Enantioselective synthesis transannular reactions

Norzoanthamine is a heptacychc alkaloid originally isolated from marine zoanthids. In addition to its complex molecular structure, norzoanthamine is well-known for its potent antiosteoporotic activity. In their studies toward the total synthesis of norzoanthamine, Yang and co-workers developed a 12-step enantioselective synthesis of the highly functionalized and stereochemically complex ABC ring system. A transannular Michael reaction cascade was... 

Enantioselective desymetrization by a-deprotonation/tran-sannular C—H insertion of cyclooctene oxide (i.e., 173) was reported by Hodgson and co-workers for synthesis of bicycle[3.3.0] octanes, intermediates that are useful for pol-yquinane synthesis. The best yields and enantioselec-tivities of 175 were obtained when 173 was treated with j-PrLi and (—)-a-isosparteine (Scheme 20.42). Application of this reaction in natural product synthesis is yet to be reported. The same research group also reported expanding the scope of the reaction to synthesis of indolizidine 177 by a similar transannular reaction of 176. ... 

An enantioselective biomimetic synthesis of longithorone A was accomplished on the basis of proposed biosynthesis. " The syntheses of two [12]-paracyclophanes 105 and 107 are realized by applying ene-yne metatheses macrocyclization to 104 and 106, which are synthesized from the common substrate 103. Longtholone A is constructed using intermolecular and transannular Diels-Alder reactions followed by oxidation (Scheme 40). 

The first total synthesis of (+)-arteannuin M was completed by L. Barriault et al. using a tandem oxy-Cope/transannular ene reaction as the key step to construct the bicyclic core of the natural product. The tandem reaction proceeded with high diastereo- and enantioselectivity. 

Whereas the examples above used substrate control for stereoselective transannular aldol or related reactions, reagent control has also been reported for the transannular aldol reactions. One example is synthesis of the musk ordorants (R)-muscone and (R,Z)-5-muscenone by Knopff and co-workers. It involved enantioselective formation of 73 by the transannular aldol condensation of the symmetrical macrocyclic 1,5-diketone 72 using sodium ephedrate for desymmetrization (Scheme 20.19). The reaction was assumed to proceed by a reversible transannular aldol reaction followed by an enantioselective dehydration reaction. 

SCHEME 20.21. The organocatalytic enantioselective transannular aldol reaction in the synthesis... 

Since intramolecular transannular aldol reactions create two new rings and at least two new stereogenic centers in a single process, the corresponding cyclic p-hydroxy ketones are useful for the synthesis of polycyclic natural products. The trons-4-fluoro proline 48 is superior to (S)-proline in catalysis of this type of reaction, affording excellent diastereoselectivity and enantioselectivity (Scheme 28.4). The utility of this reaction has been demonstrated in a total synthesis of (-l-)-hirustene (50), is a fungal metabolite first isolated from the basidiomycete Coriolus consors [27]. 

An enantioselective biomimetic synthesis of (—)-longithorone A was accomplished on the basis of the proposed biosynthesis [llj. Two [12]-paracyclophanes 25 and 26 were synthesized from common intermediate 27 by applying ene-yne metathesis macrocyclization in 42 and 31% yields, respectively. Intermolecular Diels-Alder reaction of 25 and 26 provided 32. Deprotection followed by oxidation gave 33, which spontaneously gave longithorone A via transannular Diels-Alder reaction (Scheme 6.8). 

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