Synthesis of molluscicidal agent cyanolide a macrolactone from D-(-)-Pantolactone

Article abstract of DOI:10.1021/jo101782q

An efficient synthesis of potent molluscicidal agent cyanolide A, a glycosidic 16-membered macrolide, starting from D-(-)-pantolactone is reported. Highly stereoselective aldol, oxa-Michael addition, and Yamaguchi macrolactonization are the key steps in the present synthesis.

Full text of DOI:10.1021/jo101782q

pubs.acs.org/joc
approaches to eradicate or control this disease is to interrupt
Synthesis of Molluscicidal Agent Cyanolide A
Macrolactone from D-(-)-Pantolactone‡
the life cycle by eliminating the snail vector. Niclosamide is
currently the only molluscicide recommended by WHO for
snail control which kill snails at all stages of the lifecycle.4
However, these molluscicides are toxic to nontarget animals
like fish and may have long-term detrimental effects on the
aquatic environment. Different groups have examined sev-
eral other molluscicides to date and none have been found to
be superior to niclosamide.5 At the beginning of this year,
Gerwick et al. isolated 1.2 mg of cyanolide A (1), a new and
highly potent molluscicidal agent from a Papua New Guinea
collection of Lyngbya bouillonii, as part of the program to
screen natural products for activities to tropical diseases.6
Compound 1 showed significant molluscicidal activity
against Biomphalaria glabrata (LC50: 1.2 μM) as well as
modest brine shrimp toxicity (LC50: 10.8 μM). It is relatively
noncytotoxic when tested against H-460 human lung adeno-
carcinoma and Neuro-2a mouse neuroblastoma cell lines
suggesting that it can be a potential lead compound for
treating waterways infested with schistosomiasis-carrying
snails of the genus Biomphalaria.6
Atul K. Hajare, Velayutham Ravikumar, Shaik Khaleel,
Debnath Bhuniya, and D. Srinivasa Reddy*,†
Discovery Chemistry, Advinus Therapeutics Ltd., Quantum
Towers, Plot No. 9, Rajiv Gandhi Infotech Park, Phase-I,
Hinjewadi, Pune, 411057, India. †Present address: National
Chemical Laboratory (CSIR, India), Organic Chemistry
Division, Dr. Homi Bhabha Road, Pune 411008, India.
ds.reddy@ncl.res.in; dsreddy88@yahoo.com
Received September 10, 2010
The structure of cyanolide A (1) was elucidated by using
extensive NMR spectroscopic analysis as a glycosidic 16-
membered macrolide with structural similarities to pre-
viously known clavosolides.7,8 Immediately, Hong’s group
from Duke University completed the first stereoselective
synthesis of 1 in two complementary routes, dimerization-
glycosylation and glycosylation-dimerization from readily
available starting materials.9 This led to the confirmation of
proposed absolute configuration and provided an access to
additional quantities of natural product. The interesting
chemical structure and potent molluscicidal activity of cya-
nolide A (1) prompted us to undertake the synthesis of this
compound. It also fits well with our group’s strategy to use
An efficient synthesis of potent molluscicidal agent cya-
nolide A, a glycosidic 16-membered macrolide, starting
from D-(-)-pantolactone is reported. Highly stereoselec-
tive aldol, oxa-Michael addition, and Yamaguchi macro-
lactonization are the key steps in the present synthesis.
Schistosomiasis (also known as bilharzia or snail fever) is
considered to be one of the important tropical parasitic
disease, with severe socioeconomic consequences for mil-
lions of people worldwide.1 The disease is endemic to many
countries with large populations and is second only to
Malaria.2 Although it can be treated with the currently
available drug praziquantel, the treatment is expensive,
and also relying solely on a single drug to treat more than
200 million people is not successful.3 One of the possible
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Zhu, Y. C. Parasitol. Res. 2008, 103, 405–412. (d) Gawish, F. A.; El-Sherbini,
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Pannell, L. K.; Beutler, J. A.; Boyd, M. R. J. Nat. Prod. 2002, 65, 1303–1306.
(8) Synthesis of related clavosolides: (a) Barry, C. S.; Elsworth, J. D.;
Seden, P. T.; Bushby, N.; Harding, J. R.; Alder, R. W.; Willis, C. L. Org. Lett.
2006, 8, 3319–3322. (b) Smith, A. B., III; Simov, V. Org. Lett. 2006, 8, 3315–
3318. (c) Son, J. B.; Hwang, M. H.; Lee, W.; Lee, D. H. Org. Lett. 2007, 9,
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8, 661–664. (f ) Chakraborty, T. K.; Reddy, V. R.; Gajula, P. K. Tetrahedron
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‡ Advinus Publication No.: ADV-A-008.
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2000, 77, 41–51. (b) Steinmann, P.; Keiser, J.; Bos, R.; Tanner, M.; Utzinger,
J. Lancet Infect. Dis. 2006, 6, 411–425.
(2) 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.
(3) (a) Cioli, D.; Pica-Mattoccia, L. Parasitol. Res. 2003, 90, S3–9. (b)
Bergquist, R. Acta Trop. 2008, 108, 65–68. (c) 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 Neglected Trop. Dis. 2009, 3, e504.
(4) (a) Bull. W. H. O. 1980, 58, 681-689. (b) World Health Organiza-
tion, The control of schistosomiasis; WHO Technical Report Series 830,
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DOI: 10.1021/jo101782q
r
Published on Web 12/31/2010
J. Org. Chem. 2011, 76, 963–966 963
2010 American Chemical Society

Hajare et al.
JOCNote
SCHEME 1. Retrosynthetic Analysis
FIGURE 1. (A) Proposed transition state during oxa-Michael ad-
dition to form tetrahydropyran ring. (B) Compound 2 with high-
lighted protons which showed nOes.
SCHEME 2. Synthesis of Cyanolide A (1)a
the pantolactone chiral pool for the synthesis of biologically
interesting natural products.10
Retrosynthetically, cyanolide A (1) can be accessed from
monomer 2 through dimerization followed by glycosidation.
Compound 2 could be prepared from an acyclic intermediate 3
through an intramolecular oxa-Michael cyclization to form
tetrahydropyran ring (Figure 1). The stereoselective reduction
of acyclic β-hydroxy ketone 4 would provide 3 with syn-1,3-
diol moiety (Scheme 1). Compound 4 could be prepared from
commercially available D-(-)-pantolactone by using routine
functional group transformations including a key stereoselec-
tive aldol reaction.
aReagents and conditions: (a) BF3 Et2O, CH2Cl2, -78 °C, 1 h, 37%
3
(56% based on starting material recovery); (b) (i) catecholborane, THF,
-10 °C, 3 h, 68%, (ii) 2,2-dimethoxypropane, PPTS, DCM, rt, 3 h, 88%;
(c) (i) TBAF, THF, 60 °C, 3 h, 93%, (ii) (COCl)2, DMSO, Et3N, DCM,
-78 °C, 1 h, 92%, (iii) Ph3PdCHCOOEt, toluene, reflux, 48 h, 71%; (d)
PTSA, CHCl3, reflux, 20 h, 83%; (e) (i) LiOH H2O, H2O:MeOH:THF
3
(1:1:2), rt, 18 h, 93%, (ii) 2,4,6-trichlorobenzoyl chloride, Et3N, THF,
DMAP, toluene, reflux, 4 h, 48%, (iii) Pd(OH)2, MeOH, H2, rt, 20 h,
Our synthesis commenced from D-(-)-pantolactone by
converting it into known aldehyde 5 essentially following the
conditions reported in the literature.11 The Mukaiyama aldol
reaction of enolsilane (prepared from methyl ethyl ketone)
with aldehyde 5 at -78 °C in CH2Cl2 by slow addition of
˚
60%; (f) MeOTf, MS 4A, Et2O, 25 °C (known step, ref 9).
with catecholborane followed by protection of the resulting
diol as acetonide. The syn-1,3-diol relationship was established
by comparing 13C chemical shifts of the acetal methyl carbons
and acetal carbons of acetonides prepared from syn- and anti-
1,3-diols.14 Compound 6 was converted to R,β-unsaturated
ester 7 by using the sequence of TBS deprotection, Swern
oxidation followed by Horner-Wittig reaction. Having the
intermediate 7 in hand, the key tetrahydropyran ring forma-
tion was attempted with use of a catalytic amount of
p-toluenesulfonic acid. To our delight, deprotection of acetonide
followed by oxa-Michael cyclization took place in a single pot
to provide the fragment 2 in a highly stereoselective fashion
(Scheme 2).9,15 The observed stereoselectivity (dr > 95:5,
BF3 OEt2 proceeded with an excellent 1,3-anti induction
3
(>95% diastereoselectivity based on NMR) to give product
4 in moderate yield.12 Compound 6 was prepared utilizing
Evans’ protocol13 for stereoselective reduction of acyclic β-
hydroxy ketone 4 to syn-1,3-diol (dr, 9:1, judged by HPLC)
(11) Ball, M.; Baron, A.; Bradshaw, B.; Omori, H.; MacCormick, S.;
Thomas, E. J. Tetrahedron Lett. 2004, 45, 8737–8740. Complete experi-
mental details are provided in the Supporting Information.
(12) Selected reviews and examples of 1,3-anti induction, using Mukaiya-
ma aldol reaction: (a) Mahrwald, R. Chem. Rev. 1999, 99, 1095–1120.
(b) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506–7525.
(c) Peuchmaur, M.; Wong, Y. S. J. Org. Chem. 2007, 72, 5374–5379.
(d) Yokokawa, F.; Asano, T.; Shioiri, T. Tetrahedron 2001, 57, 6311–6327.
(e) Keck, G. E.; Welch, D. S.; Vivian, P. K. Org. Lett. 2006, 8, 3667–3670.
(13) Evans, D. A.; Hoveyda, A. H. J. Org. Chem. 1990, 55, 5190–5192.
(14) Rychnovsky, S. D.; Rogers, J. B.; Yang, G. J. Org. Chem. 1993, 58,
3511–3515. See details in the Supporting Information.
(15) For related cyclization to form tetrahydropyran ring, see: Liu, J.;
Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121–6123.
964 J. Org. Chem. Vol. 76, No. 3, 2011

Hajare et al.
JOCNote
judged by 1H NMR) can be explained based on the transition
state A. The stereochemistry of substituents on the tetrahy-
dropyran ring was established by using nOe’s (see highlighted
protons and nOe’s in B). Ester hydrolysis of 2 followed by
dimerization with Yamaguchi’s lactonization protocol16 fur-
nished 16-membered macrolide, which was subsequently con-
verted to macrocyclic diol 8 by the deprotection of benzyl
groups. Macrolide 8 was previously reported as a penultimate
precursor in the synthesis of 1. It was well-characterized by
Hong’s group, which includes X-ray crystal structure, and the
were evaporated under reduced pressure. The resulting residue
was taken in water and washed with n-pentane. Then the
aqueous layer was acidified by 1.0 N HCl and extracted
with ethyl acetate. The ethylacetate layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated
to give 64 mg (93%) of [(2S,4S,6R)-4-benzyloxy-6-((R)-2-
hydroxybutyl)-3,3-dimethyltetrahydropyran-2-yl]-acetic acid
as a white solid. Mp 162-163 °C; [R]22.1D þ11.5 (c 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 0.89 (t, J=7.6 Hz, 3H), 0.90 (s,
3H), 0.95 (s, 3H), 1.42-1.58 (m, 4H), 1.65 (dd, J=20.4, 10.0
Hz, 1H), 1.85 (d, J=12.0 Hz, 1H), 2.43 (s, 2H), 3.17 (dd, J =
11.2, 3.2 Hz, 1H), 3.54 (dd, J=8.4, 3.6 Hz, 1H), 3.67 (t, J=10.4
Hz, 1H), 3.87-3.90 (m, 1H), 4.43 (d, J=11.6 Hz, 1H), 4.64 (d,
J=11.6 Hz, 1H), 4.95 (br s, 1H), 7.27-7.35 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 9.6, 13.6, 22.7, 29.7, 33.7, 34.9, 38.6, 40.9,
71.3, 74.1, 77.8, 81.3, 81.9, 127.6, 127.7, 128.5, 138.8, 174.4; IR
(neat) 1728, 3459 cm-1; LCMS=351.2 [M þ H]þ.
same was glycosilated to yield 1.9 The spectral data(1Hand13
C
NMR) of the macrolide 8 from our lab were compared with
those of Hong’s group and both were found to be identical.
Specific rotation of our sample 8 showed [R]23D -38.8 (c 0.33,
CHCl3) compared to that of the literature [R]25D -36.3 (c 0.56,
CHCl3).9
To a stirred solution of the above [(2S,4S,6R)-4-benzyloxy-
6-((R)-2-hydroxybutyl)-3,3-dimethyltetrahydropyran-2-yl]-
acetic acid (70 mg, 0.2 mmol) in THF (1.0 mL) was added
triethylamine (40 μL, 0.3 mmol) followed by 2,4,6-trichloro-
benzoyl chloride (40 μL, 0.3 mmol), then the mixture was
stirred at room temperature for 3 h. The solid was filtered
and the filtrate was diluted with toluene (6 mL) and then added
dropwise to a solution of 4-dimethylaminopyridine (122 mg,
1.0 mmol) in toluene (40 mL) at reflux (125 °C) over a period of
3 h. After refluxing for an additional 4 h, the reaction mixture
was cooled to room temperature and concentrated. The crude
product was partitioned between water (15 mL) and ethyl
acetate (30 mL), and the aqueous layer was extracted with
ethyl acetate. The combined organic layer was washed with
brine, dried over anhydrous sodium sulfate, concentrated, and
purified by column chromatography (10% ethyl acetate in
hexanes) to give 32 mg (48%) of (1S,5R,7R,9S,11S,15R,
17R,19S)-9,19-bis-benzyloxy-5,15-diethyl-10,10,20,20-tetra-
methyl-4,14,21,22-tetraoxatricyclo[15.3.1.17,11]docosane-3,13-
dione. [R]22.3D þ9.2 (c0.5, CHCl3);1HNMR(400MHz, CDCl3) δ
0.85-0.89 (m,12H), 0.94 (s, 6H), 1.30 (ddd, J=12.0, 12.0Hz, 2H),
1.58-1.67 (m, 6H), 1.86-1.93 (m, 2H), 2.04-2.10 (m, 2H), 2.29
(dd, J=15.2, 9.2 Hz, 2H), 2.39 (d, J = 14.0 Hz, 2H), 3.16 (dd, J =
11.6, 4.4 Hz, 2H), 3.36-3.41 (m, 4H), 4.44 (d, J=12.0 Hz, 2H),
4.67 (d, J=12.0 Hz, 2H), 4.90 (ddd, J=8.0, 6.8, 6.8 Hz, 2H),
7.26-7.34 (m, 10 H); 13C NMR (100 MHz, CDCl3) δ 9.4, 13.2,
22.3, 27.9, 33.1, 35.1, 38.3, 41.1, 70.8, 73.2, 74.6, 80.9, 82.0, 127.2,
128.0, 138.6, 172.1; IR (neat) 1738 cm-1; LCMS=665.5 [M þ
H]þ; HRMS (ESI) m/z calcd for C40H57O8 [M þ H]þ 665.4053,
found 665.4047.
In short, we have achieved the formal synthesis of cyanolide
A (1), a potent molluscicidal agent, through Hong’s inter-
mediate, macrolide 8, starting from D-(-)-pantolactone in
a highly stereoselective manner. Choosing readily available
pantolactone and highly stereoselective Mukaiyama aldol
reaction, oxa-Michael addition to form tetrahydropyran ring,
and dimerization with Yamaguchi’s lactonization are the
salient features of this synthesis. As L-(þ)-pantolactone is also
commercially available, our route can be used for the synthesis
of the unnatural enantiomer of cyanolide A and other ana-
logues which may show improved molluscicidal activity.
Experimental Section
[(2S,4S,6R)-4-Benzyloxy-6-((R)-2-hydroxybutyl)-3,3-di-
methyltetrahydropyran-2-yl]acetic Acid Ethyl Ester (2). To a
stirred solution of (E)-(S)-5-benzyloxy-6-((4R,6R)-6-ethyl-2,
2-dimethyl[1,3]dioxan-4-yl)-4,4-dimethyl-hex-2-enoic acid eth-
yl ester 7 (110 mg, 0.3 mmol) in chloroform (5 mL) was added
p-toluenesulfonic acid monohydrate (8 mg, 0.15 mmol) then the
mixture was refluxed for 20 h. The reaction mixture was cooled
to room temperature, diluted with chloroform, washed with
saturated sodium bicarbonate solution, water, and brine, dried
over anhydrous sodium sulfate, concentrated, and purified by
column chromatography (9% ethyl acetate in hexanes) to give
82 mg (83%) of [(2S,4S,6R)-4-benzyloxy-6-((R)-2-hydroxy-
butyl)-3,3-dimethyltetrahydropyran-2-yl]acetic acid ethyl ester
2 as a colorless oil. [R]22.5D þ9.5 (c 1.0, CHCl3); 1H NMR (400
MHz, CDCl3) δ 0.91 (t, J=7.2 Hz, 3H), 0.91 (s, 3H), 0.95 (s, 3H),
1.26 (t, J=6.8 Hz, 3H), 1.40-1.54 (m, 4H), 1.57-1.67 (m, 1H),
1.85-1.89 (m, 1H), 2.38-2.48 (m, 2H), 3.17 (dd, J=11.6, 4.8 Hz,
1H), 3.49 (br s, 1H), 3.53 (dd, J=9.2, 3.2 Hz, 1H), 3.62 (t, J=10.0
Hz, 1H), 3.79 (dd, J=13.2, 6.8 Hz, 1H), 4.11-4.21 (m, 2H), 4.43
(d, J=12.0 Hz, 1H), 4.64 (d, J=12.0 Hz, 1H), 7.28-7.35 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 9.9, 13.6, 14.3, 22.7, 30.2,
33.8, 35.1, 38.5, 42.0, 61.1, 71.2, 73.4, 77.9, 81.0, 82.0, 127.6,
127.7, 128.5, 138.8, 172.5; IR (neat) 1733, 3533 cm-1; LCMS=
379.3 [M þ H]þ; HRMS (ESI) m/z calcd for C22H35O5 [M þ H]þ
379.2484, found 379.2482.
Palldium hydroxide (10 mg) was added to a solution of
(1S,5R,7R,9S,11S,15R,17R,19S)-9,19-bis-benzyloxy-5,15-di-
ethyl-10,10,20,20-tetramethyl-4,14,21,22-tetraoxatricyclo-
[15.3.1.17,11]docosane-3,13-dione (30 mg) in methanol (4 mL)
then the mixture was stirred under hydrogen atmospheric
pressure (using balloon) for 20 h. The reaction mixture was
then filtered through a Celite bed. Filtrate was concentrated
and purified by column chromatography (60% ethyl acetate in
hexanes) to give 13 mg (60%) of (1S,5R,7S,9S,11S,15R,17S,
19S)-5,15-diethyl-9,19-dihydroxy-10,10,20,20-tetramethyl-
4,14,21,22-tetraoxatricyclo[15.3.1.17,11]docosane-3,13-dione
(1S,5R,7S,9S,11S,15R,17S,19S)-5,15-Diethyl-9,19-dihy-
droxy-10,10,20,20-tetramethyl-4,14,21,22-tetraoxatricyclo[15.3.1.
17,11]docosane-3,13-dione (8). To a stirred solution of [(2S,4S,
6R)-4-benzyloxy-6-((R)-2-hydroxybutyl)-3,3-dimethyltetra-
hydropyran-2-yl]acetic acid ethyl ester 2 (75 mg, 0.2 mmol) in a
mixture of THF:methanol:water (2:1:1, 2.0 mL) was added
lithium hydroxide monohydrate (33 mg, 0.8 mmol) at room
temperature. After the mixture was stirred for 20 h, volatiles
8 as a white solid. Mp 132-134 °C; [R]22.7 -38.8 (c 0.33,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.83 (s, 6H), 0.87 (dd,
J=7.2, 7.2 Hz, 6H), 0.93 (s, 6H), 1.33 (ddd, J=12.0, 11.6, 11.6
Hz, 2H), 1.52-1.60 (m, 6H), 1.83-1.91 (m, 4H), 2.29 (dd, J=
15.6, 8.8 Hz, 2H), 2.40 (dd, J=15.6 Hz, 2H), 3.40 (d, J=8.0 Hz,
2H), 3.43-3.49 (m, 4H), 4.91 (ddd, J = 7.6, 6.8, 6.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 9.7, 12.6, 22.4, 28.3, 35.4, 37.3,
38.8, 41.0, 73.8, 75.1, 75.4, 80.8, 172.2; IR (neat) 1726, 3409
cm-1; LCMS=485.4 [M þ H]þ; HRMS (ESI) m/z calcd for
(16) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
C
26H45O8 [M þ H]þ 485.3114, found 485.3097. The spectral
J. Org. Chem. Vol. 76, No. 3, 2011 965

Hajare et al.
JOCNote
data (1H and 13C NMR) of the macrolide 8 from our lab were
compared with those of Hong’s group9 and both were found to
be identical.
appreciated. We thank Dr. Hong for providing copies of
NMR spectra of compound 8. A.K.H. thanks Prof. Y. L. N.
Murthy, Andhra University for registration of his Ph.D.
Acknowledgment. We are grateful to Drs. Rashmi Bar-
bhaiya and Kasim Mookhtiar for their support and encour-
agement. Help from the analytical department is highly
Supporting Information Available: Experimental proce-
dures, spectral data, and copies of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
966 J. Org. Chem. Vol. 76, No. 3, 2011