Published on Web 01/11/2007
Total Synthesis of (+)-Nakadomarin A
Ian S. Young and Michael A. Kerr*
Contribution from the Department of Chemistry, UniVersity of Western Ontario,
London, Ontario N6A 5B7, Canada
Received November 10, 2006; E-mail: makerr@uwo.ca
Abstract: The total synthesis of (+)-nakadomarin A is described. A three-component cycloaddition of a
hydroxylamine, aldehyde, and cyclopropane to form a highly functionalized tetrahydro-1,2-oxazine serves
as the foundation for this synthesis. The resulting oxazine is formed as a single diastereomer with the
absolute configuration being dictated by the chirality of the cyclopropane. Other key steps include:
desymmetrization of a malonate by reduction, Heck cyclization and pyrrolidine formation, and ring-closing
metathesis to form both cycloalkenes. Overall, the synthesis required 23 linear steps from the cyclopropane,
which in turn is available (six steps) in optically pure form from commercially available D-mannitol.
Introduction
The manzamines represent one of the most architecturally
beautiful classes of alkaloids and have presented the synthetic
chemist with a formidable challenge.1 Nakadomarin A (Figure
1), isolated by Kobayashi from an Okinawan sea sponge in
1997,2 is unique, as it is the only known member of the
manzamine family to contain a furan ring. Kobayashi has
postulated that ircinal is a common intermediate in the biosyn-
thesis of both nakadomarin A2 and the manzamines,3 although
the route to nakadomarin A is much less obvious. Nakadomarin
A contains a range of potentially useful bioactivities (anticancer,
antifungal, and antibacterial), but the limited availability of
natural material (6 mg isolated from 1 kg of wet sponge) has
prohibited further screening.2
In addition to the potentially useful biological activities,
nakadomarin A appeals to us as synthetic chemists due to its
unique and demanding structure. The tetracyclic core consists
of an angularly fused 6/5/5/5 ring system (containing three
different heterocycles) and is flanked with fused 8-membered
and bridging 15-membered rings. The tetracyclic core contains
4 stereogenic carbons including an all-carbon stereocenter. The
intrigue of nakadomarin A has not gone unnoticed in the
synthetic community, and several model studies have been
reported.4 Only recently has Nishida reported syntheses of both
Figure 1. Nakadomarin A and related manzamines.
the unnatural and the natural enantiomers.5 Herein, we present
a concise and efficient asymmetric synthesis of nakado-
marin A.
In 2003, we reported that nitrones 1 react with cyclopro-
panediesters 2 under the influence of Yb(OTf)3 to form highly
functionalized tetrahydro-1,2-oxazines 3, as single regioisomers
and diastereomers (dr > 15:1 3,6-cis).6a The initial publication
was followed by an improved protocol in which the nitrone is
generated in situ from a hydroxylamine and aldehyde.6b This
three-component procedure greatly increased the substrate scope
of this methodology and allowed for the incorporation of a wide
variety of substituents. Because of the limited number of natural
products that contain the oxazine motif (phyllantidine and the
FR900482 family being the most well-known examples), a
methodology to convert the oxazine ring to a more prevalent
heterocycle was developed.7 Through reductive cleavage of the
nitrogen-oxygen bond of 4 and treatment of the resulting
aminoalcohol 5 with MsCl, pyrrolidines 6 bearing a 2,5-trans
relationship were produced (Scheme 1).7 Examination of the
natural product literature revealed that nakadomarin A contains
the exact substitution pattern (2,5-trans relationship and qua-
ternary center) present in the pyrrolidines generated by this
methodology.
(1) Total syntheses of ircinal A and related manzamines: (a) Winkler, J. D.;
Axten, J. M. J. Am. Chem. Soc. 1998, 120, 6425. (b) Martin, S. F.;
Humphrey, J. M.; Ali, A.; Hillier, M. C. J. Am. Chem. Soc. 1999, 121,
866. For a comprehensive review on the manzamine alkaloids: Hu, J.-F.;
Hamann, M. T.; Hill, R.; Kelly, M. Alkaloids 2003, 60, 207.
(2) (a) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem.
1997, 62, 9236. (b) Kobayashi, J.; Tsuda, M.; Ishibashi, M. Pure Appl.
Chem. 1999, 71, 1123.
(3) Kondo, K.; Shigemori, H.; Kikuchi, Y.; Ishibashi, M.; Sasaki, T.; Kobayashi,
J. J. Org. Chem. 1992, 57, 2480.
(4) (a) Nilson, M. G.; Funk, R. L. Org. Lett. 2006, 8, 3833. (b) Ahrendt,
K. A.; Williams, R. M. Org. Lett. 2004, 6, 4539. (c) Leclerc, E.; Tius,
M. A. Org. Lett. 2003, 5, 1171. (d) Magnus, P.; Fielding, M. R.; Wells,
C.; Lynch, V. Tetrahedron Lett. 2002, 43, 947. (e) Fu¨rstner, A.; Guth, O.;
Duffels, A.; Seidel, G.; Liebl, M.; Gabor, G.; Mynott, R. Chem.-Eur. J.
2001, 7, 4811. (f) Nagata, T.; Nishida, A.; Nakagawa, M. Tetrahedron
Lett. 2001, 42, 8345. (g) Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel, G.
J. Am. Chem. Soc. 1999, 121, 11108.
(5) (a) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003, 125,
7484. (b) Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed.
2004, 43, 2020.
(6) (a) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023. (b)
Young, I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139.
(7) Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953.
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10.1021/ja068047t CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 1465-1469
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