Enantioselective staudinger synthesis of β-lactams catalyzed by a planar-chiral nucleophile

Article abstract of DOI:10.1021/ja012427r

The development of efficient methods for the stereoselective generation of β-lactams is an important goal, due to their biological activity and their utility as synthetic intermediates. The Staudinger reaction, an overall [2 + 2] cycloaddition of a ketene

Full text of DOI:10.1021/ja012427r

Published on Web 02/01/2002
Enantioselective Staudinger Synthesis of â-Lactams Catalyzed by a
Planar-Chiral Nucleophile1
Brian L. Hodous and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received October 25, 2001
Table 1. Comparison of the Effectiveness of Planar-Chiral
Heterocycles as Catalysts for the Staudinger Synthesis of
â-Lactams
The development of efficient methods for the stereoselective
generation of â-lactams is an important goal, due to their utility as
synthetic intermediates and to their biological activity.2 Currently,
an array of widely used antibiotics are based on the â-lactam subunit
(e.g., penicillins and cephalosporins). During recent years, however,
the need for new â-lactam (and other) antibiotics has been growing,
as a consequence of the emergence of strains of bacteria that are
resistant to existing drugs.3 In addition to their significance as targets
for medicinal chemistry, enantiopure â-lactams also serve as
versatile chiral building blocks in organic synthesis. The commercial
semisynthesis of the anticancer agent paclitaxel (Taxol), which is
produced from a protected baccatin III through reaction with a
â-lactam to install the â-amino acid-derived side chain, represents
one particularly prominent example of this latter role.4
The Staudinger reaction, an overall [2 + 2] cycloaddition of a
ketene with an imine, provides an efficient, convergent route to
â-lactams (eq 1).5 Although a number of chiral auxiliary-based
asymmetric Staudinger processes have been described,5b only one
investigation of enantioselective catalysis of this transformation has
been reported.6,7 In that study, Lectka demonstrated that, using a
quinine derivative as the catalyst, highly stereoselective coupling
of a range of monosubstituted ketenes, as well as one symmetrical
disubstituted ketene, could be achieved; on the other hand, only
one imine (1) was shown to be a suitable reaction partner.
entry
catalyst
ee (%)a
entry
catalyst
ee (%)a
1
2
3
(-)-2
(+)-3
(-)-4
<5
<5
<5
4
5
(+)-5
(-)-6
85
85
a Average of two runs.
and 3). Fortunately, however, both of the FeC5Me5-derived catalysts
(5 and 6) afford the desired â-lactam in good enantiomeric excess
(85% ee; entries 4 and 5).
On the basis of these observations, we chose to focus our
attention on asymmetric Staudinger reactions catalyzed by PPY
derivative 6, and we were pleased to discover that this complex
efficiently couples hexamethyleneketene with a diverse set of imines
(Table 2, entries 1-5).10 Thus, imines derived from aromatic (entries
1 and 2), R,â-unsaturated (entry 3), and aliphatic (entries 4 and 5)
aldehydes undergo cycloaddition in uniformly good-to-excellent
enantioselectivities and yields. Relative to prior work on catalytic
asymmetric Staudinger reactions, the broad scope with respect to
the imine component is noteworthy, especially the challenging,
readily enolizable imine depicted in entry 5.11 With regard to the
ketene component, not only cyclic, but also acyclic, symmetrical
disubstituted ketenes are suitable substrates (entries 6-7).12
In the case of catalytic asymmetric Staudinger reactions of imines
with unsymmetrical disubstituted ketenes, we need to control not
only enantioselectivity but also diastereoselectivity. We have
determined that PPY derivative 6 is in fact an effective catalyst
for reactions of this family of ketenes, furnishing two new
contiguous (one quaternary13 and one tertiary) stereocenters with
very good stereoselection and yield (Table 3). As with symmetrical
ketenes, catalyst 6 is versatile, coupling a range of unsymmetrical
ketenes and imines with comparatively little variation in stereo-
selectivity.14 We believe that Staudinger reactions catalyzed by 6
proceed through the pathway outlined in Figure 1.6
Several years ago, we initiated a program focused on the
application of planar-chiral heterocycles (e.g., 2-6) as catalysts
for asymmetric reactions of ketenes. As one part of this investiga-
tion, we determined that azaferrocene 2 catalyzes the enantio-
selective addition of alcohols to ketenes.8 In this report, we describe
a second application of planar-chiral heterocycles to reactions of
ketenes; specifically, in work that complements the pioneering study
of Lectka, we establish that PPY (PPY ) 4-(pyrrolidino)pyridine)
derivative 6 is an effective catalyst for the asymmetric Staudinger
reaction of symmetrical and unsymmetrical disubstituted ketenes
with a range of imines, furnishing the target â-lactams with very
good stereoselection.
In our initial investigation of the Staudinger reaction, we surveyed
the planar-chiral heterocycles (2-6) that we have found to be most
useful for other nucleophile-catalyzed processes.9 As illustrated in
Table 1, for the coupling of hexamethyleneketene with N-(2-
furfurylidene)-4-methylbenzenesulfonamide, azaferrocene 2 is inef-
fective (entry 1). Similarly, FeC5Ph5-bound planar-chiral pyridine
derivatives 3 and 4 provide essentially racemic product (entries 2
As noted earlier, interest in the synthesis of enantiopure â-lactams
derives in part from their potential utility as chiral building blocks.2
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10.1021/ja012427r CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Catalytic Enantioselective Staudinger Reactions of
Symmetrical Disubstituted Ketenes with a Range of Imines
In summary, we have demonstrated that a planar-chiral derivative
of PPY is an excellent catalyst for enantioselective Staudinger
reactions. A range of symmetrical and unsymmetrical disubstituted
ketenes couple with a wide array of imines to provide â-lactams
with very good stereoselection and yield; this work represents a
considerable expansion in the scope of this important process.
Current efforts are focused on exploring the breadth and the
mechanism of this and related nucleophile-catalyzed asymmetric
reactions of ketenes.
Acknowledgment. We thank Ivory D. Hills for assistance with
X-ray crystallography. Support has been provided by Bristol-Myers
Squibb, Merck, the National Institutes of Health (National Institute
of General Medical Sciences, R01-GM57034), Novartis, and Pfizer.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
a Average of two runs. b Reaction was started at -40 °C. c Reaction was
run at 35 °C in 1:1 toluene/THF with 1.5 equiv of ketene.
References
Table 3. Catalytic Enantioselective Staudinger Reactions of
Unsymmetrical Disubstituted Ketenes with a Range of Imines
(1) Dedicated to Professor Robert H. Grubbs on the occasion of his 60th
birthday.
(2) (a) The Chemistry of â-Lactams; Page, M. I., Ed.; Chapman and Hall:
London, 1997. (b) Chemistry and Biology of Beta-Lactam Antibiotics;
Morin, R. B., Gorman, M., Eds.; Academic: New York, 1982; Volumes
1-3. (c) The Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH:
New York, 1993; pp 295-368. (d) ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New
York, 1996; Vol. 1B, Chapters 1.18-1.20. (e) Synthesis of â-Lactam
Antibiotics; Bruggink, A., Ed.; Kluwer: Dordrecht, Netherlands, 2001.
(f) Ojima, I.; Delaloge, F. Chem. Soc. ReV. 1997, 26, 377-386. Ojima, I.
Acc. Chem. Res. 1995, 28, 383-389. (g) Juaristi, E. EnantioselectiVe
Synthesis of â-Amino Acids; Wiley-VCH: New York, 1997.
(3) For an overview, see: Niccolai, D.; Tarsi, L.; Thomas, R. J. Chem.
Commun. 1997, 2333-2342.
(4) For leading references, see: Kingston, D. I. Chem. Commun. 2001, 867-
880.
(5) (a) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51-123. (b) For leading
references to the asymmetric synthesis of â-lactams via the Staudinger
reaction, see: Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur.
J. Org. Chem. 1999, 3223-3235. Georg, G. I.; Ravikumar, V. T. In The
Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York,
1993; pp 295-368.
a Average of two runs.
(6) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III; Lectka,
T. J. Am. Chem. Soc. 2000, 122, 7831-7832. The yield of â-lactam, based
on the acid chloride precursor to the ketene, ranges from 36 to 65% (six
examples). See also: Wack, H.; Drury, W. J., III; Taggi, A. E.; Ferraris,
D.; Lectka, T. Org. Lett. 1999, 1, 1985-1988.
(7) For four other methods for the catalytic enantioselective synthesis of
â-lactams, see: (a) Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989,
111, 931-934. (b) Watanabe, N.; Anada, M.; Hashimoto, S.-i.; Ikegami,
S. Synlett 1994, 1031-1033. Doyle, M. P.; Kalinin, A. V. Synlett 1995,
1075-1076. (c) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org.
Chem. 1995, 60, 4999-5004. (d) Fujieda, H.; Kanai, M.; Kambara, T.;
Iida, A.; Tomioka, K. J. Am. Chem. Soc. 1997, 119, 2060-2061. Tomioka,
K.; Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara, T.; Nomura, Y.;
Kanai, M.; Koga, K. Chem. Commun. 1999, 715-716. Unfortunately,
none of these methods is general and highly enantioselective.
Figure 1. Proposed mechanism for enantioselective Staudinger reactions
catalyzed by PPY derivative 6.
(8) Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121,
2637-2638.
(9) (a) For an overview, see: Fu, G. C. Acc. Chem. Res. 2000, 33, 412-420.
(b) For more recent work, see: Arai, S.; Bellemin-Laponnaz, S.; Fu, G.
C. Angew. Chem., Int. Ed. 2001, 40, 234-236.
We have established that the â-lactams generated by our catalytic
asymmetric Staudinger reactions can be ring-opened with amines
to afford â-amino amides (eq 2) and with LiAlH4 to furnish
N-protected γ-amino alcohols (eq 3). As expected, the enantiomeric
and diastereomeric purity of the â-lactam is preserved during these
transformations.
(10) Optimization (e.g., of concentration) of the initial reaction conditions led
to improved enantioselectivity (Table 1, entry 5 vs Table 2, entry 2).
(11) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75-77.
(12) Generation of diethylketene proceeds more cleanly in toluene/THF than
in toluene alone; therefore, the Staudinger reactions of this substrate were
run in toluene/THF (Table 2, entries 6 and 7).
(13) For a recent review of catalytic asymmetric methods that generate
quaternary stereocenters, see: Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388-401. See also: Fuji, K. Chem. ReV. 1993,
93, 2037-2066.
(14) (a) Under otherwise identical conditions, in the absence of catalyst, no
â-lactam is generated. (b) Almost identical stereoselectivity is observed
with 1% catalyst, but the rate of product formation is very slow. (c)
Approximately 80% of the catalyst can be recovered at the end of the
reaction. (d) Phenylmethylketene reacts with N-(2-furfurylidene)-4-
methylbenzenesulfonamide to give the â-lactam product with dr ) 2: 1
(major diastereomer: 84% ee).
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