Preparation of quaternary center

The enantioselective construction of quaternary carbon centers is invariably a challenging goal41. The double alkylation of a nonracemic jS-hydroxy ester is a useful preparative method from a collection of procedures which are used to reach this objective. In Table 3 the results from the preparation of quaternary centers by this method are shown. 

Likewise, the TFA salts of diamines 6 and 19a mediate Michael addition of a,a-disubstituted aldehydes to nitrostyrene allowing the preparation of quaternary centers [32, 33] (Scheme 2.45). The enantioselectivity of the transformation increases with the steric demand of the aldehyde, which results in diminished reactivity. 

The uncatalyzed traditional Claisen rearrangement of allyl vinyl ethers is still very much in use, especially for the preparation of quaternary centers of carbocyclic systems. The rearrangement is highly exothermic, but generally requires temperatures of 150-200 C and is therefore limited to thermally stable compounds. 

The overall reaction makes it possible to perform intramolecular caibozincations [65-71] via a radical cyclization. This useful preparation of cyclopentylmethylzinc derivatives proceeds with excellent stereoselectivity and allows preparation of quaternary centers. After cyclization, the zinc organometallic can be transmetallated with CuCN-2LiCl and made to react with a broad range of electrophiles such as acid chlorides, allylic and alkynyl halides, ethyl propiolate, 3-iodo-2-cyclohexen-l-one, and nitroolefins such as nitrostyrene, leading to products of type 40 (see Section 9.6.9 Scheme 9-34) [65,70]. 

These approaches led to ternary stereogenic centers. Brian Stoltz has found J. Am. Chem. Soc. 2004,126, 15044) that the Pd-mediated conversion of 7 to 8 can be induced to proceed in high enantiomeric excess. This appears to be a general method for the preparation of quaternary stereogenic centers. Wacker oxidation followed by aldol condensation converted 8 into the bicyclic enone 9. 

The preparation of a-selenoketones, esters, nitriles and related compounds can easily be performed via alkylation of the corresponding enolates or stabilized carbanions [21]. These compounds have found many synthetic applications in radical chemistry. In Eq. (9), a typical example involving a ketone is depicted [22]. The stability of a-selenoketones such as 41 is remarkable. Similar reactions with lactones have been performed. For instance, this approach has been applied to the stereoselective synthesis of oxygen-containing rings to either faces of a bicyclic structure [23]. The approach based on a-selenenylation/radical allyla-tion compares favorably with classical enolate allylation procedures, which usually leads to mixture of mono- and diallylated compounds. Furthermore, this strategy is excellent for the preparation of quaternary carbon centers [24] as shown by the conversion of 43 to 45, a key intermediate for the synthesis of fredericamycin A, [Eq. (10)] [25]. Similar reactions with sulfoxides [26] and phosphonates [27] have also been reported. 

The silane 94b (SAN-58-035 for the synthesis see Reference 166) is an inhibitor of the acyl-CoA cholesterol acetyltransferase167,168 which has been tested clinically and experimentally as a potential lipid-lowering and anti-atherosclerotic drug. 94b is reported to be 8.7 times more potent in the inhibition of cholesterol ester uptake by cells than its carbon analogue 94a22. Moreover, the silicon agent is considerably easier to prepare than the carbon counterpart. In this context it should be pointed out that a special benefit of silicon versus carbon chemistry is the greater ease with which many types of quaternary centers can be constructed. 

Maryanaoff and McComsey have more directly utilized the 3-aza-Cope rearrangement for preparation of quaternary carbon centers via transfer of an allyl group from a quaternary ammonium salt. As illustrated below, reaction of 236 proceeds smoothly in what is predominantly a [3,3]-sigmatropic process to give 237. Reduction of the iminium ion 237 provides... 

In the last example, cis-carbocupration of alkynoic ester 14 provides a weakly nucleophilic and configurationally imstable 1-alkoxycarbonyl alkenylcopper intermediate (15) the presence of HMPA as additive was crucial to avoid erosion of the E/Z stereoselectivity in the alkylation step with electrophile 16 [39, 40]. Under these conditions, 3,3-disubstituted allylboronates 17 were prepared in over 20 1 selectivity, and these reagents were subsequently employed in the stereoselective preparation of quaternary carbon centers (Section 6.4.2.2). 

Quaternary salts have been prepared from a number of these bases. 7-(Dialkylaminoalkyl)amino-l,2,3a,4-tetraazaindenes (132) were prepared and converted into mono-quaternary salts, but no structures were assigned to the salts and the quaternary center may well be in the side-chain. When this ring system carries 3-methyl and 5-alkyl or... 

Two closely related methods for the diastereoselective preparation of <5-oxo esters have been developed. The first method uses the chelated lithio enamine 2. These Michael donors are readily available from the tert-butyl ester of L-valine and jS-oxo esters. The Michael addition of this lithio enamine 2 to 2-(arylmethylene)propanedioates, followed by hydrolytic removal of the auxiliary, provides d-oxo esters with contiguous quaternary and tertiary carbon centers with high diastereoselectivity59 60. 

Despite the favorable thermodynamics associated with the cyclization of unsaturated organolithiums, the isomerization is often sluggish when the ring closure involves generation of a quaternary center or formation of a strained framework. In such cases it has been found that addition of lithiophilic Lewis bases such as THF or TMEDA facilitate the reaction.7 9 The preparation of cuparene, a sterically congested sesquiterpene possessing two adjacent quaternary centers, illustrates the methodology.11... 

IH of hindered aminoalkenes has been developed as a route to heterocycles containing quaternary centers a to the nitrogen atom (Eq. 4.21) [134]. For these reactions, the easy-to-prepare catalyst precursors [(MejSiCpljLnMejj prove very efficient. 

The asymmetric synthesis of a galanthamine alkaloid relies also on the intramolecular Heck reaction for the preparation of the benzo[h]furan-based key intermediate with a crucial chiral quaternary center, which eventually leads to the synthesis of (-)-galanthamine <00JA11262>. A similar approach towards the construction of galanthamine ring system via an intramolecular Heck reaction has also been investigated <00SL1163>. 

The asymmetric arylation of ketone enolates represents an attractive method for the preparation of optically active carbonyl compounds with a stereogenic quaternary center at the a-position to the carbonyl group. Such types of compounds are important intermediates for natural product synthesis. Replacement of BINAP by 109 provides... 

Furthermore, Rueping and coworkers applied their reaction conditions to the cyanation of ketimines [54]. The use of A-benzylated imines derived from aryl-methyl ketones generally gave comparable yields, but lower enantioselectivities. However, this method furnished Strecker products bearing a quaternary stereogenic center, which are valuable intermediates for the preparation of optically active a,a-disubstituted a-amino acids. 

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. 

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. 

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