Stereocontrol in organic synthesis using silicon-containing compounds. A synthesis of (-)-tetrahydrolipstatin using the alkylation of a β-silyl ester and the hydroboration of an allylsilane

Article abstract of DOI:10.1039/a804275f

Conjugate addition of bis(Z-tridec-1-enyl)cuprate Z-10 to (5S)-1-[(Z)-3′-dimethyl(phenyl)silylprop-2-enoyl]-5-(trityloxymethyl) pyrrolidin-2-one Z-6 gave the 3A-imide Z-12. Subsequent enolate n-hexylation of the benzyl ester Z-13a derived from this imide gave the 2R,3S-ester Z-14a. Reduction of the ester group and protection of the alcohol as its TBDMS group gave the allylsilane (Z)(7 R,8S)-7-(tert-butyldimethylsilyloxymethyl)-8-dimethyl(phenyl)silylhenicos-9-ene Z-15. Hydroboration-oxidation gave the 7R,8S,10S-alcohol 16. Protection of the C-10 hydroxy as its benzyl ether, removal of the silyl protecting group and oxidation gave (2R,3S,5S)-5-benzyloxy-3-dimethyl(phenyl)silyl-2-hexylhexadecanoic acid 19. Silyl-to-hydroxy conversion, β-lactone formation, and hydrogenolysis gave the known alcohol (3S,4S)-3-hexyl-4-[(S)-2′-hydroxytridecyl]oxetan-2-one 22, from which tetrahydrolipstatin 1 was prepared by a conventional esterification. Each of the stereochemistry determining steps, 4 → Z-6, 7 → E-8, E-8 → Z-9, Z-6 + Z-10 → Z-12, Z-13a → Z-14a and Z-15 → 16, took place with a remarkably high level of open-chain stereocontrol.

Full text of DOI:10.1039/a804275f

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Stereocontrol in organic synthesis using silicon-containing
compounds. A synthesis of (؊)-tetrahydrolipstatin using the
alkylation of a â-silyl ester and the hydroboration of an allylsilane
Ian Fleming* and Nicholas J. Lawrence
Department of Chemistry, Lensfield Road, Cambridge, UK CB2 1EW
Conjugate addition of bis(Z-tridec-1-enyl)cuprate Z-10 to (5S)-1-[(Z)-3Ј-dimethyl(phenyl)silylprop-2-
enoyl]-5-(trityloxymethyl)pyrrolidin-2-one Z-6 gave the 3R-imide Z-12. Subsequent enolate n-hexylation
of the benzyl ester Z-13a derived from this imide gave the 2R,3S-ester Z-14a. Reduction of the ester group
and protection of the alcohol as its TBDMS group gave the allylsilane (Z)(7R,8S)-7-(tert-butyldimethyl-
silyloxymethyl)-8-dimethyl(phenyl)silylhenicos-9-ene Z-15. Hydroboration–oxidation gave the 7R,8S,10S-
alcohol 16. Protection of the C-10 hydroxy as its benzyl ether, removal of the silyl protecting group and
oxidation gave (2R,3S,5S)-5-benzyloxy-3-dimethyl(phenyl)silyl-2-hexylhexadecanoic acid 19. Silyl-to-
hydroxy conversion, â-lactone formation, and hydrogenolysis gave the known alcohol (3S,4S)-3-hexyl-4-
[(S)-2Ј-hydroxytridecyl]oxetan-2-one 22, from which tetrahydrolipstatin 1 was prepared by a conventional
esterification. Each of the stereochemistry determining steps, 4 → Z-6, 7 → E-8, E-8 → Z-9,
Z-6 ϩ Z-10 → Z-12, Z-13a → Z-14a and Z-15 → 16, took place with a remarkably high level of
open-chain stereocontrol.
with retention of configuration4 can be carried out at an
Introduction
appropriate stage, after the C-5 hydroxy has been protected. We
therefore need to make the β-silyl ester 3, or a derivative of it, in
an enantiomerically enriched state, for which we also have
methods already developed.5 We published a preliminary
account6 of how we were able to put these methods together to
synthesise (Ϫ)-tetrahydrolipstatin, and we now report our work
in full.
The esterase inhibitor, tetrahydrolipstatin 1,1 supports on its
carbon skeleton a 1,3-relationship and a 1,2-relationship of
exactly the kind that our synthetic methods controlling stereo-
chemistry are able to solve (Scheme 1). The 1,3-relation-
NHCHO
O
Results and discussion
O
O
O
Our method for the control of absolute stereochemistry in the
synthesis of β-silyl carbonyl compounds uses either the conju-
gate addition of a silylcuprate reagent to an α,β-unsaturated
imide derived from Koga’s chiral auxiliary 5, or the conju-
gate addition of a carbon-based cuprate to a β-silylated α,β-
unsaturated imide derived from the same auxiliary. In this case
only the latter method will work, since we need the double bond
between C-4 and C-5, and if it were present in the imide the
silylcuprate would attack C-5 instead of C-3. We therefore
made the β-silyl α,β-unsaturated imide Z-6 from the acetylenic
acid 4 (Scheme 2), choosing the cis double bond so that the
5
3
2
n-C11H23
C6H13-n
1
syn-1,3-diol
n-C11H23
OH
OH
2
CO2H
5
3
C6H13-n
2
Si-to-OH
PhMe2Si
O
O
i, ii, iii
hydroboration of a
cis double bond
PhMe2Si
CO2H
N
SiMe2Ph
CO2R
O
4
n-C11H23
Ph3CO
LiN
stereoselectively anti alkylation
Z-6 60%
Ph3CO
3
5
O
O
Scheme 1
ii, iii
CO2H
PhMe2Si
N
PhMe2Si
ship between C-3 and C-5 is that of a 1,3-diol 2, where we
must differentiate the two hydroxy groups in order to make the
β-lactone without risk of δ-lactone formation. Hydroboration
of a cis allylsilane 3, can be expected to set up the masked diol
with the correct syn relationship,2 and with the two hydroxy
groups about as well differentiated as they could possibly be.
The 1,2-relationship between C-2 and C-3 is that which can be
achieved by alkylation of an enolate carrying a β-silyl group 3,3
and conversion of the phenyldimethylsilyl group into a hydroxy
Ph3CO
E-6
Scheme 2 Reagents: i, H2, Lindlar; ii, (COCl)2, CH2Cl2; iii, 5
product of the conjugate addition will be the enantiomer with
the natural absolute configuration. We also prepared the trans
isomer E-6, which we have made before,5 in order to have
J. Chem. Soc., Perkin Trans. 1, 1998
2679

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available for analytical purposes the diastereoisomer of the
conjugate addition product.
O
O
n-C11H23
2CuLi
PhMe2Si
N
+
We needed the double bond in the ester 3 to be cis, and were
particularly happy, given how much of the stereochemistry was
to be controlled by silicon to use it to control the double bond
geometry too. A completely regioselective and syn stereospecific
silyl-cupration7 of the terminal acetylene 7 gave only the trans
vinylsilane E-8, and bromodesilylation then gave the cis vinyl
bromide Z-9, cleanly with inversion of configuration, as
expected (Scheme 3).8 We then prepared the cuprate Z-10 from
Ph3CO
Z-10
i
E-6
PhMe2Si
O
O
n-C11H23
N
Ph3CO
11 >95:5, 75%
n-C11H23
7
i, ii
vii, viii, ix
SiMe2Ph
PhMe2Si
O
O
n-C11H23
n-C11H23
N
SiMe2Ph
E-8 95%
Z-8 75%
Ph3CO
iii, iv
iii, iv
n-C11H23
Z-6
n-C11H23
2CuLi
n-C11H23
2CuLi
n-C11H23
Br
Br
i
i
Z-10
E-10
Z-9 96%
E-9 95%
PhMe2Si
O
O
PhMe2Si
O
O
v, vi
v, vi
n-C11H23
N
n-C11H23
N
n-C11H23
2CuLi
n-C11H23
2CuLi
Ph3CO
Ph3CO
E-12 73%
Z-10
E-10
Z-12 95:5, 94%
Scheme 4 Reagent: i, MgBr2
Scheme 3 Reagents: i, (PhMe2Si)2CuLiؒLiCN; ii, NH4Cl, H2O; iii, Br2;
iv, NaOMe; v, Li, Et2O; vi, 0.5 equiv. CuBrؒSMe2; vii, BuLi, PhMe2-
SiCl; viii, (c-C6H11)2BH; ix, AcOH
PhMe2Si
O
O
PhMe2Si
O
O
n-C11H23
the bromide by halogen–lithium exchange, and coordination
of two of the vinyllithium groups to one copper() ion. For
comparisons later on, we also wanted the trans isomer E-10,
which we made by the complementary route using syn reduc-
tion of the silylated acetylene to give the cis vinylsilane Z-8,
and bromination, again with inversion, to give the trans vinyl
bromide E-9.
N
n-C11H23
N
Ph3CO
Z-12
Ph3CO
E-12
i or ii
ii
For reference, we carried out the conjugate addition of the
vinylcuprate Z-10 to the trans β-silylenone E-6 that we have
used before. With magnesium bromide to coordinate the two
oxygen atoms of the imide, the nucleophile attacks anti to the
trityloxymethyl group to give as the only detectable product
PhMe2Si
PhMe2Si
n-C11H23
CO2R
93%
CO2But
n-C11H23
R = Bn
Z-13a
E-13b 43%
1
(>95:5, H NMR) the diastereoisomer 11 (Scheme 4). For the
b R = But 85%
synthesis itself, we carried out the conjugate addition of the cis
vinylcuprate Z-10 to the cis β-silylenone Z-6. Attack anti to the
trityloxymethyl group now gave largely the diastereoisomer
Z-12, and, since we had both diastereoisomers, we were able
to measure (1H NMR) the degree of selectivity reliably
(95:5). Again for reference purposes, we also prepared the
trans imide E-12 from the trans vinylcuprate E-10. This com-
pound appeared (1H NMR) to have the usual high degree of
diastereoisomeric purity, but since we did not need to know the
degree of enantiomeric purity of this compound reliably, we did
not prepare the missing member of this quartet by treating the
trans imide E-6 with the trans vinylcuprate E-10.
We removed the chiral auxiliary by treating the imide Z-12
with lithium benzyl oxide to give the benzyl ester Z-13a
(Scheme 5), and presumably with the ratio of enantiomers the
same as the ratio of diastereoisomers. We were now ready to
control the relative stereochemistry between C-2 and C-3 by
alkylation of the enolate derived from the ester Z-13a, which
took place, as far as we could tell, with complete selectivity in
favour of the anti isomer Z-14a. A vinyl or aryl group attached
to the stereogenic centre has frequently been particularly
effective in this respect, which is why we chose to deal with this
iii, iv
iii, iv
PhMe2Si
PhMe2Si
n-C11H23
CO2R
CO2But
C6H13-n
E-14b 51% >95:5
n-C11H23
C6H13-n
R = Bn
Z-14a
85% >95:5
b R = But 75% >95:5
Scheme 5 Reagents: i, BnOLi; ii, ButOLi; iii, LDA; v, n-C6H13I
relationship before the hydroboration. We were also hopeful
that, with a branched α-carbon, the ester might not be reduced
by the hydroborating reagent, but this was not the case—we
were unable to avoid reducing the ester group, even after
making the tert-butyl ester Z-14b in place of the benzyl. We
were able to isolate the diol, but all attempts to interrupt the
reduction before it had gone to completion gave us only the
alcohol derived from reduction of the ester group, but with
the double bond intact. For reference later on, we also prepared
the tert-butyl ester E-14b, starting with the trans imide E-12.
2680
J. Chem. Soc., Perkin Trans. 1, 1998

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Unable to avoid the over-reduction, we reduced the ester
Z-14a deliberately, protected the primary alcohol group as its
tert-butyldimethylsilyl ether Z-15, and then carried out the
hydroboration–oxidation reaction, which took place with high
(>95:5) stereocontrol to give, as far as we could tell, only the
syn isomer 16 (Scheme 6). Although this was very much the
OBn SiMe2Ph
CO2H
OBn OH
i
CO2H
n-C11H23
n-C11H23
C6H13-n
C6H13-n
19
20
ii
PhMe2Si
PhMe2Si
O
O
CO2But
C6H13-n
iii
n-C11H23
CO2Bn
C6H13-n
OH
O
OBn
O
n-C11H23
5
n-C11H23
n-C11H23
C6H13-n
22 92%
C6H13-n
Z-14a
E-14b
21 76%
i, ii
i, ii
iv, iii, v
PhMe2Si
PhMe2Si
NHCO2Bn
n-C11H23
OTBS
C6H13-n
n-C11H23
OTBS
C6H13-n
NHCHO
CO2H
O
23
O
O
O
Z-15 91%
E-15 100%
n-C11H23
C6H13-n
iii, iv
OH
iii, iv
1
89%
SiMe2Ph
OH
SiMe2Ph
Scheme 7 Reagents: i, Hg(OAc)2, AcOOH, AcOH; ii, PhSO2Cl, Py; iii,
H2, Pd/C; iv, DCC, 23, DMAP, DMF; v, AcOCHO
n-C11H23
OTBS
n-C11H23
OTBS
C6H13-n
C6H13-n
rotation. We knew that this recrystallisation was removing
the 5% of enantiomer, which must have been present through-
out. That one recrystallisation was enough, confirmed that
both of the other steps controlling relative stereochemistry,
Z-13a → Z-14a and Z-15 → 16, must have taken place
with a very high level of stereoselectivity, remarkable for the
fact that both of them were genuinely open-chain control,
without any rings or cyclic transition structures. Curiously,
although the alcohol 22 was known, none of the earlier syn-
theses of tetrahydrolipstatin13,14,15,16 had used it as an inter-
mediate, preferring instead to use its diastereoisomer at C-5 and
a Mitsunobu inversion to attach the leucine residue. Two more
recent syntheses have also adopted this tactic.17 Nevertheless,
we, and others since,18,19 easily esterified the alcohol 22 with the
leucine derivative 23 using dicyclohexylcarbodiimide. We then
removed the benzyloxycarbonyl protecting group and replaced
it with the formyl to give tetrahydrolipstatin 1, identical (mp,
16 68% >95:5
17 59% 80:20
v
OBn SiMe2Ph
OBn SiMe2Ph
vi, vii, viii
n-C11H23
CO2H
C6H13-n
19 61%
n-C11H23
OTBS
C6H13-n
18 91%
Scheme 6 Reagents: i, LiAlH4; ii, ButMe2SiCl, imidazole; iii, 9-BBN;
iv, NaOH, H2O2; v, BnOC(᎐NH)CCl3, TfOH; vi, TBAF; vii, PDC; viii,
᎐
Jones
result we expected from our work with similar systems,2 we
checked that we were not being deceived by the diastereo-
isomer 16 having a 1H NMR spectrum unresolved from its C-5
diastereoisomer. To prepare the 3,5-anti isomer 17, we merely
had to reduce the ester E-14b with a trans double bond in place
of the cis, and subject the silyl ether E-15 to hydroboration–
oxidation. Although the stereoselectivity in the hydroboration
was, as usual with a trans double bond, less impressive, the
diastereoisomers proved to be easily distinguished, and there
1
1
mixed mp, rotation, H NMR and mixed H NMR) with an
authentic sample.
Experimental
General
The standard aqueous work-up referred to below involved the
addition of aqueous ammonium chloride (adjusted to pH 8 by
the addition of aqueous ammonia) to the reaction mixture,
extraction with diethyl ether (2–3×), and separation of the
ether layers, which were dried (Na2SO4) and evaporated under
reduced pressure. Ether refers to diethyl ether.
1
was no trace of any of the distinctive H NMR signals of the
anti isomer 17 in the spectrum of the syn isomer 16. To avoid
the formation of a δ-lactone later on, we protected the hydroxy
group as its benzyl ether 18, necessarily using the acid-catalysed
method of ether formation,9 since the standard base-catalysed
method would have given a silyl ether by displacement of the
phenyl group.10 We then restored the correct oxidation level to
the acid 19.
The silyl-to-hydroxy conversion gave the β-hydroxy acid 20,
for which we were able to use, for the first time in a syn-
thesis, one of our newly developed one-pot procedures.4 We did
not purify this intermediate but subjected it immediately to
benzenesulfonyl chloride11 to make the β-lactone 21, and
removed the protecting group. We obtained the known lactone
22,12 our first crystalline intermediate, in good overall yield for
the three steps (Scheme 7). One recrystallisation served to give
the enantiomerically and diastereomerically pure material, as
judged by its sharp and correct melting point and optical
3-Dimethyl(phenyl)silylprop-1-ynoic acid 4
Ethynyldimethyl(phenyl)silane20 (10 g) in THF (20 cm3) was
added to methylmagnesium chloride (3 mol dmϪ3 in THF, 40
cm3) at 0 ЊC. The mixture was stirred at room temperature for
2 h. Carbon dioxide was bubbled through the solution at Ϫ23 ЊC
for 30 min and at room temperature for 2 h. Hydrochloric acid
(1 mol dmϪ3, 100 cm3) was added and the mixture extracted
with hexane. The extracts were dried (Na2SO4) and evaporated
under reduced pressure to give the acid 4 (12.6 g, 99%);
Rf(hexane–EtOAc, 1:1) 0.17 (streak); νmax(film)/cmϪ1 3500–
2400 (OH), 2180 (C᎐C), 1680 (CO), 1250 (SiMe) and 1110
᎐
(SiPh); δH(CDCl3) 9.0–8.0 (1 H, br, OH), 7.60–7.32 (5 H, m, Ph)
J. Chem. Soc., Perkin Trans. 1, 1998
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and 0.51 (6 H, s, SiMe2); δC(CDCl3) 157.4, 134.0, 133.6, 130.1,
128.1, 95.4, 95.0 and Ϫ2.0; m/z 204 (0.4%, Mϩ), 189 (0.5,
M Ϫ Me), 161 (25, M Ϫ CO2 ϩ H), 160 (20, M Ϫ CO2), 145
(100, M Ϫ CO2 Ϫ Me) and 137 (20, MePhSiOH) (Found: Mϩ,
204.0618. C11H12O2 requires M, 204.0606).
83.6 mmol) was added over 2 min to a slurry of copper() cyan-
ide (3.74 g, 41.9 mmol) in THF (50 cm3) at 0 ЊC. The mixture
was stirred at 0 ЊC for 20 min and cooled to Ϫ78 ЊC. Tridec-1-
yne (5.7 g, 31.7 mmol) was added in ether (15 cm3) and the
mixture stirred 2 h, and for a further 30 min at 0 ЊC. The reac-
tion was quenched with aqueous ammonium chloride and fil-
tered over Celite. The aqueous layer was extracted with ether,
and the organic layers were dried (Na2SO4) and evaporated
under reduced pressure. Chromatography (SiO2, hexane) gave
the vinylsilane (10.5 g, 95%); Rf(hexane) 0.51; νmax(film)/cmϪ1
(Z)-3-Dimethyl(phenyl)silylprop-1-enoic acid
The acid 4 (12.8 g, 62.7 mmol) was hydrogenated in methanol
(100 cm3) over palladium (10% on BaSO4, 1 g) in the presence
of quinoline (20 cm3) for 3 h. The mixture was filtered over
Celite after 1 equivalent of hydrogen (1405 cm3) had been con-
sumed. Evaporation under reduced pressure gave the acid
(8.2 g, 64%) as prisms, mp 101–103 ЊC; Rf(hexane–EtOAc, 1:1)
1610 (C᎐C), 1245 (SiMe) and 1110 (SiPh); δ (CDCl ) 7.54–7.32
᎐
H
3
(5 H, m, Ph), 6.12 (1 H, dt, J 18.5 and 6.2, SiCH᎐CH), 5.74
᎐
(1 H, dt, J 18.5 and 1.4, SiCH᎐CH), 2.13 (2 H, m, CH᎐
᎐
᎐
0.62; νmax(CH Cl ) 3500–2000 (OH), 1700 (CO), 1600 (C᎐C),
1248 (SiMe) and 1118 (SiPh); δH(CDCl3) 11.0 (1 H, br, OH),
CHCH2), 1.40–1.20 (18 H, m, CH2), 0.88 (3 H, t, J 6.6, Me) and
0.31 (6 H, s, SiMe2); m/z 316 (6%, Mϩ), 301 (40, M Ϫ Me), 162
(30, M Ϫ C11H22), 161 (30, M Ϫ C11H23), 135 (50, PhMe2Si) and
121 (100, MePhSiH) (Found: Mϩ, 316.2572. C21H36Si requires
M, 316.2586).
᎐
2
2
7.57–7.32 (5 H, m, Ph), 6.85 (1 H, d, J 14.3, SiCH᎐CH), 6.58
᎐
(1 H, d, J 14.3, SiCH᎐CH) and 0.47 (6 H, s, SiMe ); δ (CDCl )
᎐
2
C
3
172.0, 153.8, 138.7, 135.4, 133.6, 128.9, 127.7 and Ϫ2.2; m/z 206
(0.8%, Mϩ), 205 (1.5, M Ϫ H), 191 (100, M Ϫ Me), 137 (20,
MePhSiOH), 135 (100, PhMe2Si) and 129 (60, M Ϫ Ph)
(Found: C, 64.05; H, 6.75; Mϩ, 206.0747. C11H14O2Si requires
C, 64.05; H, 6.85%; M, 206.0763).
(Z)-1-Bromotridec-1-ene Z-9
Bromine (0.45 cm3, 8.75 mmol) was added to the vinylsilane E-8
(2.77 g, 8.75 mmol) in dichloromethane (20 cm3) at Ϫ78 ЊC and
stirred for 10 min. Sodium sulfite (1 g) and methanol (10 cm3)
were added at Ϫ78 ЊC and the mixture stirred for 10 min. The
still cold mixture was poured into saturated aqueous sodium
sulfite and extracted with pentane. The extracts were dried
(Na2SO4) and evaporated under reduced pressure. Freshly pre-
pared sodium methoxide (1 mol dmϪ3 in MeOH, 11 cm3) was
added to the crude dibromide in methanol (10 cm3) at 0 ЊC. The
solution was stirred at 0 ЊC for 1 h and at room temperature for
2 h. Standard aqueous work-up and chromatography (SiO2,
hexane) gave the vinyl bromide (2.19 g, 96%); Rf(hexane) 0.64;
(5S)-1-[(Z)-3Ј-Dimethyl(phenyl)silylprop-2-enoyl]-5-(trityloxy-
methyl)pyrrolidin-2-one Z-6
Oxalyl chloride (1.53 cm3) was added to the alkenoic acid (1.67
g) in dichloromethane (15 cm3). One drop of DMF was added,
the mixture warmed to room temperature, stirred for 1 h and
the solvent evaporated under reduced pressure. n-Butyllithium
(1.6 mol dmϪ3 in hexane, 4.6 cm3) was added to a solution of
the lactam21 (2.68 g) in THF (5 cm3) at Ϫ20 ЊC to give the
lithium salt 5. After 20 min the mixture was cooled to Ϫ78 ЊC
and a solution of the crude acid chloride in THF (10 cm3)
added. The mixture was warmed to room temperature and
stirred for 30 min. Standard aqueous work-up and chrom-
atography (SiO2, hexane–EtOAc, 3:1) gave the amide (3.68 g,
94%) as prisms, mp 104–106 ЊC (from hexane); [α]D20 Ϫ109.7 (c
20.5 in CHCl3); Rf(hexane–EtOAc, 3:1) 0.60; νmax(CDCl3) 1733
(CO), 1670 (CO), 1248 (SiMe) and 1112 (SiPh); δH(CDCl3) 7.88
νmax(film)/cmϪ1 1623 (C᎐C); δ (CDCl ) 6.12 (1 H, dt, J 6.9 and
᎐
H
3
1.2, CH᎐CHBr), 6.07 (1 H, q, J 6.9, CH᎐CHBr), 2.17 (2 H, m,
᎐
᎐
CH C᎐CHBr), 1.40–1.20 (18 H, m, CH ) and 0.87 (3 H, t, J 6.4,
᎐
2
2
Me); m/z 260 (5%, Mϩ), 162 (5, M Ϫ C8H16), 97 (65, C7H13), 83
(80, C6H11), 69 (75, C5H9), 57 (100, C4H9) and 55 (70, C4H7)
(Found: Mϩ 260.1149. C13H25Br requires M, 260.1139).
(1 H, d, J 14.1, SiCH᎐CH), 7.61–7.58 (2 H, m, m-SiPh), 7.43–
1-Dimethyl(phenyl)silyltridec-1-yne
᎐
7.20 (18 H, m, o- and p-SiPh and 3 × Ph), 6.78 (1 H, d, J 14.1,
Tridec-1-yne (2.0 g) was stirred with butyllithium (1.6 mol
dmϪ3, 7.5 cm3) in THF (10 cm3) for 30 min, and then refluxed
with chlorodimethyl(phenyl)silane (1.8 g) for 18 h. Standard
work-up gave the ethynylsilane (3.04 g, 86%); Rf(hexane) 0.32;
SiCH᎐CH), 4.44 (1 H, m, CHN), 3.58 (1 H, dd, J 3.9 and 9.7,
᎐
CHACHBOCPh3), 3.15 (1 H, dd, J 2.5 and 9.7, CHAHBOCPh3),
2.98 (1 H, dt, J 17.9 and 10.3, NCOCHACHB), 2.50 (1 H, ddd,
J 17.9, 9.2 and 2.4, NCOCACHB), 2.00 (2 H, m, COCH2CH2),
0.47 (3 H, s, SiMeAMeB) and 0.44 (3 H, s, SiMeAMeB);
δC(CDCl3) 176.3, 165.9, 149.5, 143.7, 139.5, 138.0, 133.6, 128.7,
128.6, 128.0, 127.6, 127.2, 87.1, 64.0, 56.6, 33.1, 21.2, Ϫ1.7 and
Ϫ2.3; m/z 545 (3%, Mϩ), 530 (30, M Ϫ Me), 302 (15,
M Ϫ CPh3) and 243 (100, CPh3) (Found: C, 76.5; H, 6.50; N,
2.50; Mϩ, 545.2382. C35H35NO3Si requires C, 77.0; H, 6.45; N,
2.55%; M, 545.2386).
νmax(film)/cmϪ1 2170 (C᎐C), 1250 (SiMe) and 1115 (SiPh);
᎐
δ (CDCl ) 7.63–7.34 (5 H, m, Ph), 2.26 (2 H, t, J 7.0, CH C᎐C),
᎐
2
H
3
1.50 (2 H, m, CH CH C᎐C), 1.40–1.20 (16 H, m, CH ), 0.88
᎐
2
2
2
(3 H, t, J 6.6, Me) and 0.38 (6 H, s, SiMe2); δC(CDCl3) 137.8,
133.7, 129.3, 127.8, 109.7, 82.3, 32.0, 29.7 (×2), 29.6, 29.4, 29.2,
28.9, 28.7, 22.8, 20.0, 14.2 and Ϫ0.5; m/z 314 (0.1%, Mϩ), 299
(60, M Ϫ Me), 135 (100, PhMe2Si) and 121 (50, MePhSiH)
(Found: Mϩ, 314.2454. C21H34Si requires M, 314.2430).
Tridec-1-yne 7
(Z)-1-Dimethyl(phenyl)silyltridec-1-ene Z-8
Bromoundecane (5.13 cm3, 22.9 mmol) was added to a slurry of
lithium acetylide–ethylenediamine complex (3.06 g, 33 mmol)
in DMSO (15 cm3) at 0 ЊC. The mixture was warmed to room
temperature and stirred for 2 h. Standard aqueous work-up and
chromatography (SiO2, hexane) gave tridecyne22 (4.13 g, 100%);
Rf(hexane) 0.47; νmax(film)/cmϪ1 3310 (᎐CH) and 2120 (C᎐C);
The ethynylsilane (2.34 g) and dicyclohexylborane (8 mmol)
were stirred in THF (7 cm3) at room temperature for 2 h. Acetic
acid (1.2 cm3) was added and the mixture stirred for a further
1 h. Water was added, and the organic layer washed with
aqueous sodium hydrogen carbonate (saturated, 100 cm3), dried
(Na2SO4) and the solvent removed under reduced pressure.
Chromatography of the residue [SiO2, light petroleum (bp 30–
40 ЊC)] gave the vinylsilane (2.04 g, 87%); Rf(hexane) 0.49;
᎐
᎐
δ (CDCl ) 2.17 (2 H, td, J 7.0 and 2.6, CH C᎐CH), 1.93 (1 H, t,
᎐
2
H
3
J 2.6, C᎐CH), 1.50–1.20 (18 H, m, CH ) and 0.87 (3 H, t, J 6.6,
᎐
2
Me); δC(CDCl3) 84.7, 68.0, 31.9, 29.6 (2), 29.5, 29.4, 29.1, 28.8,
28.5, 22.7, 18.4 and 14.1; m/z 165 (0.2%, M Ϫ Me), 151 (0.5,
M Ϫ Et), 109 (15, C8H13), 95 (50, C7H11), 82 (55, C6H10), 81
(100, C6H9), 67 (70, C5H7) and 55 (50, C4H7) (Found:
Mϩ Ϫ Me, 165.1648. C12H21 requires M Ϫ Me, 165.1644).
νmax(film)/cmϪ1 1605 (C᎐C), 1250 (SiMe) and 1110 (SiPh);
᎐
δH(CDCl3) 7.56–7.31 (5 H, m, Ph), 6.42 (1 H, dt, J 14 and 7.4,
SiCH᎐CH), 5.61 (1 H, dt, 14 and 1.1, SiCH᎐CH), 2.00 (2 H, m,
᎐
᎐
CH CH᎐CH), 1.25 (18 H, m, CH ), 0.88 (3 H, t, J 6.6, Me) and
᎐
2
2
0.37 (6 H, s, SiMe2); δC(CDCl3) 151.1, 139.8, 133.7, 128.8,
127.7, 126.4, 33.8, 32.0, 29.7 (×2), 29.6 (×2), 29.5, 29.4, 29.3,
22.7, 14.1 and Ϫ0.8; m/z 316 (21%, Mϩ), 301 (50, M Ϫ Me), 162
(50, M Ϫ C11H22), 161 (50, M Ϫ C11H23), 135 (85, PhMe2Si) and
(E)-1-Dimethyl(phenyl)silyltridec-1-ene E-8
The silyllithium reagent23 (1.14 mol dmϪ3 in THF, 73.3 cm3,
2682
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
121 (100, MePhSiH) (Found: Mϩ, 316.2577. C21H36Si requires
and 135 (20, PhMe2Si) (Found: Mϩ, 727.4463. C48H61NO3Si
M, 316.2586).
requires M, 727.4420). The diastereoisomer Z-12 was not
detectable (1H NMR).
(E)-1-Bromotridec-1-ene E-9
This was prepared in the same way as the vinyl bromide Z-9
from the vinylsilane Z-8 (1.93 g) to give the vinyl bromide (1.62
(5S)-1-[(E)(3ЈR)-3Ј-Dimethyl(phenyl)silylhexadec-4Ј-enoyl]-5-
(trityloxymethyl)pyrrolidin-2-one E-12
This was prepared in the same way as the allylsilane Z-12, from
the vinyl bromide E-9 (1.4 g) and the lactam Z-6 (1.15 g) to give
the allylsilane (1.12 g, 73%); [α]D21 Ϫ35.0 (c 1.3 in CHCl3);
Rf(hexane–EtOAc, 5:1) 0.43; νmax(film)/cmϪ1 1740 (CO), 1690
g, 95%); Rf(hexane) 0.61; νmax(film)/cmϪ1 1620 (C᎐C) and 930
᎐
(trans-CH᎐CH); δ (CDCl ) 6.16 (1 H, dt, J 13.5 and 7.0,
᎐
H
3
CH᎐CHBr), 5.99 (1 H, dt, J 13.5 and 1.2, CH᎐CHBr), 2.00
᎐
᎐
(2 H, m, CH CH᎐CH), 1.37–1.20 (18 H, m, CH ) and 0.87 (3 H,
᎐
2
2
t, J 6.5, Me); δC(CDCl3) 138.3, 104.0, 32.9, 31.9, 29.63 (×2),
27.56, 29.4, 29.3, 29.0, 28.6, 22.7 and 14.1; m/z 260 (3%, Mϩ),
162 (3, M Ϫ C7H14), 148 (5, M Ϫ C8H16), 97 (60, C7H13), 83 (70,
C6H11), 69 (75, C5H9), 57 (100, C4H9) and 55 (70, C4H7) (Found:
Mϩ, 260.1122. C13H25Br requires M, 260.1140).
(CO) and 1600 (C᎐C); δ (CDCl ) 7.53–7.47 (2 H, m, o-SiPh),
᎐
H 3
7.36–7.14 (18 H, m, CPh3, m- and p-SiPh), 5.27–5.11 (2 H, m,
CH᎐CH), 4.38 (1 H, m, CHN), 3.36 (1 H, dd, J 9.7 and 4.5,
᎐
CHAHBOCPh3), 3.21 (1 H, dd, J 16.4 and 11.7, SiCHCHAHB),
3.14 (1 H, dd, J 9.7 and 2.9, CHAHBOCPh3), 2.83 (1 H, dt,
J 17.7 and 10.5, NCOCHACHB), 2.71 (1 H, dd, J 16.4 and 3.1,
SiCHCHACHB), 2.25 (1 H, ddd, J 11.7, 7.6 and 3.1, SiCH),
2.10–1.80 (4 H, m, CH2 and COCH2CH2), 1.25 (18 H, m, CH2),
0.87 (3 H, t, J 6.6, Me), 0.31 (3 H, s, SiMeAMeB) and 0.29 (3 H,
s, SiMeAMeB); δC(CDCl3) 176.1, 173.4, 143.6, 137.3, 134.1,
129.3, 129.2, 129.1, 128.5, 127.8, 127.7, 86.9, 63.8, 56.6, 36.3,
33.0, 32.7, 31.9, 29.8, 29.7 (×2), 29.5, 29.3, 29.1, 27.9, 22.7, 21.0,
14.1, Ϫ4.3 and Ϫ5.3; m/z 727 (5%, Mϩ), 712 (1, M Ϫ Me), 649
(5, M Ϫ C6H6), 484 (5, M Ϫ CPh3), 243 (100, CPh3) and 135
(50, PhMe2Si) (Found: Mϩ, 727.4440. C48H61NO3Si requires M,
727.4220).
(5S)-1-[(Z)-(3ЈR)-3Ј-Dimethyl(phenyl)silylhexadec-4Ј-enoyl]-5-
(trityloxymethyl)pyrrolidin-2-one Z-12
The vinyl bromide Z-9 (2.95 g, 11.3 mmol) in ether (20 cm3) was
added to lithium wire (containing 1% Na, 300 mg, 13 mmol) at
Ϫ20 ЊC and stirred for 3 h. The resulting vinyllithium was
added to copper bromide–dimethyl sulfide complex24 (1.16 g,
5.65 mmol) in THF (32 cm3) and dimethyl sulfide (16 cm3) at
Ϫ40 ЊC, stirred for 30 min and cooled to Ϫ78 ЊC. A slurry of
the lactam Z-6 (2.43 g, 4.45 mmol) and anhydrous magnesium
bromide25 (4.36 g) in THF (30 cm3) was added very slowly to
the cuprate. After complete addition, the mixture was stirred at
Ϫ78 ЊC for 1 h and warmed to 0 ЊC over 90 min. Standard
aqueous work-up and chromatography (SiO2, hexane–EtOAc,
20:1 and then 10:1) gave an inseparable mixture (5:95) of 11
and the allylsilane (3.06 g, 94%); [α]D20 Ϫ26.3 (c 1.63 in CHCl3);
Rf(hexane–EtOAc, 5:1) 0.44; νmax(film)/cmϪ1 1740 (CO), 1695
Benzyl (Z)(3R)-3-dimethyl(phenyl)silylhexadec-4-enoate Z-13a
The lactam Z-12 (1.61 g) in THF (7 cm3) was added to lithium
benzyl oxide [prepared from n-butyllithium (1.6 mol dmϪ3 in
hexane, 7.7 cm3) and benzyl alcohol in THF (10 cm3)] and
stirred at room temperature for 24 h. Standard aqueous work-
up and chromatography (SiO2, hexane–EtOAc, 10:1) gave the
ester (0.95 g, 93%); [α]D20 Ϫ12.7 (c 1.90 in CHCl3); Rf(hexane–
EtOAc, 5:1) 0.60; νmax(film)/cmϪ1 1730 (CO), 1250 (SiMe) and
1110 (SiPh); δH(CDCl3) 7.57–7.44 (2 H, m, o-SiPh), 7.38–7.27
(8 H, m, CH2Ph, m- and p-SiPh), 5.31 (1 H, dt, J 10.8 and 7.0,
(CO) and 1600 (C᎐C); δ (CDCl ) 7.55–7.50 (2 H, m, o-SiPh),
᎐
H
3
7.37–7.14 (18 H, m, CPh3, m- and p-SiPh), 5.23 (1 H, dt, J 10.9
and 6.8, SiCHCH᎐CH), 5.05 (1 H, t, J 10.9, SiCHCH᎐CH),
᎐
᎐
4.39 (1 H, m, CHN), 3.34 (1 H, dd, J 9.6 and 4.4, CHAHB-
OCPh3), 3.17 (1 H, dd, J 16.4 and 11.4, SiCHCHAHB), 3.13
(1 H, m, CHACHBOCPh3), 2.81 (1 H, dt, J 17.8 and 10.2,
NCOCHAHB), 2.73 (1 H, dd, J 16.4 and 3.0, SiCHCHACHB),
2.61 (1 H, td, J 11.4 and 3.0, SiCH), 2.10–1.80 (4 H, m, NCO-
CH2CH2 and CH2), 1.24 (18 H, m, CH2), 0.87 (3 H, t, J 6.6,
Me), 0.33 (3 H, s, SiMeAMeB) and 0.30 (3 H, s, SiMeAMeB);
δC(CDCl3) 176.1, 173.4, 143.6, 137.2, 134.1, 129.8, 129.5, 129.1,
128.9, 128.5, 127.8, 127.1, 127.1, 86.9, 63.9, 56.6, 37.2, 33.0,
31.9, 29.7, 29.6, 29.5, 29.3, 27.6, 24.0, 22.7, 21.0, 14.1, Ϫ4.4 and
Ϫ5.3; m/z 727 (5%, Mϩ), 484 (4, M Ϫ CPh3), 243 (100, CPh3)
and 135 (35, PhMe2Si) (Found: Mϩ, 727.4492. C48H61NO3Si
requires M, 727.4420). The ratio of isomers was determined by
integration of the SiMe2 signals in the 1H NMR spectrum.
SiCHCH᎐CH), 5.08 (1 H, m, SiCHCH᎐CH), 5.02 (1 H, d,
᎐
᎐
J 12.1, CHAHBPh), 4.97 (1 H, d, J 12.1, CHAHBPh), 2.55 (1 H,
td, J 11.3 and 3.5, SiCH), 2.42 (1 H, dd, J 14.6 and 3.5, CHAHB-
CO), 2.22 (1 H, dd, J 14.6 and 11.7, CHAHBCO), 2.00–1.80
(2 H, m, CH2), 1.25 (18 H, m, CH2), 0.88 (3 H, t, J 6.5, Me),
0.28 (3 H, s, SiMeAMeB) and 0.27 (3 H, s, SiMeAMeB);
δC(CDCl3) 173.3, 136.7, 134.0, 130.0, 129.2, 128.4, 128.2, 128.0,
127.7, 66.1, 35.5, 31.9, 29.7, 29.6, 29.5, 29.4, 27.6, 25.1, 22.7,
14.1, Ϫ4.6 and Ϫ5.4; m/z 478 (0.04%, Mϩ), 463 (0.5, M Ϫ Me),
400 (2, M Ϫ C6H6), 387 (4, M Ϫ C7H7) and 135 (100, PhMe2Si)
(Found: Mϩ, 478.3236. C31H46O2Si requires M, 478.3267).
tert-Butyl (Z)(3R)-3-dimethyl(phenyl)silylhexadec-4-enoate
Z-13b
(5S)-1-[(Z)(3ЈS)-3Ј-Dimethyl(phenyl)silylhexadec-4Ј-enoyl]-5-
(trityloxymethyl)pyrrolidin-2-one 11
This was prepared in the same way as the benzyl ester Z-13a,
from the lactam Z-12 (1.98 g, 2.72 mmol) and lithium tert-butyl
oxide (30 mmol), stirring for 48 h to give the allylsilane (1.03 g,
85%); Rf(hexane–EtOAc, 5:1) 0.64; νmax(film)/cmϪ1 1730 (CO)
and 1250 (SiMe); δH(CDCl3) 7.50–7.47 (2 H, m, o-SiPh), 7.37–
7.30 (3 H, m, m- and p-SiPh), 5.28 (1 H, dt, J 10.9 and 7.0,
This was made in the same way as the allylsilane Z-12 from the
vinylcuprate Z-10 (1.02 mmol) and the lactam E-65 (187 mg,
0.34 mmol) to give the allylsilane (188 mg, 75%); [α]D20 Ϫ23.9 (c
2.98 in CHCl3); Rf(hexane–EtOAc, 5:1) 0.44; νmax(film)/cmϪ1
1740 (CO), 1690 (CO) and 1600 (SiPh); δH(CDCl3) 7.57–7.50
(2 H, m, o-SiPh), 7.44–7.10 (18 H, m, CPh3, m- and p-SiPh),
SiCHCH᎐CH), 5.08 (1 H, m, SiCHCH᎐CH), 2.50 (1 H, td,
᎐
᎐
5.25 (1 H, dt, J 10.8 and 6.8, SiCHCH᎐CH), 5.12 (1 H, t,
J 11.5 and 3.4, SiCH), 2.28 (1 H, dd, J 14.4 and 3.4, SiCHCHA-
CHB), 2.04 (1 H, dd, J 14.4 and 11.5, SiCHCHACHB), 2.00–1.80
(2 H, m, CH2), 1.37 (9 H, s, But), 1.25 (18 H, m, CH2), 0.88
(3 H, t, J 6.6, Me), 0.28 (3 H, s, SiMeAMeB) and 0.27 (3 H, s,
SiMeAMeB); m/z 444 (2.4%, Mϩ), 443 (6, M Ϫ H), 309 (95,
M Ϫ PhMe2Si) and 135 (100, PhMe2Si) (Found: Mϩ, 444.3404.
C28H48O2Si requires M, 444.3423).
᎐
J 10.8, SiCHCH᎐CH), 4.30 (1 H, m, CHN), 3.43 (1 H, dd, J 9.7
᎐
and 4.3, CHACHBOCPh3), 3.20–3.11 (2 H, m, CHAHBOCPh3
and SiCHCHACHB), 2.84 (1 H, dt, J 18.3 and 10.5, NCOCHA-
CHB), 2.64 (1 H, m, SiCHCHACHB), 2.41 (1 H, m, NCOCHA-
CHB), 2.28 (1 H, m, SiCH), 2.00–1.80 (4 H, m, NCOCH2CH2
and CH2), 1.25 (18 H, m, CH2), 0.88 (3 H, t, J 6.5, Me), 0.324
(3 H, s, SiMeAMeB) and 0.321 (3 H, s, SiMeAMeB); δC(CDCl3)
175.8, 173.3, 143.6, 137.0, 134.1, 129.2, 129.0, 128.7, 128.5,
127.8, 127.5, 127.0, 86.9, 63.7, 56.7, 37.9, 33.0, 31.0, 29.7, 29.64,
29.60, 29.5, 29.3, 27.6, 23.9, 22.6, 21.1, 14.1, Ϫ4.6 and Ϫ5.1;
m/z 727 (2%, Mϩ), 485 (6, M Ϫ CPh3 ϩ H), 243 (100, CPh3)
Benzyl (Z)(2R,3S)-3-dimethyl(phenyl)silyl-2-hexylhexadec-4-
enoate Z-14a
This was prepared in the same way as the ester Z-13b, from the
ester Z-13a (150 mg), to give the allylsilane (150 mg, 85%); [α]D20
J. Chem. Soc., Perkin Trans. 1, 1998
2683

View Article Online
Ϫ21.4 (c 2.33 in CHCl3); Rf(hexane–EtOAc, 5:1) 0.65;
νmax(film)/cmϪ1 1730 (CO), 1250 (SiMe) and 1110 (SiPh);
δH(CDCl3) 7.52–7.46 (2 H, m, o-SiPh), 7.40–7.26 (8 H, m, CH2-
(3 H, t, J 6.1, Me), 0.28 (3 H, s, SiMeAMeB) and 0.27 (3 H, s,
SiMeAMeB); m/z 259 (0.1%, M Ϫ Me) and 135 (100, PhMe2Si)
(Found: Mϩ Ϫ Me, C24H42OSi requires M Ϫ Me, 359.2770).
Ph, m- and p-SiPh), 7.35 (1 H, dt, J 10.8 and 7.2, SiCHCH᎐
᎐
CH), 4.82 (1 H, d, J 12.5, OCHACHBPh), 4.75 (1 H, d, J 12.5,
CHAHBPh), 2.43 (2 H, m, SiCHCH), 1.90–1.80 (2 H, m, CH2),
1.25–1.10 (28 H, m, CH2), 0.85 (6 H, m, 2 × Me), 0.29 (3 H, s,
SiMeAMeB) and 0.24 (3 H, s, SiMeAMeB); δC(CDCl3) 175.5,
137.5, 136.1, 134.2, 130.5, 128.4, 128.2, 128.0, 127.7, 127.5,
127.0, 65.7, 46.1, 31.9, 31.6, 30.6, 29.7–29.1 (m), 22.7, 22.6,
14.1, 14.0, Ϫ3.4 and Ϫ4.3; m/z 471 (1.2%, M Ϫ CH2Ph) and
135 (100, PhMe2Si) (Found: Mϩ Ϫ CH2Ph, 471.3693.
C37H58O2Si requires M Ϫ CH2Ph, 471.3658).
(3R,5S)-3-Dimethyl(phenyl)silylhexadecane-1,5-diol
Hydroboration (BH3ؒTHF, 2 equiv., 0 ЊC, 2 h)2 of the allyl-
silane Z-13a (117 mg) gave the diol (20.1 mg, 18%); Rf(hexane–
EtOAc, 3:1) 0.21; νmax(film)/cmϪ1 3300 (OH), 1250 (SiMe) and
1110 (SiPh); δH(CDCl3) 7.55–7.28 (5 H, m, Ph), 3.76–3.40 (3 H,
m, CHOH and CH2OH), 2.30 (2 H, s, OH), 1.80–1.10 (25 H, m,
CH2 and CH2SiCHCH2), 0.88 (3 H, t, J 6.0, Me), 0.36 (3 H, s,
SiMeAMeB) and 0.28 (3 H, s, SiMeAMeB); m/z 374 (0.2%,
M Ϫ H2O), 359 (0.3, M Ϫ Me Ϫ H2O), 205 (50), 137 (50,
MePhSiOH) and 135 (100, PhMe2Si) (Found: Mϩ Ϫ H2O,
374.2991. C24H42OSi requires M Ϫ H2O, 374.3004).
tert-Butyl (Z)(2R,3S)-3-dimethyl(phenyl)silyl-2-hexylhexadec-
4-enoate Z-14b
The ester Z-13b (365 mg) was added to LDA (0.24 mol dmϪ3 in
THF, 3.4 cm3) at Ϫ78 ЊC and the mixture stirred for 30 min.
Iodohexane (0.74 cm3) was added and the mixture stirred at
Ϫ78 ЊC for 1 h and warmed to 0 ЊC over 1 h. Standard aqueous
work-up gave the allylsilane (324 mg, 75%); Rf(hexane–EtOAc,
5:1) 0.72; νmax(film)/cmϪ1 1725 (CO), 1250 (SiMe) and 1110
(SiPh); δH(CDCl3) 7.52–7.47 (2 H, m, o-SiPh), 7.36–7.29 (3 H,
(Z)(2R,3S)-3-Dimethyl(phenyl)silyl-2-hexylhexadec-4-en-1-ol
Hydroboration (9-BBN, 1.3 equiv., reflux, 3 h)2 and oxidation
of the allylsilane Z-14b (80 mg) gave, after chromatography
(SiO2, hexane–EtOAc, 5:1), the starting material (30 mg, 38%)
and the alcohol (24 mg, 29%); Rf(hexane–EtOAc, 5:1) 0.50;
νmax(film)/cmϪ1 3400 (OH), 1250 (SiMe) and 1110 (SiPh);
δ (CDCl ) 7.52–7.33 (5 H, m, Ph), 5.35 (2 H, m, CH᎐CH),
᎐
H
3
m, m- and p-SiPh), 5.30 (1 H, dt, J 11.8 and 6.8, SiCHCH᎐CH),
3.50–3.30 (3 H, m, CH2OH and CHOH), 2.00–1.00 (32 H, m,
CH2 and SiCHCH), 0.87 (6 H, m, 2 × Me), 0.32 (3 H, s, SiMeA-
MeB) and 0.29 (3 H, s, SiMeAMeB); δC(CDCl3) 138.6, 133.9,
130.6, 128.9, 127.7, 127.3, 65.7, 41.6, 41.9, 31.8, 30.3, 29.8, 29.6,
29.5, 29.4, 28.6, 28.0, 27.6, 22.7, 22.6, 14.1, 14.0, Ϫ3.1 and
Ϫ3.4; m/z 457 (0.1%, M Ϫ Me), 306 (6, M Ϫ PhMe2SiOH), 152
(5, PhMe2SiOH) and 135 (100, PhMe2Si) (Found: Mϩ Ϫ H,
457.3847. C30H54OSi requires M Ϫ H, 457.3866).
᎐
5.14 (1 H, m, SiCHCH᎐CH), 2.46 (1 H, dd, J 11.8 and 7.5,
᎐
SiCH), 2.34 (1 H, m, COCH), 1.90–1.80 (2 H, m, CH2), 1.39
(9 H, s, But), 1.25–1.20 (28 H, m, CH2), 0.86 (6 H, m, 2 × Me)
and 0.29 (6 H, s, SiMe2); m/z 528 (1.6%, Mϩ), 457 (4,
M Ϫ C5H11), 443 (5, M Ϫ C6H15), 309 (90, M Ϫ C6H14 Ϫ
PhMe2Si) and 135 (100, PhMe2Si) (Found: Mϩ, 528.4334.
C34H60O2Si requires M, 528.4362).
tert-Butyl (E)(3R)-3-dimethyl(phenyl)silylhexadec-4-enoate
E-13b
This was prepared in the same way as the benzyl ester Z-13a,
from the lactam E-12 (2.98 g), to give the allylsilane (0.78 g,
43%); Rf (hexane–EtOAc, 5:1) 0.64; νmax(film)/cmϪ1 1730 (CO)
and 1250 (SiMe); δH(CDCl3) 7.49–7.45 (2 H, m, o-SiPh), 7.36–
(Z)(7R,8S)-7-(tert-Butyldimethylsilyloxymethyl)-8-dimethyl-
(phenyl)silylhenicos-9-ene Z-15
The ester Z-14a (1.87 g) in ether (20 cm3) was added to a slurry
of lithium aluminium hydride (0.7 g) in ether (20 cm3) and
stirred at 0 ЊC for 3 h. Standard aqueous work-up gave crude
alcohol [Rf(hexane–EtOAc, 5:1) 0.47] which was stirred with
imidazole (0.91 g) and tert-butylchlorodimethylsilane in DMF
(20 cm3) at room temperature for 1 h. Standard aqueous
work-up and chromatography (SiO2, hexane–EtOAc, 10:1)
gave the allylsilane (1.75 g, 91%); [α]D20 Ϫ21.4 (c 2.33 in CHCl3);
Rf(hexane–EtOAc, 5:1) 0.74; νmax(film)/cmϪ1 1250 (SiMe);
δH(CDCl3) 7.52–7.47 (2 H, m, o-SiPh), 7.35–7.28 (3 H, m, m-
7.31 (3 H, m, m- and p-SiPh), 5.24 (2 H, m, SiCHCH᎐CH),
᎐
2.30–2.10 (3 H, m, SiCHCH2), 1.94 (2 H, m, CH2), 1.37 (9 H, s,
But), 1.24 (18 H, m, CH2), 0.87 (3 H, t, J 6.4, Me) and 0.26 (6 H,
s, SiMe2); m/z 444 (4%, Mϩ), 373 (10, M Ϫ C5H11), 310 (25,
M Ϫ PhMe2Si ϩ H), 155 (40, C11H23) and 135 (100, PhMe2Si)
(Found: Mϩ, 444.3428. C28H48O2Si requires M, 444.3423).
and p-SiPh), 5.35 (1 H, dt, J 11.4 and 7.0, SiCHCH᎐CH), 5.21
᎐
tert-Butyl (E)(2R,3S)-3-dimethyl(phenyl)silyl-2-hexylhexadec-
4-enoate E-14b
This was prepared in the same way as the ester Z-14b, from the
ester E-13b (220 mg), to give the allylsilane (132 mg, 51%);
Rf(hexane–EtOAc, 5:1) 0.72; νmax(film)/cmϪ1 1725 (CO), 1250
(1 H, t, J 11.4, SiCHCH᎐CH), 3.36 (1 H, dd, J 9.5 and 4.9,
᎐
CHACHBO), 3.20 (1 H, dd, J 9.5 and 8.4, CHACHBO), 2.53
(1 H, dd, J 11.7 and 3.3, SiCH), 2.00–1.50 (3 H, m, SiCHCH
and CH2), 1.30–1.15 (28 H, m, CH2), 0.86 (15 H, m, 2 × Me and
But), 0.29 (3 H, s, SiMeAMeBPh), 0.26 (3 H, s, SiMeAMeBPh),
Ϫ0.04 (3 H, s, SiMeAMeBBut) and Ϫ0.06 (3 H, s, SiMeAMeB-
But); m/z 515 (0.5%, M Ϫ But), 440 (0.5, M Ϫ TBDMSOH),
427 (1, M Ϫ TBDMSOCH2), 379 (10, M Ϫ PhMe2Si Ϫ But),
365 (12, M Ϫ PhMe2Si Ϫ But Ϫ Me), 209 (50, PhMe2SiOSi-
Me2) and 135 (100, PhMe2Si) (Found: Mϩ Ϫ But, 515.4113.
C36H68OSi2 requires M Ϫ But, 515.4104).
(SiMe) and 970 (trans-CH᎐CH); δ (CDCl ) 7.52–7.46 (2 H, m,
᎐
H
3
o-SiPh), 7.33–7.29 (3 H, m, m- and p-SiPh), 5.14 (2 H, m,
SiCHCH᎐CH), 2.29 (1 H, m, SiCH), 2.08 (1 H, dt, J 3.2 and
᎐
6.7, COCH), 1.94 (2 H, m, CH2), 1.45 (2 H, m, CH2), 1.38 (9 H,
s, But ), 1.25–1.10 (26 H, m, CH2), 0.88 (6 H, m, 2 × Me), 0.29
(3 H, s, SiMeAMeB) and 0.28 (3 H, s, SiMeAMeB); m/z 528
(1, Mϩ), 472 (1, M Ϫ C4H8), 457 (2, M Ϫ C5H11), 444 (5,
M Ϫ C6H14), 309 (70, M Ϫ C6H14 Ϫ PhMe2Si) and 135 (100,
PhMe2Si) (Found: Mϩ, 528.4360. C34H60O2Si requires M,
528.4362).
(E)(7R,8S)-7-(tert-Butyldimethylsilyloxymethyl)-8-dimethyl-
(phenyl)silylhenicos-9-ene E-15
This was prepared in the same way as the allylsilane Z-15, from
the ester E-14b (119 mg), to give the allylsilane (130 mg, 100%);
Rf(hexane–EtOAc, 5:1) 0.74; νmax(film)/cmϪ1 1250 (SiMe);
δH(CDCl3) 7.50–7.46 (2 H, m, o-SiPh), 7.34–7.28 (3 H, m,
(Z)(3R)-3-Dimethyl(phenyl)silylhexadec-4-en-1-ol
Hydroboration (9-BBN, 1.5 equiv., 4 h, room temperature)2 of
the allylsilane Z-13a (93 mg) gave a mixture of the starting
material (52 mg, 56%) and the alcohol (23 mg, 32%); Rf(hexane–
EtOAc, 3:1) 0.47; νmax(film)/cmϪ1 3350 (OH), 1250 (SiMe) and
1110 (SiPh); δH(CDCl3) 7.51–7.26 (5 H, m, Ph), 5.34 (1 H,
m- and p-SiPh), 5.21 (2 H, m, SiCHCH᎐CH), 3.37 (1 H, dd,
᎐
J 9.6 and 4.8, CHAHBO), 3.25 (1 H, t, J 9.6, CHACHB), 2.10
(1 H, m, SiCH), 1.96 (2 H, m, CH2), 1.30–1.10 (28 H, m, CH2),
0.86 (15 H, m, 2 × Me and But), 0.28 (3 H, s, SiMeAMeBPh),
0.25 (3 H, s, SiMeAMeBPh), Ϫ0.03 (3 H, s, SiMeAMeBBut) and
Ϫ0.04 (3 H, s, SiMeAMeBBut); m/z 515 (0.2%, M Ϫ But), 440
(1, M Ϫ TBDMSOH), 427 (0.5, M Ϫ TBDMSOCH2), 379 (12,
dt, J 11.0 and 7.0, SiCHCH᎐CH), 5.14 (1 H, t, J 11.0, Si-
᎐
CHCH᎐CH), 3.63–3.44 (2 H, m, CH OH), 2.10 (1 H, td, J 11.6
᎐
2
and 2.6, SiCH), 2.00–1.10 (23 H, CH2, SiCHCH2 and OH), 0.88
2684
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
M Ϫ PhMe2Si Ϫ But), 365 (12, M Ϫ PhMe2Si Ϫ But Ϫ Me),
209 (20, PhMe2SiOSiMe2) and 135 (100, PhMe2Si) (Found:
Mϩ Ϫ But, 515.4086. C36H68OSi2 requires M Ϫ But, 515.4104).
m, CH2Ph, m- and p-SiPh), 4.34 (2 H, s, CH2Bn), 3.52–3.43
(3 H, m, CH2OH and CHOBn), 1.60–1.17 (34 H, m, CH2 and
SiCHCH), 0.87 (3 H, t, J 6.5, MeA), 0.85 (3 H, t, J 6.7, MeB),
0.33 (3 H, s, SiMeAMeB) and 0.32 (3 H, s, SiMeAMeB); m/z 551
(0.003%, M Ϫ Me), 165 (12, PhCH2OSiMe2), 135 (100, PhMe2-
Si) and 91 (100, CH2Ph) (Found: Mϩ Ϫ Me, 551.4280. C37H62-
O2Si requires M Ϫ Me, 551.4284).
(7R,8S,10S)-7-(tert-Butyldimethylsilyloxymethyl)-8-dimethyl-
(phenyl)silylhenicosan-10-ol 16
Hydroboration (9-BBN, 10 equiv., 24 h, reflux)2 and oxidation,
of the allylsilane Z-15 (250 mg) gave the alcohol (177 mg, 68%);
[α]D20 Ϫ4.3; Rf(hexane–EtOAc, 5:1) 0.59; νmax(film)/cmϪ1 3450
(OH) and 1250 (SiMe); δH(CDCl3) 7.52–7.47 (2 H, m, o-SiPh),
7.35–7.30 (3 H, m, m- and p-SiPh), 3.58 (2 H, dd overlying br m,
J 10.4 and 6.1, CHAHBOSi and CHOH), 3.40 (1 H, t, J 10.4,
CHACHBOSi), 3.70 (2 H, m, CH2), 1.30–1.10 (32 H, m, CH2
and SiCHCH), 0.88 (15 H, m, 2 × Me and But), 0.31 (3 H, s,
SiMeAMeBPh) and 0.29 (3 H, s, SiMeAMeBPh), 0.01 (3 H, s,
SiMeAMeBBut) and Ϫ0.01 (3 H, s, SiMeAMeBBut); δC(CDCl3)
139.2, 133.9, 128.8, 127.7, 70.9, 66.2, 40.8, 37.9, 34.4, 31.9,
31.8, 30–29 (m), 26.1, 25.9, 22.7, 22.6, 20.2, 18.2, 14.12, 14.07,
Ϫ2.7, Ϫ3.1, Ϫ5.3 and Ϫ5.4; m/z 575 (0.2%, M Ϫ Me), 533 (1,
M Ϫ But), 209 (30, PhMe2SiOSiMe2) and 135 (100, PhMe2Si)
(Found: Mϩ Ϫ Me, 575.4712. C36H70O2Si2 requires M Ϫ Me,
575.4680). The diastereoisomer 17 was not detectable (1H
NMR).
(2R,3S,5S)-5-Benzyloxy-3-dimethyl(phenyl)silyl-2-hexylhexa-
decanoic acid 19
The alcohol (1.62 g, 2.86 mmol) and PDC26 (3.3 g, 8.60 mmol)
were stirred in DMF (25 cm3) at room temperature for 2 h.
Chromatography of the solution (SiO2, hexane–EtOAc, 5:1)
gave the aldehyde (1.41 g, 88%). Jones’ reagent27 (2.5 cm3, 6.7
mmol) was added to the aldehyde in acetone (50 cm3). The
mixture was stirred at 0 ЊC for 45 min. The solvent was removed
under reduced pressure and chromatography (SiO2, hexane–
EtOAc, 5:1) gave the acid 19 (0.96 g, 62%); [α]D20 ϩ19.2 (c 2.7 in
CHCl3); Rf(hexane–EtOAc, 5:1) 0.40; νmax(film)/cmϪ1 3500–
2300 (OH), 1700 (CO), 1250 (SiMe) and 1110 (SiPh);
δH(CDCl3) 7.52–7.49 (2 H, m, o-SiPh), 7.35–7.26 (8 H, m, C2Ph,
m- and p-SiPh), 4.44 (1 H, d, J 11.5, CHAHBPh), 4.32 (1 H, d,
J 11.5, CHACHBPh), 3.40 (1 H, m, CHOBn), 2.52 (1 H, m,
CHCO2H), 1.70–1.10 (33 H, m, CH2 and SiCH), 0.87 (6 H, m,
2 × Me), 0.35 (3 H, s, SiMeAMeB) and 0.32 (3 H, s, SiMeAMeB);
m/z 580 (0.1%, Mϩ), 565 (0.7, M Ϫ Me), 503 (4, M Ϫ Ph), 472
(5, M Ϫ BnOH), 135 (60, PhMe2Si) and 91 (100 CH2Ph)
(Found: Mϩ, 580.4296. C37H60O3Si requires M, 580.4314).
(7R,8S,10R)-7-(tert-Butyldimethylsilyloxymethyl)-8-dimethyl-
(phenyl)silylhenicosan-10-ol 17
This was prepared in the same way as the alcohol 16, from the
allylsilane E-15 (127 mg), to give a mixture of the alcohols 16
and 17 (1:4, 70 mg, 59%); [α]D Ϫ15.8 (c 1.00 in CHCl3);
Rf(hexane–EtOAc, 5:1) 0.59; νmax(film)/cmϪ1 3400 (OH) and
1250 (SiMe); δH(CDCl3) 7.51–7.47 (2 H, m, o-SiPh), 7.34–7.30
(3 H, m, m- and p-SiPh), 3.57 (1 H, dd, J 10.4 and 5.1, CHA-
CHBO), 3.44 (1 H, t, J 10.4, CHACHBO), 3.20 (1 H, m, CHOH),
2.94 (1 H, s, OH), 1.70–1.15 (31 H, m, SiCH and CH2), 0.88
(15 H, m, CH2 and But), 0.32 (6 H, s, SiMe2Ph), 0.02 (3 H, s,
SiMeAMeBBut) and 0.00 (3 H, s, SiMeAMeBBut); δC(CDCl3)
139.0, 133.8, 128.9, 127.7, 72.8, 64.4, 41.0, 37.6, 32.2, 31.9, 31.7,
30–29.4 (m), 28.3, 25.9, 25.7, 22.8, 22.7, 22.6, 18.2, 14.1, 14.0,
Ϫ3.0, Ϫ3.2 and Ϫ5.3; m/z 533 (0.4%, M Ϫ But) and 135 (100,
PhMe2Si) (Found: Mϩ Ϫ But, 533.4247. C36H70O2Si2 requires
M Ϫ But, 533.4210). The isomer ratio was determined from the
13C NMR spectrum.
(2S,3S,5S)-5-Benzyloxy-3-hydroxy-2-hexylhexadecanoic acid 20
The silyl acid 19 (43 mg) and mercuric acetate (30 mg) were
stirred in peracetic acid (15% in AcOH, 1 cm3) at room tem-
perature for 3 h. Chromatography (SiO2, Et2O), gave the
hydroxy acid (13 mg, 38%); Rf(hexane–EtOAc, 1:1) 0.20;
νmax(film)/cmϪ1 3400–2400 (OH); δH(CDCl3) 7.36–7.29 (5 H, m,
Ph), 4.67 (1 H, d, J 11.2, CHACHBOBn), 4.40 (1 H, d, J 11.2,
CHACHBOBn), 3.94 (1 H, dt, J 9.8 and 3.0, CHOH), 3.75 (1 H,
ddd, J 13.7, 7.0 and 3.2, CHOBn), 2.35 (1 H, ddd, J 9.2, 6.0 and
3.0, CHCO2H), 1.75 (33 H, CH2 and OH) and 0.87 (6 H, m,
2 × Me); δC(CDCl3) 176.3, 137.4, 128.7, 128.0, 127.9, 80.3,
72.3, 70.6, 51.7, 38.5, 33.0, 31.9, 31.6, 29.8, 29.6, 29.5, 29.3,
29.1, 27.2, 24.3, 22.7, 22.5, 14.1 and 14.0; m/z 460 (0.5%,
M Ϫ 2 × H), 338 (1, M Ϫ C7H8O2), 123 (1, C7H7O2), 105 (40,
PhCO) and 91 (100, PhCH2) (Found: Mϩ Ϫ 2 × H, 460.3527.
C29H50O4 requires M Ϫ 2 × H, 460.3553).
(7R,8S,10S)-10-Benzyloxy-7-(tert-butyldimethylsilyloxymethyl)-
8-dimethyl(phenyl)silylhenicosane 18
The alcohol 16 (1.9 g) was stirred in cyclohexane (30 cm3) and
dichloromethane (30 cm3) with benzyl trichlorobenzylacetim-
idate9 (1.5 cm3) and trifluoromethansulfonic acid (0.15 cm3) at
room temperature for 30 min. Standard aqueous work-up and
chromatography (SiO2, hexane–EtOAc, 10:1) gave the benzyl
ether (1.99 g, 91%); Rf(hexane–EtOAc, 5:1) 0.57; νmax(film)/
cmϪ1 1250 (SiMe); δH(CDCl3) 7.51–7.47 (2 H, m, o-SiPh), 7.35–
7.26 (8 H, m, CH2Ph, m- and p-SiPh), 4.34 (2 H, s, CH2Ph), 3.34
(2 H, m, CH2OTBDMS), 3.22 (1 H, m, CHOBn), 1.60–1.13
(34 H, m, CH2 and SiCHCH), 0.87 (15 H, m, But and 2 × Me),
0.31 (3 H, s, SiMeAMeBPh), 0.29 (3 H, s, SiMeAMeBPh) and
Ϫ0.01 (6 H, s, SiMe2But); m/z 665 (0.2%, M Ϫ Me), 623 (0.5,
M Ϫ But), 209 (25, PhMe2SiOSiMe2), 135 (100, PhMe2Si) and
91 (60, PhCH2) (Found: Mϩ Ϫ Me, 665.5203. C42H73O2Si2
requires M Ϫ Me, 665.5149).
(3S,4S)-4-[(S)-2Ј-Benzyloxytridecyl]-3-hexyloxetan-2-one 21
The silyl acid 19 (0.8 g) and mercuric acetate (1 g) were stirred
in peracetic acid (30 cm3) at room temperature for 18 h. The
solvent was evaporated under reduced pressure. Standard
aqueous work-up and chromatography (SiO2, Et2O–Me2CO,
1:1) gave crude hydroxy acid, which was dissolved in pyridine
(50 cm3) at 0 ЊC. Benzenesulfonyl chloride (6 cm3) was added
and the mixture stirred at 0 ЊC for 15 h. Standard aqueous
work-up and chromatography (SiO2, hexane–EtOAc, 3:1) gave
the lactone (0.46 g, 76%); Rf(hexane–EtOAc, 3:1) 0.6; νmax
-
(CH2Cl2) 1825 (lactone CO); δH(CDCl3) 7.35–7.25 (5 H, m, Ph),
4.54 (1 H, d, J 11.5, CHACHBPh), 4.41 (1 H, d, J 11.5, CHA-
CHBPh), 4.40 (1 H, m, CHOCO), 3.50 (1 H, m, C11CHO), 3.24
(1 H, dt, J 4 and 7.5, CHCO2), 2.15 (1 H, dt, J 14.4 and 6.5,
OCHCHAHBCHO), 1.90 (1 H, m, OCHCHAHBCHO), 1.50–
1.20 (30 H, m, 15 × CH2) and 0.86 (6 H, m, 2 × Me); m/z 338
(0.1%, M Ϫ PhCHO), 275 (0.8, M Ϫ C10H17O2), 107 (20,
PhCH2O) and 91 (100, PhCH2) (Found: Mϩ Ϫ PhCHO,
338.3180. C29H48O3 requires M Ϫ PhCHO, 338.3184).
(2R,3S,5S)-5-Benzyloxy-3-dimethyl(phenyl)silyl-2-hexylhexa-
decan-1-ol
Tetrabutylammonium fluoride (1 mol dmϪ3 in THF, 30 cm3)
was added to the silyl ether 18 (1.99 g) and the mixture stirred at
room temperature for 1 h. Standard aqueous work-up and
chromatography (SiO2, hexane–EtOAc, 10:1) gave the alcohol
(1.62 g, 98%); [α]D20 ϩ2.3 (c 1.8 in CHCl3); Rf(hexane–EtOAc,
5:1) 0.40; νmax(film)/cmϪ1 3400 (OH), 1250 (SiMe) and 1110
(SiPh); δH(CDCl3) 7.53–7.38 (2 H, m, o-SiPh), 7.36–7.26 (8 H,
(3S,4S)-3-Hexyl-4-[(S)-2Ј-hydroxytridecyl]oxetan-2-one 22
The benzyl ether 21 (0.46 g) and palladium (10% on charcoal,
1 g) were stirred in THF (20 cm3) under hydrogen for 15 h.
Filtration and chromatography (SiO2, hexane–EtOAc, 3:1)
J. Chem. Soc., Perkin Trans. 1, 1998
2685

View Article Online
2 I. Fleming and N. J. Lawrence, J. Chem. Soc., Perkin Trans. 1, 1992,
3309.
gave the alcohol12 (0.34 g, 92%) as needles mp 64–65 ЊC (lit.12
mp 64.5–65.5 ЊC); [α]D20 Ϫ15.3 (c 1.2 in CH2Cl2) (lit.12 [α]D Ϫ15);
Rf(hexane–EtOAc, 3:1) 0.40; νmax(film)/cmϪ1 3600 (OH), 1820
3 R. A. N. C. Crump, I. Fleming, J. H. M. Hill, D. Parker, N. L. Reddy
and D. Waterson, J. Chem. Soc., Perkin Trans. 1, 1992, 3277.
4 I. Fleming, R. Henning, D. C. Parker, H. E. Plaut and P. E. J.
Sanderson, J. Chem. Soc., Perkin Trans. 1, 1995, 317.
5 I. Fleming and N. D. Kindon, J. Chem. Soc., Perkin Trans. 1, 1995,
303.
6 I. Fleming and N. J. Lawrence, Tetrahedron Lett., 1990, 31, 3645.
7 I. Fleming, T. W. Newton and F. Roessler, J. Chem. Soc., Perkin
Trans. 1, 1981, 2527.
8 A. W. P. Jarvie, A. Holt and J. Thompson, J. Chem. Soc. (B), 1969,
852; R. B. Miller and G. McGarvey, J. Org. Chem., 1979, 44, 4623.
9 T. Iversen and D. R. Bundle, J. Chem. Soc., Chem Commun., 1981,
1240.
10 C. C. Price and J. R. Sowa, J. Org. Chem., 1967, 32, 4126; K. Tamao,
T. Yamauchi and Y. Ito, Chem. Lett., 1987, 171; I. Fleming, S. K.
Patel and C. J. Urch, J. Chem. Soc., Perkin Trans. 1, 1989, 115; P. F.
Hudrlik, Y. M. Abdallah and A. M. Hudrlik, Tetrahedron Lett.,
1992, 33, 6747; S. C. Archibald and I. Fleming, Tetrahedron Lett.,
1993, 34, 2387; A. Barbero, D. C. Blakemore, I. Fleming and R. N.
Wesley, J. Chem. Soc., Perkin Trans. 1, 1997, 1329.
11 W. Adam, J. Baeza and J.-C. Liu, J. Am. Chem. Soc., 1972, 94, 2000;
S. Mageswaran and M. U. S. Sultanbawa, J. Chem. Soc., Perkin
Trans. 1, 1976, 884; J. Mulzer, A. Pointer, A. Chucholowski and
G. Brüntrup, J. Chem. Soc., Chem Commun., 1979, 52.
12 S. Kondo, K. Uotani, M. Miyasmoto, T. Hazato, H. Naganawa,
T. Aoyagi and H. Umezawa, J. Antibiotics, 1978, 31, 797.
13 P. Barbier and F. Schneider, Helv. Chim. Acta, 1987, 70, 196.
14 P. Barbier, F. Schneider and U. Widmer, Helv. Chim. Acta, 1987, 70,
1412.
15 P. Barbier and F. Schneider, J. Org. Chem., 1988, 53, 1218.
16 A. Pommier, J.-M. Pons, P. Kocienski and L. Wong, Synthesis, 1994,
1294.
17 S. Hanessian, A. Tehim and P. Chen, J. Org. Chem., 1993, 58, 7768;
B. Giese and M. Roth, J. Braz. Chem. Soc., 1996, 7, 243.
18 S. C. Case-Green, S. G. Davies and C. J. R. Hedgecock, Synlett,
1991, 781.
(lactone C᎐O); δ (CDCl ) 4.46 (1 H, dt, J 4.1 and 6.5,
᎐
H
3
CHOCO), 3.76 (1 H, m, CHOH), 3.30 (1 H, ddd, J 8.5, 6.8 and
4.0, CHCO), 2.00–1.15 (33 H, m) and 0.87 (6 H, m, 2 × Me);
δC(CDCl3) 171.4, 76.2, 69.3, 56.7, 41.1, 37.6, 31.9, 31.5, 29.6,
29.54, 29.5, 29.3, 28.9, 27.8, 26.7, 25.4, 22.6, 22.5, 14.1 and 14.0.
(S)-1Ј-[(2ЉS,3ЉS)-3Љ-Hexyl-4Љ-oxooxetan-2Љ-yl]methyldodecyl
(S)-N-formylleucinate (tetrahydrolipstatin) 1
DCC (167 mg) and (S)-N-(benzyloxycarbonyl)leucine 23 (418
mg) were stirred in dichloromethane (6 cm3) at 0 ЊC for 15 min.
The solvent was evaporated under reduced pressure and the
residue dissolved in DMF (5 cm3) and added to a solution of
the alcohol (56 mg) and DMAP (15 mg) in DMF (1 cm3). The
mixture was stirred at room temperature for 1 h. Standard
aqueous work-up and chromatography (SiO2, hexane–EtOAc,
3:1) gave N-CBz-protected ester, Rf(hexane–EtOAc, 3:1) 0.50,
which was stirred with palladium (10% on charcoal, 100 mg) in
THF (10 cm3) under hydrogen at room temperature for 4 h. The
solution was filtered over Celite and evaporated under reduced
pressure. The crude residue was stirred with formic acetic
anhydride (0.2 cm3) in dichloromethane (0.5 cm3) at room tem-
perature for 15 min. Standard aqueous work-up and chroma-
tography (SiO2, hexane–EtOAc, 3:1) gave tetrahydrolipstatin
(69 mg, 89%) as an amorphous solid mp 40–41 ЊC (lit. mp
43 ЊC,1 41–42.5 ЊC,13 40–42 ЊC,14,15 40–41 ЊC,16,17,18 42–43 ЊC19);
[α]D25 Ϫ33.4 (c 1.33 in CHCl3) {lit. [α]D20 Ϫ32 (c 1 in CHCl3),1 [α]D20
Ϫ34.45 (c 1 in CHCl3),13 [α]D20 Ϫ33 (c 0.36 in CHCl3),14,15 [α]D20
Ϫ31.2 (c 0.5 in CHCl3),16 [α]D Ϫ33 (CHCl3),17 [α]D20 Ϫ31.8 (c 0.37
in CHCl3),18 [α]D25 Ϫ34.58 (c 0.96 in CHCl3)19}; νmax(CHCl3) 1825
(lactone CO), 1740 (NHCO2) and 1695 (NHCHO); δH(CDCl3)
8.20 and 8.05 (1 H, s and d, J 7, NHCHO), 5.93 (1 H, d, J 9,
NH), 5.02 (1 H, m, CHOleucine), 4.67 (1 H, dt, J 4.5 and 8.5,
CHNH), 4.28 (1 H, 5-line m, lactone CHOCO), 3.20 (1 H, dt,
J 4.0 and 7.5, lactone CHCO), 2.15 (1 H, dt, J 14.7 and 7.8,
OCHCHAHBCHO), 1.98 (1 H, dt, J 14.7 and 4.5, OCHCHA-
HBCHO), 1.90–1.20 (33 H, m, 15 × CH2 and Me2CHCH2), 0.95
(6 H, d, J 5.1, CHMe2) and 0.87 (6 H, m, 2 × Me); δC(CDCl3)
171.9, 170.8, 160.9, 74.7, 72.6, 56.9, 49.6, 41.3, 38.6, 34.0, 31.8,
31.4, 29.6 (2C), 29.5, 29.4, 29.3, 28.9, 27.6, 26.6, 25.0, 24.8, 22.8,
22.5, 21.7, 14.1 and 14.0.
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22 J. Klein and E. Gurfinkel, Tetrahedron, 1970, 26, 2127.
23 M. V. George, D. J. Peterson and H. Gilman, J. Am. Chem. Soc.,
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25 C. L. Stevens and S. J. Dykstra, J. Am. Chem. Soc., 1954, 76, 4402.
26 E. J. Corey and G. Schmidt, Tetrahedron Lett., 1979, 399.
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Acknowledgements
We thank the SERC (now EPSRC) for a studentship (N. J. L.),
and Dr P. Barbier of Hoffmann-La Roche for a gift of
tetrahydrolipstatin.
References
Paper 8/04275F
Received 5th June 1998
Accepted 3rd July 1998
1 E. Hochuli, E. Kupfer, R. Maurer, W. Meister, Y. Mercadel and
K. Schmidt, J. Antibiotics, 1987, 40, 1086.
2686
J. Chem. Soc., Perkin Trans. 1, 1998