Synthesis, asymmetric

86 % optical purity. It is also of interest that the earlier asymmetric synthesis of the mirror image of the enone (41) has now been extended by Grieco from the steroid 

L-a-Amino-esters, via Schiff s bases of ajS-unsaturated aldehydes and 1,4-addition of Grignard reagents, have provided asymmetric syntheses of j8-disubstituted aldehydes (43) (60—100% optical yields). Two groups have independently described the asymmetric a-alkylation of ketones [(44) (45)], utilizing imines of a-amino-acid derivatives (L-proline and D-phenylalanine). 

Other reactions described, with varying degrees of success, have been chiral epoxidation, chiral hydrogenation, chiral iodination, and chiral reduction of keto-groups. One of the last reactions is especially interesting in using a chiral phase-transfer catalyst. Finally, Johnson and his co-workers have reported in full the asymmetric induction in their steroid synthesis via polyene cyclization [e.g. (46) (47) with ca. 90 % optical purity].  

A similar procedure using a-methoxylalkylphosphonium salts provides a route to ketones. Masked reactive functionalities have achieved fundamental importance in 

In designing a multistep synthesis, one must consider aspects of stereochemistry as well as functionality. In the chapters dealing with individual reactions, many examples were given in which the aspects of stereochemistry were a direct consequence of the reaction mechanism. For example, hydroboration-oxidation involves a syn addition followed by oxidation with retention of configuration. The generalization, widely but not universally correct, that reagents attack molecules from the sterically less hindered side was also illustrated on numerous occasions. 

We now wish to consider how these elements of stereochemistry come into play in synthesis. It is important to know how reaction stereochemistry is controlled by structural features of the reactant molecules. This topic can be broadly covered by the term asymmetric synthesis, which has been defined as a reaction in which an achiral unit in an ensemble of substrate molecules is converted by a reactant into a chiral unit in such a manner that the stereoisomeric products are produced in unequal amounts. Thus, we will be dealing with methods for controlling the configuration of newly formed chiral centers. As will be seen, these methods often depend on the fact that reagents attack molecules along the less hindered path. 

Morrison and H. S. Mosher, Asymmetric Organic Reactions, Prentice-Hall, Englewood Qiffs, NJ, 1971. 

Perhaps the simplest case of asymmetric synthesis to visualize is a reaction between an achiral molecule and a chiral reagent in such a way that a new chiral center is created at the reaction site. One such reaction is the Meerwein-Ponndorf-Verley reduction of ketones with aluminum salts of optically active alcohols. The 

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Much effort has been placed in the synthesis of compounds possessing a chiral center at the phosphoms atom, particularly three- and four-coordinate compounds such as tertiary phosphines, phosphine oxides, phosphonates, phosphinates, and phosphate esters (11). Some enantiomers are known to exhibit a variety of biological activities and are therefore of interest Oas agricultural chemicals, pharmaceuticals (qv), etc. Homochiral bisphosphines are commonly used in catalytic asymmetric syntheses providing good enantioselectivities (see also Nucleic acids). Excellent reviews of low coordinate (coordination numbers 1 and 2) phosphoms compounds are available (12). 

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaHy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphoms [7723-14-0] produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-Hthiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has Httie commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

Although not of industrial importance, several asymmetric syntheses of (R)-pantolactone (9) have been developed. Stereoselective abstraction of the j Z-proton of the achiral 1,3-propanediol derivative (23) by j -butyUthium-(-)-sparteine, followed by carboxylation and hydrolysis, results in (R)-pantolactone in 80% yield and 95% ee (53). 

Two- and three-component Hantzsch reactions using C-glycosylated reagents have been reported as an alternate method for conducting asymmetric syntheses of 1,4-dihydropyridines." ° Reaction of 109, 110 and 97 generate 111 with Ri = sugar. Alternatively, 112 and 113 produce 111 with Ri = sugar. While the yields were acceptable (60-90%), the diastereomeric ratio varied from 30-60%. 

Direct addition of Grignard reagents to Zincke-derived chiral pyridinium salts such as 99, meanwhile, allowed subsequent reduction to 1,2,3,6-tetrahydropyridines (e.g., 100, Scheme 8.4.32). This strategy provided entry to asymmetric syntheses of (-)-lupetidin and (+)-solenopsin. Tetrahydropyridines prepared by reduction of chiral... 

Chiral bicyclic lactams as useful precursors and templates for asymmetric syntheses 97CC1. 

Absolute asymmetric syntheses of heterocycles under physical fields 98CRV2391. 

Asymmetric syntheses of heterocycles by conjugate addition reactions 98EJO2051. 

Asymmetric syntheses of heterocycles using carbohydrates as chiral auxiliaries 97T14823. 

Asymmetric syntheses of (3-lactams by Staudinger ketene-imine cycloaddition reaction 98KGS1448, 99EJ03223. 

Although very efficient, the broad application of the direct preparation is restricted due to the limited number of pure starting enantiomers. The design of a multistep process that includes asymmetric synthesis is cumbersome and the development costs may be quite high. This approach is likely best suited for the multi-ton scale production of commodity enantiomers such as the drugs ibuprofen, naproxen, atenolol, and albuterol. However, even the best asymmetric syntheses do not lead to products in an enantiomerically pure state (100 % enantiomeric excess). Typically, the product is enriched to a certain degree with one enantiomer. Therefore, an additional purification step may be needed to achieve the required enantiopurity. 

Martens, J. Asymmetric Syntheses with Amino Acids, 125, 165—246 (1984). 

Asymmetric Syntheses with Aziridinecarboxylate and Aziridinephosphonate Building Blocks... 

The chemistry of aziridine-2-carboxylates and phosphonates has been discussed in part in several reviews covering the literature through 1999 [1-3], This chapter is intended to give an overview of asymmetric syntheses using chiral nonracemic aziridine-2-carboxylates and -phosphonates with particular emphasis on their applications as chiral building blocks in asymmetric synthesis since 2000. Some overlap with earlier reviews is necessary for the sake of continuity. 

A variety of methods for the asymmetric syntheses of aziridine-2-carboxylates have been developed. They can be generally classified into eight categories based on the key ring-forming transformation and starting materials employed (i) cyclization of hydroxy amino esters, (ii) cyclization of hydroxy azido esters, (iii) cyclization of a-halo- and ot-sulfonyloxy-(3-amino esters, (iv) aziridination of ot, 3-unsaturated esters, (v) aziridination of imines, (vi) aziridination of aldehydes, (vii) 2-carboxylation of aziridines, and (viii) resolution of racemic aziridine-2-carboxylates. 

More recently, Davis and co-workers developed a new method for the asymmetric syntheses of aziridine-2-carboxylates through the use of an aza-Darzens-type reaction between sulfinimines (N-sulfinyl imines) and a-haloenolates [62-66]. The reaction is highly efficient, affording cis- N-sulfmylaziridine-2-carboxylic esters in high yield and diastereoselectivity. This method has been used to prepare a variety of aziridines with diverse ring and nitrogen substituents. As an example, treatment of sulfinimine (Ss)-55 (Scheme 3.18) with the lithium enolate of tert-butyl bromoacetate gave aziridine 56 in 82% isolated yield [66],... 

Asymmetric Syntheses with Aziridinecarboxylate and Aziridinephosphonate Building Blocks 3.2.1.8 Resolution of Racemic Aziridine-2-carboxylates... 

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