chemistry may be achieved by the use of tributytin hydride,10
zinc-mediated reduction,9,11 or hydrogenolysis over Pd-C.12
These reactions afford the desired products; however, they
go through relatively harsh conditions, often give poor yields,
and suffer from low stereoselectivity. In the present report
we disclose a convenient and stereoselective reduction of
R-bromo-6-hydroxyalkylpenicillanates by tributylphosphine,
a reaction that affords the corresponding debrominated
â-lactams in good yields. We provide mechanistic insight
into the stereoselectivity that is found in this reaction.
Scheme 2
Reduction of R-bromocarbonyl compounds with triph-
enylphosphine in a protic solvent, such as methanol, is a
useful and convenient reaction.13 Chern and co-workers have
reported that in the case of either benzyl or allyl R-bromo-
penicillanate reduction with tributylphosphine in methanol
gave the corresponding penicillanate esters without loss of
the ester moiety.14 Our previous investigation of the reduction
of 6R-bromo-6â-(hydroxylmethyl)penicillanate (2a) with
tributylphosphine in methanol1 suggested that this reaction
would provide the desired â-lactam derivatives under mild
conditions. The use of tributylphosphine in methanol resulted
predominantly in the stereoselective formation of 6R-
(hydroxylmethyl)penicillanate (4a), with inversion of ster-
eochemistry.
ester (4b) predominantly (0 °C for 30 min).15 However, the
use of triphenylphosphine, even at room temperature for 6
h, gave no reaction. A likely explanation here is that
tributylphosphine is a more nucleophilic reagent than tri-
phenylphosphine, since the model for the reactive intermedi-
ate (vide infra) does not implicate sterics as a likely reason
for this large difference. The reaction with tributylphosphine
was then carried out in 2-propanol and in tert-butyl alcohol
(Scheme 2). In contrast to the case in methanol, the reaction
of 2b with tributylphosphine in 2-propanol gave a predomi-
nance of ester 5b over 4b (2.3:1). Treatment in a bulkier
solvent, tert-butyl alcohol, improved the ratio of 5b over 4b
(3.9:1). However, as stereoselectivity improved in favor of
5b as the size of the alcohol increased from 2-propanol to
tert-butyl alcohol, the yield suffered. The reaction in tert-
butyl alcohol did not go to completion. It is interesting to
note that treatment of the epimeric 6â-bromo-6R-(hydroxyl-
methyl)penicillanate ester 3b with tributylphosphine in
methanol gave the 6R-substituted penicillanate ester in nearly
the same ratio of isomers as that for the reaction with 6R-
bromopenicillanate (Scheme 2). The reduction of 3b took
place with retention of stereochemistry, which was opposite
to the case of the reduction of 2b in methanol.
We have investigated the scope of this reaction further
(Scheme 2). The reaction of 2b with tributylphosphine in
methanol gave the corresponding 6R-substituted penicillanate
(6) Rasmussen, B. A.; Bush, K. Antimicrob. Agents Chemother. 1997,
41, 223-232.
(7) Bush, K.; Mobashery, S. How â-Lactamases Have Driven Pharma-
ceutical Drug Discovery: from Mechanistic Knowledge to Clinical
Circumvention. In ResolVing the Antibiotic Paradox: Progress in Under-
standing Drug Resistance and DeVelopment of New Antibiotics; Rosen, B.
P., Mobashery, S., Eds.; Plenum Press: New York, 1998; pp 71-98.
(8) (a) Clayton, J. P. J. Chem. Soc. C 1969, 2123-2127. (b) Sacripante,
G.; Just, G. J. Org. Chem. 1987, 52, 3659-3661.
(9) For examples, see: (a) Yoshida, A.; Hayashi, T.; Takeda, N.; Oida,
S.; Ohki, E. Chem. Pharm. Bull. 1981, 10, 2899-2909. (b) Leanza, W. J.;
DiNinno, F.; Muthard, D. A.; Wilening, R. R.; Wildonger, K. J.; Ratcliffe,
R. W.; Christensen, B. G. Tetrahedron 1983, 39, 2505-2513. (c) Fujimoto,
K.; Iwano, Y.; Hirai, K.; Sugawara, S. Chem. Pharm. Bull. 1986, 34, 999-
1014.
The results of the reaction of tributylphosphine in methanol
with a number of 6-bromopenicillanate ester derivatives are
summarized in Table 1. In all cases, the R-substituted
(10) For examples, see: (a) Ziegler, C. B., Jr.; Fields, T. L. Tetrahedron
1993, 49, 3919-3932. (b) Hanessian, S.; Alpegiani, M. Tetrahedron 1989,
45, 941-950. (c) Foulds, C. D.; Kosmirak, M.; Sammes, P. G. J. Chem.
Soc., Perkin. Trans. 1 1985, 963-968. (d) Hirai, K.; Iwano, Y.; Fujimoto,
K. Tetrahedron Lett. 1982, 23, 4021-4024.
(11) For examples, see: (a) DiNinno, F.; Beattie, T. R.; Christensen, B.
G. J. Org. Chem. 1977, 42, 2960-2965. (b) Quallich, G. J.; Bordner, J.;
Elliott, M. L.; Morrissey, P.; Volkmann, R. A.; Wroblewska-Adams, M.
M. J. Org. Chem. 1990, 55, 367-370. (c) Altamura, M.; Bedeschi, A.;
Marchi, M.; Visentin, G.; Francalanci, F. Heterocycles 1991, 32, 1671-
1679.
(13) (a) Borowitz, I. J.; Brossman, L. I. Tetrahedron Lett. 1962, 471-
474. (b) Borowitz, I. J.; Virkhaus, R. J. Am. Chem. Soc. 1963, 85, 2183-
2184. (c) Borowitz, I. J.; Kibby, K. C.; Virkhaus, R. J. Org. Chem. 1966,
42, 4031-4037.
(14) Chern, J.-W.; Huang, M.; Tien J-H.; Pai, S.-H. Heterocycles 1988,
27, 1349-1351.
(15) Typical experimental procedure: Tri-n-butylphosphine (95%, 332
µL, 1.27 mmol) was added to a solution of bromide 3b (386 mg, 0.810
mmol) in methanol (20 mL) at 0 °C, and the reaction mixture was stirred
for 30 min. After concentration under reduced pressure, the residual oil
was purified by silica gel column chromatography using a gradient solvent
system (hexane/ethyl acetate ) 10/1 to 5/1 to 1/1 to 1/3) to give a mixture
of the two isomers (307 mg, 95%). The ratio was determined by 1H NMR
of the crude product (R:â ) 6.7:1).
(12) For examples, see: (a) Girijavallabhan, V. M.; Ganguly, A. K.;
McCombie, S. W.; Pinto, P.; Rizvi, R. Tetrahedron Lett. 1981, 22, 3485-
3488. (b) Rossi, R. L.; Kapilani, L. V.; Morrissey, P.; Retsema, J. A. J.
Med. Chem. 1990, 33, 291-297.
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Org. Lett., Vol. 2, No. 18, 2000