Catalytic asymmetric staudinger reactions to form β-lactams: An unanticipated dependence of diastereoselectivity on the choice of the nitrogen substituent

Article abstract of DOI:10.1021/ja052058p

There are relatively few methods for the catalytic asymmetric synthesis of β-lactams, and those that have been reported are generally cis selective. This communication describes the first catalytic enantioselective Staudinger reactions that preferentially furnish trans β-lactams (trans = relationship of Ph to R¹). The key to this method is the use of an N-triflyl protecting group for the imine. Along with serving as interesting targets in their own right, N-triflyl β-lactams readily react with nucleophiles to generate useful families of compounds, such as γ-amino alcohols and β-amino acids. Copyright

Full text of DOI:10.1021/ja052058p

Published on Web 07/30/2005
Catalytic Asymmetric Staudinger Reactions to Form â-Lactams: An
Unanticipated Dependence of Diastereoselectivity on the Choice of the
Nitrogen Substituent
Elaine C. Lee, Brian L. Hodous, Enda Bergin, Crystal Shih, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received March 31, 2005; E-mail: gcf@mit.edu
Long before the biological activity1 or the synthetic utility2 of
â-lactams was appreciated, Staudinger developed the first method
for their synthesis by coupling a ketene with an imine.3 This
convergent strategy has endured as a particularly attractive approach
to generating this important family of compounds.4 In the case of
Staudinger reactions of monosubstituted ketenes, which have been
intensively studied, the cis â-lactam is typically the predominant
product.5 If the trans diastereomer is desired, it can be accessed
through epimerization of the cis isomer under basic conditions.
Staudinger reactions of disubstituted ketenes are much less com-
mon,4 despite the fact that â-lactams that bear two R substituents
are an important class of target molecules.6 Only one method has
been described for the diastereo- and enantioselective synthesis of
R,R-disubstituted â-lactams through a catalytic asymmetric Staudinger
reaction (eq 1);7,8 as indicated, this process preferentially affords
the cis isomer.9 Of course, for such â-lactams, the trans diastereomer
cannot be generated from the cis isomer through simple base-in-
duced epimerization. Therefore, for R,R-disubstituted â-lactams,
it is necessary to develop a Staudinger reaction that is itself trans
selective. In this report, we describe the achievement of this objective.
tams not only with generally good trans diastereoselectiVity but
also with useful enantioselectiVity (Table 1, entries 1-9).12 In addi-
tion, we have examined one coupling of a symmetrical disubstituted
ketene (entry 10); gratifyingly, the desired â-lactam is generated
in excellent enantiomeric excess (98%).
As mentioned earlier, â-lactams are interesting targets due not
only to their bioactivity but also to their utility as precursors to
other important families of compounds. To the best of our
knowledge, only one report has described the synthesis of an
N-triflyl â-lactam,13 and there have been no investigations of their
reactivity. We have established that a range of derivatizations of
N-triflyl â-lactams can be achieved in good yield without an erosion
in stereochemical purity, furnishing protected γ-amino alcohols,
â-amino acids, and â-amino amides (eqs 3-5). Furthermore, the
triflyl group can be reductively removed (eq 6).14
While attempting to improve upon the process illustrated in eq
1, we made the exciting discovery that the cis/trans selectivity of
Staudinger reactions catalyzed by PPY derivative 1 (PPY )
4-(pyrrolidino)pyridine) can be effectively controlled through the
appropriate choice of the N-protecting group of the imine. Thus,
ketenes couple with N-tosyl imines to predominantly generate cis
â-lactams, whereas reactions with N-triflyl imines preferentially
furnish the trans isomers (e.g., eq 2)!
Naturally, we were intrigued by the remarkable dependence of
the cis/trans diastereoselectivity on the choice of the N-sulfonyl
group (eq 2). Interestingly, the differing electrophilicity of the
imines leads to divergent behavior in the presence of catalyst 1;
whereas there is no evidence by 1H NMR of an interaction between
the catalyst and an N-tosyl imine (eq 7), the catalyst reacts
quantitatively with an N-triflyl imine to furnish adduct A (eq 8).15
Aware of the paucity of methods for the catalytic asymmetric
synthesis of â-lactams,10 we decided to optimize and to investigate
the scope of this interesting new trans-selective Staudinger reaction,
which produces two adjacent stereocenters (one all-carbon quater-
nary11 and one tertiary). We were pleased to determine that a range
of ketenes and N-triflyl imines couple to furnish an array of â-lac-
It is tempting to suggest that the origin of the different cis/trans
preferences for Staudinger reactions of N-tosyl/triflyl imines cata-
lyzed by 1 may lie in the divergent reactivity depicted in eqs 7 and
8, that is, that these two classes of imines couple with ketenes by
9
11586
J. AM. CHEM. SOC. 2005, 127, 11586-11587
10.1021/ja052058p CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Catalytic Asymmetric Synthesis of Highly Substituted
trans â-Lactamsa
be the consequence of a novel pathway for Staudinger reactions of
this class of highly electrophilic imines. We have demonstrated
that, along with serving as interesting targets in their own right, N-
triflyl â-lactams readily react with nucleophiles to generate other
useful families of compounds, including γ-amino alcohols and â-
amino acids. Additional synthetic and mechanistic studies of cata-
lytic asymmetric Staudinger reactions are underway.
entry
R
R1
trans:cis
ee (%)b
yield (%)c
1
2
Et
Ph
Ph
Ph
86:14
98:2
97:3
96:4
97:3
81:19
81:19
80:20
98:2
-
63
81
63
85
69
82
99
84
94
98
60
83
72
84
80
76
89
79
76
62
Acknowledgment. We thank Dr. Peter Mueller and Dr. Ivory
D. Hills for X-ray crystallographic assistance, and Dr. Kevin M.
McCauley for a preliminary NMR study. Support has been provided
by the NIH (National Institute of General Medical Sciences: R01-
GM57034; National Cancer Institute: Training Grant CA009112),
Merck, and Novartis.
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.
Me
i-Bu
Me
Me
Me
Me
Me
Me
Ph
3
4
4-FC6H4
4-(CF3)C6H4
4-(OMe)C6H4
o-tolyl
2-BrC6H4
2-naphthyl
Ph
5
6
7
8
9
10
a All data are the average of two experiments. b Enantiomeric excess of
the trans diastereomer. c Yield of the mixture of diastereomers.
References
(1) For leading references, see: (a) The â-Lactamases: A Major Cause of
Resistance of â-Lactam Antibiotics and â-Lactamase Inhibitors; Masc-
aretti, O. A., Ed.; Bentham: Hilversum, Netherlands, 1999. (b) Compre-
hensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon: New York, 1996; Chapters 1.18-1.20. (c)
Chemistry and Biology of Beta-Lactam Antibiotics; Morin, R. B., Gorman,
M., Eds.; Academic: New York, 1982; Vols. 1-3.
(2) For leading references, see: (a) Alcaide, B.; Almendros, P. Curr. Med.
Chem. 2004, 11, 1921-1949. (b) Deshmukh, A. R. A. S.; Bhawal, B.
M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr.
Med. Chem. 2004, 11, 1889-1920. (c) Singh, G. S. Tetrahedron 2003,
59, 7631-7649. (d) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide,
M. Synlett 2001, 1813-1826.
(3) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51-123.
(4) For reviews of the Staudinger reaction, see: (a) Palomo, C.; Aizpurua, J.
M.; Ganboa, I.; Oiarbide, M. Curr. Med. Chem. 2004, 11, 1837-1872.
(b) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org.
Chem. 1999, 3223-3235. (c) Georg, G. I.; Ravikumar, V. T. In The
Organic Chemistry of â-Lactams; Georg, G. I., Ed.; VCH: New York,
1993; pp 295-368.
(5) For leading references to uncommon trans-selective processes, see: (a)
Liang, Y.; Jiao, L.; Zhang, S.; Xu, J. J. Org. Chem. 2005, 70, 334-337.
(b) ref 4b.
Figure 1. A mechanism for nucleophile-catalyzed Staudinger reactions:
a “ketene-first” pathway.
(6) For example, see: (a) Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch,
K. J. Am. Chem. Soc. 1995, 117, 8258-8270. (b) Sandanayaka, V. P.;
Prashad, A. S.; Yang, Y.; Williamson, R. T.; Lin, Y. I.; Mansour, T. S.
J. Med. Chem. 2003, 46, 2569-2571.
(7) (a) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578-1579.
(b) In addition, Lectka has described a catalytic asymmetric Staudinger
reaction of a symmetrical disubstituted ketene (for which there is no issue
of diastereoselectivity): Taggi, A. E.; Hafez, A. M.; Wack, H.; Young,
B.; Drury, W. J., III; Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-
7832.
(8) For pioneering studies of catalytic asymmetric Staudinger reactions, see:
(a) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III;
Lectka, T. J. Am. Chem. Soc. 2000, 122, 7831-7832. (b) France, S.; Shah,
M. H.; Weatherwax, A.; Wack, H.; Roth, J. P.; Lectka, T. J. Am. Chem.
Soc. 2005, 127, 1206-1215 and references therein.
(9) We use the terms cis and trans as a shorthand means of describing the
position of the C3 aryl group relative to the C4 substituent.
(10) For leading references, see: (a) France, S.; Weatherwax, A.; Taggi, A.
E.; Lectka, T. Acc. Chem. Res. 2004, 37, 592-600. (b) Magriotis, P. A.
Angew. Chem., Int. Ed. 2001, 40, 4377-4379.
(11) For leading references to methods for the synthesis of all-carbon quaternary
stereocenters, see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363-5367. (b) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105-10146.
(12) Notes: (a) The stereoselectivity is sensitive to the choice of reaction
temperature (-78 °C to room temperature) and solvent (CH2Cl2 and/or
toluene). (b) Under identical conditions, but in the absence of catalyst,
no â-lactam is produced. (c) If desired, the catalyst can generally be
recovered in >70% yield.
Figure 2. A mechanism for nucleophile-catalyzed Staudinger reactions:
an “imine-first” pathway.
distinct mechanisms. Lectka has proposed that Staudinger reactions
of N-tosyl imines catalyzed by a quinine derivative proceed through
the pathway illustrated in Figure 1,8 and we believe that this is the
mechanism for reactions of N-tosyl imines catalyzed by 1. One
speculative suggestion is that N-triflyl imines, on the other hand,
react through the pathway outlined in Figure 2, wherein adduct A
of eq 8 serves as an intermediate. We are currently pursuing experi-
ments designed to test this as well as other possible explanations
for the striking dependence of diastereoselectivity on the N-
protecting group.16
(13) Firestone, R. A.; Barker, P. L.; Pisano, J. M.; Ashe, B. M.; Dahlgren, M.
E. Tetrahedron 1990, 46, 2255-2262.
(14) For the use of this reagent to remove a Ts group from a sulfonamide,
see: Nayak, S. K. Synthesis 2000, 1575-1578.
(15) For an X-ray crystal structure of A, see the Supporting Information.
(16) Some preliminary observations: (1) On the basis of a 1H NMR study, we
believe that the resting state of the catalyst during Staudinger reactions
of N-triflyl imines may be adduct B (Figure 2). (2) An initial kinetics
investigation indicates that (a) the rate law is first-order in catalyst and
zero-order in ketene and imine; (b) there is a substantial normal R
secondary kinetic isotope effect for reactions of undeuterated versus
monodeuterated imines.
In conclusion, relatively few methods have been described for
the catalytic asymmetric synthesis of â-lactams, and those that have
been reported are typically cis selective. In this investigation, we
have developed the first catalytic enantioselective Staudinger reac-
tions that provide trans â-lactams. Interestingly, the key to this
method is the use of an N-triflyl protecting group for the imine.
We have suggested that the unusual trans diastereoselectivity may
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