extreme case, where R3 ) H, gave better yields (54-87%).
An X-ray crystallographic analysis of a single crystal
structure of a diazoketone (R1 ) Bn, R2 ) Boc, and R3 )
H) clearly indicated that the migrating group is anti to the
diazo group, which should favor the Wolff rearrangement.
In contrast, when R3 ) Bn, a group which is sterically larger
than H and Me, the Wolff rearrangement reaction gave a
complex mixture at various temperatures, suggesting that the
predominant population is rotomer B, which is less inclined
toward the Wolff rearrangement reactions8 (Scheme 3). The
fact that a higher yield can be obtained at a higher
temperature6 implies the relative ease of rotation of the diazo
group around the C1-C2 bond at higher temperatures
(Scheme 3).7
The ketenes generated from the Wolff rearrangement
reactions are trapped with electrophiles to give the desired
products. It is at this stage that a new chiral center is created.
It is most likely that an intermediate ketene hemiacetal is
generated9 and then tautomerized to the final product
(Scheme 3). We tentatively assume that the most stable
conformation of the transition state of tautomerization is the
one resembling the lowest energy conformation of the final
product, as shown in Scheme 4.10,11 The proton may approach
the larger R1, R2, and R3, the higher the diastereomeric ratio
is. Furthermore, R4 points away from the R1 and R2 groups
and consequently imposes much less influence on the
prochiral center than R1 and R2 do. The model we have
proposed here is in harmony with the experimental results
obtained so far.
In summary, we have developed a novel method to extend
one carbon atom with concomitant introduction of one chiral
center using the Wolff rearrangement reaction. The new
chiral center is controlled by the chiral resident group in the
molecules. The stereochemistry of the reactions could also
potentially be controlled by chiral auxiliaries4a,12 and chiral
ligands.4a The results of these efforts will be reported in due
course. In short, the methodology described in this Letter is
complementary to existing methods13,14 and will find a variety
of applications in synthetic organic chemistry and medicinal
chemistry.
Acknowledgment. We thank Dr. D. Delorme and Profes-
sor S. Hanessian for helpful discussions, Dr. R. Schmidt for
HPLC analysis, Dr. M. Simard for X-ray crystallographic
analyses, and the Industrial NSERC Fellowships to K.F. and
C.S.
Supporting Information Available: Experimental pro-
cedures, characterization data, chemical correlations, X-ray
structures, and the temperature effects. This information is
Scheme 4
OL006146K
(10) Solution NMR studies and a single-crystal X-ray crystallography
analysis6 suggest that the most likely lowest energy conformation of the
anti product is the one as shown in Scheme 4.
(11) Molecular modeling studies of the ketene hemiacetal and the anti
and syn products suggest that the most likely transition state may be the
one resembling the lowest energy conformation of the final product, as
shown in Scheme 4, i.e., a later-transition state. The molecular modeling
studies were performed using a Sybyl software package, version 6.0, with
a SiliconGraphics workstation.
from one side of the ketene hemiacetal such that the strain
between R1 and R3, as well as between R2 and R3 could be
released to the maximum extent in the transient state. Hence,
(12) For trapping of ketenes generated from acid chlorides, with chiral
alcohols to control the stereochemistry, see: Larsen, R. D.; Corley, E. G.;
Davis, P.; Reider, P. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111,
7650.
(13) For recent reviews on synthesis of â-amino acids, see: (a) Cole,
D. Tetrahedron 1994, 50, 9517. (b) Enders, D.; Beltray, W.; Raabe, G.;
Runsink, J. Synthesis 1994, 1322.
(14) For a stereoselective synthesis of R-alkylated-â-amino acid deriva-
tives using anionic chemistry, see: Podlech, J.; Seebach, D. Liebigs Ann.
1995, 1217, and references therein. For a stereoselective synthesis of
R-alkylated-â-amino acid derivatives using free radical chemistry, see:
Hanessian, S.; Yang, H.; Schaum, R. J. Am. Chem. Soc. 1996, 118, 2507,
and references therein.
(7) Kaplan, F.; Meloy, G. K. J. Am. Chem. Soc. 1966, 88, 950.
(8) For discussion of the effects of conformation on Wolff rearrangement,
see: (a) Bartz, W.; Regitz, M. Chem. Ber. 1970, 103, 1463. (b) Kaplan, F.;
Mitchell, M. L. Tetrahedron Lett. 1979, 9, 759. (c) Tomioka, H.; Okuno,
H.; Izawa, Y. J. Org. Chem. 1980, 45, 5278. (d) Tomioka, H.; Kondo, M.;
Izawa, Y. J. Org. Chem. 1981, 46, 1090. (e) Toscano, J. P.; Platz, M. S.;
Nikolaev, V.; Popik, V. J. Am. Chem. Soc. 1994, 116, 8146. (f) Wang,
J.-L.; Toscano, J. P.; Platz, M. S.; Nikolaev, V.; Popik, V. J. Am. Chem.
Soc. 1995, 117, 5477. See also ref 3b.
(9) For some recent discussions about the regioselectivity of additions
to ketenes, see: (a) Sung, K.; Tidwell, T. T. J. Am. Chem. Soc. 1998, 120,
3043. (b) Allen, A. D.; Tidwell, T. J. Org. Chem. 1999, 64, 266.
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