Enantioselective, NHC-catalyzed bicyclo-β-lactam formation via direct annulations of enals and unsaturated N-sulfonyl ketimines

Article abstract of DOI:10.1021/ja0778592

A wide range of α,β-unsaturated aldehydes, including 3-alkyl derivatives, undergo N-heterocyclic carbene (NHC)-catalyzed annulations with N-sulfonyl ketimines under mild conditions to provide bicyclo[3.2.0]lactams with outstanding diastereo- and enantioselectivity. This concise route to β-lactams established four new chiral centers in a single operation. Although this process could occur via the intermediacy of a catalytically generated homoenolate equivalent, the stereochemical outcome supports a tandem or concerted aza-Benzoin/oxy-Cope reaction as the key bond-forming step. Copyright

Full text of DOI:10.1021/ja0778592

Published on Web 12/20/2007
Enantioselective, NHC-Catalyzed Bicyclo-â-Lactam Formation via Direct
Annulations of Enals and Unsaturated N-Sulfonyl Ketimines
Ming He and Jeffrey W. Bode*,†
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106-9510
Received October 13, 2007; E-mail: bode@sas.upenn.edu
Table 1. Enantioselective, NHC-Catalyzed â-Lactam Formation
The synthesis and properties of â-lactams maintain a rarefied
place in the history of organic reactions, structure, and therapeutic
applications.1 It is therefore no surprise that chemical methods
leading to the direct and facile synthesis of â-lactams, particularly,
catalytic enantioselective methods, remain among the most prized
targets for reaction development.2 To this end, important advances
have emerged from Doyle,3a Lectka,3b Fu,3c,d and others.2
with 3-Alkyl Enals (see eq 1 for reaction scheme)a
We have recently pioneered N-heterocyclic carbene (NHC)-
promoted annulations of enals via the catalytic generation of reactive
species.4,5 As part of these studies, we demonstrated that NHC-
catalyzed reactions of enals and certain R,â-unsaturated ketones
afford enantioenriched cyclopentenes via a cascade process featuring
a crossed-benzoin/oxy-Cope rearrangement.6,7 The mechanistic
postulate intrinsic to these annulations anticipates a method that
could lead to the formation of a stable â-lactone or â-lactam
annulation product. We now document a successful, highly enantio-
and diastereoselective synthesis of enantiomerically pure bicyclic
â-lactams via a remarkable annulation process of 3-alkyl or 3-aryl
enals and chalcone-derived imines8 (eq 1).
We initially dismissed enantioselective â-lactam formation as
unviable due to the high probability of competing enal dimerization
or aza-Diels-Alder reaction, as we have previously reported highly
enantioselective triazolium-catalyzed annulations between unsatur-
ated N-sulfonyl aldimines and electron-deficient enals.9 Our studies,
however, noted that the reaction outcomes of similar or even
identical substrate pairs can be modulated by judicious choices of
precatalyst (triazolium vs imidazolium),9 amine base (DBU vs
NEt3),10 and substrates (electron-deficient versus 3-alkyl or 3-aryl
enals). Our initial forays identified a new reaction of trans-2-butenal
and the N-para-methoxybenzene sulfonyl imine of chalcone,11
DBU, and chiral N-mesityl-substituted triazolium precatalyst 1
(Table 1, entry 1).12 The relative and absolute stereochemistry was
established by X-ray analyses as a bicyclo[3.2.0]lactam wherein
all of the substituent groups are situated on the same face. Optimi-
zation of the conditions selected, for 3-alkyl enals, EtOAc as the
preferred solvent. Notably, prior studies had shown that 3-alkyl
enals were either poor substrates or inert to NHC-catalyzed C-C
bond-forming reactions under mild conditions. Even acrolein was
a viable substrate, albeit in diminished yield due to a competing
Diels-Alder reaction (entry 3).
a Ar ) 4-MeOC6H4. All reactions were performed at 0.1 M for 15 h.
Except in entry 5, only a single diastereomer was detected in unpurified
reaction mixtures. b Isolated yield after chromatography. c Determined by
HPLC or SFC. d With 3-methyl-2-butenal. e Under the conditions employed
in Table 2: 78% yield, 99% ee, 5:1 dr. f Diastereomeric ratio.
Scheme 1. Effect of Catalytic Base on Lactam Stereochemistry
Cinnamaldehyde derivatives were also viable substrates under
the conditions shown in Table 1 but led to the lactam products as
mixtures of diastereomers (Scheme 1). We discovered a pronounced
effect of the catalytic base on the diastereoselectivity. When the
reactions were performed in CH3CN using DMAP as the catalytic
base,13 a slower but cleaner reaction resulted, leading to formation
of the desired product in 9:1 dr. A slight modification of these
conditions improved the dr and was directly applicable to both
† Present address: Department of Chemistry, University of Pennsylvania.
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C O M M U N I C A T I O N S
Table 2. Enantioselective, NHC-Catalyzed â-Lactam Formation
outcome allows subsequent lactamization to form the â-lactam and
release the catalyst. The trans isomer from cinnamaldehyde sub-
strates may be produced via an alternative mechanism featuring
conjugate additions of catalytically generated homoenolates, which
Nair demonstrated to prefer the trans products in a cyclopentene-
forming annulation.7 The high preference for this process, rather
than NHC-catalyzed Diels-Alder reaction, arises from the use of
nonactivated enals which are slow to undergo protonation at the
â-position.10
with 3-Aryl Enals (see eq 1 and Scheme 1 for conditions)a
In summary, we have documented a highly enantio- and
diastereoselective direct annulation of enals, including 3-alkyl enals,
and chalcone-derived imines that takes advantage of a powerful
benzoin/oxy-Cope strategy. This process allows direct access to
cyclopentyl-fused â-lactams in an operationally simple process that
establishes four contiguous stereocenters.
Acknowledgment. Partial support for this work was provided
by the National Science Foundation (CHE-0449587). Unrestricted
support from Amgen, AstraZeneca, Eli Lilly, Boehringer Ingelheim,
and Bristol Myers Squibb is gratefully acknowledged. J.W.B. is a
fellow of the Packard Foundation, the Beckman Foundation, the
Sloan Foundation, and a Cottrell Scholar. We thank Justin Struble
for catalyst preparation and Guang Wu (UCSB) for X-ray analyses.
Supporting Information Available: Experimental procedures and
characterization data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
References
a Ar ) 4-MeOC6H4. All reactions were performed at 0.1 M with 1.4
equiv of enal, 1.0 equiv of imine, 10 mol % of 1, and 30 mol % of DMAP
for 24-36 h. b Isolated yield after chromatography. c Determined by HPLC
or SFC analysis. d The ratio of diastereomers was determined by 1H NMR
analyses of unpurified reaction mixtures.
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Scheme 2. Postulated Catalytic Cycle (ent-1 is shown as the
NHC)
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Supporting Information for examples.
electron-deficient and electron-rich cinnamaldehyde and chalcone-
imine derivatives (Table 2).14
The stereochemical outcome provides further support for a
tandem, or possibly concerted, crossed-benzoin/oxy-Cope reaction
as the key bond-forming step (Scheme 2).6 The cis-relative
configuration of the cyclopentane substituents would arise from a
boat oxy-Cope transition state that maximizes secondary orbital
overlap between the Breslow intermediate and the unsaturated
imine. The remaining stereocenter is established by a reversible
intramolecular Mannich reaction, wherein only one stereochemical
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