Stereoselective reduction of α-bromopenicillanates by tributylphosphine

Article abstract of DOI:10.1021/ol000185e

Diastereoselective reduction of 6-bromo-6-substituted penicillanate esters has been achieved by treatment with tributylphosphine to give 6-substituted penicillanate esters. This reaction would appear to proceed through a phosphonium β-lactam enolate speci

Full text of DOI:10.1021/ol000185e

ORGANIC
LETTERS
2000
Vol. 2, No. 18
2889-2892
Stereoselective Reduction of
r-Bromopenicillanates by
Tributylphosphine
Akihiro Ishiwata, Lakshmi P. Kotra, Kazuyuki Miyashita, Tsuyoshi Nagase, and
Shahriar Mobashery*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan 48202-3489
som@mobashery.chem.wayne.edu
Received July 12, 2000
ABSTRACT
Diastereoselective reduction of 6-bromo-6-substituted penicillanate esters has been achieved by treatment with tributylphosphine to give
6-substituted penicillanate esters. This reaction would appear to proceed through a phosphonium â-lactam enolate species, followed by a
diastereoselective protonation. This method has the advantage of being simple to carry out and it is mild, gives high diastereoselectivity, and
should tolerate a number of functional groups in the substrates. Implications of these observations are discussed.
We have described recently the use of 6R-hydroxyalkyl-
penicillanates as effective mechanism-based inhibitors for
class A â-lactamases, the most common bacterial resistance
enzymes for â-lactam antibiotics.1-4 These molecules acylate
the active site serine of these drug resistance enzymes readily,
and the 6R-hydroxyalkyl moiety of the acyl-enzyme species
becomes poised to prevent the travel of the hydrolytic water
to the ester carbonyl, resulting in a considerable longevity
to the species, which accounts for enzyme inhibition.
Furthermore, carbapenem antibiotics possess the 6R-1R-
hydroxyethyl moiety, which renders them resistant to the
action of â-lactamases.5 Recent findings indicate that the
pocket where the hydrolytic water fits in the active sites of
class A â-lactamases has undergone some evolutionary
restructuring to give rise to a novel group of these enzymes
which are capable of turning over the carbapenem antibiot-
ics.3,6,7 Therefore, there is considerable interest in 6R-
hydroxyalkylpenicillanates, and we are currently in the
process of investigating the properties of a series of these
inhibitors with different 6R-hydroxyalkyl groups in inhibition
of â-lactamases.
R,R-Dibromopenicillanate ester 11,8 is conveniently con-
verted to derivatives 2 and 3.1,9 A good approach for
syntheses of 6-substituted penicillanates is reduction of
R-bromo-â-lactams (Scheme 1). This type of reductive
Scheme 1
(1) Miyashita, K.; Massova, I.; Taibi, P.; Mobashery, S. J. Am. Chem.
Soc. 1995, 117, 11055-11059.
(2) Maveyraud, L.; Massova, I.; Birck, C.; Miyashita, K.; Samama, J.
P.; Mobashery, S. J. Am. Chem. Soc. 1996, 118, 7435-7440.
(3) Mourey, L.; Miyashita, K.; Sware´n, P.; Bulychev, A.; Samama, J.
P.; Mobashery, S. J. Am. Chem. Soc. 1998, 120, 9383-9385.
(4) Golemi, D.; Maveyraud, L.; Vakulenko, S.; Tranier, S.; Ishiwata,
A.; Kotra, L. P.; Samama, J. P.; Mobashery, S. J. Am. Chem. Soc. 2000,
122, 6132-6133.
(5) Hashizume, T.; Yamaguchi, A.; Hirata, T.; Sawai, T. Antimicrob.
Agents Chemother. 1984, 25, 149. Kropp, H.; Gerckens, L.; Sundelof, J.
G.; Kahan, F. M. ReV. Inf. Dis. 1985, 7, Suppl 3, S389.
10.1021/ol000185e CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/17/2000

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.
2890
Org. Lett., Vol. 2, No. 18, 2000

â-lactam enolates in methanol. However, the reason for the
diastereoselectivity has not been made clear, although it
would appear to be influenced by both electrostatic17 and
steric factors. The favorable electrostatic contribution to the
reaction applies in the case of the small electrophile, when
it would approach from the more electron rich â-face of
enolate. However, when a bulkier electrophile is used, this
trajectory for approach is not possible because of consider-
able steric encumbrance. The computational model for the
structure of compound 6 (Figure 1) shows that there is an
Table 1. Reaction of Tributylphosphine in Methanol with
6-Bromopenicillanate Ester Derivatives
compd
R1
R
yield/% ratio (R:â)
4c
4d
4e
4a
4b
4f
(R)-CH3CH(OH)
(R)-CH3CH2CH(OH) p-NO2Bn
(CH3)2C(OH)
CH2OH
CH2OH
p-NO2Bn
95
98
93
95
95
80
(100% R)
(9.4:1)
(7.0:1)
(7.8:1)
(6.7:1)
(10:1)
p-NO2Bn
p-NO2Bn
CHPh2
CH2OTBDMS
CHPh2
penicillanate ester was obtained stereoselectively. In the case
of the 6-bromo-6-(1R-hydroxyethyl)penicillanate ester, the
reaction gave exclusively the R isomer. In addition, protection
of the hydroxyl group as a tert-butyldimethylsilyl (TBDMS)
ether in the side chain at C6 also gave 6R-substituted
penicillanate ester predominantly, without cleavage of the
TBDMS ether.
These results indicate that the reactions of both 6R- and
6â-bromopenicillanate esters with tributylphosphine must go
through the same intermediate. The effect of the size of the
alcohol (Scheme 2) suggests that the â-selective protonation
should not be an intramolecular process via the hydroxyl
groups in the various side chains at C6 but an intermolecular
one by an electrophile. Also, the outcome of the reaction
with the TBDMS ether at the C6 substituents (to give 4f),
which obviously cannot donate the proton, indicates that the
reaction mechanism involves a diastereoselective intermo-
lecular protonation by the solvent. We propose that the key
intermediate is the phosphonium â-lactam enolate 6. It has
Figure 1. Stereoview of the time-averaged structure from 85 ps
of dynamics simulations performed on the energy-minimized
species 6. The gray arrow shows the direction for â-attack at C6
and the white arrow indicates that for R-attack.
increasing steric constraint on the â-face of the compound
(indicated by the gray arrow) as the side chain at C6 varies
from hydroxymethyl to hydroxyisopropyl. Because of this
reason, when the solvent, which also serves as the proton
source for the reaction, is changed from methanol to
2-propanol to tert-butyl alcohol, the approach of the alcohol
from the â-face (for protonation) becomes less favored,
giving a diminished yield for the 6R-product. As shown in
the molecular model of compound 6 (Figure 1), the R-face
of the molecule (indicated by a white arrow) is also sterically
hindered, although to a lesser extent than the corresponding
â-face (due to the bulk at the C6 substituent). Hence, the
approach of a bulky proton donor such as tert-butyl alcohol
from either the R- or â-face of 6 will be difficult, but less
so in the former case. This effect translates into a low yield
for the reaction with bulkier proton donors but gives
considerably greater selectivity for the formation of the 6â-
hydroxyalkylated penicillanate product.
previously been reported that several types of â-lactam
enolates (e.g., lithium, sodium, magnesium, and zinc) can
be generated,9,11,16 and when treated with an electrophile (e.g.,
carbonyl compounds or proton), the addition occurred
predominantly from the â-face. These findings are consistent
with our results for the reaction of tributylphosphonium
We have shown in this Letter that the tributylphosphine-
mediated reduction of 6-bromo-6-substituted penicillanate
esters gives diastereoselectivity that can be controlled to give
the predominance of one isomer over the other on the basis
(16) For examples, see: (a) Durst, T.; LeBelle, M. J. Can. J. Chem.
1972, 50, 3196-3201. (b) Kuhlein, K.; Jensen, H. Liebigs Ann. Chem. 1974,
369-402. (c) Durst, T.; Van Den Elzen, R.; Legault, R. Can. J. Chem.
1974, 52, 3206-3208. (d) Mukerjee, A. K.; Singh, A. K. Synthesis 1975,
547-589.
(17) Karn, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W. J. J. Am.
Chem. Soc. 1987, 109, 650-663.
Org. Lett., Vol. 2, No. 18, 2000
2891

of the reaction conditions. This reduction is excellent for
the preparation of 6R-substituted penicillanate esters from
6R-bromopenicillanates. The likely intermediate for this
reaction is the tributylphosphonium â-lactam enolate, which
is readily protonated from the â-face. The protonation occurs
from this face mainly because of the electrostatic interaction
between the intermediate and proton donor, a process that
is influenced by the size of the latter. This method has the
advantage of being simple to carry out and it is mild, gives
high diastereoselectivity, and should tolerate a number of
functional groups in the substrates. We have also provided
a mechanistic and structural rationale for the outcome of the
reactions. This reaction and the principles delineated herein
for its diastereoselectivity should find applications in other
systems in the immediate future.
Acknowledgment. This research was supported by the
National Institutes of Health.
Supporting Information Available: Experimental pro-
cedures, characterization of compounds 2b, 3b, 2d, 3f, 4b,
5b, 4d, and 4f, and computational protocol. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL000185E
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Org. Lett., Vol. 2, No. 18, 2000