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Organic Chemistry Highlights

Total Synthesis

Monday, October 6, 2014
Douglass F. Taber
University of Delaware

The Kan Synthesis of the Streptomyces Alkaloid SB-203207

The alkaloid SB-203207 (3), isolated from a Streptomyces species by a SmithKline Beecham group, was shown to inhibit isoleucyl tRNA synthetase with an IC50 of less than 2 nM. Toshiyuki Kan of the University of Shizuoka envisioned (Org. Lett. 2014, 16, 1646. DOI: 10.1021/ol5002973) that the carbocyclic core of 3 could be assembled by the Rh-mediated cyclization of 1 to 2.

The authors had already demonstrated (Org. Lett. 2008, 10, 169. DOI: 10.1021/ol701940f) the cyclization of 1 to 2. For the assembly of 3, they needed to scale up the preparation of 1. To this end, they required the mandelamide 5 and the aldehyde 8. To prepare 5, they devised a new preparation of diazoacetates, condensation with bromoacetyl bromide followed by exposure to the bis sulfonamide. The aldehyde 8 was prepared from the acid 6 (commercial, or Org. Synth. 1998, 75, 195. DOI: 10.15227/orgsyn.075.0195). The preparation of the third component of 3, the acid 9, had been described earlier by Banwell and Easton (Bioorg. Med. Chem. 2003, 11, 2687. DOI: 10.1016/S0968-0896(03)00237-2).

The cyclization of 1 proceeded smoothly with 0.1% loading of the Rh catalyst, to give 2 in 72% de (85:15 ratio of enantiomers of the carbocyclic core). The enantiomeric excess could be upgraded by recrystallization of a later intermediate. The ester 2 was exchanged with allyl alcohol to give 10, presumably with recovery of the liberated chiral auxiliary 4.

Formaldehyde added to the β-keto ester 10 from the more open face. Hydride addition from that same face then delivered the diol 11. The allyl ester was removed, and the free acid was activated with SOCl2 then condensed with ammonia to give the primary amide. Ozonolysis followed by acidic methanol led to cyclization onto the amide, allowing ready differentiation of the two ends of the alkene. Reduction completed the preparation of the lactam 12.

The nitrogen was sulfonylated, then the activated lactam was opened with assistance from the liberated primary alcohol. After acetal hydrolysis, the sulfonamide added to the aldehyde to give, after dehydration, the enamide 13. Inversion of the carboxyl converted the hydroxy acid to the urethane, that was formylated with the modified Vilsmeier reagent. Protection and deprotection followed by methylation then delivered the vinylogous amide 14.

The oxime of 14 was dehydrated to the nitrile, that was readily carried on to the aldehyde 15. The aldehyde resisted oxidation to the corresponding carboxylic acid. Eventually it was found that the derived cyanohydrin could be oxidized. The acid was protected as the benzhydryl ester to give 16. Both the Boc and the MOM group were removed by B-bromocatechol borane, opening the way to acylation with the acid 9. The nitrile was hydrated to the primary amide using the Parkins catalyst. In the last stage, the protecting groups were removed by hydrogenation, to give alkaloid SB-203207 (3).

D. F. Taber, Org. Chem. Highlights 2014, October 6.