Ring contraction, natural product synthesis

The synthesis of triazoles by 1,3-dipolar cycloaddition between azides and alkynes has been extensively studied recently with numerous synthetic applications in the field of click chemistry. However, the Huisgen cycloaddition between azides 39 and alkenes 40 (Scheme 41.9) although less studied offers interesting opportunities for the stereoselective formation of C N bonds in the context of natural products synthesis. The triazolines 41 thus formed are in fact good precursors of aziridines via ring contraction and expulsion of N2. 

It should be noted, however, that the 1,3-dipolar cycloaddition chemistry of diazo compounds has been used much less frequently for the synthesis of natural products than that of other 1,3-dipoles. On the other hand, several recent syntheses of complex molecules using diazo substrates have utilized asymmetric induction in the cycloaddition step coupled with some known diazo transformation, such as the photochemical ring contraction of A -pyrazolines into cyclopropanes. This latter process often occurs with high retention of stereochemistry. Another useful transformation involves the conversion of A -pyrazolines into 1,3-diamines by reductive ring-opening. These and other results show that the 1,3-dipolar cycloaddition chemistry of diazo compounds can be extremely useful for stereoselective target-oriented syntheses and presumably we will see more applications of this type in the near future. 

Cyclopropanone cleavage with elimination 72 can also lead to ring contraction as in the synthesis of the trans acid 74 from natural pulegone13 70. Bromination gives the unstable dibromide 71 that is immediately treated with ethoxide to initiate the Favorskii rearrangement. The product is a mixture of cis and trans isomers of the ester 73 but hydrolysis under vigorous conditions (reflux in aqueous ethanol) epimerises the ester centre and gives exclusively the trans acid 74. 

A different outcome in the presence of an additional vinylic oxygen was observed by Overman s group (Scheme 52). The formation of the five-membered cyclic ether (108) is rationalized in terms of an SnCU-mediated acetal ring opening of (105), subsequent cyclization of (106) to (107), followed by a ring contraction to (108) by a pinacol-type rearrangement. This stereocontrolled reaction proved to be applicable to the synthesis of related natural products. ... 

The first asymmetric total synthesis of the macrocyclic lactone metabolite (+)-pyrenolide D was accomplished in the laboratory of D.Y. Gin. The natural product has a densely functionalized polycyclic structure and its absolute configuration had to be established. The key step of the synthesis was a stereoselective oxidative ring-contraction of a 6-deoxy-D-gulal, which was prepared from anomeric allylic sulfoxide via the Mislow-Evans rearrangement. 

This last section will detail S3Uitheses of pyrroles by the transformation of other heteroeyelie systems. Ring contraction approaches to pyrroles have been reviewed <05COC261>. Boger reported an additional example of his reductive ring contraetion of 1,2-diazines to pyrroles in a reported total synthesis of the marine natural product, ningalin D <05JA10767>. 

A concise synthesis of biologically important Vinca alkaloid ( )-3H-epivincamine was accomplished. A central step in the synthesis consists of rhodium-catalyzed intramolecular [3-l-2]-cycloaddition of a-diazo amide 223 which provides the cycloadduct 224, which has the core skeleton of the natural product, in excellent yield with complete diastereoselectivity (Scheme 70). Further, a reductive ring opening of the cyclo adduct followed by a decar-boethoxylation reaction and a base-induced keto-amide ring contraction reaction furnished ( )-3H -epivincamine (225) [171]. 

Another interesting Wolff-mediated ring contraction applied to the total synthesis of natural products was realized in the course of an approach to the DEF ring system of fredericantycin, a natural product with potent antibiotic and antitumor activities f Scheme In this case, the... 

This application of the RBR to the synthesis of hirsutellones A-C serves to delineate its impressive scope as a strategic connection in the total synthesis of highly conplex, strained cyclic natural products. The high-yielding ring-formation and ring-contraction reactions deserve special note fSchemes 8.34 and 8.35T... 

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