Angewandte
Chemie
with respect to the other three pairs. Thus, when analyzed in
conjunction with optical rotation or chiral-phase chromatogra-
phy, one isomer from each of the diastereomeric pairs (that is, a
total of four) contains the minimum stereoarrayneeded to
establish the relative and absolute configuration of FR252921.
[8] Available NMR spectroscopic data were most consistent with an
anti configuration of the methyl and hydroxy groups at C12 and
C13.
[9] The 4-amino-(3R)-hydroxy-(2S)-methylbutanoyl subunit occurs
in other bioactive natural products; see, for example: D. Amans,
V. Bellosta, J. Cossy, Angew. Chem. 2006, 118, 6002 – 6004;
Angew. Chem. Int. Ed. 2006, 45, 5870 – 5874.
[10] For an alternative synthesis of 2 and its Z,E isomer, see: B. B.
Snider, T. Liu, J. Org. Chem. 2000, 65, 8490 – 8498.
[11] The CrCl2 methodologyproved impractical logisticallyon a
large scale. Wittig olefination with commercial 2-(triphenyl-
phosphoranylidene)propionaldehyde furnished an 8:1 mixture
of E and Z isomers in moderate yield.
[12] S.-i. Fukuzawa, H. Matsuzawa, S.-i. Yoshimitsu, J. Org. Chem.
2000, 65, 1702 – 1706.
[13] Z. Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian, R. A.
Widenhoefer, J. Am. Chem. Soc. 2006, 128, 9066 – 9073.
[14] B. Liang, T. Novak, Z. Tan, E. Negishi, J. Am. Chem. Soc. 2006,
128, 2770 – 2771.
Scheme 6. Diastereomers of FR252921.
[15] J. P. Wolfe, R. A. Singer, B. H. Yang, S. L. Buchwald, J. Am.
Chem. Soc. 1999, 121, 9550 – 9561.
[16] D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981, 103,
2127 – 2129.
[17] M. J. Schnermann, F. A. Romero, I. Hwang, E. Nakamaru-
Ogiso, T. Yagi, D. L. Boger, J. Am. Chem. Soc. 2006, 128, 11799 –
11807.
[18] M. Reggelin, B. Junker, T. Heinrich, S. Slavik, P. Buehle, J. Am.
Chem. Soc. 2006, 128, 4023 – 4034.
[19] K. Iseki, S. Oishi, Y. Kobayashi, Tetrahedron 1996, 52, 71 – 84.
[20] Retention of the silyl protecting group on the hydroxy group at
C13 improved the yield of the macrolactonization significantly
(50–55%). Regrettably, desilylation of the macrocycle (for
example, with HF, HF/pyridine, nBuN4F, nBu4NF/HOAc, pyr-
idinium p-toluenesulfonate) after lactonization engendered a
host of complications, including intra/intermolecular Michael
addition, b elimination, trans lactonization, and, most notably, a
facile E/Z isomerization of the triene.
melting point and optical rotation. Thus, we established that
FR252921 has the configuration 12S,13R,18R.[1]
Received: January24, 2007
Published online: May8, 2007
Keywords: configuration determination ·immunosuppressants ·
.
macrocycles · natural products · total synthesis
[1] K. Fujine, M. Tanaka, K. Ohsumi, M. Hashimoto, S. Takase, H.
Ueda, M. Hino, T. Fujii, J. Antibiot. 2003, 56, 55 – 61. The
1H NMR spectrum of FR252921 appears to have been recorded
in [D6]dimethyl sulfoxide rather than in CD2Cl2.
[2] Presented in part at the 229th American Chemical Society
National Meeting, San Diego, CA, March 13 – 17, 2005, ORGN
abstract 417.
[21] A. B. Jones, A. Villalobos, R. G. Linde, S. J. Danishefsky, J. Org.
Chem. 1990, 55, 2786 – 2797.
[22] For a review on macrolactonization, see: A. Parenty, X. Moreau,
J.-M. Campagne, Chem. Rev. 2006, 106, 911 – 939.
[23] Among the manyprocedures attempted, those described in the
following articles also proved unsatisfactory: a) O. Mitsunobu,
Synthesis 1981, 1 – 28; b) E. J. Corey, K. C. Nicolaou, J. Am.
Chem. Soc. 1974, 96, 5614 – 5616; c) Y. Oohashi, K. Fukumoto, T.
Mukaiyama, Bull. Chem. Soc. Jpn. 2005, 78, 1508 – 1519; d) J.
Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull.
Chem. Soc. Jpn. 1979, 52, 1989 – 1993.
[3] For the purported synthesis of the 12R,13R,18R diastereomer
(numbering as in Scheme 1), see: S. Yu, F. Liu, D. Ma,
Tetrahedron Lett. 2006, 47, 9155 – 9157. However, the NMR
spectroscopic data are consistent with a Z isomer of the triene
unit (see reference [20]).
[4] For a nonstereoselective, biogenic synthesis from pseudotrienic
acid A, see: A. Pohanka, A. Broberg, M. Johansson, L. Kenne, J.
Levenfors, J. Nat. Prod. 2005, 68, 1380 – 1385.
[5] K. Fujine, F. Abe, N. Seki, H. Ueda, M. Hino, T. Fujii, J. Antibiot.
2003, 56, 62 – 67.
[6] K. Fujine, H. Ueda, M. Hino, T. Fujii, J. Antibiot. 2003, 56, 68 –
71.
[24] I. Shiina, M. Kubota, R. Ibuka, Tetrahedron Lett. 2002, 43, 7535 –
7539.
[7] There are four possible enantiomeric pairs that correspond to
the structural formula of FR252921. Each pair is diastereomeric
Angew. Chem. Int. Ed. 2007, 46, 4527 –4529
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