Quaternary carbon chiral construction

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. 

The asymmetric cyclopropanation of a-bromocyclohexenone with cyanoacetate 31 has been achieved under phase-transfer conditions by the use of cinchona alkaloid-derived catalyst, which constructs chiral quaternary carbons on the cyclopropane... 

As mentioned above, the enantioselective Michael addition of P-keto esters to a,P-unsaturated carbonyl compounds represents a useful method for the construction of densely functionalized chiral quaternary carbon centers. One characteristic feature of designer chiral phase-transfer catalyst lh in this type of transformation is that it enables the use of a,p-unsaturated aldehydes as an acceptor, leading to the... 

Another application of camphor-based chiral auxiliaries is the use in stereoselective Diels-Alder cycloadditions (Chapter 26), especially for the construction of quaternary carbon centers. One example, shown in Scheme 5.12, uses a camphor-derived lactam 30 as the auxiliary.54... 

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. 

Chiral Non-racemic Bicyclic Lactams Vehicles for the Construction of Natural and Unnatural Products Containing Quaternary Carbons. Romo, D, Meyers, A. I. Tetrahedron 1991, 47, 9503. 

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 . 

In a similar manner, aldehydes can also be enantioselectively alkylated by this procedure. However, the enantiomeric excess obtained is much lower (47%). A special application of this method is the enantioselective alkylation of aldehydes for the construction of quaternary stereogenic centers. An example is the formation of the chiral quaternary carbon in 4-methyl-4-phenylcyclohex-2-en-1-one in high enantiomeric excess using this methodology (eq 4). ... 

The method for producing chiral 1,2-diol units is also applicable to the construction of asymmetric quaternary carbons contained in aldol units. In the presence of a chiral promoter consisting of the chiral diamine 1, tin(II) trifluoromethanesulfonate, and di-n-butyltin diacetate, various optically active a-alkoxy-a-methyl- -hydroxy thioesters and esters are synthesized in good yields with high stereoselectivities (eqs 28 and 29). ... 

The Ireland variant of the Claisen rearrangement relies on the generation of the vinyl moiety of the double unsaturated system by enolization of an ester. The principle of this technique is given in Scheme 11.42 and it allows the transformation of allylic alcohol 177 into 180 via ester 178 and the ketene acetal 179. Application of this chemistry to the construction of the chiral quaternary carbon atom of the zaragozic acid core is shown in Scheme 11.47 [142]. Additional examples of this rearrangement are found in Section 11.5.2.2. 

The asymmetric induction in the formation of 214 stems from an eiiantiodifferentiation of two double bonds. The intramolecular jr-enantiofacial discrimination (cf. Scheme 3-49 for the intermolecular version) has also been successful, as shown by the asymmetric construction of quaternary carbon centers in the preparation of spirooxindoles 217 from 216 (Scheme 3-51). It is amazing that each product enantiomer was obtained selectively by careful choice of reaction conditions and, remarkably, by applying exactly the same enantiomer of the chiral phosphane ligand [122]. 

Construction of the chiral quaternary carbon in the discovery directed toward l-(4-isopropyl-4-phenyl-4-cyanobutyl)-4-[2-( -fluorophenoxy)ethyl]piperazine, the novel neuroprotective agent E 2050 03YGK67. 

Asymmetric alkylation of P-keto carbonyl derivatives under phase-transfer conditions is a very convenient and useful way to construct a chiral quaternary carbon center. In 2002, Dehmlow and coworkers reported the asymmetric benzylation of the cyclic (3-ketoester, 2-(tert-butoxycarbonyl)cyclopentanone (70) in the presence of the cinchoninium PTC 72 in excellent chemical yield with 46% ee (Scheme 6.21) [46]. 

The efEcient, highly enanhoselective construction of quaternary carbon centers on P-keto esters under phase-transfer conditions has been achieved using N-spiro chiral quaternary ammonium bromide 9h as a catalyst [46]. This system has a broad generality in terms of the structure of P-keto esters and alkyl halides (Scheme 11.11). The resultant alkylahon products 54 can be readily converted into the corresponding P-hydroxy esters 55 and P-amino esters 56, respechvely. 

The chiral auxiliary mediated aza-Claisen rearrangement of /V-allylketcnc. V.O-acetals also allows the diastereoselective construction of quaternary carbon centers642. Butyllithium proved to be an unsuitable base for the neutralization step in this case because the increased steric hindrance at C-l causes C-2 nucleophilic addition to become competitive with C-l deprotonation. However, this problem can be overcome by the use of lithium tov-butoxide or lithium isopropoxide. This is shown for the achiral. V-allylketene A. O-aceta] precursor 8. 

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