Biaryl lactams

Ruhland et al. used both the Suzuki and Heck (see above) reactions on solid support in their generation of libraries of biaryl- and styryl-substituted [3-lactams.45 A preliminary investigation was performed into the most generally suitable catalytic system for preparation of their libraries. This featured coupling of phenylboronic acid with a resin-bound iodophenyl [3-lactam 32 (Scheme 36) the latter compound had been formed from a... 

Benzyltriethylammonium chloride, (56-37-1), 66, 204 68, 220 N-Benzyl-N-(trimethylsilyl)methylamine Benzenemethanamine, N [(trimethyl-silyI)methyl]- (53215-95-5), 67, 133 BETA-LACTAM, 65, 135, 140 BIARYL SYNTHESIS, 66, 67... 

In 2005, the group of Alcaide has reported the regiocontrolled preparation of biaryl-2-azetidinones (I and II, Fig. 17), via aryl-aryl radical cyclization and/or rearrangement of (3-lactam-tethered haloarenes [286]. 

Applications of Suzuki and Heck cross-coupling reactions were adopted by Gallop and coworkers [131] to prepare diverse biaryl- and styryl-substituted (3-lactams on solid support. The catalyst system, [PdCl2(dppf)]-TEA, was found to be efficient to promote C-C bond formation around a (3-lactam template (Schemes 26 and 27). 

Fused tetracyclic biaryl-2-azetidinones have been prepared by the radical cyclization of aryl /3-lactam-tethered haloarenes. Azetidin-2-one 504, having an extra radical acceptor on C-3, underwent radical cyclization with tributyltin hydride to give the biaryl-2-azetidinone 505 in a low yield, with debrominated 3-phcnoxyA-phcnyl-l -(/ -methoxy-phenyl)-2-azetidinone as the main product (60% yield) (Equation 82). But when the azetidinones 506 (Rz = R6 = H) bearing an extra link (O) on the radical precursor at C-3 or N-l of the /3-lactam ring were treated with tributyltin hydride, the expected cyclization products 507 were obtained. If azetidinones 506 (Rz = OMe, or Me R6 = H, OMe, or Me) were treated in the same way then the tetracyclic azetidinones 508 were produced (Equation 83) <2005T7894>. 

Several structural features of (-)-rhazinilam 3 raise interesting synthetic challenges the axially chiral phenyl-pyrrole A-C biaryl bond, the fused pyrrole-piperidine C-D rings, the stereogenic quaternary carbon (C-20) ortho to the phenyl-pyrrole axis, the nine-membered lactam firing. Three racemic (Smith, Sames, Magnus) and one asymmetric (Sames) total syntheses have been published to date, which all proceed via construction of the pyrrole ring and diastereoselective control of the axial chirality by the central chirality at C-20. 

These extensive SAR studies have shown that the rigid biaryl/nine-membered lactam structure of rhazinilam adopting a boat-chair conformation is an essential feature for its antimitotic properties. Moreover, the absolute aR configuration of the biaryl axis is, as in the allocolchicine and stegane series, absolutely required for biological... 

The addition of a lipophilic ring pharmacophore to this bicyclic aryl or biaryl structure, e.g., phenyl, methoxyphenyl, ethylthiophenyl, imidazolyl, pyrazolyl, or pyridyl, generates the second inhibitor subfamily full-length inhibitors consisting of three modules, such as meribendan or CI-930 (112-115, Figure 9.26) [102,103]. Again, the middle pharmacophore can be incorporated into the lactam module (116,117) or into the additional lipophilic part of the inhibitor (118,119). Extreme condensation of the pharmacophores, so as to incorporate all three modules into one tricyclic system, resulted in inhibitors 120 and 121. 

Similarly, Wallace s group reported the condensation of L-valinol onto configurationally unstable 2 -formylbiphenyl-2-carboxylic acid to give the corresponding lactam as a mixture of two diastereomers in excellent yield. The biaryl axis of the major diastereomer had the (S)-configuration, as shown in Scheme 5.31. 

The presence of one chiral center in the starting material should induce the formation of a single atropoisomer of the biarylic system. The iodoaryl 124, prepared in few classic steps, placed in the presence of palladium diacetate, the monophosphine DavePhos and potassium carbonate as base afforded the expected lactam 127 isolated as a single stereoisomer with moderate yield (47%). In a similar manner, the lactam 129, precursor of the rhazinal 123, was obtained after treatment of the iodoaryl 128 in the same reaction conditions. The C(sp )—C(sp ) bond formation was achieved following this suggested mechanism A nucleophilic attack... 

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