A highly stereoselective synthesis of chiral α-amino-β-lactams via the Kinugasa reaction employing ynamides

Article abstract of DOI:10.1021/ol801257j

(Chemical Equation Presented) A highly stereoselective synthesis of chiral α-amino-β-lactam through an ynamide-Kinugasa reaction is described. In addition, a mechanistic model is illustrated here to rationalize the observed diastereoselectivity, which depends on both the initial [3 + 2] cycloaddition step and the subsequent protonation for which both are highly selective.

Full text of DOI:10.1021/ol801257j

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3477-3479
A Highly Stereoselective Synthesis of
Chiral r-Amino-ꢀ-lactams via the
Kinugasa Reaction Employing
Ynamides†
Xuejun Zhang, Richard P. Hsung,* Hongyan Li, Yu Zhang, Whitney L. Johnson,
and Ruth Figueroa
DiVision of Pharmaceutical Sciences and Department of Chemistry, 777 Highland
AVenue, UniVersity of Wisconsin, Madison, Wisconsin 53705-2222
rhsung@wisc.edu
Received June 3, 2008
ABSTRACT
A highly stereoselective synthesis of chiral r-amino-ꢀ-lactam through an ynamide-Kinugasa reaction is described. In addition, a mechanistic
model is illustrated here to rationalize the observed diastereoselectivity, which depends on both the initial [3 + 2] cycloaddition step and the
subsequent protonation for which both are highly selective.
Since Staudinger’s first preparation,1 ꢀ-lactams have captured
the attention of synthetic and medicinal communities for
nearly a century.2–6 Rendered famous by penicillin, those
substituted with R-amino groups are among the most sought
after ꢀ-lactams. Consequently, an impressive array of ste-
reoselective approaches toward chiral R-amino-ꢀ-lactams has
been reported.4–6 While the Kinugasa reaction7,8 represents
an elegant approach toward ꢀ-lactams, it has remained
relatively unexplored until recently, and this is particularly
true in the development of enantioselective protocols.9–11
With such immense significance, we recognized the unique
potential of an ynamide-Kinugasa reaction. As shown in
Scheme 1, reactions of chiral ynamides 112,13 with nitrones
in a Kinugasa manner would not only lead to a stereoselective
manifold for constructing ꢀ-lactams, but also more impor-
(4) For reviews on synthetic approaches, see:(a) Miller, M. J. Acc. Chem.
Soc. 1986, 19, 49. (b) Hart, D. J.; Ha, D. C. Chem. ReV. 1989, 89, 1447.
(c) Ghosez, L.; Marchand-Brynaert, J. In ComprehensiVe Organic Syntheses;
Trost, B.,; Flemming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 5, p 85.
(d) Van der Steen, F. H.; Van Koten, G. Tetrahedron 1991, 47, 7503. (e)
Hegedus, L. S. Acc. Chem. Soc. 1995, 28, 299. (f) Ojima, I. Acc. Chem.
Soc. 1995, 28, 383. (g) Ojima, I.; Delaloge, F. Chem. Soc. ReV 1997, 26,
377. (h) DeKimpe, N. In ComprehensiVe Heterocyclic Chemistry II ;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Padwa, A.,. Eds.; Pergamon:
Oxford, UK, 1996; Vol. 1B. (i) Palomo, C.; Aizpurua, J. M.; Inaki, G.;
Oiarbide, M. Eur. J. Org. Chem. 1999, 3223. (j) Synthesis of ꢀ-Lactams
Antibiotics. Chemistry, Biocatalysis and Process Integration; Bruggink, A.,
Ed.; Kluwer: Dordrecht, The Netherlands, 2001. (k) Taggi, A. E.; Hafez,
A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10. (l) France, S.; Weatherwax,
† This paper is dedicated in memory of Dr. Christopher R. Schmid
(1959–2007) of Eli Lilly.
(1) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51.
(2) (a) Page, M. I. The Chemistry of ꢀ-Lactams;, Blackie Academic and
Professional: New York, 1992. (b) The Organic Chemistry of ꢀ-Lactams;
Georg, G. I., Ed.; VCH: New York, 1993
.
(3) (a) Masaretti, O. A.; Boschetti, C. E.; Danelon, G. O.; Mata, E. G.;
Roveri, O. A. Curr. Med. Chem. 1995, 1, 441. (b) Neuhaus, F. C.;
Georgopadaku, N. H. In Emerging Targets in Antibacterial and Antifungal
Chemotherapies; Sutcliffe, J., Georgopadaku, N. H., Eds.; Chapman and
Hall: New York, 1992. (c) The Chemistry and Biology of ꢀ-Lactams
Antibiotics; Morin, R. B., Gorman, M., Eds.; Academic Press: New York,
A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37592
.
(5) For Rh-catalyzed asymmetric manifolds, see:(a) Doyle, M. P.; Pieters,
R. J.; Tauton, J.; Pho, H. Q.; Padwa, A.; Hertzog, D. L.; Precedo, L. J.
Org. Chem. 1991, 56, 820. (b) Anada, M.; Watanabe, N.; Hashimoto, S.
Chem. Commun. 1998, 1517. (c) Davioli, P.; Moretti, I.; Prati, F.; Alper,
H. J. Org. Chem. 1999, 64, 518.
1982
.
10.1021/ol801257j CCC: $40.75
Published on Web 07/10/2008
2008 American Chemical Society

Scheme 1
.
An Ynamide-Kinugasa Reaction
Scheme 2. Establishing the Feasibility and Stereochemistry
tantly provide a direct synthesis of chiral R-amino-ꢀ-lactams
(see 4). We report here a highly stereoselective ynamide-
Kinugasa reaction.
The feasibility of an ynamide-Kinugasa reaction was
readily established by employing ynamide 5 (Scheme 2).
With 0.2 equiv of CuCl and 4.0 equiv of Cy2NMe, the
reaction of 5 with N-benzylidene-N-phenylnitrone proceeded
effectively in CH3CN at rt to give ꢀ-lactam cis-6a14 in 73%
yield as the major isomer. X-ray structural analysis unam-
biguously revealed that the relative stereochemistry between
the R- and ꢀ-carbons is cis. This suggests that the minor
isomer(s) could be cis-6b and/or trans-6a/6b with a/b
isomers differing at the ꢀ-carbon stereochemistry.
rate (entries 2 and 3 versus 1); (2) CuI is also feasible as a
catalyst and can be more effective than CuCl (entries 3, 6,
8, 13, and 15); and (3) the minor isomer b was assigned as
trans initially based on proton coupling constants15 (entries
5-7, 11, and 13) and was confirmed later via NOE
experiments (vide infra).
An immediate application of this reaction is the preparation
of chiral R-amino-ꢀ-lactams (Scheme 3). Toward this goal,
The scope of this reaction is distinctly diverse. As shown
in Table 1, we found several interesting features: (1)
Sterically more encumbered auxiliaries retard the reaction
Table 1. Scope of the Ynamide-Kinugasa Reaction
(6) For asymmetric Staudinger reactions, see:(a) Taggi, A. E.; Hafez,
A. M.; Wack, H.; Young, B.; Ferraris, D.; Lectka, T. J. Am. Chem. Soc.
2002, 6626. (b) Hafez, A. M.; Dudding, T.; Wagerle, T. R.; Shah, M. H.;
Taggi, A. E.; Lectka, T. J. Org. Chem. 2003, 68, 5819. (c) Hodous, B. L.;
Fu, G. C. J. Am. Chem. Soc. 2002, 124, 1578. Also see: (d) Tomioka, K.;
Fujieda, H.; Hayashi, S.; Hussein, M. A.; Kambara, T.; Nomura, Y.; Kanai,
M.; Koga, K. Chem. Commun. 1999, 715.
(7) Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun. 1972,
466.
(8) For reviews, see: (a) Evans, D. A.; Kleinbeck, F.; Ru¨ping, M. In
Asymmetric Synthesis - The Essentials; Christmann, M., Bra¨se, S., Eds.;
Wiley-VCH, Verlag GmbH & Co. KGaA : Weinheim, Germany, 2007; p
72. (b) Pal, Ghosh, S. C.; Chandra, K.; BVasak, A. Synlett 2007, 2321. (c)
Marco-Contelles, J. Angew. Chem., Int. Ed. 2004, 42, 2198. (d) Also see
Okuro, K.; Enna, M.; Miura, M.; Nomura, M. J. Chem. Soc. Chem.
Commun. 1993, 1107. (e) Ding, L. K.; Irwin, W. J. J. Chem. Soc. Perkin
Trans. 1 1976, 2382.
(9) For recent asymmetric accounts, see:(a) Lo, M. M.-C.; Fu, G. C.
J. Am. Chem. Soc. 2002, 124, 4572. (b) Shintani, R.; Fu, G. C. Angew.
Chem., Int. Ed. 2003, 115, 4216. (c) Ye, M-C.; Zhou, J.; Huang, Z-Z.;
Tang, Y. Chem. Commun. 2003, 2554. (d) Ye, M.-C.; Zhou, J.; Tang, Y.
J. Org. Chem. 2006, 71, 3576. (e) Coyne, A. G.; Muller-Bunz, H.; Guiry,
P. J. Tetrahedron: Asymmetry 2007, 18, 199.
(10) For an earliest account, see:Miura, M.; Enna, M.; Okuro, K.;
Nomura, M. J. Org. Chem. 1995, 60, 4999.
(11) For stereoselective approaches, see:(a) Pal, R.; Basak, A. Synlett
2007, 1585. (b) Pal, R.; Basak, A. Chem. Commun. 2006, 2992. (c) Basak,
A.; Ghosh, S. C.; Bhowmick, T.; Das, A. K.; Bertolasi, V. Tetrahedron
Lett. 2002, 43, 5499. (d) Basak, A.; Mahato, T.; Bhattacharya, G.;
Mukherjee, B. Tetrahedron Lett. 1997, 38, 643.
(12) For reviews on ynamides, see:(a) Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
(b) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379. (c)
Katritzky, A. R.; Jiang, R.; Singh, S. K. Heterocycles 2004, 63, 1455.
(13) For recent references on the chemistry of ynamides, see:(a)
Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung, R. P.; Yao, P.-Y.;
Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361. (b) You, L.; Al-Rashid, Z. F.;
Figueroa, R.; Ghosh, S. K.; Li, G.; Lu, T.; Hsung, R. P. Synlett 2007, 1656.
(c) Hashimi, A. S. K.; Salathe, R.; Frey, W. Synlett 2007, 1763. (d) For a
special issue dedicated to the chemistry of ynamides, see: Tetrahedron-
Symposium-In-Print: Chemistry of Electron-Deficient Ynamines and Yna-
mides. Tetrahedron 2006, 62, Issue No. 16.
a Reaction conditions are as shown in Scheme 2 unless otherwise
indicated. All are isolated yields. b dr is determined by using 1H NMR. All
isomers a are cis. The minor isomer b is trans. c 0.2 equiv of CuI was
used, and the reaction was run at 0 °C to rt. d With 0.2 equiv of CuCl, the
yield was 13%. e nd: not determined. f With 0.2 equiv of CuCl, yield was
71% and dr ) 91:9. g With 0.2 equiv of CuCl, yield was 48% and dr )
86:14. h PMP: p-methoxyphenyl. i With 0.2 equiv of CuCl and 4.8 equiv
of Hu¨nig’s base, yield was 54% and dr ) 87:13.
(14) See the Supporting Information.
(15) The range of proton couple constants for our cis-ꢀ-lactams is
5.0-5.6 Hz, and it is 2.0-2.4 Hz for trans-ꢀ-lactams.
3478
Org. Lett., Vol. 10, No. 16, 2008

On the basis of the assumption that the more reactive of
the two π-bonds is the one conjugated with the nitrogen lone
pair (all in red), the Cu(I)-promoted nitrone-[3 + 2]
cycloaddition via intermediate A could diverge into two
pathways that would determine the ꢀ-carbon stereochemistry.
The preferred pathway would involve the approaching nitrone
with its vinyl hydrogen (in red) being syn to HA on the chiral
auxiliary and the larger R group (c-hex in blue) anti to HA
to minimize steric interactions. This pathway would lead to
intermediate B (skipping respective intermediates 2 and 3
shown in Scheme 1), and while B could undergo protonation
at the more open bottom face away from the phenyl rings,
it would lead to the trans-isomer a that was not observed
from most of these reactions. Therefore, we reason that a
facially selective protonation takes place instead via inter-
mediate C on the top face to give cis-27a because C is more
stable than B given the presence of allylic strain.
On the other hand, the less favorable cycloaddition
pathway would involve the larger R group approaching syn
relative to HA on the auxiliary, and should lead to minor
isomers b via related intermediate D. We believe a facially
selective protonation also occurs here in D to provide trans-
27b as the most dominant minor isomer. Intriguingly,
B3LYP-6-31G* calculations reveal that trans-27a is ∼2.50
kcal mol-1 more stable than cis-27a, and trans-27b is ∼4.86
kcal mol-1 more stable than cis-27b. This implies that for
the major reaction pathway, a facially selective protonation
gives the kinetic product cis-27a, whereas a selective
protonation in the minor reaction pathway gave the more
stable trans-27b. Resubjecting cis-27b to the same reaction
conditions did not lead to any R-epimerization or observation
of trans-27b. Therefore, despite being more stable, trans
isomers are not likely derived from R-epimerizations of their
respective cis isomers.
Scheme 3. Synthesis of Chiral R-Amino-ꢀ-lactams
we prepared cis-27a in 44-62% yield from 11 with an a:b
ratio of in the range of 10:1-19:1. Hydrogenation with Boc-
protection followed by oxidative removal of the PMP group
in cis-27a with use of CAN provided chiral R-amino-ꢀ-
lactam 29. An R-epimerization of cis-27a via refluxing in
toluene in the presence of DBU for 40 h afforded trans-
27a, which could be converted to the isomeric R-amino-ꢀ-
lactam 31 through the same sequence used for cis-27a.
During the isolation of cis-27a, we were able to attain a
clean sample of the minor isomer trans-27b and confirmed
its relative stereochemistry between the R- and ꢀ-carbons
using NOE experiments.14 We also isolated a small sample
of cis-27b and spectroscopically observed a trace amount
of trans-27a. Neither had been seen in other reactions. The
assignment of cis-27b was confirmed through R-epimeriza-
tion to trans-27b with DBU.14 With these assignments, this
ynamide-Kinugasa reaction became very intriguing from a
stereochemical perspective. A unified mechanistic model is
proposed in Scheme 4.
We have described here a highly stereoselective ynamide-
Kinugasa reaction and featured its application as a stereo-
selective manifold for constructing chiral R-amino-ꢀ-lactam.
A proposed model reveals that the observed selectivity
requires both the initial cycloaddition and subsequent pro-
tonation to be stereoselective.
Scheme 4. A Proposed Mechanistic Model
Acknowledgement. Authors thank the NIH (GM066055)
for support and Dr. Victor Young and Ben Kucera (Univer-
sity of Minnesota) for X-ray analysis.
Supporting Information Available: Experimental pro-
1
cedures as well as H NMR spectra and characterizations.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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