5 mmol) in methanol (75 cm3), and the mixture stirred
at room temperature for 4 h. The reaction mixture was then
filtered and the filtrate concentrated under reduced pressure.
The residue was dissolved in ether (75 cm3) and the ether solu-
tion washed with water (25 cm3), dried (MgSO4) and concen-
trated under reduced pressure. Chromatography of the residue
using light petroleum–ether (8:1) as eluent gave the epoxide 31
(2.72 g, 92%).
Aqueous hydrogen chloride (1 ; 120 cm3) was added to the
acetonide 26 (37.9 g, 0.119 mol) in tetrahydrofuran (660 cm3)
and the mixture stirred for 12 h at room temperature. Ethyl
acetate (300 cm3) was added, the layers were separated and the
aqueous layer was extracted with ethyl acetate (2 × 200 cm3).
The organic extracts were washed with saturated aqueous
sodium hydrogen carbonate, dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using
light petroleum–ethyl acetate (2:1) as eluent gave the starting
material 26 (3.2 g, 8%), followed by the title compound 29 (23.4
g, 71%) (Found: M+ + H, 277.1846. C13H29O4Si requires M,
277.1835); νmax/cmϪ1 3540–3190, 3080, 1640, 1251, 1102, 1056,
1028, 917, 860 and 835; δH 5.77 (1 H, m, 6-H), 5.08 (2 H, m,
7-H2), 4.79 (2 H, s, OCH2O), 3.94 (2 H, m, 2-H and 4-H), 3.63 [3
2-[(3S,4R)-4-tert-Butyldimethylsilyloxy-3,5-dimethylhexyl]-1,3-
dithiane 32
Butyllithium (1.6  in hexane; 11.9 cm3, 18.9 mmol) was added
dropwise to 1,3-dithiane (3.8 g, 22.8 mmol) in tetrahydrofuran
(40 cm3) at Ϫ40 ЊC and the solution stirred for 2 h. The iodide
376
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17 (4.2 g, 11.4 mmol) in tetrahydrofuran (20 cm3) was added
and the solution stirred at Ϫ20 ЊC for 14 h. Saturated aqueous
ammonium chloride (20 cm3) and ether (60 cm3) were added.
The aqueous layer was extracted with ether (3 × 25 cm3) and the
organic extracts washed with water (30 cm3) and brine (30 cm3),
dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue using ether–light petroleum as
eluent gave the alkylated dithiane 32 (3.54 g, 87%). A small
sample was distilled using a Kugelrohr, bp 120–121 ЊC/0.05
mmHg) to give the title compound 32, [α]D Ϫ6.1 (c 0.61, CHCl3)
(Found: C, 59.8; H, 10.8; S, 17.85. C18H38OS2Si requires C, 59.9;
H, 10.55; S, 17.7%. Found: M+ + H, 363.2210. C18H39OS2Si
requires M, 363.2212); νmax/cmϪ1 1460, 1250, 1045, 835 and 770;
δH 4.01 (1 H, t, J 6.5, 2-H), 3.23 (1 H, t, J 4.5, 4Ј-H), 2.84 (4 H,
m, 4-H2 and 6-H2), 2.13 (1 H, m), 1.92–1.54 (6 H, m), 1.27 (1 H,
m), 0.91 [9 H, s, SiC(CH3)3], 0.90 (3 H, d, J 7, CH3), 0.88 and
0.87 (each 3 H, d, J 6, CH3) and 0.05 [6 H, s, Si(CH3)2]; δC 81.2
(d), 47.9 (d), 37.2 (d), 33.7 (t), 30.9 (d), 30.4 (2 × t), 29.2 (t), 26.0
(q), 20.9 (q), 18.3 (q), 18.3 (s), 18.1 (q), 16.6 (q), Ϫ3.8 (q) and
Ϫ4.0 (q); m/z (EI) 361 (M+ Ϫ H, 2%), 347 (15), 319 (17) and 305
(100).
(t), 40.1 (t), 35.6 (t), 31.5 (d), 28.0 (d), 28.0 (t), 20.6 (q), 17.2 (q)
and 13.9 (q); m/z (CI) 268 (M+ + H, 100%).
Ethyl (5R,7S,2E)-7,8-isopropylidenedioxy-2-methyl-5-(2-tri-
methylsilylethoxymethoxy)oct-2-enoate 35
Ozone was bubbled through the alkene 26 (2.0 g, 6.28 mmol)
in methanol (50 cm3) at Ϫ78 ЊC until the appearance of a blue
colour indicated an excess of ozone. After flushing with oxygen,
dimethyl sulfide (7.2 cm3, 88 mmol) was added and the reaction
allowed to warm slowly to room temperature. After 1 h at room
temperature the solution was concentrated under reduced pres-
sure. The residue was dried azeotropically with benzene, then
dissolved in benzene (60 cm3) and the stabilised ylide 34 (3 g,
7.64 mmol) was added. The solution was stirred at room tem-
perature for 16 h, concentrated under reduced pressure and
chromatography of the residue gave the title compound 35 (2.3
g, 90%), [α]D Ϫ11.57 (c 0.98, CHCl3); νmax/cmϪ1 1709, 1646,
1378, 1368, 1249, 1028, 861 and 837; δH 6.80 (1 H, br t, J 7.5,
3-H), 4.74 and 4.72 (each 1 H, d, J 7, OHCHO), 4.2 (3 H, m,
OCH2CH3 and 7-H), 4.05 (1 H, dd, J 6, 8, 8-H), 3.92 (1 H, m,
5-H), 3.63 [2 H, m, OCH2CH2Si(CH3)3], 3.52 (1 H, t, J 7.5,
8-HЈ), 2.47 (2 H, t, J 6.5, 4-H2), 1.85 (3 H, d, J 1, 2-CH3), 1.70 (2
H, m, 6-H2), 1.39 and 1.34 (each 3 H, s, CH3), 1.29 (3 H, t, J 7,
OCH2CH3), 0.94 [2 H, m, CH2Si(CH3)3] and 0.02 [9 H, s,
Si(CH3)3]; δC 167.7 (s), 137.1 (s), 129.7 (s), 108.5 (s), 93.0 (t),
73.9 (d), 73.1 (d), 69.8 (t), 65.8 (t), 60.4 (t), 39.2 (t), 34.3 (t), 26.9
(q), 25.7 (q), 18.0 (t), 14.2 (q), 12.6 (q) and Ϫ1.5 (q); m/z 387
(M+ Ϫ 15).
(2ЈR,4ЈR,3ЉS,4ЉR)-2-[2-Hydroxy-4-(2-trimethylsilylethoxy-
methoxy)hept-6-enyl]-2-(4-tert-butyldimethylsilyloxy-3,5-
dimethylhexyl)-1,3-dithiane 33
tert-Butyllithium (1.67  in pentane; 16.4 cm3, 27.4 mmol) and
tetramethylethylenediamine (8.25 cm3, 54.5 mmol) were added
to the 2-alkyldithiane 32 (27.4 mmol) in tetrahydrofuran (90
cm3) at Ϫ20 ЊC, and the solution stirred for 2 h. The epoxide 31
(3.53 g, 13.7 mmol) in tetrahydrofuran (25 cm3) was added.
After 1 h at Ϫ20 ЊC, the reaction was allowed to warm to Ϫ5 ЊC
and was then quenched by the addition of water (30 cm3). After
dilution with ether (150 cm3), separation and extraction of the
aqueous layer with ether (2 × 75 cm3), the organic extracts were
washed with water (50 cm3) and brine (50 cm3), dried (MgSO4)
and concentrated under reduced pressure. Chromatography of
the residue using light petroleum–ether as eluent gave the title
compound 33 (8.2 g, 97%), [α]D Ϫ10.8 (c 0.81, CHCl3) (Found:
M+, 620.3791. C31H64O4S2Si2 requires M, 620.3785); νmax/cmϪ1
3580–3280, 3080, 1640, 1471, 1463, 1252, 1097, 1055, 1027, 920,
860 and 838; δH 5.83 (1 H, m, 6Ј-H), 5.09 (2 H, m, 7Ј-H2), 4.76 (2
H, s, OCH2O), 4.21 (1 H, m, 2Ј-H), 3.92 (1 H, m, 4Ј-H), 3.66 [3
H, m, OCH2CH2Si(CH3)3 and OH], 3.26 (1 H, t, J 4.5, 4Љ-H),
2.86 (4 H, m, 4-H2 and 6-H2), 2.34 (2 H, t, J 4.5, 5-H2), 2.31–
1.20 (12 H, m), 0.99 [2 H, m, CH2Si(CH3)3], 0.94–0.86 (18 H, m,
3 × CH3 and SiC(CH3)3], 0.07 and 0.05 (each 3 H, s, SiCH3) and
0.03 [9 H, s, Si(CH3)3]; m/z (CI) 621 (M+ + H, 7%) and 503
(100).
(5R,7S,2E)-7,8-Isopropylidenedioxy-2-methyl-5-(2-trimethyl-
silylethoxymethoxy)oct-2-enol 36
Diisobutylaluminium hydride (1  in tetrahydrofuran; 7.97
cm3, 7.97 mmol) was added to the unsaturated ester 35 (1.43 g,
3.56 mmol) in tetrahydrofuran (17 cm3) at Ϫ78 ЊC and the mix-
ture stirred at Ϫ78 ЊC for 2 h and then at room temperature for
1 h. After cooling to Ϫ78 ЊC, methanol (1.76 cm3) was added
and the solution stirred at room temperature for 1 h. Water
(1.00 cm3) was added and the resultant gelatinous precipitate
stirred with Celite until a granular solid was obtained. After
filtration through a Celite bed and washing the filter cake with
ethyl acetate, concentration of the filtrate under reduced pres-
sure gave the title compound 36 (1.27 g, 99%), [α]D Ϫ15.24 (c
0.93, CHCl3) (Found: C, 59.6; H, 10.3. C18H36O5Si requires C,
59.95, H, 10.5%); νmax/cmϪ1 3570–3240, 1378, 1369, 1250, 1058,
1030, 862 and 838; δH 5.46 (1 H, br t, J 7, 3-H), 4.75 and 4.69
(each 1 H, d, J 7.5, OHCHO), 4.20 (1 H, m, 7-H), 4.05 (1 H, dd,
J 6, 8, 8-H), 4.02 (2 H, br s, 1-H2), 3.83 (1 H, m, 5-H), 3.64 [2 H,
m, OCH2CH2Si(CH3)3], 3.52 (1 H, t, J 7.5, 8-H), 2.32 (2 H, m,
4-H2), 1.7 (2 H, m, 6-H2), 1.68 (3 H, s, 2-CH3), 1.39 and 1.34
(each 3 H, s, CH3), 0.95 [2 H, m, CH2Si(CH3)3] and 0.03 [9 H, s,
Si(CH3)3]; m/z 361 (M+ + H), 360 (M+) and 345 (M+ Ϫ 15).
(2R,4S,6R,8R,9S)-4-Hydroxy-8-isopropyl-9-methyl-2-prop-2-
enyl-1,7-dioxaspiro[5.5]undecane 4
Hydrogen fluoride (40% in water; 4.4 cm3) was added to the 2,2-
dialkyldithiane 33 (7.26 g, 11.7 mmol) in aqueous acetonitrile
(55 cm3) and the solution stirred at room temperature for 4 h.
Ethyl acetate (100 cm3) and water (30 cm3) were added, the
mixture separated and the aqueous layer extracted with ethyl
acetate. The organic extracts were washed with saturated aque-
ous sodium hydrogen carbonate, dried (MgSO4) and concen-
trated under reduced pressure. Chromatography of the residue
using light petroleum–ethyl acetate (7:1) as eluent gave the title
compound 4 (2.74 g, 87%), [α]D +78.0 (c 0.82, CHCl3) (Found:
(5R,7S,2E)-7,8-Isopropylidenedioxy-2-methyl-5-(2-trimethyl-
silylethoxymethoxy)oct-2-enyl bromide 37
Triphenylphosphine (445 mg, 2.81 mmol) in dichloromethane
(1.5 cm3) was added to the alcohol 36 (540 mg, 1.5 mmol) and
carbon tetrabromide (548 mg, 1.65 mmol) in dichloromethane
(3 cm3) at such a rate that the temperature did not exceed 0 ЊC
and the mixture stirred at 0 ЊC until all the alcohol had been
consumed (TLC). Silica gel was added and the slurry evaporated
under reduced pressure. Chromatography of the residue using
light petroleum–ether (6:1) gave the title compound 37 (503 mg,
79%), [α]D Ϫ13.07 (c 0.96, CHCl3); νmax/cmϪ1 1377, 1368, 1246,
1210, 1154, 1096, 1051, 1026, 858 and 833; δH 5.65 (1 H, m,
3-H), 4.74 and 4.70 (each 1 H, d, J 5.5, OHCHO), 4.21 (1 H, m,
7-H), 4.06 (1 H, dd, J 6, 8, 8-H), 3.98 (2 H, s, 1-H2), 3.84 (1 H, m,
5-H), 3.63 [2 H, m, OCH2CH2Si(CH3)3], 3.52 (1 H, t, J 8, 8-HЈ),
2.33 (2 H, m, 4-H2), 1.79 (3 H, s, 2-CH3), 1.68 (2 H, m, 6-H2),
1.41 and 1.36 (each 3 H, s, CH3), 0.96 [2 H, m, CH2Si(CH3)3]
and 0.05 [9 H, s, Si(CH3)3]; m/z 409, 407 (M+ Ϫ 15).
C, 71.3; H, 10.6. C16H28O3 requires C, 71.6; H, 10.5%); νmax
/
cmϪ1 3480–3120, 1640, 1378, 1005 and 977; δH 5.86 (1 H, m,
2Ј-H), 5.07 (2 H, m, 3Ј-H2), 4.13 (1 H, m, 4-H), 3.61 (1 H, m,
2-H), 3.04 (1 H, dd, J 2, 9.5, 8-H), 2.30 and 2.21 (each 1 H, m,
1Ј-H), 1.98 (2 H, m, 3-Heq and 5-Heq), 1.87 (1 H, d of septets, J
2, 7, 1Љ-H), 1.69–1.41 (6 H, m, 9-H, 10-H2, 11-H2 and OH), 1.26
(1 H, dd, J 11, 12, 5-Hax), 1.14 (1 H, q, J 12, 3-Hax), 0.94 and
0.82 (each 3 H, d, J 7, CH3) and 0.80 (3 H, d, J 6, CH3); δC 135.3
(d), 116.7 (t), 97.3 (s), 78.0 (d), 67.5 (d), 64.9 (d), 44.9 (t), 40.4
J. Chem. Soc., Perkin Trans. 1, 1997
377

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(5R,7S,2E)-7,8-Isopropylidenedioxy-2-methyl-5-(2-trimethyl-
silylethoxymethoxy)oct-2-enyl iodide 38
CH2Si(CH3)3], 0.86 (3 H, d, J 6, 2-CH3) and 0.03 [9 H, s,
Si(CH3)3]; δC 136.5 (s), 121.3 (d), 108.6 (s), 93.8 (t), 74.6 (d),
73.4 (d), 69.6 (t), 68.2 (t), 65.3 (t), 44.4 (t), 38.8 (t), 33.5 (d),
33.2 (t), 29.9 (q), 25.7 (q), 17.9 (t), 16.5 (q), 16.0 (q) and Ϫ1.7
(q); m/z (CI) 420 (M+ + NH4, 12%), 403 (M+ + H, 10) and 227
(100).
Iodine (608 mg, 2.4 mmol) was added to the allylic alcohol 36
(360 mg, 1.0 mmol), triphenylphosphine (522 mg, 1.96 mmol)
and imidazole (152 mg, 1.22 mmol) in acetonitrile–ether (2:3; 4
cm3) at 0 ЊC. The mixture was stirred at 0 ЊC for 30 min, diluted
with ether (4 cm3) and washed with saturated aqueous sodium
thiosulfate (3 cm3), aqueous copper() sulfate (3 cm3) and water
(3 cm3). After being dried (MgSO4) and concentrated under
reduced pressure at 0 ЊC, the slurry was suspended in 1:1
pentane–ether and filtered through a short plug of silica. Con-
centration of the filtrate at 0 ЊC gave the iodide 38 which was
dissolved in tetrahydrofuran and used immediately in the next
step or stored at Ϫ20 ЊC in the dark; δH 5.73 (1 H, t, J 7.6, 3-H),
4.74 and 4.70 (each 1 H, d, J 7, OHCHO), 4.21 (1 H, m, 7-H),
4.06 (1 H, dd, J 6, 8, 8-H), 3.95 (2 H, s, 1-H2), 3.83 (1 H, m,
5-H), 3.64 [2 H, m, OCH2CH2Si(CH3)3], 3.53 (1 H, t, J 8, 8-HЈ),
2.26 (2 H, m, 4-H2), 1.81 (3 H, s, 2-CH3), 1.68 (2 H, m, 6-H2),
1.41 and 1.36 (each 3 H, s, CH3), 0.96 [2 H, m, CH2Si(CH3)3]
and 0.04 [9 H, s, Si(CH3)3].
(2R,4S,6R,8R,9S)-4-tert-Butyldimethylsilyloxy-9-methyl-8-iso-
propyl-2-prop-2-enyl-1,7-dioxaspiro[5.5]undecane 42
tert-Butyldimethylsilyl chloride (6.2 g, 41.5 mmol) in anhydrous
dimethylformamide (5 cm3) was added to the spiroacetal 4 (7.4
g, 27.6 mmol) and imidazole (4.7 g, 69.0 mmol) in dimethyl-
formamide (10 cm3) and the solution stirred at room tem-
perature for 16 h. Water (50 cm3) and ether (50 cm3) were added
and the layers separated. The aqueous layer was extracted with
ether (3 × 50 cm3) and the organic extracts washed with water
(25 cm3) and brine (25 cm3), dried (MgSO4) and concentrated
under reduced pressure. Chromatography of the residue using
ether–light petroleum as eluent gave the title compound 42 (9.58
g, 91%), [α]D +68.4 (c 0.95, CHCl3); νmax/cmϪ1 1641, 1462, 1385,
1254, 1189, 1131, 1088, 1068, 1008, 981, 910, 872, 836 and 775;
δH 5.87 (1 H, m, 2Ј-H), 5.06 (2 H, m, 3Ј-H2), 4.13 (1 H, m, 4-H),
3.57 (1 H, m, 2-H), 3.03 (1 H, dd, J 2, 9.5, 8-H), 2.25 (2 H, m,
1Ј-H2), 1.86 (3 H, m, 1Љ-H, 3-Heq and 5-Heq), 1.54 (5 H, m, 9-H,
10-H2 and 11-H2), 1.30 (1 H, dd, J 11, 12, 5-Hax), 1.18 (1 H, q, J
11.5, 3-Hax), 0.95 (3 H, d, J 7, CH3), 0.90 [9 H, s, SiC(CH3)3],
0.82 (3 H, d, J 7, CH3), 0.79 (3 H, d, J 6.5, 9-CH3) and 0.07 [6 H,
s, Si(CH3)2]; m/z (CI) 383 (M+ + H, 36%), 325 (11) and 251
(100).
(4S)-3-[(2R,7R,9S,4E)-2,4-Dimethyl-9,10-isopropylidenedioxy-
7-(2-trimethylsilylethoxymethoxy)dec-4-enoyl]-4-isopropyl-
oxazolidin-2-one 40
Lithium diisopropylamide (2.86 mmol) in tetrahydrofuran (5
cm3) was generated at 0 ЊC, cooled to Ϫ78 ЊC and the oxazol-
idinone 39 (504 mg, 2.72 mmol) in tetrahydrofuran (5 cm3) was
added. After 45 min, the iodide 38 (640 mg, 1.36 mmol) in
tetrahydrofuran (3 cm3) was added and the solution was
allowed to warm to Ϫ15 ЊC and stirred at this temperature for
14 h whereupon it was quenched by the addition of water (5
cm3) and diluted with ether (15 cm3). The aqueous layer was
separated, extracted with ether (3 × 15 cm3) and the organic
extracts washed with water (15 cm3) and brine (15 cm3), dried
(MgSO4) and concentrated under reduced pressure. Chrom-
atography of the residue, using light petroleum–ether (2:1) as
eluent, gave the title compound 40 (504 mg, 70%), [α]D + 24.6 (c
1.18, CHCl3) (Found: C, 61.75; H, 9.55; N, 2.65. C27H49NO7Si
requires C, 61.45; H, 9.35; N, 2.65%); νmax/cmϪ1 1779, 1700,
1387, 1369, 1301, 1248, 1207, 1057, 1028, 861 and 838; δH 5.21
(1 H, t, J 7, 5Ј-H), 4.76 and 4.70 (each 1 H, d, J 7, OHCHO),
4.46 (1 H, m, 4-H), 4.24 (2 H, m, 5-H2), 4.05 (1 H, dd, J 6, 8,
10Ј-H), 3.98 (1 H, m, 9Ј-H), 3.77 (1 H, m, 7Ј-H), 3.63 [2 H, t, J
8.5, OCH2CH2Si(CH3)3], 3.51 (1 H, t, J 7.5, 10Ј-HЈ), 2.53 (1 H,
dd, J 5.5, 13, 3Ј-H), 2.28 (3 H, m, 2Ј-H and 6Ј-H2), 1.99 (1 H,
dd, J 9, 13, 3Ј-HЈ), 1.67 [3 H, m, (CH3)2CH and 8Ј-H2], 1.67 (3
H, s, 4-CH3), 1.39 and 1.34 (each 3 H, s, CH3), 1.06 (3 H, d, J
6.5, 2Ј-CH3), 0.94 [2 H, m, CH2Si(CH3)3], 0.90 and 0.86 (each
3 H, d, J 7, CH3) and 0.02 [9 H, s, Si(CH3)3]; m/z (CI) 545
(M+ + NH4, 15%), 410 (100).
Ethyl (2E)-4-[(2R,4S,6R,8R,9S)-4-tert-butyldimethylsilyloxy-
9-methyl-8-isopropyl-1,7-dioxaspiro[5.5]undecan-2-yl]-2-
methylbut-2-enoate 44
Following the procedure outlined above for the synthesis of the
ester 35, the alkene 42 (7.08 g, 18.5 mmol) gave, after chrom-
atography using light petroleum–ether (12:1) as eluent, the title
compound 44 (5.5 g, 69%), [α]D +49.7 (c 1.24, CHCl3) (Found:
M+ Ϫ C4H9, 411.2558. C22H39O5Si requires M, 411.2557); νmax
/
cmϪ1 1712, 1654, 1461, 1387, 1260, 1251, 1082, 1008, 981, 873,
836 and 777; δH 6.88 (1 H, dt, J 1.5, 7.5, 3-H), 4.19 (2 H, q, J 7,
OCH2CH3), 4.14 (1 H, m, 4Ј-H), 3.63 (1 H, m, 2Ј-H), 3.00 (1 H,
dd, J 2, 9.5, 8Ј-H), 2.33 (2 H, m, 4-H2), 1.84 (3 H, m, 1Љ-H,
3Ј-Heq and 5Ј-Heq), 1.85 (3 H, d, J 1, 2-CH3), 1.63 (1 H, m,
10Ј-Hax), 1.48 (4 H, m, 9Ј-H, 10Ј-Heq and 11Ј-H2), 1.28 (5 H, m,
5Ј-Hax, 3Ј-Hax and OCH2CH3), 0.94 (3 H, d, J 7, CH3), 0.90 [9
H, s, SiC(CH3)3], 0.81 (3 H, d, J 7, CH3), 0.76 (3 H, d, J 6,
9Ј-CH3) and 0.06 [6 H, s, Si(CH3)2]; δC 168.3 (s), 138.8 (d), 129.1
(s), 97.3 (s), 78.1 (d), 67.0 (d), 65.6 (d), 60.3 (t), 45.3 (t), 41.2 (t),
35.5 (t), 34.8 (t), 31.3 (t), 31.3 (d), 28.1 (d), 28.0 (t), 25.8 (q), 20.8
(q), 17.2 (q), 14.1 (q), 13.9 (q), 12.4 (q) and Ϫ4.9 (q); m/z (CI)
469 (M+ + H, 39%), 411 (21) and 337 (100).
(2R,7R,9S,4E)-2,4-Dimethyl-9,10-isopropylidenedioxy-7-(2-tri-
methylsilylethoxymethoxy)dec-4-enol 41
(2E)-4-[(2R,4S,6R,8R,9S)-4-tert-Butyldimethylsilyloxy-9-
methyl-8-isopropyl-1,7-dioxaspiro[5.5]undecan-2-yl]-2-methyl-
but-2-enol 45
The oxazolidinone 40 (568 mg, 1.08 mmol) in ether (4 cm3) was
added to a suspension of lithium aluminium hydride (41 mg,
1.08 mmol) in ether (2 cm3) at 0 ЊC. After stirring at this tem-
perature for 3 h, the reaction was quenched by the addition of
water (41 µl), 15% aqueous sodium hydroxide (41 µl) and water
(123 µl). After filtering, the filtrate was concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ether (3:1) as eluent gave the title compound 41 (290
mg, 67%), [α]D Ϫ15.3 (c 0.72, CHCl3) (Found: C, 59.6; H, 10.3.
C21H42O5Si requires C, 59.7; H, 10.05%); νmax/cmϪ1 3590–3180,
1378, 1368, 1249, 1213, 1152, 1100, 1053, 1030, 858 and 834; δH
5.20 (1 H, t, J 7, 5-H), 4.75 and 4.70 (each 1 H, d, J 7,
OHCHO), 4.21 (1 H, m, 9-H), 4.05 (1 H, dd, J 6, 8, 10-H), 3.79
(1 H, m, 7-H), 3.64 [2 H, t, J 8.5, OCH2CH2Si(CH3)3], 3.51
(1 H, t, J 5.5, 10-HЈ), 3.44 (2 H, m, 1-H2), 2.28 (3 H, m), 2.09
(1 H, m), 1.71 (4 H, m, 8-H2 and 2-H and OH), 1.63 (3 H, s,
4-CH3), 1.39 and 1.34 (each 3 H, s, CH3), 0.95 [2 H, m,
Following the procedure outlined above for the synthesis of the
alcohol 36, the ester 44 (3.0 g, 6.4 mmol) gave, after chrom-
atography using light petroleum–ether (4:1) as eluent, the title
compound 45 (2.7 g, 99%), [α]D +44.1 (c 1.06, CHCl3) (Found:
M+ Ϫ C4H9, 369.2493. C20H37O4Si requires M, 369.2491); νmax
/
cmϪ1 3560–3150, 1460, 1385, 1255, 1217, 1188, 1163, 1132,
1086, 1068, 1010, 982, 871, 836 and 775; δH 5.50 (1 H, m, 3-H),
4.12 (1 H, m, 4Ј-H), 4.03 (2 H, br s, 1-H2), 3.56 (1 H, m, 2Ј-H),
3.01 (1 H, dd, J 2, 9.5, 8Ј-H), 2.22 (2 H, m, 4-H2), 1.86 (3 H, m,
1Љ-H, 3Ј-Heq and 5Ј-Heq), 1.69 (3 H, d, J 1, 2-CH3), 1.65 (1 H, m,
10Ј-Hax), 1.47 (4 H, m, 9Ј-H, 10Ј-Heq and 11Ј-H2), 1.30 (1 H, dd,
J 11, 12, 5Ј-Hax), 1.19 (1 H, q, J 11.5. 3Ј-Hax), 0.94 (3 H, d,
J 7, CH3), 0.90 [9 H, s, SiC(CH3)3], 0.82 (3 H, d, J 6.5, CH3),
0.77 (3 H, d, J 6, 9Ј-CH3), 0.07 [6 H, s, Si(CH3)2]; δC 136.6 (s),
122.4 (d), 97.3 (s), 78.0 (d), 68.9 (t), 67.7 (d), 65.7 (d), 45.4 (t),
378
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
41.0 (t), 35.6 (t), 33.6 (t), 31.4 (d), 28.1 (t), 28.1 (d), 25.8 (q), 20.8
(q), 18.1 (s), 17.3 (q), 13.9 (q), 13.7 (q) and Ϫ4.9 (q); m/z (CI)
444 (M+ + NH4, 50%) and 427 (M+ + H, 100).
(2R,4E)-6-[(2R,4S,6R,8R,9S)-4-tert-Butyldimethylsilyloxy-
9-methyl-8-isopropyl-1,7-dioxaspiro[5.5]undecan-2-yl]-2,4-
dimethylhex-4-enyl(triphenyl)phosphonium iodide 2
A solution of triphenylphosphine (186 mg, 0.75 mmol) and the
iodide 49 (274 mg, 0.47 mmol) in acetonitrile (0.9 cm3) was
heated under reflux for 72 h, diluted with acetonitrile (10 cm3)
and washed with light petroleum until only the phosphonium
salt remained in the acetonitrile layer (TLC). After drying
(MgSO4), the acetonitrile solution was concentrated under
reduced pressure to give the title compound 2 (336 mg, 84%) as a
foam which was used without further purification; νmax/cmϪ1
1587, 1438, 1383, 1253, 1185, 1109, 1084, 1062, 1007, 978, 867,
844, 775 and 635; δH 7.92–7.62 (15 H, m, ArH), 5.24 (1 H, t, J 7,
5-H), 4.09 (1 H, m, 4Ј-H), 3.74 (1 H, m, 2Ј-H), 3.52 (2 H, m,
1-H2), 2.95 (1 H, br d, J 5.5, 8Ј-H), 2.05 (4 H, m, 3-H2 and
6-H2), 1.76 (4 H, m, 2-H, CHMe2, 3Ј-Heq and 5Ј-Heq), 1.53 (1 H,
m, 9Ј-H), 1.37 (4 H, m, 10Ј-H2, 11Ј-H2), 1.39 (3 H, s, 4-CH3),
1.24 (1 H, dd, J 10.5, 12, 5Ј-Hax), 1.13 (1 H, q, J 11, 3-Hax), 0.94
(3 H, d, J 6, 2-CH3), 0.88 (3 H, d, J 7, CH3), 0.86 [9 H, s,
SiC(CH3)3], 0.78 and 0.71 (each 3 H, d, J 6, CH3) and 0.05 [6 H,
s, Si(CH3)2]; m/z (FAB) 713 (M+, 45%).
(4S)-3-{(2R,4E)-6-[(2R,4S,6R,8R,9S)-4-tert-Butyldimethyl-
silyloxy-9-methyl-8-isopropyl-1,7-dioxaspiro[5.5]undecan-2-yl]-
2,4-dimethylhex-4-enoyl}-4-isopropyloxazolidin-2-one 47
Following the procedure outlined for the synthesis of 40, the
alcohol 45 (1.01 g, 2.37 mmol) was converted via the iodide 46
to the title compound 47 (1.23 g, 87%), [α]D +60.2 (c 1.04,
CHCl3) (Found: M+ Ϫ C4H9, 536.3406. C29H50NO6Si requires
M, 536.3407); νmax/cmϪ1 1781, 1699, 1458, 1384, 1298, 1244,
1200, 1117, 1082, 1006, 978, 859, 833 and 772; δH 5.27 (1 H, t, J
7, 5Ј-H), 4.46 (1 H, m, 4-H), 4.26 (1 H, t, J 9, 5-H), 4.24 (1 H,
dd, J 3.5, 9, 5-HЈ), 4.16 (1 H, m, 4Љ-H), 3.98 (1 H, m), 3.52 (1 H,
m, 2Љ-H), 3.02 (1 H, dd, J 2, 9.5, 8Љ-H), 3.52 (1 H, dd, J 5.5, 13),
2.27 (2 H, m), 2.09 (1 H, m), 2.0 (1 H, dd, J 9, 13), 1.82 (3 H, m),
1.67 (3 H, s, 4Ј-CH3), 1.63 (1 H, m), 1.45 (4 H, m), 1.29 (1 H, dd,
J 11, 12, 5Љ-Hax), 1.15 (1 H, q, J 11.5, 3Љ-Hax), 1.07 (3 H, d, J 7,
CH3), 0.96 (3 H, d, J 7, CH3), 0.92 (3 H, d, J 4, CH3), 0.89 [9 H,
s, SiC(CH3)], 0.85 and 0.81 (each 3 H, dd, J 7, CH3), 0.77 (3 H,
d, J 6, CH3) and 0.06 [6 H, s, Si(CH3)2]; m/z (CI) 611
(M+ + NH4, 12%), 594 (M+ + H, 16) and 462 (100).
Acknowledgements
We thank the SERC (EPSRC) for a studentship (to P. G. S.).
(2R,4E)-6-[(2R,4S,6R,8R,9S)-4-tert-Butyldimethylsilyloxy-9-
methyl-8-isopropyl-1,7-dioxaspiro[5.5]undecan-2-yl]-2,4-
dimethylhex-4-enol 48
References
Following the procedure outlined for the synthesis of alcohol
41, the oxazolidinone 47 (2.51 g, 476 mmol) was reduced to the
title compound 48 (1.94 g, 99%), [α]D +49.8 (c 0.86, CHCl3)
(Found: M+ Ϫ C4H9, 411.2926. C23H43O4Si requires M,
411.2930); νmax/cmϪ1 3540–3140, 1458, 1383, 1250, 1184, 1124,
1086, 1066, 1008, 980, 870, 834 and 772; δH 5.27 (1 H, t, J 7, 5-
H), 4.11 (1 H, m, 4Ј-H), 3.5 (3 H, m, 1-H2 and 2Ј-H), 3.03 (1 H,
dd, J 2, 9.5, 8Ј-H), 2.16 (3 H, m, 3-H and 6-H2), 1.76 (4 H, m, 3-
HЈ, CHMe2, 3Ј-Heq and 5Ј-Heq), 1.65 (3 H, s, 4-CH3), 1.62 (2 H,
m, 2-H), 1.5 (5 H, m, 9Ј-H, 10Ј-H2 and 11Ј-H2), 1.30 (1 H, dd, J
11, 12, 5Ј-Hax), 1.20 (1 H, q, J 11.5, 3Ј-Hax), 0.95 (3 H, d, J 6,
2-CH3), 0.89 [12 H, CH3 and SiC(CH3)3], 0.82 (3 H, d, J 7,
CH3), 0.78 (3 H, d, J 6, 9Ј-CH3) and 0.07 [6 H, s, Si(CH3)2]; δC
135.7 (s), 122.4 (d), 97.3 (s), 77.7 (d), 68.4 (t), 68.1 (d), 65.8 (d),
45.4 (t), 44.4 (t), 41.0 (t), 35.5 (t), 34.1 (t), 33.6 (d), 31.5 (d), 28.1
(d), 28.0 (t), 25.8 (q), 20.8 (q), 18.1 (s), 17.2 (q), 16.6 (q), 6.0 (q),
13.9 (q) and Ϫ4.9 (q); m/z (CI) 469 (M+ + H, 24%), 411 (M+ Ϫ
57, 3) and 337 (100).
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(2R,4E)-6-[(2R,4S,6R,8R,9S)-4-tert-Butyldimethylsilyloxy-9-
methyl-8-isopropyl-1,7-dioxaspiro[5.5]undecan-2-yl]-2,4-
dimethylhex-4-enyl iodide 49
Iodine (321 mg, 1.27 mmol) was added to the alcohol 48 (246
mg, 0.53 mmol), triphenylphosphine (281 mg, 1.04 mmol) and
imidazole (81 mg, 1.16 mmol) in acetonitrile–ether (2:3; 3 cm3)
at 0 ЊC. The mixture was stirred at 0 ЊC for 30 min, and then
diluted with ether (10 cm3), washed with saturated aqueous
sodium thiosulfate (5 cm3), aqueous copper() sulfate (5 cm3)
and water (5 cm3), dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue using light
petroleum–ether (20:1) as eluent gave the title compound 49
(274 mg, 89%), [α]D +36.7 (c 0.4, CHCl3); νmax/cmϪ1 1457, 1383,
1250, 1184, 1128, 1084, 1065, 1007, 980, 870, 834 and 772; δH
5.31 (1 H, t, J 6.5, 5-H), 4.13 (1 H, m, 4Ј-H), 3.55 (1 H, m, 2Ј-
H), 3.24 (1 H, dd, J 4.5, 9.5, 1-H), 3.10 (1 H, dd, J 6, 9.5, 1-HЈ),
3.05 (1 H, dd, J 2, 9.5, 8Ј-H), 2.19 (2 H, m, 6-H2), 2.07 (1 H, dd,
J 7.5, 13.5, 3-H), 1.85 (4 H, m, 3-HЈ, CHMe2, 3-Heq and 5-Heq),
1.64 (2 H, m, 9Ј-H and 2-H), 1.61 (3 H, s, 4-CH3), 1.46 (4 H, m,
10Ј-H2 and 11Ј-H2), 1.30 (1 H, dd, J 11, 12, 5Ј-Hax), 1.19 (1 H, q,
J 11.5, 3Ј-Hax), 0.97 (3 H, d, J 6, CH3), 0.96 (3 H, d, J 7, CH3),
0.90 [9 H, s, SiC(CH3)3], 0.82 (3 H, d, J 7, CH3), 0.79 (3 H, d, J
6, CH3) and 0.07 [6 H, s, Si(CH3)2]; m/z (CI) 579 (M+ + H, 29%)
and 447 (100).
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J. Chem. Soc., Perkin Trans. 1, 1997
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Paper 6/05892B
Received 27th August 1996
Accepted 24th October 1996
21 E. J. Corey, H. Shirahama, H. Yamamoto, S. Terashima,
A. Venkateswarlu and T. K. Schaaf, J. Am. Chem. Soc., 1971, 93,
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380
J. Chem. Soc., Perkin Trans. 1, 1997