SCHEME 1
SCHEME 2
Having (+)-9 in good quantities in hand, we next investigated
its conversion to 8 (Scheme 2). Bromohydrine formation with
NBS in water followed by oxidation smoothly gave rise to the
R-bromo ketone 10 in 62% yield (2 steps). Utilizing the well-
known process of rapid ring opening of cyclopropylmethyl
radicals, upon treatment of 10 with tributyltin hydride, 8 was
rapidly obtained in excellent yield (94%) by the exclusive fission
of the exocyclic cyclopropane bond. Unfortunately, the optical
purity of 8 was somewhat reduced (91% ee) compared to the
starting material. In the same way, (ent)-8 is obtained from (-)-
9. Alternatively, the transformation of (+)-9 to 8 could also be
achieved with Et3B/O2, however, in this case the results were
inferior (65% yield, 71% ee).
8 appears to be considerably more stable compared to 7: it
can be stored at -20 °C over months with no epimerization or
isomerization being observed, and even upon standing in
solution (CH2Cl2) for several hours at room temperature, no
loss of optical purity is observed. A broad variety of function-
alizations can be performed (Scheme 3) with 8, such as the
conjugate addition of nucleophiles with or without the combina-
tion of trapping the resulting enolate with electrophiles, cy-
cloadditions, hydrogenations, or dihydroxylations. For all
transformations, complete anti selectivity was observed. How-
ever, reactions carried out with basic reagents gave rise to some
erosion of the stereochemistry, which could be remedied by a
recrystallization of some of the products. This complication was
especially severe in the addition of 2-nitropropane in the
presence of DBU, for which 17 was only obtained in racemic
form. Apparently, under basic conditions at room temperature
(20 °C) for several hours R-deprotonation and thus racemization
of 8 occurs.
inexpensive heteroarenes,11 we have been able to synthesize as
a starting point for â-aminocyclopropanecarboxylic acids12 the
bicyclic adduct 9,13,14 enantiomerically pure in either form, by
cyclopropanation of N-Boc-pyrrole, followed by enzymatic
resolution14. However, the latter step was not amenable to
accessing optically pure 9 on a large scale, making an alternative
desirable. Unfortunately, we were not able to render the
cyclopropanation of pyrrole with diazaoacetates asymmetric by
employing a suitable chiral catalyst, in contrast to the use of
furans as starting materials.15 However, we discovered that
(rac)-9 can be separated in its enantiomers by simulated moving
bead (SMB) chromatography,16 having cellulose-tris-(3,5-dim-
ethylphenylcarbamate) Chiralcel OC (20 µm) as the stationary
phase, with extraordinary productivity (separation of 1958 g of
(rac)-9/kg stationary phase and day). The SMB chromatography
was performed on a 160 g scale with ethanol as an eluent and
with a feed concentration of 20 g/L to provide (+)-9 (73 g,
99.8% ee) and (-)-9 (75 g, 98.3% ee), along with 6 g of
recovered (rac)-9 (Scheme 1).
(6) van der Deen, H.; Cuipier, A. D.; Hof, R. P.; van Deveren, A.;
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643. (b) Gnad, F.; Polschak, M.; Reiser, O. Tetrahedron Lett. 2004, 45,
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Org. Lett. 2003, 5, 941. (d) Chhor, R. B.; Nosse, B.; So¨rgel, S.; Bo¨hm, C.;
Seitz, M.; Reiser, O. Chem.sEur. J. 2003, 9, 260.
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As a further application, the conversion of (ent)-8 into the
pharmacologically active (S)-enantiomer17 of Vigabatrin18 could
be demonstrated (Scheme 4), which is being commercialized
as Sabril in racemic form for the treatment of epilepsy.19
Conjugate reduction of the enone (ent)-8, followed by N-Boc
deprotection, afforded 18,20 which could be recrystallized to
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Reiser, O. J. Org. Chem. 2000, 65, 8960.
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M.; Bo¨hm, C.; Seitz, M.; Reiser, O. Tetrahedron: Asymmetry 2003, 14,
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(18) (a) Trost, B. M.; Bunt, R. C.; Lemoine, R. C.; Calkins, T. L. J. Am.
Chem. Soc. 2000, 122, 5968. (b) Chandrasekhar, S.; Mohapatra, S.
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Z. Y.; Knaus, E. E. Tetrahedron 1994, 50, 5569. (e) Wey, Z. Y.; Knaus, E.
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J. Org. Chem. 1992, 57, 6169.
(16) For recent applications of this technique, see: (a) Garcia, A. L. L.;
Carpes, M. J. S.; de Oca, A. C. B. M.; dos Santos, M. A. G.; Santana, C.
C.; Correia, C. R. D. J. Org. Chem. 2005, 70, 1050. (b) McCoy, M. Chem.
Eng. News 2000, 78 (June 19), 17.
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1211. (b) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773.
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2174 J. Org. Chem., Vol. 71, No. 5, 2006