Studies toward the AB ring system of the tetrapetalone natural products

Abstract

Synthetic efforts toward the rapid assembly of the AB ring system of the tetrapetalones is described. Key to this work was the use of [3+2] cycloaddition/oxidative extrusion methodology to furnish functionalized aryl enones. The Nazarov cyclization of these substrates was examined, and optimized to generate the AB ring carbon skeleton. Then, Pd-catalyzed cross-coupling were conducted, and conditions were identified that enabled installation of the requisite C14-N bond.

Total Syntheses of (+)- and (−)-Tetrapetalones A and C

“…Perhaps most significant among these are the efforts of Frontier who prepared an O-methyl derivative of racemic tetrapetalone A aglycone in a 27-step sequence (Figure 1d). 8 However, neither demethylation of this intermediate nor further advancement toward the natural product were reported. Herein we detail our efforts which culminate in complete syntheses of (+)-and (−)-tetrapetalones A and C in 18 and 19 steps, respectively.…”

“…In the roughly 15 years since their isolation, considerable effort has been focused on developing syntheses of the tetrapetalones. Despite elegant work from the groups of Sarpong (Figure c), Porco, Pettus, Hong, and most recently Frontier, a completed total synthesis has yet to be realized. Perhaps most significant among these are the efforts of Frontier who prepared an O- methyl derivative of racemic tetrapetalone A aglycone in a 27-step sequence (Figure d) .…”

Synthesis of 3,6-Dihydro-2H-1,2-oxazines via Dimethylsulfoxonium Methylide Addition to α,β-Unsaturated Nitrones

“…(Z)-N-((E)-2-Methyl-3-phenylallylidene)methanamine oxide (1n). 22 The compound 1n (1.40 g, 53% yield, 15.0 mmol scale) was obtained as an oil after purification by silica gel column chromatography (AcOEt/MeOH = 10/1, 6/1). 1 H NMR (CDCl 3 , 400 MHz): δ 8.26 (s, 1H), 7.36−7.19 (m, 5H), 6.93 (s, 1H), 3.78 (s, 3H), 2.18 (s, 3H).…”

Synthetic Studies toward the Tetrapetalones: Diastereoselective Construction of a Putative Intermediate

“…We conjecture that Frontier’s mono -methylation and reduction conditions should provide the desired arrangement of methyl and hydroxyl functionality. However, completion of the nonracemic glycosylated natural product would require us to develop an asymmetric method to introduce the stereogenic ethylene motif into compound 8 and repeat our synthetic efforts to this point.…”

“…They differ only slightly by tetramic acid substituents, yet their many structural motifs present numerous synthetic challenges when considered separately. This family of natural products piqued the interest of several synthetic groups, , including the racemic synthesis of the tetrapetalone A-Me aglycon by Frontier and the enantioselective total synthesis of the natural products 1 and 3 by Wood …”