Halides enantioselective synthesis

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

Alkenylcarbene complexes react with in situ-generated iodomethyllithium or dibromomethyllithium, at low temperature, to produce cydopropylcarbene complexes in a formal [2C+1S] cycloaddition reaction. This reaction is highly diastereoselective and the use of chiral alkenylcarbene complexes derived from (-)-8-phenylmenthol has allowed the enantioselective synthesis of highly interesting 1,2-disubstituted and 1,2,3-trisubstituted cyclopropane derivatives [31] (Scheme 9). As in the precedent example, this reaction is supposed to proceed through an initial 1,4-addition of the corresponding halomethyllithium derivative to the alkenylcarbene complex, followed by a spontaneous y-elimi-nation of lithium halide to produce the final cydopropylcarbene complexes. 

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. 

A procedure for enantioselective synthesis of carboxylic acids is based on sequential alkylation of the oxazoline 8 via its lithium salt. Chelation by the methoxy group leads preferentially to the transition state in which the lithium is located as shown. The lithium acts as a Lewis acid in directing the approach of the alkyl halide. This is reinforced by a steric effect from the phenyl substituent. As a result, alkylation occurs predominantly from the lower face of the anion. The sequence in which the groups R and R are introduced... 

Scheme 17 illustrates enantioselective synthesis of a-amino acids by phase-transfer-catalyzed alkylation (46). Reaction of a protected glycine derivative and between 1.2 and 5 equiv of a reactive organic halide in a 50% aqueous sodium hydroxide-dichloromethane mixture containing 1-benzylcinchoninium chloride (BCNC) as catalyst gives the optically active alkylation product. Only monoalkylated products are obtained. Allylic, benzylic, methyl, and primary halides can be used as alkylating agents. Similarly, optically active a-methyl amino acid derivatives can be prepared by this method in up to 50% ee. 

Comins and Green have recently developed a new method for the enantioselective synthesis of 4-substituted phenylalanines based on Pd-catalyzed cross-coupling reactions of a protected boronophenyl alanine with aromatic halides. These reactions proceed with good to excellent yields, and furnish the desired products with high enantiomeric purities [25]. 

Chiral quaternary carbon centers. Meyers et al. have reported an enantioselective synthesis of chiral ot,(t-disubstituted- y-keto acids (6) via the lactam 3 prepared from l-valinol (1) and the y-keto acid 2. Alkylation of 3 with primary alkyl halides gives mainly the endo-isomer (4). /dkylation of 4 also proceeds with endo-selectivity to give 5 with a... 

Alcohols can be obtained from many other classes of compounds such as alkyl halides, amines, al-kenes, epoxides and carbonyl compounds. The addition of nucleophiles to carbonyl compounds is a versatile and convenient methc for the the preparation of alcohols. Regioselective oxirane ring opening of epoxides by nucleophiles is another important route for the synthesis of alcohols. However, stereospe-cific oxirane ring formation is prerequisite to the use of epoxides in organic synthesis. The chemistry of epoxides has been extensively studied in this decade and the development of the diastereoselective oxidations of alkenic alcohols makes epoxy alcohols with definite configurations readily available. Recently developed asymmetric epoxidation of prochiral allylic alcohols allows the enantioselective synthesis of 2,3-epoxy alcohols. 

Salto, T., Sakairi, M., Akiba, D. Enantioselective synthesis of aziridines from imines and alkyl halides using a camphor-derived chiral sulfide mediator via the imino Corey-Chaykovsky reaction. Tetrahedron Lett. 2001,42, 5451-5454. 

Studies in the nineteen-eighties revealed that some Maimich-type reactions of imines with silyl enolates can be controlled with high diastereoselectivity, and that use of a chiral auxiliary enables highly enantioselective synthesis of -aminocarbo-nyl compounds [186]. Some Lewis acids, for example TMSOTf and zinc halides, were also found to be effective in catalytic quantities [187-190] although the original method requires a stoichiometric amount of TiCU [185]. In the last decade, further progress has been made by development of new acid catalysts. 

This chiral auxiliary has been applied to the enantioselective synthesis of a-alkyl carboxylic acids such as (5 )-2-methyl-4-pentenoic acid. A retrosynthetic analysis of the carbon skeleton of 2-methyl-4-pentenoic acid suggests preparation by alkylation of the enolate of a propanoyl group with an allyl halide. 

In most of the palladium-catalysed domino processes known so far, the Mizoroki-Heck reaction - the palladium(0)-catalysed reaction of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - has been apphed as the starting transformation accordingly to our classification (Table 8.1). It has been combined with another Mizoroki-Heck reaction [6] or a cross-coupling reaction [7], such as Suzuki, Stille or Sonogashira reactions. In other examples, a Tsuji-Trost reaction [8], a carbonylation, a pericyclic or an aldol reaction has been employed as the second step. On the other hand, cross-couphng reactions have also been used as the first step followed by, for example, a Mizoroki-Heck reaction or Tsuji-Trost reactions, palladation of alkynes or allenes [9], carbonylations [10], aminations [11] or palladium(II)-catalysedWacker-type reactions [12] were employed as the first step. A novel illustrative example of the latter procedure is the efficient enantioselective synthesis of vitamin E [13]. 

When nonsynunetrical secondary alkyl halides are involved, a stereogenic center is produced in the coupling reaction. The Ni(lI)/Pybox-based systems have also proved useful in the context of enantioselective synthesis. Asymmetric crosscoupling of functionalized alkylzinc halides with secondary a-bromoamides (e.g.,... 

Procedures for enantioselective synthesis of chiral amines and halides based on alkylboranes have been developed by applying the methods discussed earlier to homochiral organoborane intermediates. 

An N-acyliminium ion was utilized as the electrophile in a key step of Hiemstra s enantioselective synthesis of the unnatural enantiomer of gelse-dine (148, Scheme 11.24) [123]. In this synthetic endeavor it was discovered that treatment with iodide promotes the participation of the allene as the nucleophile to give the cyclized vinyl iodide 147 in 42 % yield. This finding is related to Overman s previous investigations of halide-promoted iminium ion cyclizations with alkynes as the nucleophilic cyclization terminators (cf. 149 150) [124]. The allene cyclization step (145 146—>147) afforded a rapid route to the skeleton of gelsedine (148), thus enabling the total synthesis of this natural product [123]. 

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