Enantioselective total synthesis of shahamin K [3]

Full text of DOI:10.1021/ja015802o

J. Am. Chem. Soc. 2001, 123, 4851-4852
4851
Scheme 1
Enantioselective Total Synthesis of Shahamin K
Alec D. Lebsack, Larry E. Overman,* and
Robert J. Valentekovich
Department of Chemistry, 516 Rowland Hall
UniVersity of California, IrVine, California 92697-2025
ReceiVed March 12, 2001
ReVised Manuscript ReceiVed April 10, 2001
Scheme 2
Several highly oxidized diterpenes having a rearranged spon-
gian skeleton have been isolated from marine sponges and
nudibranches.1 Dorid nudibranches are shell-less marine mollusks,
which are believed to have acquired the spongian-related com-
pounds from sponges on which they feed.1 An example of one
such diterpene is macfarlandin E (3, also called aplyviolacene),
which is found in both nudibranches and sponges.2 In 1991
Andersen and co-workers reported the isolation of shahamin K
(1) from the skin extracts of a dorid nudibranch Chromodoris
gleniei found in coastal waters of Sri Lanka.3 The gross structure
and relative stereochemistry of 1 were secured by NMR studies,
whereas the absolute configuration was not determined.3 The
common structural features of rearranged spongian diterpenes,
exemplified by 1-4, are a cis-hydroazulene unit and an attached
highly oxidized six-carbon fragment, the latter of which occurs
in a variety of cyclic and bicyclic motifs. Biological properties
of rearranged spongian diterpenes have been little investigated,
although antimicrobial and fish anti-feedant activities have been
documented.2a,4,5 We report herein the first total synthesis of a
rearranged spongian diterpene; this synthesis confirms the relative
and absolute stereochemistry of (+)-shahamin K and introduces
a useful extension of our Prins-pinacol approach for constructing
carbocyclic skeleta.6
the two attached rings. Stereocontrol in this pivotal event would
derive from the facial bias of each coupling partner: preferential
reaction of 6 from the convex R face and 5 from the face opposite
the acetoxymethyl substituent.7 The cis-fused ketone precursor
of 6 was seen to derive from ring-enlarging cyclopentane
annulation of cyclohexyl precursor 7.6
Our synthesis plan is outlined in retrosynthetic format in
Scheme 1. Michael addition of cyclopentenone electrophile 5 and
cis-hydroazulene enolate 6 was envisaged to construct the
challenging C8-C14 σ-bond and relate the stereochemistry of
The synthesis began with cyclohexanone 8,8 which was
transformed to rac-9 using an improved version of a procedure
developed earlier (Scheme 2).9 Kinetic resolution of rac-9 by
reaction with 0.2 equiv of (R)-oxazaborolidine 10 and 0.6 equiv
of BH3‚THF at -78 °C provided the easily separable cyclohexa-
none (S)-9 (44% yield, 94% ee) and alcohol 11 (49% yield, 79%
ee).10,11 Addition of (E)-1-propenyllithium to (S)-9 at -100 °C,
(1) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1-49. Also earlier reviews
in this series.
(2) (a) Clardy, J.; Cun-Leng, H.; Faulkner, D. J.; Molinski, T. F.; Van
Duyne, G. D. J. Org. Chem. 1986, 51, 4564-4567. (b) Hambley, T. W.;
Poiner, A.; Taylor, W. C. Tetrahedron Lett. 1986, 27, 3281-3282.
(3) Andersen, R. J.; Desilva, E. D.; Dumdei, E.; Miao, S. C.; Morris, S. A.
J. Nat. Prod. 1991, 54, 993-997.
(4) (a) Sullivan, B.; Faulkner, D. J. J. Org. Chem. 1984, 49, 3204-3206.
(b) Bobzin, S. C.; Faulkner, D. J. J. Nat. Prod. 1991, 54, 225-232.
(5) In recent studies, the related spongian-derived marine metabolite
norrisolide was identified as the first compound to induce irreversible effects
in Golgi organization: Takizawa, P. A.; Yucel, J. K.; Veit, B.; Faulkner, D.
J.; Deerinck, T.; Soto, G.; Ellisman, M.; Malhotra, V. Cell 1993, 73, 1079-
1090.
(6) (a) Hirst, G. C.; Howard, P. N.; Overman. L. E. J. Am. Chem. Soc.
1989, 111, 1514-1515. (b) Johnson, T. O., Jr.; Overman. L. E. Tetrahedron
Lett. 1991, 32, 7361-7365. (c) Ando, S.; Minor, K. P.; Overman, L. E. J.
Org. Chem. 1997, 62, 6379-6387. (d) Hirst, G. C.; Johnson, T. O., Jr.;
Overman, L. E. J. Am. Chem. Soc. 1993, 115, 2992-2993. (e) Minor, K. P.;
Overman, L. E. Tetrahedron 1997, 53, 8927-8940. (f) Overman, L. E.;
Pennington, L. P. Can. J. Chem. 2000, 78, 732-738.
(7) Few methods exist for relating the stereochemistry of attached rings.6f
For a recent example of the use of a similar strategy, see: Kishi, Y.; Wang,
W. Org. Lett. 1999, 7, 1129-1132.
(8) Available in two steps and 70% yield from 3-methyl-2-cyclohexenone,
see: Boxler, D.; Grieco, P. A.; Makaki, Y. J. Org. Chem. 1975, 40, 2261-
2263.
(9) Montgomery, J.; Overman, L. E. J. Org. Chem. 1993, 58, 6476-6479.
(10) (a) Kishi, Y.; Kurosu, M. J. Org. Chem. 1998, 63, 6100-6101. (b)
Corey, E. J.; Bakshi, R. K.; Shibata, S. J. J. Am. Chem. Soc. 1987, 109, 5551-
5553. (c) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012.
10.1021/ja015802o CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/26/2001

4852 J. Am. Chem. Soc., Vol. 123, No. 20, 2001
Communications to the Editor
followed by silylation of the resulting alcohol with N-(trimethyl-
silyl)imidazole12 gave a single silyl ether 7 in high yield.13a
Exposure of 7 to 2 equiv of dimethyl(methylthio)sulfonium
tetrafluoroborate (DMTSF)14 at -45 f 0 °C in CH2Cl2 initiated
the Prins-pinacol reaction to produce cis-hydroazulene 12, a 5:1
mixture of â and R sulfide epimers, in 80% yield.15 The structure
of 12 was confirmed by oxidation of the major â epimer to provide
the crystalline sulfone 13.13b The related ring-enlarging cyclo-
pentane annulation of the dimethyl acetal analogue of 7 could
not be realized, because Prins cyclization in this case took place
by a 5-exo pathway.16
Scheme 3
Installation of the exocyclic methylene was complicated by the
propensity of 12 to epimerize under basic conditions. However,
transformation of this intermediate to 14 could be accomplished
in 84% yield using a modified Peterson sequence. Oxidation of
14 with m-chloroperoxybenzoic acid (m-CPBA) followed by
oxidative desulfonylation17 of the resulting mixture of epimeric
sulfones provided hydroazulenone 15 in 62% overall yield.
Survey experiments established that the cyclopentenone Michael
acceptor had to carry an additional activating group for the C8
quaternary center to be formed efficiently. Using enantiopure
R-sulfonyl ketone 5,18 the pivotal union with the thermodynamic
lithium enolate of 15 occurred cleanly at -78 °C to deliver a
single adduct 16 in 72% yield (Scheme 3). The structure of this
product was confirmed by removal of the sulfone19 to provide
crystalline 17.13c
To transform the cyclopentanone side chain to the required
pyranone unit, â-keto sulfone 16 was reduced with SmI2 and the
resulting samarium enolate was acetylated at -78 °C with acetic
anhydride in the presence of 4-(N,N-dimethylamino)pyridine
(DMAP) to give enol acetate 18 in 88% yield (Scheme 3).
Reduction of the ketone of this intermediate with 1.5 equiv of
(R)-oxazaborolidine 1010b and 1.5 equiv of BH3‚THF gave 19 in
90% yield (ds >10:1).20 Transformation of the secondary alcohol
of 19 to an acetate followed by chemoselective dihydroxylation
of the enol acetate functionality of 20 delivered R-hydroxy ketone
21 in 87% yield. Cleavage of 21 with Pb(OAc)4 followed by
reduction of the resulting aldehyde with NaBH4 and lactonization
using the Mukaiyama reagent21 provided (+)-shahamin K (1) in
57% yield from 21. The optical rotation of synthetic 1, [R]D
+83.4, compared well with that reported for the natural isolate,
[R]D +84.0, as did all other spectral and analytical properties.
In summary, this study demonstrates that the alkene participant
in a Prins-pinacol construction of a cis-fused carbocycle does not
need to be biased to favor endo-cyclization if the initiating
electrophile is a R-thiocarbenium ion. The enantioselective total
synthesis of (+)-shahamin K was accomplished in 18 linear steps
and 4.2% yield from cyclohexanone 8, constituting the first total
synthesis of a rearranged spongian diterpene. Moreover, this
synthesis establishes the absolute sterochemistry of (+)-shahamin
K and defines a strategy that should be useful for preparing other
rearranged spongian diterpenes and their analogues.
(11) Enantiopurity was determined by HPLC analysis using a Chiracel
OD-H column.
(12) Heathcock, C. H.; Jennings, R. A.; von Geldern, T. W. J. Org. Chem.
1983, 48, 3428-3431.
(13) The structure of this intermediate was determined by single-crystal
X-ray analysis. The authors have deposited coordinates for this compound
with the Cambridge Crystallographic Data Centre. The coordinates can be
obtained, on request, from the Director, Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge, CB2 1EZ, U.K., of the corresponding
racemate, CCDC 159420 (a), CCDC 159421 (b), and CCDC 159422. (c)
(14) Kim, J. K.; Pau, J. K.; Caserio, M. C. J. Org. Chem. 1979, 44, 1544-
1550.
(15) For other examples of using DMTSF to activate dithio acetals for
cationic cyclization reactions, see: Trost, B. M.; Murayama, E. J. Am. Chem.
Soc. 1981, 103, 6529-6530. Also see ref 6e.
(16) In our earlier investigations of related transformations of unsaturated
dimethyl acetals,6a,d the alkene was biased to favor endo-cyclization (terminal
vinyl or 1-substituted alkenyl). In the case at hand, the termini of the alkene
are equally substituted, whereas the allylic siloxy substituent should disfavor
endocyclization by virtue of its inductive effect. The reason(s) why ring-
enlarging cyclopentane annulation is favored by use of an R-thiocarbenium
initiator is not understood and is the subject of active investigation.
(17) Little, R. D.; Myong, S. O. Tetrahedron Lett. 1980, 21, 3339-3342.
(18) Available in three steps (see Supporting Information) from a readily
available enantiopure cyclopentanone: He, M.; Nakayama, M.; Tanimori, S.;
Tsubota, M. Synth. Commun. 1997, 27, 2371-2378.
Acknowledgment. We thank NIH (NS-12389) for financial support
and Pharmacia (A.D.L.) and NIH (NRSA Award to R.J.V., GM-17537)
for fellowship support. We thank Professor Raymond Andersen for
1
providing a copy of H NMR spectra of natural 1 and Dr. Joseph Ziller
and Dr. John Greaves for X-ray and mass spectrometric analyses. NMR
and mass spectra were determined at UCI with instruments purchased
with the assistance of NSF and NIH.
(19) Hahn, G.; Molander, G. A. J. Org. Chem. 1986, 51, 1135-1138.
(20) Attempted reduction of 18 with NaBH4 led to partial cleavage of the
enol acetate, while reduction with BH3‚THF proceeded with 4:1 diastereo-
selection to provide 19 in 50% yield. Competing hydroboration was not a
problem when reduction of 18 was carried out using the borane complex of
oxazaborolidine 10.8c
Supporting Information Available: Experimental procedures for
nonroutine transformations: preparation of 1, 5, 7, (S)-9, 11, 12, 13, 15,
16, 17, 18, and 19; 1H and 13C NMR spectra for all new compounds
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Mukaiyama, T.; Saigo, K.; Shimada, E.; Usui, M. Chem. Lett. 1975,
10, 1045-1048.
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