Y-Lactams, formation

Recently, Yu and co-workers developed an operationally simple catalytic system based on [RuCl2(/>-cymene)]2 for stereoselective cyclization of a-diazoacetamides by intramolecular carbenoid C-H insertion.192 /3-Lactams were produced in excellent yields and >99% m-stereoselectivity (Equation (53)). The Ru-catalyzed reactions can be performed without the need for slow addition of diazo compounds and inert atmosphere. With a-diazoanilide as a substrate, the carbenoid insertion was directed selectively to an aromatic C-H bond leading to y-lactam formation (Equation (54)). 

The reaction of a-methoxycarbonyl-a-diazoacetamides is best catalyzed by Rh2(S-PTTL)4 or related catalysts [2,10]. Again, there is competition between /3-lac-tam and y-lactam formation. The chemistry has been applied to the synthesis of a variety of/3-lactam derivatives, as illustrated in Scheme 6 [11]. Rh2(S-PTTL)4-cata-... 

F. Kjeldsen and R. A. Zubarev, Secondary losses via y-lactam formation in hot electron capture dissociation A missing link to complete de Novo sequencing of proteins /. Am. Chem. Soc., 125 (2003) 6628-6629. 

Diazoacetamides are robust diazo substrates, but they generally give lower enantioselection, and regioselectivity for y-lactam formation is dependent on the substituents on carbon at which insertion occurs (e.g. eq 5). With A(-(n-butyl)-A -(f-butyl)diazoacetamide the ratio of y P-lactam is 88 12. A significant improvement in enantioselection (up to 78% ee) occurs with the use of the oxazolidinone analog of Rh2(55 -MEPY)4. ... 

Scheme 3 Intramolecular y-Lactam Formation with Activated Arginine Derivatives ...

However, when the W-alkyl sustituents are tied back in a cyclic structure, as in the example in Eq. (50), y-lactam formation is rendered more unfavourable geometrically and 3-lactam formation becomes the sole reaction pathway with nearly complete enantiocontrol (97% ee) [68]. 

During coupling, the nucleophilic side-chain of arginine is susceptible to y-lactam formation [54] (Scheme 20.7). This irreversible reaction will effectively render the activated arginine derivative inactive during the coupling reaction. 

During normal synthesis this may not be apparent as a significant problem, because the coupling reaction will occur before substantial y-lactam formation occurs. In a difficult coupling reaction, however, y-lactam formation may become more favorable than coupling. In these circumstances, extending the reaction time will not promote completion of the coupling. This was shown recently with the mi-... 

Another reaction that has been extensively studied is the y-lactam formation. The initial cyclization study using a secondary amide tether did not afford any desired product. It was believed that the predominant trans conformation of the secondary amide prevented the cyclization (Figure 2-16). In fact, the protected enynes with a tertiary amide linked were readily transformed into a variety of y-lactams. Under the optimized conditions, enyne-amide 475 afforded functionalized y-lactams 476 in high yield and good-excellent enantioselectivities... 

Scheme 14.14 y-Lactam formation reactions via homoenolate intermediates. 

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