Vinylogous 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... 

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. 

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. 

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. 

A distinct route was followed by Winkler et al. and included the application of the known vinylogous amide [2+2] photocycloaddition, refro-Mannich fragmentation, Mannich closure cascade (pharM) sequence. Two methodologies for the synthesis of the requisite pentacycle were described. The transannular photocyloaddition of an 18-membered amide and photocycloaddion of an acyclic vinylogous amide, followed by macrolactamization of the derived pharM closure product was used to generate the ABODE system (see Scheme 32) [95]. 

An intramolecular photocycloaddition of a vinylogous amide tethered at C-3 of a 1-acylindole has also been achieved in a stereospecific reaction, in which the cyclobutane adduct (332) undergoes a retro-Mannich reaction to give the imino ketone (333), a synthetic precursor of vindorosine (Scheme 104) <90JA8971>. 

The excellent stereoselectivity of the above photocycloaddition reaction is explained by the preferred approach of the vinylogous amide from the a-face of the indole 45. The approach of the amide from the p-face 46, (Scheme 10) is disfavored because of the steric interaction of the indole aromatic ring and the R substituent alpha to the vinylogous amide. 

The appropriately substituted vinylogous amides can imdergo an intramolecular photocycloaddition-retro-Mannich-Mannich sequence. This sequence is analogous to the photocycloaddition-retro-aldol-aldol sequence shown in the formation of 19 from 15 (vide supra). Thus, irradiation of 110 leads to the formation of ketoimine 112, the product of photoaddition followed by rerra-Mannich fragmentation. Reaction of 112 with 1 equiv of trimethyloxonium tetrafluoroborate, followed by treatment of the resulting iminium ketone with aqueous hydrochloric acid, provides the photocycloaddition-re/ro-Mannich-Mannich product 113 in 50% yield from the acyclic photosubstrate 110. ... 

The photocycloaddition-retro-Mannich-Mannich methodology is featured in a concise synthesis of mesembrine. Irradiation of vinylogous amide 114 effects photocycloaddition-re/ro-Maimich sequence to give product 116 via the cyclobutane intermediate 115. Methylation with trimethyloxonium tetrafluoroborate followed by treatment with DMAP produces mesembrine in 84% yield. Other applications include construction of the bicyclic core of peduncularine and synthetic approaches to hetisine alkaloids and 8-substituted 6-azabicyclo[3.2.1]octan-3-ones. ... 

I, 5-dicarbonyl compounds and their interesting and varied chemistry, e.g., the formation of cyclohexenones from aldol condensation of the products. As an extension of the de Mayo reaction (the photocycloaddition of enolated /i-diketones to double bonds) enol esters, enol ethers, vinylogous esters and amides, and dioxinone have been employed as the enone components. Some intermolecular examples have already been discussed in Section 1.6.1.4.2.1.6. (cf. Table 4, entries 2 and 3) and some intramolecular systems are collected in Table 5, entries 10,... 

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