Reagent controlled asymmetric synthesis

Asymmetric Induction at the Allylic Alcohol Centre AE is anti-Selective No Asymmetric Induction from Remote Allylic Alcohol Centre Reagent Control Asymmetric Synthesis of Diltiazem Summary of Sharpless Epoxidation... 

Tarchonanthuslactone (27) has been isolated from a compositae, tarchonanthus trilobus (57). All of the known syntheses of optically active 27 reported thus far involve substrate-control and >14 steps (58-61). Our 7-step reagent-controlled asymmetric synthesis begins with the allylboration of acetaldehyde, followed by osmylation, periodate cleavage, a second allylboration, esterification, and ring-closing metathesis reaction sequence (Scheme 9). 

The synthesis of 112 was then modified to provide a single enantiomer. This called for an asymmetric synthesis of cyclization substrate 111. This was accomplished by Midland reduction of ketone 113 to provide 114 with excellent enantioselectivity (Steroids-21). Alkylation of 114 with the appropriate bromide (prepared from 2-methylfuran according to the procedures described on Steroids-18), followed by a few well-precedented reactions, gave 115, and thence 111 and 112. Application of the Midland reduction is notable. This is a relatively early application of a reagent-controlled asymmetric synthesis. It is also notable that the Midland method works extremely well on alkyl alkynyl ketones (because they look like aldehydes to the reagent) and thus, is well-suited to this application. ... 

Reagent-controlled asymmetric cyclopropanation is relatively more difficult using sulfur ylides, although it has been done. It is more often accomplished using chiral aminosulfoxonium ylides. Finally, more complex sulfur ylides (e.g. 64) may result in more elaborate cyclopropane synthesis, as exemplified by the transformation 65 66 ... 

Asymmetric ylide reactions such as epoxidation, cyclopropanation, aziridination, [2,3]-sigmatropic rearrangement and alkenation can be carried out with chiral ylide (reagent-controlled asymmetric induction) or a chiral C=X compound (substrate-controlled asymmetric epoxidations). Non-racemic epoxides are significant intermediates in the synthesis of, for instance, pharmaceuticals and agrochemicals. 

In principle, asymmetric synthesis involves the formation of a new stereogenic unit in the substrate under the influence of a chiral group ultimately derived from a naturally occurring chiral compound. These methods can be divided into four major classes, depending on how this influence is exerted (1) substrate-controlled methods (2) auxiliary-controlled methods (3) reagent-controlled methods, and (4) catalyst-controlled methods. 

The substrate-controlled reaction is often called the first generation of asymmetric synthesis (Fig. 1-30, 1). It is based on intramolecular contact with a stereogenic unit that already exists in the chiral substrate. Formation of the new stereogenic unit most often occurs by reaction of the substrate with an achiral reagent at a diastereotopic site controlled by a nearby stereogenic unit. 

Double asymmetric synthesis was pioneered by Horeau et al.,87 and the subject was reviewed by Masamune et al.88 in 1985. The idea involves the asymmetric reaction of an enantiomerically pure substrate and an enantiomerically pure reagent. There are also reagent-controlled reactions and substrate-controlled reactions in this category. Double asymmetric reaction is of practical significance in the synthesis of acyclic compounds. 

Lewis acids of chiral metal aryloxides prepared from metal reagents and optically active binaphthol derivatives have played a significant role in asymmetric synthesis and have been extensively studied.23 However, in Diels-Alder reactions, the asymmetric induction with chiral metal aryloxides is, in most cases, controlled by steric interaction between a dienophile and a chiral ligand. This kind of interaction is sometimes insufficient to provide a high level of enantioselectivity. 

The poor diastereoselectivity of the reactions of chiral aldehydes and achiral allylboronates appeared to be a problem that could be solved by recourse to the strategy of double asymmetric synthesis.f Our studies thus moved into this new arena of asymmetric synthesis, our objective being the development of a chiral allylboron reagent capable of controlling the stereochemical outcome of reactions with chiral aldehydes independent of any diastereofacial preference on the part of the carbonyl reaction partner. 

In the first step, stereochemical information contained in a matrix-complex is transferred to the substrate by the formation of a matrix-substrate complex in such a way that the substrate in the second step will be able to differentiate the direction of attack of a reagent. In the reaction chain the MS-complex may appear as an intermediate or a transition state. The transition from the MS-complex to the product may proceed in a reversible or in a nonreversible reaction. Therefore the product ratio of an asymmetric synthesis is not necessarily controlled by kinetic parameters, although this may often be the case. 

Chiral synthesis, also called asymmetric synthesis, is synthesis which preserves or introduces a desired chirality. Principally, there are three different methods to induce asymmetry in reactions. There can be either one or several stereogenic centres embedded in the substrate inducing chirality in the reaction (i.e. substrate control) or an external source providing the chiral induction (i.e. reagent control). In both cases the obtained stereoselectivity reflects the energy difference between the diastereomeric transition states. 

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