Cu(I)/Bis(azaferrocene)-catalyzed enantioselective synthesis of β-lactams via couplings of alkynes with nitrones

Article abstract of DOI:10.1021/ja025833z

As a consequence of the wide-ranging significance of β-lactams (e.g., use as drugs and as chiral building blocks), a great deal of effort has been dedicated to the development of methods for their stereoselective synthesis. Although considerable progress has been achieved, nearly all of the approaches that have been described are based on the use of chiral precursors; direct catalytic enantioselective routes to β-lactams are rare as well as limited in scope. In this communication, we establish that, using a new C₂-symmetric planar-chiral bis(azaferrocene) ligand, we can generate β-lactams with very good enantiomeric excess and cis diastereoselection via catalytic enantioselective Kinugasa reactions (couplings of alkynes with nitrones). Appealing attributes of this process include the ready availability of the starting materials, the functional-group tolerance of the reaction, and the convergency of the approach. Copyright

Full text of DOI:10.1021/ja025833z

Published on Web 04/05/2002
Cu(I)/Bis(azaferrocene)-Catalyzed Enantioselective Synthesis of â-Lactams via
Couplings of Alkynes with Nitrones
Michael M.-C. Lo and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 6, 2002
â-Lactams are an intensively studied family of heterocycles, due
primarily to their biological activity.1 Historically, they are best
known for their use as powerful antibiotics (e.g., penicillins and
cephalosporins), but more recently they have received attention for
other therapeutic attributes, such as their capacity to lower
cholesterol levels.2 In addition to their importance as bioactive
compounds, â-lactams serve as useful building blocks in synthetic
organic chemistry (e.g., the commercial semisynthesis of the anti-
cancer agent paclitaxel (Taxol) employs a â-lactam for the
installation of the â-amino acid-derived side chain3).1
As a consequence of their wide-ranging significance, a great deal
of effort has been dedicated to the development of methods for the
stereoselective synthesis of â-lactams.1 Although considerable
progress has been achieved, nearly all of the approaches that have
been described are based on the use of chiral, nonracemic
disappointingly, we observed moderate stereoselection. Fortunately,
however, our ligand design allows us to readily modify the chiral
environment of the bis(azaferrocene). Accordingly, we synthesized
new, methyl-substituted ligand 2 (from commercially available
precursors;1 direct catalytic enantioselective routes to â-lactams are
rare. In fact, to the best of our knowledge, only five such methods
have been reported: the rhodium-catalyzed carbonylation of an
aziridine (kinetic resolution),4 the rhodium-catalyzed intramolecular
compounds in three steps and a resolution), optimized the reaction
insertion of an R-diazo amide into a C-H bond,5 the copper-
catalyzed coupling of an alkyne with a nitrone (see below),6 the
aminoether-catalyzed reaction of ester enolates with imines,7 and
the alkaloid-catalyzed ketene-imine cycloaddition.8 While each of
these discoveries represents an important advance toward the
objective of a general method for the catalytic enantioselective
synthesis of â-lactams, each suffers from significant limitations in
scope or stereoselection.9
conditions, and obtained good stereoselectivity (Table 1, entry 1).14
We have investigated the impact on stereoselection of the
electronic character of the N-bound aromatic group of the nitrone
(Table 1).15 Generation of the â-lactam proceeds with excellent
cis diastereoselectivity irrespective of the nature of the aromatic
ring (∼95:5; entries 1-5). With regard to enantioselectivity, the
more electron-rich the aromatic group, the higher the ee; there is,
however, a tradeoff between ee and yield (entries 1-4). The very
good diastereo- and enantioselection that we obtain with the 4-anisyl
substituent (entry 2) is particularly noteworthy, since this is a
common N-protecting group for â-lactams.16 A comparison of
entries 4 and 5 reveals that we can enhance the stereoselectivity
and the yield by lowering the reaction temperature.
Focusing on 4-anisyl-protected substrates, we turned our attention
to determining the scope with respect to the nitrone component
(Table 2). We established that CuCl/2 is effective for the catalytic
enantioselective formation of â-lactams from a variety of nitrones,
with substituents on carbon ranging from aromatic (entries 1-3)
to alkyl (entry 4) to acyl (entry 5).
We have also investigated the scope of this process with respect
to the alkyne component, focusing on couplings with alkyl- and
acyl-substituted nitrones (3 and 4, respectively, in Table 3). Both
families react with aromatic alkynes to generate â-lactams with
excellent diastereo- and enantioselectivity (entries 1-3 and 5).
Although alkyl-substituted acetylenes are converted to the desired
product with somewhat lower stereoselection (entry 4), alkenyl-
substituted substrates furnish good de and ee (entry 6). It is worth
noting that, since Brønsted base-catalyzed cis f trans isomerization
of â-lactams is well-established,17 our enantioselective Cu/2-
catalyzed process effectively provides stereoselective access to all
four of the possible isomers.
We were intrigued by a report of Kinugasa in 1972 that describes
a convergent route to â-lactams through the reaction of a copper
acetylide with a nitrone.10,11 Appealing features of this process
include the ready availability of the starting materials (terminal
alkynes and nitrones) and its high functional-group tolerance (e.g.,
alcohols, halides, amines, and esters). Miura subsequently deter-
mined that the Kinugasa reaction can be accomplished with a
catalytic amount of copper in conjunction with a terminal alkyne,
and he provided the only description of asymmetric catalysis of
this powerful transformation.6 Miura examined one substrate pair
(phenylacetylene and N,R-diphenylnitrone) and obtained a maxi-
mum ee of 57% (10% CuI, 20% bisoxazoline ligand; 50% yield;
probably ∼2:1 cis:trans). In this communication, we establish that,
using a new C2-symmetric planar-chiral bis(azaferrocene) ligand
(2), we can achieve catalytic enantioselective Kinugasa reactions
that generate â-lactams with good enantiomeric excess and cis
diastereoselection (eq 1).
We have reported that bis(azaferrocene) ligand 1 furnishes useful
stereoselectivity in copper-catalyzed cyclopropanations of olefins12
and ring expansions of oxetanes.13 In our initial studies of the
Kinugasa reaction, we examined the utility of 1 in the coupling of
phenylacetylene with N,R-diphenylnitrone under Miura’s conditions;
* To whom correspondence should be addressed. E-mail: gcf@mit.edu.
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J. AM. CHEM. SOC. 2002, 124, 4572-4573
10.1021/ja025833z CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Catalytic Asymmetric Synthesis of â-Lactams: Variation
prepared from symmetrical or unsymmetrical disubstituted ketenes
and a variety of imines with enantiomeric excesses up to 98%.18
of the N-Substituenta
Acknowledgment. Support has been provided by Bristol-Myers
Squibb, Novartis, and Pfizer. Funding for the MIT Department of
Chemistry Instrumentation Facility has been furnished in part by
NSF CHE-9808061 and NSF DBI-9729592.
% ee,
cis
isolated yield
cis isomer (%)
entry
R
cis:trans
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). X-ray crystallographic file
(CIF). This material is available free of charge via the Internet at http://
pubs.acs.org.
1
2
3
Ph
95:5
95:5
94:6
94:6
95:5
77
85
72
67
71
69
53
74
79
91
4-(MeO)C6H4
4-BrC6H4
4-(EtO2C)C6H4
4-(EtO2C)C6H4
4
5b
References
a All data represent the average of two runs. b Run at -20 °C.
(1) For reviews, see: (a) The Chemistry of â-Lactams; Page, M. I., Ed.;
Blackie Academic & Professional: New York, 1992. (b) Chemistry and
Biology of â-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. (d) Compre-
hensiVe 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)
EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997.
Table 2. Catalytic Asymmetric Synthesis of â-Lactams: Scope
with Respect to the Nitrone Componenta
% ee,
cis
isolated yield
cis isomer (%)
(2) For a discussion, see: Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis,
H. R., Jr.; Yumibe, N.; Clader, J. W.; Burnett, D. A. J. Med. Chem. 1998,
41, 973-980. See also: http://www.sch-plough.com/news/2002/research/
20020318.html(accessed March 2002).
(3) For leading references, see: Kingston, D. G. I. Chem. Commun. 2001,
867-880.
(4) Calet, S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111, 931-934.
(5) (a) McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.; Murphy, E.;
Doyle, M. P. Tetrahedron Lett. 1992, 33, 5983-5986. (b) Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Daniel, K. L. Tetrahedron Lett.
1992, 33, 7819-7822. Doyle, M. P.; Kalinin, A. V. Synlett 1995, 1075-
1076. (c) Watanabe, N.; Anada, M.; Hashimoto, S.-i.; Ikegami, S. Synlett
1994, 1031-1033. Hashimoto, S.-i.; Watanabe, N.; Anada, M.; Ikegami,
S. J. Synth. Org. Chem., Jpn. 1996, 54, 988-999. Anada, M.; Watanabe,
N.; Hashimoto, S.-i. Chem. Commun. 1998, 1517-1518. Anada, M.;
Hashimoto, S.-i. Tetrahedron Lett. 1998, 39, 9063-9066.
entry
R
cis:trans
1
Ph
95:5
93:7
93:7
93:7
91:9
85
90
83
89
72
53
50
46
57
42
2
4-(F3C)C6H4
4-(MeO)C6H4
Cy
3b
4
5
PhCO
a All data represent the average of two runs. b Run at rt.
Table 3. Catalytic Asymmetric Synthesis of â-Lactams: Scope
with Respect to the Alkyne Componenta
(6) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995, 60,
4999-5004.
(7) (a) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 2060-2061. (b) Tomioka, K.; Fujieda, H.; Hayashi,
S.; Hussein, M. A.; Kambara, T.; Nomura, Y.; Kanai, M.; Koga, K. Chem.
Commun. 1999, 715-716.
(8) Taggi, A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III; Lectka,
T. J. Am. Chem. Soc. 2000, 122, 7831-7832.
(9) (a) Rhodium-catalyzed carbonylation of an aziridine (kinetic resolution):
scope ) two examples, both 1-tert-alkyl-2-phenyl aziridines; g1 equiv
of ligand was used. (b) Rhodium-catalyzed intramolecular insertion of an
R-diazo amide into a C-H bond: scope ) effective for the synthesis of
certain bicyclic systems and of 4-substituted-1-tert-butyl-3-methoxycar-
bonyl-2-azetidinones. (c) Copper-catalyzed coupling of an alkyne with a
nitrone: scope ) one example; ee: 57%; cis:trans ∼2:1; yield: 50%. (d)
Aminoether-catalyzed reaction of ester enolates with imines: scope )
one enolate. (e) Alkaloid-catalyzed ketene-imine cycloaddition: scope
) one imine; yields: 36-65%.
% ee,
cis
isolated yield
cis isomer (%)
entry
nitrone
R
cis:trans
1b
2b
3b
4b
5c
6c
3
3
3
3
4
4
Ph
>95:5
>95:5
92:8
71:29
90:10
90:10
92
93
91
73(70)
90
65
57
60
43(17)
56
4-(F3C)C6H4
4-(MeO)C6H4
PhCH2
(10) Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 1972, 466-
467.
(11) For examples of applications of the Kinugasa reaction by others, see: (a)
Ding, L. K.; Irwin, W. J. J. Chem. Soc., Perkin Trans. 1 1976, 2382-
2386. (b) Dutta, D. K.; Boruah, R. C.; Sandhu, J. S. Indian J. Chem.
1986, 25B, 350-353. Dutta, D. K.; Boruah, R. C.; Sandhu, J. S.
Heterocycles 1986, 24, 655-658. (c) Basak, A.; Bhattacharya, G.; Bdour,
H. M. M. Tetrahedron 1998, 54, 6529-6538.
Ph
1-cyclohexenyl
91
45
a All data represent the average of two runs. The values in parentheses
provide data for the trans isomer. b Run at -20 °C. c Run at -40 °C.
(12) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 10270-10271.
(13) Lo, M. M.-C.; Fu, G. C. Tetrahedron 2001, 57, 2621-2634.
(14) The use of a sterically demanding trialkylamine (1.0 equiv or less) as the
base is essential to obtain good cis diastereoselectivity in the reaction.
(15) The reaction proceeds much more slowly when the substituent on nitrogen
is an alkyl group.
(16) (a) Wild, H. In The Organic Chemistry of â-Lactams; Georg, G. I., Ed.;
VCH: New York, 1993; Chapter 1. (b) Greene, T. W.; Wuts, P. G. M.
ProtectiVe Groups in Organic Synthesis, 3rd ed.; Wiley: New York, 1999;
pp 636-637.
In conclusion, we have developed the first versatile system for
the copper-catalyzed asymmetric coupling of alkynes with nitrones
to form â-lactams. In terms of scope and stereoselection, this
method compares favorably with previously reported strategies for
the catalytic enantioselective synthesis of this important family of
heterocycles. Other appealing attributes of this process include the
ready availability of the starting materials, the functional-group
tolerance of the reaction, and the convergency of the approach.
Note Added in Proof: We have recently communicated that,
using a planar-chiral heterocycle as the catalyst, â-lactams can be
(17) For examples, see: (a) Reference 6. (b) Fujisawa, T.; Ichikawa, M.; Ukaji,
Y.; Shimizu, M. Tetrahedron Lett. 1993, 34, 1307-1310. (c) Shimizu,
M.; Kume, K.; Fujisawa, T. Chem. Lett. 1996, 545-546.
(18) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578-1579.
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