Solid-state photodimerization of 2-phenylethenyl enamides. Total syntheses of the enamide containing natural products (+/-)-anchinopeptolide D, (+/-)-cycloanchinopeptolide D, and (-)-salicylihalamide A

Enamides 1.3a--c and 1.6 crystallize in alpha-packing modes with short intermolecular distance of 3.7--4.0 A between alkene carbon atoms of adjacent molecules related by a center of symmetry. Irradiation at 350 nm of these crystalline tertiary phenylethenyl enamides affords head-to-tail dimers 1.8a--c and 1.9, respectively, in 87--92% yield, in marked contrast to the E to Z isomerization that is the exclusive reaction upon solution irradiation of enamides 1.3a--c and 1.6.;The first synthesis of (+/-)-anchinopeptolide D (2.4) has been accomplished in seven steps in 10% overall yield from octopamine hydrochloride (2.17), N-(Boc)glycine ( 2.16), and 5-amono-2hydroxypentanoic acid (2.22). The key step is the aldol dimerization and hemiaminal formation of alpha-keto amide 2.26, which gives primarily protected anchinopeptolide D 2.27 under kinetically controlled conditions. Cycloanchinopeptolide D (2.31) has been prepared by the unprecedented head-to-head photodimerization of the two hydroxystyrylamides of 2.4 using the hydrophobic effect in water to force the two side chains into close proximity so that [2+2] cycloaddition is faster than trans to cis double bond isomerization. Coupling of amide 2.21 with pyroglutamic acid affords the naturally occurring tripeptide 2.35, which had been assigned glutamic acid structure.;A 16-step synthesis of the novel cytotoxin (-)-salicylihalamide A (3.1) starting from aldehyde 3.18 has been achieved in 5% overall yield with minimal use of protecting groups. The macrolide core 3.10 was generated by ring closing metathesis. The key step is the efficient introduction of N-((1E)alkenyl)-(2 Z,4Z)-heptadienamide side chain by addition of (1 Z,3Z)-hexadienylcuprate (3.38), which was generated in situ from ethylcuprate and acetylene, to alkenyl isocyanate (3.75). This approach should be useful for the preparation of analogues for the biological study.