Concise Total Synthesis of (-)-Calycanthine, (+)-Chimonanthine, and (+)-Folicanthine

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114207298/ABSTRACT

Mohammad Movassaghi* and Michael A. Schmidt

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

This is quite an intriguing paper on total synthesis of three related natural products (ACIEE EarlyView). The methods used in these syntheses are also very interesting and efficient. The three target natural products are (+)-chimonanthine (1), (+)-folicanthine (2), and (-)-calycanthine (3).

The retrosynthesis analysis of these compounds consisted of the key disconnection of the 3a-3a' bond of a key common intermediate to arrive at monomeric radical 6 and subsequently bromide precursor 7, which should be available in a short number of steps from commercially available methyl ester of L-tryptophan 8.

Therefore, 8 was subjected to neat phosphoric acid, followed N-sulfonylation to give hexahydropyrroloindole (+)-9 in multigram scale in >99% de, and >99% ee. Upon obtaining 9, it was subjected to a sequence of hydrolysis, acyl chloride formation, and radical decarboxylation using tris(TMS) silane and AIBN to give 10 in excellent yield and ee (see below).

Next, 10 was brominated. Unfortunately, ee deteriorated during this process. This was believed to be due to tautomerization to tryptamine during the reaction (ring opening) in the presence of trace acid. Using acid scavenger in this step did not improve outcome. Therefore, the endo-methyl ester group at C2 was kept to be cleaved later as it was believed that the presence of this group increase stability of the compound.

Therefore, subjecting 9 to benzylic bromination directly afforded (+)-11 in good yield while maintaining excellent ee. The key radical dimerization step was first attempted through activation with Mn(CO)5 generated by photolytic cleavage of Mn2(CO)10. The reaction did not work very well both with 0.5 and 1.0 equiv of the reagent.

From what could be gathered in the paper, it sounded that dimerization of these radicals was expected to be a second-order process whose success largely depended on high concentration of the monomeric radical. Therefore, monomeric radical needed to be generated faster in the reaction to accrue high enough concentration. This was finally achieved using a more reactive reducing agent, [CoCl(PPh3)3]. Upon further adjustment with solvents and concentrations, the most optimal conditions were found to be in acetone (0.1 M) at rt for 15 min, which could give the desired dimeric compound in 60% yield with greater than 99% ee on a 3-gram scale!

This mechanism of this process was proposed to be either abstraction of bromine atom to give the radical which then combined outside of the solvent cage or oxidative addition of Co(I) to give Co(III) species, followed by homodimerization, C-Co bonds fragmentation and a C-C bond formation within the solvent cage.

After smooth procession of dimerization, 14 was decarboxylated using the same sequence as above (hydrolysis, acid chloride formation, and reduction with silane). The next step, desulfonylation of nitrogen, was tricky as both photolytic cleavage and strong reductive conditions failed. This was finally achieved with mild sodium amalgam and sodium phosphate dibasic in excellent yield and ee. The next and last step to give (+)-1 involved reduction of bis methyl ester with Red-Al.

Equilibration study of 1 in NMR tube using acetic acid-d4 and D2O was found that 1 was in equilibrium with 3 as a 85:15 mixture (3:1). Later 3 was isolated in 54% yield. This equilibrium was confirmed by subjecting pure 3 to equilibration conditions and the same mixture was obtained. Subsequently, 1 was converted to 2 via reductive amination using aq formaldehyde and NaBH(OAc)3 in quantitative yield.

Equilibration of 1 to 3 in acidic conditions (heating in acetic acid/water) still baffles me. Formally, it looks like a sigma-bond metathesis process happening across the C3a-C3a' bond, although this is not likely. This could be a good mechanism problem.

A commendable synthesis!