C O M M U N I C A T I O N S
be optimal, providing the desired glycoside 7 in 62% isolated yield
(R:â ) 1:6).15 Subsequent cleavage of the tert-butyl ester with
trifluoroacetic acid followed by saponification of the residual acetate
with NH3/MeOH leads to hydroxy acid 8 in 74% yield over both
steps and sets the stage for the envisaged cyclodimerization reaction.
In line with our expectations, this macrocyclization is highly
responsive to admixed alkali metal cations. While exposure of
compound 8 to 2-chloro-1,3-dimethylimidazolinium chloride16 and
DMAP in CH2Cl2 (0.02 M) at 0 °C in the absence of any further
additive furnished a mixture of cyclic monomer (28%), the desired
cyclic dimer 9 (37%), and several other oligomeric products (35%),
the addition of KH led not only to an increased reaction rate but
also to a significant improvement of the product distribution in favor
of 9. Under optimized conditions, product 9 is obtained in 71%
isolated yield. Since the effect exerted by NaH or Cs2CO3 is much
less pronounced,12 this outcome is deemed to reflect the ability of
the K+ cation to preorganize the cyclization precursor for directed
macrodilactonization. Importantly, this convergent approach is
inherently flexible and favorably compares with the previously
published route7 to a more truncated version of the cycloviracin
core in all relevant respects.
The NMR spectra of 9, the deprotected compound 10, and the
unsymmetrical derivative 11 (R1 * R2) match those reported for
1, suggesting that the absolute stereochemistry of cycloviracin B
is (3R,3′R). To corroborate this notion, the analogous (3S,3′S)-
configured lactide 12 was prepared following the same sequence
of reactions (the required aglycone (S)-5 is easily obtained by
Noyori reduction of 4 using (S)-BINAP as the ligand).11 Notably,
the spectral data of 12 are significantly altered, with the high-field
shift of the anomeric C-atoms at δ ) 100.3 ppm being particularly
diagnostic.12 These marked shift differences between lactides 9 and
12 allow the unambiguous assignment of the stereochemistry at
the branching points in the cycloViracin core as 3R,3′R. We believe
that they also pertain to the closely related glucokinase activator
glucolipsin A 13, the anomeric center of which resonates at δ )
104.5 ppm.17 Therefore, we confidently ascribe the (3R,3′R)-
configuration to this molecule as well.
one can exclude that 2 contains a lactide unit similar to the one
found in 1 or 13, independent of whether one assumes an (R,R)-,
(S,S)-, or (R,S)-configuration at the branching points. Hence, the
structure proposed for the fattiViracins clearly needs reVision. One
possibility might be a different connectivity pattern involving an
-OH group farther down the lateral chain of the compound to form
an expanded macrolactone ring.19
Acknowledgment. Generous financial support by the DFG
(Leibniz award to A.F.), the Alexander von Humboldt-Foundation
(postdoctoral fellowship for J.M.), and the Fonds der Chemischen
Industrie is gratefully acknowledged. We thank Prof. Uyeda,
Kumamoto University, Japan, for providing a small sample of 2.
Supporting Information Available: Experimental details and full
set of NMR data (PDF). This material is available free of charge via
the Internet at http:pubs.acs.org.
References
(1) (a) Tsunakawa, M.; Komiyama, N.; Tenmyo, O.; Tomita, K.; Kawano,
K.; Kotake, C.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45, 1467. (b)
Tsunakawa, M.; Kotake, C.; Yamasaki, T.; Moriyama, T.; Konishi, M.;
Oki, T. J. Anitbiot. 1992, 45, 1472.
(2) (a) Uyeda, M.; Yokomizu, K.; Miyamoto, Y.; Habib, E.-S. E. J. Antibiot.
1998, 51, 823. (b) Yokomizo, K.; Miyamoto, Y.; Nagao, K.; Kumagae,
E.; Habib, E.-S. E.; Suzuki, K.; Harada, S.; Uyeda, M. J. Antibiot. 1998,
51, 1035. (c) Habib, E.-S. E.; Yokomizo, K.; Murata, K.; Uyeda, M. J.
Antibiot. 2000, 53, 1420.
(3) Habib, E.-S. E.; Yokomizo, K.; Nagao, K.; Harada, S.; Uyeda, M. Biosci.
Biotechnol. Biochem. 2001, 65, 683.
(4) This applies to all 13 individual fattiviracins known to date.
(5) (a) Fu¨rstner, A.; Mu¨ller T. J. Am. Chem. Soc. 1999, 121, 7814. (b) Fu¨rstner,
A.; Mu¨ller, T. J. Org. Chem. 1998, 63, 424. (c) Fu¨rstner, A.; Radkowski,
K.; Grabowski, J.; Wirtz, C.; Mynott, R. J. Org. Chem. 2000, 65, 8758.
(d) Lehmann, C. W.; Fu¨rstner, A.; Mu¨ller, T. Z. Kristallogr. 2000, 215,
114.
(6) (a) Fu¨rstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072. (b) Fu¨rstner,
A.; Konetzki, I. Tetrahedron 1996, 52, 15071.
(7) Velarde, S.; Urbina, J.; Pena, M. R. J. Org. Chem. 1996, 61, 9541.
(8) Fu¨rstner, A. In Templated Organic Synthesis; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, 2000; p 249.
(9) For our strategic goals see: Fu¨rstner, A. Synlett 1999, 1523.
(10) Shortcut synthesis: (a) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996,
61, 3942. (b) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792.
(11) Review: Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994.
(12) For details and a full set of spectral data see the Supporting Information.
(13) Wang, Y.; Mao, J.; Cai, M. Synth. Commun. 1999, 29, 2093.
(14) (a) Schmidt, R. R. Angew. Chem. 1986, 98, 213; Angew. Chem., Int. Ed.
Engl. 1986, 25, 212. (b) Schmidt, R. R.; Kinzy, W. AdV. Carbohydr. Chem.
Biochem. 1994, 50, 21.
(15) TMSOTf in CH2Cl2/MeCN provides similar results (68%, R:â ) 1:5).
(16) (a) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984. (b) See also:
Garcia, D. M.; Yamada, H.; Hatakeyama, S.; Nishizawa, M. Tetrahedron
Lett. 1994, 35, 3325.
(17) Qian-Cutrone, J.; Ueki, T.; Huang, S.; Mookhtiar, K. A.; Ezekiel, R.;
Kalinowski, S. S.; Brown, K. S.; Golik, J.; Lowe, S.; Pirnik, D. M.; Hugill,
R.; Veitch, J. A.; Klohr, S. E.; Whitney, J. L.; Manly, S. P. J. Antibiot.
1999, 52, 245.
In view of the foregoing, however, a rather puzzling situation
as to the actual structure of the fattiviracins ensues. In contrast to
the cycloviracins, which give rise to only one set of signals for
both units forming the lactide, all members of the fattiviracin family
invariably show inequivalent subunits.2,4 Although the presence of
an (3R,3′S)-configured core which might explain this phenomenon
would be highly surprising from the biosynthesis viewpoint, we
could not rigorously exclude this possibility except by synthesis.
Since a cyclodimerization approach is obviously unsuitable for this
purpose, a stepwise macrocyclization protocol had to be pursued
en route to 14 comprising a highly productive Yamaguchi macro-
lactonization as the key step.7,12,18
(18) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
The anomeric centers in the unsymmetrical lactide 14 resonate
at δ ) 104.5/99.1 ppm,12 showing that the differently configured
subunits can be reliably distinguished by NMR. These values,
however, do not correlate at all with those reported for 2. Therefore,
(19) For a patent disclosing structures relevant in this context see: Hyoda, T.;
Tsuchira, Y.; Sekine, A.; Amano, T. Jpn. Kokai Tokkyo Koho Jpn. Pat.
11246587 (1999-09-14).
JA0175791
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