Epimeric natural products

The epimeric (+)-a-allokainic acid was constructed by the unsaturated imide/ alkyne alkylative coupling of 9 with trimethylaluminum in 73% yield and 97 3 diastereoselectivity (Scheme 8.11) [33]. This was followed by silyl to carbonate protecting group transposition, stereoselective aUylic reduction, and removal of protecting groups to afford (+)-a-allokainic acid. The complementary nature of these two stereodivergent approaches allowed access to both epimeric natural products. 

A classic diagnostic use of such stereochemical requirements, due to Ruzicka, is the ring contraction induced in natural products containing the 4,4-dimethyl-5a-3 -ol system (94). The epimeric, axial 3a-alcohols (95) dehydrate without ring contraction. Barton suggested that it is necessary for the four reacting centers (hydroxyl, C-3, C-4, C-5) to be coplanar for ring contraction to occur, and this is only the case with the 3)5-alcohol. 

Acetoxy-21-nor-5a-cholestan-20-one (73a) as well as the free alcohol (73b) react with methylmagnesium iodide to give a mixture of epimeric diols (74). After treatment with acetic anhydride and subsequent hydrogenation over reduced platinum oxide this mixture alfords 3j5-acetoxy-5oc-cholestane (75) which is identical with the natural product. This synthesis has been used to prepare the 21- C compound (75) in a total yield of 18... 

Quinidine, a natural product epimeric with quinine at Cg and C9, was accessed through the diastereoisomeric trans epoxide prepared from 86 by SAD, in this case by using AD-mix a [2b, 41]. 

Intramolecular Diels-Alder reactions employing furan as the diene component are an effective step in the synthesis of many natural products, but difficulties are sometimes encountered due to the poor dienic character of the aromatic ring. Using CDs can help to overcome this problem. Thus, when 73 is heated in water at 89 °C for only 6h a 20% epimeric 1 2 mixture of 74 and 75 is... 

Ishikawa s synthesis of ( )-0-methylkinamycin C (54) represents a distinct approach to the kinamycins that hinges on a key Diels-Alder reaction to establish the tetracyclic skeleton of the natural products. Additional key steps in the sequence include a substrate-directed dihydroxylation, substrate-directed reduction, and spontaneous epimerization of an a-hydroxyketone intermediate. 

Among the many natural products that may be considered in this category are the alkaloids 6-hydroxycrinamine (26a) and haemanthidine (26b), which are epimeric in the solid. It is found (71) that in solid 26a the hydroxyl attached to C-6 is trans to the pyrrolidine ring, whereas for both compounds, there is NMR evidence for epimerization at C-6 in solution (72). 

The synthesis of oxazole- and dihydrooxazole-containing cyclic peptides has gained considerable interest in view of the structural characterization of the natural products. In fact, in various cases a final structural elucidation was provided only by total synthesis as originally proposed structures had to be corrected because of epimerization, difficult stereochemical assignment, and/or impurities.1523,524,554,5551... 

Obtaining the correct stereochemistry at an asymmetric centre is crucial in the total syntheses of natural products. Moreover, pharmacological properties are closely related to the correct stereochemistry. Thus, the epimerization reaction, which enables equilibration of C-3 epimers,... 

The cumbersome route in Scheme 269 had been prompted by frustrated attempts to prepare the dianion of acid 32 on the microscale. A reexamination of this reaction on a larger scale showed that warming of a THF solution of 32 with two equivalents of LDA at 50 °C for 2 h led to an orange solution of dianion. Addition of methyl iodide then gave rise to a single diastereomerically pure homologous acid, 41, in nearly quantitative yield (Scheme 3). The stereochemical identity of 41 was reasonably assumed to be erythro from its conversion to the natural product 1. The possibility of epimerization at some stage in this process was ruled out by the clean conversion of threo acid 37 to 9-epiartemisinin 29. 

The natural products epothilone A and B are structurally different from taxol but have similar anticancer activity. Significantly, they have been reported to be much more active against cell lines exhibiting multiple-drug resistance [26], Taylor and co-workers at the University of Notre Dame have recently published an elegant, formal total synthesis of epothilone A [27], In this work, the authors used the CLC form of Burkholderia cepacia (formerly Pseudomonas cepacia) lipase (ChiroCLEC -PC) to resolve a key alcohol intermediate by selective acylation with vinyl acetate in /-butyl methyl ether (Fig. 6). The enantioselectivity was >20 1 at 47% conversion and efficiently provided gram quantities of the desired (R) alcohol. Since the unreacted (S) alcohol can easily be epimerized by a simple oxidation-reduction sequence and the catalyst reused without significant loss in activity, the method is ideally suited for scale-up. 

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