Optically active chelated lithium

The results of this study suggest that optically active chelated lithium reagents may be used generally for asymmetric synthesis according to the scheme ... 

Oxo esters are accessible via the diastereoselective 1,4-addition of chiral lithium enamine 11 as Michael donor. The terr-butyl ester of L-valine reacts with a / -oxo ester to form a chiral enamine which on deprotonation with lithium diisopropylamide results in the highly chelated enolate 11. Subsequent 1,4-addition to 2-(arylmethylene) or 2-alkylidene-l,3-propanedioates at — 78 °C, followed by removal of the auxiliary by hydrolysis and decarboxylation of the Michael adducts, affords optically active -substituted <5-oxo esters232 (for a related synthesis of 1,5-diesters, see Section 1.5.2.4.2.2.1.). In the same manner, <5-oxo esters with contiguous quaternary and tertiary carbon centers with virtually complete induced (> 99%) and excellent simple diastereoselectivities (d.r. 93 7 to 99.5 0.5) may be obtained 233 234. 

Anti diastereoselectivity gives the optically active (S)-p-hydroxy ester while syn diastereoselectivity leads to the (/ )-P-hydroxy ester, via a chelated six-membered transition state (eq 3). Since the anti intermediate is more stable, the (S)-P-hydroxy ester predominates under thermodynamic conditions (Table 1, entry 1). Higher diastereoselectivity is achieved by changing the counterion from lithium to a more chelating one such as zinc (Table 1, entry 2). On the other hand, in order to obtain diastereoselection under kinetic control, zirconium enolates (prepared by treating the lithium enolate with Dichlorobis(cyclopentadienyl)zirconium) are used, leading to the (/ )-p-hydroxy ester (Table 1, entry 3) in high yield. 

Evans s oxazolidinones 1.116 and 1.117 are a class of chiral auxiliaries that has been widely applied [160, 167, 261, 411]. Deprotonation of 7/-acyl-l,3-oxa-zolidin-2-ones 5 30 and 5.31 smoothly gives chelated Z-enolates, which then suffer alkylation between -78 and -30°C on their least hindered face [167, 1036]. After hydrolysis, the corresponding enantiomeric acids are obtained according to the auxiliary that was used (Figure 5.21). Due to the low reactivity of lithium enolates, sodium analogs are preferred in some cases [411, 862, 1036], This methodology has been applied to the synthesis of chiral a-arylpropionic acid anti-inflammatory drugs [1037, 1038], natural products [1039, 1040], and a-substituted optically active 3-lactams en route to nonracemic a,a-disubstituted aminoacids [136,1041]. 

While this work was in progress an alternate method of asymmetric synthesis via hydride transfer was reported, in which the asymmetric center of the chiral moiety is not sacrificed (3, p. 204). This method uses the reaction product of LiAlH4 and varying amounts of optically active amino carbinols, such as ( — )-quinine, (-f)-cinchonidine, and ( — )-ephedrine, to reduce prochiral substrates. In this system the hydride anion species is sigma bonded to the optically active residue, and a maximum of three hydrides are available for further reaction. The aminocarbinols could sometimes be recovered for reuse. In the instant system the chiral chelating agent forms coordinate bonds to the lithium cation, and four hydrides are available for subsequent reaction. 

Subsequently, a large number of methods have been developed for the preparation of optically active a-aminophosphonates nucleophilic addition of lithium dibenzyl phosphonate to the spironitrone [26] Lewis add-catalyzed addition of diethyl H-phosphonate to A -galactosyUmine [27] addition of lithium diethyl phosphonate to chiral chelating imines [28]. 

Optically active a,a-disubstituted acetic acids have also been obtained using oxazoline intermediates. The oxazoline can be alkylated via the lithium derivative. Subsequent deprotonation gives a new enolate which is considered to have the chelated structure shown. 

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