Total Synthesis of (−)-Kopsifoline A and (+)-Kopsifoline E

Abstract

We report the first total synthesis of (−)-kopsifoline A and (+)-kopsifoline E. Our synthetic strategy features a biogenetically inspired regioselective C17-functionalization of a versatile intermediate containing the pentacyclic core of aspidosperma alkaloids. The vinylogous urethane substructure of this intermediate affords (−)-kopsifoline D via C3−C21 bond formation under the Mitsunobu reaction conditions, while it enables selective C17-functionalization en route to (−)-kopsifoline A and (+)-kopsifoline E.

Total Synthesis of (–)-Voacinol and (–)-Voacandimine C

“…29 We envisioned accessing the pentacyclic N-oxide 9 via chemoselective oxidation of vinylogous urethane (-)-10, an advanced intermediate used in our synthesis of kopsifolines A and E. Our synthesis of the key hexacyclic enamine 8 commenced with derivatization of vinylogous urethane (-)-10 (Scheme 2), a C21-oxygenated variant of tabersonine 37 that we have previously prepared in enantiomerically enriched form in ten steps from a readily available indole derivative. 29,36,38 We found that treatment of vinylogous urethane (-)-10 (90% ee) with peracetic acid (1.3 equiv) 29,39 provided the desired N9-oxidation (70%) while minimizing a competitive C3-oxidation. 40 Subsequent unveiling of the primary alcohol afforded the N-oxide alcohol 9 in 96% yield (Scheme 2).…”

“…29 Treatment of enamine 8 with excess sodium triacetoxyborohydride (10 equiv) afforded (-)-deoxoapodine (4) in 64% yield from alcohol 9, significantly increasing the overall yield for alkaloid 4 from 21% to 29% from a common tetracyclic precursor. 29,36 Given the sensitivity of enamine 8 toward isolation, we considered its conversion to the corresponding α-aminonitrile as a more stable surrogate. [41][42][43][44][45][46] Exposure of enamine 8 to in situ generated hydrogen cyanide in hexafluoroisopropanol afforded the C8-aminonitrile 11 (ca.…”

Total Synthesis of (−)-Voacinol and (−)-Voacandimine C

“…Exposure of N-oxide 9 to modified Polonovski–Potier reaction conditions involving trifluoroacetic anhydride (4.0 equiv) and polystyrene-bound 2- tert -butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (PS-BEMP, 6.0 equiv) led to the formation of the corresponding unsaturated C8-iminium ion, which upon methanolysis of the primary trifluoroacetate gave the desired F-ring and offered the hexacyclic enamine 8 (Scheme ). Treatment of enamine 8 with excess sodium triacetoxyborohydride (10 equiv) afforded (−)-deoxoapodine ( 4 ) in 64% yield from alcohol 9 , significantly increasing the overall yield for alkaloid 4 from 21% to 29% from a common tetracyclic precursor. , This strategy provides a new route to (−)-deoxoapodine ( 4 ) by the application of our biosynthesis-inspired dehydrative etherification on a more advanced pentacyclic substrate containing the C2-vinylogous urethane to introduce the F-ring …”

“…Enamine 8 could be obtained from N9-oxide alcohol 9 through a biogenesis-inspired dehydrative etherification . We envisioned accessing the pentacyclic N-oxide 9 via chemoselective oxidation of vinylogous urethane (−)- 10 , an advanced intermediate used in our synthesis of kopsifolines A and E …”

Semi-syntheses and interrogation of indole-substituted Aspidosperma terpenoid alkaloids

“…Furthermore, such a strategy in association with the panel of tool compounds could facilitate the medicinal chemistry advancement of Aspidosperma alkaloids in other disease areas including Alzheimer's disease. 17 Future work will focus on regioselective C17 functionalization with inspiration from precedent reports, 30,31 and the exploration of halogenated derivatives to further expand the scope of this strategy.…”