Total synthesis, structural revision, and absolute configuration of (+)-clavosolide A

Article abstract of DOI:10.1021/ol052851n

Enantioselective synthesis of 3, a revised structure for clavosolide A, was completed. Both ¹H and ¹³C NMR spectra of the natural and synthetic compounds were identical, and optical rotation measurements identified the absolute confi

Full text of DOI:10.1021/ol052851n

ORGANIC
LETTERS
2006
Vol. 8, No. 4
661-664
Total Synthesis, Structural Revision,
and Absolute Configuration of
(+)-Clavosolide A
Jung Beom Son, Si Nae Kim, Na Yeong Kim, and Duck Hyung Lee*
Department of Chemistry, Sogang UniVersity, Shinsoo-dong 1, Mapo-gu,
Seoul 121-742, Korea
dhlee@sogang.ac.kr
Received November 24, 2005
ABSTRACT
Enantioselective synthesis of 3, a revised structure for clavosolide A, was completed. Both 1H and 13C NMR spectra of the natural and synthetic
compounds were identical, and optical rotation measurements identified the absolute configuration of the natural clavosolide A as the enantiomer
of 3.
Marine sponges have provided an inexhaustible supply of
bioactive metabolites.1 There was a report by Fu2 that the
crude extract of the sponge Myriastra claVosa collected from
Palau in 1998 contains clavosines A-C, a potent cytotoxin
and inhibitor of protein phosphatase 1 and 2A. However,
Faulkner and Rao3 isolated a suite of unusual metabolites,
clavosolides A (1) and B (2), from the crude extract of the
sponge M. claVosa from the Philippines in 2002 and proposed
the structure of these two compounds based on the extensive
spectroscopic data. These structures, further supported by
Erickson’s report in 2002,4 are quite unique because they
are not related to any known sponge metabolites so far. We
completed an enantioselective synthesis of the proposed
structure of clavosolide A (1);5 however, we found that the
1H and 13C NMR spectra of synthetic 1 were different around
the cyclopropyl region from that of proposed structure of 1.
Based on this discrepancy, we proposed that the correct
structure of clavosolide A should be 3, which was further
corroborated by an independent synthesis of 1 by Willis.6
While this manuscript was in preparation, Willis and co-
workers reported the synthesis of 1 and have reached the
same conclusion that the correct structure of clavosolide A
should be its diastereomer 3 (Figure 1).
(4) Erickson, K. L.; Gustafson, K. R.; Pannell, L. K.; Beutler, J. A.;
Boyd, M. R. J. Nat. Prod. 2002, 65, 1303-1306.
(5) (a) Lee, D. H.; Son, J. B.; Kim, N. Y. Abstracts of Papers, 229th
national Meeting of the American Chemical Society, San Diego, Mar 13-
17, 2005; American Chemical Society: Washington, DC, 2005; ORGN-
592. (b) For a review on the misassigned natural products, see: Nicolaou,
K. C.; Snyder, S. A. Chasing molecules that were never there: Misassigned
natural products and the role of chemical synthesis in modern structure
elucidation. Angew. Chem., Int. Ed. 2005, 44, 1012-1044.
(1) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1-49.
(2) Fu, X.; Schmitz, F. J.; Kelly-Borges, M.; McCready, T. L.; Holmes,
C. F. B. J. Org. Chem. 1998, 63, 7957-7963.
(6) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.; Harding,
J. R.; Willis, C. L. Chem. Commun. 2005, 40, 5097-5099.
(3) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 386-388.
10.1021/ol052851n CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/25/2006

precursor 13. Intermediate 13, with all the substituents at
the equatorial position in the tetrahydropyran ring, would
be constructed via intramolecular 1,4-addition of hydroxyl
group at C7 to the conjugated ester moiety at C2-C3 of 12.
Subsequent stereoselective aldol reaction between ketone 7
and aldehyde 8 was expected to provide the desired (5S)-
configuration in 12.
The synthesis of methyl ketone 7 is summarized in Scheme
2. Brown’s asymmetric methallylation7 of aldehyde 4, which
Scheme 2. Synthesis of Methyl Ketone 7
Figure 1. Proposed structure 1 and revised structure 3.
We report herein the enantioselective synthesis of 3
and the determination of the absolute configuration of
(+)-clavosolide A.
Retrosynthetic analysis for 3 is illustrated in Scheme 1.
We envisioned that completion of the synthesis of 3 relied
was prepared from D-mannitol according to the literature
report,8 produced homoallylic alcohol 5 (>97:3 by 1H NMR)
in 75% yield.
Scheme 1. Retrosynthesis of Clavosolide A (3)
Protection of the corresponding secondary alcohol with
PMB imidate provided the PMB ether 5. Methyl ketone 7
was prepared in four steps from 5 via deprotection of the
primary silyl ether, bromination of the primary alcohol,
reduction9 of the bromide 6 by lithium aluminum hydride,
and ozonolysis of the double bond in the presence of
pyridine.
1,5-Anti-selective aldol reaction of dibutylboron enolate
of 7 with aldehyde 810 in ether at -78 °C proceeded
1
successfully to give the â-hydroxy ketone 9 (>96:4 by H
NMR) in 93% yield (Scheme 3).11 1,3-Anti-selective reduc-
tion of 9 using tetramethylammonium triacetoxyborohy-
dride12 in CH3CN-AcOH was followed by treatment of the
resulting anti-1,3-diol with 2,2-dimethoxypropane to produce
acetonide 10. The primary silyl ether group of 10 was
(7) (a) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org.
Chem. 1986, 51, 432-439. (b) Akiyama, S.; Hooz, J. Tetrahedron Lett.
1973, 14, 4115-4118. (c) Brown, H. C.; Jadhav, P. K.; P. Perumal, P. T.
Tetrahedron Lett. 1984, 25, 5111-5114.
(8) (a) Hong, J. H.; Oh, C. H.; Cho, J. H. Tetrahedron Lett. 2003, 59,
6103-6108. (b) Morikawa, T.; Sasaki, T.; Hanai, R.; Shibuya, A.; Taguchi,
T. J. Org. Chem. 1994, 59, 97-103.
(9) (a) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1980, 45, 849-
856. (b) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1982, 47, 276-
280.
(10) For the preparation of aldehyde 8, see: (a) Hosakawa, T.; Yamanaka,
T.; Itotani, M.; Murahashi, S. I. J. Org. Chem. 1995, 60, 6159-6167. (b)
Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron. 2002, 58, 5909-5922. (c)
Paterson, I.; Flarence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am.
Chem. Soc. 2001, 123, 9535-9544.
on the coupling of diol 17 and the activated sugar moiety
16, which was expected to be derived from D-xylose, via a
Schmidt-type glycosylation. The C2-symmetric nature of diol
17 allowed us to disconnect two ester linkages at the same
time, making this strategy highly convergent from a simple
(11) (a) Evans, D. A.; Colleman, P. J.; Cote, B. J. Org. Chem. 1997, 62,
788-789. (b) Evans, D. A.; Cote, B.; Coleman, P. J.; Connell, B. T. J. Am.
Chem. Soc. 2003, 125, 10893-10898.
(12) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
662
Org. Lett., Vol. 8, No. 4, 2006

Activated sugar moiety 16 was prepared as follows
(Scheme 4). D-Xylose was treated with excess MeI in DMSO
Scheme 3. Synthesis of Hydroxyl Acid 14
Scheme 4. Synthesis of Imidate 16
to give per-methylated derivative16 as a mixture of epimers
(â/R ) 3:1), which was subsequently brought to hemiacetal
15 under strongly acidic conditions.
The free hydroxy group in 15 was then converted to
corresponding imidate, thereby delivering 1617 with the same
epimeric ratio (R/â ) 3:1) in 81% yield. With key building
blocks 14 and 16 in hand, we are now in the final stage for
the completion of 3 (Scheme 5). Dimerization of monomer
Scheme 5. Total Synthesis of Clavosolide A (3)
unmasked by TBAF, and subsequent Dess-Martin oxidation
of the primary hydroxyl group afforded aldehyde 11 in 76%
yield.
Aldehyde 11 was then converted to the (E)-R,â-conjugated
ester using the Horner-Wadsworth-Emmons protocol,13 and
the acetonide protecting group was removed under acidic
conditions to provide 1,3-diol 12. Finally, key intermediate
13 was prepared by stereoselective intramolecular conjugate
addition reaction14 of the C7-hydroxyl group under strong
basic conditions with moderate diastereoselectivity (3,7-syn/
3,7-anti ) 11:1) in 82% yield. After an unambiguous
structural confirmation by NOESY experiment,15 secondary
alcohol 13 was converted to hydroxyl acid 14, a key
intermediate for the cyclization, via a three-step sequence:
protection of the secondary hydroxyl group with TBSOTf
(69%), deprotection of PMB group by DDQ in CH2Cl2
(88%), and basic hydrolysis of ester group in THF-H2O-
MeOH (81%).
14 proceeded cleanly using the macrolactonization protocol
of Yamaguchi in slightly modified conditions.18 Removal
of the TBS-protecting groups by TBAF in THF provided
diol 17 in 41% overall yield in two steps. Finally, BF3-
assisted glycosylation between donor 16 and acceptor 17 in
the presence of molecular seives provided the target com-
pound 3 as a white solid19 in 11% yield.
The 1H NMR spectra of the compound isolated by
Faulkner3 and synthetic compound 3 are identical in all
respects, including chemical shifts, coupling constants, and
(13) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(14) (a) Evans, D. A.; Ripin, D. H.; Halstead, D. P.; Campos, K. R. J.
Am. Chem. Soc. 1999, 121, 6816-6826. (b) Vakalopoulos, A.; Hoffmann,
H. M. R. Org. Lett. 2001, 3, 177-180. (c) Micalizio, G. C.; Pinchuk, A.
N.; Roush, W. R. J. Org. Chem. 2000, 65, 8730-8736. (d) Bhattacharjee,
A.; Soltani, O.; De Brabander, J. K. Org. Lett. 2002, 4, 481-484. (e)
Schneider, C.; Schuffehauer, A. Eur. J. Org. Chem. 2000, 65, 73-82. (f)
Edmunds, A. J. F.; Trueb W. Tetrahedron Lett. 1997, 38, 1009-1012. (g)
White, J. D.; Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.;
Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J. J. Am. Chem. Soc. 2001,
123, 6816-6826.
(16) (a) Wang, H.; Sun, L.; Glazebnik, S.; Zhao, K. Tetrahedron Lett.
1995, 36, 2953-2956. (b) J. Schraml, E. Petrakova, O. Pihar, J. Hirsch, V.
Chvalovsky, Chem. Commun. 1983, 48, 1829-1841.
(17) Furstner, A.; Albert, M.; Mlynarski, J.; Matheu, M.; DeClercq, E.
J. Am. Chem. Soc. 2003, 125, 13132-13142.
(18) Inanaga, J.; Hirata, K.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989-1993.
(19) Clavosolide A and B were isolated as a slightly greenish viscous
oil, probably due to some impurities.
(15) See the Supporting Information for the 2D-NOESY spectrum.
Org. Lett., Vol. 8, No. 4, 2006
663

Figure 2. 1H NMR spectra of synthetic compound 3 and isolated compound 1. Reprinted with permission from Rao, M. R.; Faulkner, D.
J. J. Nat. Prod. 2002, 65, 386-388.
patterns (Figure 2). Also, the chemical shifts in 13C NMR
spectra of the natural and the synthetic materials are
indistinguishable.20
Structural revision of clavosolide A and determination of
the absolute configuration of natural (-)-clavosolide A
followed accordingly.
Finally, the optical rotation of synthetic compound 3
was measured to be [R]D +52.0 (c 0.165, CHCl3),3 which is
in contrast to the reported value of [R]D -48.5 (c 1,
CHCl3)3 for the isolated compound 1. Therefore, we con-
cluded that natural (-)-clavosolide A must be an antipode
of 3.
Acknowledgment. This research was assisted financially
by the Korea Research Foundation (KRF-2002-070-C00058).
The instrument facilities of the Organic Chemistry Research
Center (OCRC) at Sogang University were also helpful.
In summary, the enantioselective synthesis of 3 was
accomplished in 20 steps, in which 1,5-anti-selective aldol
reaction of 7 with 8 and stereoselective intramolecular
conjugate addition of 12 were utilized as key transformations.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) See the Supporting Information.
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