Stereogenic centers cyclic molecules

In the discussion of the stereochemistry of aldol and Mukaiyama reactions, the most important factors in determining the syn or anti diastereoselectivity were identified as the nature of the TS (cyclic, open, or chelated) and the configuration (E or Z) of the enolate. If either the aldehyde or enolate is chiral, an additional factor enters the picture. The aldehyde or enolate then has two nonidentical faces and the stereochemical outcome will depend on facial selectivity. In principle, this applies to any stereocenter in the molecule, but the strongest and most studied effects are those of a- and (3-substituents. If the aldehyde is chiral, particularly when the stereogenic center is adjacent to the carbonyl group, the competition between the two diastereotopic faces of the carbonyl group determines the stereochemical outcome of the reaction. 

Apart from cyclic or acyclic transition state geometry further distinctions of diastereoselec-tion have to be made with respect to the way in which the chiral center is attached to the reactive site. The term auxiliary control is used if a chiral subunit, e.g., an alcohol or an amine, is fixed covalently to the unsaturated substrate and then removed by bond cleavage after the addition. In contrast, if the stereogenic center remains part of the molecule after the addition, the term substrate control is applied (these definitions are given in Section A. 1.). 

An alternative concept is asymmetric desymmetrization of a prochiral molecule of type 83. The starting materials 83 have three keto groups and one carbon atom bearing at least three substituents. A prerequisite is the presence of a prochiral carbon atom with two identical substituents bearing a keto functionality (Scheme 6.39, Eq. (2)). This type of asymmetric intramolecular aldol reaction proceeds with formation of cyclic ketols of type 84 with two stereogenic centers. Dehydration can subsequently be performed, leading to optically active enones of type 85. The two types of intramolecular aldol reaction are shown conceptually in Scheme 6.39. 

When the alkene is cyclic, or the insertion step forms a quaternary center, a substitution product is not obtained. For example, stereospecific syn addition of an arylpalladium halide 13 to cyclohexene generates cyclohexylpalladium(II) intermediate 14 (Scheme 6-3). The C—Pd cr-bond in this intermediate is anti to H and syn elimination to form a substitution product is not possible. However, elimination of cis hydrogen H is possible and generates allylic product 15. This pathway of the Heck reaction is particularly important in complex molecule construction since a new stereogenic center is produced. 

The cinchona alkaloids have opened up the field of asymmetric oxidations of alkenes without the need for a functional group within the substrate to form a complex with the metal. Current methodology is limited to osmium-based oxidations. The power of the asymmetric dihydroxylation reaction is exemplified by the thousands (literally) of examples for the use of this reaction to establish stereogenic centers in target molecule synthesis. The usefulness of the AD reaction is augmented by the bountiful chemistry of cyclic sulfates and sulfites derived from the resultant 1,2-diols. 

As mentioned previously, reactions of cyclic molecules that involve formation of stereogenic centers are similar to those of acyclic systems in that they can proceed with clean retention or inversion of configuration, or a mixture of the two. Reaction of sodium azide (NaN3) and cis-4-rert-butyl-l-bromocyclohexane gives... 

The diastereoselectivity obtained for reactions on a ring makes it possible to use a cyclic molecule to fix a stereocenter in an acyclic target, as seen in the formation of 154 from 152. Diol 152 had been prepared by a multistep sequence, with control of the stereocenters. When this diol was subjected to oxidation with MCPBA lactone 153 was formed. Subsequent ring opening with methanolic potassium carbonate led to the acyclic fragment 154, with six contiguous stereogenic centers whose stereochemistry had been fixed in the cyclic... 

Cyclic molecules may have stereogenic centers and it is possible to generate enantiomers and/or diastereomers. Problems of identifying the stereogenic center and the number of stereoisomers arise with some cyclic molecules that do not as acute in acyclic molecules. This section will focus on these problems. 

When a molecule has two or more stereogenic (chiral) centers, there are a maximum of 2" stereoisomers, where n = the number of chiral centers. When a molecule has two or more chiral centers, diastereomers are possible. Diastereomer is the term for two or more stereoisomers that are not superimposable and not mirror images. A diastereomer that has symmetry such that its mirror image is superimposable is called a meso compound. If there is no symmetry, cyclic molecules can have enantiomers and diastereomers. If there is symmetry in one diastereomer, cyclic compounds can have meso compounds 23, 24, 25, 26, 27, 28, 29, 30, 48, 49, 59, 60, 62,63,67,68,69, 70, 71, 75, 78, 79. 

This synthesis illustrates one strategy for the preparation of acyclic molecules containing multiple stereogenic centers — use cyclic structures to control stereochemistry and then liberate the acyclic structure. The strategy is not unlike several of the Cecropia juvenile hormone syntheses we examined, where stereoselective olefin synthesis was the goal. Whereas three pieces are ultimately assembled, the synthesis of the central fragment is linear and there was a price to pay for this approach. It is long. 

The successful synthesis and resolution of a chiral thiol attached to a cyclic phosphate unit (38), that eontained a C-stereogenic center, allowed the preparation of chiral self-assembled monolayers on gold. The monolayers were used to promote the heterogeneous nucleation and growth of erystals from nonaqueous solutions of an organie molecule (the parent phencyphos) of similar structure to the compound present in the monolayer (Scheme 13). °... 

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