A chemoenzymatic total synthesis of the phytotoxic undecenolide (-)-cladospolide A.

Article abstract of DOI:10.1039/b401829j

An eleven-step synthesis of the title compound (1) from biocatalytically-derived and enantiomerically pure 'building blocks' alcohol (R)-(-)-9 and ester 13 is described. Attempts to construct the twelve-membered lactone ring of cladospolide A in a direct manner by using a ring-closing metathesis (RCM) reaction failed. However, a ten-membered lactone 19, could be constructed by such means and this was then subject to a two-carbon homologation sequence involving, inter alia, Wadsworth-Horner-Emmons and Yamaguchi lactonisation reactions in the closing stages of the synthesis. The impact of substituent stereochemistries and protecting groups on the RCM reaction leading to various ten-membered lactones is also described.

Full text of DOI:10.1039/b401829j

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A chemoenzymatic total synthesis of the phytotoxic undecenolide
(؊)-cladospolide A
Martin G. Banwell* and David T. J. Loong
Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra ACT 0200, Australia.
E-mail: mgb@rsc.anu.edu.au
Received 6th February 2004, Accepted 5th May 2004
First published as an Advance Article on the web 23rd June 2004
An eleven-step synthesis of the title compound (1) from biocatalytically-derived and enantiomerically pure
‘building blocks’ alcohol (R)-(Ϫ)-9 and ester 13 is described. Attempts to construct the twelve-membered lactone
ring of cladospolide A in a direct manner by using a ring-closing metathesis (RCM) reaction failed. However,
a ten-membered lactone, 19, could be constructed by such means and this was then subject to a two-carbon
homologation sequence involving, inter alia, Wadsworth–Horner–Emmons and Yamaguchi lactonisation
reactions in the closing stages of the synthesis. The impact of substituent stereochemistries and protecting
groups on the RCM reaction leading to various ten-membered lactones is also described.
Despite their rather intriguing biological profiles, the
Introduction
cladospolides have only received limited attention as synthetic
targets. The first of only two distinct total syntheses of
compound 1 was reported by Mori and Maemoto in 1987 7 and
used enantiopure ethyl (R)-3-hydroxybutanoate, derived by
enzymatic reduction of ethyl acetoacetate, as the source of C11
stereochemistry. Kinetic resolution of a diastereoisomeric
mixture of allylic alcohols using Sharpless asymmetric epox-
idation chemistry was employed to assemble the cis-vicinal diol
moiety associated with target 1 while the macrocyclic ring was
constructed via a Yamaguchi lactonisation reaction. The
synthesis was accomplished in 16 steps and 2.6% overall yield.
A closely related approach was described by Ichimoto et al. in
the same year.8 Solladié’s synthesis of cladospolide A was first
reported in 1994 9 and cleverly exploited chiral sulfoxides in
the construction of a hydroxy-acid that was also subject to a
Yamaguchi lactonisation reaction to assemble the undecenolide
ring. This synthesis required 20 steps but proceeded in an
impressive 5% overall yield. The activities just described would
seem to represent the full extent of published work associated
with efforts to prepare compounds 1–4.
Our own interest in developing an approach to cladospolide
A arose from our recently described total syntheses of the
18-membered macrolide (ϩ)-aspicillin10 and the nonenolide
(Ϫ)-microcarpalide.11 Each of these employed, as the pivotal
step, a ring-closing metathesis (RCM) reaction to construct the
target macrolides. This method for macrocyclic ring formation
has become increasingly popular in the last few years but at the
time the work described here was commenced its utilisation in
the construction of undecenolide natural products had not
been reported.12 Consequently, we now detail13 an 11-step
and enantioselective total synthesis of cladospolide A, from
biocatalytically-derived starting materials, that employs a RCM
process as the pivotal step. This work has revealed some
constraints that apply in the application of this process to the
construction of 10- and 12-membered macrolides.
Cladospolides A–D (1–4, respectively) comprise the currently
known members of a class of undecenolides isolated from
various Cladosporium species of fungi.1–4 The first two members
were described by Isogai and co-workers1,2 and the structures,
including absolute stereochemistries, established by several
means including Mosher ester analysis5 and a single-crystal
X-ray structure determination.5 Congener 3 was isolated in
1995 by Fukuda and co-workers3 and its structure inferred
by spectroscopic comparisons with compounds 1 and 2.
Cladospolide D was described much more recently (2001)4
and the configurations at C5 and C11 remain undefined.
Cladospolides A–C have been shown to inhibit shoot elon-
gation in rice seedlings and isomer 2 does so without causing
signs of necrosis, thus suggesting that this compound, at least,
inhibits gibberellin biosynthesis.3 Remarkably, cladospolide
A also inhibits root elongation in lettuce seedlings whilst
cladospolide B, which only varies in the configuration about the
double bond and at C4, has the opposite effect.2 Cladospolide
D (4) exhibits antimicrobial activity against Mucor racemosus
and Pyricularia oryzae with IC50 values of 0.15 and 29 µg mLϪ1,
respectively.4 This is the only member of the family to display
such properties which may be attributed to the presence of the
highly electron-deficient ∆2-double bond and its consequent
capacity to react, in a Michael fashion, with biologically
relevant nucleophiles. Cladospolide B, together with the
butenolide isocladospolide B, have recently been isolated from
the Indonesian sponge-derived fungus I965215 by Ireland and
co-workers.6
Results and discussion
The retrosynthetic analysis employed in developing our initial
approach to cladospolide A is shown in Fig. 1. Thus, following
on from our synthesis of (ϩ)-aspicillin,10 we supposed that
application of RCM chemistry to the triene 5 followed by
selective hydrogenation of the non-conjugated double bond
within the undecenolide so-formed would lead, after
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
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Fig. 1
deprotection of the vicinal-diol moiety, to target 1. Compound
5 would, in turn, be prepared through a Wadsworth–Horner–
Emmons (WHE) reaction between aldehyde 6 and phosphono-
acetate 8. It was envisaged that the former substrate could be
prepared from the cis-1,2-dihydrocatechol 7 which is readily
obtained on a large scale and in enantiomerically pure form
by microbial dihydroxylation of chlorobenzene using a gene-
tically engineered strain of E. coli that over expresses the
responsible enzyme, viz. toluene dioxygenase.14 The latter
substrate should be accessible through trans-esterification of
methyl phosphonoacetate with the known15 (R)-pent-4-en-2-ol
[(R)-(Ϫ)-9]. This combined use of WHE and RCM chemistries
was attractive because of the high degree of convergency that
should follow.
Construction of the first ‘building block’ 6 proved straight-
forward and this was obtained by the route shown in Scheme 1.
Thus, in keeping with earlier reports from these laboratories16
as well as those of Boyd et al.17a and Hudlicky and co-
workers,17b cis-1,2-dihydrocatechol 7 was reduced to the
corresponding tetrahydrocatechol 10 (75%) using dihydrogen in
the presence of rhodium on alumina. Protection of the diol
moiety within the latter as the bis-TBDMS ether 11 (100%)
proceeded smoothly under standard conditions.18 A methanolic
solution of compound 11 was then subject to ozonolysis and
the resulting ozonide cleaved with sodium borohydride under
carefully controlled conditions to give the aldehydic ester 12.
This was subject to a conventional Wittig methylenation
reaction and the resulting ω-unsaturated ester 13 was
immediately reduced with DIBAL-H to give the targeted
aldehyde 6 (55% from 11).
With aldehyde 6 in hand attention was focused on production
of the phosphonoacetate 8 and the corresponding S-enantio-
mer. Whilst Brown and co-workers have reported19 generating
the necessary chiral alcohol precursor (R)-(Ϫ)-9 via enantio-
selective allylation of acetaldehyde, for the purposes of obtain-
ing preparatively useful quantities of this material we turned to
enzymatic methods that would be capable of resolving the
commercially available racemate ( )-9. To these ends, and
guided by earlier reports,20 the racemic material was converted
into the corresponding butyrates and five commercially
available lipases were screened for their capacity to effect
enantioselective hydrolysis of these esters in either aqueous
phosphate buffer at pH 7.3 or a hydrocarbon solvent. The
enantiomeric excesses of the unreacted esters were determined
by chiral capillary GLC at the 24 and 48 h time points and the
results of such analyses are summarised in Table 1. These
suggested that Candida antarctica lipase B (CA or CALB) was
especially effective and at the 24 h mark a ca. 80% ee of one
enantiomeric form of the ester was formed. Comparison of the
optical rotation of the isolated and enantiomerically enriched
butyrate ester with literature values21 established that the
S-isomer had been obtained. This outcome is consistent with
expectations, based on both crystallographic studies and
molecular modelling of CALB,22,23 that the R-butyrate should
be hydrolysed preferentially by this enzyme. Furthermore, a
time-course experiment revealed (Table 2) that the highest
enantiomeric excesses of residual S-butyrate were observed
after 2 h. However, whilst this protocol enabled the formation
of highly enantiomerically enriched (R)-(Ϫ)-9, recovery and
subsequent chemical hydrolysis of the butyrate ester of the (S)-
enantiomer proved difficult. As a consequence an alternate
method for production of the enantiomerically enriched forms
of the target alcohols was sought and ultimately identified.
Thus, exposure of the racemate ( )-9 to CALB in vinyl acetate,
which serves as both reaction solvent and acyl donor, resulted
(Scheme 2) in the recovery of essentially enantiomerically pure
Scheme 1 Reagents and conditions: (i) dihydrogen (1 atm.), 5% Rh on
Al2O3 (7 mol%), ethanol, 18 ЊC, 1.5 h; (ii) TBDMS-Cl (4 mol equiv.),
imidazole (8 mol equiv.), DMF, 18 ЊC, 6 h; (iii) O3 (excess), methanol,
Ϫ78 ЊC, ca. 20 min, then NaBH4 (1.1 mol equiv.), 0 ЊC, ca. 10 min; (iv)
Scheme 2 Reagents and conditions: (i) vinyl acetate (neat), CALB,
30 ЊC, 1 h; (ii) pH 7.3 aq. phosphate buffer, CALB, 30 ЊC, 16 h;
(iii) (MeO)2P(O)CH2CO2Me (2 mol equiv.), DMAP (0.74 mol equiv.),
toluene, 112 ЊC, 18 h.
Ph3P᎐CH2 (2.5 mol equiv.), 4:3 v/v THF–toluene, 0–18 ЊC, ca. 1 h; (v)
᎐
DIBAL-H (1.8 mol equiv.), hexane, Ϫ78 ЊC, 1 h.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
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Table 1 Lipase screening for capacity to effect the enantioselective hydrolysis of the butyrate esters of ( )-9 at 30 ЊC
Entry
Lipase/10 mg
Reaction time/h
Medium
Substrate/mg
ees (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
None
None
CC
PP
PS
AK
AK
CA
None
CC
PP
PS
48
48
48
48
48
48
48
48
24
24
24
24
24
24
24
Buffer
Buffer
Buffer
Buffer
Buffer
Buffer
Iso-octane
Buffer
Iso-octane
Buffer
Buffer
Buffer
Buffer
Iso-octane
Buffer
102.3
113.2
107.8
102.4
103.9
101.0
100.9
109.8
102.3
103.8
101.1
104.8
102.3
102.0
100.5
0
0
Ϫ1
10
68
81
1
66
1
16
1
63
77
0
AK
AK
CA
79
CC = Candida cylindriceae lipase (ex Sigma); PP = Porcine pancreatic lipase (ex Sigma); PS = lipase PS (ex Amano); AK = lipase AK (ex Amano);
CA = Candida antarctica lipase B (ex Novo Nordisk); buffer = pH 7.3 aqueous phosphate buffer; ees = enantiomeric excess of reaction substrate
(as determined by GLC analysis on a chiral column).
Table 2 Time dependence of ees in the CALB-catalysed hydrolysis of
the butyrate esters of ( )-9 at 25 ЊC
to give triene 5 (81%), the substrate required in the pivotal step
of the proposed synthesis, namely the RCM. Unfortunately,
and despite many attempts to secure an alternate outcome,
exposure of compound 5 to either the Grubbs’-I26 or Grubbs’-
II27 catalysts failed to give the desired product 15 (Scheme 3).
Rather, the unwanted cyclohexene 16 (100%) proved to be the
only isolable product of reaction. Clearly this product arises via
an RCM involving the two olefinic moieties incorporated
within the carboxylic acid fragment of ester 5. Consequently,
a number of attempts were made to protect the carbonyl-
conjugated double bond through addition of various thiols
in a Michael-addition process, specifically via nucleophilic
epoxidation with hydroperoxy anions and related species and,
in desperation, by conjugate reduction with Stryker’s reagent.28
Unfortunately, none of these approaches delivered any useful
outcomes and the inability to achieve the desired conversions is
attributed, in part at least, to the sterically congested nature of
the β-carbon within compound 5, a situation caused by the
proximate and bulky tert-butyldimethylsilyloxy groups.
Reaction time/h
ees a (%)
0.5
1
2
4
8
65
70
93
82
81
78
30
a ees = enantiomeric excess of reaction substrate (as determined by GLC
analysis on a chiral column).
Table 3 Time dependence of eep and ees in the CALB-catalysed
hydrolysis of the acetate esters of ( )-9 at 30 ЊC
Reaction time/h
eep a (%)
ees a (calculated) (%)
0.25
0.5
1
92
90
80
63
48
80
99
2
100
a eep = enantiomeric excess of reaction product, viz. acetate of 14; a
calculated value for ees is recorded because direct measurement was not
possible.
(>99.9% ee) alcohol (S)-(ϩ)-9 (60% yield) and the chromato-
graphically separable acetate, 14, of (R)-(Ϫ)-9, the latter being
obtained in 80% yield and ca. 75% ee. Time-course experiments
revealed (Table 3) that optimal results were obtained after run-
ning the reaction at 30 ЊC for 1–2 h. In order to improve the
enantiomeric purity of the acetate, 14, of the (R)-alcohol this
was subjected to reaction with CALB in pH 7.3 phosphate
buffer thus affording the required compound (R)-(Ϫ)-9 in
>99.9% ee as judged by chiral GLC analysis of the derived
acetate. This two-step resolution protocol could be run on a
multi-gram scale and the so-called E-value24 for this process is
ca. 36. With pure samples of compound (R)-(Ϫ)-9 available by
such means the corresponding phosphonoacetate, viz. 8, was
readily obtained, in 93% yield, by heating the alcohol with
trimethyl phosphonoacetate in refluxing toluene and in the
presence of the trans-acylation catalyst N,N-dimethylamino-
pyridine (DMAP).25 The spectroscopic data obtained on
the product phosphonoacetate were fully in accord with the
assigned structure.
Scheme 3 Reagents and conditions: (i) NaH (1.7 mol equiv. wrt 8),
THF, 0–18 ЊC, ca. 2.5 h; (ii) Grubbs’-II catalyst (ca. 20 mol%), DCM,
18 ЊC, 18 h.
The foregoing results clearly required a revision of the
originally proposed approach (Fig. 1) to (Ϫ)-cladospolide A.
One possibility would be to couple the carboxylic acid, 17,
derived from ester 18 with alcohol (R)-(Ϫ)-9 so as to form ester
18 which can only engage in one mode of RCM, namely that
leading to compound 19. Hydrogenation of the double bond
within this last compound would then lead to a saturated
lactone which could be reduced to the corresponding lactol.
The open-chain form of this last species would then be expected
to participate in a WHE reaction to deliver a substrate that
could participate in a macrolactonisation reaction and thereby
furnish a protected form of (Ϫ)-cladospolide A. In seeking to
establish such a route, the saponification of ester 13 with
sodium hydroxide was examined and it became apparent that
elevated temperatures (50 ЊC) were required and the yields of
In keeping with the retrosynthetic analysis (Fig. 1) and our
earlier work10 on the synthesis of (ϩ)-aspicillin, the anion
derived from compound 8 reacted smoothly with the aldehyde 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
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the acid 17 obtained on acidic work-up were rather modest
(65%), presumably because undesired desilylation reactions
were occurring. Attempts to couple various activated forms of
this acid with alcohol (R)-(Ϫ)-9 failed to deliver the required
ester 18 in preparatively useful quantities. Success was finally
realised when the Yonemitsu modification29 of the Yamaguchi
esterification reaction30 was employed and under such con-
ditions (see Experimental) compound 18 was obtained in
quantitative yield. Subjection of this last compound to RCM
using Grubbs’-II catalyst27 afforded the expected unsaturated
lactone 19, as a single geometric isomer and presumably with
the illustrated Z-configuration, in 73% yield (at 75% con-
version). In an effort to improve on the yields obtained in this
step the acetonide 20 was prepared by standard methods but
this reacted even less efficiently in the RCM process delivering
product 21 in only 40% yield (at 85% conversion). Intriguingly,
changing the stereochemistry at the carbon (C1Ј) bearing the
methyl group had a significant impact on the efficiency of
this type of reaction. Thus, the C1Ј-epimer of 18, namely
compound 22, which was readily prepared from acid 17 and
alcohol (S)-(ϩ)-9, engages in reaction with Grubbs’-II catalyst
to give lactone 23 in 84% yield. The related acetonide 24 was
converted into the corresponding lactone 25 in 65% yield and
in this case small amounts of what is presumed to be the
corresponding E-isomer of the product were observed.
In an effort to develop some understanding of the origins of
the rather distinct behaviours of substrates 18, 20, 22 and 24
in these RCM reactions, we undertook molecular mechanics
and AM1 semi-empirical single-point energy calculations to
determine the relative energies of the respective products,
namely compounds 19, 21, 23 and 25. These calculations, which
were carried out using the Spartan program and involved con-
formational searching using a Monte Carlo algorithm, revealed
that each macrolide existed in multiple low energy conform-
ations. The non-weighted average energy of all of these was
determined and by such means it was established that the order
of stability of the product macrolides was 19 > 23 ӷ 25 > 21.
This correlates to some extent, at least, with the yields of 73, 84,
65 and 40%, respectively, observed for the reactions leading to
these products. Such results support the proposition that the
transition state for the RCM reaction might be product-like and
that, therefore, the ground-state energies of the products should
give some guide as to the ease with which they can be formed by
such means. It seems to follow, therefore, that, at least in the
present cases, the entropic advantages conferred on the RCM
process through the use of an acetonide moiety are significantly
out-weighed by the increased strain (relative to TBS-protected
equivalents) that this same unit is likely to engender at the
transition state for the reaction. In more general terms, it
seems likely that theoretical determinations of the relative
stabilities of the products of RCM reactions leading to
10-membered macrolides will provide a useful guide as to the
protecting group regimes most likely to be useful in delivering
the targeted products in an efficient manner.
Despite the rather disappointing yields observed in the RCM
process leading to it, sufficient quantities of compound 19
could be accumulated to allow for completion of a synthesis of
target 1. Thus, the double bond within lactone 19 could be
removed by hydrogenation (Scheme 4) under standard con-
ditions and the resulting saturated equivalent (93%) reduced
to lactol 26 with DIBAL-H. This last compound proved to
be rather unstable but, nevertheless, readily participated in a
WHE reaction with the anion derived from trimethyl phos-
phonoacetate to give the E-configured α,β-unsaturated ester 27
(45% from 19). Saponification of this ester proceeded smoothly
using sodium hydroxide at 18 ЊC to give, after acidic work-up,
the seco-acid 28 which was not isolated but immediately
subjected to a Yamaguchi lactonisation protocol30 and thus
affording the targeted lactone 29 in 89% (from ester 27). Inter-
estingly, attempts to effect the desired lactonisation reaction
using the Yonemitsu protocol29 did not yield any cyclised
material at all.
The acquisition of lactone 29 provided a bis-TBS ether-
protected form of (Ϫ)-cladospolide A and attention was thus
focused on the final deprotection step so as to reveal the natural
product. In the event this step proved troublesome because
the compound was both acid- and base-sensitive. The use of
TBAF18 as a fluoride ion source only resulted in decomposition
Scheme 4 Reagents and conditions: (i) dihydrogen (1 atm.), 10% Pd on C (cat.), ethanol, 18 ЊC, 11 h; (ii) DIBAL-H (ca. 2 mol equiv.), toluene,
Ϫ78 ЊC, 0.5 h; (iii) (MeO)2P(O)CH2CO2Me (2.4 mol equiv.), NaH (1.7 mol equiv.), THF, 0–18 ЊC, ca. 2 h; (iv) NaOH (2.5 M aq. solution, 42 mol
equiv.), ethanol, 18 ЊC, 18 h; (v) 2,4,6-trichlorobenzoyl chloride (1 mol equiv.), triethylamine (1.2 mol equiv.), THF, 18 ЊC, 2 h then DMAP (5 mol
equiv.), toluene, 112 ЊC, 1 h; (vi) Zn(BF4)2 (1.2 mol equiv.), MeCN, 18 ЊC, 24 h.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
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(perhaps via retro-aldol-type processes) while use of the milder
TASF31 reagent generated a variety of unidentified silicon-
containing materials. Exposure of lactone 29 to 1% HCl in
ethanol only resulted in lactone cleavage and formation of the
ethyl analogue of methyl ester 27. Some success was observed
when a HF-pyridine complex was used but the yields of target
1 were poor (20%). In the end the use of zinc tetrafluoroborate
in acetonitrile at 18 ЊC, as described by Ranu et al.,32 give the
best result. Thus, under these conditions and after column
chromatography, (Ϫ)-cladospolide A (1) was obtained as a
white, crystalline solid in 73% yield. The physical and spectral
data acquired on this material were in excellent agreement with
those reported1 for the natural product.
The synthesis detailed above provides target 1 in 11 steps
and 4% overall yield from the biocatalytically-derived and
enantiomerically pure starting materials cis-1,2-dihydro-
catechol 7 and alcohol (R)-(Ϫ)-9. The procedures used here
should be amenable to the preparation of the other
cladospolides and works directed towards such ends are now
underway in these laboratories.
Reactions employing air- and/or moisture-sensitive reagents
and intermediates were carried out under an atmosphere of dry,
oxygen-free nitrogen in flame-dried apparatus. Tetrahydrofuran
(THF) and diethyl ether were dried using sodium metal and
then distilled, as required, from sodium benzophenone ketyl.
Methanol was distilled from magnesium methoxide. Dichloro-
methane was distilled from calcium hydride. N,N-Dimethyl-
formamide (DMF) was heated at reflux over calcium hydride
for 16 h then distilled and stored over 3 Å molecular sieves.
Organic solutions obtained from work-up of reaction mixtures
were dried with anhydrous magnesium sulfate (MgSO4) then
concentrated under reduced pressure on a rotary evaporator
with the water bath temperature generally not exceeding 40 ЊC.
Buffer solution of pH 7.3 was prepared by dissolving potassium
dihydrogenphosphate (85 g) and sodium hydroxide (14.5 g)
in water (950 mL). GC analyses were carried out using an
Agilent/HP 6890-5973 gas chromatograph fitted with
a
25QC2/CYDEX-B 0.25 mm capillary column supplied by SGE
(Melbourne) and heated at 50–80 ЊC. Peaks were detected using
a flame ionisation detector operating at 300 ЊC and helium was
employed as carrier gas (flow rate ca. 35 cm sϪ1). Molecular
mechanics and AM1 semi-empirical calculations were carried
out using the Spartan ’02 for Macintosh program as supplied
by Wavefunction Inc. of Irvine, CA.
Experimental
Unless otherwise specified, proton (1H) and carbon (13C) NMR
spectra were recorded on a Varian Gemini 300 or Varian Mer-
cury 300 spectrometer operating at 300 MHz for proton and 75
MHz for carbon nuclei. Chemical shifts were recorded as
δ values in parts per million (ppm). Spectra were acquired in
deuterochloroform (CDCl3) at 20 ЊC unless otherwise stated.
For spectra recorded in CDCl3, the peak due to residual CHCl3
(δ 7.26) was used as the internal reference while the central peak
(δ 77.0) of the CDCl3 ‘triplet’ was used as the reference for
proton-decoupled spectra. Spectral data are recorded as
follows: chemical shift (δ) [relative integral, multiplicity,
coupling constant(s) J (Hz)] where multiplicity is defined as:
s = singlet; d = doublet; t = triplet; q = quartet or quintet; m =
(1S,2S )-3-Chloro-3-cyclohexene-1,2-diol (10)
5% Rh on alumina (1.20 g, 7 mol%) was added to a magnetic-
ally stirred solution of diol 7 (10.4 g, 71 mmol) in absolute
ethanol (350 mL), and the reaction vessel was evacuated then
flushed three times with dihydrogen. The resulting black slurry
was then stirred at 18 ЊC for 1.5 h under dihydrogen whereupon
TLC analysis indicated the absence of starting material. As a
consequence, the reaction mixture was filtered through a pad of
Celite and the filtrate concentrated under reduced pressure
to give an off-white solid. This material was subject to flash
chromatography (2:15:3 v/v/v methanol–diethyl ether–hexane
elution) and concentration of the relevant fractions (Rf 0.3,
diethyl ether) gave the title compound 10 16,17 (7.90 g, 75%) as
white crystals, mp 115–116 ЊC; [α]D Ϫ174 (c 0.30, methanol);
(Found: C, 48.64; H, 6.15; Cl, 23.93. C6H9ClO2 requires C,
48.50; H, 6.10; Cl 23.86%); νmax/cmϪ1 3270, 2932, 2834, 1651,
1462, 1432, 1356, 1332, 1295, 1155, 1124, 1096, 1054, 1002, 984,
923, 820, 787, 690, 591; δH 5.99 (1 H, dd, J 3.5 and 4.5), 4.16
(1 H, m), 3.94 (1 H, dt, J 3.8 and 9.2), 2.70 (2 H, broad s), 2.31
(1 H, m), 2.11 (1 H, m), 1.88–1.70 (2 H, complex m); δC 131.0
(C), 128.4 (CH), 70.5 (CH), 68.9 (CH), 25.2 (CH2), 23.8 (CH2);
multiplet or combinations of the above. Infrared spectra (νmax
)
were recorded on either a Perkin-Elmer 1800 Fourier Trans-
form Infrared Spectrophotometer or a Perkin-Elmer Spectrum
One instrument. Samples were analyzed as KBr discs (for
solids) or as thin films on KBr plates (for liquids/oils). Low and
high resolution MS spectra were recorded on an AUTOSPEC
spectrometer or a Kratos Analytical Concept ISQ instrument,
the latter being located at the University of Tasmania. Optical
rotations were determined on a Perkin-Elmer 241 polarimeter
at the sodium D line (598 nm) using spectroscopic grade
chloroform (unless otherwise specified) at 20 ЊC and at the
concentrations (c) (g 100 mLϪ1) indicated. Measurements were
carried out in a cell with a path length of 1 dm. Melting points
(mp) were recorded on a Reichert hot-stage apparatus and
are uncorrected. Elemental analyses were performed by the
Australian National University Microanalytical Services Unit
based in the Research School of Chemistry, The Australian
National University, Canberra, Australia. Analytical thin layer
chromatography (TLC) was conducted on aluminium-backed
0.2 mm thick silica gel 60 F254 plates (Merck) and the
chromatograms were visualised under a 254 nm UV lamp and/
or by treatment with an anisaldehyde–sulfuric acid–ethanol
(3 mL:4.5 mL:200 mL) dip or, occasionally, with a phos-
phomolybdic acid–ceric sulfate–sulfuric acid–water (37.5 g:7.5
g:37.5 mL:720 mL) dip, followed by heating. The quoted
retardation factors (Rf) have been rounded to the first decimal
place. Flash chromatography was conducted according to the
method of Still and co-workers33 using silica gel 60 (mesh size
0.040–0.063 mm) as the stationary phase and the analytical
reagent (AR) grade solvents indicated. Many starting materials
and reagents were available from the Aldrich Chemical
Company or EGA-Chemie and were used as supplied or, in the
case of stable liquids, simply distilled. Drying agents and other
inorganic salts were purchased from AJAX or BDH Chemicals.
m/z (EI) 150 and 148 (Mϩ , 2 and 7%), 106 and 104 (45 and
ؒ
100%). Calc. for C6H935ClO2 (M): 148.0290. Found: 148.0291.
{[(1S,2S )-3-Chloro-3-cyclohexene-1,2-diyl]bis(oxy)}bis[(1,1-di-
methylethyl)]dimethylsilane (11)
A mixture of diol 10 (1.78 g, 12 mmol), TBDMS-Cl (7.29 g, 48
mmol) and imidazole (6.60 g, 97 mol) was treated with DMF
(20 mL) and the resulting solution stirred at 18 ЊC for 6 h then
partitioned between water (50 mL) and ethyl acetate (20 mL).
The separated aqueous phase was extracted with ethyl acetate
(3 × 40 mL) and the combined organic fractions washed
successively with NaOH (1 × 20 mL of a 1 M aqueous
solution), water (1 × 20 mL) and brine (1 × 20 mL) before being
dried (MgSO4), filtered and concentrated under reduced
pressure to give a yellow oil. Subjection of this material to flash
chromatography (hexane elution) and concentration of the
relevant fractions (Rf 0.3 in 2:98 v/v ethyl acetate–hexane) gave
the title compound 11 (4.53 g, 100%) as a clear, colourless oil,
[α]D Ϫ13 (c 7.40); νmax/cmϪ1 2955, 2929, 2894, 2857, 1649, 1472,
1463, 1362, 1255, 1144, 1115, 1080, 1021, 997, 965, 917, 869,
833, 776, 674, 590; δH 5.81 (1 H, dd, J 2.8 and 4.5), 4.03 (1 H, d,
J 3), 3.77 (1 H, dt, J 3.1 and 11.6), 2.28–1.90 (3 H, complex m),
1.54 (1 H, m), 0.93 (9 H, s), 0.92 (9 H, s), 0.17 (3 H, s), 0.14 (3 H,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
2054

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s), 0.10 (3 H, s), 0.09 (3 H, s); δC 132.2 (C), 126.5 (CH), 74.0
(CH), 72.4 (CH), 26.2 (3 × CH3), 26.0 (3 × CH3) 25.2 (CH2),
24.1 (CH2), 18.5 (C), Ϫ4.2 (CH3), Ϫ4.3 (CH3), Ϫ4.4 (CH3),
Ϫ4.6 (CH3) (one signal obscured or overlapping); m/z (EI) 377
solution) added to dissolve the precipitate so formed (ca. 2 mL).
The mixture was extracted with diethyl ether (2 × 15 mL) and
the combined organic fractions washed with brine (1 × 5 mL)
before being dried (MgSO4), filtered and concentrated under
reduced pressure to give the title aldehyde 6 (183mg, 90%) as a
light-yellow oil. This material was pure enough to use in the
next step of the reaction sequence. A portion of this material
was subjected to flash chromatography (2.5:97.5 v/v ethyl acet-
ate–hexane elution) to give a spectroscopically pure sample of
compound 6 as a clear, colourless oil. νmax/cmϪ1 2954, 2930,
2858, 1736, 1642, 1472, 1361, 1255, 1117, 1004, 911, 832, 777,
671; δH 9.61 (1 H, m), 5.79 (1 H, m), 5.06–4.94 (2 H, complex
m), 3.94–3.88 (2 H, complex m), 2.14–2.03 (2 H, complex m),
1.75–1.56 (2 H, complex m), 0.92 (9 H, s), 0.88 (9 H, s), 0.08 (9
H, br s), 0.07 (3 H, s); δC 203.5 (CH), 138.0 (CH), 114.8 (CH2),
80.7 (CH), 74.8 (CH), 32.7 (CH2), 29.2 (CH2), 25.7(9)
(3 × CH3), 25.7(7) (3 × CH3), 18.2 (C), 18.1 (C), Ϫ4.3 (CH3),
Ϫ4.7 (CH3 – two signals overlapping), Ϫ4.9 (CH3); m/z (EI)
ϩ
ϩ
ؒ
ؒ
and 375 [(M Ϫ H ) , each <1%], 363 and 361 [(M Ϫ CH3 ) , 2
ϩ
ؒ
and 5], 341 [(M Ϫ Cl ) , 9], 321 and 319 (30 and 81), 218 (31),
ϩ
ؒ
147 (100), 113 (52). Calc. for C19H37O2Si2 (M Ϫ Cl ) : 341.2332.
Found: 341.2325.
(2S,3S )-2,3-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-
6-heptenoic acid methyl ester (13)
A magnetically stirred solution of alkene 11 (109 mg, 0.29
mmol) in methanol (6 mL) was cooled to Ϫ78 ЊC then treated
with a stream of ozone until a blue colour persisted and TLC
analysis indicated the absence of starting material (ca. 20 min).
The excess ozone was removed by purging the reaction mixture
with a stream of nitrogen (10 min) and the resulting colourless
solution was then placed in an ice-bath. After 15 min NaBH4
(12.6 mg, 0.33 mmol) was added in two portions over 10 min
whereupon TLC analysis indicated the disappearance of the
ozonolysis product. As a result, the reaction mixture was
quenched with NH4Cl (1 × 5 mL of a saturated aqueous
solution) then extracted with dichloromethane (3 × 5 mL). The
combined organic fractions were dried (MgSO4), filtered and
concentrated under reduced pressure to give aldehyde 12 as an
unstable, yellow oil. δH 9.80 (1 H, s), 4.10 (1 H, d, J 6), 4.01 (1 H,
dd, J 6 and 15), 3.71 (3 H, s), 2.56–2.48 (2 H, complex m), 2.03–
1.8 (2 H, complex m), 0.88 (9 H, s), 0.84 (9 H, s), 0.08 (9 H, s),
0.07 (3 H, s). This material was used immediately in the next
step of the reaction sequence.
A magnetically stirred solution of methyltriphenylphos-
phonium bromide (299 mg, 0.74 mmol) in THF (2 mL) main-
tained at 0 ЊC under an atmosphere of nitrogen was treated
with potassium bis(trimethylsilyl)amide (1.52 mL of a 0.5 M
solution in toluene, 0.76 mmol). The resulting yellow mixture
was allowed to warm to 18 ЊC over 0.5 h then re-cooled to 0 ЊC
and treated, via cannula, with a solution of aldehyde 12
(obtained as described immediately above) in THF (6 mL).
After 1 h at 18 ЊC the reaction mixture was treated with NH4Cl
(10 mL of a saturated aqueous solution) and water (10 mL)
then extracted with diethyl ether (3 × 10 mL). The combined
organic phases were washed with water (1 × 5 mL) and brine
(1 × 5 mL) before being dried (MgSO4), filtered and concen-
trated under reduced pressure to give a yellow oil. Subjection of
this material to flash chromatography (2:98 v/v ethyl acetate–
hexane elution) and concentration of the relevant fractions (Rf
0.6 in 5:95 v/v ethyl acetate–hexane) gave the title compound 13
ϩ
ϩ
ؒ
373 [(M ϩ H) , 0.06%], 357 [(M Ϫ CH3 ) , 0.6], 343 (0.5), 315
ϩ
ؒ
[(M Ϫ C4H9 ) , 6], 231 (79), 199 (82), 73 (100). Calc. for
C19H41O3Si2 (M ϩ H)ϩ: 373.2594. Found: 373.2595.
General procedure used in screening of lipases for enantio-
selective hydrolysis of the butyrate esters derived from alcohol
( )-9
A mixture of the specified amount (see Table 1) of the butyrate
ester20 of alcohol ( )-9 in the relevant medium (2 mL) was
treated with the appropriate lipase (10 mg). The resulting
suspension was kept at 30 ЊC on an orbital shaker for the
specified time then diluted with ethyl acetate (1 mL) and
agitated by vigorous shaking. The emulsified supernatant was
removed by pipette and placed in a centrifuge tube which was
spun at 200 rpm for 3 min. The resulting clear and now lipase-
free supernatant was removed and subjected to chiral GLC
analysis (see introductory comments to Experimental section
for details) to determine the enantiomeric excess of the residual
ester {Rt for S-enantiomer = 5.2 min at 80 ЊC; Rt for
R-enantiomer = 5.8 min at 80 ЊC; Rt for R-4-penten-2-ol [(Ϫ)-9]
= 7.9 min at 80 ЊC}. Results from the relevant experiments are
shown in Table 1.
Time-course experiment associated with the CALB-catalysed
hydrolysis of the butyrate esters derived from alcohol ( )-9
A vigorously stirred mixture of the butyrate esters (509 mg)
derived from alcohol ( )-9 and pH 7.3 buffer (10 mL) was
treated with CALB (50 mg). The resulting slurry was stirred at
25 ЊC and aliquots (1.0 mL) were removed for analysis at the
time points specified in Table 2. Each aliquot was placed in
(72 mg, 61% over 3 steps) as a yellow oil, [α]D Ϫ9 (c 0.30); νmax
/
cmϪ1 2953, 2930, 2857, 1755, 1472, 1255, 1123, 835, 777; δH 5.80
(1 H, m), 5.05–4.91 (2 H, complex m), 4.10 (1 H, d, J 5.4), 3.95
(1 H, dd, J 5.2 and 10.3), 3.70 (3 H, s), 2.16–2.04 (2 H, complex
m), 1.82–1.55 (2 H, complex m), 0.90 (9 H, s), 0.87 (9 H, s), 0.07
(3 H, s), 0.06 (3 H, s), 0.05 (3 H, s), 0.04 (3 H, s); δC 172.8 (C),
138.6 (CH), 114.4 (CH2), 75.6 (CH), 74.0 (CH), 51.6 (CH3),
32.1 (CH2), 28.4 (CH2), 25.8 (3 × CH3), 25.7 (3 × CH3), 18.2
(C), 18.0 (C), Ϫ4.6 (CH3), Ϫ4.7 (CH3), Ϫ5.1 (CH3), Ϫ5.3
a
centrifuge tube with ethyl acetate (500 µL), treated
with NaHCO3 (1 mL of a saturated aqueous solution) and
vigorously shaken. The tubes were spun at 200 rpm for 3 min,
frozen at Ϫ20 ЊC then the liquid supernatant was removed and
subject to chiral GLC analysis to determine the enantiomeric
excess (ees) of the residual ester.
(S )-4-Penten-2-ol [(S )-(؉)-9] and acetic acid (R)-1-methylbut-
3-enyl ester (14)
ϩ
ϩ
ؒ
ؒ
(CH3); m/z (EI) 387 [(M Ϫ CH3 ) , 4.8%], 345 [(M Ϫ C4H9 ) ,
72], 318 (19), 285 (16), 261 (17), 199 (69), 147 (38), 73 (100).
(a) Time-course experiment. ( )-4-Penten-2-ol [( )-9] (502
mg, 5.83 mmol) was dissolved in vinyl acetate (502 mg, 537 µL,
5.83 mmol) and CALB (53 mg) then added in one portion. The
resulting slurry was stirred at 30 ЊC and aliquots (1 drop) were
removed for analysis at the times specified in Table 3. These
aliquots were diluted with ethyl acetate (200 µL) then placed
in a centrifuge tube and spun at 200 rpm for 3 min. The
supernatant was decanted into vials for chiral GLC analysis.
Results from the relevant experiments are shown in Table 3.
ϩ
ؒ
Calc. for C19H39O4Si2 (M
387.2389.
Ϫ
CH3 ) : 387.2387. Found:
(2S,3S )-2,3-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-
6-heptenal (6)
DIBAL-H (1.0 µL of a 1 M solution in hexane, 1.00 mmol) was
added in three portions over 1 h to a magnetically stirred
solution of ester 13 (222 mg, 0.55 mmol) in hexane (16 mL)
maintained at Ϫ78 ЊC under a nitrogen atmosphere. The
reaction mixture was then quenched with NH4Cl (10 mL
of a saturated aqueous solution) and sufficient HCl (1 M aq.
(b) Preparative experiment. ( )-4-Penten-2-ol [( )-9] (9.85 g,
0.11 mol, 1 equiv.) was dissolved in vinyl acetate (9.84 g, 0.11
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
2055

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mol, 1 mol equiv.) and the resulting solution treated with
CALB (1 g). The ensuing slurry was stirred at 30 ЊC for 1 h and
then filtered through a glass frit to remove the immobilised
enzyme particles. The filtrate was loaded onto a tall pad of
TLC-grade silica which was then eluted with dichloromethane.
In this manner two fractions, A and B, were obtained.
Concentration of fraction A (Rf 0.7 in 1:9 v/v ethyl acetate–
hexane) at 0 ЊC using a water aspirator and a dry-ice condenser
gave acetate 14 (5.63 g, 80%, 75% ee).
Concentration of fraction B (Rf 0.3 in 1:9 v/v ethyl acetate–
hexane) at 0 ЊC using a water aspirator and a dry-ice condenser
gave alcohol (S)-(ϩ)-9 (2.74 g, 60%, 99% ee as determined by
analysis of the derived acetate; Rt for S-enantiomer = 9.1 min at
50 ЊC; Rt for R-enantiomer = 11.2 min at 50 ЊC).
maintained at 0 ЊC under a nitrogen atmosphere was treated,
via cannula, with a solution of compound 8 (80 mg, 0.34 mmol)
in THF (1 mL). The resulting mixture was allowed to warm
to 18 ЊC over 0.66 h then re-cooled to 0 ЊC and a solution of
aldehyde 6 (109 mg, 0.29 mmol) in THF (1.5 mL) was added
via cannula at 0 ЊC. After re-warming to 18 ЊC over 1.25 h,
the reaction mixture was quenched with NH4Cl (10 mL of a
saturated aqueous solution) and the separated aqueous layer
extracted with diethyl ether (3 × 10 mL). The organic fractions
were combined, washed with water (1 × 5 mL) and brine (1 × 5
mL) before being dried (MgSO4), filtered and concentrated
under reduced pressure to give a yellow oil that was subjected to
flash chromatography (2:98 v/v ethyl acetate–hexane elution).
Concentration of the relevant fractions (Rf 0.1) gave the title
compound 5 (173 mg, 81% from compound 6). [α]D Ϫ3 (c 0.70);
νmax/cmϪ1 3078, 2932, 2891, 2858, 1721, 1650, 1644, 1467, 1361,
1257, 1168, 1109, 987, 914, 835, 776; δH 6.92 (1 H, dd, J 5.7 and
15.8), 5.93 (1 H, dd, J 1.5 and 15.8), 5.88–5.69 (2 H, complex
m), 5.13–4.92 (5 H, complex m), 4.14 (1 H, m), 3.66 (1 H, m),
2.34 (2 H, m), 2.11 (2 H, m), 1.62 (2 H, m), 1.25 (3 H, d, J 6.3),
0.91 (9 H, s), 0.89 (9 H, s), 0.07 (3 H, s), 0.04(3) (3 H, s), 0.03(8)
(3 H, s), 0.03(1) (3 H, s); δC 165.7 (C), 148.7 (CH), 138.5 (CH),
133.6 (CH), 121.9 (CH), 118.0 (CH2), 114.4 (CH2), 75.5 (CH),
75.3 (CH), 70.0 (CH), 40.4 (CH2), 32.7 (CH2), 29.0 (CH2),
26.0(0) (3 × CH3), 25.9(9) (3 × CH3), 19.6 (CH3), 18.3 (C), 18.2
(C), Ϫ4.0(5) (CH3), Ϫ4.1(4) (CH3), Ϫ4.3 (CH3), Ϫ4.6 (CH3);
(R)-4-Penten-2-ol [(R)-(؊)-9]
A slurry of phosphate buffer (50 mL, pH 7.3), CALB (2.10 g)
and acetate 14 (17.6 g, 0.14 mol, 75% ee), obtained as described
immediately above, was stirred vigorously at 30 ЊC for 16 h then
cooled to 18 ЊC and filtered through a pad of Celite. The filter
cake was washed with diethyl ether (6 × 100 mL) and the separ-
ated aqueous layer extracted with dichloromethane (3 × 200
mL). The combined organic fractions were then washed with
brine (1 × 200 mL) before being dried (MgSO4), filtered and
concentrated under reduced pressure at 0 ЊC on a rotary evap-
orator fitted with a water aspirator and a dry-ice condenser.
The resulting light-yellow oil was subject to flash column
chromatography (1:3 v/v ether–pentane elution) and concen-
tration of the relevant fractions (Rf 0.3 in 1:9 v/v ethyl acetate–
hexane) by evaporation at atmospheric pressure then afforded
the title compound (R)-(Ϫ)-9 (7.23 g, 60%) as a ca. 50 mol%
solution in diethyl ether. GLC analysis of the derived acetate
established it was of >99% ee.
ϩ
ϩ
ؒ
m/z (EI) 483 [(M ϩ H) , >1%], 467 [(M Ϫ CH3 ) , 1], 425
ϩ
ؒ
[(M Ϫ C4H9 ) , 39], 398 (38), 284 (33), 225 (31), 199 (82), 151
(43), 147 (58), 73 (100). Calc. for C25H47O4Si2 (M Ϫ CH3 ) :
ϩ
ؒ
467.3013. Found: 467.3014.
[(1S,2R)-3-Cyclohexene-1,2-diyl-bis(oxy)]bis[(1,1-dimethyl-
ethyl)]dimethylsilane (16)
Grubbs’-II catalyst (7.5 mg, 0.01 mmol) was added to a
magnetically stirred solution of compound 5 (24 mg, 0.05
mmol) in degassed dichloromethane (50 mL) maintained under
a nitrogen atmosphere at 18 ЊC. The reaction mixture was
stirred for a further 18 h whereupon TLC analysis indicated the
absence of starting material. P(CH2OH)3 (100 mg) and silica
(ca. 2 g) were added and the resulting mixture stirred at 18 ЊC
for a further 1 h then filtered and concentrated under reduced
pressure to give a dark-yellow oil. Subjection of this material to
flash chromatography (2:98 v/v diethyl ether–hexane elution)
and concentration of the relevant fractions (Rf 0.7) gave the title
compound 16 (17 mg, 100%) as a clear, colourless oil. [α]D Ϫ119
(c 0.46); νmax/cmϪ1 3029, 2932, 2888, 2857, 1467, 1392, 1252,
1117, 1022, 955, 869, 834, 776; δH 5.69 (1 H, m), 5.58 (1 H, m),
4.07 (1 H, m), 3.78 (1 H, dt, J 2.8 and 9.7), 2.19 (1 H, m), 2.05–
1.84 (2 H, complex m), 1.55 (1 H, m), 0.91 (18 H, s), 0.09 (3 H,
s), 0.08 (9 H, s); δC 128.8, 128.7, 71.0, 68.6, 26.6, 26.1(4),
26.1(3), 24.3, 18.5, Ϫ4.1, Ϫ4.2, Ϫ4.3, Ϫ4.6 (one signal obscured
(Dimethoxyphosphinyl)acetic acid (1R)-1-methyl-3-butenyl ester
(8)
A magnetically stirred solution of DMAP (42 mg, 0.34 mmol)
in toluene (10 mL) maintained at 18 ЊC under a nitrogen
atmosphere was treated, dropwise, with alcohol (R)-(Ϫ)-9 (200
µL, 0.46 mmol). Trimethyl phosphonoacetate (150 µL, 0.93
mmol) was then added dropwise and the resulting solution
heated at reflux for 18 h. The cooled reaction mixture was
quenched with NH4Cl (5 mL of a saturated aqueous solution)
and the separated aqueous layer extracted with ethyl acetate
(3 × 10 mL). The organic fractions were combined, washed with
water (1 × 5 mL) and brine (1 × 5 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
give a dark-yellow residue which was purified by flash column
chromatography (ethyl acetate elution). Concentration of the
relevant fractions (Rf 0.5) gave the title compound 8 as a light-
yellow oil (101 mg, 93%). [α]D ϩ79 (c 1.13); νmax/cmϪ1 2957,
2854, 1733, 1642, 1454, 1272, 1116, 1032, 850, 805; δH 5.69 (1 H,
m), 5.03 (2 H, m), 4.93 (1 H, m), 3.76 (3 H, m), 3.72 (3 H, m),
2.90 (2 H, d, J 21.6), 2.27 (2 H, m), 1.18 (3 H, d, J 6.3); δC 164.8
(C, d, J 6.0), 133.0 (CH), 117.7 (CH2), 71.6 (CH), 53.0 (CH3, d,
J 2.3), 52.9 (CH3, d, J 2.3), 39.9 (CH2), 33.5 (CH2, d, J 134.5),
ϩ
ؒ
or overlapping); m/z (EI) 341 [(M Ϫ H ) , 0.9%], 327 [(M Ϫ
ϩ
ϩ
ؒ
ؒ
CH3 ) , 6], 285 [(M Ϫ C4H9 ) , 8], 184 (34), 147 (100), 127 (62),
ϩ
ؒ
79 (53), 73 (59). Calc. for C17H35O2Si2 (M Ϫ CH3 ) : 327.2176.
Found: 327.2173.
(2S,3S )-2,3-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-
6-heptenoic acid (1R)-1-methyl-3-butenyl ester (18)
ϩ
ϩ
ؒ
19.2 (CH3); m/z (EI) 237 [(M ϩ H) , 4%], 195 [(M – C3H5 ) , 3],
169 (22), 151 (100), 109 (55). Calc. for C9H18O5P (M ϩ H)ϩ:
237.0892. Found: 237.0895.
A magnetically stirred solution of ester 13 (216 mg, 0.54 mmol)
in ethanol (20 mL) maintained at 18 ЊC was treated with a
solution of NaOH (108 mg, 2.7 mmol) in water (2 mL). The
ensuing mixture was heated to 50 ЊC for 13 h then cooled,
treated with NH4Cl (1 × 10 mL of a saturated aqueous
solution) and extracted with dichloromethane (3 × 20 mL). The
combined organic fractions were dried (MgSO4), filtered and
concentrated under reduced pressure to give the crude acid 17,
[α]D Ϫ5 (c 0.10); νmax/cmϪ1 3078, 2953, 2930, 2896, 2858, 1723,
1642, 1471, 1463, 1255, 1126, 836, 777; δH 9.60 (1 H, broad s),
5.78 (1 H, m), 4.99 (2 H, m), 4.17 (1 H, d, J 3.6), 3.93 (1 H, m),
Compound ent-8, [α]D Ϫ77 (c 0.85), was prepared from (S)-
(ϩ)-9 and trimethyl phosphonoacetate by the method defined
above. The derived NMR, IR, and MS spectral data were
identical with those obtained from ester 8.
(2E,4R,5S )-4,5-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-2,8-
nonadienoic acid (1R)-1-methyl-3-butenyl ester (5)
A magnetically stirred suspension of NaH (13.8 mg of a 60%
dispersion in mineral oil, 0.58 mmol) in THF (1 mL)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
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Ϫ5.1 (CH3), Ϫ5.4 (CH3); m/z (EI) 428 (Mϩ , 2%), 413 [(M Ϫ
ϩ ϩ
ؒ
2.09 (2 H, m), 1.69 (2 H, m), 0.91 (9 H, s), 0.88 (9 H, s), Ϫ0.09
(3 H, s), Ϫ0.10 (3 H, s), Ϫ0.13 (6 H, s); δC 175.2 (C), 138.4 (CH),
138.1 (CH2), 75.9 (CH), 74.5 (CH), 32.1 (CH2), 29.1 (CH2), 25.8
(3 × CH3), 25.7 (3 × CH3), 18.2 (C), 18.0 (C), Ϫ4.5 (CH3), Ϫ4.7
(CH3), Ϫ5.0 (CH3), Ϫ5.2 (CH3); m/z (EI) 331 [(M Ϫ C4H9 ) ,
80%], 199 (88), 171 (71), 147 (47), 75 (66), 73 (100).
ؒ
ؒ
CH3 ) , 3], 371 [(M Ϫ C4H9 ) , 76], 239 (80), 211 (43), 171 (53),
147 (69), 95 (64), 75 (58), 73 (100). Calc. for C22H44O4Si2 Mϩ
428.2778. Found: 428.2777.
:
ؒ
ϩ
ؒ
(4R,5S )-5-But-3-enyl-2,2-dimethyl-1,3-dioxolane-4-carboxylic
A magnetically stirred solution of the acid 17, obtained as
described above, in toluene (18 mL) maintained at 0 ЊC under a
nitrogen atmosphere was treated sequentially with DMAP
(69 mg, 0.56 mmol), alcohol (R)-(Ϫ)-9 (290 µL of a 2.3 M
solution in diethyl ether, 0.67 mmol) and triethylamine (390 µL,
2.8 mmol) then cooled to 0 ЊC and 2,4,6-trichlorobenzoyl
chloride (95 µL, 0.56 mmol) added dropwise. The ensuing white
slurry was stirred for an additional 0.75 h then the reaction
mixture treated with NaHCO3 (5 mL of a saturated aqueous
solution) and the separated aqueous layer extracted with diethyl
ether (3 × 20 mL). The combined organic fractions were washed
with brine (1 × 5 mL) before being dried (MgSO4), filtered and
concentrated under reduced pressure to give a dark-yellow
residue. Subjection of this material to gravity column
chromatography (2:98 v/v ethyl acetate–hexane elution) and
concentration of the relevant fractions (Rf 0.3 in 5:95 v/v ethyl
acetate–hexane) gave the title compound 18 (158 mg, 65 %) as a
clear, colourless oil. [α]D Ϫ5 (c 0.80); νmax/cmϪ1 3079, 2931,
2857, 1752, 1642, 1468, 1380, 1255, 1123, 994, 914, 835, 777; δH
5.86–5.69 (2 H, complex m), 5.14–4.92 (5 H, complex m), 4.14
(1 H, d, J 3.2), 3.95 (1 H, m), 2.34 (2 H, m), 2.09 (2 H, m), 1.67
(2 H, m), 1.24 (3 H, d, J 6.3), 0.92 (9 H, s), 0.89 (9 H, s), 0.09
(3 H, s), 0.08 (3 H, s), 0.07 (3 H, s), 0.06 (3 H, s); δC 171.4 (C),
138.6 (CH) 133.5 (CH), 117.9 (CH2), 114.4 (CH2), 76.3 (CH),
74.7 (CH), 70.6 (CH), 40.2 (CH2), 32.2 (CH2), 29.3 (CH2), 25.9
(3 × CH3), 25.7 (3 × CH3), 19.3 (CH3), 18.3 (C), 18.1(C), Ϫ4.3
(CH3), Ϫ4.7(8) (CH3), Ϫ4.8(2) (CH3), Ϫ5.2 (CH3); m/z (EI) 456
acid (precursor to ester 20)
TBAF (1.1 mL of a 1 M solution in THF, 1.1 mmol) was added
dropwise to a magnetically stirred solution of ester 13 (223 mg,
0.55 mmol) in THF (6 mL) maintained at 0 ЊC under a nitrogen
atmosphere. The ensuing mixture was brought to 18 ЊC, stirred
at this temperature for 2 h, then treated with water (5 mL)
and NaHCO3 (5 mL of a saturated aqueous solution). The
separated aqueous fraction was extracted with diethyl ether
(2 × 10 mL) and the combined organic fractions then washed
with brine (1 × 5 mL) before being dried (MgSO4), filtered and
concentrated under reduced pressure to give a yellow oil. This
material was dissolved in 2,2-dimethoxypropane (6 mL) con-
taining p-toluenesulfonic acid (9 mg) and the resulting and
magnetically stirred solution maintained under a nitrogen
atmosphere at 18 ЊC for 18 h. NaHCO3 (10 mL of a saturated
aqueous solution) was added to quench the reaction mixture
and the separated aqueous fraction was extracted with ethyl
acetate (3 × 10 mL). The combined organic fractions were
washed with brine (1 × 5 mL) then dried (MgSO4), filtered and
concentrated under reduced pressure to give methyl (4R,5S)-5-
but-3-enyl-2,2-dimethyl-1,3-dioxolane-4-carboxylate (42 mg,
35% from 13).
A magnetically stirred solution of this
compound (39 mg, 0.18 mmol) in ethanol (3 mL) was treated
with NaOH (100 mg, 2.5 mmol) dissolved in water (2 mL) and
maintained at 18 ЊC for 3 h. The ensuing mixture was acidified
with HCl (4 mL of a 1 M aqueous solution) and extracted with
dichloromethane (3 × 10 mL). The combined organic fractions
were washed with brine (1 × 5 mL), then dried (MgSO4), filtered
and concentrated under reduced pressure to give an off-white
solid which was resuspended in dichloromethane (10 mL),
filtered through glass wool and concentrated under reduced
pressure to give the title carboxylic acid (35 mg, 100 %) as a
pale-yellow solid. Mp 91–94 ЊC, [α]D Ϫ5 (c 0.01); (Found: C,
63.00; H, 9.15. C12H20O4 requires: C, 63.14; H, 8.83%);
νmax/cmϪ1 3436, 3076, 2983, 2934, 1607, 1440, 1373, 1243, 1218,
1167, 1077, 912, 869, 757; δH 5.80 (1 H, m), 5.05 (2 H, m), 4.58
(1 H, m), 4.40 (1 H, m), 2.40–2.05 (3 H, complex m), 1.80 (1 H,
m), 1.60 (3 H, s), 1.40 (3 H, s) (signal due to CO2H not
ϩ
ϩ
(Mϩ , >1%), 441 [(M Ϫ CH3 ) , >1], 399 [(M Ϫ C4H9 ) , 35%],
372 (23), 331 (98), 315 (42), 273 (12), 258 (22), 199 (100), 171
(41), 155 (39), 133 (54), 115 (37), 73 (76). Calc. for C20H39O4Si2
ؒ
ؒ
ؒ
ϩ
ؒ
(M Ϫ C4H9 ) : 399.2387. Found: 399.2391.
(3S,4S,7Z,10R)-3,4-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-
3,4,5,6,9,10-hexahydro-10-methyl-2H-oxecin-2-one (19)
A magnetically stirred solution of diene 18 (125 mg, 0.27 mmol)
in degassed dichloromethane (140 mL) maintained under a
nitrogen atmosphere was treated, via cannula, with a solution
of Grubbs’-II catalyst (35 mg, 0.04 mmol, 15 mol%) in
dichloromethane (10 mL). The resulting mixture was stirred
at 18 ЊC for 24 h then P(CH2OH)3 (ca. 50 mg) and silica gel
(ca. 200 mg) were added to the reaction mixture. The resulting
slurry was stirred at 18 ЊC for 1 h then filtered through a pad of
TLC-grade silica gel which was washed with dichloromethane
(1 × 10 mL). The combined filtrates were concentrated under
reduced pressure and the light-yellow oil thus obtained subject
to flash chromatography (2:98 v/v diethyl ether–hexane elution)
and thereby affording two fractions, A and B.
ϩ
ؒ
observed); m/z (EI) 185 [(M Ϫ CH3 ) , 100%], 125 (19), 116
(12), 97 (51), 79 (33), 69 (30), 59 (62). Calc. for C9H13O4
ϩ
ؒ
(M Ϫ CH3 ) : 185.0814. Found 185.0818.
(4R,5S )-5-But-3-enyl-2,2-dimethyl-1,3-dioxolane-4-carboxylic
acid (1R)-1-methylbut-3-enyl ester (20)
A magnetically stirred solution of (4R,5S)-5-but-3-enyl-2,2-
dimethyl-1,3-dioxolane-4-carboxylic acid (26 mg, 0.13 mmol) in
toluene (4 mL) maintained at 0 ЊC under a nitrogen atmosphere
was treated with DMAP (16 mg, 0.13 mmol), alcohol (R)-(Ϫ)-9
(60 µL of a 4.5 M solution in diethyl ether, 0.27 mmol) and
triethylamine (92 µL, 0.66 mmol). 2,4,6-Trichlorobenzoyl
chloride (22 µL, 0.14 mmol) was added dropwise over 1 min
and the resulting white slurry stirred for an additional 0.75 h
at 0 ЊC then quenched with NaHCO3 (5 mL of a saturated
aqueous solution) and extracted with diethyl ether (3 × 20 mL).
The combined organic fractions were washed with brine (1 × 5
mL) then dried (MgSO4), filtered and concentrated under
reduced pressure to give a dark-yellow residue. Subjection of
this material to gravity column chromatography (2:98 v/v ethyl
acetate–hexane elution) and concentration of the relevant
fractions (Rf 0.3 in 1:3 v/v ethyl acetate–hexane) gave the title
compound 20 (19 mg, 54 %) as a clear, colourless oil. [α]D ϩ30
(c 0.50); νmax/cmϪ1 3078, 2982, 2935, 1754, 1642, 1452, 1377,
1265, 1192, 1093, 995, 916, 869, 790; δH 4.23 (2 H, m), 5.16–4.94
Concentration of fraction A [Rf 0.3(0) in 5:95 v/v ethyl
acetate–hexane] afforded the starting diene 18 (32 mg, 26%
recovery) which was identical, in all respects, with an authentic
sample.
Concentration of fraction B [Rf 0.2(8) in 5:95 v/v ethyl acet-
ate–hexane] gave the title compound 19 (61 mg, 73% yield at
75% conversion) as a clear, colourless oil. [α]D ϩ0.8 (c 7.40);
νmax/cmϪ1 2931, 2857, 1729, 1465, 1374, 1255, 1155, 1073, 957,
885, 837, 777, 716, 674; δH 5.47–5.33 (2 H, complex m), 5.10
(1 H, m), 4.28 (1 H, d, J 0.7), 3.98 (1 H, dd, J 4.7 and 10.9), 2.73
(1 H, m), 2.38 (1 H, m), 2.04–1.82 (3 H, complex m), 1.68–1.53
(1 H, complex m), 1.32 (3 H, d, J 6.5), 0.93 (9 H, s), 0.89 (9 H,
s), 0.09 (3 H, s), 0.07 (3 H, s), 0.06 (3 H, s), 0.04 (3 H, s); δC 172.6
(C), 133.7 (CH), 124.7 (CH), 78.4 (CH), 74.5 (CH), 70.5 (CH),
34.6 (CH2), 32.1 (CH2), 25.8 (3 × CH3), 25.6 (3 × CH3), 22.7
(CH2), 20.2 (CH3), 18.3 (C), 18.0 (C), Ϫ4.8 (CH3), Ϫ4.9 (CH3),
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
2057

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(5 H, m), 4.52 (1 H, d, J 6.7), 4.32 (1 H, m), 2.44–2.09 (4 H,
complex m), 1.72–1.52 (2 H, complex m), 1.62 (3 H, s), 1.38
(3 H, s), 1.25 (3 H, d, J 6.3); δC 169.9 (C), 137.4 (CH), 133.3
(CH), 118.1 (CH2), 115.2 (CH2), 110.3 (C), 77.2 (CH), 77.1
(CH), 71.2 (CH), 40.2 (CH2), 30.3 (CH2), 29.2 (CH2), 27.0
(CH3), Ϫ4.7(9) (CH3), Ϫ4.8(2) (CH3), Ϫ5.2 (CH3); m/z (EI) 455
ϩ ϩ
ؒ
ؒ
[(M Ϫ H ) , 1%], 399 [(M Ϫ C4H9 ) , 2], 345 (32), 243 (31), 215
(34), 199 (65), 185 (43), 147 (52), 133 (21), 115 (42), 73 (100).
ϩ
ؒ
Calc. for C20H39O4Si2 (M Ϫ C4H9 ) : 399.2387. Found:
399.2386.
ϩ
ؒ
(CH3), 25.7 (CH3), 19.5 (CH3); m/z (EI) 253 [(M Ϫ CH3 ) ,
85%], 155 (14), 125 (26), 116 (16), 97 (100), 79 (39), 69 (89).
Calc. for C14H21O4 (M Ϫ CH3 ) : 253.1440. Found: 253.1439.
(3S,4S,7Z,10S )-3,4-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-
3,4,5,6,9,10-hexahydro-10-methyl-2H-oxecin-2-one (23)
ϩ
ؒ
Diene 22 (31 mg, 0.07 mmol) was subjected to the conditions
defined above for ring-closing metathesis. After subjection of
the product mixture to flash chromatography (2:98 v/v diethyl
ether–hexane elution) and concentration of the relevant
fractions (Rf 0.4 in 8:92 v/v ethyl acetate hexane), the title
compound 23 (25 mg, 84%) was obtained as a clear, colourless
oil. [α]D Ϫ27 (c 0.80); νmax/cmϪ1 2954, 2930, 2886, 2859, 1750,
1595, 1460, 1428, 1253, 1173, 1136, 1077, 995, 836, 757; δH 5.55
(2 H, m), 5.03 (1 H, m), 4.34–4.20 (2 H, complex m), 3.01 (1 H,
m), 2.18 (1 H, m), 1.99 (1 H, m), 1.88–1.56 (2 H, complex m),
1.37 (1 H, m), 1.24 (3 H, d J 6.7), 0.95 (9 H, s), 0.90 (9 H, s), 0.12
(3 H, s), 0.07 (3 H, s), 0.06 (6 H, m); δC 171.8 (C), 134.9 (CH),
122.7 (CH), 74.9 (CH), 72.9 (CH), 70.7 (CH), 30.6 (CH2), 26.0
(3 × CH3), 25.8 (3 × CH3), 23.6 (CH2), 18.5 (C), 18.2 (C), 17.8
(CH3), Ϫ4.6 (CH3), Ϫ4.8 (CH3), Ϫ4.9 (CH3), Ϫ5.1 (CH3) (one
(3aS,6R,8Z,11aS )-3a,6,7,10,11,11a-Hexahydro-2,2,6-tri-
methyl-1,3-dioxolo[4,5-c]oxecin-4-one (21)
Diene 20 (13 mg, 0.05 mmol) was subjected to the conditions
defined above for the ring-closing metathesis of congener 18
(and yielding macrolide 19). Subjection of the resulting mixture
to the specified work-up procedures afforded a light–yellow
oil which was subject to flash chromatography (1:3 v/v diethyl
ether–hexane elution). In this manner two fractions, A and B,
were obtained.
Concentration of fraction A [Rf 0.3(2)] afforded the starting
diene 20 (2 mg, 15% recovery) which was identical, in all
respects, with an authentic sample.
Concentration of B [Rf 0.3(5)] gave a clear colourless oil
tentatively identified as the title compound 21 (4 mg, 40% at
85% conversion). δH 5.59–5.38 (2 H, complex m), 4.94 (1 H, m),
4.53 (1 H, m), 4.28 (1 H, m), 2.43–2.04 (4 H, complex m), 1.66–
1.58 (2 H, complex m), 1.60 (3 H, m), 1.29 (3 H, m), 1.27 (3 H,
m). These data compare favourably with those derived from the
more stable congener 19. It is this comparison which provides
the major basis for the assignment of the illustrated structure to
compound 21.
signal obscured or overlapping); m/z (EI) 428 (Mϩ , <1%), 413
ؒ
ϩ
ϩ
ؒ
ؒ
[(M Ϫ CH3 ) , 2], 371 [(M Ϫ C4H9 ) , 68], 355 (11), 327 (46),
239 (99), 211 (100), 195 (82), 171 (80), 147 (81). Calc. for
C22H44O4Si2 Mϩ : 428.2778. Found: 428.2785.
ؒ
(2S,3S )-2,3-Dihydroxyhept-6-enoic acid (1R)-1-methylbut-3-
enyl ester (precursor to ester 24)
TBAF (600 µL of a 1 M solution in THF, 0.60 mmol) was
added dropwise to a magnetically stirred solution of compound
22 (115 mg, 0.25 mmol) in THF (5 mL) maintained at 0 ЊC
under a nitrogen atmosphere. The ensuing mixture was brought
to 18 ЊC and stirred for 2 h at this temperature then treated
sequentially with water (5 mL) and NaHCO3 (5 mL of a satur-
ated aqueous solution). The separated aqueous phase was
extracted with dichloromethane (3 × 20 mL) and the combined
organic fractions washed with NaHCO3 (1 × 5 mL of a satur-
ated aq. solution) and brine (1 × 5 mL) then dried (MgSO4),
filtered and concentrated under reduced pressure to give a light-
yellow oil. Subjection of this material to flash chromatography
(2:3 v/v ethyl acetate–hexane elution) and concentration of the
relevant fractions (Rf 0.3) gave the title compound (43 mg, 76%)
as pale-yellow needles. Mp 36–38 ЊC; [α]D Ϫ5 (c 0.53); νmax/cmϪ1
3431, 3077, 2978, 2929, 1730, 1641, 1445, 1212, 1125, 1078, 995,
915; δH 5.87–5.65 (2 H, complex m), 5.14–4.93 (4 H, complex
m), 4.18 (1 H, d, J 3.7), 3.83 (1 H, dt, J 3.4 and 9.9), 2.87 (2 H,
broad s), 2.40–2.20 (3 H, complex m), 2.12 (1 H, m), 1.64 (1 H,
m), 1.47 (1 H, m), 1.27 (3 H, d, J 6.3); δC 172.3 (C), 137.9 (CH),
133.1 (CH), 118.3 (CH2), 115.1 (CH2), 74.1 (CH), 72.5 (CH),
72.4 (CH), 40.1 (CH2), 30.7 (CH2), 29.9 (CH2), 19.5 (CH3).
Satisfactory MS data could not be obtained for this compound.
(2S,3S )-2,3-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-
6-heptenoic acid (1S )-1-methyl-3-butenyl ester (22)
A magnetically stirred solution of ester 13 (106 mg, 0.27 mmol)
in ethanol (10 mL) maintained at 18 ЊC was treated with a
solution of NaOH (212 mg, 5.3 mmol) in water (2 mL). The
ensuing mixture was heated to 50 ЊC for 13 h, then cooled,
acidified with NH4Cl (1 × 10 mL of a saturated aqueous
solution) and extracted with dichloromethane (3 × 20 mL). The
combined organic fractions were dried (MgSO4), filtered and
concentrated under reduced pressure to give the crude acid 17
which was dissolved in toluene (30 mL) and the resulting
solution maintained under a nitrogen atmosphere at 18 ЊC
whilst being treated with DMAP (1.9 mg, 16 mmol), alcohol
(S)-(ϩ)-9 (98 µL, ca. 0.95 mmol) and triethylamine (1 mL, 7.2
mmol). The resulting mixture was cooled to 0 ЊC and 2,4,6-
trichlorobenzoyl chloride (1 mL, 6.4 mmol) added dropwise.
The resulting white slurry was warmed to 18 ЊC, maintained at
this temperature for 0.75 h then diluted with diethyl ether (20
mL) and poured into NaHCO3 (10 mL of a saturated aqueous
solution). The separated aqueous solution was extracted with
diethyl ether (3 × 50 mL) and the combined organic fractions
were washed with HCl (1 × 10 mL of 1 M aqueous solution),
water (1 × 15 mL) and brine (1 × 15 mL) before being dried
(MgSO4), filtered and concentrated under reduced pressure to
give a yellow oil. Subjection of this material to gravity column
chromatography (2:98 v/v ethyl acetate–hexane elution) and
concentration of the relevant fractions (Rf 0.5 in 1:9 ethyl
acetate–hexane) gave the title compound 22 (33.5 mg, 65 %) as
a clear, colourless oil. [α]D Ϫ10 (c 0.90); νmax/cmϪ1 3078, 2953,
2931, 2893, 2857, 2893, 1753, 1468, 1380, 1254, 1156, 1124, 993,
914, 886, 777; δH 5.87–5.66 (2 H, complex m), 5.16–4.88 (5 H,
complex m), 4.12 (1 H, d, J 3.3), 3.94 (1 H, ddd, J 3.4, 4.9 and
6.9), 2.44–1.95 (4 H, complex m), 1.84 Ϫ1.52 (2 H complex m),
1.24 (3 H, d, J 6.3), 0.91 (9 H, s), 0.88 (9 H, s), 0.08 (3 H, s), 0.07
(3 H, s), 0.06(2) (3 H, s), 0.05(5) (3 H, s); δC 171.4 (C), 138.6
(CH), 133.6 (CH), 117.9 (CH2), 114.4 (CH2), 76.3 (CH), 74.8
(CH), 70.8 (CH), 40.2 (CH2), 32.1 (CH2), 29.3 (CH2), 25.9
(3 × CH3), 25.7 (3 × CH3), 19.3 (CH3), 18.3 (C), 18.1 (C), Ϫ4.3
(4R,5S )-5-But-3-enyl-2,2-dimethyl-1,3-dioxolane-4-carboxylic
acid (1S )-1-methylbut-3-enyl ester (24)
A magnetically stirred solution of (2S,3S)-2,3-dihydroxyhept-
6-enoic acid (1R)-1-methylbut-3-enyl ester (40 mg, 0.17 mmol)
in 2,2-dimethoxypropane (2 mL) was treated, in one portion,
with p-toluenesulfonic acid (3.4 mg). The resulting mixture was
maintained under a nitrogen atmosphere at 18 ЊC for 18 h then
NaHCO3 (10 mL of a saturated aqueous solution) was added to
quench the reaction mixture. The separated aqueous fraction
was extracted with ethyl acetate (3 × 10 mL) and the organic
fractions were combined, washed with brine (1 × 5 mL) then
dried (MgSO4), filtered and concentrated under reduced
pressure to give the title compound 24 (18.6 mg, 40%) as a light-
yellow oil. [α]D ϩ24 (c 0.20); νmax/cmϪ1 3078, 2982, 2937, 1753,
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
2058

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1727, 1642, 1452, 1377, 1268, 1190, 1092, 994, 916, 869, 789;
δH 5.88–5.66 (2 H, complex m), 5.15–4.96 (5 H, complex m),
4.51 (1 H, d, J 6.7), 4.31 (1 H, m), 2.45–2.08 (4 H, complex m),
1.72–1.50 (2 H, complex m), 1.61 (3 H, s), 1.38 (3 H, s), 1.26 (3
H, d, J 6.2); δC 169.7 (C), 137.3 (CH), 133.3 (CH), 118.1 (CH2),
115.2 (CH2), 110.3 (C), 71.5 (CH), 40.2 (CH2), 30.5 (CH2), 29.4
(CH2), 27.1 (CH3), 25.8 (CH3), 19.6 (CH3) (two signals
obscured or overlapping). Satisfactory EIMS data could not be
obtained for this compound.
Thus, a magnetically stirred suspension of NaH (19 mg of
a 60% dispersion in mineral oil, 0.48 mmol) in THF (3 mL)
maintained at 0 ЊC under a nitrogen atmosphere was treated
dropwise with trimethyl phosphonoacetate (135 µL, 0.66
mmol). The mixture was warmed to 18 ЊC over 0.5 h and a
solution of the lactol 26 (obtained as described above) in THF
(3 mL) was added via cannula at 0 ЊC. After re-warming to
18 ЊC over a period of 1 h, the reaction mixture was diluted
with diethyl ether (10 mL) and quenched with NH4Cl (10 mL of
a saturated aqueous solution). The separated aqueous fraction
was extracted with diethyl ether (3 × 10 mL) and the combined
organic fractions washed with brine (1 × 10 mL) before being
dried (MgSO4), filtered and concentrated under reduced
pressure to give a light-yellow oil. Subjection of this material to
flash chromatography (2:3:5 v/v/v dichloromethane–diethyl
ether–hexane elution) and concentration of the relevant
fractions (Rf 0.3) gave the title compound 27 (66 mg, 48% from
saturated lactone) as a clear, colourless oil. [α]D Ϫ3 (c 0.43);
νmax/cmϪ1 3369, 2931, 2857, 1728, 1660, 1466, 1255, 1166, 1111,
836, 776; δH 6.96 (1 H, dd, J 5.4 and 15.7), 5.96 (1 H, dd, J 1.5
and 15.7), 4.14 (1 H, m), 3.76 (1 H, m), 3.73 (3 H, s), 3.63 (1 H,
m), 1.59 (1 H, broad s), 1.54–1.23 (10 H, complex m), 1.17 (3 H,
d, J 6.2), 0.90 (9 H, s), 0.86 (9 H, s), 0.05 (3 H, s), 0.02 (6 H, s),
0.01 (3 H, s); δC 166.7 (C), 149.2 (CH), 120.9 (CH), 76.1 (CH),
75.5 (CH), 68.0 (CH), 51.5 (CH3), 39.3 (CH2), 33.4 (CH2), 29.9
(CH2), 26.0 (3 × CH3), 25.9 (3 × CH3), 25.8 (CH2), 25.0 (CH2),
23.5 (CH3), 18.3 (C), 18.2 (C), Ϫ4.1 (CH3), Ϫ4.3 (CH3), Ϫ4.4
(3aS,6S,8Z,11aS )-3a,6,7,10,11,11a-Hexahydro-2,2,6-trimethyl-
1,3-dioxolo-[4,5-c]oxecin-4-one (25)
Diene 24 (10.2 mg, 0.04 mmol) was subjected to the conditions
defined above for ring-closing metathesis and after purification
by flash chromatography (1:3 v/v diethyl ether–hexane elution)
and concentration of the relevant fractions (Rf 0.4 in 1:3 v/v
ethyl acetate hexane) a yellow oil, tentatively assigned as the
title compound 25 (5.8 mg, 64%), was obtained. δH 5.47 (2 H,
m), 4.99 (1 H, m), 4.52 (1 H, m), 4.29 (1 H, m), 2.38–2.05 (4 H,
complex m), 1.68–1.53 (5 H, complex m), 1.38 (6 H, m); δC
169.9 (C), 129.5 (CH), 128.6 (CH), 77.9 (CH), 77.2 (CH), 71.8
(CH), 39.3 (CH2), 30.2 (CH2), 29.4 (CH2), 26.9 (CH3), 25.7
(CH3), 19.8 (CH3) (one signal obscured or overlapping). These
data compared favourably with those derived from the more
stable congener 23. At present, it is this comparison that
provides the major basis for the assignment of the illustrated
structure to compound 25.
ϩ
ؒ
(CH3), Ϫ4.7 (CH3); m/z (EI) 473 [(M Ϫ CH3 ) , 0.3%], 431
ϩ
ؒ
[(M Ϫ C4H9 ) , 7], 399 (56), 259 (55), 171 (30), 147 (76),
109 (44), 89 (40), 75 (57) 73 (100). Calc. for C21H43O5Si2 (M Ϫ
(3S,4S,10R)-3,4-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-10-
methyl-2-oxecanone (precursor to lactol 26)
ϩ
ؒ
C4H9 ) : 431.2649. Found: 431.2653.
10% Palladium on charcoal (23 mg, 20 wt%) was added to a
magnetically stirred solution of alkene 19 (112 mg, 0.260 mmol)
in absolute ethanol (3 mL). A balloon of dihydrogen was
attached and the reaction vessel evacuated and flushed with
dihydrogen three times. The resulting black suspension was
stirred under an atmosphere of dihydrogen at 18 ЊC for 11 h,
then filtered through a pad of Celite. Concentration of the
filtrate under reduced pressure gave a grey-yellow oil which was
subjected to flash chromatography (1:9 v/v diethyl ether–hexane
elution). Concentration of the relevant fractions (Rf 0.3 in 5:95
v/v ethyl acetate–hexane) gave the title compound (104 mg,
93%) as a clear, colourless oil. [α]D Ϫ2 (c 0.77); νmax/cmϪ1 2931,
2857, 1724, 1470, 1363, 1276, 1253, 1171, 1154, 1082, 976, 836,
777, 675; δH 5.03 (1 H, m), 4.27 (1 H, d, J 1.2), 4.01 (1 H, m),
1.93–1.35 (10 H, complex m), 1.26 (3 H, d, J 6.5), 0.93 (9 H, s),
0.88 (9 H, s), 0.08 (3 H, s), 0.06 (6 H, s), 0.04 (3 H, s); δC 172.7
(C), 77.7 (CH), 75.4 (CH), 72.5 (CH), 31.5 (CH2), 31.1 (CH2),
26.0 (3 × CH3), 25.7 (3 × CH3), 25.5 (CH2), 23.7 (CH2), 21.4
(CH2), 20.7 (CH3), 18.4 (C), 18.2 (C), Ϫ4.6 (CH3), Ϫ4.7 (CH3),
(3E,5R,6S,12R)-5,6-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-
12-methyloxacyclododec-3-en-2-one (29)
A magnetically stirred solution of methyl ester 27 (28 mg, 0.06
mmol) in ethanol (3 mL) was treated with NaOH (1 mL of a 2.5
M aqueous solution). The ensuing mixture was allowed to stir
at 18 ЊC for 18 h then acidified to pH 3 (with 1 M aqueous HCl)
and extracted with ethyl acetate (5 × 12 mL). The combined
organic phases were washed with brine (1 × 5 mL) then dried
(MgSO4), filtered and concentrated under reduced pressure to
give the carboxylic acid 28 as a light-yellow oil. This unstable
material was immediately dissolved in THF (1 mL) containing
triethylamine (10 µL, 0.07 mmol) and the resulting and
magnetically stirred solution was treated with 2,4,6-trichloro-
benzoyl chloride (9 µL, 0.06 mmol) and, after 2 h, diluted
with toluene (70 µL). The ensuing mixture was added, over ca.
10 min and via cannula, to a solution of DMAP (37 mg, 0.3
mmol) in refluxing toluene (10 mL). The resulting mixture was
heated at reflux for 1 h then cooled, quenched with NaHCO3 (5
mL of a saturated aqueous solution) and extracted with ethyl
acetate (3 × 20 mL). The combined organic fractions were
washed with brine (1 × 5 mL) then dried (MgSO4), filtered and
concentrated under reduced pressure to give a light-yellow oil.
Subjection of this material to flash chromatography (5:95 v/v
diethyl ether–hexane elution) and concentration of the relevant
fractions (Rf 0.3) gave the macrolactone 29 (22.5 mg, 89%) as a
clear, colourless oil. [α]D Ϫ23 (c 0.18); νmax/cmϪ1 2932, 2858,
1723, 1649, 1466, 1364, 1254, 1159, 1074, 1003, 835, 777;
δH 6.76 (1 H, dd, J 4.7 and 15.8), 6.15 (1 H, dd, J 1.6 and 15.8),
5.08 (1 H, m), 4.43 (1 H, m), 3.53 (1 H, dm, J 8.9), 1.90–1.05 (10
H, complex m), 1.28 (3 H, d, J 6.6), 0.92 (9 H, s), 0.90 (9 H, s),
0.09 (3 H, s), 0.06 (3 H, s), 0.05(2) (3 H, s), 0.04(8) (3 H, s);
δC 168.4 (C), 147.8 (CH), 121.7 (CH), 76.6 (CH), 75.7 (CH),
72.9 (CH), 32.2 (CH2), 30.7 (CH2), 27.7 (CH2), 26.1 (3 × CH3),
26.0 (3 × CH3), 25.8 (CH2), 23.4 (CH2), 19.4 (CH3), 18.5 (C),
Ϫ4.9 (CH3), Ϫ5.2 (CH3); m/z (EI) 430 (Mϩ , 2%), 415 [(M Ϫ
ؒ
ϩ
ϩ
ؒ
ؒ
CH3 ) , 3], 373 [(M Ϫ C4H9 ) , 54%], 304 (27), 241 (56), 213
(51), 147 (58), 133 (45), 109 (50), 73 (100). Calc. for C22H46O4Si2
Mϩ : 430.2935. Found: 430.2936.
ؒ
(2E,4R,5S,11R)-4,5-Bis{[(1,1-dimethylethyl)dimethylsilyl]oxy}-
11-hydroxy-2-dodecenoic acid methyl ester (27)
DIBAL-H (500 µL of a 1 M solution in hexane, 0.50 mmol) was
added to a magnetically stirred solution of the lactone derived
from the hydrogenation of compound 19 (119.4 mg, 0.28 mmol)
in toluene (6 mL) maintained at Ϫ78 ЊC under a nitrogen
atmosphere. Stirring was continued for 0.5 h then the reaction
quenched by adding NaK tartrate (10 mL of a 1 M aqueous
solution) and the resulting mixture warmed to 0 ЊC over an
additional 0.5 h. The separated aqueous fraction was extracted
with diethyl ether (3 × 30 mL) and the combined organic frac-
tions washed with water (1 × 5 mL) and brine (1 × 5 mL) before
being dried (MgSO4), filtered and concentrated under reduced
pressure to give lactol 26 as an unstable, yellow oil which was
used immediately in the next step of the reaction sequence.
18.4 (C), Ϫ4.4 (2 × CH3), Ϫ4.6(7) (CH3), Ϫ4.7(0) (CH3); m/z
ϩ
(EI) 456 (Mϩ , 3%), 399 [(M Ϫ C4H9 ) , 27%], 371 (13), 241
ؒ
ؒ
(34), 216 (51), 198 (62), 147 (87), 109 (53), 73 (100). Calc. for
C24H48O4Si2 Mϩ : 456.3091. Found: 456.3090.
ؒ
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 2 0 5 0 – 2 0 6 0
2059

View Online
8 I. Ichimoto, M. Sato, M. Kirihata and H. Ueda, Chem. Express,
1987, 2, 495.
(؊)-Cladospolide A (1)
A magnetically stirred solution of lactone 29 (20 mg, 0.04
mmol) in acetonitrile (500 µL) was treated with Zn(BF4)2 (45 µL
of a 5 M aqueous solution) and the resulting mixture main-
tained at 18 ЊC for 24 h then diluted with water (2 mL) and
extracted with diethyl ether (5 × 2 mL). The combined organic
fractions were dried (Na2SO4), filtered and concentrated under
reduced pressure to give a yellow oil. Subjection of this material
to flash chromatography (diethyl ether elution) and concen-
tration of the relevant fractions (Rf 0.3) gave the title compound
1 (7.3 mg, 73%) as a white solid. Mp 90–91 ЊC (lit.1 mp
92–93 ЊC), [α]D Ϫ53 (c 0.20) {lit.7 [α]D Ϫ49 (c 0.23 in CHCl3)};
νmax/cmϪ1 3469, 2939, 2865, 1714, 1647, 1461, 1270, 1165, 1126,
1031, 995, 881, 756, 668; δH 6.80 (1 H, dd, J 5.7 and 16.0), 6.21
(1 H, dd, J 1.5 and 16.0), 5.13 (1 H, m), 4.56 (1 H, m), 3.67 (1 H,
ddd, J 1.5, 3.2 and 9.8), 2.50 (2 H, broad s), 1.84–1.11 (8 H,
complex m), 1.29 (3 H, d, J 6.4), 0.87 (2 H, m); δC 167.7, 145.5,
122.2, 74.7, 72.9, 32.5, 30.7, 28.2, 25.1, 22.6, 19.1 (one signal
obscured or overlapping); m/z (EI) 229 [(M ϩ H)ϩ, 0.4%], 211
(2), 184 (5), 127 (17), 109 (36), 102 (100), 84 (66). Calc. for
C12H21O4 (M ϩ H)ϩ: 229.1440. Found: 229.1441.
9 G. Solladié, A. Almario and C. Dominguez, Pure Appl. Chem., 1994,
66, 2159; G. Solladié and A. Almario, Tetrahedron: Asymmetry,
1995, 6, 559.
10 M. G. Banwell and K. J. McRae, Org. Lett., 2000, 2, 3583.
11 M. G. Banwell and D. T. J. Loong, Heterocycles, 2004, 62, 713.
12 For other examples of the synthesis of 10-membered rings by RCM,
see: A. Fürstner, K. Radkowski, C. Wirtz, R. Goddard, C. W.
Lehmann and R. Mynott, J. Am. Chem. Soc., 2002, 124, 7061;
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13 Aspects of this work have been reported in preliminary form:
M. G. Banwell, K. A. Jolliffe, D. T. J. Loong, K. J. McRae and
F. Vounatsos, J. Chem. Soc., Perkin Trans. 1, 2002, 22.
14 For a comprehensive discussion on the production and synthetic
utility of cis-1,2-dihydrocatechols, see: T. Hudlicky, D. Gonzalez
and D. T. Gibson, Aldrichim. Acta, 1999, 32, 35.
15 M. V. R. Reddy, A. J. Yucel and P. V. Ramachandran, J. Org. Chem.,
2001, 66, 2512.
16 M. G. Banwell, G. S. Forman and D. C. R. Hockless, Indian
J. Chem., Sect. B, 1999, 38, 1011; M. G. Banwell, A. J. Edwards and
D. T. J. Loong, ARKIVOC, 2004(x), 53.
17 (a) D. R. Boyd, N. D. Sharma, H. Dalton and D. A. Clarke, Chem.
Commun., 1996, 45; (b) D. Gonzalez, V. Schapiro, G. Seoane,
T. Hudlicky and K. Abboud, J. Org. Chem., 1997, 62, 1194.
18 E. J. Corey and A. Venkateswarlu, J. Am. Chem. Soc., 1972, 94,
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Acknowledgements
19 U. S. Racherla and H. C. Brown, J. Org. Chem., 1991, 56, 401 and
We thank Dr Ken McRae and Ms Filisaty Vounatsos for
preliminary experiments and Dr Kate Jolliffe for useful
discussions. Dr Gregg Whited (Genencor International Inc.,
Palo Alto) is warmly thanked for providing us with generous
quantities of compound 7.
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