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. 2010 May 26;132(20):7119-37.
doi: 10.1021/ja1009458.

Scalable total syntheses of N-linked tryptamine dimers by direct indole-aniline coupling: psychotrimine and kapakahines B and F

Timothy Newhouse  1 , Chad A Lewis, Kyle J Eastman, Phil S Baran
Affiliations

Scalable total syntheses of N-linked tryptamine dimers by direct indole-aniline coupling: psychotrimine and kapakahines B and F

Timothy Newhouse et al. J Am Chem Soc. .

Abstract

This report details the invention of a method to enable syntheses of psychotrimine (1) and the kapakahines F and B (2, 3) on a gram scale and in a minimum number of steps. Mechanistic inquiries are presented for the key enabling quaternization of indole at the C3 position by electrophilic attack of an activated aniline species. Excellent chemo-, regio-, and diastereoselectivities are observed for reactions with o-iodoaniline, an indole cation equivalent. Additionally, the scope of this reaction is broad with respect to the tryptamine and aniline components. The anti-cancer profiles of 1-3 have also been evaluated.

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Figures

Figure 1
Figure 1
A sampling of polymeric indole alkaloids with carbon-carbon linkages between indole subunits.
Figure 2
Figure 2
Representatives of the subgroup of oxidatively conjoined tryptamines containing nitrogen to carbon connectivity.
Figure 3
Figure 3
Possible biosynthetic routes to dimeric tryptamines containing the N1-C3 bond.
Figure 4
Figure 4
Direct oxidative dimerization of a tryptamine to give N1-C3 bond formation.
Figure 5
Figure 5
Oxidative coupling reactions for the introduction of heteroatom substituents to indole C2.
Figure 6
Figure 6
(A) Nature’s presumed biosynthesis leads to the invention of a direct indole-aniline oxidative coupling reaction. (B) Known reactivity suggests issues of chemo- and regioselectivity.
Figure 7
Figure 7
Some possible mechanisms for N-C bond formation.
Figure 8
Figure 8
Introduction of various electrophiles to indole C3.
Figure 9
Figure 9
Potential electrophilic aniline species
Figure 10
Figure 10
Mechanistic proposal for the indole-aniline oxidative coupling reaction.
Figure 11
Figure 11
Scope of tryptamine and aniline oxidative coupling reaction.
Figure 12
Figure 12
Initial retrosynthetic analysis of the kapakahines.
Figure 13
Figure 13
Failure to observe isomerization to the desired α-carboline.
Scheme 1
Scheme 1
Structural reassignment of the melatonin oxidative dimerization product.a aReagents and conditions: (a) Co(salen)2 (0.18 equiv), O2, DCM, 23 °C, 24 h, 35%.
Scheme 2
Scheme 2
Failure of the necessary bond migration. a Reagents and conditions: (a) Zn (20 equiv), AcOH, 23 °C, 1 h, 96%; (b) N-chlorosuccinimide (1.1 equiv), DCM, 0 → 23 °C, 1 h, 94%; (c) K2CO3 (100 equiv), MeOH, 23 °C, 2 h, 93%.
Scheme 3
Scheme 3
Stepwise synthesis of N1-C2 linked tryptamine dimer 39.a aReagents and conditions: (a) 33 (4.0 equiv), CuI (1.0 equiv), (±)-trans-N,N′-dimethyl-1,2-cyclohexanediamine (0.20 equiv), K3PO4 (11 equiv), 1,4-dioxane, 101 °C, 24 h; (b) TFA/DCM (1:4), 23 °C, 1 h, 21 % (2 steps).
Scheme 4
Scheme 4
Synthesis of a C3-N-functionalized pyrroloindoline.a aReagents and conditions: (a) (i) N-chlorosuccinimide (1.1 equiv), Et3N (1.0 equiv), DCM, 0 → 23 °C, 1.5 h, (ii) indoline (1.4 equiv), 0 → 23 °C, 12 h, 59%; (b) DBU (1.0 equiv), C12H25SH (2.0 equiv), DCM, 23 °C, 2 h; (c) NCS (1.1 equiv), Et3N (1.2 equiv), DCM, 0 → 23 °C, 15 min; indoline (2.0 equiv), 12 h, 18% 49 and 45% 51.
Scheme 5
Scheme 5
Comparison of order of addition for oxidative cyclization.
Scheme 6
Scheme 6
Reactions of anilines with the chloroindolenine, 50.a aReagents and conditions: (a) (i) N-chlorosuccinimide (1.5 equiv), Et3N (1.5 equiv), DCM, 0 → 23 °C, 15 min; (ii) aniline (2.0 equiv), 23 °C, 8 h, 28%; (b) p-iodoaniline (1.5 equiv), N-halosuccinimide (1.5 equiv), Et3N (1.5 equiv), DCM, −45 → 23°C, 3 h.
Scheme 7
Scheme 7
Nucleophilic displacement of a 3-halopyrroloindoline by an aniline nucleophile.a aReagents and conditions: (a) N-bromosuccinimide (1.4 equiv), DCM, 23 °C, 1 h, 84%; (b) aniline (6.3 equiv), K3PO4 (1.9 equiv), DMSO, 100 °C, 24 h, 12%; (c) TFA/DCM (1:5), 0 °C, 0.5 h, quant.
Scheme 8
Scheme 8
Photochemical generation of a phenylnitrenium ion in the synthesis of 89, along with subsequent decomposition.a aReagents and conditions: (a) 33 (1.0 equiv), hν, benzene, 23 °C, 24 h, 2%; (b) TFA/DCM (1:10), 23°C, 2 h, 91%.
Scheme 9
Scheme 9
Synthesis of a chimonanthine isomer, 104.a aReagents and conditions: (a) o-iodoaniline (1.2 equiv), N-iodosuccinimide (1.5 equiv), MeCN/MeOH (20:1), −45 °C, 1 h, 63%; (b) 103 (3.0 equiv), Pd(dppf)Cl2•DCM (0.20 equiv), Cs2CO3 (2.0 equiv), LiCl (1.0 equiv), NMP, 100 °C, 1 h, 92%; (c) sodium bis(2-methoxyethoxy)aluminum hydride (11 equiv), toluene, 110 °C, 30 min, 86%.
Scheme 10
Scheme 10
Initial route to psychotrimine precursor 107.a aReagents and conditions: (a) 33 (3.0 equiv), CuI (0.30 equiv), (±)-trans-N,N′-dimethyl-1,2-cyclohexanediamine (0.60 equiv), K2CO3 (7.0 equiv), 1,4-dioxane, 101 °C, 20 h, 45%; (b) o-iodoaniline (1.2 equiv), N-iodosuccinimide (1.5 equiv), MeCN:MeOH 20:1, −45 °C, 1 h, 24%; (c) 103 (7 equiv), Pd(OAc)2 (0.3 equiv), K2CO3 (3.5 equiv), LiCl (1.0 equiv), DMF, 90 °C, 0.5 h, 70%.
Scheme 11
Scheme 11
Total synthesis of psychotrimine (1).a aReagents and conditions: (a) o-iodoaniline (1.2 equiv), N-iodosuccinimide (3.0 equiv), Et3N (1.2 equiv), MeCN, −45 → 23 °C, 1 h, 61–67%, 25–30% 105; (b) Pd(OAc)2 (0.21 equiv), Na2CO3 (2.6 equiv), LiCl (0.9 equiv), 103 (2.7 equiv), DMF, 102 °C, 20 min, 85%; (c) CuI (0.32 equiv), (±)-trans-N,N′-dimethyl-1,2-cyclohexanediamine (0.60 equiv), K2CO3 (7.0 equiv), 33 (3.0 equiv), 1,4-dioxane, 101 °C, 9 h, 89%; (d) sodium bis(2-methoxyethoxy)aluminum hydride (22 equiv), toluene, 110 °C, 30 min, 89%.
Scheme 12
Scheme 12
Failure to observe direct α-carboline ring system.a aReagents and conditions: (a) o-iodoaniline (1.2 equiv), N-chlorosuccinimide (2.0 equiv), triethylamine (1.2 equiv), MeCN −45 → 4 °C, 2.5 h, 25%; (b) o-iodoaniline (1.2 equiv), N-iodosuccinimide (1.6 equiv for 102b, 1.55 equiv for 102a, 102c), MeCN −45 → −35 °C, 2.5 h.
Scheme 13
Scheme 13
Preparation of the tripeptide fragment (116). a aReagents and conditions: (a) CuCN (0.9 equiv), LiCl (1.8 equiv), Zn (3.6 equiv), TMSCl (0.1 equiv), Br(CH2)2Br (0.2 equiv), DMF, −20 → 23 °C, 11 h, 60%; (b) LiOH (1.2 equiv), THF/H2O 1:1, 0 °C, 0.5 h; H2N-Ala-Leu-OBn (1.1 equiv), EDC (1.2 equiv), HOBt (1.4 equiv), THF, 0 → 23 °C, 10 h, 97% (two steps).
Scheme 14
Scheme 14
Two routes to the pyrroloindoline-containing macrocycle (124). Reagents and conditions: (a) 116 (2.0 equiv), Pd(dppf)Cl2•DCM (0.20 equiv), Cs2CO3 (2.0 equiv), LiCl (1.0 equiv), DMF, 100 °C, 1.5 h, 55%; (b) 10% Pd/C (0.20 equiv), H2, MeOH, 1 h (c) HATU (3.0 equiv), HOBt (2.5 equiv), iPr2NEt (2.2 equiv), DMF, 6 h, 41% (2 Steps); (d) Et2NH/DCM, 1:3, 1 h, quant; HATU (2.0 equiv), HOBt (1.5 equiv), Et3N (2.0 equiv), 22% and 125 25% (2 steps); (e) Pd(OAc)2 (0.34 equiv), NaOAc (6 equiv), LiCl (0.96 equiv), DMF, 100 °C, 12 h, 67%.
Scheme 15
Scheme 15
Successful isomerization to the desired α-carboline (132).a aReagents and conditions: (a) 10% Pd/C (0.20 equiv), H2, MeOH, 1 h; (b) EDC (3.0 equiv), HOAt (6.0 equiv), DCM/DMF (20:1), 12 h, 70% (124:132, 1:11).
Scheme 16
Scheme 16
Completion of kapakahines F, 2, and B, 3. Reagents and conditions: (a) LiOH, THF/H2O/MeOH (40:2:1), 1 h; HATU (4.0 equiv); TFA/DCM (1:6), 0.5 h; (d) LiOH, THF/H2O/MeOH (40:2:1), 1 h; (COCl)2 (4.0 equiv), Et3N (1.0 equiv), DCM, 1 h; TFA/DCM (1:10), 1 h, 64% (three steps); (f) Boc-Phe-OH (1.2 equiv), EDC (2.0 equiv), HOBt (1.8 equiv), Et3N (3.0 equiv), DCM 1 h; TFA/DCM (1:10), 1 h, 81% (two steps).
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