Total synthesis of the marine metabolite (-)-clavosolide D

Article abstract of DOI:10.1021/ol800386d

The first total synthesis of the marine natural product (-)-clavosolide D is described confirming the structure of the unsymmetrical 16- membered diolide glycosylated by permethylated D-xylose moieties. Following efficient assembly of the two tetrahydropyrans using stereoselective Prins cyclizations, the side chains were introduced via an allylation/isomerization/anti cyclopropanation sequence; the final macrolactonization step was achieved under Yamaguchi conditions.2008 American Chemical Society.

Full text of DOI:10.1021/ol800386d

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1637-1640
Total Synthesis of the Marine Metabolite
)-Clavosolide D
(−
Peter T. Seden, Jonathan P. H. Charmant, and Christine L. Willis*
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
chris.willis@bristol.ac.uk
Received February 19, 2008
ABSTRACT
The first total synthesis of the marine natural product (
−)-clavosolide D is described confirming the structure of the unsymmetrical 16-
membered diolide glycosylated by permethylated -xylose moieties. Following efficient assembly of the two tetrahydropyrans using stereoselective
D
Prins cyclizations, the side chains were introduced via an allylation/isomerization/anti cyclopropanation sequence; the final macrolactonization
step was achieved under Yamaguchi conditions.
The clavosolides are a family of unusual diolides isolated
from extracts of the marine sponge Myriastra claVosa
collected in the Philippines.1 Following extensive spectro-
scopic and molecular modeling studies, the structure of
clavosolide A was assigned as a symmetrical 16-membered
ring dilactone assembled on a functionalized tetrahydropyran
core with permethylated D-xylose moieties. The macrocycle
is further adorned by two cyclopropyl containing side-chains
which were originally assigned the configuration 10S,10′S,-
11S,11′S. Following the total synthesis of this compound,
we proposed a revised structure for the natural product in
which the side-chains possess the 10R,10′R,11R,11′R con-
figuration.2 The unusual architecture of the clavosolides has
attracted significant synthetic interest,3 and this proposed
revised structure has been confirmed by total synthesis.4
Clavosolide B differs from clavosolide A in the extent of
methylation of the D-xylose residues, and indeed, the
structure has been confirmed recently by total synthesis.5
In 2002 Gustafson and co-workers isolated a small quantity
(0.2 mg) of an additional natural product, clavosolide D, from
extracts of M. claVosa.1b While the limited mass of this
sample made complete spectral characterization difficult, it
was proposed that unlike clavosolides A and B, the mac-
rodiolide core of clavosolide D is unsymmetrical encompass-
ing both tetra-and trisubstituted THPs, the latter lacking a
methyl group at C4′. Herein we describe the first total
synthesis of clavosolide D confirming its structure. By
analogy to the revised structures of clavosolides A and B,
on planning a synthetic strategy to this marine natural product
we assumed that it possesses side-chains with the 10R,10′R,-
11R,11′R configuration (Figure 1).
(1) (a) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 386. (b)
Erickson, K. L.; Gustafson, K. R.; Pannell, L. K.; Beutler, J. A.; Boyd, M.
R. J. Nat. Prod. 2002, 65, 1303.
(2) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.; Harding,
J. R.; Willis, C. L. Chem. Commun. 2005, 5097.
(3) Further synthetic investigations on the originally proposed structure
of clavosolide A include: (a) Chakraborty, T. K.; Reddy, V. R. Tetrahedron
Lett. 2006, 47, 2099. (b) Yakambram, P.; Puranik, V. G.; Gurjar, M. K.
Tetrahedron Lett. 2006, 47, 3781.
(4) (a) Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D. H. Org. Lett. 2006,
8, 661 and 3411. (b) Smith, A. B., III; Simov, V. Org. Lett. 2006, 8, 3315.
(c) 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. (d) Chakraborty, T.
K.; Reddy, V. R.; Chattopadhyay, A. K. Tetrahedron Lett. 2006, 47,
7435.
(5) Son, J. B.; Hwang, M-H.; Lee, W.; Lee, D-H. Org. Lett. 2007, 9,
3897.
10.1021/ol800386d CCC: $40.75
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Published on Web 03/21/2008

catalytic quinuclidine to form enol ether 3 followed by
addition of TFA giving, after hydrolysis of the trifluoroac-
etate, the required tetrahydropyran 4 in 65% overall yield
from homoallylic alcohol 2 with the creation of three new
Scheme 2. Synthesis of Tetrahydropyran 6
Figure 1. Clavosolides A, B, and D.
In the four reported total syntheses of clavosolide A,4 the
aglycone was assembled and the final step was glycosylation
of the symmetrical parent diol, leading to a statistical mixture
of [R,R]-, [â,â]-, and [R,â]-anomers resulting in yields in
the range 12-21% of the required [â,â]-isomer. Thus, in
designing the synthetic strategy to clavosolide D we aimed
to introduce the permethylated D-xylose residues immediately
following assembly of the two functionalized THPs which,
in turn, were to be constructed using Prins cyclizations
(Scheme 1). Further challenges to be addressed in the total
asymmetric centers. The next stage was glycosidation of
alcohol 4 with a permethylated D-xylose derivative. Lee and
co-workers used a Schmidt-type glycosidation in their
synthesis of clavosolide B which gave a 1:1 mixture of
anomers, and the required â-anomer was isolated in 47%
yield.5 We favored the use of a modification of the Nicolaou
NBS glycosidation protocol7 using a thioglycoside in the
presence of acetonitrile to enhance â-selectivity.8 It has been
reported that benzylic methylene groups may be oxidized in
the presence of NBS,9 and indeed, initially this proved
problematic. However, when the known2 thioglycoside 5 was
pretreated with 1 equiv of NBS at -40 °C in acetonitrile
followed by addition of tetrahydropyran 4, the required
â-glycoside 6 was isolated in 59% yield, as well as the
R-glycoside 7 (21% yield) with no observed benzylic
oxidation.
Scheme 1. Retrosynthesis of Clavosolide D
With gram quantities of 6 in hand, we next turned our
attention to the construction of the trisubstituted THP IV
(Scheme 1) again using a Prins cyclization to construct the
heterocycle. Brown allylation10 of 3-benzyloxypropanal using
(-)-DIPCl and allylmagnesium bromide gave (S)-homoal-
lylic alcohol 8 in 93% yield and 85% ee (as determined via
the Mosher’s ester derivative). Interestingly, treatment of 8
with methyl propiolate and quinuclidine followed by addition
of TFA gave, after mild hydrolysis, a 4:1 mixture of the
required trisubstituted THP 10 and the epimer 11. This
reduced stereocontrol in the formation of the trisubstituted
THP compared with the tetrasubstituted ring 4, has precedent
in the work of Hart and Bennett11 who reported that a TFA
synthesis were the efficient stereocontrolled introduction of
the required cyclopropyl side-chains and a stepwise macro-
lactonization using suitable orthogonal protection of inter-
mediates I and II.
The synthesis began with construction of tetrasubstituted
tetrahydropyran 4 using our previously described approach
(Scheme 2).4c First (S)-homoallylic alcohol 2 was prepared
in 94% yield by treatment of 3-benzyloxypropanal with
Nokami’s menthone derived crotyl transfer reagent 1.6 The
pivotal Prins cyclization was achieved in a single-pot process
by treatment of alcohol 2 first with methyl propiolate and
(7) Nicolaou, K. C.; Seitz, S. P.; Papahatjis, D. P. J. Am. Chem. Soc.
1983, 105, 2430.
(8) Ratcliffe, A. J.; Fraser-Reid, B. J. Chem. Soc., Perkin Trans. 1 1990,
747.
(9) Dakir, M.; Auhmani, A.; Itto, M. Y. A.; Mazoir, N.; Akssira, M.;
Pierrot, M.; Benharref, A. Synth. Commun. 2004, 34, 2001.
(10) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(b) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401.
(11) (a) Hart, D. J.; Bennett, C. E. Org. Lett. 2003, 5, 1499. (b) Bennett,
C. E.; Figueroa, R.; Hart, D. J.; Yang, D. Heterocycles 2006, 70, 119.
(6) (a) Nokami, J.; Nomiyama, K.; Shafi, S. M.; Kataoka, K. Org. Lett.
2004, 6, 1261. (b) Nokami, J.; Ohga, M.; Nakamoto, H.; Matsubara, T.;
Hussain, I.; Kataoka, K. J. Am. Chem. Soc. 2001, 123, 9168.
1638
Org. Lett., Vol. 10, No. 8, 2008

mediated cyclization of the analogous homoallylic enol ether
with a benzyloxymethyl side-chain (rather than the benzy-
loxyethyl side-chain in 9) resulted in a 1:1 mixture of
epimeric alcohols accompanied by a bicyclic byproduct.
These results implicate participation of the oxygen containing
side-chain in formation of both the R-alcohol and the
byproduct. NBS-mediated glycosidation of alcohol 10 with
thioglycoside 5 under the optimized conditions described
above gave the required pure trisubstituted tetrahydropyran
12 in 63% yield along with 21% of the R-anomer 13.
The next stage in the synthesis of clavosolide D was to
elaborate the side-chains of the tetrahydropyrans to esters I
and II possessing the anti cyclopropylcarbinyl moieties
(Scheme 1). In our synthesis of clavosolide A4c the cyclo-
propyl side-chain of I was introduced via a nonselective
Nozaki-Hiyama-Kishi propenylation12 to give a 1:1 mixture
of epimeric alcohols; recycling of the unwanted 9R-epimer
to the required 9S-allylic alcohol proved problematic.4c Thus,
ideally a more efficient method was required. Inspired by a
recent report by Hannesian and co-workers13 on the use of
a thermally modified Grubbs second generation catalyst to
effect the migration of terminal alkenes to an internal
position, we investigated an allylation/isomerization/anti
cyclopropanation strategy for the introduction of the required
cyclopropyl side-chains (Scheme 4).
Scheme 4. Elaboration of the Side Chains
Scheme 3. Synthesis of Tetrahydropyran 12
similar three-step protocol was used for conversion of
trisubstituted tetrahydropyran 12 to homoallylic alcohol 19.
The unwanted epimeric alcohol 17 was inverted under
Mitsunobu conditions16 giving, after selective hydrolysis of
the resultant ester, the required homoallylic alcohol 19 in
76% yield over the two steps.
Homoallylic alcohol 18 was further elaborated to the
required fragment 22, as shown in Scheme 4. First, the
secondary alcohol 18 was protected as the TBS ether prior
to isomerization of the alkene using Grubbs second genera-
tion catalyst in methanol13 to give predominantly (E)-alkene
20 (δH 5.32, ddq, J ) 15.5, 7.5, 1.4, 10H; δH 5.50, dq, J )
15.5, 6.4, 11H). Treatment of 20 with Et2Zn and CH2ICl17
gave the required anti cyclopropyl derivative 22 as the major
product. The second fragment 23, assembled on a trisubsti-
tuted THP, was prepared in 43% overall yield from 19 using
the same approach.
With the two key monomers 22 and 23 in hand, the final
stages of the convergent synthesis of clavosolide D involved
initial coupling of the two fragments followed by macro-
lactonization. We elected to couple acid 24 derived from
the tetrasubstituted THP 22 with alcohol 25 from the
trisubstituted THP 23. We were concerned that in the
penultimate step it may be problematic to selectively cleave
the methyl ester to seco acid 28. Interestingly, Paterson and
co-workers had been faced with a similar hurdle in their
Facile conversion of tetrasubstituted tetrahydropyran 6 to
aldehyde 14 was followed by a Brown allylation10 of 14
which gave the required alcohol 18 as a single diastereomer
but in only 18% yield. In contrast, an indium-mediated
allylation14 of 14 gave a 1:1 mixture of epimeric alcohols
16 and 18 in excellent yield which were readily separated
by column chromatography. Neither homoallylic alcohol was
crystalline, and so NMR analysis of the (R)-Mosher’s ester
derivatives15 was employed to identify the correct diastere-
omer to carry forward in the synthesis of clavosolide D. A
(12) 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.
(13) Hanessian, S.; Giroux, S.; Larsson, A. Org. Lett. 2006, 8, 5481.
(14) Chan, T. H.; Li, C. J.; Lee, M. C.; Wei, Z. Y. Can. J. Chem. 1994,
72, 1181.
(16) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380.
(17) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974.
(15) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
Org. Lett., Vol. 10, No. 8, 2008
1639

tection of the allyl ester of 27 then yielded hydroxy acid 28
which was immediately cyclized to give the required diolide
29 (m/z 865.4559 [MNa]+) as a white crystalline solid. The
X-ray structure confirms the overall connectivity and relative
stereochemistry shown in Figure 2. Furthermore there was
an excellent correlation of the 1H and 13C NMR data in both
Scheme 5. Completing the Total Synthesis of (-)-Clavosolide
D
Figure 2. Molecular structure determined by X-ray diffraction.
Water molecules and the secondary components of disordered atoms
have been omitted for clarity.
CDCl3 and C6D6 of synthetic clavosolide D with those of
the natural product.
In conclusion, the first synthesis of (-)-clavosolide D has
been achieved via stereoselective Prins cyclizations to create
the two glycosidated tetrahydropyrans 6 and 12 in 37% and
31% overall yield, respectively, from 3-benzyloxypropanal.
The cyclopropyl side-chains were introduced using an
efficient allylation/isomerization/anti cyclopropanation se-
quence. Acid 24 and alcohol 25 were coupled then depro-
tection to seco acid 28 and cyclization furnished the target
16-membered ring diolide 29 in 43% yield over the four
steps. These studies confirm the structure of clavosolide D
as the unsymmetrical 16-membered diolide assembled on
tetrasubstituted and trisubstituted THPs glycosylated by
permethylated D-xylose moieties and further adorned with
cyclopropyl side-chains with the (10R,10′R,11R,11′R) ster-
eochemistry.
elegant synthesis of swinholide A and, after exploring various
conditions, had found that Ba(OH)2 could be used to effect
the required transformation in quantitative yield.18 However,
model studies on our system under a range of conditions,
including with Ba(OH)2, were not encouraging. Hence, we
deemed it prudent to convert the methyl ester to an allyl
ester which could be removed selectively under palladium
mediated conditions.5,19 Methyl ester 23 was hydrolyzed, and
then the hydroxy acid converted to allyl ester 25 using Cs2-
CO3 and allyl bromide. Acid 24 was readily prepared by
hydrolysis of methyl ester 22 using TMSONa. Acid 24 and
alcohol 25 were cleanly coupled under modified Yamaguchi
conditions,20 and the required ester 26 isolated in 94% yield.
Treatment of 26 with TBAF gave hydroxy ester 27. Depro-
Acknowledgment. We are grateful to EPSRC for funding
(P.T.S.), Professor K. R. Gustafson (National Cancer Insti-
tute) for kindly supplying NMR spectra of the natural
product, Dr. Alan Silcock and Ms. Cecile Descombes (Pfizer
Ltd, UK.) for assistance with LC-MS of clavosolide D and
the National Crystallographic Service at the University of
Southampton for collection of single-crystal X-ray diffraction
data.
Supporting Information Available: Preparation and
characterization of new compounds described in the paper.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Paterson, I.; Yeung, K. S.; Ward, R. A.; Smith, J. D.; Cumming, J.
G.; Lamboley, S. Tetrahedron, 1995, 51, 9467.
(19) Bavetsias, V.; Bisset, G. M. F.; Jarman, M. Synth. Commun. 1995,
25, 947.
(20) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
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