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Organic Chemistry Highlights

Total Synthesis

Monday, September 3, 2018
Douglass F. Taber
University of Delaware

The Smith Synthesis of Nahuoic Acid Ci(Bii)

The nahuoic acids, exemplified by nahuoic acid Ci(Bii) (4), produced by a Streptomyces strain isolated from a tropical marine sediment, are the first known S-adenosylmethionine competitive inhibitors of the histone lysine methyltransferase SETD8 enzyme. Amos B. Smith III of the University of Pennsylvania devised a modular synthesis of 4, combining 1 with 2 to give 3 (J. Am. Chem. Soc. 2017, 139, 13668. DOI: 10.1021/jacs.7b08683).

The preparation of 2 employed the author's Anion Relay Protocol. The addition of 6 to 5 gave, after silyl transfer, an intermediate dithianyl anion, that opened the epoxide 7, leading to 8. Hydrolysis of the dithiane followed by diastereoselective reduction led to 9, that was protected with 10, then opened with 11 to give 12. Protection of the secondary alcohol then completed the assembly of 2.

The Diels-Alder cycloaddition of 14 to 13 to give 15 was facile, but proceeded in low ee. After careful optimization using a Ti-Taddol catalyst, this was raised to 86% ee, that on recrystallization could be improved further to 98% ee. Reduction followed by hydrolysis and protection led to 16, that was selectively hydrogenated, then converted to the diol and protected with 17 to give the acetonide 18. After oxidation to 19, conjugate addition followed by coupling of the derived enol triflate with methyl magnesium bromide and deprotection completed the construction of 1.

The convergent coupling of 1 with 2 following the Micalizio protocol proceeded to give 3 with high regio, diastereo and geometric control. Cross metathesis with methyl methacrylate followed by deprotection and saponification then completed the synthesis of nahuoic acid Ci(Bii) (4).

D. F. Taber, Org. Chem. Highlights 2018, September 3.