Catalytic, asymmetric synthesis of β-lactams [11]

Full text of DOI:10.1021/ja001754g

J. Am. Chem. Soc. 2000, 122, 7831-7832
7831
Table 1. Diastereoselectivity in the Nucleophile-Catalyzed
Reaction of Methylphenylketene 3b with Imine 2a
Catalytic, Asymmetric Synthesis of â-Lactams
Andrew E. Taggi, Ahmed M. Hafez, Harald Wack,
Brandon Young, William J. Drury, III, and Thomas Lectka*
Department of Chemistry
Johns Hopkins UniVersity, 3400 North Charles Street
Baltimore, Maryland 21218
ReceiVed May 22, 2000
The paramount importance of â-lactams (1) to pharmaceutical
science and biochemistry has been well established.1 New chiral
â-lactams are in demand as antibacterial agents, and their recent
discovery as mechanism-based serine protease inhibitors2 has kept
interest in their synthesis at a high level.3 However, most chiral
methodology is auxiliary-based; only one catalytic, asymmetric
synthesis of the â-lactam ring system is known, affording product
in modest enantioselectivity.4 Many asymmetric auxiliary-based
â-lactam syntheses rely on the reaction of imines with ketenes, a
process that generally proceeds without a catalyst.3 We recently
accomplished a catalyzed reaction of imines and ketenes by
making the imine component non-nucleophilic, as in electron-
deficient imino ester 2a.5 In this contribution, we report the
catalytic, asymmetric reaction of imine 2a6 and ketenes 3 to
produce â-lactams diastereoselectively and enantioselectively
employing chiral nucleophilic amines as catalysts.7
a Reactions run with 10 mol% catalyst at -78 °C and allowed to
slowly warm to room temperature overnight.
catalyzed by 10 mol % bifunctional amine 4a gave a cis/trans dr
of 3/97. A significant role for the H-bond contact in 4a is sug-
gested, as the sterically similar catalyst 4b, which does not contain
a hydrogen bond donor, gave low diastereoselectivity (dr ) 34/
66). Similarly, when catalyst 4a is used in the presence of a small
quantity (10 mol %) of DMSO (a good hydrogen bond acceptor),
the diastereoselectivity also erodes (dr ) 40/60), implying an
intramolecular H-bonding role for the electrophilic amide hydro-
gen. Remarkably, when benzimidazole 4c is the catalyst, the
opposite (cis) diastereomer is highly favored (dr 98/2).
The successful development of diastereoselective amine-based
catalysts prompted us to screen optically active cinchona alkaloid
derivatives as potential enantioselective and diastereoselective
catalysts.9 The reaction of imine 2a and ketene 3a, catalyzed by
10 mol % benzoylquinine (BQ, 6a)10 affords product in toluene
at -78 °C in 20% yield and 0% ee. We found that use of THF
under similar conditions at -78 °C affords product in 35% yield
and in 70% ee; running the reaction with minimal solvent
increases the yield (92%) but annihilates enantioselectivity (0%).
The most notable discovery was made when the reaction was
run in higher dilution, (i.e., the concentration of imine, ketene,
and catalyst were reduced by a factor of 10, to 0.1, 0.1, and 0.01
mM, respectively) affording product in 99% ee in THF at -78
°C,11 although under these conditions the yield (36%) is still
modest. Similarly, although we successfully employed meth-
ylphenylketene 3b in highly diastereoselective reactions, it turned
out to be a capricious substrate in enantioselective reactions.
We then turned our attention to other, more reactive mono-
ketenes, a fact that mandates their syntheses in situ from acid
chlorides.12 This transformation presents its own problemssthe
use of amine bases as dehydrohalogenating agents generates
ammonium salts as interfering byproducts and often leaves
When imine 2a is mixed with test electrophile diphenylketene
3a, it does not react at -78 °C and only very sluggishly at higher
temperatures. However, in the presence of suitable nucleophilic
catalysts, the reaction occurs smoothly to afford rac-â-lactam 1a
in good chemical yields at room temperature (eq 1, R′ ) R′′ )
Ph). As a first step toward an asymmetric â-lactam synthesis, we
examined the diastereoselective amine catalyzed reaction. Me-
thylphenylketene 3b (R′ ) Me, R′′ ) Ph), which reacts with imine
2a to form two diastereomers (trans-1b R′ ) Ph, R′′ ) Me; cis-
1b R′ ) Me, R′′ ) Ph), was our test electrophile (Table 1). The
cis-trans diastereomeric ratio (dr) produced in the reaction of
2a and 3b catalyzed by triethylamine is about 1/1. We thought
that a catalyst containing a nucleophilic center in tandem with
an electrophilic center (e.g., a hydrogen bond donor) could
potentially rigidify a proposed activated complex and afford
products in higher dr.8 As expected, the reaction of 2a and 3b
(1) For a general review: De Kimpe, N. In ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Padwa, A.
Eds.; Pergamon: Oxford, 1996; Vol 1B, p 507.
(2) For a general account: Wilmouth, R. C.; Kassamally, S.; Westwood,
N. J.; Sheppard, R. J.; Claridge, T. D. W.; Aplin, R. T.; Wright, P. A.;
Pritchard, G. J.; Schofield, C. J. Biochemistry 1999, 38, 7989.
(3) Review: Palomo, C.; Aizpurua, J. M.; In˜aki, G.; Oiarbide, M. Eur. J.
Org. Chem. 1999, 3223, 3.
(4) (a) Davoli, P.; Moretti, I.; Prati, F.; Alper. H. J. Org. Chem. 1999, 64,
518. (b) Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111, 931.
(5) Wack, H.; Drury, W. J., III; Taggi, A. E.; Ferraris, D.; Lectka, T. Org.
Lett. 1999, 1, 1985.
(6) We have used R-imino ester 2a in the catalytic, asymmetric synthesis
of R-amino acid derivatives: (a) Drury, W. J., III; Ferraris, D.; Cox, C.; Young,
B.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 11006. (b) Ferraris, D.; Young,
B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548. Imine 2a
was first used in work by: (c) Tschaen, D. H.; Turos, E.; Weinreb, S. M. J.
Org. Chem. 1984, 49, 5058.
(7) Ring opening of â-lactams under mild conditions provides access to
various optically pure â-amino acid derivatives whose synthesis is of recent
interest, see: Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
8959.
(8) Hydrogen bond contacts have been postulated to play similar roles in
the Baylis-Hillman reaction: Ameer, F.; Drewes, S. E.; Freese, S.; Kaye, P.
T. Synth Commun. 1988, 18, 495.
(9) For other, excellent uses of cinchona alkaloids in asymmetric synthesis
see: Ester synthesis; (a) Samtleben, R.; Pracejus, H. J. Prakt. Chem. 1972,
314, 157. Lactone synthesis; (b) Wynberg, H.; Staring, E. G. J. J. Am. Chem.
Soc. 1982, 104, 166. Ketene dimerization; (c) Calter, M. A. J. Org. Chem.
1996, 61, 8006. (d) Calter, M. A.; Guo, X. J. Org. Chem. 1998, 63, 5308.
Baylis-Hillman reaction; (e) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.;
Hatakeyama, S. J. Am. Chem. Soc. 1999, 120, 10219. Osmylation reactions;
(f) Kolb, H. C.; VanNieuwenzhe, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483. Phase-transfer catalysis; (g) Corey, E. J.; Bo, Y.; Busch-Petersen,
J. J. Am. Chem. Soc. 1999, 120, 13000. (h) O’Donnell, M. J.; Bennett, W.
D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353. Peptide based catalysis; (i)
Jarvo, E. R, Copeland, G. T.; Papaioannou, N.; Bonitatebus, P. J. Jr.; Miller,
S. J. J. Am. Chem. Soc. 1999; 121; 11638.
(10) Pracejus, H.; Maetie, H.; J. Prakt. Chem. 1964, 24, 195.
(11) For further details on the conduct of this reaction, including stereo-
chemical proofs, see the Supporting Information.
10.1021/ja001754g CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/02/2000

7832 J. Am. Chem. Soc., Vol. 122, No. 32, 2000
Communications to the Editor
Table 2. Reaction of Ketenes 3 and Imine 2a Catalyzed by BQ 6a
to Form â-Lactams 1a
Scheme 1. Catalytic, Shuttle-Base Route to Optically Active
â-Lactams 1
residual base that catalyzes the â-lactam reaction racemically. For
example, the use of Hu¨nig’s base to generate phenylketene in
situ with BQ catalyst 6a afforded racemic product 1c in low yield
at -78 °C in THF or toluene. One interesting approach to the
synthesis of ketenes in situ would be the use of the strong organic
base “proton sponge” 7 as a non-nucleophilic deprotonating agent.
However, simply mixing 1 equiv of 7 and acid chloride 5c at
low temperature does not produce detectable amounts of ketene.
Although 7 is a strong thermodynamic base, it is hindered and
kinetically slow at deprotonating carbon-based acids.14 Ideally,
to make 7 effective as an HCl sink, a “relay” or “shuttle” base,
that is, one that is thermodynamically weaker but kinetically active
would serve to liberate HCl from the acid chloride and transfer
it to 7, which then precipitates as its HCl salt. Along those lines,
we found that toluene precipitates salts well and affords the best
conditions for monoketenes. In practice, BQ (6a) serves as an
excellent shuttle base when added to the solution of phenylacetyl
chloride 5c and 7 in toluene at low temperature; a yellow solution
of phenylketene 3c was formed along with a white precipitate
over the course of a few minutes (Scheme 1).13 Imino ester 2a
was then added to the solution at -78 °C, and the characteristic
ketene color disappeared over the course of 2 h to give cis-lactam
1c in 96% ee (65% yield, 99/1 dr, Table 2, entry 2).15 In this
reaction, BQ plays two distinct catalytic roles as a dehydroha-
logenation agent and a nucleophilic catalyst.
We obtained other â-lactams from a variety of in situ generated
ketenes (Table 2). For example, ethylketene 3d (generated from
butyryl chloride 5d) affords cis-diastereomer 1d in 57% yield16
and 99% ee (entry 3).17 Phenoxyketene 3e (from phenoxyacetyl
chloride 5e) also produced the cis-diastereomer 1e (45%) and 99%
ee (entry 4). Other oxygen-substituted ketenes (acetoxyketene and
benzyloxyketene) afforded products in high enantio- and diaste-
reoselectivity (entries 5 and 6).18 These â-lactams have historically
presented a challenge for asymmetric synthesis due to the lack
of a suitable chiral auxiliary on oxygen.3 In analogy to our
successful results using catalyst 4a in a diastereoselective reaction,
we sought to screen quinuclidine catalyst 6b (note the similar
a Reactions run with 10 mol% catalyst (0.13 mmol ketene, 0.13 mmol
imine, and 0.14 mmol proton sponge) at -78 °C f 25 °C for 5 h in
2 mL of toluene. b Run in 10 mL of THF solvent. c Dr determined using
1H NMR and confirmed by HPLC. d Yield of major diastereomer.
in an effort to gauge the effects on diastereoselectivity. In fact,
we found that this catalyst affords product 1c with high ee (89%)
and good yield (65%) for phenylketene 3c with the cis diastere-
omer favored (dr ) 91/9). When the reaction is run under standard
conditions in a solvent that can compete for hydrogen bond
donors, such as propionitrile, the dr erodes to 1/1, once again
implying a role for the hydrogen bond in the activated complex.19
The tosyl group on â-lactams can be readily removed by
treatment with 2 equiv. SmI2 in THF at room temperature for 20
min.20 For example, 1g afforded the deprotected product in 90%
yield. This procedure is simple, mild, tolerates a number of
functional groups on the â-lactam, and should prove useful for
other â-lactam deprotections.
In conclusion, we have reported the first highly enantioselective
synthesis of the â-lactam ring system using a nucleophile-
catalyzed reaction of electron-deficient ketenes and imines. Our
methodology is being applied to the synthesis of other biologically
active classes of â-lactams, including R-amino-â-lactams, and
further reports will be forthcoming.
Acknowledgment. T.L. thanks DuPont and Eli Lilly for support, the
Dreyfus Foundation for a Teacher-Scholar Award, and the Sloan
Foundation for a Fellowship. The authors also thank Drs. Victor G.
Young, Jr., and Maren Pink (Minnesota) for obtaining the crystal structure
of cis-1b and 1c.
Supporting Information Available: Experimental procedures includ-
ing the synthesis and characterization of compounds, stereochemical
proofs, and crystal structure data for cis-1b (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
relationship of the amide proton donor to the nucleophilic center)
JA001754G
(12) Nelson, S. G.; Peelen, T. J.; Wan, Z. J. Am. Chem. Soc. 1999, 121,
9742. Additional information can be found in: Tidwell, T. T. Ketenes; John
Wiley & Sons: New York, 1995.
(13) A procedure for the in situ generation of ketenes, utilizing basic
scavenger resins, is under development and will be published in due course.
(14) (a) Hibbert, F.; Emsley, J. AdV. Phys. Org. Chem. 1990, 26, 255. (b)
Alder, R. W. Chem. ReV. 1989, 89, 1215.
(18) Ring opening of these â-lactams provides entry to various syn-alkyl-
substituted aspartic acids. For a previous synthesis from â, â-disubstituted
R-enamides through catalytic hydrogenation, see: (a) Burk, M. J.; Gross, M.
F.; Martinez, J. P. J. Am. Chem. Soc. 1995, 117, 9375. Synthesis from
â-lactams; (b) Palomo, C.; Aizpurua, J. M.; Ontoria, J. M.; Iturburu, M.
Tetrahedron Lett. 1992, 33, 4823.
(15) See the Supporting Information for general procedures.
(16) The nonoptimal yields may be due to slow polymerization of the imine.
(17) â-Lactam 1d has been investigated by DuPont-Merck as an inhibitor
of human elastase: Firestone, R. A.; Barker, P. L.; Pisano, J. M.; Ashe, B.
M.; Dahlgren, M. E. Tetrahedron 1990, 46, 2255.
(19) In propionitrile solvent, benzoylquinine 6a functions as a highly
diastereoeselective catalyst, yielding product 1c with a dr of 95/5.
(20) SmI2 is known to deprotect N-benzyloxy â-lactams: (a) Romo, D.;
Rzasa, R. M.; Shea, H. A.; Park, K.; Langenhan, J. M.; Sun, L.; Akhiezer,
A.; Liu, J. O. J. Am. Chem. Soc. 1998, 120, 12237.