Dipolar with chiral templates

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

Independently, Harwood also demonstrated the role of chiral-templated isomunchnones in 1,3-dipolar cycloaddition reactions. Thus using the rhodium(II)-catalyzed decomposition of diazo carbonyl compounds, Harwood and co-workers explored cycloadditions of isomunchnone derivatives of (5R)- and (55)-phenyloxazin-2,3-dione. Along with the work of Padwa (vide supra), these reactions appear to represent the first examples of chiraUy templated isomunctmone 1,3-dipolar cycloadditions. For example, reaction of 471 under standard rhodium acetate conditions in the presence of NPM affords a mixture of endo-472 and exo-473 adducts (Fig. 4.146). A-Methylmaleimide and DMAD react with 471 similarly. 

On the methodological front of these broadly based endeavors, we have exploited pericyclic processes such as the dipolar cycloadditions of nitrile oxides together with the aldol reaction and related constructions as tactical devices for the formation of new carbon-carbon bonds with high levels of stereochemical control Another important focus of these explorations has been upon the development of techniques for the manipulation and refunctionalization of hydropyrans, since this structural subunit is not only common to a variety of natural substances, but it may also be effectively exploited as a conformationally-biased template for the stereoselective construction of various skeletal arrays present in numerous natural products. In this context, we have devised a novel and highly effective strategy for the asymmetric syntheses of oxygenated natural products. The fundamental approach features the intermediacy of the hydro-3-pyranones 12, which may be accessed from the chiral furfuryl carbinols 10 via the hydroxy enediones 11 by well-established oxidative techniques (Scheme 1). A critical element of this overall planll is that the hydro-3-pyranones 12 are admirably endowed with differentiated functionality that is suitable for further elaboration by reaction with selected nucleophiles... 

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