Enantioselective synthesis alkylation

The target molecule above contains a chiral center. An enantioselective synthesis can therefore be developed We use this opportunity to summarize our knowledge of enantioselective reactions. They are either alkylations of carbanions or addition reactions to C = C or C = 0 double bonds ... 

Silyl ethers serve as preeursors of nucleophiles and liberate a nucleophilic alkoxide by desilylation with a chloride anion generated from CCI4 under the reaction conditions described before[124]. Rapid intramolecular stereoselective reaction of an alcohol with a vinyloxirane has been observed in dichloro-methane when an alkoxide is generated by desilylation of the silyl ether 340 with TBAF. The cis- and tru/u-pyranopyran systems 341 and 342 can be prepared selectively from the trans- and c/.y-epoxides 340, respectively. The reaction is applicable to the preparation of 1,2-diol systems[209]. The method is useful for the enantioselective synthesis of the AB ring fragment of gambier-toxin[210]. Similarly, tributyltin alkoxides as nucleophiles are used for the preparation of allyl alkyl ethers[211]. 

Enantioselective synthesis of tryptophans has been accomplished via alkylation of 2,5-diethoxy-3,6-dihydropiperazines by the method developed by Schbllkopf[18]. For example, I> - -)-6-methoxytryptophan ethyl ester was prepared using l-(phcnylsulfonyl)-3-(bromomethyl)-6-methoxyindolefor alkyl-ationfl 9],... 

A novel approach to azabicyclic ring systems, based on an epoxide-initiated electrophilic cyclization of an alkyl azide, has been developed by Baskaran. A new stereo- and enantioselective synthesis of the 5-hydroxymethyl azabicyclic framework 91a, present in (+)- and (-)-indolizidines 167B and 209D, for example, was... 

Allylmetal reagents which hear alkyl or aryl groups at both termini are stereogenic and usually add aldehydes w ith a high degree of reagent-induced stereoselectivity (Section D.3.3.1.5.1.). Some of these reagents have been prepared in enantiomerically enriched form and used in enantioselective synthesis. Table 4 collects some representative examples. 

The alkylation of an enolate creates a new stereogenic center when the a-substituents are nonidentical. In enantioselective synthesis, it is necessary to control the direction of approach and thus the configuration of the new stereocenter. 

The syntheses in Schemes 13.45 and 13.46 illustrate the use of oxazolidinone chiral auxiliaries in enantioselective synthesis. Step A in Scheme 13.45 established the configuration at the carbon that becomes C(4) in the product. This is an enolate alkylation in which the steric effect of the oxazolidinone chiral auxiliary directs the approach of the alkylating group. Step C also used the oxazolidinone structure. In this case, the enol borinate is formed and condensed with an aldehyde intermediate. This stereoselective aldol addition established the configuration at C(2) and C(3). The configuration at the final stereocenter at C(6) was established by the hydroboration in Step D. The selectivity for the desired stereoisomer was 85 15. Stereoselectivity in the same sense has been observed for a number of other 2-methylalkenes in which the remainder of the alkene constitutes a relatively bulky group.28 A TS such as 45-A can rationalize this result. 

Phosphine ligands based on the ferrocene backbone are very efficient in many palladium-catalyzed reactions, e.g., cross-coupling reactions,248 Heck reaction,249 amination reaction,250 and enantioselective synthesis.251 A particularly interesting example of an unusual coordination mode of the l,l -bis(diphenylphosphino)ferrocene (dppf) ligand has been reported. Dicationic palladium(II) complexes, such as [(dppf)Pd(PPh3)]2+[BF4 ]2, were shown to contain a palladium-iron bond.252,253 Palladium-iron bonds occur also in monocationic methyl and acylpalladium(II) complexes.254 A palladium-iron interaction is favored by bulky alkyl substituents on phosphorus and a lower electron density at palladium. 

Izquierdo et al. reported the enantioselective synthesis of 5-O-methylthioswainsonine 53 from a derivative a d-glucose as a single stereoisomer. Intramolecular alkylation of the tosylate precursor 52 created the bicyclic system in the final step of the synthesis as outlined in Equation (17) <1996TA2567>. 

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. 

Enantioselective Synthesis by Tandem Catalytic RCM and Catalytic Alkylation... 

The availability of oxepins that bear a side chain containing a Lewis basic oxygen atom (entry 2, Table 6.4) has further important implications in enantioselective synthesis. The derived alcohol, benzyl ether, or methoxyethoxymethyl (MEM) ethers, in which resident Lewis basic heteroatoms are less sterically hindered, readily undergo diastereoselective uncatalyzed alkylation reactions when treated with a variety of Grignard reagents [17]. The examples shown below (Scheme 6.7) demonstrate the excellent synthetic potential of these stereoselective alkylations. 

The studies summarized above clearly bear testimony to the significance of Zr-based chiral catalysts in the important field of catalytic asymmetric synthesis. Chiral zircono-cenes promote unique reactions such as enantioselective alkene alkylations, processes that are not effectively catalyzed by any other chiral catalyst class. More recently, since about 1996, an impressive body of work has appeared that involves non-metallocene Zr catalysts. These chiral complexes are readily prepared (often in situ), easily modified, and effect a wide range of enantioselective C—C bond-forming reactions in an efficient manner (e. g. imine alkylations, Mannich reactions, aldol additions). 

Scheme 1. Catalytic enantioselective aldehyde alkylation affords the chiral macrocyclic alcohol 3 in Oppolzer s total synthesis of muscone (1993).

A method for enantioselective synthesis of carboxylic acid derivatives is based on alkylation of the enolates of /V-acyl oxazolidinones.59 The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

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... 

C. Lemaire, S. Gillet, S. Guillouet, A. Plenevaux, J. Aerts, A. Luxen, Highly enantioselective synthesis of no-carrier-added 6-[ F]fluoro-L-DOPA by chiral phase-transfer alkylation, Eur. J. Org. Chem. 13 (2004) 2899-2904. 

The enantioselective synthesis of a-amino acids is an important goal in preparative organic chemistry89. The use of l,3-oxazolidin-5-ones for this purpose has already been shown. A number of examples utilizing six-membered heterocycles exist whereby the basic idea remains the same i.e., the nonracemic enolate is attacked preferentially from the less hindered side because of a built-in auxiliary bias which can be removed in the alkylation step in order to liberate the nonracemic a-amino acid90. 

For the enantioselective synthesis of a-alkyl-a-phenylglycines the enolates 2, derived from (S)-3,6-dihydro-3-phenyl-2i/-l,4-oxazin-2-ones, 1, were alkylated91. (S)-l is available from an (S)-a-hydroxy acid (R1 = i-Pr, C6H5, Bn) and racemic phenylglycine in five steps. The yields of the alkylation step are around 90%, but the diastereoselectivity is strongly dependent on R1. 

Special cases arc the enantioselective synthesis of chiral aldehydes using 1-phenyl-l-ethanamine under optimized conditions (see Table 5), and the remarkable asymmetric induction observed in the alkylation of polymer-bound imines at room temperature (see Table 2). 

Recently, Nicolaou et al.167) reported an elegant asymmetric synthesis of the ionophore antibiotic X-14547 A (153) isolated at Hoffmann-La Roche from Strepto-myces antibioticus NRRL 8167. The key step in this synthesis was an enantioselective a-alkylation of n-butanal via its SAMP-hydrazone (151) to produce the intermediate (152). The asymmetric induction as determined by NMR-spectra of the product SAMP-hydrazone, was 95 % e.e. 

In addition to the results described, enantioselective access to 2-phosphino alcohols could be accomplished, too [71]. Starting from a borane-protected a-phosphino aldehyde hydrazone 91 as the key intermediate and available by two different approaches, the enantioselective synthesis of the desired 2-phosphino alcohols 93 could be accomplished. Thus, the electrophilic phosphinylation of aldehyde hydrazones 90 (via route I with the chlorodiphenylphosphine-borane adduct or via route II with chlorophosphines and subsequent phosphorus-boron bond formation) and the alkylation of phosphino acetaldehyde-SAMP hydrazones 92 (route III) was carried out (Scheme 1.1.26). 

Davis et al. [88] described the asymmetric synthesis of a-substituted primary sulfonamides involving the diastereoselective a-alkylation of N-sulfonylcamphor-imine dianions, while Huart and Ghosez reported an enantioselective synthesis of bicyclic cyclopentenones via a stereoselective 1,4-addition of metallated enan-tiopure sulfonamides to cyclic enones [89]. 

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