Metal diastereoselective alkylation

Only few allyltitanium reagents bearing a removable chiral auxiliary at the allylic residue are known. The outstanding example is a metalated 1-alkyl-2-imidazolinone14, derived from (—)-ephedrine, representing a valuable homoenolate reagent. After deprotonation by butyllithium, metal exchange with chlorotris(diethylamino)titanium, and aldehyde or ketone addition, the homoaldol adducts are formed with 94 to 98% diastereoselectivity. 

Evans and Takacs23 demonstrated a diastereoselective alkylation based on metal ion chelation of a lithium enolate derived from a prolinol-type chiral auxiliary. This method can provide effective syntheses of a-substituted carbox-... 

A special case of diastereoselective alkylation reaction via azaenolates is the intramolecular cyclization of metalated 4,5-dihydro-2-(5-iodohexyl)-4,4-dimethyloxazole which furnishes the thermodynamically less favored cri-2-methylcyclopentanecarboxylic acid derivative 8 preferentially32. 

Diketones react diastereoselectively with the dilithio compounds 475 obtained by the ortho and a-directed metallation of alkyl aryl thioethers and sulfones to give the fra r-thiochroman-3,4-diols and their 1,1-dioxides (Scheme 166) <1998S1098>. o-Bromophenyl sulfones 476 yield the 3,4-disubstituted thiochroman dioxide by a radical cyclization the trans isomer is the predominant or even exclusive product (Equation 160) <1995SL943>. 

The Novartis Institute for BioMedical Research in Basel, Switzerland, and the University of Hull, UK, performed the diastereoselective alkylation of metal-stabilized enolates using a pressure-driven microreactor at — 100°C, whereby increased conversions and diastereoselectivity were observed compared to the batch process [20]. 

Metal enolates as synthons in organic chemistry TABLE 17. Diastereoselective alkylations of glycinamides... 

Diastereoselective carbon-carbon bond formation at the a-position to the amine nitrogen may be accomplished as shown in Scheme 37. Propargylamine is converted into the silylated amidine, which is metallated with n-butyllithium. After alkylation, the metallation and alkylation are repeated with a second alkyl halide to obtain the fully alkylated derivative. Thus, optically active a-substituted propargy-lamines and amino acids are obtained by hydrolysis of the amidine function and oxidative cleavage.- ... 

The structurally novel bicyclic oxazinone was prepared based on D-glucopyranose. The lithium enolates of these compounds undergo highly diastereoselective alkylation reactions with reactive alkyl halides, in modest yields. Use of the phosphazene P4 base enhanced the yields of these processes, suggesting that metal enolate aggregation is at least partly... 

Another classic in asymmetric synthesis is Oppolzer s sultam 91 [48], and various JV-acyl derivatives 92 were used - inter alia - for diastereoselective alkylations. Early attempts for enolate generation from amides 92 were plagued by competing deprotonation at carbon 10, adjacent to the sulfonyl group, but regioselective metallation at the a-carbonyl position was achieved by treatment with -butyllithium, LICA, or NaHMDS. The method is applicable not only to the sultam derived from propionic acid 92 (R = Me) but also to substituted and... 

In parallel with the interest in -oxa-substituted carbanions, there has been much interest in their -aza-substituted counterparts. In this regard, Meyers pioneered the preparation of substituted carbamine carbanions (Scheme 13.8) [51-53] and recognized the power of a methodology based on such intermediates for the synthesis of a wide range of alkaloids. The ability of formamidine derivatives of tetrahydroisoquinoline (cf. 50) to participate effectively in metalation with LDA had already been demonstrated. The use of optically active, silylated l-phenyl-2-aminopropane-l,3-diol as a chiral auxiliary was shown to lead to the configurationally stable organolithium species 51, which took part in diastereoselective alkylation reactions. When l-bromo-4-chlorobutane was employed as the electrophile, the sequence provided access to benzoquinolizine 52 in 90 % ee and 70 % overall yield [51]. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

Metalated Ally lie Sulfones I.5.2.2.2.I. Metalated Alkyl Sulfones Simple Diastereoselection... 

While the notion that the alkoxides derived from aliphatic alcohols are poor nucleophiles toward 7r-allylmetal complexes has prevailed over the years, much progress made in the recent past has rendered the transition metal-catalyzed allylic alkylation a powerful method for the O-allylation of aliphatic alcohols. In particular, owing to the facility of five- and six-membered ring formation, this process has found extensive utility in the synthesis of tetrahydrofurans (THFs) (Equation (29))150-156 and tetrahydropyrans (THPs).157-159 Of note was the simultaneous formation of two THP rings with high diastereoselectivity via a Pd-catalyzed double allylic etherification using 35 in a bidirectional synthetic approach to halichondrin B (Equation (30)).157 The related ligand 36 was used in the enantioselective cyclization of a Baylis-Hillman adduct with a primary alcohol (Equation (31)).159... 

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