Total synthesis of cyanolide A and confirmation of its absolute configuration

Article abstract of DOI:10.1021/ol101022z

(Figure presented) The tandem allylic oxidation/oxa-Michael reaction promoted by the gem-disubstituent effect and the 2-methyl-6-nitrobenzoic anhydride (MNBA)-mediated dimerization were explored for the efficient and facile synthesis of cyanolide A.

Full text of DOI:10.1021/ol101022z

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2880-2883
Total Synthesis of Cyanolide A and
Confirmation of Its Absolute
Configuration
Hyoungsu Kim and Jiyong Hong*
Department of Chemistry, Duke UniVersity, Durham, North Carolina 27708
jiyong.hong@duke.edu
Received May 4, 2010
ABSTRACT
The tandem allylic oxidation/oxa-Michael reaction promoted by the gem-disubstituent effect and the 2-methyl-6-nitrobenzoic anhydride (MNBA)-
mediated dimerization were explored for the efficient and facile synthesis of cyanolide A.
Schistosomiasis (also known as bilharzia) is a chronic,
debilitating parasitic disease caused by trematode flatworms
of the genus Schistosoma and the second most socioeco-
nomically devastating parasitic disease after malaria.1 More
than 207 million people are infected worldwide, with an
estimated 700 million people at risk in more than 70 endemic
countries.2 In sub-Saharan Africa, more than 200000 deaths
per year are attributed to schistosomiasis.
Due to the lack of a vaccine, patient therapy is heavily
dependent on chemotherapy with praziquantel, which cur-
rently is the only available treatment against all forms of
schistosomiasis.3 Despite the success of praziquantel, relying
solely on a single drug to treat 200 million people is of
concern. Less than 10% of people requiring treatment are
reported to obtain praziquantel. In addition, there are
concerns over drug resistance and side effects.4
An even greater challenge to schistosomiasis control is
the complex lifecycle of the parasite that requires both an
aquatic snail vector and a mammalian host to complete their
reproductive cycle.1 Snails such as the genus Biomphalaria
act as intermediate hosts in the life cycle of the parasitic
trematodes. As a result, eradicating the disease in the
mammalian host with a drug like praziquantel does not
protect against reinfection from recurring exposure to water
containing snail hosts. Therefore, molluscicides have been
considered the most promising means to break the transmis-
sion cycle of the parasite.5 Niclosamide is the most widely
used molluscicide available and effectively kills snails at all
stages of the lifecycle.6 However, it possesses major
disadvantages, including high cost, low water solubility and
dispersibility, and hazardous environmental effects. As a
result, considerable effort has been devoted to the identifica-
tion of novel molluscicides,7 but none have proved effective
enough to substitute niclosamide.
(1) Ross, A. G.; Bartley, P. B.; Sleigh, A. C.; Olds, G. R.; Li, Y.;
Williams, G. M.; McManus, D. P. N. Engl. J. Med. 2002, 346, 1212–1220.
(2) Chitsulo, L.; Engels, D.; Montresor, A.; Savioli, L. Acta Trop. 2000,
77, 41–51.
Recently, Gerwick and co-workers used a simple mollus-
cicidal bioassay to screen marine cyanobacterial extracts and
(3) Cioli, D.; Pica-Mattoccia, L. Parasitol. Res. 2003, 90, S3–9.
(4) Melman, S. D.; Steinauer, M. L.; Cunningham, C.; Kubatko, L. S.;
Mwangi, I. N.; Wynn, N. B.; Mutuku, M. W.; Karanja, D. M. S.; Colley,
D. G.; Black, C. L.; Secor, W. E.; Mkoji, G. M.; Loker, E. S. PLoS. Negl.
Trop. Dis. 2009, 3, e504.
(5) Perrett, S.; Whitfield, P. J. Parasitol. Today 1996, 12, 156–159.
(6) Andrews, P.; Thyssen, J.; Lorke, D. Pharmacol. Ther. 1982, 19, 245–
295.
(7) Whitfield, P. J. Trans. R. Soc. Trop. Med. Hyg. 1996, 90, 596–600.
10.1021/ol101022z  2010 American Chemical Society
Published on Web 05/21/2010

Scheme 1 summarizes our approach for the stereoselective
synthesis of cyanolide A (1) from the readily available 1,3-
dithiane 7 and chiral epoxide 8. Since there were reports that
final glycosylation reactions of structurally similar substrates
with xylose derivatives generally gave the possible R,R- and
R,ꢀ-anomers in addition to the desired ꢀ,ꢀ-anomer with low
diastereoselectivities and yields,10 we decided to explore two
complementary routes to 1, dimerization-glycosylation and
glycosylation-dimerization strategies. In the dimerization-
glycosylation route, we envisioned that 1 could be assembled
by a glycosylation of macrolide 2 with a xylose derivative.
Macrolide 2 could be prepared by an asymmetric ethylation of
2,6-cis-tetrahydropyran methyl ester 5 followed by a dimeriza-
tion of hydroxy ester 4. In the glycosylation-dimerization route,
the synthesis of 1 could be accomplished by a dimerization of
monomer 3 appendaged with the xylose moiety. Monomer 3
could be prepared by glycosylation followed by asymmetric
ethylation of 2,6-cis-tetrahydropyran methyl ester 5. The tandem
allylic oxidation/oxa-Michael reaction of diol 6, which was
previously reported by our group,11 was anticipated to stereo-
selectively provide the key intermediate 2,6-cis-tetrahydropyran
methyl ester 5.
Scheme 1. Retrosynthetic Plan for Cyanolide A (1)
Scheme 2
.
Tandem Oxidation/Oxa-Michael and NHC-Catalyzed
Oxidation To Give the THP Ester 5
reported the isolation and structure elucidation of cyanolide
A (1, Scheme 1), a new molluscicidal agent obtained from
a Papua New Guinea collection of Lyngbya bouillonii.8
Compound 1 is a dimeric glycosidic macrolide consisting
of a central 16-membered macrocycle fused with two
tetrahydropyrans and two xylose residues. The structure and
relative stereochemistry of 1 were determined by extensive
NMR spectroscopic analysis, but the absolute configuration
of 1 was tentatively assigned on the basis of a natural
D-configuration for the xylose residue and its structural
similarities to clavosolides A-D.9 It exhibited highly potent
molluscicidal activity against Biomphalaria glabrata (LC50
) 1.2 µM) but showed modest brine shrimp toxicity (LC50
) 10.8 µM).
Due to both the great potential as a promising mollusci-
cidal compound for controlling schistosomiasis-carrying
snails of the genus Biomphalaria and the scarcity (0.1%
isolation yield) of cyanolide A (1), we sought to develop an
efficient and facile synthetic route that would be amenable
to the synthesis of gram-scale quantities of 1 and also to the
synthesis of analogues for further biological studies. Herein,
we report two efficient, facile, and complementary routes to
1 through a tandem allylic oxidation/oxa-Michael reaction
promoted by the gem-disubstituent effect and 2-methyl-6-
nitrobenzoic anhydride (MNBA)-mediated dimerization.
The synthesis of cyanolide A (1) started with the preparation
of diol 6 for tandem reaction (Scheme 2). The coupling of the
known 1,3-dithiane 712 and chiral epoxide 813 smoothly
(10) (a) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.;
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Reddy, V. R.; Chattopadhyay, A. K. Tetrahedron Lett. 2006, 47, 7435–
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A. R. J. Chem. Soc., Perkin Trans. 1 1992, 163–169. (b) Taylor, E. C.;
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Org. Lett., Vol. 12, No. 12, 2010
2881

proceeded to set the stage for the key tandem allylic oxidation/
oxa-Michael reaction. The one-pot allylic oxidation/oxa-Michael/
oxidation of 6 (MnO2, CH2Cl2, 25 °C, 4 h, then dimethyl
triazolium iodide, MnO2, DBU, MeOH, MS 4 Å, 25 °C,
12 h)11,14 afforded the desired 2,6-cis-tetrahydropyran methyl
ester 5 (88%) as a single diastereomer without a trace of the
diastereomeric 2,6-trans-tetrahydropyran methyl ester. The
relative stereochemistry of the 2,6-disubstituted tetrahydro-
pyran 5 was determined to be cis by extensive 2D NOESY
study (see the Supporting Information). The excellent ste-
reoselectivity observed in the oxa-Michael reaction was
probably due to a highly rigid chairlike transition state
induced by “double gem-disubstituent effects” of C4-gem-
dimethyl and C5-1,3-dithiane groups. Importantly, the se-
quence of 1,3-dithiane coupling and tandem reaction was
highly stereoselective, operationally simple, and robust, and
it could be performed on a gram-scale.
Scheme 3. Total Synthesis of Cyanolide A (1) via
Dimerization-Glycosylation Strategy
Having established an efficient and facile synthetic route
to gram-quantities of the key intermediate 2,6-cis-tetrahy-
dropyran 5, the dimerization-glycosylation route was first
explored (Scheme 3). To stereoselectively install the C9-
hydroxyl group, we investigated the utility of 3-exo-mor-
pholinoisoborneol (MIB)-catalyzed asymmetric addition of
Et2Zn.15 Deprotection of the PMB group in 5 followed by
Parikh-Doering oxidation of the resulting alcohol 9 provided
aldehyde 10. Asymmetric ethylation of 10 in the presence
of Et2Zn and (+)-MIB provided the desired secondary
alcohol 4 in 86% yield (dr ) 7:1).16 The configuration of
the C9 stereocenter was assigned as (R) using Kakisawa’s
extension of Mosher’s method17 and later confirmed by
single-crystal X-ray analysis of 11.
With monomeric unit 4 in hand, we turned our attention
to dimerization to complete the synthesis of 1. Recently, in
a related transformation, we found that Shiina’s lactonization
protocol with MNBA18 appeared to be an excellent method
for macrolactonization owing to its remarkable efficiency and
simple operation.11,19 Hydrolysis of 4 under basic conditions
followed by dimerization of the corresponding hydroxy
carboxylic acid (MNBA, DMAP, toluene, 90 °C, 12 h)
smoothly proceeded to provide dimeric macrolide 2 (53%
for two steps). Deprotection of the 1,3-dithiane group and
NaBH4-reduction of the corresponding ketone completed the
synthesis of cyanolide A aglycone 11.
anomeric (33%) and R,R-anomeric (13%) isomers. The low
yield and stereoselectivity of the glycosylation reaction have
been observed with structurally similar substrates.10 The
synthetic cyanolide A (1) proved identical in all respects with
the authentic natural product.8 The optical rotation of our
synthetic 1 ([R]25D -55.5, c 0.33, CHCl3) was in agreement
After exploring a number of glycosylation conditions,
glycosylation of 11 with phenyl thioglycoside 1210a in the
presence of MeOTf20 proceeded smoothly to give the desired
ꢀ,ꢀ-anomeric cyanolide A (1) (21%) along with ꢀ,R-
with that of the natural 1 ([R]23 -59, c 0.6, CHCl3),
D
confirming the absolute stereochemistry of 1 proposed by
Gerwick and co-workers.8
(14) Maki, B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331–4334
.
(15) (a) Nugent, W. A. Chem. Commun. 1999, 1369–1370. (b) Chen,
Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 12225–
12231.
Even though the dimerization-glycosylation route success-
fully completed the synthesis of 1, we thought that the final
glycosylation step was not stereoselective and efficient enough
for the generation of a variety of carbohydrate analogues for
biological studies. To establish a more efficient method for the
(16) (-)-MIB-catalyzed asymmetric ethylation of 10 afforded C9-epi 4
with a higher diastereoselectivity (dr >20:1).
(17) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
(18) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
Chem. 2004, 69, 1822–1830. (b) Shiina, I.; Fukui, H.; Sasaki, A. Nat. Protoc.
2007, 2, 2312–2317.
(20) (a) Lo¨nn, H. J. Carbohydr. Chem. 1987, 6, 301–306. (b) Watanabe,
H.; Nakada, M. J. Am. Chem. Soc. 2008, 130, 1150–1151. NBS-promoted
glycosylation of 11 (NBS, CH3CN, MS 4 Å, -40 to 0 °C, 2 h) gave a
lower stereoselectivity.
(19) (a) Shiina, I.; Katoh, T.; Nagai, S.; Hashizume, M. Chem. Rec.
2009, 9, 305–320. (b) Scha¨ckel, R.; Hinkelmann, B.; Sasse, F.; Kalesse,
M. Angew. Chem., Int. Ed. 2010, 49, 1619–1622
.
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Org. Lett., Vol. 12, No. 12, 2010

PMB-deprotection of 14, TPAP-oxidation, and (+)-MIB-
catalyzed asymmetric addition of Et2Zn afforded the desired
C9(R) secondary alcohol 3 with good diastereoselectivity (dr
) 6:1, 81%). Hydrolysis of the methyl ester group in 3 and
MNBA-mediated dimerization of the resulting hydroxy
carboxylic acid provided cyanolide A (1) with excellent yield
(93% for two steps). The chemoselective nature of tandem
allylic oxidation/oxa-Michael reaction, the efficiency of
dithiane coupling reactions, and the improved stereoselec-
tivity in the glycosylation step enabled an efficient and facile
synthesis of cyanolide A (1) (10 steps, 22% overall yield
from the readily available known 7 and 8).
Scheme 4. Total Synthesis of Cyanolide A (1) via
Glycosylation-Dimerization Strategy
In summary, we completed the stereoselective synthesis
of cyanolide A (1) from the readily available 1,3-dithiane 7
and chiral epoxide 8 through two complementary routes,
dimerization-glycosylation and glycosylation-dimerization.
We applied a tandem allylic oxidation/oxa-Michael reaction
of 6 to the synthesis of 2,6-cis-tetrahydropyran 5. For the
dimerization step, we explored the MNBA-mediated lacton-
ization protocol to demonstrate its high efficiency and simple
operation. The glycosylation-dimerization route proved
more efficient for the synthesis of 1. Comparison of synthetic
1 ([R]25D) with natural 1 enabled the confirmation of the
absolute stereochemistry of the natural product. These
synthetic routes would be broadly applicable to the efficient
synthesis of a diverse set of cyanolide A (1) analogues for
further biological studies.
installation of the xylose moiety, we investigated an alternative
glycosylation-dimerization route (Scheme 4).
The key intermediate 2,6-cis-tetrahydropyran 5 was con-
verted to secondary alcohol 13 by deprotection of the 1,3-
dithiane group in 5 followed by NaBH4-reduction of the
corresponding ketone.21 Glycosylation of 13 with phenyl
thioglycoside 12 in the presence of MeOTf smoothly
proceeded to afford the desired ꢀ-anomeric monomer 14
(66%) along with R-anomeric monomer (18%).22 We were
pleased to observe the improved stereoselectivity in the
glycosylation step (1.3:1 to 3.7:1).23
Acknowledgment. This work was supported by Duke
University. We are grateful to Marina Dickens for the X-ray
crystal structure determination and the NCBC (Grant No.
2008-IDG-1010) for funding of NMR instrumentation.
Supporting Information Available: General experimental
procedures including spectroscopic and analytical data for
1-7, 9, 11, 13, and 14 along with copies of 1H and 13C NMR
spectra; detailed assay procedure. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) The relative stereochemistry at the C5-position in 13 was determined
by 2D NMR analysis of its corresponding acetate (see the Supporting
Information).
(22) NBS-promoted glycosylation of 13 (NBS, CH3CN, MS 4 Å, -40
to 0 °C, 2 h) gave a complex reaction mixture due to partial deprotection
of PMB group under the reaction conditions.
OL101022Z
(23) (a) Seden, P. T.; Charmant, J. P. H.; Willis, C. L. Org. Lett. 2008,
10, 1637–1640. (b) Chakraborty, T. K.; Reddy, V. R.; Gajula, P. K.
Tetrahedron 2008, 64, 5162–5167.
Org. Lett., Vol. 12, No. 12, 2010
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