Total synthesis of cyanolide A

Article abstract of DOI:10.1039/c0ob00971g

The total synthesis of cyanolide A has been achieved in 14 steps from commercially available (S)-2-ethyloxirane, exploiting the palladium-catalyzed intramolecular alkoxycarbonylation as the key step to construct the tetrasubstituted cis-tetrahydropyran ring with high stereoselectivity.

Full text of DOI:10.1039/c0ob00971g

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Total synthesis of cyanolide A†
Zhen Yang,a Xingang Xie,a Peng Jing,a Gaoyuan Zhao,a Jiyue Zheng,a Changgui Zhaoa and Xuegong She*a,b
Received 2nd November 2010, Accepted 29th November 2010
DOI: 10.1039/c0ob00971g
The total synthesis of cyanolide A has been achieved in 14
steps from commercially available (S)-2-ethyloxirane, exploit-
ing the palladium-catalyzed intramolecular alkoxycarbony-
lation as the key step to construct the tetrasubstituted cis-
tetrahydropyran ring with high stereoselectivity.
However, its high price, poor water solubility, and potential
toxicity toward fish are considered major drawbacks.8 Up to now,
not any molluscicides have been proved effective enough to replace
niclosamide.6,9,10
Cyanolide A (1), a glycosidic macrolide consisting of a 16-
membered macrocycle, owns a C2 symmetric structure. The
interesting structure and highly potent biological activity against
the snail vector Biomphalaria glabrata have attracted considerable
interest in the synthetic community. Recently, Hong and co-
workers have disclosed the first total synthesis of 1 using a tandem
allylic oxidation/oxa-Michael reaction strategy to assemble the
tetrahydropyran ring.11
Our retrosynthetic analysis was illustrated in Scheme 1. We
envisioned that 1 would be accessible by dimerization of its
monomer 2, which itself might be generated via glycosylation
of alcohol 3. Critically, we anticipated that cis-tetrahydropyran
ring structure could be obtained by means of palladium-catalyzed
intramolecular alkoxycarbonylation of diol 4a or 4b, which would
be derived from ester 5. For ester 5, it could be easily prepared from
commercially available (S)-2-ethyloxirane (6) via SmI2-promoted
Evans-Tishchenko reduction.
An efficient synthesis of diols 4a and 4b from commercially
available (S)-2-ethyloxirane is outlined in Scheme 2. Treatment of
6 with the lithium anion of 2-allyl-1,3-dithiane 7 afforded alcohol
8 in 90% yield. Removing the 1,3-dithiane group of 8 followed by a
SmI2-promoted Evans-Tishchenko reduction12 generated 5 in 85%
yield for two steps. Ozonolysis of 5 gave the crude aldehyde 10,
which was subjected directly to Barbier-type reaction13 with prenyl
bromide to yield diols 4a and 4b (1 : 1 mixture, 58% total yield for
two steps), which were separated by column chromatography.
In our first attempts, we made an effort to reduce the use
of protecting group in our synthesis. Thus, the Pd-catalyzed
intramolecular alkoxycarbonylation14 was carried out with 4a.
It was unfortunate that the propionate protecting group was
cleavaged to give diol A (Scheme 3), in which two unmasked
secondary hydroxyl groups were difficult to be discriminated for
further functionalization. Moreover, the stereochemistry of C9 in
diol A should be inverted to meet the required stereochemistry
of natural cyanolide A (1). For this consideration, we decided
to conduct the C9 stereochemistry inversion before conduction
of the palladium-catalyzed intramolecular alkoxycarbonylation.
As depicted in Scheme 4, treatment of diol 4a with 2,2-
dimethoxypropane followed by LiAlH4 easily produced alcohol
12 in 89% yield for two steps. Using a Mitsunobu reaction with
Cyanolide A (1) (Fig. 1), a new and highly potent molluscicidal
agent against the snail vector Biomphalaria glabrata (LC50 =
1.2 mM), was isolated from extracts of a Papua New Guinea
collection of Lyngbya bouilloni by Gerwick and co-workers in
2010.1 Schistosomiasis, a disease caused by parasitic worms, is
most commonly found in Asia, Africa, and South America,
especially in areas where the water contains numerous freshwater
snails, which may carry the parasite.2 Although it has a low
mortality rate, schistosomiasis continues to be one of the most
prevalent parasitic infections worldwide, with an estimated 207
million people currently infected and 779 million people at risk
of infection.3,4 A major problem in controlling schistosomiasis
infection, however, is the complex lifecycle of the worm. The
helminths require both an aquatic snail host and a mammalian
host to complete their reproductive cycle. Niclosamide (Baylus-
cide, LC100 = 4.6 mM) is the most widely used molluscicide
available, effectively killing snails at all stages of the lifecycle.5,6,7
Fig. 1 Structure of cyanolide A (1).
aState Key Laboratory of Applied Organic Chemistry, Department of
Chemistry, Lanzhou University, Lanzhou, 730000, People’s Republic of
China
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou
Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou,
730000, People’s Republic of China. E-mail: shexg@lzu.edu.cn; Fax: +86-
931-8912582; Tel: +86-931-8912276
† Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/c0ob00971g
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Scheme 1 Retrosynthetic analysis of cyanolide A (1).
Scheme 2 Synthesis of diols 4a and 4b.
With key intermediate 3 in hand, we proceeded to the synthesis
of natural product 1 (Scheme 6). Glycosylation of 3 with phenyl
thioglycoside 16 in the presence of MeOTf furnished the desired
b-anomeric monomer 17 in 62% isolated yield along with a small
amout of a-anomeric monomer (~5 : 1).11 Deprotecting the PMP
group of 17 with ammonium cerium(IV) nitrate (CAN) provided
alcohol 2 in 80% yield.15 Its optical rotation ([a]2D0 = -42.0, c 0.66,
CHCl3) was essentially identical to the value reported by Hong
and co-workers ([a]2D5 = -46.6, c 0.66, CHCl3). Then alcohol 2
was converted to the natural cyanolide A (1) in two steps as
described by Kim and Hong (ref. 11). The optical rotation of
our synthetic ([a]2D0 = -50.0, c 0.42, CHCl3) was in agreement with
the isolated natural product ([a]2D3 = -59.0, c 0.60, CHCl3) and
the value reported by Hong and co-workers ([a]2D5 = -55.5, c 0.33,
CHCl3).11
Scheme 3 Pd-catalyzed intramolecular alkoxycarbonylation with 4a.
4-methoxyphenol, alcohol 12 was converted into PMP ether 13
accompanying the stereoinversion. Deprotection of the acetonide
group afforded the corresponding 1,3-diol 14 in a reasonable 78%
yield for two steps. At this point, we turned our attention to
the construction of tetrahydropyran ring. Fortunately, subjecting
diol 14 to the Pd-catalyzed intramolecular alkoxycarbonylation
reaction smoothly provided the desired intermediate 3 in 75%
isolated yield as a single isomer.
Similarly, diol 4b was transformed to 5-epi-3 in five steps
with excellent 57% total yield. Oxidation of 5-epi-3 with Dess–
Martin periodiane and subsequent NaBH4-reduction of the
corresponding ketone 15 gave alcohol 3 in 86% yield for two steps
(Scheme 5).
In summary, an enantioselective total synthesis of cyanolide A
(1) has been achieved with the longest linear sequence of 14 steps.
Central to this venture was the efficient Pd-catalyzed intramolec-
ular alkoxycarbonylation to construct the tetrasubstituted cis-
tetrahydropyran ring core with high stereoselectivity. The applica-
tion of SmI2-promoted Evans-Tishchenko reduction, Barbier-type
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Scheme 4 Synthesis of alcohol 3.
reaction and Mitsunobu reaction, reduced the use of protecting
groups to some certain extent. Synthesis toward cyanolide A
(1) further demonstrates the value of Pd-catalyzed cyclyzation
technology. It is flexible and therefore should be suitable for the
synthesis of several other similar natural products.16
We are grateful for the generous financial support by the MOST
(2010CB833200), the NSFC (20872054, 20732002) and program
111.
Notes and references
1 A. R. Pereira, C. F. McCue and W. H. Gerwick, J. Nat. Prod., 2010, 73,
217.
2 The Carter Center. “Schistosomiasis Control Program”. Retrieved
2008-07-17.
3 P. Steinmann, J. Keiser, R. Bos, M. Tanner and J. Utzinger, Lancet
Infect. Dis., 2006, 6, 411.
4 L. Chitsulo, D. Engels, A. Montresor and L. Savioli, Acta Trop., 2000,
77, 41.
Scheme 5 Synthesis of alcohol 3 from 4b.
5 World Health Organization. Report of the Scientific Working Group
Meeting on Schistosomiasis; Geneva, Switzerland, November 14-16,
2005.
6 K. A. Ribeiro, C. M. de Carvalho, M. T. Molina, E. P. Lima, E. Lopez-
Montero, J. R. Reys, M. B de Oliveira, A. V. Pinto, A. E. Santana and
M. O Goulart, Acta Trop., 2009, 111, 44.
7 S. Perrett and P. J. Whitfield, Parasitol. Today, 1996, 12, 156.
8 J. R. Dai, W. Wang, Y. S. Liang, H. J. Li, X. H. Guan and Y. C. Zhu,
Parasitol. Res., 2008, 103, 405.
9 C. Socolsky, S. A. Borkosky, Y. Asakawa and A. Bardon, J. Nat. Prod.,
2009, 72, 787.
10 S. M. Rawi, H. El-Gindy and A. Abd-El-Kader, Ecotoxicol. Environ.
Saf., 1996, 35, 261.
11 J. Y. Hong and H. S. Kim, Org. Lett., 2010, 12, 2880.
12 D. A. Evans and A. H. Hoveyda, J. Am. Chem. Soc., 1990, 112, 6447.
13 C. Petrier and J. L. Luche, J. Org. Chem., 1985, 50, 910.
14 (a) J. D. White, J. Hong and L. A. Robarge, Tetrahedron Lett., 1999,
40, 1463; (b) K. R. Hornberger, C. L. Hamblett and J. L. Leighton, J.
Am. Chem. Soc., 2000, 122, 12894.
15 D. Gao and G. A. O’Doherty, J. Org. Chem., 2005, 70, 9932.
16 (a) M. R. Rao and D. J. Faulkner, J. Nat. Prod., 2002, 65, 386; (b) K.
L. Erickson, K. R. Gustafson, L. K. Pannell, J. A. Beutler and M. R.
Boyd, J. Nat. Prod., 2002, 65, 1303.
Scheme 6 Total synthesis of cyanolide A (1).
986 | Org. Biomol. Chem., 2011, 9, 984–986
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