Natural stereochemical control

In spite of the fact that biotechnology rather than chemical processing will probably provide the future greatly needed chirally pure compounds (ref. 1), we believe that simple chemical reactions starting from chiral natural compounds and proceeding under stereochemical control will eventually retain full importance. On the above grounds, we report on simple reactions which start from a-aminoacids, as an example of utilization of natural compounds, and move to related bromine containing compounds (Fig. 1). 

As far as I am aware, neither of these compounds has been synthesised. Can you devise routes Stereochemical control is essential lor (69) but the chiral centre to which the vinyl group is attached in (68) is unimportant as both epimers are natural products. 

Some general considerations governing the nature of selective enantiomeric interactions for both gas and liquid chromatographic phases (at least of the bonded monomeric ligand type) have been forthcoming [721,742,754,756,781,782,790). It is generally assumed that three points of simultaneous interaction at least one of which must be stereochemically controlled, are required to distinguish the chirality of a molecule. These... 

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. 

Uncatalysed Diels-Alder reactions usually have to be carried out at relatively high temperatures (normally around 100 °C)73, often leading to undesired side reactions and retro-Diels-Alder reactions which are entropically favoured. The Diels-Alder reaction became applicable to sensitive substrates only after it was realized that Lewis acids (e.g. A Clg) are catalytically active56. As a consequence, Diels-Alder reactions can now be carried out at temperatures down to — 100°C85. The use of Lewis acid catalysts made the [4 + 2]-cycloaddition applicable to the enantioselective synthesis of many natural compounds51,86. Nowadays, Lewis acid catalysis is the most effective way to accelerate and to stereochemically control Diels-Alder reactions. Rate accelerations of ten-thousand to a million-fold were observed (Table 7, entries A and B). 

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. 

This alkynone thermolysis has served as the key step in several natural product syntheses. The considerations that lead to regio- and stereochemical control are illustrated by an elegant synthesis of clovene 725. Thermolysis of the symmetrical alkynone 4 could lead to three different enones, two of which (5 and 6) arc illustrated. In fact, only 8-methyltricyclo[8.3.1.01 5]dodec-3-en-2-one (5) is isolated, in 80% yield. The structure of 5 was confirmed by straightforward conversion to the tricyclic hydrocarbon clovene. The outcome of the thermolysis was anticipated, as it had previously been observed that C-H insertion is most facile when the intermediate alkylidene can achieve coplanarity with the target C-H bond. In this system, such coplanarity is achievable only via the boat conformation of one of the two symmetrical rings. 

Pericyclic reactions are concerted reactions that take place in a single step without any intermediates, and involve a cyclic redistribution of bonding electrons. The concerted nature of these reactions gives fine stereochemical control over the generation of the product. The best-known examples of this reaction are the Diels-Alder reaction (cyclo-addition) and sigmatropic rearrangement. 

The stereochemistry of ketene to alkcne cycloadditions is such that retention of the alkene configuration is observed. Furthermore, in cycloadditions with unsymmetrically substituted ketenes the larger of the two ketene substituents ends up as with respect to the adjacent alkene substituent (or eiulo in cycloalkene cycloadditions). This stereochemical outcome was originally attributed to the concerted [ff2a + n2a] nature of kctcnc to alkene cycloadditions,21 although more recent experimental and theoretical evidence indicate that these reactions are asynchronous and in some cases in which polarized double bonds are involved actual zwittcrions may be intermediates.9 1195 Also in certain cases the endo product in ketene to alkene cycloadditions may be the thermodynamic product from equilibration studies.22,23 Nevertheless, stereochemical control can be achieved in most such reactions as shown by the examples of 12,24 13,29 14,25 15,26 16,27 and 17.28... 

Aldol reactions enjoy great recognition as a useful tool for the synthesis of building blocks in natural product and drug synthesis [42, 182]. The stereochemistry of the stereogenic centers formed can be controlled by various means. Besides chiral auxiliaries, catalytic methods with chiral Lewis acids, organocatalysts, or catalytic antibodies were established for stereochemical control [183-187]. 

The process of enamine alkylation has found widespread application in natural product synthesis188. Since the overall sequence involves the reaction of a nitrogen moiety with a ketone to form a reactive intermediate, modification of the process through the use of chiral enamine seemed ideal for asymmetric induction. Previous attempts to obtain stereochemical control were for a long time unsuccessful, because proper attention had not been directed to the involvement of two reactive conformations, interconvertible... 

Yamamoto and Maruoka investigated the reaction of chiral acetals with organoaluminum reagents. Unprecedented regio- and stereochemical control was observed in the addition of trialkylaluminums to chiral a,/3-unsaturated acetals derived from optically pure tartaric acid diamide [83]. The course of the reaction seemed to be highly influenced by the nature of substrates, solvents, and temperature. These findings provide easy access to optically active a-substituted aldehydes (84), /3-substituted aldehydes (85), a-substituted carboxylic acids (86), or allylic alcohols (87). Because optically pure RJi)- and (5,5)-tartaric acid diamides are both readily available, this method enables the predictable synthesis of both enantiomers of substituted aldehydes, carboxylic acids, and allylic alcohols from a,/3-unsaturated aldehydes (Sch. 54). 

Coordination catalysts also permit stereochemical control about the carbon-carbon double bond. By their use, isoprene has been polymerized to a material virtually identical with natural rubber c/j-I,4-polyisoprene. (See Sec. 8.25.)... 

The versatility of the Claisen rearrangement for the synthesis of functionally substituted y, 8-unsaturated carbonyl compounds has been greatly enhanced by the introduction of various vinyl ether appendages. These not only participate in the stereochemical control of the rearrangement, but also determine the nature of the functional group in the product (-CHO, -COR, -COOH, -COOR, -CONR2). 

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