Bent but not broken: cyclic oligoprolines are accessed in a reaction that effectively bends rigid oligoproline peptides (see scheme; TBDMS=tert-butyldimethylsilyl). The stitching is accomplished during macrocyclization enabled by aziridine aldehydes and isocyanides. Molecular modeling studies suggest that electrostatic attraction between the termini of the linear peptide is pivotal for macrocyclization. The macrocycles were studied by circular dichroism with a polyproline II structure being observed in larger macrocycles.

Lewis acid promoted substitution reactions employing Meldrum's acid and 5-methyl Meldrum's acid as carbon-based leaving groups are described which transform unstrained quaternary and tertiary benzylic C(sp(3))-C(sp(3)) bonds into C(sp(3))-X bonds (X = C, H, N). Importantly, this reaction has a broad scope in terms of both suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).

The asymmetric formation of all-carbon quaternary benzylic stereocenters containing a methyl substituent was realized by the enantioselective copper-catalyzed 1,4-addition of dimethylzinc to alkylidene Meldrum's acids in the presence of a chiral phosphoramidite. Copper source and ligand optimization studies are presented, as well as the scope and limitations of dimethylzinc addition to various alkylidene Meldrum's acids. Good to excellent yields and enantioselectivities were obtained.The catalytic asymmetric formation of all-carbon quaternary stereocenters remains an important goal in organic chemistry. 1 Conjugate addition of organometallic reagents to carbonyl-, nitro-, and sulfone-activated tri-and tetrasubstituted alkenes, has become a general and efficient method to access this structural motif. 2 A number of research groups, 3 along with ours, 4 have reported the enantioselective copper-catalyzed addition of organoaluminum, organozinc, and Grignard reagents. The rhodiumcatalyzed addition of alkenyl-and arylboronic acids was also described. 5 From these synthetic strategies towards the formation of all-carbon quaternary stereocenters, aryl, alkenyl, and alkyl groups were introduced.Our group 4 has established that alkylidene Meldrum's acids 1 are excellent electrophiles 6 to access all-carbon benzylic quaternary stereocenters through enantioselective copper-catalyzed conjugate addition of organozinc reagents in the presence of commercially available chiral phosphoramidite 7 ligand 3a. Excellent conversions, yields, and enantioselectivities in the formation of 2 were achieved (Scheme 1). We also demonstrated that the pattern of substitution of the arene moiety impacted the efficiency of the reaction as well as the enantioselectivity of the conjugate addition.Despite the superior electrophilicity of alkylidene Meldrum's acids 1 towards organozinc reagents, the addition of dimethylzinc lacked generality. The conjugate addition of dimethylzinc to Meldrum's acid indelydine 1a gave >99% conversion, 98% isolated yield, and 99% ee. 4c However, less reactive alkylidene 1b led to a poor 35% conversion (Scheme 2). 4c Scheme 1 Enantioselective copper-catalyzed 1,4-addition of dialkylzinc reagents to alkylidene Meldrum's acids 1 Scheme 2 Dimethylzinc addition to alkylidene Meldrum's acids The commonality of methyl-containing all-carbon quaternary stereocenters in bioactive natural products prompted us to optimize the enantioselective methyl delivery to alkylidene Meldrum's acids 1. A limited number of reports have appeared in the literature regarding asymmetric addition of methyl groups for the formation of all-carbon quaternary carbons. Hoveyda showed that the poorly nucleophilic dimethylzinc reacted with highly activated alkenes such as nitroalkenes, 3n and cycloalkenones bearing a carboxylate group at the 2-or 3-position, 3m,k in the presence of a copper catalyst, to yield all-carbon quaternary stereocenters in good yields and enantioselectivities. Our group obtained limited success on the addition of dimethylzinc to ...

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Dioxane derivatives R 0470 Enantioselective Copper-Catalyzed Conjugate Addition of Dimethylzinc to 5-(1-Arylalkylidene) Meldrum's Acids. -The reaction conditions are optimized with respect to the copper salt catalyst and the phorphoramidite ligand. -(WILSILY, A.; LOU, T.; FILLION*, E.; Synthesis 2009, 12, 2066-2072; Dep. Chem., Univ. Waterloo, Waterloo, Ont. N2L 3G1, Can.; Eng.) -Mais 43-167