Asymmetric reactions, of lithium

Stoichiometric and catalytic asymmetric reactions of lithium enolate esters with imines have been developed using an external chiral ether ligand that links the components to form a ternary complex.36 The method affords /i-lactams in high enantiomeric excess. 

Introduction Since we had already developed the novel asymmetric addition of lithium acetylide to ketimine 5, we did not spend any time on investigating any chiral resolution methods for Efavirenz . Our previous method was applied to 41. In the presence of the lithium alkoxide of cinchona alkaloids, the reaction proceeded to afford the desired alcohol 45, as expected, but the enantiomeric excess of 45 was only in the range 50-60%. After screening various readily accessible chiral amino alcohols, it was found that a derivative of ephedrine, (1J ,2S) l-phenyl-2-(l-pyrrolidinyl)propan-l-ol (46), provided the best enantiomeric excess of 45 (as high as 98%) with an excellent yield (vide infra). Prior to the development of asymmetric addition in detail, we had to prepare two additional reagents, the chiral modifier 46 and cyclopropylacetylene (37). 

On the other hand, asymmetric addition of lithium acetylide in the presence of the ephedrine derivative 46 is a homogeneous reaction and reveals great detail about the reaction mechanism. 

Starting from optically active 1-chlorovinyl p-tolyl sulfoxide derived from 2-cyclohex-enone, the asymmetric synthesis of cyclopropane derivative (85) was realized (equation 23) . Addition reaction of lithium enolate of tert-butyl acetate to 83 gave the adduct (84) in 96% yield with over 99% ee. Treatment of the latter with i-PrMgCl in a similar way as described above afforded optically pure (15,6/ )-bicyclo[4.1.0]hept-2-ene (85) in 90% yield. 

Asymmetric hydraxylation of lithium enolates of esters and amides.2 Hydroxylation of typical enolates of esters with ( + )- and (-)-l is effected in 75-90% yield and with 55-85% ee. The reaction with amide enolates with ( + )- and ( — )-l results in the opposite configuration to that obtained with ester enolates and with less enantioselectivity. Steric factors appear to predominate over metal chelation. 

The catalytic asymmetric Mannich reaction of lithium enolates with imines was reported in 1997 using an external chiral ligand [36]. First, it was found that reactions of lithium enolates with imines were accelerated by addition of external chiral ligands. Then, it was revealed that reactions were in most cases accelerated in the presence of excess amounts of lithium amides. A small amount of a chiral source was then used in the asymmetric version [(Eq. (8)], and chiral ligands were optimized to achieve suitable catalytic turnover [37]. 

Early investigations of asymmetric aldol reactions with chiral carbohydrate auxliliaries were carried out by Heathcock [152] and Bandraege [159], but often only low stereoselectivities were observed. In additional studies. Banks et al. [73] used oxazinone auxiliaries for aldol reactions, which had been employed for other asymmetric reactions. The lithium enolate of the A-acylated oxazinone 226 reacted with benzaldehyde, furnishing exclusively the iyn-aldols 227A and 227B in a ratio of 10 1 (Scheme 10.76). 

The phosphination procedure (18) was applied for functionalization of brominated beads and membranes. This same procedure was also the final step in the sequence for the attachment of the asymmetric phosphorus-containing ligand DIOP to the polymeric support. The phosphination involved the reaction of lithium diphenylphosphide prepared by a literature route (19) with the -Br groups. 

Furthermore, optically active alkynyl alcohols, useful intermediates for the synthesis of several optically active natural products, were obtained by the asymmetric addition of lithium acetylides to aldehyde in the presence of chiral ligand 2a Enhanced enantioselectivity in this reaction depends apparently on the substituent group in the acetylene moiety. As shown in Table 8, use of trialkylsilylacetylides gave the best results Various optically active ethynyl alcohols were obtained by the reaction of lithium trimethylsilylacetylide with aliphatic aldehydes, as summarized in Table 9... 

A chiral (3, (3, (3 -trifluoro-2 -propanol (14) was used for asymmetric protonation of lithium enolate (15) (Scheme 4.8) [43]. The determining factor for the product chirality in this reaction was found to be the chirality of carbinol carbon, but another chirality of the sulfinyl sulfur also affects the enantiomeric excess of the product. Thus, a binary chelation of the chiral fluorinated alcohol to the lithium was suggested. 

The reactions of aldehydes with enolates of acetic esters (MeCOOG ) 1.18 (R = H) are often poorly selective [66, 147, 209, 408, 1186, 1258], For this reason, the asymmetric synthesis of acetate aldols is usually performed by reduction of a-bromo analogs with BU3S11H [1254] or from sulfoxides [1049] (see below). However, the reactions of lithium or magnesium enolates of monoacetates of (hols... 

Brinkmeyer and Kapoor have now found that acetylenic ketones, RC= CCOR, are reduced by LiAlH4 and 1 at — 78° with the highest enantiomeric selectivity observed to date. Thus CH3Ce CCOCH2CH(CH3)2 is reduced to the corresponding (R)-alcohol with an enantiomeric excess of 827 . Similar asymmetric reductions were observed with seven other ketones of this type. Propargylic ketones are readily available by reaction of lithium acetylides with aldehydes followed by Jones oxidation of the propargylic alcohols. 

More recently, Davis and co-workers developed a new method for the asymmetric syntheses of aziridine-2-carboxylates through the use of an aza-Darzens-type reaction between sulfinimines (N-sulfinyl imines) and a-haloenolates [62-66]. The reaction is highly efficient, affording cis- N-sulfmylaziridine-2-carboxylic esters in high yield and diastereoselectivity. This method has been used to prepare a variety of aziridines with diverse ring and nitrogen substituents. As an example, treatment of sulfinimine (Ss)-55 (Scheme 3.18) with the lithium enolate of tert-butyl bromoacetate gave aziridine 56 in 82% isolated yield [66],... 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

Chiral imines derived from 1-phenylethanone and (I. Sj-exo-l, 7,7-trimethyIbicyclo-[2.2.1]heptan-2-amine [(S)-isobornylamine], (.S>1-phenylethanamine or (R)-l-(1-naphthyl) ethanamine are transformed into the corresponding (vinylamino)dichloroboranes (e.g., 3) by treatment with trichloroborane and triethylamine in dichloromethane. Reaction of the chiral boron azaenolates with aromatic aldehydes at 25 "C, and subsequent acidic hydrolysis, furnishes aldol adducts with enantiomeric excesses in the range of 2.5 to 47.7%. Significantly lower asymmetric inductions are obtained from additions of the corresponding lithium and magnesium azaenolates. Best results arc achieved using (.S )-isobornylamine as the chiral auxiliary 3. 

Reaction of benzylideneaniline with optically active methyl p-tolyl sulphoxide 449 in the presence of lithium diethylamide produces the corresponding jS-anilinosulphoxide 450 with 100% asymmetric induction. Its reductive desulphurization with Raney nickel leads to the enantiomerically pure amine 451524 (equation 270). When the same optically active... 

Solladie and coworkers545 confirmed the earlier result of Nishihata and Nishio546 that the carbonation of the a-sulphinyl carbanion proceeds under kinetic control with retention of configuration at the metallated carbon atom. However, they also found that the stereochemical outcome of this reaction depends on other factors. They observed that 90% of asymmetric induction may be achieved under kinetic control (reaction time < 0.5 min) by using a base with low content of lithium salts, a result consistent with an electrophilic assistance by the lithium cation (equation 286)545. 

Demailly and coworkers195 found that the asymmetric induction increased markedly when optically active methyl pyridyl sulfoxide was treated with an aldehyde. They also synthesized (S)-chroman-2-carboxylaldehyde 152, which is the cyclic ring part of a-tocopherol, by aldol-type condensation of the optically active lithium salt of a,/3-unsaturated sulfoxide. Although the diastereomeric ratio of allylic alcohol 151 formed from lithium salt 149 and 150 was not determined, the reaction of 149 with salicylaldehyde gave the diastereomeric alcohol in a ratio of 28 72196. 

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