Total synthesis of the marine natural product (-)-clavosolide A

Article abstract of DOI:10.1021/ol0611705

The total synthesis of the marine metabolite clavosolide A is reported which confirms the structure and absolute configuration of the natural product as the symmetrical diolide glycosylated by permethylated D-xylose moieties, 2.

Full text of DOI:10.1021/ol0611705

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3319-3322
Total Synthesis of the Marine Natural
Product ( )-Clavosolide A
−
Conor S. Barry,† Jon D. Elsworth,† Peter T. Seden,† Nick Bushby,‡
John R. Harding,‡ Roger W. Alder,† and Christine L. Willis*,†
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.,
and AstraZeneca UK Ltd., Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
chris.willis@bristol.ac.uk
Received May 12, 2006
ABSTRACT
The total synthesis of the marine metabolite clavosolide A is reported which confirms the structure and absolute configuration of the natural
product as the symmetrical diolide glycosylated by permethylated D-xylose moieties, 2.
The clavosolides A-D are a family of unusual diolides
isolated from extracts of the marine sponge Myriastra
claVosa collected in the Phillipines.1 The structure of
clavosolide A was assigned originally as diolide 1 on the
basis of extensive spectroscopic studies combined with
molecular modeling (Figure 1). It is an unusual symmetrical
16-membered ring dilactone assembled on a functionalized
tetrahydropyran core with a permethylated xylose moiety
which was assumed to have the more usual D-configuration.
The macrocycle is further adorned by two cyclopropyl-
containing side chains which were assigned the configuration
9S,9′S,10S,10′S,11S,11′S.
We recently completed the first total synthesis of the
proposed structure of clavosolide A (1).2 However, from the
spectral data it was apparent that while the synthetic material
Figure 1. Originally proposed structure of clavosolide A (1)1 and
proposed revised structure 22 for the natural product.
† University of Bristol.
‡ AstraZeneca UK.
(1) (a) Rao, R. M.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 386. (b)
Erickson, K. L.; Gustafson, K. R.; Pannell, L. K.; Beutler, J. A.; Boyd, M.
J. Nat. Prod. 2002, 65, 1303.
was closely related to the natural product, they were not the
same. Following extensive NMR studies combined with
evidence from the X-ray structure of a diastereomer, we
10.1021/ol0611705 CCC: $33.50
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Published on Web 06/28/2006

Figure 2. Models of (9S,10S,11S)-diastereomer 1 and (9S,10R,11R)-diastereomer 2 with NMR assignments.
proposed that 1 is in fact a diastereomer of the natural product
and that clavosolide A has the 9S,9′S,10R,10′R,11R,11′R side
chain 2 (Figure 1).2
symmetrical dimers 1 and 2 was conducted using molecular
mechanics energy minimization calculations (Figure 2). The
ring adopts a similar conformation in both cases with an
elongated diolide ring with the tetrahydropyrans and cyclo-
propyl groups lying almost in the plane of the ring. In the
model of the synthetic diolide 1, one of the cyclopropyl
protons (13-H) is considerably closer to the carbonyl group
of the ring than the other 13-H, which would account for
the difference in their chemical shifts (∆δ ) 0.39 ppm) in
Recently, Charkaborty and Reddy have completed a total
synthesis of 1 using a radical-mediated strategy to assemble
the tetrahydropyran ring,3 while Gurjar and co-workers have
reported the synthesis of the monomeric unit toward clavo-
solide A.4 Furthermore Lee and co-workers5 have described
the first total synthesis of the proposed revised structure 2
for clavosolide A. Interestingly, while their spectral data were
in good agreement with that reported for the natural product,
the optical rotation was [R]D +52.0 (c 0.165, CHCl3),
whereas for clavosolide A [R]D -48.5 (c 1, CHCl3)1a was
reported; hence, Lee concluded that 2 is the antipode of
clavosolide A. This would imply that, rather unexpectedly,
clavosolide A must be derived from L-xylose.
Herein, we describe the total synthesis of 2. The spectral
data for 2 are in accord with the literature for clavosolide
A1a and that reported by Lee.5 However, in contrast to Lee,
we found that the optical rotation is in agreement with that
for the natural product. Hence we conclude that clavosolide
A has structure 2 with the permethylated glycoside moieties
derived from D-xylose.
1
the H NMR spectrum of 1.
In contrast in the proposed structure 2 of the natural
product, neither of the 13-protons comes within the deshield-
ing region of the carbonyl group; hence, as expected, they
have similar chemical shifts (∆δ ) 0.11 ppm). Furthermore,
the chemical shifts of the signals assigned to 11-H in diolides
1 and 2 are consistent with the models. In the model of 2,
11-H points toward the diolide ring and resonates downfield
(at δ 0.83) compared with the signal assigned to 11-H in 1
which resonates at δ0.60 and is directed away from the ring.
Thus, these in silico studies are entirely consistent with the
proposed revised structure 2 for clavosolide A.
Our synthetic approach to diolide 2 involved assembly of
the tetrahydropyran core 6 via a stereoselective Prins
cyclization, introduction of the cyclopropyl side chain, then
dimerization, and finally glycosidation. We have previously
reported6 the enantioselective synthesis of 6 using a Nokami
crotyl transfer reaction with the menthone-derived tertiary
alcohol 37 and 3-benzyloxypropanal to prepare the (S)-
homoallylic alcohol 4 (Scheme 1). Treatment of 4 with
methyl propiolate and catalytic N-methylmorpholine gave
Prior to embarking on the synthesis of diolide 2, molecular
modeling using Spartan was undertaken to gain further
support for the proposed assignment2 of the stereochemistry
of the cyclopropyl side chains of the natural product and to
rationalize the NMR data. A conformational search of the
(2) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.; Harding,
J. R.; Willis, C. L. Chem. Commun. 2005, 5097.
(3) Chakraborty, T. K.; Reddy, V. R. Tetrahedron Lett. 2006, 47, 2099.
(4) Yakambram, P.; Puranik, V. G.; Gurjar, M. K. Tetrahedron Lett. 2006,
47, 3781.
(5) Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D. H. Org. Lett. 2006, 8,
661; erratum Org. Lett. 2006, 8, 3411.
(6) Barry, C. S.; Bushby, N.; Harding, J. R.; Willis, C. L. Org. Lett.
2005, 7, 2683.
(7) (a) Nokami, J.; Nomiyama, K.; Shafi, S.; Kataoka, K. Org. Lett. 2004,
6, 1261. (b) Nokami J.; Ohga, M.; Nakamoto, H.; Matsubara, T.; Hussain,
I.; Kataoka, K. J. Am. Chem. Soc. 1991, 123, 9168.
3320
Org. Lett., Vol. 8, No. 15, 2006

Scheme 1. Synthesis of Tetrahydropyran 6
Scheme 2. Synthesis of Monomer 13
enol ether 5. The pivotal cyclization was achieved by a TFA-
mediated Prins reaction to create the three new asymmetric
centers in tetrahydropyran 6 with complete stereocontrol in
a single pot process. Some ester hydrolysis occurred, but
acid 7 was readily methylated with diazomethane giving ester
6 in 88% overall yield from 5.
the stereochemistry of these alcohols was reported previ-
ously.2 The (R)-alcohol 11 could be converted to the required
(S)-isomer 10 by a straightforward two-step oxidation/
reduction using Dess-Martin periodinane11 followed by
standard Luche reduction conditions. To establish the
required configuration of the side chain of 2, a stereoselective
anti cyclopropanation of (S)-alcohol 10 was required. This
was achieved using a bulky protecting group on the second-
ary alcohol. Thus, allylic alcohol 10 was first protected as
the TBS ether and then treatment with Et2Zn and CH2ICl12
gave a 4:1 mixture of diastereomers (91% total yield of the
diastereomers) in favor of the required anti product 12.
Following purification of 12 by column chromatography, the
TBS ether was removed selectively under mild conditions
leaving the TIPS protecting group intact giving 13 in 55%
yield from 10.
Having prepared the monomer 13, then the key dimeriza-
tion to diolide 15 was investigated. Methyl ester 13 was
hydrolyzed under mild conditions using TMSONa followed
by AcOH to give hydroxy acid 14 in 99% yield. For the
synthesis of 1 we had used the Corey-Nicolaou protocol13
to effect dimerization, which gave the required product in
53% yield.2 However, on treatment of hydroxy acid 14 under
similar conditions using 2,2′-bipyridyl disulfide and Ph3P
followed by heating the resultant thiol ester in toluene, a
significant amount of the cyclic tetramer, ESI m/z 1665.1306
[MNa]+ was formed along with the required dimer, ESI m/z
843.5614 [MNa]+. Even using very dilute solutions, forma-
tion of the tetramer proved problematic. Both Chakraborty3
and Lee5 had effected the dimerization of analogous TBS-
While the synthesis of enol ether 5 from alcohol 4 gave
reasonable yields (68%), it proved problematic on a large
scale. The reaction took several days to reach completion at
room temperature and required an excess of methyl propi-
olate resulting in the formation of an unwanted byproduct
8,8 which proved difficult to remove. Hence, we have
reinvestigated this reaction. Aggarwal and co-workers have
used quinuclidine to good effect in the Baylis-Hillman
reaction,9 and indeed, we found that it proved to be an
excellent catalyst in the synthesis of 5. Slow addition of
methyl propiolate to alcohol 4 in the presence of catalytic
quinuclidine gave the required enol ether 5 in 88% isolated
yield after just 5 h at room temperature. Since formation of
enol ether 5 and subsequent Prins cyclization to tetrahydro-
pyran 6 are both conducted in CH2Cl2 and quinuclidine is
used in only catalytic amounts, it proved possible to telescope
the two reactions into a single step by simply adding TFA
to the mixture containing alcohol 4, methyl propiolate, and
quinuclidine once enol ether formation was complete (moni-
tored by TLC).
With gram quantities of tetrahydropyran 6 in hand, it was
next converted to aldehyde 9, and then a Nozaki-Hiyama-
Kishi coupling10 of 9 with (E)-1-bromo-1-propene in the
presence of CrCl2 and catalytic NiCl2 gave a 1:1 mixture of
allylic alcohols 10 and 11 (Scheme 2). The assignment of
(8) Matsuya, Y.; Hayashi, K.; Nemoto, H. J. Am. Chem. Soc. 2003, 125,
646.
(9) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68,
692.
(10) (a) Takai, K.; Tagashira, M.; Kuroda, T.; Oshima, K.; Utimoto, K.;
Nozaki, H. J. Am. Chem. Soc. 1986, 108, 6048. (b) Jin, H.; Uenishi, J.;
Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644.
(11) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(12) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974.
(13) Corey, E. J.; Nicolaou, K. C. J. Am. Chem. Soc. 1974, 96, 5614.
Org. Lett., Vol. 8, No. 15, 2006
3321

protected hydroxy acids by a modified Yamaguchi proce-
dure14 in their syntheses of 1 and 2, respectively. Treatment
of 14 with 2,4,6-trichlorobenzoyl chloride and Et3N followed
by heating in toluene with DMAP gave the dimer. Removal
of the TIPS protecting group using TBAF gave the aglycone
15 in 53% overall yield from hydroxy acid 14. To complete
the synthesis of clavosolide A, glycosidation of 15 was
investigated using a modification of the Nicolaou NBS
glycosylation protocol.15 Ratcliffe and Fraser-Reid16 have
reported that addition of CH3CN leads to enhanced â-selec-
tivity in glycosidation reactions, and hence, 15 was reacted
with thioether 16 (prepared in good yield from D-xylose2)
in the presence of NBS and CH3CN. This gave the expected
mixture of [R,R]- and [R,â]-anomers as well as the required
[â,â]-anomer 2, which was isolated in 18% yield. In the 1H
NMR spectrum of 2, the signal assigned to 15-H (and 15′H)
appeared as a doublet (J 8 Hz) at δ 4.27 consistent with the
axial-axial relationship of 15-H and 16-H. There was an
excellent correlation of the spectral data of the synthetic
clavosolide A 2 with those reported for the natural product
by Rao and Faulkner1a and by Lee and co-workers.5 Our
product was a white solid with [R]D -38.0 (c 1, CHCl3),
while the natural product had been isolated as a greenish oil
(the color was ascribed to the high chlorophyll content of
the extract) from M. claVosa, [R]D -48.5 (c 1, CHCl3),1a
and hence, we concluded that the natural product is indeed
2, (-)-clavosolide A. Concurrent with this work, Smith and
Simov17 completed the total synthesis of 2, and Lee18
amended the value for their optical rotation from that given
previously5 to -39.7 (c 0.055, CHCl3) in accord with
(-)-clavosolide.
product (-)-clavosolide A which is the symmetrical diolide
2 glycosylated with permethylated D-xylose moieties. The
total synthesis of clavosolide A was achieved via an efficient
assembly of the tetrasubstituted tetrahydropyran core from
3-benzyloxypropanal in 76% yield and with complete ste-
reocontrol. Following the stereoselective creation of the
required cyclopropyl side chain, dimerization and glycosi-
dation gave the target compound 2.
Scheme 3. Completing the Synthesis of (-)-Clavosolide A
Acknowledgment. We are grateful to EPSRC, Astra-
Zeneca UK Ltd., and the University of Bristol for funding
(to C.S.B., J.D.E., and P.T.S.) and Professor A. B. Smith III
(University of Pennsylvania) for valuable discussions.
In conclusion, the studies described herein confirm the
structure and absolute configuration of the marine natural
Supporting Information Available: Preparation and
characterization of the compounds described in the paper.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(15) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 105, 2430.
(16) Ratcliffe, A. J.; Fraser-Reid, B. J. Chem. Soc., Perkin Trans. 1,
1990, 747.
(17) Smith, A. B., III; Simov, V. Org. Lett. 2006, 8, 3315.
OL0611705
(18) Smith, A. B., III. Personal communication. See the Addition and
Correction by Professor Lee (ref 5).
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