Angewandte
Communications
Chemie
Scheme 2. Total synthesis of reserpine (1). Reagents and conditions: a) 6 (1.0 equiv), 7 (2.0 equiv), Zn/Cu (3.0 equiv), dibromomethane (cat.),
MeCN, 238C, 1 h; then Zn/Cu (3.0 equiv), NH4Cl (sat. in MeOH), 238C, 35 min, 27%; b) H2SO4 (10% aq.), 1,4-dioxane, 1008C, 4 h, 50%;
c) NaHMDS (1.0m in THF, 1.3 equiv), Ph3P+CH2OCH3Clꢀ (1.1 equiv), THF, 08C, 1.5 h, 60%; d) 11 (1.1 equiv), AcOH, 1258C, 1.5 h; e) CbzCl
(1.2 equiv), CH2Cl2/NaHCO3(aq.) (1:1), 238C, 1 h, 61% for two steps; f) Boc2O (3.0 equiv), DMAP (0.1 equiv), MeCN, 238C, 2 h, 90%; g) K2CO3
(3.0 equiv), MeSO2NH2 (1.0 equiv), K3Fe(CN)6 (3.0 equiv), OsO4 (4% wt/wt, 10 mol%), tBuOH/H2O (1:1), 238C, 11 h, 65%; h) Na2CO3
(1.5 equiv), Pb(OAc)4 (1.5 equiv), CH2Cl2, 238C, 30 min; i) Pd/C (10% wt/wt, 10 mol%), H2 (1 atm), EtOAc, 13 h, 23% for two steps; j) 2-methyl-
2-butene (4.7 equiv), NaH2PO4 (4.3 equiv), NaClO2 (4.3 equiv), tBuOH/H2O/acetone (1:1:0.6), 238C, 1.5 h; k) TMSCHN2 (20 equiv), MeOH/
toluene (1:3), 0 to 238C, 20 min, 43% for two steps; l) AcOH, 1258C, 3 h; m) Boc2O (3.0 equiv), DMAP (0.1 equiv), MeCN, 238C, 2 h, 3-epi-
21:31% for two steps and recovered 21:65%; n) l-proline (50 mol%), nitrosobenzene (2.0 equiv), DMF, 238C, 12 h; then re-subject: l-proline
(50 mol%), nitrosobenzene (2.0 equiv), DMF, 238C, 35 h, 60%; o) AcOH/Ac2O/DMSO (1:6:10), 238C, 10 h, 64%; p) Raney Niꢀ , H2 (1 atm),
EtOH, 238C, 1 h, 65%; q) 27 (3.5 equiv), Et3N (4.5 equiv), DMAP (1.0 equiv), 238C, 9 h; then silica gel, toluene, 1208C, 2.5 h, 61% for two steps.
Ac2O=acetic anhydride, AcOH=acetic acid, Boc2O=di-tert-butyl dicarbonate, Boc=tert-butyloxycarbonyl, Cbz=carboxybenzyl, CbzCl=benzyl
chloroformate, DMAP=N,N’-(dimethylamino)pyridine, DMF=N,N’-dimethylformamide, DMSO=dimethylsulfoxide, EtOAc=ethyl acetate,
NaHMDS=sodium bis(trimethylsilyl)amide, TMS=trimethylsilyl.
more, internal differentiation of C16/C20 by engaging the
secondary aliphatic nitrogen center (N1) in 4 could provide
a direct entry to the entire reserpine pentacyclic core
structure (e.g. 5). Finally, a late-stage regioselective (and
countra-steric) C17 oxygenation and a stereoselective C18
ketone reduction would need to be addressed to complete the
total synthesis.
As shown in Scheme 2, our synthetic studies began with
the preparation of the bicyclic ketoaldehyde 9. Reductive
[4+3] cycloaddition[4] between the acetoxyfulvene 6[5] and
tetrabromoacetone 7[6] afforded the bicyclic enol acetate 8,
which was subjected to enol acetate hydrolysis with concom-
itant aldehyde epimerization to afford 9 in 14:1 d.r.[7] One-
carbon homologation of 9 was carefully performed by
an aldehyde reacting partner, 10 proved equally competent[8]
in the reaction with the tryptamine 11 to deliver the
tetrahydro-b-carboline 14 after sequential Cbz and Boc
protection of the intermediate 12. At this juncture, the stage
was set for the rupture of the [3.2.1]-bicyclic domain of 14 and
examination of the feasibility of the proposed internal
desymmetrization. In this context, 14 was first subjected to
OsO4-catalyzed alkene dihydroxylation in the presence of
[9]
K3Fe(CN)6 as the co-oxidant to afford the diol 15. In
contrast, dihydroxylation of 14 under the Upjohn conditions
(NMO)[10] led to an intractable mixture of over-oxidized
products, presumably because of the electron-rich nature of
the methoxy-substituted tetrahydro-b-carboline (see below).
Treatment of 15 with Pb(OAc)4 led to a mixture diol-cleavage
products containing predominantly the bis-hemiacetal 16
instead of its parent dialdehyde. Subjecting this mixture of
compounds under Pd/C-mediated hydrogenation conditions
in EtOAc[11] cleanly delivered the ketoaldehyde 19 as the only
detectable constituent in the crude reaction mixture (by
1H NMR analysis). The formation of 19 most likely proceeded
through the initial hydrogenolysis with removal of the Cbz
engaging
solely
its
aldehyde
functionality
(Ph3P+CH2OCH3Clꢀ, NaHMDS), furnishing the methyl
enol ether 10 as an inconsequential mixture of geometrical
isomers. In this manner, our proposed symmetrical reserpine
E-ring precursor 10 was readily prepared and ready for the
attachment of the tryptamine domain. In contrast to the
conventional Pictet–Spengler protocol that usually required
2
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
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