Quaternary carbon asymmetric induction

Since the stereochemistry of the newly created quaternary carbon center was apparently determined in the second alkylation process, the core of this method should be applicable to the asymmetric alkylation of aldimine Schiffbase 42 derived from the corresponding a-amino adds. Indeed, di-alanine-, phenylalanine- and leucine-derived imines 42 (R1 = Me, CH2Ph, i-Bu) can be alkylated smoothly under similar conditions, affording the desired non-coded amino acid esters 43 with excellent asymmetric induction, as exemplified in Table 5.7 [19]. 

The formation of a quaternary carbon center by the radical-mediated allylation of an a-iodolactone was examined for substrate 341 by Murakata, Jono, and Hos-hino [71]. Lewis acids for this reaction were prepared from a bis-sulfonamide and tri-methylaluminum in dichloromethane. Other aluminum compounds were employed in the preparation of the catalyst but all resulted in similar or lower asymmetric induction. The Lewis acid was complexed with the lactone and then the allylation procedure in Sch. 44 was performed. It was found that superior asymmetric induction could be achieved if the Lewis acid was prepared from the ligand with two equivalents of trimethylaluminum. It was also interesting that some turnover could be achieved, as indicated by the data obtained from use of 50 mol % catalyst. 

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]. 

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]. 

Michael reaction of a-substituted t-butyl cyanoacetates to t-butyl prop3moate establishes a quaternary carbon center in the adducts. Excellent asymmetric induction is achieved by much more bulky ammonium salt. ... 

Strecker reaction to establish a new stereocenter is subject to asymmetric induction, capable of creating either a tertiary" or quaternary carbon atom in the presence of 59. The peptido-imine 60 proves to be an excellent ligand for the Ti(IV)-mediated cyanation of aldimines. On catalysis of the bicyclic guanidine 61 the addition of HCN to A-benzhydrylaldimines affords a-amino nitrile derivatives with moderate to good ee. ... 

Cyclopropanone acetals with a quaternary carbon atom in chiral form can be established by addition of bisoxazoline-ligated allylzinc reagents to the cyclopropenes.The t-BuLi/(-)-sparteine combination favors Br-Li exchange and also promotes enantioselection in the intramolecular addition of aryllithium to an o-alkenyl side chain (e.g., indoline synthe-j.ijj) I28.I29 Moderate asymmetric induction is shown in the hydroarylation of norbomene in the presence of 63. 

A 2,2-disubstituted chromane system was asymmetrically constructed by application of intramolecular oxa-Michael addition reaction through 6-exo-trig mode cyclization [57]. Good asymmetric induction at the quaternary carbon was observed when Z-alkene was treated with the same guanidine 17 used in asymmetric carba-Michael reaction in Table 4.5 (Scheme 4.18). 

Difluoroboroxycarbene complexes have been further applied to stereoselective Diels-Alder reaetions. The [4+2]-cycloaddition of alkenyl(difluoroboroxy)-carbene chelate 90 with 2-amino-1,3-dienes 91 afforded the spiroeyclic carbene complex 92 with variable diastereoselectivity (Scheme 40). [92] An extension of this reaction to chiral aminodiene 93 led to the cycloadduct 94 featuring three stereogenic centers including a quaternary carbon in moderate yields but with high asymmetric induction (Scheme 41). [92]... 

Chen and coworkers employed the cinchona alkaloid-derived catalyst 26 to direct Mannich additions of 3-methyloxindole 24 to the A-tosylimine 25 to afford the all-carbon quaternary center of oxindole 27 with good enantioselectivity (84% ee) [22]. The outcome of this Mannich reaction is notable in that it provided very good selectivity for the anti diastereomer (anti/syn 94 6). The mechanism of asymmetric induction has been suggested to involve a hydrogen bonding network between the cinchona alkaloid 26, the oxindole enolate of 24, and the imine electrophile 25 (Scheme 7). Asymmetric allylic alkylation of oxindoles with Morita-Baylis-Hillman carbonates has been reported by the same group [23]. 

The asymmetric Heck reaction can be used to synthesise quaternary carbon centres. During studies towards the synthesis of 3,3-disubstituted oxindoles. Overman and coworkers have shown how the use of silver salts can change the sense of asymmetric induction of the cyclised product. Thus, the iodide (10.131) can be converted into the product (10.132) with the (S)-enantiomer predominating, when the reaction is run in the presence of silver salts. In the absence of silver salts, the (J )-enantiomer is the major product. 

A contribution to the synthesis of oxoindoles equipped with quaternary stereocenters of high stereochemical purity was made by Smith et al. [15] in 2009. Nitrones 31 derived from Garner s aldehyde cycloadd readily to ketenes 32, a process that intensifies its asymmetric induction with increasing size of the protecting group (PG). An initially proposed ionic addition to the quaternary carbon of the ketene was subsequently mled out through computational methods [16]. The weak N-O... 

The asymmetric induction in the formation of362 stems from a differentiation of two enantiotopic double bonds in the same molecule. The intramolecular discrimination between the two enantiofaces of the same double bond (cf Scheme 8.73 for another intramolecular version) has also been achieved, for example, with the asymmetric constmction of quaternary carbon centers in the preparation of spirooxindoles 365 from 364 (Scheme 8.75). It is particularly noteworthy that either of the two product enantiomers could be obtained selectively by careful adaptation of the reaction conditions, yet with exactly the same enantiomer of the chiral phosphine Hgand [205]. 

There has been interest in employing chiral catalysts in phase-transfer reactions in order to achieve absolute asymmetric synthesis. Chirality may be contained in the carbon skeleton, or the nitrogen of the quaternary ammonium salt catalyst, or in a combination of these. However, unless the nucleophilic or basic anion forms a very tight ion pair with the ammonium cation so that it is associated on only one face of the tetrahedron, simple chiral tetralkylammonium salts will be incapable of producing a significant amount of asymmetric induction. ... 

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