Total Synthesis of Kanamienamide

Abstract

Kanamienamide is a novel enol ether containing enamide with a single digit micromolar inhibitory activity against cancer cell lines. An efficient and convergent total synthesis of kanamienamide has been developed for the first time, which features a Cu-mediated amide coupling with vinyl iodide at the late stage. Other key transformations include Evans asymmetric alkylation, CBS asymmetric reduction, ring-closing metathesis reaction, and Stork-Zhao-Wittig olefination. This strategy is amenable for facile analogue preparation and SAR studies.

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…These molecules are organized under various transformations in the following sequence: 1) ring‐closing metathesis, 2) cross metathesis, 3) ring‐closing alkyne metathesis, and 4) ring‐closing enyne metathesis. 1) Ring‐closing metathesis : kanamienamide ( 37 ), [100] (+)‐chinensiolide B ( 38 ), [101] BMS‐846372 ( 39 ), [102] daphniyunnine B core ( 40 ), [103] clavilactone D ( 41 ), [104] pechueloic acid ( 42 ), [105] (−)‐deoxoapodine ( 43 ), [106] zephyranthine ( 44 ), [107] palodesangrens core ( 45 ), [108] (−)‐stemaphylline ( 46 ), [109] pavidolide B ( 47 ), [110] 7‐deoxypancratistatin ( 48 ), [111] (+)‐4‐ ɑ ‐dehydroxycrinamabine ( 49 ), [112] (−)‐elymoclavine ( 50 ), [113] viridin ( 51 ), [114] (−)‐crinane ( 52 ), [112] conduramine B‐1( 53 ), [115] ellipticine quinone ( 54 ), [116] (−)‐tegafur ( 55 ), [117] tetraponerine ( 56 ), [118] (−)‐cermizine B ( 57 ), [119] (Figure 7) (±)‐lycojaponicm ( 58 ), [120] (−)‐zeylenol ( 59 ), [121] aphanamal ( 60 ), [122] (+)‐epiquinamide ( 61 ), [123] erythrinane core ( 62 ), [124] (−)‐pseudodistomin E ( 63 ), [125] toxicodenane A ( 64 ), [126] ipomoeassin F ( 65 ), [127] scholarisine K ( 66 ), [128] panal core ( 67 ), [129] (+)‐crotanecine ( 68 ), [130] gagunin E analogue ( 69 ), [131] R‐(−)‐ ɑ ‐cuparenone ( 70 ), [132] citreamicin‐η core ( 71 ), [133] brianthein A core ( 72 ), [134] (+)‐cryptoconcatone H ( 73 ), [135] neomarchantin A ( 74 ), [136] (+)‐methynolide ( 75 ), [137] 10‐epi‐tirandamycin ( 76 ), [138] greensporone C ( 77 ), [139] 5′‐hydroxy‐zearalenone ( 78 ), [140] cheloviolene A ( 79 ), [141] crassifoside F c...…”