Amides photocycloaddition

Winkler and his co-workers have previously reported the vinylogous amide photocycloaddition. In their present account, the highly diastereoselec-tive cyclization of (73) to afford (74) is described. This product affords a basis for a synthetic strategy towards the manzanine alkaloids. 

An intramolecular vinylogous amide photocycloaddition, retro-Mannich fragmentation and final Mannich cyclization cascade provided a useful method for the synthesis of the complex ABCE ring system [91], The preparation of the requisite photosubstrate is outlined in Scheme 28. After cluomatographic separation, the cis alcohol was irradiated and led to the formation of aminals in a 2 1 ratio. Equilibration studies of the Swem oxidation products revealed that exposure of the minor diketone to sodium methoxide in methanol effected conversion to the manzamine-unlike... 

Scheme 28. Synthesis of the ABCE core of 1 via an intrrramolecular amide photocycloaddition.

A Highly Stereoselective Approach to the Synthesis of Manzamine Alkaloids via the Intramolecular Vinylogous amide Photocycloaddition. Winkler, J. D. Siegel,... 

An Approach to the Synthesis of the Manzamine Alkloids via the Vinylogous Amide PhotocycloAddition/Retro-Mannich Fragmetation/Mannich Closure Cascade (pharM). Winkler, J. D. Stelmach, J. E. Siegel, M. G. Haddad, N. Axten, J. and Daily III, W. P. Isr. J. Chem. 1997, 37, 47. 

Winkler JD, Scott RD et al (1990) Asymmetric induction in the vinylogous amide photocycloaddition reaction. A formal synthesis of vindorosine. J Am Chem Soc 112 8971-8975... 

A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type lb entry to functionalized pyrroles <060L4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. 

In recent investigations about the intramolecular meto-addition processes, the effects of heteroatoms in the linking chains are obvious. Blakemore and Gilbert reported the photoreaction of 185 linked by the amide group [240], Pho-toinduced intramolecular electron transfer can be inhibited by /V-acetyl or N-car-bomethoxy groups. Fluorescence is then observed from the arene chromophore and intramolecular meta photocycloaddition occurs through high selectivity. 

Photocycloaddition ofVinylogous Amides and Esters (Substrate Classes A2 and A3)... 

Basler, B., Schuster, O., and Bach, T. (2005) Conformationally constrained p-amino acid derivatives by intramolecular [2 + 2]-photocycloaddition of a tetronic acid amide and subsequent lactone ring opening. Journal of Organic Chemistry, 70, 9798-9808. 

The utility of /f-enaminones (vinylogous amides) and / -enamidones (vinylogous imides) has been successfully demonstrated in both inter- and intramolecular [2 + 2] photocycloaddition reactions. The vinylogous amide, which reacts as a /Mieteroatom substituted enone, serves as the nitrogen analogue of the enol form of a / -diketone in the de Mayo reaction24. 

The photocycloaddition of vinylogous amides is not limited to substrates in which the chromophore is constrained in a five- or six-membered ring, and several groups have recently described the photocycloaddition of acyclic vinylogous amides. Tietze and coworkers reported that irradiation of 92 gives the bicyclic product 95 in quantitative yield (Scheme 22)43. The authors proposed that the observed product 95 could be the result of cycloaddition from the tautomeric form of the chromophore, followed by fragmentation of the resulting cycloadduct 93 to the imino-aldehyde 94, which condensed to the observed product. 

Winkler and coworkers have coupled the photocycloaddition and retro-Mannich fragmentation of an acyclic vinylogous amide with a subsequent Mannich closure to produce perhydroindole structures as outlined in Scheme 2445. The acyclic secondary... 

The extension of this intramolecular photocycloaddition-retro-Mannich-Mannich sequence to -substituted secondary vinylogous amides, the photochemistry of which had been originally reported by Schell and Cook (Scheme 18), was also examined... 

While some of the mechanistic details for the examples described in this chapter have not yet been fully elucidated, it is clear from the scope of the examples discussed herein that the photochemistry of enaminones and enamidones is a fascinating research area. The novel sequence for the annelation of imidazole rings onto a preexisting structure, the synthesis of perhydroindoles via vinylogous amide [2 + 2] photocycloaddition chemistry and the enamide cyclization reactions all underscore the enormous utility of these chromophores in the development of new reactions and novel synthetic methods. 

Introduction of chiral auxiliaries in the starting materials is very attract for applications to organic synthesis. However, to be of synthetic interest, chiral auxiliaries have to be inexpensive, readily introduced on the starting ma rial, inert in the conditions of irradiation, and readily removed from the photo ducts. Even if the first requirements can be easily satisfied with chiral ket esters, and amides, it is often difficult to avoid side reactions involving auxiliary [63]. In order to control all the asymmetric centers created in the in molecular photocycloadditions of cyclic enones with alkenes, esters of c alcohols were first considered. Although menthyl and bomyl derivatives ga only low de, 8-phenylmenthyl esters produced a far better asymmetric inducti [64]. The facial selectivity was found to depend on the syn/anti nature of t cycloadducts and the structure and location of the chiral auxiliary on either tl enone or the alkenyl moiety. More surprisingly the selectivity also depe strongly on the nature of the solvent (Scheme 21). 

Another unique example was observed for the recently isolated marine natural product, alter amide A (209), isolated from a symbiotic bacteria (Alteromonas sp.) found on the sponge Halichondria okadai. It was found that the tetraene core of this compound underwent intramolecular [4 - - 4]-photocycloaddition upon exposure to sunlight (equation 9). Deliberate irradiation led to a quantitative conversion to cyclooctadiene 210. 

The degree of asymmetric induction in the photocycloaddition reaction can be quite high with substrates containing a stereogenic center. Winkler, Scott and Williard have reported that irradiation of 1-tryptophan-derived vinylogous amide 107 led to the isolation of ketoimine 108 in 91% yield as a single diastereomer . Closure to the tetracyclic portion of the aspidosperma ring system 109 was achieved in two steps by formation of the silyl enol ether with LDA and r-butyl dimethylsilyl triflate followed by treatment with tetrabutylammonium fluoride (TBFA). Conversion of 109 to 110 with >97% optical purity was then achieved. As 110 is an intermediate in Biichi s synthesis of vindorosine, the sequence outlined in Scheme 26 represents a formal total synthesis of vindorosine. 

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