A-Methylene-y-lactams

TiCU additive is employed. "BFvEt O additive is employed. The allyllead reagent is formed in situ according to ref. 2, its structure is not known. Ar = 3,4,5-trimethoxyphenyl. The product isolated is the a-methylene-y-lactam. 

Asymmetric synthesis of a-methylene-y-lactams. The organozinc reagents derived from 2-(bromomethyl)acrylatcs react with imincs to form a-mcthylene-y-lactams. Use of (S)-l-phenylglycinc as the chiral auxiliary for the imine provides these products in >95% ec. 

Cycloaddition. W-(Diphenylmethylene)-4-methylben-zenesulfonamide (2) has been used as a dienophile in a hetero [3 + 2] cycloaddition. Dipolar trimethylenemethane (TMM, 21), generated by means of thermolysis of methylenecyclopropane (22), undergoes [3 + 2] cycloaddition with the reagent to regio-selectively afford the acetal of the a-methylene-y-lactam product 23. This product is quite acid-sensitive and may he isolated as the corresponding a-alkyhdene-y-amino ester. The cycloadduct serves as a synthetic precursor to y-amino acid derivatives (eq 13). 

F. Pan, J.-M. Chen, Z. Zhuang, Y.-Z. Fang, S. X.-A. Zhang, W.-W. Liao, Org. Biomol. Chem. 2012, 10, 2214—2217. Construction of highly functional a-amino nitriles via a novel multicomponent tandem organocatalytic reaction a facile access to a-methylene y-lactams. 

Chemoselective reduction of 3-aryl-2-diethoxyphosphoryl-4-nitroalk-anoates (77) provided the corresponding a-diethoxyphosphoryl-y-lactams (78) in a completely diastereoselective manner (Scheme 24). These products were useful substrates in the synthesis of mono-(3-substituted a-methylene-y-lactams (79), which constituted heteroatom analogues of biologically active exo-methylene cyclopentanoids. Cytotoxicities of (79) were also evaluated. 

Scheme 4.5 Diastereoselective synthesis of a-methylene-y-lactams trans-2 b.

In a similar manner, simple Baylis-Hillman alcohols 62 were transformed into P,y-disubstituted-a-methylene-y-lactams 29b (Scheme 4.16) [48]. The sequential treatment of alcohols 62 with HBr, DABCO (l,4-diazabicyclo(2.2.2]octane), and a nitroalkane 51 afforded the requisite 2-methylene-4-nitroalkanoates 63 as two diastereoisomers in a 1 1 ratio. Subsequent standard transformations involving reduction of the nitro group and lactamization gave the final products 29b as mixtures of two diastereoisomers with the ratio originating from the substitution... 

Scheme 4.16 Synthesis of p,y-disubstituted-a-methylene-y-lactams 29b from Baylis-Hillman alcohols 62.

Such a synthetic approach was employed by Corey et al. [58] for the synthesis of optically active a-methylene-y-lactam 101 (Scheme 4.27). The starting acrylamide 100 was prepared in six steps from the cheap and readily available N-4-methoxybenzoyl r-threonine methyl ester. The quinuclidine-catalyzed intramolecular asymmetric Morita-Baylis-Hillman reaction of 100 was followed by the conversion of the introduced alcohol moiety into a bromomethyldimethylsilyl ether 101. The a-methylene-y-lactam 101 with two adjacent quaternary stereogenic centers was formed in high yield as a mixture of two diastereoisomers in 9 1 dr. Interestingly, it was a key intermediate in the total synthesis of natural product salinosporamide A (102) that was accomplished in eight steps. 

Moreover, in the case of six-membered heterocycles, the possibility to introduce various alkoxy substituents in the 3-position to afford 107 was demonstrated when the cyclization was performed in the presence of the alcohol cosolvent. Disappointingly, application of the same approach for the preparation of a-methylene-y-lactams proved unsuccessful as the initially formed adduct 109 underwent dehydration to afford 110 as the only product. 

A general approach to a-methylene-y-lactams 29b with diverse substitution pattern employing 2-diethoxyphosphoryl-4-nitroalkanoates 127 was recently established by the research groups of Janecki and Krawczyk (Scheme 4.34) [28d,e, 63, 64]. These key intermediates were obtained via the addition of ethyl diethoxyphos-phorylacetate to ( )-l-aryl-2-nitro-l-butenes [28e]. Alternative methods relying on... 

Scheme 4.34 Preparation of a-methylene-y-lactams 29b from the a-diethoxyphosphoryl-y-...

Scheme 4.37 Stereoselective synthesis of y-alkylidene-a-methylene-y-lactams 141.

A -Trimethylsilylaldimines. Aldehydes, even enolizable ones, undergo Peterson reactions with LHDMS to give N-trimethylsilylaldimines (eq 13), which are valuable intermediates for a variety of systems, including primary amines, /3-lactams, and a-methylene-y-lactams (eq 14). Extension of this chemistry to include a-keto ester substrates allows for the preparation of a-amino esters. 

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