Enantioselective synthesis stereospecific reactions

Nucleophilic additions to (cyclohexadienone)Fe(CO)3 complexes (218) occur in a dia-stereospecific fashion (Scheme 56)197. For example, the Reformatsky reaction of ketone (218a) affords a simple diasteromeric alcohol product19715. The reduction of (1-carbo-methoxycyclohexa-l,3-dien-5-one)Fe(CO)3 (218b) to give 219 has been utilized in the enantioselective synthesis of methyl shikimate. In a similar fashion, cycloadditions of (2-methoxy-5-methylenecyclohexa-l,3-diene)Fe(CO)3 (220) occur in a diastereospecific fashion198. 

The stereospecific desulfinylation of sulfinyloxiranes has been widely reported and used in stereo- and enantioselective synthesis . When the reaction is performed at low temperature with an excess of f-BuLi, the resulting lithiooxirane can be trapped by various electrophiles including carbonyl compounds, chloroformates and chlorocarbamates as well as TMSCl (Scheme 56). Here again, retention of configuration was observed at -100°C. 

The sequential approach is also common in proposals written by synthetic chemists (a multistep synthesis is inherently step by step). Vyvyan (excerpt 13N), for example, proposes a strategy to synthesize a select group of heliannuols (alleo-pathic natural products isolated from the sunflower) in an optically pure form. One approach that he will explore involves enantioselective cross-coupling reactions between an alkyl zinc reagent and an aryl bromide. He begins with experiments that will utilize recently developed catalysts and produce products with known optical rotation data. Subsequent reactions are described that will lead potentially to the desired stereospecific heliannuols A and D. 

An alternate approach comprises replacing the pendant sugar by either a carbo-cyclic or a heterocyclic ring. The enantioselective synthesis starts by formation of the imide (45-3) by reaction of the aion from the chiral auxiliary (45-2), derived from S-phenylalaninol and the pentene ester (45-1). Treatment of the product with triethyl amine and the trifalate from dibutylboronic acid leads to the transient enol borate (45-4). Aldol addition of that enol to acrolein proceeds stereospecifically to the alcohol (45-5) due to the transfer of chirality from the chiral auxiliary. 

The (Z)-vinylic cyanocuprates also react with epoxides (e.g., 198) giving the (Z)-homoallylic alcohols (e.g., 199).41,270 The reaction is stereospecific and offers the possibility of its application in enantioselective synthesis (Scheme 109). 

The additions of allyl-, crotyl-, and prenylborane or -boronate reagents to aldehydes are among the most widely studied, well developed, and powerful reactions in stereoselective synthesis. The additions not only display excellent levels of absolute induction in enantioselective synthesis, but also exhibit superb levels of reagent control in diastereoselective additions. The additions of ( )- or (Z)-crotyl pinacol boronates to aldehydes have been observed to give predominantly 1,2-anti- and 1,2-syn-substituted products, respectively (Scheme 5.3) [31, 50]. The inherent stereospecificity of the reaction is consistent with a closed, cyclic Zimmerman-Traxler transition state structure [51], In the accepted model, coordination of the aldehyde to the allylation reagent results in synergistic activation of both the electrophile and the nucleophile... 

Allylic alcohols can be converted to epoxy-alcohols with tert-butylhydroperoxide on molecular sieves, or with peroxy acids. Epoxidation of allylic alcohols can also be done with high enantioselectivity. In the Sharpless asymmetric epoxidation,allylic alcohols are converted to optically active epoxides in better than 90% ee, by treatment with r-BuOOH, titanium tetraisopropoxide and optically active diethyl tartrate. The Ti(OCHMe2)4 and diethyl tartrate can be present in catalytic amounts (15-lOmol %) if molecular sieves are present. Polymer-supported catalysts have also been reported. Since both (-t-) and ( —) diethyl tartrate are readily available, and the reaction is stereospecific, either enantiomer of the product can be prepared. The method has been successful for a wide range of primary allylic alcohols, where the double bond is mono-, di-, tri-, and tetrasubstituted. This procedure, in which an optically active catalyst is used to induce asymmetry, has proved to be one of the most important methods of asymmetric synthesis, and has been used to prepare a large number of optically active natural products and other compounds. The mechanism of the Sharpless epoxidation is believed to involve attack on the substrate by a compound formed from the titanium alkoxide and the diethyl tartrate to produce a complex that also contains the substrate and the r-BuOOH. ... 

As mentioned in Sect. 2.2, phosphine oxides are air-stable compounds, making their use in the field of asymmetric catalysis convenient. Moreover, they present electronic properties very different from the corresponding free phosphines and thus may be employed in different types of enantioselective reactions, m-Chloroperbenzoic acid (m-CPBA) has been showed to be a powerful reagent for the stereospecific oxidation of enantiomerically pure P-chirogenic phos-phine-boranes [98], affording R,R)-97 from Ad-BisP 6 (Scheme 18) [99]. The synthesis of R,R)-98 and (S,S)-99, which possess a f-Bu substituent, differs from the precedent in that deboranation precedes oxidation with hydrogen peroxide to yield the corresponding enantiomerically pure diphosphine oxides (Scheme 18) [99]. 

Because of the specificity and the enantioselectivity of some enzyme-catalyzed reactions, the application of enzymes is increasingly important in asymmetric induction and kinetic resolution in organic synthesis. A large number of publications were recently reviewed, focusing on utilization of enzymes and microorganisms to stereospecific hydrolysis and other reactions to produce pure stereoisomers (2,3). However, the use of an enzyme as a catalyst has usually been limited to small-scale experiments in the laboratory. 

Highly enantioselective alkylations a to acyclic diene complexes have been developed. Deprotonation of (91) with LDA to form an ester enolate, followed by reaction with iodomethane, gives the alkylated prodnct (92) in excellent yield with 82% ee (Scheme 153). Stereospecific remote alkylation was used in a synthesis toward macrolactin A (Scheme 154). In the synthetic seqnence, the primary... 

The enantioselective total synthesis of the complex bioactive indole alkaloid enf-WIN 64821 was accomplished by L.E. Overman and co-workers." This natural product is a representative member of the family of the C2-symmetric bispyrrolidinoindoline diketopiperazine alkaloids. The stereospecific incorporation of two C-N bonds was achieved using the Mitsunobu reaction to convert two secondary alcohol functionalities to the corresponding alkyl azides with inversion of configuration. The azides subsequently were reduced to the primary amines and cyclized to the desired ib/s-amidine functionality. 

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