Journal of the American Chemical Society
Communication
2
4a
Unfortunately, attempts at thermal solvolysis of 18b provide
alkenes exclusively (entry 3). However, ionization of 18b with a
(5) (a) Ko
̈
nig, G. M.; Wright, A. D; Angerhofer, C. K. J. Org. Chem.
1
996, 61, 3259. (b) Wattanapiromsakul, C.; Chanthathamrongsiri, N.;
26
Bussarawit, S.; Yuenyongsawad, S.; Plubrukarn, A.; Suwanborirux, K.
Can. J. Chem. 2009, 87, 612.
weak, oxophilic Lewis acid, Sc(OTf) , in the presence of 15
equiv of TMSCN and in the absence of any other solvent
provides 19a with high stereoselectivity and little elimination
entry 4). Notably, the major diastereomer derives from
inversion of configuration and suggests either (1) attack of a
contact ion pair or (2) departure of the trifluoroacetate
coincident with attack by the TMSCN nucleophile (structure
0). It should be noted that addition of TMSCN to a 4-tert-
butyl-1-methylcyclohexyl carbocation in dichloromethane is
reported to proceed with primarily the opposite selectivity to
yield an axial isonitrile. Application of this new method to
penultimate intermediate 17 also effects elimination of the C11
alcohol and provides 3 in good yield and high diastereose-
lectivity.
In conclusion, we have disclosed a short synthesis of 3, which
is a low nanomolar antimalarial agent and the most potent of
the amphilectene isocyanoterpenes. The synthesis of 3 relies on
a new dendrimeric variant of the Danishefsky diene which
allows rapid assembly of polycycles from linear unsaturated
polyenes. Furthermore, we have uncovered a potentially useful,
chemoselective inversion of tertiary alcohols with TMSCN; this
reactivity is currently being explored. We anticipate that the
approach reported herein will be applicable to the asymmetric
3
(6) Limited material precluded bioassay is several cases: Wright, A.
D.; McCluskey, A.; Robertson, M. J.; MacGregor, K. A.; Gordon, C. P.;
Guenther, J. Org. Biomol. Chem. 2011, 9, 400.
(
(7) For 1, see: (a) Piers, E.; Llinas-Brunet, M. J. Org. Chem. 1989, 54,
1
483. (b) Piers, E.; Llinas-Brunet, M.; Oballa, R. M. Can. J. Chem.
1993, 71, 1484. For 2, see: (c) Miyaoka, H.; Okubo, Y. Synlett 2011,
4, 547. For a 26 step ICT synthesis, see also: (d) Piers, E.; Romero,
M. A. Tetrahedron 1993, 49, 5791.
2
(
8) (a) Pronin, S. V.; Tabor, M. G.; Jansen, D. J.; Shenvi, R. A. J. Am.
Chem. Soc. 2012, 134, 2012. (b) Pronin, S. V.; Shenvi, R. A. Nat. Chem.
012, 4, 915.
9) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach; Wiley: West Sussex, U.K., 2009.
10) For a review, see: Hopf, H.; Sherburn, M. S. Angew. Chem., Int.
Ed. 2012, 51, 2298.
11) For example: (a) Bradford, T. A.; Payne, A. D.; Willis, A. C.;
19
2
(
(
(
Paddon-Row, M. N.; Sherburn, M. S. Org. Lett. 2007, 9, 4861. Cyclic
dienophiles are uniquely stereoselective, see: (b) Kwon, O.; Park, S. B.;
Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 13402.
(
12) (a) Danishefsky, S. J. Acc. Chem. Res. 1981, 14, 400.
b) Danishefsky, S. J. Aldrichimica Acta 1986, 59.
13) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H. J. Am. Chem.
Soc. 2002, 124, 4628.
14) Inokuchi, T.; Okano, M.; Miyamoto, T.; Madon, H. B.; Takagi,
M. Synlett 2000, 1549.
15) There is another low, near-equal-energy configuration available
(
(
(
2
7
synthesis of the entire amphilectene family,
related
isocyanoterpenes, and easily derived analogs which could
constitute a new arsenal of medicines in the fight against
malaria.
(
to the amphilectene tricycle 16 by inversion of stereochemistry at both
the C8 and C12 bridgehead carbons. An alternative choreography of
steps (i.e., initial conjugate addition to 15) yields this alternative
stereoisomer.
ASSOCIATED CONTENT
Supporting Information
■
(16) Hayakawa, I.; Asuma, Y.; Ohyoshi, T.; Aoki, K.; Kigoshi, H.
*
S
Tetrahedron Lett. 2007, 48, 6221.
Experimental procedures and spectroscopic data for all new
(
(
17) Johnson, C. R.; Tait, B. D. J. Org. Chem. 1987, 52, 281.
18) Kitano, Y.; Chiba, K.; Tada, M. Tetrahedron Lett. 1998, 39, 1911.
(19) Okada, I.; Kitano, Y. Synthesis 2011, 24, 3997.
(20) Corey, E. J.; Magriotis, P. J. Am. Chem. Soc. 1987, 109, 287.
AUTHOR INFORMATION
(21) The method of Mukaiyama was not successful in our hands.
See: Masutani, K.; Minowa, T.; Hagiwara, Y.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 2006, 79, 1106.
22) Assigned by 13C NMR: Crews, P.; Naylor, S.; Hanke, F. J.;
(
Notes
Hogue, E. R.; Kho, E.; Braslau, R. J. Org. Chem. 1984, 49, 1371.
(23) Elakovich, S. D.; Traynham, J. G. J. Org. Chem. 1973, 38, 873.
The authors declare no competing financial interest.
(24) (a) Hughes, E. D.; Ingold, C. K.; Martin, R. J. L.; Meigh, D. F.
Nature 1950, 166, 679. (b) Doering, W. v. E.; Zeiss, H. H. J. Am.
Chem. Soc. 1953, 75, 4733.
ACKNOWLEDGMENTS
■
This work was supported by an ADI grant from TSRI and a
very generous donation of equipment and supplies from
Exelixis. We thank the Baran lab for use of their microwave
reactor and the Yu lab for use of their LCMS.
(25) Winstein, S.; Clippinger, E.; Fainberg, A. H.; Heck, R.;
Robinson, G. C. J. Am. Chem. Soc. 1956, 78, 328.
(26) Ferraris, D.; Drury, W. J., III; Cox, C.; Lectka, T. J. Org. Chem.
1998, 63, 4568.
(
27) For examples of asymmetric Danishefsky Diels−Alder reactions
with alkene dienophiles, see: Sudo, Y.; Shirasaki, D.; Harada, S.;
Nishida, A. J. Am. Chem. Soc. 2008, 130, 12588. Hiraoka, S.; Harada,
S.; Nishida, A. J. Org. Chem. 2010, 75, 3871.
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dx.doi.org/10.1021/ja310129b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX