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. 2019 May 29;141(21):8431-8435.
doi: 10.1021/jacs.9b03576. Epub 2019 May 16.

Calyciphylline B-Type Alkaloids: Total Syntheses of (-)-Daphlongamine H and (-)-Isodaphlongamine H

Cedric L Hugelshofer  1 , Vignesh Palani  1 , Richmond Sarpong  1
Affiliations

Calyciphylline B-Type Alkaloids: Total Syntheses of (-)-Daphlongamine H and (-)-Isodaphlongamine H

Cedric L Hugelshofer et al. J Am Chem Soc. .

Abstract

The first total synthesis of the complex hexacylic Daphniphyllum alkaloid (-)-daphlongamine H has been accomplished. Key to the success of the strategy are a complexity-building Mannich reaction, efficient cyclizations, and a highly diastereoselective hydrogenation to assemble multigram quantities of the tricyclic core bearing four contiguous stereocenters. Following construction of the hydro-indene substructure by means of a Pauson-Khand reaction, endgame redox manipulations delivered the natural product. Importantly, the synthetic studies have also given access to (-)-isodaphlongamine H and led to a revision of the reported structure of deoxyisocalyciphylline B.

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Figures

Figure 1.
Figure 1.
(A) Daphniphyllum alkaloids; (B) our retrosynthetic analysis of the calyciphylline B-type subfamily.
Scheme 1.
Scheme 1.. Gram Scale Synthesis of Tricyclic Core 16a
aReagents and conditions: (a) LDA, 8, THF, −78 °C, then 9 (44%, 53% brsm SS-10; 38%, 45% brsm RS-10); (b) NaH, THF, −78 to 23 °C (37% 8; 94% 9); (c) 4 M HCl in 1,4-dioxane, MeOH, 50 °C; (d) 2,3-dibromopropene, iPr2NEt, CH3CN, 80 °C, (77%, 2 steps, + 11% from second cycle); (e) TBSCl, imidazole, CH2Cl2, 0 to 23 °C (89%); (f) Ac2O, PhH, 90 °C (96%); (g) Hoveyda-Grubbs II catalyst, CH2CL2, 40 °C (82%); (h) LiHMDS, THF, −78 °C (90%); (i) Pd(OAc)2, PPh3, NEt3, MeCN, 50 °C (72%); (j) 50 atm H2 [lr(cod)(PCy3)(py)]PF6, CH2Cl2 23 °C; (k) 1 atm H2, Pd/C, NaHCO3, MeOH, 23 °C (58%, 2 steps, 4:1 d.r.); (l) Bu3SnH, Et3B, O2, PhH, 23 °C (91%); (m) 1 atm H2/Ar (1:1), Pd(OH)2, CH2Cl2 23 °C (87%, ≥ 20:1 d.r.). bTBS omitted for clarity.
Scheme 2.
Scheme 2.. Synthesis of Daphlongamine H (4) and Isodaphlongamine H (5)a
aReagents and conditions: (a) NaH, 4-iodo-butene, DMF, 0 °C (62%, 72% brsm); (b) TMDS, [lrCl(CO)(PPh3)2], PhMe, 23 °C (73%, + 13% from second cycle); (c) TMSOTf, CH2Cl2, −78 °C, then HCCMgBr, THF, −78 to 0 °C, then aq. 6 M HCl, 0 to 23 °C (62% 19; 17% 20); (d) Co2(CO)8, CH2Cl2, 23 °C, then TMANO·2H2O, 0 to 23 °C; (e) TBSCl, imidazole, CH2Cl2, 23 °C (69%, 2 steps); (f) LaCl3·2LiCl, THF, 23 °C, then MeLi, −25 °C (94%, ≥ 20:1 d.r.); (g) Co2(CO)8, CH2Cl2, 23 °C, then MeCN, TMANO·2H2O, −78 to 23 °C (59%); (h) NaCNBH3, BF3·Et2O, THF, 23 to 66 °C; (i) CrO3, H2SO4, H2O, acetone, 0 °C (68%, 2 steps); (j) TfOH, MeNO2, 23 °C (70%); (k) TFAA, CH2Cl2, −78 °C, then SOCl2, −78 to 0 °C (71%); (l) aq. H2O2, TFAA, CH2Cl2, 0 to 23 °C (35%); (m) LiAlH4, THF, −78 to 66 °C; (n) NaCNBH3, BF3·Et2O, THF, 23 to 66 °C; (o)CrO3, H2SO4, H2O, acetone, 0 °C; (p) cyanuric chloride, NEt3, MeCN, 23 °C (13%, 4 steps). bTBS omitted for clarity.
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