and the structure was confirmed through X-ray crystal-
lography and total synthesis.7 However to date neither the
isolation nor synthesis of the final diastereomer 4 has been
reported. Our aim was to prepare 4 which would be of
value when screening extracts from organisms known to
produce decanolides. The synthetic approach needed to be
flexible, enabling access to other diastereomers (e.g., 3), as
wellasamenablefor the incorporation of vicinal carbon-13
labels for biosynthetic studies.
Diastereomers 1, 2, and 3 have all been prepared using a
ring closing metathesis to generate the 4,5-double bond in
the cyclization step.4bÀd,8 In contrast, we proposed a
convergent route in which the two fragments A and B
would be coupled using a Yamaguchi esterification to 6
followed by a NozakiÀHiyamaÀKishi reaction (NHK) to
form the decanolide ring (Scheme 1).
and hydrolysis of the ester were achieved using aqueous
K2CO3 to give 11. The final step was conversion of the
alkyne to the (E)-vinyl iodide. It proved necessary to
protect both the acid and alcohol as the TIPS derivative
12 to provide sufficient steric hindrance for the Schwartz
hydrozirconium/iodination to proceed in good yield
without competing zirconium complexation by the ester
group.11 The exclusive formation of the E double bond
was apparent from the 1H NMR (δ 6.42, dd, J 14.5, 0.9 Hz,
5-H; δ 6.63, dd J 14.5, 6.8 Hz, 4-H). Finally hydrolysis of
the TIPS ester provided the required vinyl iodide 8.
Scheme 2. Synthesis of C1ÀC5 Fragment 8
Scheme 1. Retrosynthesis of Decanolide 4
In their synthesis of decarestrictine D 5, Pilli and Victor
used the NHK reaction to close the ring with formation of
the C6ÀC7 bond.9 The required 7S-alcohol was formed
preferentially, but the protecting groups on the 3- and
4-hydroxyl groups influenced both the yield and stereo-
selectivity of this step. We aimed to prepare both enantio-
mers of vinyl iodide 8 to further investigate how the
conformational bias in the acyclic precursor influences
the stereocontrol in NHK cyclizations.
An enzymatic reaction was used in the synthesis of the
C1ÀC5 fragment 8 required for synthesis of our first target,
diol 4. First Claisen condensation of ethyl acetate with
protected ethyl propiolate 9 gave β-keto ester 10 in 82%
yield (Scheme 2). Reduction of 10 using Saccharomyces
cerevisiae10 gave the C-3 alcohol in 88:12 er as determined
by conversion to the 2-phenylethyl ester and analysis by
chiral HPLC. Concomitant removal of the TMS group
For the synthesis of the C6ÀC10 fragment, a chemoenzy-
matic approach was again used starting in this case from
commercially available pentane-1,4-diol (Scheme 3). The
primary alcohol was protected as the trityl ether 14 to
achieve high enantioselectivity (99:1 er as determined by
chiral HPLC) in the resolution with vinyl acetate and
Amano lipase from P. cepacia.12 The resultant acetate 15
was readily hydrolyzed to the required secondary alcohol
16 in 99% yield.
With both fragments in hand, coupling to the requisite
ester was investigated and Yamaguchi conditions proved
best giving 17 in 99% yield (Scheme 4). The trityl group
was removed using Et2AlCl, thus unmasking the primary
alcohol 18. This was oxidized with DMP to provide
aldehyde 6 required for the key cyclization. Treatment of
6 with CrCl2 and NiCl2 in DMF gave a 3:1 mixture of
epimers at C6 which were readily separable by SiO2 column
chromatography. NOE studies (CDCl3) revealed the
stereochemistry of the major isomer (Figure 2).
(7) Rukachaisirikul, V.; Pramjit, S.; Pakawatchai, C.; Isaka, M.;
Supothina, S. J. Nat. Prod. 2004, 67, 1953.
(8) Mohapatra, D. K.; Ramesh, D. K.; Giardello, M. A.; Chorghade,
M. S.; Gurjar, M. K.; Grubbs, R. H. Tetrahedron Lett. 2007, 48, 2621.
(9) (a) Pilli, R. A.; Victor, M. M. Tetrahedron Lett. 1998, 39, 4421.
(b) Pilli, R. A.; Victor, M. M. J. Braz. Chem. Soc. 2001, 12, 373. (c) Pilli,
R. A.; Victor, M. M. Tetrahedron Lett. 2002, 43, 2815.
(11) Lipshutz, B. H.; Keil, R. J. Am. Chem. Soc. 1992, 114, 7919.
(12) Kim, M. J.; Lim, I. T.; Choi, G. B.; Whang, S. Y.; Ku, B. C.;
Choi, J. Y. Bioorg. Med. Chem. Lett. 1996, 6, 71.
(10) Salit, A. F.; Meyer, C.; Cossy, J.; Delouvrie, B.; Hennequin, L.
Tetrahedron 2008, 64, 6684.
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