Auxiliary-Based Methods

The first example of ligation via side-chain auxiliary, termed sugar-assisted ligation (SAL), was developed by Wong and coworkers in 2006 and involved the use of a glycopeptide whereby the reactive thiol auxiliary was appended to the C-2 

HIV-1 Tat [61]. Unfortunately, complications in the removal of the side-chain auxiliary hampered the total synthesis of the native protein in this study. 

An innovative demonstration of the manipulation of Cys residues to expand the scope of accessible ligation junctions was reported in 2008 by Okamoto and Kajihara [67]. With the aim of preparing complex glycopeptides and proteins, the 

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The discovery of viable substrate-direction represents a major turning point in the development of the Simmons-Smith cyclopropanation. This important phenomenon underlies all of the asymmetric variants developed for the cyclopropanation. However, more information regarding the consequences of this coordinative interaction would be required before the appearance of a catalytic, asymmetric method. The first steps in this direction are found in studies of chiral auxiliary-based methods. 

Upon removal of the auxiliary, an enantioenriched product could be obtained. The application of chiral auxiliary-based methods to Simmons-Smith cyclopropanation not only provided a useful synthetic strategy, but it also served to substantiate earlier mechanistic hypotheses regarding the directing influence of oxygen-containing functional groups on the zinc reagent [6dj. 

Two strategies have been adopted for asymmetric cyclopropanation. First, there are auxiliary-based methods, involving a covalently attached adjacent chiral moiety on either the olefin or the cyclopropylating agent. The second process, on the other hand, employs a chiral ligand on a metal catalyst. This method is more applicable to route b or c, and this is an issue that warrants further discussion. 

There must be enantiopure chiral information in the stereoselective step. This can be achieved either by using covalent attachment to one of the substrates (stereoselective auxiliary-based methods) or by creating a complex that is cleaved after the stereoselective elementary step under the reaction conditions and reused for the next molecule (stereoselective catalytic methods). Substrate control is observed when the substrates themselves are chiral,... 

Methods to control the absolute stereochemistry of the products obtained from the cyclocondensation reaction have also been developed. The use of both chiral auxiliary based methods and chiral catalysts have been investigated. The first and most straightforward method of controlling absolute stereochemistry is the use of a chiral and optically pure aldehyde. All of the methodology developed for the control of relative stereochemistry can then be directly applied to give optically pure cyclocondensation products. In many cases, however, the synthesis of optically pure aldehydes is difficult (if not impossible) due to their tendency to undergo racemization under the reaction conditions. This method also suffers from the fact that only chiral aldehydes can be used in the cyclocondensation reaction to get optically pure products simple and readily available achiral aldehydes can not be used. 

Chiral Auxiliary Based Methods 2.5.42 Chiral Catalysts... 

A chiral auxiliary-based method employing heteroatom binding shows considerable promise in nonracemic intermolecular Pauson-Khand chemistry. Scheme 5-3 depicts an acetylene synthetic equivalent bearing the 10-methylthioisobomeol moiety (15), which is capable of significant asymmetric induction upon Pauson-Khand cycloaddition. Loss of carbon monoxide from 15 may be effected thermally, or better yet, by reaction with IV-methylmorpholine N-... 

As an alternative to the use of auxiliaries for the asymmetric alkylation of carboxylic acid derivatives, in 2011, Zakarian and Stivala reported on the direct stereoselective alkylation of arylacetic acids with chiral lithium amide bases.This method offers an alternative to traditional auxiliary-based methods and operates through the formation of enediolates also, it builds on earlier work by Shioiri and Ando and by Koga and Matsuo . Zakarian and Stivala examined several C2-symmetric tetramines for their enan-tiodirecting power. After significant experimentation, conditions were established that used 4 equivalents of -BuLi and a slight excess of the tetramine that provided clean formation of the desired product. The enantioselectivity was found to be dependent on the quality of the -butyllithium. The reaction scope was examined with a variety of... 

Asymmetric aldol additions involving chiral ketones generally furnish products with much higher levels of induction [16, 20], These processes offer an attractive alternative to auxiliary-based methods since additional steps for auxiliary introduction and removal can thus be avoided. In particular, boron enolates have been extensively used. High stereoselectivity obtained with boron enolates is ascribed to the highly ordered nature of the cyclic chair-like transition states involved. The shorter C-B and 0-B bond distances give rise to tighter transition states, in which unfavorable non-bonded interactions between substituents are maximized, in contrast to those formed from other metal enolates [13]. Furthermore, additions of boron enolates are stereospecific, such that cis-boron enolates preferentially furnish 1,2-syn products and trans-boron enolates the 1,2-anti products [13, 14, 16]. 

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