Synthesis of Chiral Esters

The use of 9-BBN, affords a stereodefined alkylation of ethyl bromoacetate. Tris(traMS-2-methylcyclopentyl)borane fails to react with ethyl bromoacetate in the presence of potassium t-butoxide, whereas B-tra s-2-methylcyclopen-tyl-9-BBN affords ethyl(trans-2-methylcyclopentyl)acetate in 98% purity (Eq. 9.3) [3]. 

The optically active 9-R -9-BBNs prepared by this method are shown in Chart 9.1. 

Alkali metal ferf-butoxide in THF is used for their homologation-reaction. All three alkali metal ferf-butoxide in THF work equally well for the a-alkyla-tion (Eq. 9.4) of ethyl bromoacetate. 

The chiral 9-R -BBNs are utilized for the synthesis of various homologated esters, in very high optical purities (Table 9.3) [5]. 

Both (+) and (-) a-pinenes are now readily available in pure form. Consequently, it is possible by this remarkable simple procedure to achieve the synthesis of both enantiomers of functional derivatives involving carbon-atom homologation from olefins via asymmetric hydroboration. 

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Inch and his co-workers continue to use carbohydrate derivatives in the synthesis of chiral esters of phosphorus acids and for studies of the displacement reactions of these esters. For example, the tetrahydro-l,3,2-oxazaphosphorine-2-ones (74) and (76) were synthesized and cleaved to give the chiral phosphonate (75) and the chiral phosphate (77), as illustrated in Schemes 35 and 36. 2-Thiones related to (74) and (76) were also prepared and used to obtain such chiral thiophosphates as (78) from (79). Attack on the acyclic S -methyl phos-... 

Ueno and coworkers49 have developed a procedure for the synthesis of chiral sulfinic acids. Treatment of (R)-( + )-23 with disulfide 24 and tributylphosphine in THF gave (S)-( — )-25. Compound 25 was oxidized with potassium permanganate to the sulfone, which was then reduced to the sulfinic acid, (S)-( — )-26, by treatment with sodium borohydride. Conversion of 26 or an analog to an ester would lead to diastereomers. If these epimers could be separated, then they would offer a path to homochiral sulfoxides with stereogenic carbon and sulfur atoms. 

Reaction of optically active a-sulphinyl acetate 298a with prochiral carbonyl compounds proceeds with a high asymmetric induction - , the degree of which depends on the nature of substituents at the carbonyl group (equation 252 Table 22) . The jS-hydroxy sulphoxides 422 formed may be transformed to optically active p-hydroxycarboxylic esters 423 (equation 253) and optically active long-chain lactones 424 99 (equation 254). Corey and coworkers have used this method to introduce a chiral centre at C-3 in their synthesis of maytansin °°, and Papageorgiou and Benezra for the synthesis of chiral a-hydroxyalkyl acrylates 425 ° (equation 255). 

A convergent synthesis of chiral 6,5-bicyclic hexahydropyridazine derivative 394 is described. Methyl ester 391 is deprotected with perchloric acid in aqueous THF to provide the corresponding diol 392. Its cyclization is achieved by refluxing its dichloromethane solution with excess triphenylphosphine, tetrachloromethane, and triethylamine. The crude hydroxy derivative 394 is separated from triphenylphosphineoxide via the corresponding silylated derivative 393 (Scheme 60) <1995H(41)2487>. 

An enantioselective synthesis of both (R)- and (5)-a-alkylcysteines 144 and 147 is based on the phase-transfer catalytic alkylation of fert-butyl esters of 2-phenyl-2-thiazoline-4-carboxylic acid and 2-ort/ro-biphenyl-2-thiazoline-4-carboxylic acid, 142 and 145 <06JOC8276>. Treatment of 142 and 145 with alkyl halides and potassium hydroxide in the presence of chiral catalysts 140 and 141 gives the alkylated products, which are hydrolyzed to (R)- and (S)-a-alkylcysteines 144 and 147, respectively, in high enantioselectivity. This method may have potential for the practical synthesis of chiral a-alkylcysteines. 

In a closely related study, Tung and Sun discussed the microwave-assisted liquid-phase synthesis of chiral quinoxalines [80], Various L-a-amino acid methyl ester hydrochlorides were coupled to MeOPEG-bound ortho-fluoronitrobenzene by the aforementioned ipso-fluoro displacement method. Reduction under microwave irradiation resulted in spontaneous synchronous intramolecular cyclization to the corresponding l,2,3,4-tetrahydroquinoxalin-2-ones (Scheme 7.71). Retention of the chiral moiety could not be monitored during the reaction, but after release of the desired products it was found that about 10% of the product had undergone racemization. 

Chodkiewicz, W., One-pot synthesis of chiral phosphonous esters, conversion into asymmetric phosphines, ]. Organomet. Chem., 273, C55, 1984. 

The total synthesis of optically active loganin (53) was accomplished by Partridge 25), who photolyzed a solution of the chiral acetate (60) and the ester (56). The intermediate (61) rearranged to the chiral hemiacetal (62), which served as a key compound in the synthesis of chiral loganin (53)15). 

The broad range of alkenes undergoing asymmetric hydrogenation using ruthenium-based systems as catalysts has attracted the attention of chemists engaged in the synthesis of chiral biologically active natural products (Scheme 13)[60] and other pharmaceuticals (Scheme 14)[61]. a, (3-Unsaturated phosphoric acids and esters have also proved to be suitable substrates for Ru(II)-catalysed asymmetric hydrogenation [62]. 

SYNTHESIS OF CHIRAL (E)-CROTYLSILANES [3R- AND 3S-]-(4E)-NIETHYL 3-(DIMETHYLPHENYLSILYL)-4-HEXENOATE (4-Hexenoic acid, 3-(dimethylphenylsilyl)-, methyl ester,... 

Although in recent years transesterification processes of racemic alcohols have received major attention, enzymatic acylation of amines for synthetic purposes is also being employed as a conventional tool for the synthesis of chiral amines and amides [31], using CALB as the biocatalyst in the majority of these reactions [31a]. The main difference between enzymatic acylation of alcohols and amines is the use of the corresponding acyl donor, because activated esters which are of utility... 

Acylals (geminal diacetates) are frequently used as protecting groups for aldehydes because of their stability to neutral and basic conditions [8]. In addition, the acylal functionality can be converted into other useful functional groups [9]. For example a novel synthesis of chiral allylic esters has been developed using palladium-catalyzed asymmetric allylic alkylation of gem-diesters [10]. The allylation of... 

SCHEME 16. Copper-catalyzed asymmetric synthesis of chiral aUyhc esters synthesis of a natural butenoUde using aUyUc alkylation foUowed by ring-closing metathesis... 

In the Sepracor synthesis of chiral cetirizine di hydrochloride (4), the linear side-chain as bromide 51 was assembled via rhodium octanoate-mediated ether formation from 2-bromoethanol and ethyl diazoacetate (Scheme 8). Condensation of 4-chlorobenzaldehyde with chiral auxiliary (/f)-f-butyl sulfinamide (52) in the presence of Lewis acid, tetraethoxytitanium led to (/f)-sulfinimine 53. Addition of phenyl magnesium bromide to 53 gave nse to a 91 9 mixture of two diastereomers where the major diasteromer 54 was isolated in greater than 65% yield. Mild hydrolysis conditions were applied to remove the chiral auxiliary by exposing 54 to 2 N HCl in methanol to provide (S)-amine 55. Bisalkylation of (S)-amine 55 with dichlonde 56 was followed by subsequent hydrolysis to remove the tosyl amine protecting group to afford (S)-43. Alkylation of (5)-piperizine 43 with bromide 51 produced (S)-cetirizine ethyl ester, which was then hydrolyzed to deliver (S)-cetirizine dihydrochloride, (5)-4. 

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