Derivation from enantiopure natural products

There are three methods available for the enantioselective synthesis of pheromones (1) derivation from enantiopure natural products, (2) enantiomer separation (optical resolution), and (3) chemical or biochemical asymmetric synthesis. Practitioners of enantioselective synthesis must be familiar with the analytical methods for the determination of enantiomeric purity of an optically active compound. These basic methods will be explained briefly in this section, and discussed in depth through examples in the later sections of this chapter. 

The total synthesis of enantiopure natural products has been one of the key developments of the modem era of asymmetric synthesis. Since the Hajos-Wiechert reaction allows ready access to useful chiral bicyclic building blocks, the reaction has been widely employed to constmct a variety of precursors for the synthesis of steroids, vitamin D derivatives, and other natural products. The remainder of the review will look at select examples from the total synthesis literature to illustrate this point. 

Scheme 7 summarizes the synthesis of (7JR,llS)-7,ll-dimethylheptadecane (1), the female sex pheromone of the spring hemlock looper (Lambdina athasaria) by Mori [ 18]. Enantiopure alkanes are usually synthesized by coupling enantio-pure building blocks derived from natural products or compounds prepared by asymmetric synthesis. Even among hydrocarbons, chirality is very important for pheromone activity, and in this particular case meso-1 was bioactive, while neither (7R,11R)-1 nor (7S,11S)-1 showed bio activity. 

PhI=NTs in MeCN affords a copper species that is indistinguishable by ultraviolet-visible (UV-vis) spectroscopy from an identical solution derived from Cu(OTf)2. Given the strong oxidizing nature of PhI=NTs, it seems likely that both catalysts proceed through a Cu(II) species. Beyond this, little can be said with certainty. If nitrenoid formation proceeds by a two-electron oxidation of the catalyst, one would need to invoke Cu(IV) as an intermediate in this process (77). This issue is resolved if one invokes the intervention of a bimetallic complex in the catalytic cycle. However, attempted observation of a nonlinear effect revealed a linear relationship between ligand enantiopurity and product ee (77, 78). 

To be presented in the sequel, are a series of prototype reaction channels leading from simple, tautomerically fixed D-glucose derivatives to enantiopure building blocks along preparatively useful, practical protocols, followed by their utilization for the straightforward total synthesis of a series of natural and nonnatural products in optically active, enantiomerically homogeneous form. 

Enantiopure citronellal (7) which can be quantitatively derived by hydrolysis from citronellal enamine 6 can be used for the synthesis of a broad array of optically active natural products. A list of compounds produced commercially on a 7 to 1500 ton-scale annually, serving as fragrances, insect growth regulators, or intermediates in organic synthesis, is given in Table 1. 

A number of enantiomerically pure complexes have been made, and this chemistry has been used in several natural product syntheses. Enantiopure complexes are readily available from the corresponding vinylic epoxides, and in cases where diastereoselective complexation is possible, diastereoselectivities tend to be moderate (typically 3 1 -4 1). The rationale for the origin of this diastereoselectivity has been proposed to derive from a preferential complexation of a Fe(CO)4 fragment to the alkene anti to the epoxide. Since the initial vinyl epoxide is conformationally flexible, four diastereomeric itt-complexes would be produced as a consequence of anti or syn complexation to the s-trans or s-cis conformers. Isomerization of these initial 7r-complexes to alkoxy- 7r-allyl species would then enable interception of an iron-bound carbonyl ligand by the alkoxide to afford diastereomeric lactone complexes. Fortunately, equilibria between the two possible trans itt-allyl complexes and their more stable cis Tr-aUyl analogs simplifies the outcome significantly. Thus, for trans vinyl epoxides, the major diastereomer typically is the one designated as endo cis (the C-1 substituent points toward the iron atom) the minor diastereomer corresponds to the exo cis isomer (the C-1 substituent points away from the iron atom) (Scheme 51). For cis vinyl epoxides, this outcome is reversed - the exo cis isomer is the major product. 

Chiral molecules are characterized by three-dimensional handedness and can exist in two enantiomeric forms of opposite absolute configuration (AC). Most natural products and biologically active compounds are chiral and their biological and molecular functions are closely related to their chirality, that is, AC and conformation. Furthermore, many drugs derived from natural products or of purely synthetic origin are currently used in enantiopure form. Therefore, the unambiguous determination of the AC of chiral compounds is critical for the studies of natural products and biomolecular systems.1... 

Another example of the utility of this reaction is the formation of enantiopure cycloheptenones from optically pure natural products like R-carvone. Hydroxylaminomethylcyclohexene 72 derived from -carvone rearranged to provide two compounds resulting from selective rearrangement of the vinyl carbon. While the alkene migrated into conjugation under the reaction conditions providing 10% of 74, the Tiffeneau-Demjanov reaction provided entry into optically-enriched cycloheptenones. ... 

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