Methodology for Stereochemical Control

Since stereoselectivities of biocatalytic reductions are not always satisfactory, modification of biocatalysis are necessary for practical use. This section explains how to find, prepare, and modify the suitable biocatalysts, how to recycle the coenzyme, and how to improve productivity and enantioselectivity of the reactions. 

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The combination of reagents and methods can provide for stereochemical control of addition to a-substituted aldehydes.195 An application of the methodology can be found in the synthesis of (+)-discodermolide that was carried out by J. A. Marshall and co-workers and is described in Scheme 13.69. 

This chapter presents some examples of the asymmetric synthesis of complicated natural products. These examples will demonstrate that building up these molecules is unlikely if we do not use the asymmetric synthesis methodology. Excellent accounts by Masamune et al.1 and Noyori2 give a clear picture of the strategies for stereochemical control in organic synthesis. 

Cathodic cyclization reactions have supphed and continue to provide a fertile territory for the development and exploration of new reactions and the determination of reaction mechanism. Two areas that appear to merit additional exploration include the application of existing methodology to the synthesis of natural products, and, more significantly, a systematic assessment of the factors associated with the control of both relative and absolute stereochemistry. Until there is a solid foundation to which the non-electrochemist can confidently turn in evaluating the prospects for stereochemical control, it seems somewhat unlikely that electrochemically-based methods will see widespread use in organic synthesis. Fortunately, this comment can be viewed as a challenge and as a problem simply awaiting creative solution. 

Chiral Auxiliary. (/ ,/ )-( ) has been used as a chiral auxiliary to direct the stereochemistry of addition of a nucleophile to an acrylate moiety. Almost complete stereoselectivity is achieved in the addition of cyclopentanecarboxylic acid lithium dianion to the a-substituted acrylate substrate (eq 14). This methodology allows stereochemical control at the a-position of a p-amino ester and thus complements the methodology described above for the stereoselective formation of p-substituted p-amino esters. 

In recent years, cross-coupling methodology has emerged as a viable tool for enamide synthesis, and, indeed, there are a number of published protocols which employ palladium- or copper-catalyzed stereospecific amidations of vinyl halides [17]. For example, Buchwald and coworkers had recently shown that a copper-catalyzed cross-coupling of vinyl bromides or iodides proceeded with retention of stereochemistry (Scheme 9.16), though the only example using a tetrasubstituted vinyl halide, 23, lacked the need for any stereochemical control in the halide portion [18]. Based on this it seemed feasible that the desired enamide 22 could potentially be assembled via a comparable coupling between amide 24 and a stere-odefined vinyl halide such as 25. 

Note that aldol condensations I, II and III concern the creation of a relative configuration 2,3-syn, which can be easily achieved starting from the (Z)-enolates 74a-74c. Scheme 9.27 summarises the synthesis of 93 and 95, which are equivalent to fragments B and A, respectively. Compound 88 is the abovementioned Prelog-Djerassi lactonic acid 42 which is obtained in optically pure from (>98% ee). On the other hand, for the stereochemical control of the aldol condensation IV a different methodology is necessary whih involves the coupling of two structurally predefined reactants and which will not be discussed here (Scheme 9.28). An important feature of this reaction is that the coordination of Li" " with the oxygen atom at the P-position of the aldehyde 95 is mainly responsible for the observed stereoselection [22e]. 

A few examples are chosen in order to illustrate the potentialities of this remarkable methodology. In Reaction (6.6) the sequence is initiated by the removal of the PhSe group and the formation of a carbamoyl radical. It is worth mentioning that the stereochemical outcome of these cascade reactions is controlled by the stereochemistry of the oxygen-bearing asymmetric carbon in 29. Indeed, Reactions (6.6) and (6.7) show clearly the stereochemical control. On the other hand, Reactions (6.7) and (6.8) illustrate the role of R which is carried as a terminal group in the acetylenic moiety. For R = Ph the last step is the hydrogen abstraction, whereas for R = SnBus, the last step is the ejection of BusSn radical (cf. Scheme 6.7). 

The Simmons-Smith reaction " and its variants are widely used for the stereospecific synthesis of cyclopropane compounds. The methodology involves the use of copper-treated zinc metal (the zinc-copper couple) with diiodomethane to add methylene to a carbon-carbon double bond. Alternative use of diazomethane in catalytic reactions does not offer the same synthetic advantages and is usually avoided because of safety considerations. As significant as is the Simmons-Smith reaction for cyclopropane formation, its employment for organic synthesis was markedly advanced by the discovery that allylic and homoallylic hydroxyl groups accelerate and exert stereochemical control over cyclopropanation of alkenes (e.g, Eq. 21), and this acceleration has been explained by a transition state model... 

The methodology allows for a selective preparation of cyclic compounds361,390-394 as well as acyclic ones (Scheme 26.15).363,383,395-399 Stereochemical control for acyclic reactions can be increased with the use of a cyclic primer.369,372,375,400-409... 

However, the lack of stereochemical control at C-4 of newly created asymmetric center, resulting in the formation of two diastereomers, is the great disadvantage. Despite this, Comforth s methodology remains still the best choice for preparation of the selected ulosonic acids. It is a case of synthesis of nine stereoisomeric 5,7-diacetamido-3,5,7,9-tetradeoxy-2-nonulosonic acids [76]. The synthesis was performed by condensation of an appropriate 2,4-diacetamido-2,4,6-trideoxy-hexopiranoses with oxalacetic acid under basic conditions (Scheme 13), used previously in the preparation of Neu5Ac [77]. 

On the methodological front of these broadly based endeavors, we have exploited pericyclic processes such as the dipolar cycloadditions of nitrile oxides together with the aldol reaction and related constructions as tactical devices for the formation of new carbon-carbon bonds with high levels of stereochemical control Another important focus of these explorations has been upon the development of techniques for the manipulation and refunctionalization of hydropyrans, since this structural subunit is not only common to a variety of natural substances, but it may also be effectively exploited as a conformationally-biased template for the stereoselective construction of various skeletal arrays present in numerous natural products. In this context, we have devised a novel and highly effective strategy for the asymmetric syntheses of oxygenated natural products. The fundamental approach features the intermediacy of the hydro-3-pyranones 12, which may be accessed from the chiral furfuryl carbinols 10 via the hydroxy enediones 11 by well-established oxidative techniques (Scheme 1). A critical element of this overall planll is that the hydro-3-pyranones 12 are admirably endowed with differentiated functionality that is suitable for further elaboration by reaction with selected nucleophiles... 

The synthetic utility of the sulfoxide functionality is well established in organic chemistry and has been known for many years [1]. More specifically, the use of nonracemic sulfoxides in asymmetric synthesis has assumed growing importance in recent years since the chiral sulfoxide group is often able to exert significant stereochemical control in bond-forming reactions. Such advances in asymmetric synthesis have been made possible by the development of new methodology for the preparation of nonracemic sulfoxides. 

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