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Organic Chemistry Highlights

Total Synthesis

Monday, July 2, 2007
Douglass F. Taber
University of Delaware

The Padwa Synthesis of Aspidophytidine

Albert Padwa of Emory University has developed (Org. Lett. 2006, 8, 3275. DOI: 10.1021/ol061137i) a productive approach to fused indole alkaloids such as aspidophytine (3), based on the dipolar cycloaddition of the ylide derived by exposure of a diazo ketones such as 1 to a Rh(II) carboxylate catalyst.

The preparation of 1 started with the aniline 4. Ortho iodination followed by N-alkylation with 5 delivered the unsaturated ester 6. Heck cyclization no doubt intially left the alkene still conjugated with the ester, but traces of acid or base would be expected to easily isomerize this to establish the aromaticity of the five-membered indole ring. N-methylation followed by saponification then gave 8.

The preparation of 1 continued with the alkylation of 9. Hydrolysis of 10 followed by homologation and subsequent diazo transfer gave 11, which was coupled with 8 to give 1. The quaternary center established in the alkylation of 9 was carried through the synthesis, so if enantiomerically-pure material were desired, an enantioselective route to 10 would have to be devised.

The push-pull dipole 12 was constructed by exposure of 1 to Rh2(OAc)4. Loss of N2 gave the Rh carbene, which complexed with the nucleophilic amide carbonyl. The dipole 12 was not isolated, but reacted in situ with the tethered indole to give the hexacyclic adduct 2. Note that two diastereomers of 2 could have been formed, but only 2, with the bulky t-butyl ester exo, was observed.

The dipolar cycloaddition established the requisite stereochemical relationship between the three contiguous quaternary stereogenic centers of 1. It remained to adjust the functional groups around the newly-formed carbocyclic ring. Exposure to BF3.OEt2 led to ring opening, followed by trapping of the intermediate carbocation with the t-butyl ester to give the lactone 13, with concommitant loss of isobutylene. Hydrolysis and decarboxylation gave the alcohol 14, the acetate of which was removed by reduction with SmI2. The derived enol triflate 15 was reduced to the alkene, which was deoxygenated by way of the thiolactam 16.

The intramolecular dipolar cycloaddition exemplified by the conversion of 12 to 2 is a specific representative of a general and powerful approach to indole alkaloids, based on cycloaddition of an intermediate indole to a dipole or a diene. For more recent work along these lines by Professor Padwa, see Org. Lett. 2007, 9, 279, DOI: 10.1021/ol062728b and Tetrahedron 2007, 63, 5962, DOI: 10.1016/j.tet.2007.01.064.

D. F. Taber, Org. Chem. Highlights 2007, July 2.