Tetrahedron Letters
Carbocation catalyzed carboxylic acid activation in Staudinger
reaction for stereoselective synthesis of b-lactams
Ankita Rai a, Puneet K. Singh a, Prashant Shukla a, Vijai K. Rai b,
⇑
a School of Physical Sciences, Jawaharlal Nehru University, New Delhi 110 029, India
b Department of Chemistry, Guru Ghasidas Vishwavidyalaya, Bilaspur, Chhattisgarh 495 009, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel strategy to synthesize stereoselective b-lactams has been disclosed via cyclopropenium-ion-cat-
alyzed reaction of substituted acetic acids with aldimines under mild conditions. Products are formed in
high yields (86–95%) and good diastereoselectivity within 3–4 h. The new reaction is focused on the
exploration of the scope of cyclopropenium-ion catalysis and introduction of a catalytic version of
one-step Staudinger reaction for b-lactam synthesis. The reaction is effective for a range of substituted
acetic acids and aldimines.
Received 12 July 2016
Revised 28 September 2016
Accepted 5 October 2016
Available online xxxx
Keywords:
Ó 2016 Published by Elsevier Ltd.
Cyclopropenone
Carbocation activation
b-Lactam
Carboxylic acids
Aldimines
Long at the forefront of the biological relevance of b-lactams as
antibiotics coupled with their usefulness as synthons for further
functionalization, they are considered as one of the most important
aza-heterocyclic frameworks in organic chemistry.1a–g The synthe-
sis and properties of b-lactam derivatives with various functional
groups are important and maintain a rarefied place in the history
of organic reactions and pharmaceutical fields.2,3 A plethora of dis-
tinctive activities have been shown by b-lactams such as, anti-
cancer,4a antifungal,4b,c potential antimalarials,4d anti-influenza
virus,4e antihyperglycemic,4f central nervous system active
agents,4g combat of neurological diseases4h and as inhibitors.5 It
is therefore no surprise that, in current years, chemical methods
leading to the direct and facile synthesis of b-lactams, particularly,
catalytic enantioselective methods, remain among the most impor-
tant reactions for synthetic chemists.
It was Staudinger who developed the first most enduring
method for the synthesis of b-lactams by coupling of ketenes and
imines.6 This convergent strategy represents one of the most effec-
tive routes for preparing these compounds, and recently, some of
its catalytic asymmetric versions have been reported.7 In addition
to acyl halides and tertiary amines, carboxylic acids have also been
employed to generate in situ ketenes.8a With few exceptions,8b,c
the majority of these methods involve a combination of two or
three reactants that provide the required b-lactam framework in
a single step.8d–f Numerous one-step protocols for constructing
b-lactam ring have been reported in the literature using activated
carboxylic acid and imine employing acid activators.9,10 To note,
a variety of acid activators for in situ generation of ketenes have
been employed so far, viz., acetic anhydride, cyanuric chloride,
(Chloromethylene)dimethylammonium chloride, triphosgene,
1,1-carbonyldi-imidazole, ethyl chloroformate, the Mukaiyama
reagent, trifluoroacetic anhydride, p-toluenesulfonyl chloride,
phosphorus-derived reagents,10b and recently cinchona alkaloid
and isothioures.10f These conceptual approaches to accomplish
highly stereoselective azetidinone formation by the annulation of
imino compounds with an activated acid are of course high yield-
ing and well established. However, one or more of these methods
requires ultra low temperature (ꢀ78 °C), expensive reagents in sto-
ichiometric amount, tedious purification of final product, and most
importantly concomitant generation of stoichiometric by-prod-
ucts, which impacts severely on the atom efficiency, and adversely
on its large-scale applicability in industry. Furthermore, construc-
tion of b-lactam ring using oxalyl chloride is also well documented
but, except using Vilsmeier reagent, a number of products are
obtained in addition to b-lactam ring, which still opens up a chal-
lenge for exclusive synthesis of b-lactam using oxalyl chloride.11
These literature precedents and our interest in developing new
synthetic routes,12 especially using organocatalyst,12d triggered us
to search
a conceptually new, facile and efficient catalytic
⇑
Corresponding author. Tel.: +91 758 717 8627; fax: +91 775 206 0148.
activation of carboxylic acid for accessing b-lactams based on
0040-4039/Ó 2016 Published by Elsevier Ltd.