Chiral quaternary centers, enantioselective synthesis

Terrasson, V, van der Lee, A., de Figueiredo, R. M., Campagne, J.-M. (2010). Organocatalyzed cyclopropanation of alpha-substituted alpha.beta-unsaturated aldehydes enantioselective synthesis of cyclopropanes bearing a chiral quaternary center. Chemistry - A European Journal, 16,7875-7880. 

In summary, of the many chiral auxiliaries used in the asymmetric synthesis of carbonyl compounds via imines, those able to form a methoxymethyl-chclated azaenolate show the best enantioselectivities (see Tabic 7). The same is true for valine and im-leucine derivatives which form rigid chelates via their carboxyl groups. In particular, quaternary centers (see Table 6) and a-alkvl-/i-oxo esters arc effectively prepared using these chiral auxiliaries. 

Allylic substitution reaction is an important tool of enantioselective synthesis. Starting from readily available chiral allylic alcohols, products with tertiary and quaternary chiral centers can be obtained highly diastereos-electively,180,180a 181 181a 181b thus allowing an enantioselective new C-C bond formation (Scheme 60). 

The synthesis of (+)-estrone methyl ether (36) illustrates the enantioselective construction of a polycyclic target by the use of chiral auxiliary control to establish the first cyclic stereogenic center [14], In this case, the specific design of the naphthyldiazoester 32 directed Rh-mediated intramolecular C-H insertion selectively toward one of the two diastereotopic C-H bonds on the target methylene. The new ternary center so created then biased the formation of the adjacent quaternary center in the course of the alkylation. The chiral skew in the product cyclo-pentanone (35) controlled the relative and absolute course of the intramolecular cycloaddition, to give the steroid (+)-estrone methyl ether (36). 

Chiral quaternary carbon centers. Meyers et al. have reported an enantioselective synthesis of chiral ot,(t-disubstituted- y-keto acids (6) via the lactam 3 prepared from l-valinol (1) and the y-keto acid 2. Alkylation of 3 with primary alkyl halides gives mainly the endo-isomer (4). /dkylation of 4 also proceeds with endo-selectivity to give 5 with a... 

Besides stereoselective alkylations of glycine-derived enolates, enantioselective construction of chiral quaternary carbon centers from a-amino acids is one of the most challenging topics in current organic synthesis , since nonproteinogenic a,a-disubstituted amino acids often show a remarkable influence on the conformation of peptides. Moreover, they can act as enzyme inhibitors or as building blocks for the synthesis of a wide range of natural products . 

Overman and co-workers have demonstrated the feasibility of using a chiral ligand to cause asymmetric induction in an elegant enantioselective synthesis of (- -)- and (—)-physostigmine (237) (Scheme 3-53) [23a]. An intramolecular Heck reaction of the aryl iodide 234 proceeds smoothly, even though a trisubstituted double bond is being linked to the aryl moiety. This strategy allows the assembly of quaternary carbon centers in a stereoselective manner [214]. 

These conditions using the same family of chiral ligands have been recently applied to the enantioselective synthesis of N substituted quaternary carbon centers derived from ketoimines (Scheme 1.20) [84, 85]. 

Three-membered heterocycles are invested with a speeial allure that is derived from their apparent simplicity and spartan architecture. Yet these systems are multifaceted, and the literature continues to provide evidence of their diversity, both in terms of preparative routes and subsequent transformations. These smallest of heterocycles also exhibit a synthetically very useful balance between stability and reactivity. Thus, they are often employed as versatile and selective intermediates. With the potential to introduce two adjacent chiral centers with high atom economy, this methodology rightly deserves a place of prominence in synthetic organic chemistry. The utility of epoxides, for example, in the enantioselective synthesis of oxygen-substituted quaternary carbon centers has been the subject of a recent review <04COC 149>. 

Dabrowski JA, Gao F, Hoveyda AH (2011) Enantioselective synthesis of alkyne-substituted quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution reactions with ( Bu)2(alkynyl)aIuminum reagoits. J Am Chem Soc 133 4778-4781 Fananas-Mastral M, Feringa BL (2010) Copper-catalyzed regio- and enantioselective synthesis of chiral enol acetates and beta-substituted aldehydes. J Am Chem Soc 132 13152-13153... 

Very recently, Kotsuki and coworkers reported an enantioselective Robinson annulation reaction for the synthesis of cyclohexenone derivatives bearing a quaternary center. Chiral vicinal diamine-chiral Bronsted acid conjugate 168 was found to be the optimal catalyst. The reactions afforded chiral cyclohexenone with moderate yields and good enantioselectivity [75], It was proposed that simultaneous enamine activation of donor and iminium activation of acceptor were involved in the catalytic cycle (Scheme 5.47). 

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