Asymmetric syntheses of panclicins A-E via [2+2] cycloaddition of alkyl(trimethylsilyl)ketenes to a β-silyloxyaldehyde

Article abstract of DOI:10.1039/a800807h

Panclicins A-E, pancreatic lipase inhibitors from Streptomyces, were synthesised in a modular fashion starting with three alkyl(trimethylsilyl)ketenes, two amino acids and a single aldehyde component, (3R)-3-(tert-butyldimethylsilyloxy)decanal 11. The lone stereocentre in 11 which governs the stereochemistry in subsequent steps was generated by Noyori asymmetric hydrogenation. The key step, a Lewis acid catalysed [2+2] cycloaddition of alkyl(trimethylsilyl)ketenes 13a-c to 11, gave three 3-trimethylsilyloxetan-2-ones with good 1,3-asymmetric induction. After C- and O-desilylation the amino acid side chains were introduced using a Mitsunobu inversion.

Full text of DOI:10.1039/a800807h

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Asymmetric syntheses of panclicins A–E via [2؉2] cycloaddition of
alkyl(trimethylsilyl)ketenes to a â-silyloxyaldehyde
Philip J. Kocien´ski,*,a Beatrice Pelotier,a,b Jean-Marc Pons*,b and
Heather Prideauxa
a Department of Chemistry, Glasgow University, Glasgow, UK G12 8QQ
b Laboratoire de Réactivité en Synthèse Organique (RéSo), UMR CNRS 6516,
Faculté de St.-Jérôme, boite D12, 13397 Marseille Cedex 20, France
Panclicins A–E, pancreatic lipase inhibitors from Streptomyces, were synthesised in a modular fashion
starting with three alkyl(trimethylsilyl)ketenes, two amino acids and a single aldehyde component, (3R)-
3-(tert-butyldimethylsilyloxy)decanal 11. The lone stereocentre in 11 which governs the stereochemistry
in subsequent steps was generated by Noyori asymmetric hydrogenation. The key step, a Lewis acid
catalysed [2؉2] cycloaddition of alkyl(trimethylsilyl)ketenes 13a–c to 11, gave three 3-trimethylsilyloxetan-
2-ones with good 1,3-asymmetric induction. After C- and O-desilylation the amino acid side chains were
introduced using a Mitsunobu inversion.
(tert-butyldimethylsilyloxy)decanal 11, which harbours the
Introduction
2-hydroxynonyl side chain common to all the panclicins. Since
the lone stereogenic centre at C3 in aldehyde 11 controls the
stereochemistry of all the subsequent steps in the synthesis, it
was imperative that it be installed efficiently and economically.
These requirements were satisfied by the five-step route
depicted in Scheme 1. Acylation of Meldrum’s acid (6) with
Panclicins A–E 1–5 are potent pancreatic lipase inhibitors pro-
duced by Streptomyces sp. NR 0619.1 Like lipstatin,2,3 ester-
astin4 and valilactone,5 the panclicins contain a β-lactone
structure with two alkyl chains one of which bears an α-N-
formylamino acyloxy group. As inhibitors of pancreatic lipase,
panclicins C, D and E are twice as potent as tetrahydrolipstatin
(IC50 = 1.2 µ), which is marketed as an antiobesity agent.6–8
Several syntheses of tetrahydrolipstatin have been reported9–16
as have syntheses of lipstatin itself17 and valilactone.18 However,
only one synthesis of panclicin D has been described to date.19
O
O
O
CH3(CH2)6COCl, pyr
O
CH3(CH2)6
O
CH2Cl2, 0 °C → r.t., 1.5 h
O
O
O
O
NHCHO
O
6
7
MeOH, , 16 h
O
O
O
O
R
OH
O
O
H
H
Ru[(R)-BINAP]2 (cat.)
H
2 (200 psi)
Panclicin A (1) R = CH(CH3)2
Panclicin B (2) R = (CH2)2CH3
CH3(CH2)6
OMe
CH3(CH2)6
OMe
MeOH, HCl
40 °C, 48 h, 82%
99:1
8 (ca. 69% overall)
9
NHCHO
O
TBSCl
imidazole, DMF
75%
O
O
O
R
TBSO
CH3(CH2)6
O
TBSO
CH3(CH2)6
O
DIBALH
H
H
OMe
CH2Cl2, –80 °C
66%
Panclicin C (3) R = CH(CH3)2
Panclicin D (4) R = (CH2)4CH3
Panclicin E (5) R = (CH2)2CH3
TBS = SiMe2But
11
10
Scheme 1
We now report a synthesis of panclicins A–E 1–5 which features
a diastereoselective Lewis acid catalysed [2ϩ2] cycloaddition of
an alkyl(trimethylsilyl)ketene to a homochiral β-hydroxyalde-
hyde derivative. We also include some experiments relating to
the stereochemistry of the key cycloaddition step, as well as
a further refinement of our notion of the mechanism of the
cycloaddition.
octanoyl chloride followed by methanolysis of the crude inter-
mediate 7 gave methyl 3-oxodecanoate (8) in 72% overall
yield.20 Catalytic asymmetric hydrogenation21–23 of the β-keto
ester to give 9 using [(R)-(ϩ)-2,2Ј-bis(diphenylphosphino)-1,1Ј-
binaphthyl]chloro(p-cymene)ruthenium chloride installed the
requisite R-configured stereogenic centre in good yield and high
enantiomeric ratio (99:1) according to NMR spectroscopic
analysis of the Mosher ester derivative. The sequence was com-
pleted by first protecting the hydroxy function as its tert-
butyldimethylsilyl (TBS) ether to give 10 followed by reduction
of the ester to the aldehyde using DIBAL-H. The overall yield
of 11 for the five-step sequence was 28%.
Results and discussion
The similarity in structure of the five panclicins invited a
modular approach involving three alkyl(trimethylsilyl)ketenes,
two amino acids and a single aldehyde component, (3R)-3-
J. Chem. Soc., Perkin Trans. 1, 1998
1373

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(a) BuLi, THF, –80 °C
(b) RI, HMPA, r.t.
R
Yield 15+16 15:16
OEt
R
OEt
TBSO
CH3(CH2)6
O
a
b
c
(CH2)7CH(CH3)2
(CH2)9CH3
(CH2)11CH3
84%
57%
73%
83:17
94:6
92:8
12a-c
Me3SiI, Cu
70 °C, 48 h
11
O
SiMe3
Me3Si–C(R)=C=O
EtAlCl2, Et2O
–40 → 0 °C
O
O
13a-c
R
•
O
O
Me3Si
R
Me3Si
R
TBSO
TBSO
CH3(CH2)6
O
H
O
+
R
R
14
13a-c
CH3(CH2)6
H
SiMe3
SiMe3
R
Yield 12
Yield 13
15a-c
16a-c
(CH2)9CH(CH3)2
(CH2)9CH3
(CH2)11CH3
a
b
c
49%
68%
60%
50%
44%
44%
(a) HF, MeCN-H2O, r.t., 4 h
(b) separate
Scheme 2
O
O
HO
O
H
HO
O
H
+
The three alkyl(trimethylsilyl)ketenes 13a–c were prepared
by a modification of Sakurai’s procedure24 (Scheme 2). Thus
alkylation of ethoxyethynyllithium with 1-iodo-8-methyl-
nonane, 1-iododecane and 1-iodododecane gave the three
ethoxyalkyne derivatives 12a–c, respectively, in 49–68% yield.
The ethoxyalkynes 12a–c were slowly converted to the desired
silylketenes 13a–c on heating with ca. 1.5 equivalents of freshly
prepared iodotrimethylsilane but under the reaction conditions,
the silylketenes dimerised to the diketene derivatives 14a–c.
However, removal of the excess iodotrimethylsilane in vacuo,
allowed thermolysis of the diketenes at 140–170 ЊC to the
silylketenes 13a–c which were isolated as stable, colourless oils
which could be stored for several weeks at Ϫ20 ЊC.
R
R
CH3(CH2)6
CH3(CH2)6
SiMe3
SiMe3
18a-c
17a (85%), b (37%), c (66%)
TBAF•3H2O
THF, –90 °C
O
N-formylglycine
DIAD, PPh3
HO
O
H
Panclicin C (3, 70%)
Panclicin D (4, 67%)
Panclicin E (5, 87%)
R
CH3(CH2)6
THF, r.t., 18 h
H
19a (84%), b (93%), c (56%)
(S)-N-tritylalanine
DIAD, Ph3P, THF, r.t., 18 h
The [2ϩ2] cycloadditions of the three alkyl(trimethyl-
silyl)ketenes 13a–c with the aldehyde 11 were performed using
the conditions that had been previously optimised for our
synthesis of tetrahydrolipstatin,15 i.e. using ethylaluminium
dichloride as Lewis acid and diethyl ether as solvent (Scheme
3). An inseparable mixture of four diastereoisomers was
NHTr
O
O
(a) TFA
O
O
H
Panclicin A (1, 63%)
Panclicin B (2, 96%)
1
obtained from the cycloaddition and H NMR spectroscopic
(b) AcOCHO
R
CH3(CH2)6
analysis (300 MHz) of the crude reaction mixture revealed two
sets of signals (dd) at δ 4.64–4.67 (J 11.0–11.6, 1.7–1.8 Hz)
corresponding to the diastereoisomers 15a–c and at δ 4.56–4.57
(J 11.0, 1.5 Hz) corresponding to the diastereoisomers 16a–c.
Both sets of signals were accompanied by unresolved small
shoulders ascribable to the remaining two isomers (not shown)
which together accounted for less than 10% of the total isomer
distribution. By analogy with the tetrahydrolipstatin study,15
both major isomers bore the correct S configuration at C4 and
differed only in the stereochemistry at C3. The R configuration
assigned to the preponderant isomers 15a–c was deduced from
NOE studies but firmer corroborative evidence was later
gleaned from an analogue (vide infra).
H
20a (23%)
20b (63%)
Scheme 3
immediate N-formylation with formic acetic anhydride gave
pure samples of panclicins A 1 and B 2 after column chrom-
atography. Panclicins C 3, D 4 and E 5 were obtained in 67–87%
yield by direct Mitsunobu esterification of 19a–c with N-formyl-
glycine. The synthetic panclicins A–E obtained by our route
were identical by high field 1H and 13C NMR spectroscopy and
[α]D with data reported for the natural products.1
To complete the synthesis of all five panclicins, the tert-
butyldimethylsilyl protecting group was removed from 15a–c
with HF in aqueous acetonitrile and pure samples of the major
isomers 17a–c could then be obtained by column chrom-
atography. C-Desilylation occurred on brief exposure to tetra-
butylammonium fluoride (TBAF) in THF at Ϫ90 ЊC to give
the crystalline trans-disubstituted β-lactone derivatives 19a–c
selectively. However, for preparative purposes, the tandem
O-silylation and C-desilylation were best achieved without
purification of intermediates and minor diastereoisomers
removed by the easy recrystallisation of 19a–c from pentane.
Attempts to prepare panclicins A and B by direct Mitsunobu
esterification of 19a and 19b with N-formylalanine were
thwarted by the easy racemisation of the N-formylalanine resi-
due under the reaction conditions. By contrast, Mitsunobu
esterification with (S)-N-tritylalanine25,26 occurred smoothly to
give the ester derivatives 20a (23%) and 20b (63%). Removal of
the trityl group with trifluoroacetic acid (TFA) followed by
Stereochemistry and mechanism of the Lewis acid catalysed
[2؉2] cycloaddition of silylketenes to aldehydes
Our assignment of the (3R,4S) stereochemistry to the major
cycloadducts 15a–c was based on spectroscopic comparison
with the analogous major cycloadduct 21 obtained in our pre-
vious tetrahydrolipstatin synthesis wherein the stereochemistry
was ascertained by NOE analysis of the alkenylsilane 23
derived from thermolysis of the β-lactone 22 (Scheme 4).15 In
order to obtain a less convoluted and more secure assignment,
we examined the cycloaddition of aldehyde rac-25 with n-
hexyl(trimethylsilyl)ketene using ethylaluminium dichloride as
the Lewis acid (Scheme 5). Two cycloadducts rac-26a,b were
formed in 81% yield and the relative stereochemistry of the
major isomer (91% of the mixture), ascertained by X-ray crys-
tallography, corroborated the (3R,4S) stereochemistry.27 More-
over, we were able to show that the n-hexyl group on the
silylketene did not markedly influence the stereochemistry of
1374
J. Chem. Soc., Perkin Trans. 1, 1998

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Ar
Ar
11% NOE
O
190 °C
O
O
O
H
O
O
–CO2
86%
C6H13
SiMe3
C11H23
C11H23
C5H11
SiMe3
22
23
(a) HF, H2O-MeCN
(b) ArCOCl, DMAP
O
TBSO
C11H23
O
4
Ar = 3,5-dinitrophenyl
3
C6H13
SiMe3
H
Fig. 1
(3R,4S)-21
δ 4.64, dd, J 11.7, 1.9
Scheme 4
strong stereoelectronic preference for the cis orientation of
the aldehyde substituent and the trimethylsilyl group in the
cycloaddition.
In 1994 we proposed that the Lewis acid catalysed cyclo-
addition of silylketenes to aldehydes involved attack by the
nucleophilic silylketene (terminal carbon atom) on an aldehyde–
Lewis acid complex.15 Such a mechanism, although not obvi-
ous, was based on experimental evidence from Zaitseva’s
group,30,31 the high electron density of the terminal carbon
O
TBSO
TBSO
(a) O3 / CH2Cl2-MeOH
(b) Me2S, r.t., 12 h
25
24
n-C6H13(Me3Si)C=C=O
EtAlCl2 / CH2Cl2
TBSO
81%
atom of the trimethylsilylketene (Me SiCH᎐C᎐O: δ 1.65;
O
O
᎐ ᎐
3
H
TBSO
O
O
H
δC Ϫ0.3), and theoretical work from Tidwell and co-workers
on the stability of silylketenes32 together with preliminary
theoretical studies by Yamabe et al. on the [2ϩ2] cyclo-
addition.33 More recently, ab initio calculations on the Lewis
acid catalysed [2ϩ2] cycloaddition of ketene to formaldehyde
reported by Cossio and co-workers (with BH3 as a model Lewis
acid)34,35 and us (with BF3 as Lewis acid)36 lent support to such
a mechanism. Indeed, in both cases, calculations reveal prior
formation of the C᎐C bond between the terminal carbon atom
of the ketene and the carbon atom of the formaldehyde. More-
over, only a synperiplanar approach of the reactants was found
which is in agreement with our proposed mechanism. We have
also calculated at the semiempirical level, including solvation
effects (AM1/RHF-COSMO), the influence of the introduction
of a silyl (SiH3) or a trimethylsilyl group on the ketene. Apart
from an increase in the activation energy, which can be attrib-
uted to the remarkable stability of silylketenes, we found no
significant changes on the reaction profile which remains con-
certed, but asynchronous, with a pronounced ionic character.
Fig. 1 depicts a model of the transition state for the [2ϩ2]
cycloaddition of (trimethylsilyl)ketene and acetaldehyde
catalysed by BF3 which is extrapolated from the theoretical
studies based on simpler systems.37 The hydrogen atoms on the
trimethylsilyl group have been omitted for clarity.
We previously speculated that the 1,3-diastereoselectivity
observed in [2ϩ2] cycloadditions to β-silyloxy aldehydes origin-
ates from an attractive electrostatic interaction between the
aldehyde oxygen and the complexed β-silyloxy aldehyde result-
ing in a preferred conformation similar to that which would be
expected for a chelated complex.15 Indeed Zemribo and Romo38
have performed [2ϩ2] cycloadditions of (trimethylsilyl)ketene
to β-benzyloxyaldehydes using a bidentate Lewis acid (MgBr2ؒ
OEt2) and found that the diastereoselectivity is qualitatively
and quantitatively similar to our observations using monoden-
tate Lewis acids. One consequence of the electrostatic inter-
action model is that stereoselectivity should diminish with
increasing distance of the alkoxy or silyloxy substituent from
the aldehyde. Accordingly, we examined the [2ϩ2] cyclo-
addition of (trimethylsilyl)ketene with γ-silyloxyaldehyde 34 in
the presence of EtAlCl2 (Scheme 7). A mixture of four insepar-
able β-lactones 35a–d was obtained whose ratio (a:b:c:d =
50:34:10:6) was determined by NMR spectroscopy. Two cis-
isomers 35a,b were formed as the major products (84% of the
mixture) and the two trans-isomers (35c,d) accounted for 16%
C6H13
SiMe3
C6H13
SiMe3
+
H
91:9
rac-26b
rac-26a
Scheme 5
O
TBSO
C5H11
O
TBSO
C5H11
O
(Me3Si)CH=C=O
SiMe3
EtAlCl2, Et2O
60%
H
H
27
δ 3.38, d, J 6.2
rac-28acis (88%)
+
O
O
TBSO
O
H
TBSO
C5H11
O
H
TBAF•3H2O
SiMe3
THF, –80 °C
71%
C5H11
H
rac-28btrans (3%)
rac-29a (90%)
+
+
O
O
TBSO
C5H11
O
H
TBSO
C5H11
O
H
SiMe3
H
rac-29b (10%)
δ 2.90, d, J 4.1
rac-28ctrans (9%)
Scheme 6
the cycloaddition under our conditions, since the cycloaddition
of (trimethylsilyl)ketene28 with the β-silyloxyaldehyde rac-27
(Scheme 6) gave three inseparable β-lactone cycloadducts rac-
28a–c (88:3:9) in 77% yield with the cis-β-lactone 28a being the
major product. The preference for cis-cycloadducts has also
been noted by Yamamoto and co-workers using simple alde-
hydes devoid of proximate stereogenic centres.29 Selective C-
desilylation of β-lactones 28a–c led to the corresponding β-
lactones 29a,b as a 9:1 mixture of two diastereoisomers
(Scheme 6). This ratio, indicative of the 1,3-diastereoselectivity
of the reaction, is similar to the ratio obtained with n-hexyl-
(trimethylsilyl)ketene and provides additional evidence for a
J. Chem. Soc., Perkin Trans. 1, 1998
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and/or phosphomolybdic acid in ethanol. Column chrom-
CO2H
CO2H
(a) LDA, HMPA
atography was performed on Merck Kieselgel 60 (0.04–0.063
mm, 230–400 mesh) and run under pressure.
(b) allyl bromide
78%
C6H13
C6H13
Infrared spectra were recorded on a Perkin-Elmer 1600 Series
FTIR Spectrophotometer, using NaCl plates or quartz cell.
Peak intensities are defined as strong (s), medium (m) or weak
31
30
LiAlH4 78%
RO
1
(w). H NMR spectra were recorded in Fourier Transform
mode on a JEOL GX-270 and 250 and Bruker AC 300 and
AMX 400 spectrometers, 13C NMR spectra were recorded on
Jeol GX-270 and Brüker AC-300 and AMX 400 spectro-
meters. 1H chemical shifts are reported in ppm relative to
CHCl3 (δ 7.27). Coupling constants (J) are given in Hz. 13C
NMR spectra are quoted relative to CDCl3 (δ 77.1) as an
internal standard in which C᎐H coupling was analysed using
the distortionless enhancement by phase transfer (DEPT) spec-
tral editing technique with second pulses at 90 and 135Њ. C᎐H
coupling is indicated by an integer 0–3 in parentheses following
the 13C chemical shift value denoting the number of coupled
protons. Mass spectra were obtained from the mass spec-
trometry services at the Department of Chemistry at the Uni-
versity of Southampton and SmithKline Beecham, Brockham
Park. The values given are in atomic mass units (amu), followed
in parentheses by the peak intensity relative to the base peak
100%. Accurate mass determinations and low resolution mass
spectra were made on compounds purified by either distillation
or column chromatography and estimated to be at least 95%
pure by NMR spectroscopy and TLC. Combustion analyses
were conducted at the University College of London.
RO
O
(a) O3, CH2Cl2, –78 °C
C6H13
C6H13
(b) SMe2 (20 equiv.),
70%
34
32
33
R = H
TBSCl, DMAP, imidazole
CH2Cl2, r.t., 2 h
100%
R = TBS
(Me3Si)CH=C=O
EtAlCl2, Et2O
66%
O
O
TBSO
C6H13
TBSO
C6H13
O
O
SiMe3
+
SiMe3
84:16
H
H
H
H
H
H
δ 2.87, d, J 4.1
rac-35c,dtrans (c:d = 5:3)
δ 3.32, d, J 6.2
rac-35a,bcis (a:b = 5:3)
TBAF•3H2O
THF, –80 °C
100%
O
O
TBSO
C6H13
TBSO
O
H
O
H
Methyl 3-oxodecanoate 8
Octanoyl chloride (33 cm3, 191 mmol) was added dropwise to a
solution of 2,2-dimethyl-1,3-dioxane-4,6-dione 6 (Aldrich, 25
g, 173 mmol) in pyridine (900 cm3) and CH2Cl2 (150 cm3) at
0 ЊC. The cooling bath was removed and the reaction was
stirred at ambient temperature for 1.5 h and then washed with
2  HCl (3 × 100 cm3) and H2O (3 × 100 cm3). The organic
layer was dried (Na2SO4) and concentrated in vacuo to give a
dark brown–red oil which was dissolved in MeOH (100 cm3)
and refluxed for 16 h. The solvent was removed in vacuo and the
residue was dissolved in benzene (100 cm3) and washed succes-
sively with 10% aq. K2CO3 (2 × 50 cm3) and H2O (2 × 50 cm3).
The organic layer was then dried (Na2SO4) and concentrated in
vacuo to give a red–dark brown oil (33.8 g) which was purified
by column chromatography (SiO2, hexanes:ether = 1:5) to give
the title compound (25 g, 125 mmol, 72%) as a pale yellow
oil, νmax(film)/cmϪ1 2929s, 2856s, 1748s, 1718s, 1654m,
1628m; δH(270 MHz, CDCl3) 3.68 (3H, s, OMe), 3.40 (2H, s,
COCH2CO), 2.48 (2H, t, J 7.36, CH2CO), 1.61–1.43 (2H, m,
CH2), 1.33–1.10 (8H, m, 4 × CH2), 0.82 (3H, distorted t, J 7.1,
Me); δC(67.5 MHz, CDCl3) 202.9 (0), 167.8 (0), 52.33 (3), 49.1
(2), 43.12 (2), 31.7 (2), 29.1 (2), 29.0 (2), 23.5 (2), 22.7 (2), 14.1
(3); m/z (CI mode, NH3) 218 [(M ϩ NH4)ϩ, 100%], 201
[(M ϩ H)ϩ, 25].
+
C6H13
55:45
H
H
rac-36a
rac-36b
Scheme 7
of the mixture. C-Desilylation of β-lactones 35a–d led to a
55:45 mixture of the two corresponding β-lactones 36a,b
(Scheme 7). Thus the remoteness of the silyloxy group resulted
in a significant decrease in 1,3-diastereoselectivity of the reac-
tion from 80% de (β-silyloxy) to 10% de (γ-silyloxy). Moreover,
similar experiments performed on the corresponding O-benzyl
ether gave a de of ca. 20% indicating that the diastereoselectiv-
ity is insensitive to the protecting group.
In conclusion, the syntheses of panclicins A–E reported
herein together with our previous syntheses of lipstatin17 and
tetrahydrolipstatin15 expands the scope of Lewis acid catalysed
[2ϩ2] cycloaddition of alkyl(trimethylsilyl)ketenes to β-silyl-
oxyaldehydes as a general and stereoselective method for the
synthesis of β-lactones. The stereocontrol exerted by the silyl-
oxy substituent on the aldehyde component diminishes with
increasing distance from the carbonyl group in accord with a
conformational effect resulting from electrostatic interaction
between the silyloxy substituent and the carbonyl–Lewis acid
complex. Further studies on the effect of proximate substitu-
ents on the stereochemistry of the cycloaddition are in progress.
Methyl (R)-3-hydroxydecanoate 9
A Parr autoclave was charged with a solution of the keto ester 8
(2.30 g, 11.5 mmol) in methanol (20 cm3). [(R)-(ϩ)-2,2Ј-Bis-
(diphenylphosphino)-1,1Ј-binaphthyl]chloro(p-cymene)ruthen-
ium chloride (Aldrich, 9.29 mg, 0.01 mmol) and 2  HCl (0.02
cm3) were added and the mixture stirred under H2 at 200 psi at
40 ЊC for 48 h. The cooled reaction mixture was concentrated
in vacuo and the residue was dissolved in Et2O (30 cm3) and
washed with saturated aqueous sodium hydrogen carbonate.
The organic layer was dried (MgSO4), concentrated in vacuo,
and the residue was purified by column chromatography
(SiO2, hexanes:ether = 1:1) to give the title compound (1.9 g,
9.4 mmol, 82%) as a colourless oil, [α]D20 Ϫ13.5 (c 2.5, CHCl3)
{lit.,39 [α]D20 Ϫ15.7 (c 2.06, CHCl3)}; νmax(film)/cmϪ1 3441m,
2927s, 2856m, 1740s, 1438m; δH(270 MHz, CDCl3) 4.04–3.88
(1H, m, OH), 3.67 (3H, s, OMe), 3.01 (1H, br s, HCOH), 2.48
Experimental
All reactions requiring anhydrous conditions were conducted in
flame-dried apparatus under a nitrogen atmosphere. Solvents
were dried by distillation from calcium hydride for dichloro-
methane, N,N-dimethylformamide, pyridine, triethylamine and
cyclohexane or sodium and benzophenone for diethyl ether
(referred to as ether) and tetrahydrofuran. Organic extracts
were dried over MgSO4 or Na2SO4 (as specified) and evaporated
at aspirator pressure on a rotary evaporator.
All reactions were monitored by thin layer chromatography
(TLC) with Macherey-Nagel Duren Alugram Sil G/UV254
aluminium foil sheets. Compounds were visualised with UV
1376
J. Chem. Soc., Perkin Trans. 1, 1998

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(1H, dd, J 16.2, 3.7, COCHAHBCO), 2.38 (1H, dd, J 16.2, 8.8,
COCHAHBCO), 1.60–1.14 (12H, br m, 6 × CH2), 0.84 (3H, dis-
torted t, J 6.6, Me); δC(67.5 MHz, CDCl3) 173.6 (0), 68.1 (1),
51.8 (3), 41.3 (2), 36.7 (2), 31.9 (2), 29.6 (2), 29.3 (2), 25.6 (2),
22.7 (2), 14.2 (3); m/z (CI mode, NH3) 220 [(M ϩ NH4)ϩ, 97%],
203 [(M ϩ H)ϩ, 100], 185 (35). 19F NMR analysis of the
Mosher ester derivative established an ee of 98%.
stirred for 24 h. The mixture was hydrolysed with water (100
cm3), stirred for 1 h and the organic layer was extracted with
ether (3 × 200 cm3). The combined extracts were dried
(MgSO4), concentrated in vacuo and the residue was purified via
rapid column chromatography (SiO2, hexanes containing 0.5%
NEt3) to give the title compound (4.5 g, 21.4 mmol, 49%) as a
colourless oil, νmax(film)/cmϪ1 2927s, 2855s, 2272s, 1467m,
1223s; δH(270 MHz, CDCl3) 4.0 (2H, q, J 6.6, CH3CH2O), 2.10
᎐
Methyl (R)-3-(tert-butyldimethylsilyloxy)decanoate 10
(2H, t, J 6.6, CH C᎐), 1.61–1.09 (16H, m), 0.86 (6H, d, J 6.6,
᎐
2
A three-necked round-bottomed flask fitted with a magnetic
stirrer and thermometer was charged with a solution of the
hydroxy ester 9 (1.00 g, 5.0 mmol) in DMF (5 cm3). With ice-
bath cooling, imidazole (851 mg, 12.5 mmol) in DMF (5 cm3)
was added, followed by the dropwise addition of TBSCl (980
mg, 6.5 mmol) in DMF (5 cm3). The cooling bath was removed
and the mixture stirred for 16 h at room temp. The mixture was
poured into H2O (100 cm3) with stirring and the product
extracted into hexane (3 × 50 cm3). The combined organic
layers were dried (MgSO4) and concentrated in vacuo and the
residue purified by column chromatography (SiO2, hexanes:
ether = 6:1) to give the title compound (1.17 mg, 3.70 mmol,
75%) as a colourless oil, [α]D20 Ϫ14.5 (c 2.0, CHCl3); νmax(film)/
cmϪ1 2955s, 2929s, 2857s, 1744s; δH(270 MHz, CDCl3) 4.11 (1H,
app. quintet, J 5.9, CHOTBS), 3.64 (3H, s, OMe), 2.45–2.38
(2H, app. dd, J 5.9, 1.5, COCH2CO), 1.54–1.40 (2H, m, CH2),
1.40–1.17 (10H, br s, 5 × CH2), 0.85 (12H, br s), 0.05 and
0.02 (3H each, s, Me2Si); δC(67.5 MHz, CDCl3) 172.3 (0), 69.5
(1), 51.3 (3), 42.5 (2), 37.6 (2), 31.8 (2), 29.6 (2), 29.2 (2), 25.9
(3C, 3), 25.7 (2), 22.8 (2), 17.9 (0), 14.0 (3), Ϫ4.6 (3), Ϫ4.9 (3);
m/z (APCI, MeCN) 317 (M ϩ H)ϩ.
Me2CH); δC(67.5 MHz, CDCl3) 89.3 (0), 73.7 (2), 39.3 (2), 39.0
(2), 37.3 (0), 29.8 (2), 29.2 (2), 28.8 (2), 27.9 (1), 27.4 (2), 22.6
ϩ
,
(2C, 3), 17.2 (2), 14.3 (3); m/z (EI mode) 167 [(M Ϫ CHMe2)
5%], 85 (100).
᝽
1-Ethoxydodec-1-yne 12b
Reaction of ethoxyacetylene (4.58 g, 65.3 mmol) and 1-iodo-
decane (14.4 g, 53.7 mmol) according to the procedure
described above gave the title compound (7.67 g, 36.5 mmol,
68%) as a colourless oil, νmax(film)/cmϪ1 2926s, 2855s, 2272s;
δH(270 MHz, CDCl3) 4.01 (2H, q, J 7.0, CH3CH2O), 2.11 (2H,
᎐
t, J 6.9, CH C᎐), 1.34 (3H, t, J 6.9, OCH CH ), 1.27 (16H, m,
᎐
2
2
3
8 × CH2), 0.88 (3H, br t, J 6.6, Me); δC(67.5 MHz, CDCl3) 89.3
(0), 73.8 (2), 37.4 (0), 31.9 (2), 29.8 (2), 29.8 (2), 29.6 (2), 29.3
(2), 29.2 (2), 28.8 (2), 22.7 (2), 17.2 (2), 14.3 (3), 14.1 (3); m/z
(APCI, MeCN) 211 (M ϩ H)ϩ.
1-Ethoxytetradec-1-yne 12c
Reaction of ethoxyacetylene (4.68 g, 66.7 mmol) and 1-iodo-
dodecane (16.5 g, 55.7 mmol) according to the procedure
described above gave the title compound (11.6 g, 52.2 mmol,
60%) as a colourless oil, νmax(film)/cmϪ1 2923s, 2853s, 2271s,
(R)-3-(tert-Butyldimethylsilyloxy)decanal 11
1223s, 869m; δH(300 MHz, CDCl3) 4.01 (2H, q, J 7.1,
᎐
To a three-necked round-bottomed flask with stirrer and under
N2 was added a solution of ester 10 (547 mg, 1.73 mmol) in
CH2Cl2 (4 cm3). The reaction mixture was cooled to Ϫ80 ЊC
whereupon DIBAL-H (1.5  in toluene, 1.27 cm3, 1.90 mmol)
was added dropwise at a rate sufficient to maintain the temper-
ature at Ϫ80 ЊC. The mixture was then stirred at Ϫ80 ЊC for 30
min. The cooling bath was removed and a saturated aqueous
solution of ammonium chloride (2 cm3) was added followed by
2  HCl (4 cm3). The reaction was left to warm up to room
temp. The reaction was then washed with H2O (3 × 10 cm3) and
the aqueous layer extracted with CH2Cl2 (3 × 20 cm3). The
organic layers were combined, dried (MgSO4) and concentrated
in vacuo and the residue was purified via column chrom-
atography (SiO2, hexanes:EtOAc = 6:1) to give the title com-
pound (327 mg, 1.14 mmol, 66%) as a colourless oil [HRMS
(CI mode, NH3): Found, (M ϩ H)ϩ, 287.2401. C16H34O2SiϩH
requires 287.2406]; [α]D20 Ϫ0.1 (c 2.0, CHCl3); νmax(film)/cmϪ1
2955s, 2928s, 2959s, 1728s, 1255s; δH(270 MHz, CDCl3) 9.82
(1H, t, J 2.5, CHO), 4.18 (1H, app. quintet, J 5.8, HCOTBS),
2.52 (2H, app. dd, J 5.8, 2.5, COCH2CO), 1.60–1.40 (2H, m,
CH2), 1.40–1.05 (10H, br s, 5 × CH2), 0.96 (12H, br s), 0.09 and
0.08 (3H each, s, Me2Si); δC(67.5 MHz, CDCl3) 202.5 (1), 68.4
(1), 50.9 (2), 38.0 (2), 31.9 (2), 29.7 (2), 29.3 (2), 25.9 (3C, 3),
25.2 (2), 22.8 (2), 18.1 (0), 14.2 (3), Ϫ4.3 (3), Ϫ4.6 (3); m/z (CI
mode, NH3) 304 [(M ϩ NH4)ϩ, 25%], 287 [(M ϩ H)ϩ, 88], 243
(100), 229 (77), 132 (33).
CH CH O), 2.11 (2H, t, J 6.6, CH C᎐), 1.51 (20H, m,
᎐
3
2
2
10 × CH2), 1.34 (3H, t, J 7.0, CH3CH2O), 0.89 (3H, distorted t,
J 7.0, Me); δC(67.5 MHz, CDCl3) 89.4 (0), 73.9 (2), 37.5 (0),
32.1 (2), 29.9 (2C, 2), 29.8 (3C, 2), 29.5 (2), 29.4 (2), 29.0 (2),
22.8 (2), 17.4 (2), 14.5 (3), 14.2 (3); m/z (APCI, MeCN) 239
(M ϩ H)ϩ.
8-Methylnonyl(trimethylsilyl)ketene 13a
A flame-dried 50 cm3 round-bottomed flask fitted with a reflux
condenser and magnetic stirrer was charged with hexamethyl-
disilane (7.6 cm3, 37.2 mmol). With rigorous exclusion of
moisture, the mixture was warmed to 80 ЊC whereupon freshly
sublimed iodine (8.6 g, 33.9 mmol) was added slowly over 1 h
via a sealed tube connected to one of the necks of the flask with
a glass joint. The reaction mixture was heated at 80 ЊC for a
further 1 h. The reaction mixture was then cooled to room
temp. and copper powder (307 mg, 4.8 mmol) was added. The
reaction mixture was stirred for 5 min at room temp. and then
the alkoxy alkyne 12a (4.38 g, 20.8 mmol) was added dropwise
and the mixture heated at 70 ЊC for 48 h. The reaction was then
cooled and the excess iodotrimethylsilane removed in vacuo and
the crude product was distilled using a Kugelrohr apparatus to
yield the desired ketene 13a (2.63 g, 10.3 mmol, 50%) as a pale
yellow oil, bp 140 ЊC (bath)/7 mmHg; νmax(film)/cmϪ1 2955s,
2926m, 2856m, 2085s, 1251m, 840s; δH(300 MHz, CDCl3) 1.91
(2H, t, J 7.3, CH C᎐), 1.62–1.05 (13H, m), 0.88 (6H, d, J 6.6,
᎐
2
Me2C), 0.17 (9H, s, Me3Si); δC(75 MHz, CDCl3) 182.4 (0), 39.0
(2), 31.6 (2), 30.5 (2), 29.8 (2), 29.5 (1), 29.4 (2C, 2), 22.6 (2C, 3),
22.0 (2), 12.8 (0), Ϫ0.9 (3C, 3); m/z (CI mode, NH3) 255
[(M ϩ H)ϩ, 4%], 201 (99), 129 (100), 73 (92).
1-Ethoxy-10-methylundec-1-yne 12a
A three-necked round-bottomed flask was charged with THF
(50 cm3) and then ethoxyacetylene (3.07 g, 43.7 mmol) was
added. The solution was cooled to Ϫ80 ЊC. Butyllithium (1.60
 in hexanes, 31.1 cm3, 49.8 mmol) was added dropwise and the
mixture was stirred for 1 h. Hexamethylphosphoramide (16.7
cm3, 94.2 mmol) was then added dropwise while the temper-
ature was maintained at Ϫ80 ЊC and the reaction mixture was
stirred for a further 30 min. 1-Iodo-8-methylnonane 39 (9.64 g,
35.95 mmol) (for preparation see later) in THF (10 cm3) was
added and the solution allowed to warm up to room temp. and
n-Decyl(trimethylsilyl)ketene 13b
By the same procedure alkoxy alkyne 12b (1.0 g, 4.75 mmol)
gave the title compound (529 mg, 2.08 mmol, 44%) as a pale
yellow oil after Kugelrohr distillation, bp 140 ЊC (bath)/7
mmHg; νmax(film)/cmϪ1 2956m, 2926s, 2855m, 2086s, 1466m,
1251m, 841s; δ (300 MHz, CDCl ) 1.91 (2H, t, J 7.4, CH C᎐),
᎐
H
3
2
1.53–1.20 (16H, m), 0.89 (3H, t, J 7.0, Me), 0.16 (9H, s, Me3Si);
J. Chem. Soc., Perkin Trans. 1, 1998
1377

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δC(75 MHz, CDCl3) 182.5 (0), 32.1 (2), 31.8 (2), 29.7 (2C, 2),
29.5 (2C, 2), 29.3 (2), 22.8 (2), 22.2 (2), 14.3 (3), 13.0 (0), Ϫ0.8
(3C, 3); m/z (CI mode, NH3) 255 [(M ϩ H)ϩ, 50%], 170 (32), 90
(100).
11 (353 mg, 1.23 mmol) and silyl ketene 13b (445.4 mg, 1.8
mmol) gave the β-lactones 15b and 16b (427 mg, 0.78 mmol,
57%) as an inseparable mixture of diastereoisomers. Deprotec-
tion of a sample (360 mg, 0.65 mmol) with HF in acetonitrile
gave the major isomer 17b (104 mg, 0.24 mmol, 37%) as a
colourless oil which crystallised in the freezer, mp ~0 ЊC
(Found: C, 70.38; H, 12.02%. C25H50O3Si requires C, 70.36; H,
11.81%); [α]D22 Ϫ64 (c 2, CHCl3); νmax(film)/cmϪ1 3452s, 2959s,
2924s, 2854s, 1803s, 1466m, 1254s, 846s; δH(300 MHz, CDCl3)
n-Dodecyl(trimethylsilyl)ketene 13c
By the same procedure alkoxyalkyne 12c (5.0 g, 21.0 mmol)
gave the title compound (3.53 g, 12.51 mmol, 44%) as a pale
yellow oil after Kugelrohr distillation, bp 170 ЊC (bath)/0.4
mmHg; νmax(film)/cmϪ1 2956m, 2925s, 2854m, 2086s, 1251m,
4.73 (1H, dd, J 11.4, 2.3, CHOC᎐O), 3.90–3.76 (1H, m,
᎐
841m; δ (300 MHz, CDCl ) 1.91 (2H, t, J 7.4, CH C᎐), 1.54–
HCOH), 2.07–1.63 (5H, m), 1.56–1.05 (28H, m), 0.89 (6H, dis-
torted t, J 6.8, 2 × Me), 0.23 (9H, s, Me3Si); δC(75 MHz, CDCl3)
174.2 (0), 76.4 (1), 68.7 (1), 55.0 (2), 38.9 (2), 38.3 (2), 32.0 (2),
31.9 (2), 30.8 (2), 30.1 (2), 29.7 (3C, 2), 29.6 (2), 29.5 (2), 29.4
(2C, 2), 26.3 (2), 25.6 (2), 22.8 (2), 14.3 (2C, 3), Ϫ1.2 (3C, 3); m/z
(APCI, MeCN) 427 (M ϩ H)ϩ.
᎐
2
H
3
1.21 (20H, m), 0.89 (3H, distorted t, J 6.6, Me), 0.16 (9H, s,
Me3Si); δC(75 MHz, CDCl3) 182.5 (0), 32.1 (2), 31.8 (2), 30.0
(4C, 2), 29.8 (2C, 2), 29.5 (2), 22.8 (2), 22.2 (2), 14.3 (3), 13.0 (0),
Ϫ0.8 (3C, 3); m/z (CI mode, NH3) [(M ϩ NH4)ϩ, 16%], 283
[(M ϩ H)ϩ, 32], 90 (86), 35 (53).
(2ЈR,3R,4S)-3-(8-Methylnonyl)-3-trimethylsilyl-4-(2Ј-hydroxy-
nonyl)oxetan-2-one 17a and its (3S)-epimer 18a
(2ЈR,3R,4S)-3-n-Dodecyl-3-trimethylsilyl-4-(2Ј-hydroxynonyl)-
oxetan-2-one 17c
A round-bottomed flask fitted with a magnetic stirrer and
thermometer was charged with a solution of the aldehyde 11
(1.89 g, 6.60 mmol) in ether (20 cm3) and cooled to Ϫ50 ЊC.
Ethylaluminium dichloride in hexane (7.25 cm3, 7.25 mmol, 1 
in hexane) was added dropwise. The mixture was stirred at
Ϫ50 ЊC for 10 min and then a solution of the silyl ketene 13a
(2.48 g, 9.76 mmol) in ether (5 cm3) was added dropwise. The
reaction was allowed to warm to Ϫ4 ЊC, and quenched with
water. The reaction mixture was then extracted into ether
(3 × 15 cm3), the organic layers combined and dried (MgSO4)
and then concentrated in vacuo to give a pale yellow oil (3.2 g,
90%). The crude product was purified via column chroma-
tography (SiO2, hexanes:ether = 99:1) to give the β-lactones
15a and 16a (2.99 g, 5.53 mmol, 84%) as an inseparable mixture
of diastereoisomers which was dissolved in acetonitrile (30
cm3). The solution was cooled in an ice bath and hydrogen
fluoride (0.32 cm3, 48% aq.) was added dropwise. After addition
was complete, the ice bath was removed and the mixture was
stirred for 4 h at room temp. whereupon saturated aq. NaHCO3
was added to quench excess hydrogen fluoride. The reaction
was then concentrated in vacuo and the residue extracted into
ether (3 × 20 cm3). The combined ethereal extracts were washed
with saturated aq. NaHCO3 (3 × 30 cm3), dried (MgSO4) and
concentrated to give a viscous colourless oil which was purified
via column chromatography (SiO2, hexanes:ether = 5:1) to give
pure 17a (2.00 g, 4.69 mmol, 85%) as a viscous, colourless oil,
[α]D18 Ϫ57.4 (c 1, CHCl3); νmax(film)/cmϪ1 3452m, 2855s, 1800s,
1466m, 1254m, 846s; δH(300 MHz, CDCl3) 4.71 (1H, dd, J 11.0,
The cycloaddition described above starting with the aldehyde
11 (2.03 g, 7.09 mmol) and silyl ketene 13c (2.99 g, 10.6 mmol)
gave the β-lactones 15c and 16c (2.95 g, 5.18 mmol, 73%) as
an inseparable mixture of diastereoisomers. Deprotection of
the mixture (3.20 g, 5.62 mmol) with HF in acetonitrile as
described above returned pure 17c (1.7 g, 3.47 mmol, 66%) as a
viscous, colourless oil after purification by column chrom-
atography; [α]D18 Ϫ75.0 (c 1.0, CHCl3); νmax(film)/cmϪ1 3458m,
2925s, 2855s, 1803s, 1466m, 1254s, 846s; δH(300 MHz, CDCl3),
4.71 (1H, dd, J 11.0, 1.8, HCOC᎐O), 3.85–3.69 (1H, m,
᎐
HCOH), 2.05–1.65 (5H, m, CH2COCH2 and OH), 1.55–1.16
(32H, m), 0.87 (6H, distorted t, J 6.6, 2 × Me), 0.21 (9H, s,
Me3Si); δC(75 MHz, CDCl3) 174.1 (0), 76.3 (1), 68.4 (1), 54.8
(1), 39.8 (2), 38.1 (2), 31.9 (2), 31.8 (2C, 2), 30.6 (2), 29.9 (2),
29.6 (2C, 2), 29.5 (2), 29.4 (2C, 2), 29.3 (2), 29.2 (2), 26.1 (2),
25.5 (2), 22.7 (2), 22.6 (2), 14.1 (2C, 3), Ϫ1.0 (3C, 3); m/z (APCI,
MeCN) 455 (M ϩ H)ϩ.
(2ЈR,3S,4S)-3-[8-Methylnonyl]-4-(2Ј-hydroxynonyl)oxetan-2-
one 19a
To a solution of the β-lactones 17a and 18a (1.71 g, 4.01 mmol)
in THF (25 cm3) at Ϫ90 ЊC was added dropwise a solution of
TBAFؒ3H2O (1.38 g) in THF (5.0 cm3). After stirring for 15
min the reaction mixture was poured into rapidly stirred ice/
water overlaid with ether (10 cm3). The product was extracted
into ether (3 × 20 cm3), dried (MgSO4) and concentrated in
vacuo to give a white crystalline solid (1.57 g) from which the
major diastereoisomer 19a (1.3 g, 3.67 mmol, 91%) was
obtained via column chromatography (SiO2, hexanes:ether =
1:1) as a white crystalline compound which was recrystallised
from pentane to give pure 19a (1.21 g, 3.39 mmol, 84%), mp 50–
52 ЊC (Found: C, 74.57; H, 12.13%. C22H42O3 requires C, 74.52;
H, 11.94%); [α]D18 Ϫ43.1 (c 1.02, CHCl3); νmax(film)/cmϪ1 3460w,
3021s, 1815m, 1220s, 774s; δH(270 MHz, CDCl3) 4.49 (1H, over-
2.2, CHOC᎐O), 3.85–3.71 (1H, m, HCOH), 2.11–1.88 (2H, m,
᎐
OH and CHAHBCOCH2), 1.84–1.65 (3H, m, CHAHBCOCH2),
1.57–1.07 (25H, m), 0.85 (9H, distorted d, J 6.6, Me2CH and
Me), 0.20 (9H, s, Me3Si); δC(75 MHz, CDCl3) 174.1 (0), 76.3 (1),
68.4 (1), 54.8 (0), 39.8 (2), 39.0 (2), 38.1 (2), 31.8 (2), 30.6 (2),
29.9 (2), 29.8 (2), 29.5 (2C, 2), 29.4 (2), 29.2 (2), 27.9 (1), 27.3
(2), 26.1 (2), 25.5 (2), 22.6 (2C, 3), 14.1 (3), Ϫ1.0 (3C, 3); m/z (CI
mode, NH3) 427 [(M ϩ H)ϩ, 26%], 409 (100), 337 (33), 73 (27).
Through repeated chromatography of the mixture resulting
from the above reaction a sample sufficiently enriched (ca. 70%)
in isomer (2ЈR,3S,4S)-3-(8-methylnonyl)-4-[2Ј-hydroxynonyl]-
oxetan-2-one 18a was obtained and the following assignments
could be made, δH(300 MHz, CDCl3) 4.64 (1H, dd, J 10.3, 2.2,
lapping dt, J 4.4, CHOC᎐O), 3.86–3.71 (1H, m, HCOH), 3.24
᎐
(1H, td, J 11.6, 4.1, CHC᎐O), 2.15–2.05 (1H, br s, OH), 1.96–
᎐
1.60 (4H, m, CH2COCH2), 1.56–1.10 (25H, m), 0.89–0.82 (9H,
m, Me2CH and Me); δC(67.5 MHz, CDCl3) 171.9 (0), 75.8 (1),
68.4 (1), 56.6 (1), 42.0 (2), 39.1 (2), 38.2 (2), 31.9 (2), 29.9 (2),
29.6 (1), 29.5 (2C, 2), 29.4 (2), 29.3 (2), 28.0 (2), 27.8 (2), 27.4
(2), 26.9 (2), 25.5 (2), 22.7 (2C, 3), 14.2 (3); m/z (EI mode) 354
CHOC᎐O), 3.93–3.73 (1H, m, HCOH), 2.14–1.64 (4H, m,
[(M) ϩ, 6%], 182 (83), 69 (100).
᎐
᝽
CH2COCH2), 1.61–1.09 (26H, m), 0.86 (9H, Me2CH and Me),
0.21 (9H, s, Me3Si); δC(75 MHz, CDCl3) 174.2 (0), 73.8 (1), 68.2
(1), 53.2 (0), 39.5 (2), 39.0 (2), 38.2 (2), 38.0 (2), 37.0 (2), 31.8
(2), 29.8 (2), 29.5 (2), 29.4 (2), 29.2 (2), 27.9 (1), 27.3 (2), 26.7 (2),
26.2 (2), 25.5 (2), 22.6 (2C, 3), 14.1 (3), Ϫ3.3 (3C, 3).
(2ЈR,3S,4S)-3-n-Decyl-4-(2Ј-hydroxynonyl)oxetan-2-one 19b
To a solution of the β-lactone 17b (104 mg, 0.19 mmol) in THF
(1 cm3) at Ϫ90 ЊC was added dropwise a solution of TBAFؒ
3H2O (68.90 mg) in THF (0.1 cm3). After stirring for 15 min
the reaction mixture was poured into rapidly stirred ice/water
overlaid with ether (5 cm3). The product was extracted into
ether (10 cm3), dried (MgSO4) and concentrated in vacuo to give
a white crystalline solid (95 mg) which was recrystallised from
(2ЈR,3R,4S)-3-n-Decyl-3-trimethylsilyl-4-(2Ј-hydroxynonyl)-
oxetan-2-one 17b
The cycloaddition described above starting with the aldehyde
1378
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
pentane to give pure trans isomer 19b (80 mg, 0.23 mmol, 93%),
mp 55–56 ЊC (Found: C, 74.56; H, 12.17%. C22H42O3 requires C,
74.52; H, 11.94%); [α]D22 Ϫ34.4 (c 1, CHCl3); νmax(film)/cmϪ1
3019s, 2976m, 2929m, 1815m, 1212s, 766s; δH(300 MHz,
CDCl ) 4.50 (1H, app. quintet, J 4.4, HCOC᎐O), 3.84–3.69
(2ЈS,3S,4S)-3-n-Decyl-4-{2Ј-[2Љ-(N-tritylamino)propanoyloxy]-
nonyl}oxetan-2-one 20b
Reaction of β-lactone 19b (42 mg, 0.12 mmol) and N-trityl-
alanine25,26 (132 mg, 0.40 mmol) in THF (0.6 cm3) with diiso-
propyl azodicarboxylate (0.07 cm3, 0.36 mmol) and triphenyl-
phosphine (93.5 mg, 0.36 mmol) according to the procedure
described above gave the ester 20b (50 mg, 0.06 mmol, 63%) as a
viscous colourless oil, [α]D22 Ϫ1.7 (c 1.3, CHCl3); νmax(film)/cmϪ1
2826s, 2856s, 1827s, 1732s; δH(300 MHz, CDCl3) 7.56–7.47 (6H,
m, aromatic H), 7.36–7.13 (9H, m, aromatic H), 4.52–4.39 [1H,
m, HCOC(O)CN], 4.23–4.11 (1H, m, MeCH), 3.45–3.30 (1H,
m, HCOC᎐O), 3.20–3.05 (1H, dt, J 7.7, 3.9, HC᎐O), 2.77–2.62
᎐
3
(1H, m, HCOH), 3.25 (1H, td, J 7.4, 4.0, CHC᎐O), 2.05–1.96
᎐
(1H, br s, OH), 1.96–1.65 [4H, m, CH2C(OH)CH2], 1.56–1.18
(28H, m), 0.87 (6H, distorted t, J 6.6, 2 × Me); δC(75 MHz,
CDCl3) 171.9 (0), 75.8 (1), 68.5 (1), 56.6 (1), 42.0 (2), 38.2 (2),
32.0 (2), 31.9 (2), 30.8 (2), 29.7 (2C, 2), 29.6 (2C, 2), 29.5 (2),
29.4 (2), 27.8 (2), 26.9 (2), 25.6 (2), 22.8 (2C, 2), 14.2 (2C, 3); m/z
(CI mode, NH3) 372 [(M ϩ NH4)ϩ, 100%], 355 [(M ϩ H)ϩ,
35%], 337 (10).
Column chromatography of the mother liquors (SiO2, hex-
anes:ether = 1:1) gave the cis-isomer (2ЈR,3R,4S)-3-n-decyl-4-
(2Ј-hydroxynonyl)oxetan-2-one 18b (91 mg, 0.26 mmol, 8%),
mp ~0 ЊC; [α]D22 Ϫ12 (c 1, CHCl3); νmax(film)/cmϪ1 3424m, 2926s,
2855s, 1823s, 1466m, 1118m, 819m; δH(300 MHz, CDCl3) 4.90
᎐
᎐
(1H, m, NH), 2.03–1.90 [2H, m, C(O)CH2CO], 1.89–1.57 (6H,
m, 3 × CH2), 1.44 (3H, d, J 7.0, MeCN), 1.40–1.10 (24H, m),
0.92 (6H, app. q, J 6.4, 2 × Me); δC(75 MHz, CDCl3) 175.4 (0),
171.0 (0), 146.2 (3C, 0), 128.7 (6C, 1), 127.9 (6C, 1), 126.6 (3C,
1), 74.5 (1), 71.6 (1), 71.3 (0), 56.9 (1), 51.9 (1), 37.9 (2), 33.5 (2),
31.9 (2), 31.8 (2), 29.6 (2C, 2), 29.5 (2), 29.4 (2C, 2), 29.3 (2C, 2),
29.2 (2), 27.6 (2), 26.7 (2), 25.1 (2), 22.7 (2), 22.0 (3), 14.1 (2C,
3).
(1H, ddd, J 10.3, 6.3, 2.2, HCOC᎐O), 3.91–3.78 (1H, m,
᎐
HCOH), 3.71–3.59 (1H, overlapping dt, J 7.6, CHC᎐O), 1.91–
᎐
1.68 (4H, m, COCH CO and CH CC᎐O), 1.68–1.80 (29H, m),
᎐
2
2
0.89 (6H, distorted t, J 6.6, 2 × Me); δC(75 MHz, CDCl3)
172.4 (0), 72.9 (1), 68.1 (1), 52.7 (1), 38.3 (2), 37.6 (2), 32.0 (2),
31.9 (2), 29.7 (2C, 2), 29.6 (2), 29.5 (2C, 2), 29.4 (2), 27.7 (2),
25.6 (2), 25.2 (2), 24.3 (2), 22.8 (2C, 2), 14.3 (2C, 3); m/z (CI
mode, NH3) 372 [(M ϩ NH4)ϩ, 100%], 355 [(M ϩ H)ϩ, 35], 337
(12).
Panclicin A 1
The β-lactone 20a (129 mg, 0.19 mmol) was dissolved in
CH2Cl2 (3.0 cm3) under N2 at 0 ЊC. Trichloroacetic acid–CH2Cl2
(1:1, 6.4 cm3) was added dropwise to the stirring solution which
was then warmed to room temp. After 10 min triisopropylsilane
was added until the yellow colour of the reaction disappeared
and the solvents were removed in vacuo. Formic acetic
anhydride (4 cm3) was then added to the residue dropwise. The
mixture was diluted with ether (5 cm3), washed with aqueous
sodium hydrogen carbonate (3 × 5 cm3), then with water (3 × 5
cm3), dried (MgSO4), filtered and concentrated in vacuo to give
a clear oil (80 mg, 91%). The crude residue was purified via
column chromatography (hexanes:ether = 1:4) to give a clear
oil which slowly solidified to afford a solid product (70 mg, 0.15
mmol, 80%) which was recrystallised from pentane to give pure
panclicin A (55 mg, 0.12 mmol, 63%) as a white crystalline
solid, mp 53–55 ЊC (Found: C, 68.52; H, 10.25; N, 2.94%.
C26H47NO5 requires C, 68.84; H, 10.44; N, 3.09%); [α]D18 Ϫ29
(c 0.61, CHCl3) [lit.,1 [α]D25 Ϫ26 (c 1.27, CHCl3)]. The product
gave 1H NMR (300 MHz) and 13C NMR (75 MHz) data identi-
cal to those reported for the natural product.1
(2ЈR,3S,4S)-3-n-Dodecyl-4-(2Ј-hydroxynonyl)oxetan-2-one 19c
Desilylation of the β-lactone 17c (1.81 g, 3.98 mmol) in THF
(15 cm3) at Ϫ90 ЊC with TBAFؒ3H2O (1.37 g, 4.36 mmol) in
THF (5.0 cm3) as described above gave 19c (945 mg, 2.47 mmol,
62%) as a white crystalline solid after column chromatography
(SiO2, hexanes:ether = 3:1). Recrystallisation from pentane
afforded pure 19c (850 mg, 2.22 mmol, 56%), mp 54–56 ЊC
(Found: C, 75.06; H, 12.19%. C24H46O3 requires C, 75.34; H,
12.12%); [α]D18 Ϫ35.7 (c 0.98, CHCl3); νmax(film)/cmϪ1 3589w,
2928s, 2856s, 1815s, 1466m, 772m; δH(300 MHz, CDCl3) 4.40
(1H, overlapping dt, J 4.25, HCOC᎐O), 3.78–3.64 (1H, m,
᎐
HCO), 3.15 (1H, td, J 11.2, 3.7, HCC᎐O), 1.85–1.57 (4H, m,
᎐
CH2COCH2), 1.45–1.05 (33H, m), 0.77 (6H, distorted t, J 6.5,
2 × Me); δC(75 MHz, CDCl3) 171.7 (0), 75.6 (1), 68.4 (1), 56.5
(1), 41.8 (2), 38.1 (2), 31.9 (2C, 2), 29.6 (2C, 2), 29.5 (2C, 2), 29.3
(2C, 2), 29.2 (2), 27.7 (2), 26.8 (2), 25.4 (2), 22.7 (2), 22.6 (2C, 2),
15.2 (2), 14.1 (2C, 3); m/z (APCI, MeCN) 383 (M ϩ H)ϩ.
Panclicin B 2
Treatment of β-lactone 20b (46 mg, 0.07 mmol) in CH2Cl2 (1.2
cm3) with trichloroacetic acid–CH2Cl2 (2.3 cm3) as described
above gave panclicin B (30 mg, 0.07 mmol, 96%) as a viscous
colourless oil [HRMS (FAB mode, Ar): Found, (M ϩ H)ϩ,
454.3533. C26H47NO5ϩH requires M, 454.3532]; [α]D22 Ϫ21
(c 0.16, CHCl3) {lit.,1 [α]D25 Ϫ28 (c 0.94, CHCl3)}. The product
gave 1H NMR (300 MHz) and 13C NMR (75 MHz) data identi-
cal to those reported for the natural product.1
(2ЈS,3S,4S)-3-(8-Methylnonyl)-4-{2Ј-[2Љ-(N-tritylamino)-
propanoyloxy]nonyl}oxetan-2-one 20a
To a magnetically stirred solution of triphenylphosphine (667.0
mg, 2.54 mmol), N-tritylalanine25,26 (97.0 mg, 0.29 mmol) and
β-lactone 19a (300 mg, 0.84 mmol) in THF (5 cm3) was added
dropwise at 0 ЊC diisopropyl azodicarboxylate (0.50 cm3, 2.54
mmol). The reaction was stirred at 0 ЊC for 2 h and then allowed
to warm up slowly to room temp. overnight. The mixture was
concentrated in vacuo and triphenylphosphine oxide crystal-
lised from ether–hexanes and filtered. The filtrate was concen-
trated and the residue purified by column chromatography
(SiO2, hexanes:ether = 20:1) to give 20a (129 mg, 0.19 mmol,
23%) as a viscous colourless oil, [α]D18 Ϫ2.17 (c 1.29, CHCl3);
νmax(film)/cmϪ1 2926s, 2855s, 1826s, 1732s; δH(300 MHz,
CDCl3) 7.58–7.45 (5H, m, aromatic H), 7.33–7.12 (10H, m,
aromatic H), 4.50–4.35 (1H, m, CHNH), 4.21–4.05 (1H, m,
Panclicin C 3
To a magnetically stirred solution of triphenylphosphine (333.0
mg, 1.27 mmol), N-formyl glycine (151.0 mg, 1.46 mmol) and β-
lactone 19a (150.0 mg, 0.42 mmol) in THF (2 cm3) was added
dropwise at 0 ЊC diisopropyl azodicarboxylate (0.25 cm3, 1.27
mmol). The reaction was stirred at 0 ЊC for 2 h and then allowed
to warm up slowly to room temp. overnight. The mixture was
concentrated under reduced pressure and triphenylphosphine
oxide crystallised from ether–hexanes and filtered. The filtrate
was concentrated and the residue purified by column chrom-
atography (hexanes:ether = 15:1) to give panclicin C (290 mg,
0.66 mmol, 70%) as a colourless oil [HRMS (FAB mode, Ar):
Found, (M ϩ H)ϩ, 440.3336. C25H45NO5ϩH requires M,
440.3376]; [α]D18 Ϫ18 (c 0.73, CHCl3) {lit.,1 [α]D25 Ϫ20 (c 0.33,
CHCl3)}. The product gave 1H NMR (300 MHz) and 13C NMR
(75 MHz) data identical to those reported for the natural
product.1
HCOCOCN), 3.43–3.30 (1H, m, HCOC᎐O), 3.13 (1H, dt,
᎐
J 11.8, 3.7, CHC᎐O), 2.75–2.60 (1H, m, NH), 2.04–1.61 (4H, m,
᎐
CH2COCH2), 1.60–1.09 (28H, m), 0.96–0.81 (9H, m, Me2CH
and Me); δC(75 MHz, CDCl3) 175.4 (0), 171.0 (0), 146.2 (3C, 0),
128.7 (6C, 1), 127.8 (6C, 1), 126.4 (3C, 1), 74.5 (1), 71.6 (1), 71.3
(0), 56.9 (1), 51.9 (1), 39.0 (2C, 2), 37.9 (2), 33.5 (2), 31.8 (2C, 2),
29.8 (2), 29.4 (1), 29.3 (2), 29.2 (2), 28.0 (1), 27.6 (2), 27.3 (2),
26.7 (2), 25.1 (2), 22.7 (2), 22.0 (2C, 3), 14.2 (3).
J. Chem. Soc., Perkin Trans. 1, 1998
1379

View Article Online
Panclicin D 4
THF (1 cm3) at Ϫ80 ЊC under argon, was slowly added a solu-
Reaction of N-formyl glycine (107.6 mg, 1.04 mmol) and
β-lactone 19b (106 mg, 0.90 mmol) in THF (1.5 cm3) with
triphenylphosphine (235.9 mg, 0.91 mmol) and diisopropyl
azodicarboxylate (0.18 cm3, 0.90 mmol) as described above gave
panclicin D (89 mg, 0.20 mmol, 67%) as a colourless oil, [α]D20
Ϫ19 (c 0.9, CHCl3) {lit.,1 [α]D25 Ϫ23 (c 0.3, CHCl3)} [HRMS
(FAB mode, Ar): Found, MHϩ, 440.3344. C25H45NO5ϩH re-
tion of TBAFؒ3H2O (75 mg, 0.24 mmol) in THF (1 cm3). Once
the addition was completed, the mixture was stirred for a fur-
ther 30 min at the same temperature. Hydrolysis was then
carried out with five drops of a saturated aqueous NH4Cl solu-
tion, diethyl ether (5 cm3) was added and extraction was per-
formed with diethyl ether (3 × 5 cm3). The combined organic
phases were washed with brine (5 cm3), dried over MgSO4, fil-
tered and concentrated in vacuo. The crude product was puri-
fied by column chromatography (SiO2, hexanes:ether = 95:5)
to give β-lactones 29a,b (32 mg, 0.11 mmol, 71%) as a (9:1)
mixture of diastereoisomers according to 400 MHz NMR
spectroscopy of the mixture) (Found: C, 63.89; H, 10.72%.
C16H32O3Si requires C, 63.95; H, 10.73%); νmax(film)/cmϪ1
1830s, 1260m, 1130m, 840s, 780s; δH(400 MHz, CDCl3) major
isomer 29a 4.69–4.62 (1H, m), 3.87–3.80 (1H, m), 3.53 (1H,
part A of ABX system, JAB 16.3, JAX 5.8), 3.08 (1H, part B of
ABX system, JAB 16.3, JBX 4.3), 1.88 (1H, part A of ABXY
system, JAB 14.1, JAX 8.5, JAY 3.1), 1.82 (1H, part B of ABXY
system, JAB 14.1, JBX 9.2, JBY 4.8), 1.53–1.37 (2H, m), 1.32–1.18
(6H, m), 0.89 (12H, br s), 0.07 (3H, s), 0.06 (3H, s); minor
isomer 29b 3.52 (1H, part A of ABX system, JAB 16.3, JAX 7.1),
3.11 (1H, part B of ABX system, JAB 16.3, JBX 4.4); δC(50.3
MHz, CDCl3) major isomer 29a 168.6 (0), 69.1 (1), 68.9 (1),
43.6 (2), 42.0 (2), 38.0 (2), 32.0 (2), 24.4 (2), 22.7 (2), 25.9 (3,
3C), 18.1 (0), 14.1 (3), Ϫ4.3 (3), Ϫ4.7 (3).
1
quires M, 440.3376]. The product gave H NMR (300 MHz)
and 13C NMR (75 MHz) data identical to those reported for the
natural product.1
cis-Panclicin D 4
The experimental procedure for converting 17b to panclicin D 4
was applied to 18b on a 0.36 mmol scale to afford cis-4 (30 mg,
0.07 mmol, 57%) as a clear oil [HRMS (FAB mode, Ar): Found,
(M ϩ H)ϩ, 440.3340. C25H45NO5ϩH requires M, 440.3376]; [α]D22
Ϫ4.6 (c 0.7, CHCl3); νmax(film)/cmϪ1 3414s, 1822m, 1746m,
1668m, 1521w; δH(300 MHz, CDCl3) 8.27 (1H, br s, CHO),
6.21–6.04 (1H, br s, NH), 5.27–5.10 [1H, m, HCOC(O)CH2],
4.67 (1H, app. septet, J 2.9, HCOC᎐O), 4.14 (1H, dd, J 18.4,
5.9, CHAHBN), 4.03 (1H, dd, J 18.4, 5.2, CHAHBN), 3.72–3.60
(1H, m, CHC᎐O), 2.12–2.00 (1H, m, CH H CO), 1.95 (1H, dt,
J 15.4, 3.9, CHAHBCO), 1.84–1.50 [4H, m, C(O)CCH2 and
CH2CO], 1.41–1.19 (26H, m), 0.89 (6H, distorted t, J 6.6,
2 × Me); δC(75 MHz, CDCl3) 171.6 (0), 169.5 (0), 161.1 (1), 73.4
(1), 72.8 (1), 53.6 (1), 40.3 (2), 34.9 (2), 34.2 (2), 32.0 (2), 31.9
(2), 29.7 (2C, 2), 29.5 (2), 29.4 (3C, 2), 29.2 (2), 27.6 (2), 25.4 (2),
24.2 (2), 22.8 (2C, 2), 14.3 (2C, 3).
᎐
᎐
A
B
2-Allyloctanoic acid 31
Octanoic acid (4.8 cm3, 30 mmol) was added dropwise, at
Ϫ20 ЊC, to a THF solution of LDA [prepared from diiso-
propylamine (10.5 ml, 75 mmol), butyllithium (52 cm3 of a
1.5  solution in hexanes, 78 mmol) and THF (130 cm3)].
Hexamethylphosphoramide (6.8 cm3, 39 mmol) was added to
the yellow mixture and the cooling bath removed. The mixture
was allowed to stir at ambient temperature for 1 h and then
cooled to 0 ЊC whereupon freshly distilled allyl bromide (3.4
cm3, 39 mmol) was added dropwise to the resulting orange solu-
tion. After stirring at room temp. for 12 h, the mixture was
hydrolysed with saturated aqueous ammonium chloride (15
cm3) and concentrated in vacuo. The residue was partitioned
between ether (90 cm3) and 20% aqueous HCl (30 cm3). The
organic phase was washed with 20% HCl (4 × 30 cm3), the
combined aqueous portions were extracted with ether (3 × 30
cm3) and the combined organic solutions were washed with
brine, dried over MgSO4 and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, hexanes:
ether = 70:30) to give the title compound 31 (4.3 g, 23 mmol,
78%) as a pale yellow oil; νmax(film)/cmϪ1 3070m, 1730s, 1690w,
910m; δH(200 MHz, CDCl3) 5.78 (1H, ddt, J 17.0, 10.1, 6.8,
Panclicin E 5
Reaction of N-formylglycine (187 mg, 1.81 mmol) and β-
lactone 19c (200 mg, 0.52 mmol) in THF (1.5 cm3) with tri-
phenylphosphine (409 mg, 1.56 mmol) and diisopropyl
azodicarboxylate (0.31 cm3, 1.56 mmol) as described above
gave panclicin E (212 mg, 0.45 mmol, 87%) as a colourless
oil [HRMS (FAB mode, Ar): Found, (M ϩ H)ϩ, 468.3685.
C27H49NO5ϩH requires M, 468.3689]; [α]D18 Ϫ24.4 (c 0.25,
CHCl3) {lit.,1 [α]D25 Ϫ27 (c 1.21, CHCl3)}. The product gave 1H
NMR (300 MHz) and 13C NMR (75 MHz) data identical to
those reported for the natural product.1
3-Trimethylsilyl-4-[2Ј-(tert-butyldimethylsilyloxy)heptyl]-
oxetan-2-ones 28a–c
A solution of aldehyde 2740 (129 mg, 0.5 mmol) in dry Et2O
(1 cm3) was cooled at Ϫ50 ЊC under argon before a solution of
trimethylsilylketene (68 mg, 0.6 mmol) in dry Et2O (0.5 cm3)
was added. Ethylaluminium dichloride (0.6 cm3 of a 1  solu-
tion in hexanes, 0.6 mmol) was added dropwise at that temper-
ature. After 1 h stirring, the reaction was quenched with water
(3 cm3) and the aqueous phase was extracted with ether (3 × 3
cm3). The organic phases were dried over MgSO4, filtered and
concentrated in vacuo. The crude product was purified by
column chromatography (SiO2, hexanes:ether = 97:3) to yield
β-lactones 28a–c (144 mg, 0.39 mmol, 77%) as a mixture of
diastereoisomers (acis :btrans :ctrans = 88:3:9) according to 400
MHz NMR spectroscopy of the mixture, νmax(film)/cmϪ1
1815s, 1260s, 850s, 780m; δH(200 MHz, CDCl3) 28acis 4.80 (1H,
CH᎐), 5.15–5.00 (2H, m, ᎐CH ), 2.55–2.15 (3H, m, CHCH C᎐),
᎐
᎐
᎐
2
2
1.80–1.20 (10H, m, 5 × CH2), 0.88 (3H, distorted t, J 6.6, Me);
δC(50.3 MHz, CDCl3) 182.6 (0), 135.2 (1), 116.9 (2), 45.3 (2),
36.2 (1), 31.7 (2), 31.6 (2), 29.2 (2), 27.2 (2), 22.6 (2), 14.1 (3).
4-(Hydroxymethyl)decene 3241
To a stirred solution of LiAlH4 (835 mg, 22 mmol) in ether (25
cm3) at 0 ЊC, was added dropwise a solution of carboxylic acid
31 (1.84 g, 10 mmol) in ether (25 cm3). The mixture was stirred
at room temp. for 3 h and then cooled to 0 ЊC. Water (0.8 cm3)
was added dropwise followed by NaOH (0.8 cm3 of a 2.5 
aqueous solution) and finally water (1.7 cm3). The mixture was
then stirred vigorously at room temp. for 20 min. The resulting
white solid was removed by filtration and the residue washed
with ether (200 cm3). The filtrate was dried over MgSO4 and
concentrated in vacuo to yield alcohol 32 (1.645 g, 9.7 mmol,
97%) as a colourless oil, νmax(film)/cmϪ1 3400s, 3010m, 1650m;
ddd, J 10.6, 6.2, 2.7, CHOC᎐O), 3.85 (1H, m, CHOTBS), 3.38
᎐
(1H, d, J 6.2, CHC᎐O), 1.90–1.20 (10H, m, 5 × CH ), 0.92 (9H,
᎐
2
s, But ), 0.87 (3H, distorted t, Me), 0.24 (9H, s, SiMe3), 0.08 (6H,
s, SiMe2); δC(100.6 MHz, CDCl3) 28acis 170.9 (0), 70.6 (1), 68.7
(1), 45.9 (1), 40.5 (2), 38.1 (2), 31.9 (2), 25.9 (3C, 3), 24.3 (2),
22.6 (2), 18.1 (0), 14.0 (3), Ϫ1.1 (3C, 3), Ϫ4.3 (3), Ϫ4.8
(3); δH(200 MHz, CDCl3) 28ctrans 4.51 (1H, dt, J 8.9, 4.1,
CHOC᎐O), 2.90 (1H, d, J 4.1, CHC᎐O); m/z (EI mode) 315
᎐
᎐
[(M Ϫ But ) ϩ, 2%], 201 (100).
δ (200 MHz, CDCl ) 5.83 (1H, ddt, J 17.2, 10.1, 7.1, CH᎐),
᎐
H
3
᝽
5.15–4.95 (2H, m, ᎐CH ), 3.56 (2H, distorted d, J 5.8, CH OH),
᎐
2
2
4-[2Ј-(tert-Butyldimethylsilyloxy)heptyl]oxetan-2-ones 29a,b
To a stirred solution of lactones 28a–c (56 mg, 0.15 mmol) in
2.13 (2H, distorted t, J 7.1, CH C᎐), 1.70–1.45 (1H, m), 1.40–
1.20 (10H, m, 5 × CH2), 0.89 (3H, distorted t, J 6.6, Me);
᎐
2
1380
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
δC(50.3 MHz, CDCl3) 137.1 (1), 116.0 (2), 65.2 (2), 40.3 (1), 35.6
72.9 (1), 64.6 (2), 46.5 (1), 38.0 (1), 35.4 (2), 31.8 (2C, 2), 29.5
(2), 31.8 (2), 30.6 (2), 29.6 (2), 26.9 (2), 22.6 (2), 14.0 (3).
(2), 26.9 (2), 25.9 (3C, 3), 22.7 (2), 18.2 (0), 14.1 (3), Ϫ1.0 (3C,
3), Ϫ5.5 (2C, 3); m/z (EI mode) 343 [(M Ϫ But ) ϩ, 4%], 229
᝽
4-[(tert-Butyldimethylsilyloxy)methyl]decene 33
(100).
To a solution of alcohol 32 (0.85 g, 5.0 mmol), imidazole (1.36
g, 20 mmol) and 4-dimethylaminopyridine (0.03 g, 0.25 mmol)
in CH2Cl2 (15 cm3) was added at room temp. a solution of tert-
butyldimethylsilyl chloride (867 mg, 5.75 mmol) in CH2Cl2
(5 cm3). The mixture was stirred for 2 h, and concentrated in
vacuo. The residue was partitioned between water (20 cm3) and
ether (20 cm3) and the aqueous phase was extracted with ether
(3 × 10 cm3). The organic phases were dried over MgSO4, fil-
tered and concentrated in vacuo. The crude product was puri-
fied by flash chromatography (SiO2, hexanes:ether = 95:5) to
give 33 (1.42 g, 5.0 mmol, 100%) as a colourless oil; νmax(film)/
cmϪ1 2880m, 1280m, 1120s, 850s, 790m; δH(400 MHz, CDCl3)
Characteristic NMR signals attributable to the minor
diastereoisomers: δH(400 MHz, CDCl3) 35bcis 3.33 (1H, d, J 6.2,
CHC᎐O); 35c
4.41 (1H, m, HCOC᎐O), 2.87 (1H, d, J 4.1,
᎐
᎐
trans
CHC᎐O); δ (100.6 MHz, CDCl ) 35bcis 171.06 (0), 72.5 (1), 65.0
᎐
C
3
(2), 46.6 (1), 38.2 (1), 35.41 (2), Ϫ5.4 (2C, 3); 35ctrans 170.9 (0),
71.8 (1), 64.9 (2), 48.9 (1), Ϫ3.0 (2C, 3); 35dtrans 71.6 (1), 65.6 (2),
Ϫ2.9 (2C, 3).
Further elution gave (E)-5-(tert-butyldimethylsilyloxy-
methyl)undec-2-enoic acid 37 (30 mg, 0.09 mmol, 9%) as a
ButMe2SiO
CO2H
5.80 (1H, ddt, J 17.1, 10.0, 7.2, CH᎐), 4.98 (1H, ddt, J 17.1, 2.2,
᎐
C6H13
1.4, ᎐CH ), 4.96 (1H, ddt, J 10.0, 2.2, 1.3, ᎐CH ), 3.46 (1H,
᎐
᎐
trans
cis
37
part A of ABX system, JAB 9.1, JAX 5.5, CHAHBOTBS), 3.43
(1H, part B of ABX system, JAB 9.1, JBX 6.0, CHAHBOTBS),
2.10 (1H, part A of ABX2 system, JAB 14.0, JAX2 6.8, CHA-
colourless oil, νmax(film)/cmϪ1 3010s, 1730s, 1680m, 1290m,
1130m, 860s, 790m; δH(400 MHz, CDCl3) 7.06 (1H, dt, J 15.6,
H C᎐), 1.99 (1H, part B of ABX system, J 14.0, JBX2 7.1,
᎐
B
2
AB
7.7, CH CH᎐), 5.81 (1H, d, J 15.6, CHCO H), 3.50 (1H, part
CH H C᎐), 1.51 (1H, m), 1.32–1.20 (10H, m, 5 × CH ), 0.87
᎐
2
2
᎐
A
B
2
(9H, s, But ), 0.86 (3H, t, J 7.0, Me), 0.01 (6H, s, SiMe2); δC(50.3
MHz, CDCl3) 137.4 (1), 115.8 (2), 65.1 (2), 40.5 (1), 35.7 (2),
32.0 (2), 30.6 (2), 29.8 (2), 27.0 (2), 26.0 (3C, 3), 22.8 (2), 18.4
(0), 14.2 (3), Ϫ5.3 (2C, 3).
A of ABX system, JAB 10.1, JAX 4.6, CHAHBOTBS), 3.41
(1H, part B of ABX system, JAB 10.1, JBX 6.4, CHAHBOTBS),
2.31 (1H, part A of distorted ABX2 system, JAB 14.3–14.8,
JAX 6.3–6.6, CH H C᎐), 2.19 (1H, part B of distorted ABX
᎐
A
B
2
system, JAB 14.3–1.48, JBX 6.3, CH H C᎐), 1.63 (1H, m),
᎐
B
A
1.30–1.21 (10H, m, 5 × CH2), 0.87 (12H, br s, Me and
But ), 0.03 (6H, s, SiMe2); δC(50.3 MHz, CDCl3) 171.9 (0),
151.5 (1), 121.8 (1), 65.0 (2), 40.3 (1), 34.4 (2), 31.9 (2), 30.8 (2),
29.6 (2), 27.0 (2), 26.0 (3C, 3), 22.7 (2), 18.3 (0), 14.2 (3), Ϫ5.4
4-[(tert-Butyldimethylsilyloxy)methyl]nonanal 34
A solution of alkene 33 (1.38 g, 4.8 mmol) in CH2Cl2 (60 cm3)
was ozonised for 30 min at Ϫ78 ЊC. When the reaction was over
(TLC), the excess ozone was flushed with nitrogen and dimethyl
sulfide (7.3 cm3, 100 mmol) was added and the solution allowed
to warm up to room temp. and then refluxed for 24 h. The
solvents were removed in vacuo and the residual oil purified by
column chromatography (SiO2, hexanes:ether = 97:3) to yield
the aldehyde 34 (963 mg, 3.4 mmol, 70%) as a colourless oil,
νmax(film)/cmϪ1 1750s, 1480s, 1280s, 1120s, 850s, 790m; δH(200
MHz, CDCl3) 9.74 (1H, distorted t, J 2.3, CHO), 3.61 (1H, part
A of ABX system, JAB 9.9, JAX 4.5, CHAHBOTBS), 3.38 (1H,
part B of ABX system, JAB 9.9, JBX 7.3, CHAHBOTBS), 2.50–
2.25 (2H, m, CH2CHO), 1.70–1.50 (1H, m), 1.40–1.10 (10H, m,
5 × CH2), 0.86 (12H, br s, Me and But ), 0.01 (6H, s, SiMe2);
δC(50.3 MHz, CDCl3) 203.1 (1), 65.9 (2), 46.8 (2), 36.6 (1), 31.8
(2), 31.2 (2), 29.5 (2), 27.0 (2), 25.9 (3C, 3), 22.7 (2), 18.3 (0),
14.1 (3), Ϫ5.0 (2C, 3).
(2C, 3); m/z (EI mode) 271 [(M Ϫ But ) ϩ, 46%], 253 (67), 75
᝽
(100).
4-[2Ј-(tert-Butyldimethylsilyloxymethyl)octyl]oxetan-2-ones
36a,b
To a stirred solution of lactones 35a–d (152 mg, 0.38 mmol) in
THF (1.5 cm3) at Ϫ80 ЊC under argon, was slowly added a
solution of TBAFؒ3H2O (145 mg, 0.46 mmol) in THF (1.5
cm3). Once the addition was complete, the mixture was stirred
for a further 30 min at the same temperature. Hydrolysis was
then carried out with 10 drops of saturated aqueous NH4Cl
solution, diethyl ether (10 cm3) was added and extraction was
performed with diethyl ether (3 × 10 cm3). The combined
organic phases were washed with brine (10 cm3), dried over
MgSO4, filtered and concentrated in vacuo. The crude product
was purified by column chromatography (SiO2, hexanes:
ether = 95:5) to give β-lactones 36a,b (125 mg, 0.38 mmol,
100%) as a 55:45 mixture of diastereoisomers according to 400
MHz NMR spectroscopic analysis (Found: C, 65.78; H,
11.07%. C18H36O3Si requires C, 65.80; H, 11.04%); νmax(film)/
cmϪ1 1850s, 1270m, 1140s, 850s, 790s; δH(400 MHz, CDCl3)
4-[2Ј-(tert-Butyldimethylsilyloxymethyl)octyl]-3-trimethylsilyl-
oxetan-2-one 35
A solution of aldehyde 34 (287 mg, 1 mmol) in dry Et2O (3 cm3)
was cooled down to Ϫ80 ЊC before a solution of trimethyl-
silylketene (114 mg, 1.2 mmol) in dry Et2O (2 cm3) was added.
Ethylaluminium dichloride (0.5 cm3 of a 1  solution in hex-
anes, 0.5 mmol) was then slowly added and the reaction mixture
was stirred for 2 h. The mixture was then allowed to warm up to
Ϫ50 ЊC whereupon hydrolysis with water (1 drop) was carried
out at the same temperature. The mixture was allowed to
warm up to room temp., filtered through Celite, dried over
MgSO4 and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, hexanes:ether = 97:3) to give
β-lactones 35a–d (265 mg, 0.66 mmol, 66%) as a mixture of
diastereoisomers (acis :bcis :ctrans :dtrans = 50:34:10:6) according
to 400 MHz NMR spectroscopy of the mixture, νmax(film)/cmϪ1
1820s, 1270m, 1115m, 860s, 790m; δH(400 MHz, CDCl3) 35acis
major isomer 36a 4.63 (1H, m, CHOC᎐O), 3.58 (1H, part A of
᎐
ABX system, JAB 10.2, JAX 4.2, CHaHOTBS), 3.50 (1H, part A
of ABX system, JAB 16.3, J AX 5.7, CH HC᎐O), 3.44 (1H, part
᎐
a
B of ABX system, JAB 10.2, JBX 5.9, CHHbOTBS), 3.06 (1H,
part B of ABX system, JAB 16.3, JBX 4.3, CHH C᎐O), 1.84 (1H,
᎐
b
part A of ABXY system, JAB 15.8, JAX 4.1, JAY 7.4, CHCHa-
HCHO), 1.79 (1H, part B of ABXY system, JAB 15.8, JBX 3.4,
JBY 7.3, CHCHHbCHO), 1.35–1.15 (9H, m), 0.87 (12H, br s,
CH3 and But ), 0.02 (6H, s, SiMe2); minor isomer 36b (dis-
tinguishable signals) 4.68 (1H, m, CHOC᎐O), 1.95 (1H, part A
᎐
of ABX2 system, JAB 14.0, JAX 7.0, CHCHaHCHO), 1.70 (1H,
part B of ABX2 system, JAB 14.0, JBX 6.4, CHCHHbCHO);
δC(100.6 MHz, CDCl3) major isomer 36a 168.7 (0), 70.6 (1),
64.9 (2), 43.6 (2), 37.8 (1), 37.2 (2), 31.8 (2), 31.5 (2), 29.6 (2),
26.9 (2), 22.7 (2), 25.9 (3, 3C), 18.3 (0), 14.1 (3), Ϫ5.4 (3, 2C);
minor isomer 36b (distinguishable signals) 168.6 (0), 70.3 (1),
65.6 (2), 43.4 (2), 37.9 (1), 37.3 (2).
4.72 (1H, m, HCOC᎐O), 3.62 (1H, part A of ABX system, J
᎐
AB
10.1, JAX 4.0, CHAHBOTBS), 3.52 (1H, part B of ABX system,
CH H OTBS), 3.32 (1H, d, J 6.2, CHC᎐O), 1.98–1.80 (1H,
᎐
A
B
m), 1.75–1.60 (2H, m, CHCH2CHO), 1.36–1.18 (10H, m,
5 × CH2), 0.87 (12H, br s, Me and But ), 0.21 (9H, s, SiMe3),
0.05 (6H, s, SiMe2); δC(100.6 MHz, CDCl3) 35acis 171.0 (0),
J. Chem. Soc., Perkin Trans. 1, 1998
1381

View Article Online
11 P. Barbier and F. Schneider, J. Org. Chem., 1988, 53, 1218.
I2, Ph3P, imidazole
(CH3)2CH(CH2)6CH2OH
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56, 4714.
(CH3)2CH(CH2)6CH2I
CH2Cl2, r.t., 24 h
63%
38
39
Scheme 8
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1-Iodo-8-methylnonane 39
To a solution of imidazole (75.6 mg, 1.11 mmol) and triphenyl-
phosphine (107.5 mg, 0.1 mmol) in CH2Cl2 (3 cm3) at 0 ЊC was
added I2 (104 mg, 0.41 mmol). A solution of the alcohol 3842
(58 mg, 0.37 mmol) in CH2Cl2 (1 cm3) was then added slowly
and the mixture warmed to room temp., covered in foil and
stirred for a further 24 h. The mixture was shaken with aqueous
sodium thiosulfate (5%, 3 cm3). The organic layer was separated
and the aqueous layer washed with ether (3 × 5 cm3). The com-
bined layers were dried (MgSO4) and concentrated in vacuo to
leave a colourless oil. Hexane (5 cm3) was added and the result-
ing white precipitate was removed by filtration. The filtrate was
concentrated in vacuo to give iodoalkane 39 (62 mg, 0.23 mmol,
63%) as a pale yellow oil, νmax(film)/cmϪ1 2954s, 2926s, 2854s,
1465m; δH(300 MHz, CDCl3) 3.18 (2H, t, J 12.9, CH2I), 1.82
(2H, app. quintet, J 7.0, CH2), 1.65–1.09 (11H, m, 5 × CH2 and
CH), 0.86 (6H, d, J 6.6, Me2C); δC(67.5 MHz, CDCl3) 39.1 (2),
33.7 (2), 30.7 (2), 29.8 (1), 28.7 (2), 28.0 (2), 27.4 (2), 22.8 (2C,
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C, 1996, 52, 3152.
3), 7.3 (2); m/z (EI mode) 267 [(M Ϫ H) ϩ, 20%], 141 (40), 85
᝽
(76), 57 (100).
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Acknowledgements
We thank Dr Andrew Forrest and Dr Peter O’Hanlon of
SmithKline Beecham Pharmaceuticals for a CASE studentship
(H. P.) and helpful advice. The Marseille–Glasgow collabor-
ation was generously sustained by a Royal Society of Chemistry
Journals Grant to one of us (J.-M. P.).
34 B. Lecea, A. Arrieta, G. Roa, J. M. Ugalde and F. P. Cossio, J. Am.
Chem. Soc., 1994, 116, 9613.
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Chem. Soc., 1995, 117, 12 314.
36 J.-M. Pons, M. Oblin, A. Pommier, M. Rajzmann and D. Liotard,
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Paper 8/00807H
Received 29th January 1998
Accepted 23rd February 1998
1382
J. Chem. Soc., Perkin Trans. 1, 1998