Total synthesis acyclic stereocontrol

The older approaches to the penam skeleton from acyclic precursors were based on the azetidinone ring formation by [2+2] cydoaddition of ketens or enolates to imines and by cyclization of fS-amino add precursors. These methods have been reviewed by Jastrzebski and Van Koten [76] and by Marchand-Brynaert and Brule [77]. Sheehan and Henery-Logan [78] developed the first total synthesis of natural penicillin in 1957. Baldwin and coworkers [79] reported the first highly stereocontrolled total synthesis of natural penicillin. Most of the recent methods for the synthesis of nonnatural penams, however, employ 2-azetidinones with appropriate functionalities for fused ring cyclization. 

Miyashita, M. and Tanino, K. (2004) Natural product synthesis based on new acyclic stereocontrol. Stereoselective total syntheses of zincophorin, the ionophore antibiotic, and scytnphydn C, an antitumor marine macrolide./. Synth. Org. Chem. Japan, 62,1080-1094. 

Paterson, I. and Perkins, M.V. (1996) Total synthesis of (—)-denticulatins A and B using efficient methods of acyclic stereocontrol. Tetrahedron, 52,1811-1834. 

Kishi described an elegant example of a bromoetherification reaction for effecting acyclic stereocontrol (Scheme 9.29) [162], In this case, bromide 219 was isolated as a single isomer in 57 % yield upon treatment of diolefin 218 with NBS. The presence of an allylic stereogenic center with two substituents of considerably different steric demands (Me versus 4-(3-methylbut-l-ene)) in 218 leads to a system in which interactions play a dominant role in controlling the stereochemical outcome of the cyclization. These synthetic efforts leading to intermediate 219 culminated in the total synthesis of the polyether antibiotic monensin (220) [163]. 

The stereocontrol inherent in the totally regiospecific 5-exo-trig isomerizations of substituted 5-hexenyllithiums may be exploited for the stereoselective synthesis of bicyclic systems by tandem cyclization of acyclic diolefinic alkyllithiums. To date, this strategy has not been widely applied, and the first examples were reported by Bailey and Rossi who were able to cyclize the organolithiums derived from iodides 113 and 115 in the presence of TMEDA to afford the polycarbocyclic products 114 and 116 (Scheme 33)61. 

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