Kinugasa Reaction: A Direct One‐Pot Route to Highly Functionalized β‐Lactams

Abstract

The β‐lactam antibiotics are among the most commonly prescribed drugs in the world and their importance has been demonstrated by the isolation and syntheses of several classes of these agents. Of the synthetic routes used to access this interesting scaffold, the Kinugasa reaction utilizes a convergent strategy based on cycloaddition between readily available terminal alkynes and nitrones. Asymmetric versions involving chiral catalysts, chiral auxiliaries or chiral substrates have also been reported. This article gives a brief overview of the Kinugasa reaction and of recent advances since its discovery.

Kinugasa Reactions in Water: From Green Chemistry to Bioorthogonal Labelling

“…In addition to isoxazoline synthesis, nitrones are key precursors to diverse β-lactam structures through the copper(I)-catalyzed Kinugasa reaction with acetylides [ 7 , 8 ]. Since the initial report of the reaction between copper(I) acetylides and nitrones in pyridine in 1972 [ 8 ], the scope and limitations of the Kinugasa reaction have been explored by a number of research groups [ 9 , 10 , 11 ]. Recent progress in expanding the scope of the reaction has afforded the transition from requiring polar aprotic reaction media to an ‘on water’ approach, as well as employing detergents to allow for a micelle-promoted reaction to occur in aqueous medium [ 12 ].…”

Synthesis of Monobactams via the Diastereoselective Kinugasa Reaction

“…Subsequent treatment of the free carboxylic acid with Pb(OAc) 4 introduced an acetoxy substituent to the C-4 carbon atom of the azetidinone ring, providing a mixture of trans and cis compounds 12 and 13, which were separated by chromatography into pure isomers. The two-step procedure leading from 11 to the mixture of compounds 12 and 13 proceeded with relatively low overall yield (23%).…”

“…1 This two-step process, known as the Kinugasa reaction, 2,3 provided bicyclic β-lactams with high diastereoselectivity. [4][5][6][7] The configuration of both carbon atoms of the β-lactam fragment is controlled by the configuration of the nitrone substituent located next to the nitrogen atom, providing the 6,7-cis-substituted 4-oxacepham as the major product (Scheme 1). 1,[4][5][6][7] The known sensitivity of the phthaloyl protecting group to bases made transformation of the Kinugasa adducts difficult.…”

“…[4][5][6][7] The configuration of both carbon atoms of the β-lactam fragment is controlled by the configuration of the nitrone substituent located next to the nitrogen atom, providing the 6,7-cis-substituted 4-oxacepham as the major product (Scheme 1). 1,[4][5][6][7] The known sensitivity of the phthaloyl protecting group to bases made transformation of the Kinugasa adducts difficult. 8 It should be stressed, however, that in contrast to other protected aminoacetylenes, ready availability of the phthalimido compound 1 determined its use in the synthesis.…”

A New Approach to the Synthesis of 4-Phosphonylated β-Lactams

“…A copper(I)-catalyzed [3+2] cycloaddition of terminal alkynes to nitrones (Kinugasa reaction 26 ) has been frequently applied in the construction of functionalized β-lactams. [27][28][29][30][31][32][33][34][35][36] Herein, we wish to describe a new method for the synthesis of 4-phosphonylated β-lactams (4-oxoazetidin-2ylphosphonates) employing recently synthesized 37 N-methyl-C-(diethoxyphosphoryl)nitrone (12, Scheme 2) which has already found several synthetic applications. [38][39][40][41][42][43] When 3.0 equivalents of copper(I) phenylacetylide generated in situ at room temperature under an argon atmosphere was subjected to the reaction with a nitrone 12 in either DMF or acetonitrile for three days, a 22:78 mixture of isomeric phosphonates 13a and 14a was obtained in good yield in both solvents (Table 1, entry 1; procedure A 44 ).…”