A quaternary stereocenter

Hills ID, Fu GC (2003) Catalytic enantioselective synthesis of oxindoles and benzofuranones that bear a quaternary stereocenter. Angew Chem Int Ed 42 3921-3924... 

An jV-heterocyclic carbene 110 catalyzed the rearrangement of the 0-acyl carbonates 109 into their corresponding C-acylated isomers 111, generating a C-C bond and a quaternary stereocenter with high efficiency <06OL3785> The same reaction can be performed enantioselectively using TADMAP 112 <06JA925>. 

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

Scheme 6.41. Stereoselective construction of a quaternary stereocenter by allylic substitution of mesylate 195 with a boron trifluoride-modified cyano-Gilman cuprate reagent.

The first asymmetric total synthesis of (+)-lycorine is outlined in Scheme 15. While our earlier applications of the Birch reduction-alkylation of chiral benzamide 5 were focused on target structures with a quaternary stereocenter derived from C(l) of the starting benzoic acid derivative, the synthesis of 64 demonstrates that the method also is applicable to the construction of chiral six-membered rings containing only tertiary and trigonal carbon atoms. s... 

If the 3-position is a quaternary stereocenter, then Rh(I)/Tol-BINAP is the catalyst of choice for the hydroacylation process. With this catalyst, both kinetic resolutions (Eq. 20) and desymmetrization reactions (Eq. 21) may be accomplished. 

If the 3-position is a tertiary, rather than a quaternary, stereocenter, Rh(I)/Tol-BINAP effects an intriguing parallel kinetic resolution - thus, one enantiomer of the substrate selectively undergoes hydroacylation to generate a cyclobutanone, while the other enantiomer is transformed into a cyclopentanone (Eq. 22) [24]. This observation is quite interesting, given the limited number of examples of parallel kinetic resolutions, particularly catalytic processes that involve carbon-carbon bond formation, and catalytic methods for the construction of cyclobutanones. 

The potential substrates for the Strecker reaction fall into two categories ald-imines (derived from aldehydes, for which cyanide addition results in formation of a tertiary stereocenter) and ketoimines (derived from ketones, for which addition results in a quaternary stereocenter). As in the case of carbonyl cyanation, significant differences are observed between the substrate subclasses. To date, while a few catalyst systems have been found to display broad substrate scope with respect to aldimine substrates, successful Strecker reactions of ketoimines have been reported in only two cases. As is the case for all asymmetric catalytic methodologies, the breadth of the substrate scope constitutes a crucial criterion for the application of the Strecker reaction to a previously unexplored substrate. 

No diastereo- or regioisomeric products were detected, giving exclusively the fused five-membered oxacycles 186 (Scheme 65). Tetrahydrofuran-fused 2-azetidinones 186 are remarkable since they bear a quaternary stereocenter. 

Kawabata, T. Kawakami, S. Majumdar, S. Asymmetric cyclization via memory of chirality a concise access to cyclic amino acids with a quaternary stereocenter. J. Am. Chem. Soc. 

The high diastereoselective synthesis of multifunctionalized 3,4-dihydro-coumarins bearing a quaternary stereocenter was developed through tandem Michael additions of indole and its derivatives (1-methyl, 2-methyl, 4-methoxy, 5-methoxy, 5-bromo, 6-benzyloxy) to 3-nitrocoumarines (3-nitro-chromen-2-one, 6- and 7-methyl-3-nitro-chromen-2-one) followed by methyl vinyl ketone in a one-pot step. For the tandem Michael additions, after the first Michael reaction of indole (2) with 3-nitrocoumarine (51) catalyzed... 

The desymmetrization of 4-substituted-4-(3-formylpropyl)cyclohexa-2,5-dien-l-one 65 formed - in a single step - three contiguous stereocenters, including a quaternary stereocenter (Scheme 2.56). 

The formation of a quaternary stereocenter could be achieved with a,a,a-trifluoroacetone as electrophile. An enantioselective procedure for this novel carbon-carbon bond-forming process has not been reported to date, the first results with a chiral imidazolium salt as precatalyst developed by Glorius et al. resulted in only low enantiomeric excesses (12-25% ee). 

In this single cyclizalion/alkylation cascade, two C - C bonds, one C - N bond, a carbonyl group, a tertiary and a quaternary stereocenter have been generated. 

Some tethered alkene affects regioselectivity remarkably. The reaction of the diene 68 with malonate occurred at the more substituted allylic terminus proximal to the tethered alkene to give 69, having a quaternary stereocenter with... 

Oxindoles are a particular class of cyclic amides which are acidic enough to play the role of pro-nucleophiles in conjugate additions under iminium activation. In particular, the reaction between 3-alkyl substituted oxindoles and ot,p-unsaturated aldehydes leading to the formation of a quaternary stereocenter at the heterocyclic unit has been studied by several authors (Scheme 3.12). The use of 0-trialkylsilyldiarylprolinols like 31a as catalysts led... 

The Michael reaction of 2-alkyl substituted 1,3-diketones with alkynones has been carried out by Jnrgensen using chiral base 124a as the most efficient catalyst (Scheme 6.14). Importantly, this reaction not only generates a quaternary stereocenter but also delivers a highly functionalized final product containing an a,p-unsaturated ketone side chain, suitable for further... 

Scheme 1.1 Enantioselective Michael/aldol cascade reaction generating a quaternary stereocenter.

The catalyst was able to differentiate and control the reactivity of both used aldehydes, allowing the synthesis of chiral P-hydroxy aldehydes bearing a quaternary stereocenter in good results (40-95%, 50-99% de, 41-98% ee) [261]. By using this reaction protocol, the total synthesis of branched-chain natural products such as pantolactone or lyxose derivatives were successfully accomplished. 

Scheme 6.7 A cycloaddition followed by a sigmatropic rearrangement equipping an arene with a quaternary stereocenter and realized in the preparation of various oxoindoles.

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