Chiral quaternary

Pentenomycin (33), a highly oxygenated cyclopentenoid with a quaternary chiral center (Scheme 6), was prepared by a similar reaction sequence [29]. The RCM precursor 31 was prepared in eight steps from D-mannose via iodo compound 29 and aldehyde 30 (1 1 diastereomeric mixture). RCM of 31 led to the epimeric cyclopentenols 32. 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

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. 

Deprotonation at an activated 4-position has been employed extensively in asymmetric synthesis, which is the key step in the Seebach protocol for the preparation of a-alkyl amino acids.The existing alkyl group at the 5-position acts as a directing group for the alkylation and is oriented trans to the new alkyl group (Scheme 8.118). This reaction provides an efficient methodology for normally difficult stereoselective construction of a quaternary chiral center. 

The creation of all-carbon quaternary chiral centers by asymmetric conjugate addition is a challenging task. A chiral heterocyclic carbene 199 has been used as a ligand for this reaction. Chiral 3,3-disubstituted cyclohexanones 200 were obtained by this method with up to 85% ee (equation 126) . ... 

As mentioned earlier, alkylation of sugar enolates is a method of choice to introduce two different carbon chains in a defined sequence to construct a quaternary chiral center with the desired configuration [11] (see Scheme 39). Several other methods have been proposed, such as the ring opening of spirocyclopropanes [182] or the 1,4-addition of dimethylcuprate on a p-methyl-substituted enone [183]. 

A well-developed concept to achieve high stereocontrol in the formation of a quaternary chiral center has been introduced by Fraser-Reid, using the Claisen rearrangement along two lines. In the first approach a type III branched-chain sugar is prepared by Wittig... 

Kaftory performed X-ray crystallographic analyses of 20E, 20Z, and 20C, and found that crystals of 20E and 20Z were composed of single enantiomers of helical chirality, while crystals of 20C comprised a racemic mixture of enantiomers about the quaternary chiral carbon atom.1171 Irradiation of a crystal of 20E with UV light to induce photocoloration in the crystalline state resulted in the coloration only of the surface of the crystal. 

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). 

This sequence destroyed the two chiral centers of 12 that had assisted the formation of the quaternary chiral center required in 26. 

By converting the enol triflate 41 to the spiro-tricyclic dienone 42, Overman and co-workers had already shown in 1989 that the direct enantio-selective formation of quaternary chiral carbon centers ean be carried out through an intramolecular Heck reaction. While the enantioselectiv-ities were only moderate at the beginning [ 16], the same authors later succeeded in achieving the Pd(0)-BINAP-catalyzed cyclizalion of substrates of type 43 to spiro-oxindoles 44 with up to 95 % ee (Scheme 12) [17]. 

The bisferrocenylbisphosphine 15 has been reported to be an enantioselective chiral ligand for the rhodium-catalyzed asymmetric Michael addition of a-cyano carboxy-lates [85] to vinyl ketones (Scheme 2-60). The tranj-chelation of 15 generates efficient chiral surroundings around the rhodium atom to produce a quaternary chiral carbon center with up to 89% ee. 

Guijar, M K, Das, S K, Kunwar, A C, Studies towards the synthesis of the highly oxygenated bicyclic core of zaragozic acid incorporation of three quaternary chiral carbon centres, Tetrahedron Lett, 36, 1937-1940, 1995. 

Finding out how to determine stereochemistry when there is a quaternary chiral centre. 

The resulting derivatives were applied with success in the standard asymmetric allylic alkylation (up to 97 % ee) [134, 136] or in transformations involving either specific allylic substrates (2-cycloalkenyl derivatives, up to >99% ee) [135, 137], unsymmetrical substrates (monosubstituted allyl acetate, up to 83% ee) [140], or especial nucleophiles (nitroalkanes [141], iminoesters [138 a], or diketones [139, 140, 142]). Such ligands were also effective in the formation of quaternary chiral carbon through allylic substitution (eq. (6)) [138, 143], deracemiza-tion of vinyl epoxides (up to 99% ee) [144], or alkylation of ketone enolates [138 b], and deracemization of allylic derivatives [145]. 

In order to construct the sterically congested C7a quaternary chiral center in the natural product anisatin, T.P. Loh and co-workers developed an efficient strategy by way of an Eschenmoser-Claisen rearrangement. The resulting amide was converted to an e-lactone (reported by A.S. Kende) in four steps, thereby completing a concise formal synthesis of (+)-8-deoxyanisatin. Other attempted [3,3]-sigmatropic rearrangements to construct C7a stereocenter resulted in re-aromatized products. 

Radical reactions are also valuable strategies for the formation of quaternary carbon centers. An enantioselective variant of this has recently come to light utilizing aluminum as a Lewis acid complexed to a chiral binol ligand (103) in the allylation of -iodolactones 101 (Eq. (13.31), Table 13-6) [43]. It was established that diethyl ether as an additive in these reactions dramatically increases product enantioselectivities (compare entries 1 and 2, Table 13-6). Catalytic reactions were also demonstrated (entry 3) with no appreciable loss of selectivity. A proposed model for how diethyl ether functions to enhance selectivity in the enantioselective formation of these quaternary chiral centers is shown in 104. 

Another scenario for AHRs is the formation of quaternary chirality centers. Here, (3-elimination via path b is impossible (when Hb is replaced by a hydrocar-byl group). The downside, however, is that construction of such centers is difficult because it requires the insertion of trisubstituted C=C bonds, which normally react sluggishly in Heck reactions. Some of this lack of reactivity, however, can... 

Equation 12.50 demonstrates an application of AHR to form a quaternary chirality center using (M)-tol-BINAP (same as BINAP except o-tolyl replaces Ph) as the bidentate ligand.111 Another good example is shown in equation 12.51, where... 

S)-BINAP is used as the chiral ligand.112 The AHR continues to find wide use in synthesis as a means of installing tertiary and quaternary chirality centers.113... 

Chiral a,a-dialkyl-a-amino adds (aaAAs), a class of nonproteinogenic amino adds, have been extensively studied because of their important role in the fields of synthetic, medicinal, and biological chemistry. Their quaternary chiral centers... 

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