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

Published on Web 04/28/2010

Scalable Total Syntheses of N-Linked Tryptamine Dimers by

Direct Indole-Aniline Coupling: Psychotrimine and

Kapakahines B and F

Timothy Newhouse, Chad A. Lewis, Kyle J. Eastman, and Phil S. Baran*

Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,

La Jolla, California 92037

Received February 2, 2010; E-mail: pbaran@scripps.edu

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.

to chetomin⁸and the only reported polymeric cyclotryptamine

Introduction

alkaloids with the N1-C3 linkage, psychotrimine (1)⁹and

Of all the known nitrogen-bearing natural products, those

containing an indole heterocycle hold a special place in the

annals of organic chemistry. This priority position in “alkaloid

space” is due to several factors, including the interesting

structures of many of their members, their novel bioactivities,

and their historical importance in the development of organic

chemistry.¹Furthermore, certain indole alkaloids are even used

as “yardsticks” to measure progress in the art and science of

synthesis s strychnine being particularly prominent in this

regard.²

An important subset of indole alkaloids are those made up

of more than one indole subunit.³The vast majority of such

structures involve linkages between the carbon atoms of the

indoles, such as those shown in Figure 1, which have all

succumbed to elegant total syntheses.⁴A rarity among polymeric

indole alkaloids are those linked by the nitrogen atom of the

indole, such as those in Figure 2.

The ﬁrst member of this subset was isolated in 1944 and

named chaetomin (12).^5a,bIts intriguing structure was not fully

elucidated until 1978 (then renamed chetomin),^5c,dand it was

not until the very end of the 20th century that more natural

products with this peculiar connectivity were isolated.⁶In 1995,

Scheuer and co-workers isolated a family of macrocyclic

peptides, the kapakahines (2, 3), exhibiting an N1-C3 linkage

between two tryptophan subunits.⁷A decade later, more natural

products expressing this motif were isolated, including ones akin

psychotetramine (15).¹⁰These natural products have both

fascinating structures and biological functions that are of

considerable interest. For example, chetomin (12) disrupts

binding of a key cofactor in the hypoxia-inducible factor

pathway and has been shown to affect dose-dependent tumor

(4) Vinblastine: (a) Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam,

A.; Kakei, H.; Rayl, T. J.; Hwang, I.; Boger, D. L. J. Am. Chem. Soc.

2009, 131, 4904. (b) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato,

A.; Kuboyama, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc.

2002, 124, 2137. (c) Mangeney, P.; Andriamialisoa, R. Z.; Langlois,

N.; Langlois, Y.; Potier, P. J. Am. Chem. Soc. 1979, 101, 2243. (d)

Kutney, J. P.; Choi, L. S. L.; Nakano, J.; Tsukamoto, H.; McHugh,

M.; Boulet, C. A. Heterocycles 1988, 27, 1845. (e) Kuehne, M. E.;

Matson, P. A.; Bornmann, W. G. J. Org. Chem. 1991, 56, 513. (f)

Magnus, P.; Mendoza, J. S.; Stamford, A.; Ladlow, M.; Willis, P.

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Overman, L. E. J. Am. Chem. Soc. 2001, 123, 9468. (h) Govek, S. P.;

Overman, L. E. Tetrahedron 2007, 63, 8499. Quadrigemine C: (i)

Lebsack, A. D.; Link, J. T.; Overman, L. E.; Stearns, B. A. J. Am.

Chem. Soc. 2002, 124, 9008. Himastatin: (j) Kamenecka, T. M.;

Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 2993. (k)

Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed. 1998,

37, 2995. (l) Kamenecka, T. M.; Danishefsky, S. J. Chem.sEur. J.

2001, 7, 41. Perophoramidine: (m) Fuchs, J. R.; Funk, R. L. J. Am.

Chem. Soc. 2004, 126, 5068. Chimonanthine: (n) Hendrickson, J. B.;

Go¨schke, R.; Rees, R. Tetrahedron 1964, 20, 565. (o) Scott, A. I.;

McCapra, F.; Hall, E. S. J. Am. Chem. Soc. 1964, 86, 302. (p) Link,

J. T.; Overman, L. E. J. Am. Chem. Soc. 1996, 118, 8166. (q)

Movassaghi, M.; Schmidt, M. A. Angew. Chem., Int. Ed. 2007, 46,

3725. Haplophytine: (r) Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto,

K.; Fukuyama, T.; Tokuyama, H. Angew. Chem., Int. Ed. 2009, 48,

7600. (s) Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen,

D. Y. K. Angew. Chem., Int. Ed. 2009, 41, 7480. Communesin F: (t)

Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129,

13794.

(1) For numerous examples, see: Nicolaou, K. C.; Sorensen, E. J. Classics

in Total Synthesis, 1st ed.; Wiley-VCH, New York, 1996. Nicolaou,

K. C.; Snyder, S. A. Classics in Total Synthesis II, 1st ed.; Wiley-

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(2) Bonjoch, J.; Sole´, D. Chem. ReV. 2000, 100, 3455.

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Int. Ed. 2008, 47, 8170. (d) Kam, T. S.; Choo, Y. M. In The Alkaloids;

Cordell, G. A., Ed.; Academic Press: San Diego, 2006; Vol. 63, pp

181-337.

(5) (a) Waksman, S. A.; Bugie, E. J. Bacteriol. 1944, 48, 527. (b) Geiger,

W. B.; Conn, J. E.; Waksman, S. A. J. Bacteriol. 1944, 48, 531. (c)

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9

10.1021/ja1009458  2010 American Chemical Society

J. AM. CHEM. SOC. 2010, 132, 7119–7137 7119

A R T I C L E S

Newhouse et al.

Figure 2. Representatives of the subgroup of oxidatively conjoined

tryptamines containing nitrogen-to-carbon connectivity.

this gap in the capabilities of chemical synthesis.¹²This full account

describes in detail the underlying rationale, mechanism, and scope

of a method that has made possible the concise gram-scale total

syntheses of highly complex natural products, such as psycho-

trimine and those belonging to the kapakahine family.¹³

Figure 1. A sampling of polymeric indole alkaloids with carbon-carbon

linkages between indole subunits.

reduction in mice.^5fThe kapakahines, only isolated in minute

quantities (0.3 mg of kapakahine B was isolated from 840 g of

crude sponge ethanolic extract), have been reported to exhibit

promising anti-leukemia activity. Psychotrimine has been shown

to possess activity against colon and lung cancers¹¹and was

equally potent as a currently employed colon cancer therapy,

5-ﬂuorouracil.

Biosynthetic Considerations and Initial Forays

Whereas the biogenetic origins of dimeric indole alkaloids

linked at carbon are presumed to proceed via a radical

dimerization process,¹⁴the genesis of nitrogen-linked siblings

in this family is not well understood. A number of possibilities

exist for how Nature might fashion this exotic connectivity.

Perhaps the most straightforward possibility would be a radical-

or cationic-based, oxidative dimerization to directly form the

N1-C3 bond (Figure 3A). A second possibility, reminiscent

of the speculated biosynthesis of the chartelline alkaloids, hinges

on the propensity of a nitrogen substituent to migrate from C2

The absence of any direct means to synthesize these natural

products led us to consider the invention of a method to bridge

(6) For the isolation of alkaloid 13, see the following conference

report: Masashi, H.; Mitsuyoshi, S.; Hiroshi, M.; Yuji, S. Tennen Yuki

Kagobutsu Toronkai Koen Yoshishu 1994, 36, 557.

(7) (a) Nakao, Y.; Yeung, B. K. S.; Yoshida, W. Y.; Scheuer, P. J.; Kelly-

Borges, M. J. Am. Chem. Soc. 1995, 117, 8271. (b) Yeung, B. K. S.;

Nakao, Y.; Kinnel, R. B.; Carney, J. R.; Yoshida, W. Y.; Scheuer,

P. J.; Kelly-Borges, M. J. Org. Chem. 1996, 61, 7168. (c) Nakao, Y.;

Kuo, J.; Yoshida, W. Y.; Kelly, M.; Scheuer, P. J. Org. Lett. 2003, 5,

1387.

(12) (a) Marsden, S. P.; Watson, E. L.; Raw, S. A. Org. Lett. 2008, 10,

2905. (b) Toumi, M.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008,

10, 5027. (c) Espejo, V. R.; Rainier, J. D. J. Am. Chem. Soc. 2008,

130, 12894. (d) For a 16 linear step synthesis of 1 (13.2% overall

yield), see: Matsuda, Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008,

10, 125. (e) Takahashi, N.; Ito, T.; Matsuda, Y.; Kogure, N.; Kitajima,

M.; Takayama, H. Chem. Commun. 2010, 46, 2501. (f) Beaumont,

S.; Pons, V.; Retailleau, P.; Dodd, R. H.; Dauban, P. Angew. Chem.,

Int. Ed. 2010, 49, 1634.

(8) (a) Li, G.-Y.; Li, B.-G.; Yang, T.; Yan, J.-F.; Liu, G.-Y.; Zhang, G.-

L. J. Nat. Prod. 2006, 69, 1374. (b) Ding, G.; Jiang, L.; Guo, L.;

Chen, X.; Zhang, H.; Che, Y. J. Nat. Prod. 2008, 71, 1861.

(9) Takayama, H.; Mori, I.; Kitajima, M.; Aimi, N.; Lajis, N. H. Org.

Lett. 2004, 6, 2945.

(10) The relative conﬁguration of psychotetramine is not known, see: Mori,

I. M.S. Thesis, Chiba University, Japan, 2004.

(11) Yohei, M. Ph.D. Thesis, Chiba University, Japan, 2008.

(13) (a) Newhouse, T.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 10886.

(b) Newhouse, T.; Lewis, C. A.; Baran, P. S. J. Am. Chem. Soc. 2009,

131, 6360.

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7120 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

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%.

illustrated in Figure 3C, an analogous process may be operative

in a hypothetical rearrangement of 21 to 24 (via 22 and 23).

Such a scenario would require position-selective intermolecular

oxidative dimerization of tryptophan units to afford the N1-C2-

linked dimer 21. Naturally occurring alkaloids such as 21 are

not known, but heteroatom linkages at C2 of tryptophan are

precedented, such as celogentin C (Vide infra).¹⁶

A third possibility would involve direct nucleophilic displace-

ment of a halide by the indole nitrogen (Figure 3D). Although

the work of Rainier has demonstrated that such a process can

occur, it requires a strong base¹⁷and proceeds to give the

opposite diastereochemical outcome that is required for the

kapakahines via epimerization of the tryptophan R-proton. A

ﬁnal possible biogenesis invokes the “Somei hypothesis” for

dimerization via N-hydroxyindoles (26, Figure 3E) with con-

comitant loss of water.^18aSomei has demonstrated that in certain

contexts this type of bond formation is facile,^18bbut a quaternary

center cannot be formed in more than trace quantities via this

process.¹⁹The following series of experiments were designed

to interrogate the innate reactivity of molecules relevant to the

presumed biogenetic hypotheses in parts A and C of Figure 3.

Our studies commenced with the reinvestigation of the sole

example of N1-C3 tryptamine dimerization, reported in a book

chapter in 2000 (Scheme 1).²⁰The described reaction used a

cobalt(II) salen precatalyst in the presence of oxygen, conditions

that are well known to operate through an SET process.^20b,c

Figure 3. Possible biosynthetic routes to dimeric tryptamines containing

the N1-C3 bond.

to C3 of indole via a [1,5] sigmatropic rearrangement (Figure

3B). Although migration of carbon atoms from C2 to C3 is well

precedented, to our knowledge, the sole experimental demon-

stration of a nitrogen migration in such a context stems from

the total synthesis of chartelline C (19 f 20).¹⁵Thus, as

(15) (a) Baran, P. S.; Shenvi, R. A.; Mitsos, C. A. Angew. Chem., Int. Ed.

2005, 44, 3714. (b) Baran, P. S.; Shenvi, R. A. J. Am. Chem. Soc.

2006, 128, 14028.

(16) (a) Ma, B.; Litvinov, D. N.; He, L.; Banerjee, B.; Castle, S. L. Angew.

Chem., Int. Ed. 2009, 121, 6220. (b) Feng, Y.; Chen, G. Angew. Chem.,

Int. Ed. 2010, 49, 958. (c) Hu, W.; Zhang, F.; Xu, Z.; Liu, Q.; Cui,

Y.; Jia, Y. Org. Lett. 2010, 12, 956.

(14) Dimerization at carbon has extensive precedent, for example: (a)

Cheek, G. T.; Nelson, R. F. J. Org. Chem. 1978, 43, 1230. (b) Balogh-

Hergovich, E.; Speier, G. J. Chem. Soc., Perkin Trans. 1 1986, 2305.

(c) Shen, X.; Lind, J.; Eriksen, T. E.; Mere´nyi, G. J. Chem. Soc., Perkin

Trans. 2 1990, 597. (d) Dryhurst, G. Chem. ReV. 1990, 90, 795. (e)

Verotta, L.; Orsini, F.; Sbacchi, M.; Scheildler, M. A.; Amador, T. A.;

Elisabetsky, E. Bioorg. Med. Chem. 2002, 10, 2133. (f) Ishikawa, H.;

Takayama, H.; Aimi, N. Tetrahedron Lett. 2002, 43, 5637. (g)

Ishikawa, H.; Kitajima, M.; Takayama, H. Heterocycles 2004, 63,

2597. (h) Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2009,

324, 238, and references cited therein.

(17) The perturbation of pH in a restricted environment, such as an enzyme

pocket, is well known; however, the necessity for strong base reduces

the likelihood of such a transformation.

(18) (a) Somei, M. AdV. Het. Chem. 2002, 82, 101. (b) Somei, M.

Heterocycles 1999, 50, 1157.

(19) Somei has reported a 1% yield for N1-C3 bond formation when

N-hydroxymelatonin and indole (10 equiv) were treated with

MsCl: Hayashi, T.; Peng, W.; Nakai, Y.-y.; Yamada, K.; Somei, M.

Heterocycles 2002, 57, 421.

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A R T I C L E S

Newhouse et al.

Scheme 2. Failure of the Necessary Bond Migration^a

^aReagents and conditions: (a) Zn (20 equiv), AcOH, 23 °C, 1 h, 96%; (b) N-chlorosuccinimide (1.1 equiv), DCM, 0 f 23 °C, 1 h, 94%; (c) K₂CO₃(100

equiv), MeOH, 23 °C, 2 h, 93%.

Unfortunately, the only melatonin dimer observed was not 28,

but rather the constitutionally isomeric structure linked from

N1 to C2, 29 (Scheme 1, veriﬁed by X-ray crystallography).

While disappointing, this reactivity represented an opportunity

to explore the C2-to-C3 rearrangement proposed in Figure 3C.

As depicted in Scheme 2, when dimer 29 was reduced using

zinc in acetic acid, the desired tryptamine dimer 30 was isolated

in 96% yield. With the necessary oxidation state in place, dozens

of thermal and acidic conditions were screened to elicit

isomerization (PtCl₄, CuOTf, RuCl(H)(CO)(PPh₃)₃, AgNO₃,

NiCl₂, TiF₄, BF₃·OEt₂, Sc(OTf)₃, ZnCl₂, etc.), but they were

unsuccessful. The recalcitrance of this intermediate to isomerize

was compounded by its propensity to rapidly undergo oxidation

back to 29, along with other oxidation byproducts. During the

course of the Lewis acid screen, it was found that AuCl₃acted

as an electrophilic chlorine source to cleanly provide the C3-

chlorinated indolenine 31a.²¹

Isomerization reactions on this chlorinated species, 31a

(generated in a simple way using N-chlorosuccinimide, NCS),

and the related C3-methoxy indolenine, 31b (prepared by

treatment of 31a with K₂CO₃/MeOH), were also attempted by

subjection to acidic,²²basic,²³or thermal conditions. Addition-

Figure 4. Direct oxidative dimerization of a tryptamine to give N1-C3

ally, treatment of 31a with silver(I) triﬂate or 31a or 31b with

NaBH₄did not afford the desired indole connectivity (32).

Although not thoroughly explored, subjection of 29 to acidic

conditions led to signiﬁcant decomposition and recovery of

monomeric melatonin species 27.²⁴Despite these setbacks, it

was reasoned that a redox-neutral isomerization of the nitrogen

substituent from C2-to-C3 was still possible. To investigate

whether the electron-rich nature of melatonin dimer 29 somehow

prevented the isomerization reaction, the electron-neutral ana-

logue, lacking the C5 methoxy groups, was synthesized.

Cobalt-mediated oxidation conditions were attempted with

electron-neutral tryptamines; however, the N1-C2 product

bond formation.

analogous to 29 could not be detected in the reaction mixture.

Only monomeric oxidation byproducts were isolated, includ-

ing the N-formyl kynurenine (oxidative cleavage of the indole

2,3-π bond) and the C3-hydroxy pyrroloindoline.²⁵An

extensive screen of oxidants did, however, lead to the

isolation of trace amounts of an N1-C3-linked tryptamine

dimer, using Koser’s reagent (PhI(OH)OTs),²⁶as shown in

Figure 4. The continued screen of hypervalent iodine oxidants

and other transition metal oxidants did not lead to any

improvement of this nonselective reaction nor the detection

of the N1-C2 isomer. Even in the case of the hexapeptide

35, macrocyclization was not observed.

(20) (a) Adam, W.; Deutsche, F. Peroxide Chemistry: Mechanistic and

PreparatiVe Aspects of Oxygen Transfer; Wiley-VCH: Weinheim,

2000; p 542. For the use of cobalt(II) in a related transformation, see:

(b) Nishinaga, A. Chem. Lett. 1975, 273. (c) Mori, K.; Goto, M.; Sakai,

T. Chem. Pharm. Bull. 1985, 33, 4167.

(24) (a) Hugel, G.; Royer, D.; Sigaut, F.; Le´vy, J. J. Org. Chem. 1991, 56,

4631. (b) Gu¨ller, R.; Borschberg, H.-J. Tetrahedron Lett. 1994, 35,

865.

(21) For a related CuCl₂chlorination, see: ref 14b.

(22) Movassaghi, M.; Schmidt, M. A.; Ashenhurst, J. A. Org. Lett. 2008,

10, 4009.

(25) Nakagawa, M.; Okajima, H.; Hino, T. J. Am. Chem. Soc. 1977, 99,

4424.

(23) Richter, J. M.; Ishihara, Y.; Masuda, T.; Whiteﬁeld, B. W.; Llamas,

T.; Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17938.

(26) (a) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 365. (b)

Koser, G. F. Aldrichim. Acta 2001, 34, 89.

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Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

Scheme 3. Stepwise Synthesis of N1-C2-Linked Tryptamine

Dimer 39^a

Figure 5. Oxidative coupling reactions for the introduction of heteroatom

substituents to indole C2.

As shown in Scheme 4A, indoline was chosen as a tryptamine

surrogate. In the event, tryptamine 45 was treated with NCS in

the presence of Et₃N, followed by addition of indoline to furnish

C3-hydroxyindolenine 47. This product presumably arises from

rapid autoxidation of the initially formed adduct during workup.

While Fmoc removal proceeded smoothly (1,8-diazabicyclo-

[5.4.0]undec-7-ene (DBU), C₁₂H₂₅SH) to deliver 48,³⁰attempts

to reduce the resulting imine and effect isomerization were

unsuccessful (Zn/AcOH, NaBH₄/CeCl₃). It is possible that imine

reduction and dehydration did occur, followed by rapid autoxi-

dation to regenerate 48.

In order to avoid the protection/deprotection sequence, the

Fmoc-protected secondary amine was simply masked as a

methyl carbamate.³¹The methyl carbamate of tryptamine (33,

Scheme 4) was treated with NCS, which to our surprise provided

the chloroindolenine 50³²rather than its ring-chain tautomeric

C3-chloropyrroloindoline form.³³Not surprisingly, the chloro-

indolenine exhibited noticeable decomposition upon aqueous

workup or concentration. The crude chloroindolenine was then

treated with indoline, and the N1-C3-linked isomer, 49, was

obtained in 18% yield along with 45% of the C2-linked adduct

51. The exact nature of this highly interesting process is certainly

debatable, and related transformations are discussed in detail

in the Mechanistic Considerations section. We were pleased to

have rapid access to the key quaternary center expressed in

^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% (two steps).

A stepwise strategy was therefore pursued as documented in

Scheme 3. A Buchwald-Goldberg-Ullmann reaction²⁷was

well suited for the task of merging bromotryptamine 37

(available in three steps from tryptamine) and tryptamine 33,

furnishing dimer 39 after Boc-removal with triﬂuoroacetic acid

(TFA, 21%, unoptimized). Unfortunately, this compound was

also resistant to isomerization and underwent oxidative decom-

position similar to that observed with the melatonin dimer 30.

Exploration of oxidative transformations on this substrate were

not pursued due to the lengthy and low-yielding sequence to

obtain useful quantities of 39.²⁸

At this juncture it was realized and accepted that a purely

biogenetic strategy would likely not be feasible or synthetically

useful; therefore, a surrogate for tryptamine was sought out.

The work of Renfroe, Bergman, and Castle in oxidative

heterocoupling was particularly interesting in this regard,²⁹

wherein the coupling of nitrogen nucleophiles with C3-

substituted indoles to afford C2-linked indoles was achieved

simply using NCS (Figure 5).

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 f 23 °C, 1.5 h; (ii) indoline (1.4 equiv), 0 f 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 f 23 °C, 15 min; indoline (2.0 equiv),

12 h, 18% 49 and 45% 51.

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A R T I C L E S

Newhouse et al.

Table 1. Optimization of Direct Coupling with o-Iodoaniline

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.

^aIsolated yield of 53. ^bDetermined by crude ¹H NMR. ^cQuenched

after 10 min. ^dQuenched by addition of Na₂S₂O₃solution to -45 °C

reaction. ^eGram scale, +17% 52.

psychotrimine (1) and the kapakahines (2, 3); however, ef-

ﬁciencies were still low, and proceeding via an indoline or an

unfunctionalized aniline would require a number of extraneous

steps.

starting material). Returning to our initial ﬁnding in Scheme 4,

a number of different halogenating agents were evaluated

(entries 5-12). To our delight, succinimide-based halogenating

agents all delivered 53 with varying amounts of recovered

starting material. N-Iodosuccinimide (NIS) was found to be

optimal in terms of conversion, isolated yield, diastereoselec-

tivity, and scalability. If triethylamine is used, the reaction

requires 3.5 equiv of NIS (entries 8 and 9), whereas in the

absence of base only 1.1-1.5 equiv is necessary (entries 12

and 16). Remarkably, much greater efﬁciency and diastereose-

lectivity are obtained in the absence of any amine base, as a

result of the lower temperature required for the reaction to occur.

This was supported by low temperature quenching experiments,

as well as by a slight decrease in diastereoselectivity at higher

temperatures (entry 13). This fact was conﬁrmed by directly

injecting an NIS solution at low temperature to a solution of

o-iodoaniline and tryptamine while acquiring ¹H NMR data. All

of the data indicates rapid reaction at low temperature only in

the absence of base.

If o-iodoaniline could be successfully employed as a nitrogen

donor, then rapid access to these natural products would be

enabled (Figure 6A). However, as was encountered previously

(Scheme 4), issues of regio- and chemoselectivity remained (see

potential byproducts B-F in Figure 6B). Therefore, an opti-

mization study was carried out with Boc-Trp-OMe and o-

iodoaniline as an indole cation equivalent (Table 1). At the

outset, our concerns about selective access to 53 were well

founded since several oxidants screened led to either no observed

product or trace quantities along with numerous byproducts and

polymeric material. Fortunately, hypervalent iodine(III) acted

as a competent oxidant for this transformation, with Koser’s

reagent (PhI(OH)OTs) providing a local maximum of efﬁciency

(Table 1, entries 2-4).

A number of iodine(III) reagents and reaction conditions

failed to improve the yield and conversion to 53 (no recovered

Next, a solvent screen revealed that dichloromethane (DCM)

and tetrahydrofuran (THF) were not competent, whereas EtNO₂

and MeCN were preferable (entries 15-18). Finally, the addition

of MeOH as cosolvent in a ratio of 20:1 MeCN:MeOH was

found to provide the optimal efﬁciency, affording the product

in 79% yield on gram scale (entry 21). While the minor

diastereomer could be detected in minute quantities by crude

¹H NMR (ca. 50:1), removal of this contaminant by column

chromatography was simple. No product was observed when

NCS was substituted for NIS either under the optimized

conditions (entry 21 vs 22, quenched at -45 °C) or at a higher

temperature (entry 13 vs 14, quenched after 10 min). The exact

role of MeOH is not entirely clear; however, its addition does

increase solubility of the reactants at low temperature. The

divergence between NIS and NCS (summarized in Scheme 5),

and the role that the oxidant was playing, required further studies

(27) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,

124, 11684.

(28) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Angew. Chem., Int. Ed.

2009, 48, 2854.

(29) For introduction of imidazole nucleophiles to haloindolenines, see:

(a) Renfroe, H. B. 3-Substituted-2-(Heteroaryl) Indoles. U.S. Patent

4,511,573, Apr 16, 1985. Anilines: (b) Bergman, J.; Engqvist, R.;

Stålhandske, C.; Wallberg, H. Tetrahedron 2003, 59, 1033. Imidazoles:

(c) He, L.; Yang, L.; Castle, S. L. Org. Lett. 2006, 8, 1165. (d) Ma,

B.; Banerjee, B.; Litvinov, D. N.; He, L.; Castle, S. L. J. Am. Chem.

Soc. 2010, 132, 1159.

(30) Sheppeckll, J. E.; Kar, H.; Hong, H. Tetrahedron Lett. 2000, 41, 5329.

(31) For recent reviews on protecting group free synthesis, see: (a)

Hoffmann, R. W. Synthesis 2006, 3531. (b) Young, I. S.; Baran, P. S.

Nat. Chem. 2009, 1, 193.

(32) Species 50 was characterized by conducting the reaction in deuterated

solvent (¹H, ¹³C, and HSQC NMR experiments support this structural

assignment).

(33) Ohno, M.; Spande, T.; Witkop, B. J. Am. Chem. Soc. 1968, 90, 6521.

9

7124 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

Scheme 5. Comparison of Order of Addition for Oxidative Cyclization

A-D) or initial aniline oxidation (paths E-H). This seemingly

simple indole quaternization reaction is mechanistically intrigu-

ing and surprisingly complex.

Nature and Identity of the Oxidized Component

If initial indole oxidation were to occur, a structure such as

54 (Figure 7) would be formed; direct interrogation of such an

intermediate with aniline was therefore pursued. Speciﬁcally,

the chlorinated version of 54 (X ) Cl) was chosen since it is

likely to be more stable (and characterizable) than the corre-

sponding bromo and iodo analogues. This species was generated

from 33 using NCS in the presence of Et₃N (Scheme 6).

Addition of aniline to 50 afforded 62 in 28% isolated yield

along with unidentiﬁed tryptamine byproducts. However, ad-

dition of o- or p-iodoaniline did not yield coupled product;

rather, the chloroindolenine 50 and iodoaniline remained un-

reactive even after a number of hours at room temperature.

Apparently, the mildly electron-withdrawing iodine substituent

is sufﬁcient to inhibit this pathway. In contrast, the addition of

NCS to a mixture of tryptamine 33 and p-iodoaniline at 0 °C

did provide the pyrroloindoline 63 in 27% yield, along with

47% unreacted starting material. The failure of o- or p-

iodoaniline to engage the chloroindolenine 50 argues strongly

against a pathway for the oxidative coupling reaction that

proceeds via such an intermediate with NCS as an oxidant (i.e.,

paths A-E, Figure 7). Furthermore, based on these results, it

is unlikely that the indolenine 59 (path F, Figure 7) could act

as a competent electrophile at C2 or C3 for an iodoaniline.

varying the substrates and the order of addition in an attempt

to uncover the mechanistic basis for the differences in yield

and diastereoselectivity.

Mechanistic Considerations

The following sections present experimental studies to probe

the site of oxidation during direct coupling, explain the observed

diastereoselectivity, and understand the nature of the active

species. It is clear that either initial oxidation of aniline or

tryptamine coupling partners can be implicated in the ﬁrst step

of this oxidative coupling reaction, as depicted in Figure 7.

Depending on the substrate to be oxidized, several mecha-

nistic pathways can be envisaged and may be classiﬁed into

two general categories: either initial indole oxidation (paths

Figure 7. Some possible mechanisms for N-C bond formation.

9

J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010 7125

A R T I C L E S

Newhouse et al.

Scheme 6. Reactions of Anilines with the Chloroindolenine 50^a

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.

Despite the fact that 50 exists predominantly as the open-

chain tautomeric chloroindolenine, the reaction may proceed

via the corresponding pyrroloindoline³²(path A, Figure 7). Thus,

the following experiment was devised. When the 3-bromo-

pyrroloindoline 66 was treated with aniline, production of 67

was observed only at elevated temperature and in the presence

of base (Scheme 7). Structure conﬁrmation was then secured

by Boc deprotection to the oxidative coupling product 62.

While the presence of the Boc functionality prevents a direct

comparison of 66 to 55, the harsh conditions required for this

transformation suggest that a nucleophilic displacement of a

3-halopyrroloindoline is not operative in the oxidative coupling

reaction. In the context of an unprotected 3-halopyrroloindoline

(55), as would be the case in the indole-aniline coupling (path

A, Figure 7), failure to generate the C-N bond is to be expected.

Based on the studies of Witkop,³³an aniline or anilide should

react more readily as a base toward the indoline N-H,

catalyzing the 3-halopyrroloindoline’s decomposition. Indeed,

treatment of the methylcarbamate of tryptamine, 33, with

^tBuOCl, NCS, N-bromosuccinimide (NBS), or NIS, followed

by reaction with o-iodoaniline or its sodium salt, did not result

in any product formation. This further reinforces the notion that

product formation via such a halogenated tryptamine species

(54 or 55, Figure 7) does not occur in the case of o-iodoaniline

under these reaction conditions.

Since product formation is not observed for the reaction of

68 (Table 2, X ) Cl) with o- or p-iodoaniline, the effect of

order of addition was analyzed for the reaction of aniline with

either pregenerated 68 or 52/NXS. If the diastereoselectivity

observed for the chlorination step is conserved in that of the

product, that would suggest the intermediacy of a haloindolenine

68 when the oxidant is added last. Thus, Boc-Trp-OMe 52 was

reacted with NCS at low temperature and also at room

temperature to form two different ratios of chloroindolenines,

1.4:1 and 1.0:1, respectively (entries 1 and 2). When aniline

was added to the two reaction mixtures at room temperature,

the product was obtained with different degrees of diastereo-

selectivity (7.9:1 and 5.1:1, respectively), albeit in only 23%

and 34% yields, respectively. It was found that monitoring the

reaction by ¹H NMR conﬁrmed that the minor diastereomer of

68 (entry 1) reacted faster than the major diastereomer to provide

69, whereas the remaining diastereomer was largely unreactive

and decomposed upon aqueous workup.

^aReagents and conditions: (a) (i) N-chlorosuccinimide (1.5 equiv), Et₃N

(1.5 equiv), DCM, 0 f 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 f 23 °C, 3 h.

Interestingly, the addition of NIS to a mixture of the

tryptamine 33 and p-iodoaniline only afforded minute quantities

of the product 63 (4%). Instead, the double addition isomer 64

was isolated as the major product (33%), as veriﬁed by X-ray

crystallography, along with 52% recovered starting material,

33. This curious result can be explained by invoking a pathway

originating with aniline oxidation and subsequent reaction of

this oxidized species (Vide infra) with tryptamine 33 to afford

the open-chain tautomeric indolenine of 63. This indolenine can

then engage in one of two pathways: (1) ring closure to afford

the minor product 63 or (2) a pathway leading to the major

product 64 involving ﬁrst [1,5] sigmatropic rearrangement of

the aniline to the indole C2 position. After tautomerization to

the 1H indole and reaction with a second equivalent of the

oxidized p-iodoaniline species, the product 64 would be

delivered. The addition of p-iodoaniline (unactivated) to the

ring-chain tautomeric indolenine of 63, while conceivable, is

unlikely due to p-iodoaniline’s inability to react with the

chloroindolenine 54. It is possible that the difference in product

distribution between the NCS and NIS conditions results from

the generation of a more reactive oxidized aniline species,

derived from NIS as compared to NCS. This study supports

the viability of compounds of the type 60 and 61, which most

likely arise from initial oxidation of the aniline (paths G and

H). Initial oxidation of the tryptamine (paths A-D) or a route

proceeding via nucleophilic addition of an aniline to an

indolenine (paths E and F) cannot easily account for these

observations.

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Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

NBS,³⁷and DMDO^4j-l(Figure 8). Figure 8A shows a mecha-

nistic proposal from Danishefsky^38aand Crich^38bto rationalize

the observed diastereoselectivity for the phenylselenocyclization

of tryptophans. Danishefsky proposes the reversible formation

of a selenonium species with the indole 2,3-π bond, followed

by an irreversible ring closure to afford a predominance of the

kinetically favored exo diastereomer. The origin of this prefer-

ence is attributed to the greater ease of cyclization of the pre-

exo ensemble 72 relative to that of the pre-endo ensemble 71.

Speciﬁcally, there may be a steric clash between the car-

bomethoxy functionality and the indole nucleus in the pre-endo

ensemble 71 (Figure 8A) that is absent from the pre-exo

ensemble 72. Similarly, Crich posits that reversible electrophilic

attack by N-PSP leads to an early transition state, followed by

a rate-limiting ring closure. Crich attributes the preferential

formation of the exo diastereomer to greater torsional strain in

the transition state for the endo diastereomer in the formation

of the pyrrolidine ring.³⁹

Table 2. Diastereoselectivity as a Mechanistic Footprint

^aAniline (2.0 equiv), Et₃N (1.5 equiv), NXS (1.2 equiv), DCM.

Recently, de Lera has put forth an alternate mechanism for both

aminoselenation and bromination chemistry based on DFT calcula-

tions (Figure 8B).³⁷Instead of a thermodynamic preference for

the intermediate leading to the exo diastereomer (with equilibration

to starting material), de Lera proposes a higher energy transition

state in the rate-limiting step for formation of the endo diastereomer.

The endo isomer arises from activation of the indole 2,3-π bond

by the electrophile to form diastereomeric benzylic carbocations

(exo diastereomer, 74, Figure 8B), then formation of an azetidine,

75, and ﬁnally concerted rearrangement to the pyrroloindoline

product, 76. The computed energies for the diastereomeric transition

states predicts that the exo product should predominate for both

bromination and selenation.

b

Determined by crude H NMR. ^cIsolated yield of 69.

1

We next made a direct comparison to these ﬁrst two

experiments (entries 1 and 2) by reversing the order of addition,

such that the NCS was added last, either at low temperature or

at room temperature (entries 3 and 4). Interestingly, the

diastereoselectivity at low temperature was essentially the same

for both of the orders of addition (entry 1 vs 3), while the

diastereoselectivities were different for the reactions conducted

at room temperature (entry 2 vs 4, 5.1:1 and 7.6:1, respectively;

the diastereomeric ratio for the indolenines 68 would be

presumed to be 1.0:1 in both cases). Therefore, a different or

additional mechanism may be operatiVe when the order of

addition is changed, although with yields ranging from 10 to

34%, it is difﬁcult to pinpoint the origin of these effects.

Importantly, entry 5 demonstrates that the diastereoselectivity

and yield of this transformation are dependent on the oxidant

employed, even when the reactions are conducted at the same

temperature. Initial treatment of 52 with NIS followed by

addition of aniline did not lead to formation of the desired

product (entry 6). This difference in reactivity between NCS

and NBS is suggestive of either (1) the involvement of the

halogen in the stereochemistry-determining step or (2) a change

in the relative rates of two pathways. For either scenario, at least

two mechanisms must be active for this substrate pair (60, 61,

Figure 7). In light of previous discussions, the simplest interpreta-

tion of this study is that the alternative mechanism is one involving

attack of tryptamine onto an oxidized aniline species.

For the case of the DMDO oxidation of tryptophan, an

entirely different hypothesis has been suggested (Figure 8C). It

is believed that DMDO reacts irreversibly with tryptophans to

afford diastereomeric mixtures of the products (78 and 80). The

diastereoselectivity is largely dependent upon the substitution

at the carboxylic acid and amine functionalities, which supports

the hypothesis that a steric interaction determines the stereo-

chemical outcome. Unlike the selenonium and bromonium

chemistry, DMDO is known to give 1:1 mixtures of diastereo-

mers for substrates without strong steric demands.⁴⁰

Moderate exo selectivity (69) was observed for oxidation of

tryptophan with NCS followed by addition of aniline, possibly

producing an intermediate such as 81 (Figure 8D). The generally

poor ratio for exo selectivity may be attributed to the ∼1:1 dr

for the chlorination and the irreversibility of the indole oxidation

with NCS. Considering the high exo selectivity and yield

observed for the oxidative cyclization of o-iodoaniline with NIS

(Figure 8E) for substrates without sterically demanding sub-

Rationalization of the Observed Diastereoselectivity

The indole-aniline coupling reaction proceeds with strong

and often exclusive exo selectivity.³⁴It is difﬁcult to offer direct

experimental evidence that can provide a concrete rationalization

for this preference. However, the reaction of tryptophan with a

number of electrophiles has shown similar stereochemical

outcomes,³⁵including N-phenylselenylphthalimide (N-PSP),³⁶

´

(37) Lo´pez, C. S.; Pe´rez-Balado, C.; Rodr´ıguez-Gran˜a, P.; de Lera, A. R.

Org. Lett. 2008, 10, 77.

(38) (a) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.;

Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121,

11953. (b) Crich, D.; Huang, X. J. Org. Chem. 1999, 64, 7218.

(39) The postulated difference between torsional strains of the transition

states, as compared to that of the products, is suggested to arise from

differing hybridization of the carbamate nitrogen lone pair. See ref

38b for further discussion.

(34) See Figure 11 for excellent diastereoselectivities in the oxidative

coupling reaction.

(35) In the case of acid-mediated ring closure, the more stabile endo

diastereomer is obtained due to the reversibility of product formation.

See ref 38b for further explanation.

(36) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc.

1994, 116, 11143.

(40) (a) Kawahara, M.; Nishida, A.; Nakagawa, M. Org. Lett. 2000, 2,

675. (b) May, J. P.; Fournier, P.; Pellicelli, J.; Patrick, B. O.; Perrin,

D. M. J. Org. Chem. 2005, 70, 8424. (c) May, J. P.; Patrick, B. O.;

Perrin, D. M. Synlett 2006, 3403. (d) Gonza´lez-Vera, J. A.; Garc´ıa-

Lo´pez, M. T.; Herranz, R. Tetrahedron 2007, 63, 9229.

9

J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010 7127

A R T I C L E S

Newhouse et al.

Figure 8. Introduction of various electrophiles to indole C3.

stituents (e.g. Boc-Trp-OMe, 52),⁴¹a mechanism similar to

bromination and selenation seems more likely (i.e. reversible

formation of diastereomeric intermediates followed by prefer-

ential formation of the exo product). In summary, to rationalize

the high degree of diastereoselectiVity for the C3-quaternization

of Boc-Trp-OMe, a reVersible process must be inVoked.

A difference in rate among diastereomeric transition states,

leading to selective formation of the exo diastereomers 53, is

reliant upon the reversible formation of intermediate 82 or 83

(similar to 60 or 61, path G or H in Figure 7). Reversible

bonding interactions have been invoked for the case of phenyl-

nitrenium ions interacting with electron-rich arenes, lending

credence to this possibility.⁴²While the nature of a bonding

interaction for indole has not been determined, a σ- or

π-complex may be possible. For simplicity the σ-complexes

are shown in Figure 7, but π-complexes between the phenyl-

nitrenium arene and the indole can also be envisioned. If an

equilibrium with reversible bond formation of this type exists,

then a subsequent rate-limiting ring closure may lead to a

predominance of the kinetically favored product s the exo

isomer. This explanation can also account for the observed

differences in diastereomeric ratio for NCS and NBS (Table 2).

For paths G and H in Figure 7, the halogen remains associated

with the complex, stabilizing the cationic charge. The higher atomic

number halogens are expected to provide a greater extent of

stabilization for either a radical or an ionic pathway. This greater

stabilization should lead to higher levels of stereoinduction. If

π-complex formation occurs, a more favorable bonding interaction

would again be predicted for larger halogens, in turn leading to

higher degrees of diastereoselectivity.

What Is the Nature of the Electrophilic Aniline Species?

For pathways involving an N-haloaniline, the character and

extent of bonding between nitrogen and halogen could take a

(42) For reversible interactions of phenyl nitreniums with arenes, see: (a)

Robbins, R. J.; Laman, D. M.; Falvey, D. E. J. Am. Chem. Soc. 1996,

118, 8127. (b) Kung, A. C.; Falvey, D. E. J. Org. Chem. 2005, 70,

3127. (c) Chiapperino, D.; Mcllroy, S.; Falvey, D. E. J. Am. Chem.

Soc. 2002, 124, 3567. For recent studies on reversible reactions of

electrophiles with oleﬁns, see: (d) Denmark, S. E.; Collins, W. R.;

Cullen, M. D. J. Am. Chem. Soc. 2009, 131, 3490. (e) Denmark, S. E.;

Burk, M. T.; Hoover, A. J. J. Am. Chem. Soc. 2010, 132, 1232.

(41) It is also instructive to compare the high diastereoselectivity in

production of 102a-c with the poor selectivity for formation of

compound 8 in ref 40c.

9

7128 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

assume this active form. The low temperature at which N-

chloroanilines react is also suggestive of the involvement of

tryptamine-promoted N-haloaniline decomposition.⁴³

An anilino radical cation, 85, is not believed to be a discrete

intermediate. The addition of agents known to inhibit radical

reactions (BHT and O₂), including the polymerization of

aniline,⁴⁶did not affect the efﬁciency of this reaction, suggesting

that species such as 85 (Figure 9) are not long-lived if involved

at all. Also, irradiation with a sunlamp s conditions anticipated

to promote a radical pathway⁴⁷s did not result in product

formation but instead produced large amounts of insoluble

material. The possibility that the N-haloaniline reacts directly

via an S_N2-like mechanism to form an intermediate indolenine,

58 (path D, Figure 7), which proceeds to the product, cannot

be entirely ruled out.⁴⁸However, a reaction of this type most

likely cannot be considered a reversible process and therefore

cannot account for the high levels of stereoinduction.⁴⁹

Figure 9. Potential electrophilic aniline species.

Scheme 8. Photochemical Generation of a Phenylnitrenium Ion in

the Synthesis of 90, along with Subsequent Decomposition^a

The failure of many anilines to undergo this transformation

and the rapid reaction times have largely impeded other kinetic

analyses. A detailed kinetic analysis of this reaction and related

transformations will be the subject of a separate disclosure.⁵⁰

Depending on the electronic character of the aniline and the

nature of the oxidant, initial oxidation of the aniline or

tryptamine or both may be involved in product formation.

^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%.

Mechanism Summary

The oxidation of tryptamine with NCS, followed by the

addition of aniline to generate a product of the type 94, provides

data supporting the addition of aniline to C2 (93) and subsequent

migration (Figure 10A). The diastereoselectivities observed for

the oxidative coupling of aniline to tryptophan substrates require

energetically different diastereomeric transition states, resulting

in an enhanced ratio of exo products.

number of forms and may differ between halogens (Figure 9).

Gassman’s studies on the reactivity of N-chloroanilines suggest

a transient nitrenium and chloride ion pair,⁴³and it was believed

that the introduction of a tryptamine nucleophile to an N-

haloaniline would also proceed via this mechanism. While not

deﬁnitive proof, a number of experiments are consistent with

this conclusion. First, the photolysis of o-iodophenylazide

(conditions known to generate the nitrene 87 or, in acidic

solution, nitrenium 86)⁴⁴results in some product formation

(Scheme 8). The low yield of this process can be attributed to

the instability of the product and of this particular nitrene⁴⁵under

the reaction conditions. Indeed, resubjection of the product to the

reaction conditions led to substantial bond homolysis. However,

the poor efﬁciency of 33 to 90 may also reﬂect that a nitrenium

ion is not a discrete intermediate in the oxidative coupling reaction,

and N-haloanilines may require assistance from the tryptamine to

For the releVant and special case of o-iodoaniline and a

tryptamine reacting with NIS (Figure 10B), we believe a reactive

phenylnitrenium and iodide pair, 86 (Figure 9, formed from the

reaction of N-iodoaniline with tryptamine), reacts reversibly with

tryptamines to form an intermediate, 60 or 61 (Figure 7), that

proceeds to a quaternized pyrroloindoline product, 95. This

conclusion is supported by order of addition experiments,

dependence of product distribution and diastereoselectivity on

reagent, temperature, and substrate, generation and reactivity

of possible intermediates, and literature precedence. This

Figure 10. Mechanistic proposal for the indole-aniline oxidative coupling reaction.

9

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A R T I C L E S

Newhouse et al.

were found to be excellent substrates (97, 99). Although

admittedly circumstantial, this point provides further evidence

for a pathway proceeding via an electrophilic phenylnitrenium

ion⁵¹rather than nucleophilic addition of an aniline to an

oxidized tryptamine. If the latter were the case, electron-rich

anilines would be better participants for N-C bond formation

(100 is not formed with NIS). The presence of an ortho

substituent is required with only the exception of the electron-

deﬁcient substrate, p-nitroaniline, which affords useful yields

under these conditions⁵²(p-CF₃, p-I, p-Cl, p-H, p-Ph, p-Me,

p-OMe, etc. afforded only trace product). Electron-deﬁcient

tryptamines were more successful than electron-rich tryptamines

(products 98 and 101), but both electronic characters were

tolerated. Tryptophan and even dipeptide derivatives participated

well in the reaction, providing excellent diastereoselectivities

(>20:1) of 53 and 102a (for 102b,c, see Scheme 12).

Total Synthesis of Psychotrimine

With a method for direct, scalable quaternization of tryptamines

with o-iodoaniline ﬁrmly secured, its application in total

synthesis was pursued. Our efforts ﬁrst focused on the synthesis

of psychotrimine (1), which had previously been synthesized

by Takayama and co-workers.^12dA short model study was ﬁrst

conducted, in order to determine the best method for the

synthesis of the N-linked methyltryptamine dimer subunit of

psychotrimine, 104 (Scheme 9). Thus, the indole-aniline coupled

Scheme 9. Synthesis of a Chimonanthine Isomer, 104^a

Figure 11. Scope of tryptamine and aniline oxidative coupling reaction.

mechanism can account for all of the experimental observations

to date. Furthermore, the trends regarding the substrate scope

are consistent with this mechanistic picture.

Scope and Limitations of the Direct Indole-Aniline

Coupling

Analysis of the scope of the reaction revealed distinct trends

for substrate tolerance (Figure 11). Consistent with both

mechanistic considerations in the previous section and the

studies of Gassman and co-workers,⁴³electron-deﬁcient anilines

(43) (a) Gassman, P. G.; Campbell, G. A. J. Am. Chem. Soc. 1971, 93,

2567. (b) Gassman, P. G.; Campbell, G. A.; Frederick, R. C. J. Am.

Chem. Soc. 1972, 94, 3884. (c) Gassman, P. G.; Campbell, G. A. J. Am.

Chem. Soc. 1972, 94, 3891.

^aReagents and conditions: (a) o-iodoaniline (1.2 equiv), N-iodosuccin-

imide (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%.

(44) (a) Leyva, E.; Platz, M. S.; Persy, G.; Wirz, J. J. Am. Chem. Soc.

1986, 108, 3783. (b) McClelland, R. A.; Kahley, M. J.; Davidse, P. A.;

Hadzialic, G. J. Am. Chem. Soc. 1996, 118, 4794.

(45) Watt, D. S.; Kawada, K.; Leyva, E.; Platz, M. S. Tetrahedron Lett.

1989, 30, 899.

product 90 (obtained from the reaction of 33 and o-iodoaniline

with NIS in 63% yield) was subjected to Larock indolization

(46) (a) Ding, Y.; Padias, A. B.; Hall, H. K., Jr. J. Polym. Sci., Part A:

Polym. Chem. 1999, 37, 2569. (b) Wojciechowski, P. M.; Zierkiewicz,

W.; Michalska, D.; Hobza, P. J. Chem. Phys. 2003, 118, 10900. (c)

Kato, K.; Yamanouchi, K. Chem. Phys. Lett. 2004, 397, 237. (d)

Sapurina, I.; Stejskal, J. Polym. Int. 2008, 57, 1295.

(49) While a reversible π-stacking interaction could be invoked, it is difﬁcult

to envision a stereochemical preference for the exo diastereomer in

this scenario in light of the known thermodynamic bias for the endo

diastereomer: Crich, D.; Bannerjee, A. Acc. Chem. Res. 2007, 40, 151.

Qualitatively, a solution of o-iodoaniline and 33 led to a yellow

solution (both materials are initially white crystalline solids). Unfor-

tunately, UV-vis and ¹H or ¹³C NMR experiments did not allow

observation of changes indicative of π-stacking.

(50) (a) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran,

A.; Emanuelsson, E. A. C.; Blackmond, D. G. J. Org. Chem. 2006,

71, 4711. (b) Blackmond, D. G. Angew. Chem., Int. Ed. 2005, 44,

4302.

(47) Tanner, D. D. J. Am. Chem. Soc. 1964, 86, 4674.

(48) For N-C bond formation that follows second-order kinetics (not

necessarily S_N2) between arenes and activated esters of N-phenylhy-

droxylamine, see: (a) Shudo, K.; Ohta, T.; Okamoto, T. J. Am. Chem.

Soc. 1981, 103, 645. (b) Hamel, P.; Girard, Y.; Atkinson, J. G. J. Chem.

Soc., Chem. Commun. 1989, 63. (c) Novak, M.; Martin, K. A.;

Heinrich, J. L. J. Org. Chem. 1989, 54, 5430. (d) Helmick, J. S.;

Martin, K. A.; Heinrich, J. L.; Novak, M. J. Am. Chem. Soc. 1991,

113, 3459. (e) Novak, M.; Rangappa, K. S.; Manitsas, R. K. J. Org.

Chem. 1993, 58, 7813.

9

7130 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

Scheme 10. Initial Route to Psychotrimine Precursor 107^a

nonselective oxidation pathways of methyl tryptamine in Nature

would result in the formation of this product analogous to the

results from Figure 4.

Our ﬁrst route to 1 commenced with the methyl carbamate

of 7-bromotryptamine, 105 (Scheme 10). Buchwald-Goldberg-

Ullmann coupling with the tryptamine 33 afforded the dimeric

tryptamine 106 in 45% yield. The low yield resulted from a

lack of chemoselectivity in the cross-coupling (two indole NH

groups present), but this efﬁciency was signiﬁcantly greater than

with palladium-mediated methods.⁵⁴Next, o-iodoaniline was

appended to the more reactive indole, delivering 98, which was

then positioned to participate in a Larock indole ring synthesis

to afford the trimeric species 107. The low efﬁciency of this

route to the trimeric structure 107 led to the exploration of a

halogen-selective Larock route (Scheme 11).

In this sequence, the 7-bromotryptamine methyl carbamate,

105,⁵⁵was coupled to o-iodoaniline using NIS and Et₃N to

afford adduct 101 in 61-67% yield along with 25-30%

recovered starting material. Slightly lower efﬁciencies were

encountered without the use of triethylamine or when MeOH

was substituted for Et₃N. Next, a Larock indole ring synthesis

was performed to provide 109 (85% yield), leaving the bromine

handle unscathed. Unfortunately, high palladium loadings (20

mol %) were necessary to prevent starting material decomposi-

tion under the harsh reaction conditions. However, even with

these high loadings, debromination of the starting material 101

or the product 109 was not observed. Next, an N-H-selective

Buchwald-Goldberg-Ullmann coupling cleanly provided the

desired product 107 in 89% isolated yield. The methyl carbam-

ates of this trimeric species were smoothly converted to the

corresponding methylamines in the natural product, delivering

1 in 89% yield. A large excess of reagent was used to achieve

a shorter reaction time with less decomposition of psychotrimine

(1).

^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%.

to provide the requisite tryptamine dimer 34 in 92% yield.⁵³It

is conceivable that this intermediate could lead to psychotrimine,

but that would require a laborious installation of a functional

handle at C7 of the indoline. Next, conversion of the methyl

carbamates to methylamines provided access to a methyl

tryptamine dimer, 104, which may well be naturally occurring.

This constitutional isomer of chimonanthine (Figure 1) has not

been isolated to date, but it would not be surprising if

The rapid and scalable synthesis of psychotrimine (1, four

steps, 41-47% overall from 105, 2.5 g of 1 prepared) is the

result of a retrosynthetic analysis tailored to the exact substrate,

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 f 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%.

9

J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010 7131

A R T I C L E S

Newhouse et al.

Figure 12. Initial retrosynthetic analysis of the kapakahines.

Scheme 12. Failure To Observe Direct R-Carboline Ring System^a

rather than applying a preordained strategy or method to its

synthesis. While at its conception the retrosynthesis left ques-

tions of feasibility, empirical ﬁndings led to the invention of a

new method, which, as will be described in the following

section, has had further applications beyond psychotrimine (1).

Total Syntheses of Kapakahines B and F

After the successful synthesis of large quantities of psycho-

trimine (1), another, even more complex venue for oxidative

indole-aniline coupling was explored. In addition to the

hallmark N1-C3 linkage between indole subunits in psycho-

trimine, the kapakahines present a twisted⁵⁶macrocycle, a

particularly strained R-carboline ring system, and sensitive

imidazolone functionality (Figure 12).⁷Thus, the ﬁrst retrosyn-

thetic simpliﬁcation of the kapakahines was removal of this

imidazolone. Next in the plan was removal of the alanine-leucine

residues along with simpliﬁcation of the N-linked tryptophan

to o-iodoaniline, thereby giving rise to the tripeptide alkyne 116

and an indole-aniline oxidative coupling product, 117. The

R-carboline present in 117 could presumably arise from direct

formation of the six-membered ring under the standard condi-

tions of aniline-indole coupling (Figure 12).

It was quickly discovered that direct synthesis of the R-carboline

ring would not be feasible (Scheme 12A). For dipeptide 118, the

only discernible product observed was the C2-coupled aniline

isomer 119, which likely arises from the initial oxidative coupling

of aniline at indole C3 and subsequent [1,5] shift to the C2 position

to give the product 119 after tautomerization. This shift is most

likely attributable to the slowed rate of ring-closure for a six-

^aReagents and conditions: (a) o-iodoaniline (1.2 equiv), N-chlorosuc-

cinimide (2.0 equiv), triethylamine (1.2 equiv), MeCN -45 f 4 °C, 2.5 h,

25%; (b) o-iodoaniline (1.2 equiv), N-iodosuccinimide (1.6 equiv for 102b,

1.55 equiv for 102a,c), MeCN, -45 f -35 °C, 2.5 h.

membered ring relative to that for a ﬁve-membered ring. Addition-

ally, the decreased nucleophilicity of the amide in 118 relative to

carbamate functionality is expected to diminish the propensity for

cyclization. This slowed rate rendered the major pathway a steric

decompression via a [1,5] shift of the aniline to the C2 position.

Alternative conditions or substrates did not give the desired

product.⁵⁷

(51) Takeuchi, H.; Takano, K. J. Chem. Soc., Chem. Commun. 1983, 447.

(52) The increased yield for p-iodoaniline to afford 63 (27%) and 47%

recovered 33 with NCS (unoptimized) suggests that substrates can be

optimized when standard conditions fail (Scheme 6).

(53) (a) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998,

63, 7652. (b) Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39,

5355. (c) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113,

6689.

(54) (a) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L.

J. Org. Chem. 2000, 65, 1158. (b) Harris, M. C.; Buchwald, S. L. J.

Org. Chem. 2000, 65, 5327. (c) Altman, R. A.; Anderson, K. W.;

Buchwald, S. L. J. Org. Chem. 2008, 73, 5167. (d) Coste, A.; Toumi,

M.; Wright, K.; Razaﬁmahale´o, V.; Couty, F.; Marrot, J.; Evano, G.

Org. Lett. 2008, 10, 3841.

(55) The methyl carbamate was available in quantitative yield from the

commercial 7-bromotryptamine, whose preparation can be found in

ref 13a. An alternative preparation may be found in the Supporting

Information.

(56) Kapakahi is the Hawaiian word for “twisted”.

9

7132 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

Scheme 13. Preparation of the Tripeptide Fragment 116^a

121 was synthesized and used quickly due to slow decomposi-

tion. Methyl ester hydrolysis of the alkyne and peptide coupling

to H₂N-Ala-Leu-OBn⁶⁶proceeded with high efﬁciency to

provide tripeptide 116.

Larock coupling of 102b with 116 furnished 123 (Scheme

14), which contains the necessary framework to complete

kapakahine F (2). Importantly, the use of Pd(dppf)Cl₂led to a

decrease in reaction time in addition to less depreciation of yield

with increasing scale.^53bDouble deprotection of the Cbz and

benzyl ester in 123 occurred without event, and the macrocyclic

peptide coupling was attempted under standard conditions, but

isomerization of the pyrroloindoline was not observed. Instead,

the structure of the product was ﬁrmly established by HMBC

correlation to be the pyrroloindoline product 124. Alternatively,

coupling of tripeptide 126 to the secondary amine 125 provided

127, which was prepared for a Larock macrocyclization.⁶⁷

However, in this critical step the same undesired macrocyclic

intermediate, 124, was obtained. Obtaining this product provided

an opportunity to investigate the possibility of achieving an

isomerization event, as illustrated in Figure 13.

With a number of relevant substrates in hand, several

approaches for the crucial isomerization of a pyrroloindoline

to an R-carboline were evaluated (Figure 13): (A) initial

isomerization of differentially substituted pyrroloindolines hav-

ing an o-iodoaniline linked at C-3 (128), (B) isomerization with

an indole at C3 in a macrocyclic context (131), and (C)

rearrangement analogous to scenario A with aniline functionality

and where both nitrogens of tryptophan and phenylalanine are

amides (127). All three approaches outlined above were

attempted to give an R-carboline with or without imidazolone

formation. It was believed that formation of an imid-

azolone could act as a point of irreversibility, such that even if

the R-carboline were less favored, kinetic trapping could afford

the desired product.

To commence these studies, treatment of the pyrroloindoline

102a (Scheme 12) with a variety of acidic conditions (TFA,

AcOH, TMSI, SiO₂, etc.) to remove the Boc group and possibly

lead to subsequent rearrangement (Figure 13A) caused extensive

decomposition accompanied by loss of the newly coupled

aniline, analogous to that shown in Scheme 8. Removal of the

Cbz group in 102b, avoiding aryl iodide reduction or loss of

the aniline altogether, proved fruitless (NaBH₄, TMSI,

BF₃·OEt₂, Pd(OAc)₂/Et₃SiH, etc.). The Fmoc removal pro-

ceeded cleanly; however, direct isomerization to the R-carboline

with or without concomitant imidazolone formation was not

observed (BF₃·Et₂O, Sc(OTf)₃, MeOH reﬂux, etc.). Failure to

isomerize these readily obtained intermediates dictated the

necessity of a late-stage isomerization strategy (scenarios B and

C, Figure 13).

^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 f 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 f

23 °C, 10 h, 97% (two steps).

The well-documented challenge⁵⁸of forming R-carboline

systems such as that found in the kapakahines coupled with

our failure to achieve its direct synthesis (Scheme 12A)

prompted the design of a radically different approach (Scheme

12B). We reasoned that it might be possible to achieve the

conversion of the readily accessible pyrroloindoline architecture

(isomer A) into the topologically distinct, yet constitutionally

isomeric, R-carboline system (isomer B). Since these two

isomers might be in a dynamic equilibrium (favoring isomer

A), it would be necessary to achieve an irreversible kinetic trap.

While highly speculative, the powerfully simplifying nature of

this plan was enticing.

Beginning with dipeptide 120, the pyrroloindoline was

obtained by direct coupling with aniline in the absence of base,

which led to an increased rate of reaction (Scheme 11C). This

oxidative coupling tolerates a variety of typical carbamate

protecting groups on the phenylalanine amine (102a-c) and

remains exclusively exo selective (102). The absence of the endo

diastereomer by TLC, LC-MS, and crude ¹H NMR is consistent

with our studies on Boc-Trp-OMe (Vide supra). In line with

previous observations (Scheme 11A), direct formation of the

R-carboline was not observed.

In order to investigate isomerization strategies, the Larock

coupling partner tripeptide 116 was required (Scheme 13). A

route to enantiopure alkyne amino acid 122 was therefore

devised. Several methods were available, including using

Schollko¨pf’s chiral auxiliary^59,60or an asymmetric catalyst in

an alkylation strategy.⁶¹Alternatively, beginning with serine-

derived iodoalanine⁶²121, Knochel’s copper/zinc⁶³coupling to

bromo TES-acetylene⁶⁴provided large amounts of the alkyne

amino acid as a single enantiomer.⁶⁵The copper/zinc-mediated

coupling proved to be reliable on a large scale if the iodoalanine

Thus, several reactions were attempted to convert the pyr-

roloindoline 131 to the R-carboline 132 or 133 (Figure 13B).

Thermal, acidic, and basic conditions were attempted, as well as

(57) Varying the substrate or oxidant led to unproductive oxidation, double

addition, or no reaction at all.

(58) Chaetominine isolation: (a) Jiao, R. H.; Xu, S.; Liu, J. Y.; Ge, H. M.;

Ding, H.; Xu, C.; Zhu, H. L.; Tan, R. X. Org. Lett. 2006, 8, 5709.

Synthesis of chaetominine: (b) Snider, B. B.; Wu, X. Org. Lett. 2007,

9, 4913. (c) Malgesini, B.; Forte, B.; Toumi, M.; Couty, F.; Marrot,

J.; Evano, G. Org. Lett. 2008, 10, 5027. (d) Borghi, D.; Quartieri, F.;

Gennari, C.; Papeo, G. Chem.sEur. J. 2009, 15, 7922. (e) Coste, A.;

Karthikeyan, G.; Couty, F.; Evano, G. Synthesis 2009, 17, 2927.

(59) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl.

1981, 20, 798–799.

(61) Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.

(62) Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599.

(63) Yeh, M. C. P.; Knochel, P. Tetrahedron Lett. 1989, 30, 4799.

(64) Nie, X.; Wang, G. J. Org. Chem. 2006, 71, 4734.

(65) IJsselstijn, M.; Kaiser, J.; van Delft, F. L.; Schoemaker, H. E.; Rutjes,

F. P. J. T. Amino Acids 2003, 24, 263.

(60) (a) Ma, J.; Yin, W.; Zhou, H.; Cook, J. M. Org. Lett. 2007, 9, 3491.

(b) Zhou, H.; Liao, X.; Yin, W.; Ma, J.; Cook, J. M. J. Org. Chem.

2006, 71, 251. (c) Yu, J.; Wearing, X. Z.; Cook, J. M. J. Org. Chem.

2005, 70, 3963. (d) Zhou, H.; Liao, K.; Cook, J. M. Org. Lett. 2004,

6, 249. (e) Liu, X.; Deschamp, J. R.; Cook, J. R. Org. Lett. 2002, 4,

3339. (f) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.; Cook,

J. M. J. Org. Chem. 2001, 55, 4525.

(66) Boggs, N. T.; Bruton, H. D.; Craig, D. H.; Helpern, J. A.; Marsh,

H. C.; Pegram, M. D.; Vandenbergh, D. J.; Koehler, K. A.; Hiskey,

R. G. J. Org. Chem. 1982, 47, 1812.

(67) For the ﬁrst example of a macrocyclic Larock cyclization, see:

Garfunkle, J.; Kimball, F. S.; Kimball, F. S.; Trzupek, J. D.; Takizawa,

S.; Shimamura, H.; Tomishima, M.; Boger, D. L. J. Am. Chem. Soc.

2009, 131, 16036.

9

J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010 7133

A R T I C L E S

Newhouse et al.

Scheme 14. Two Routes to the Pyrroloindoline-Containing Macrocycle 124^a

^aReagents 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%

i

Pd/C (0.20 equiv), H₂, MeOH, 1 h (c) HATU (3.0 equiv), HOBt (2.5 equiv), Pr₂NEt (2.2 equiv), DMF, 6 h, 41% (two 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% (two steps); (e) Pd(OAc)₂(0.34 equiv), NaOAc (6 equiv), LiCl (0.96

equiv), DMF, 100 °C, 12 h, 67%.

Figure 13. Failure to observe isomerization to the desired R-carboline.

the use of various Lewis acids (ZrF₄, Zr(CF₃acac)₄, ZrCl₄, ZrO₂,

ZrBr₄, Zr(Ot-Bu)₄, SiO₂, AlMe₃, AlCl₃, Ti(Oi-Pr)₄, In(OTf)₃,

Zn(OTf)₂, etc.), all to no avail. Attempts to convert the corre-

sponding activated carbonyl of 131 (R ) OH, Cl, OCH₂CF₃,

OC₆F₅) to 133 by an isomerization and imidazolone trap were also

unsuccessful. The ﬁnal approach to test isomerization, scenario C

(Figure 13), was limited by the presence of the aniline functionality,

necessitating relatively mild conditions for substrate manipulation

due to the lability of this functionality (Vida supra). It was believed

that the aniline may impart a different structural bias than the indole

at the C3 position due to steric and electronic factors. Nevertheless,

a variety of conditions failed to provide isomerization to 134 or

imidazolone formation to 135.

With this information in hand, the approach involving

macrocyclization by peptide coupling (123, Scheme 15) was

reinvestigated. After extensive experimentation, it was found

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7134 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

Scheme 15. Successful Isomerization to the Desired R-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).

that EDC/HOAt-mediated macrolactamization in the absence

third mechanistic pathways rely on the well-documented rate

difference for acylation of a primary versus a secondary amine.⁷⁰

The preferential formation of the undesired macrocycle 124

using HATU, HOBt, and Hu¨nig’s base in DMF (Scheme 14,

123 f 124) is not surprising in light of literature on amide bond

formation with secondary amines such as proline.⁷¹Our

optimized conditions, avoiding the use of base and using a

minimal amount of DMF for solubility, result in a reduced rate

of peptide bond formation and are therefore expected to be more

discriminating for a primary amine (137 or 138).

The exceedingly mild conditions utilized to achieve the

topological shift of pyrroloindoline 123 to R-carboline 132 are

remarkable, given the well-documented stability of pyrrolo-

indolines and their widespread occurrence in nature. As alluded

to above, this transform dramatically simpliﬁed the structural

challenge posed by the kapakahines.

Macrocycle 132 was found to decompose slowly if left at

room temperature for extended periods, underscoring the

necessity for mild conditions for its production or manipulation.

Therefore, once the material was isolated, it was immediately

carried forward to the construction of the last ring. The

imidazolone formation was all that remained to synthesize

kapakahine F (2). It was reasoned that once the imidazolone

ring was formed and the Boc group removed, the natural product

2 should be a stable entity. Hydrolysis of the ester proceeded

uneventfully (Scheme 15), but the resulting acid could not be

stored for extended periods and was immediately processed.

Several different conditions were attempted (EDC and HOBt,

HBTU, HATU, etc.) that were successful at ring closure with

typical conversion of 85-100%. However, 5-40% of the

uncoupled acid 139 was regenerated after treatment with TFA,

which was difﬁcult to separate and detrimental to producing

the kapakahines on a large scale. Other conditions to remove

the Boc group were attempted (TMSOTf, TBSOTf, AcOH, etc.);

however, an unacceptable amount of hydrolysis still occurred.

of base⁶⁸afforded the desired carboline macrocycle 132 in 64%

isolated yield along with 6% of the pyrroloindoline 124 (easily

separable by column chromatography).⁶⁹The formation of the

R-carboline-containing macrocycle 132 may proceed through

several mechanisms, three of which are discussed here. The ﬁrst

possibility, which is easily ruled out considering the results in

Figure 13B, is that the pyrroloindoline-containing macrocycle

124 isomerizes to the product 132. Indeed, resubjection of 124

to the reaction conditions did not afford 132, establishing that

the reaction is under kinetic control.

The second possibility involves amide bond formation with

intermediate 137. Macrocyclization of intermediate 137 may

be more favorable than that of 138 due to the greater number

of degrees of freedom in the absence of the R-carboline. Amide

bond formation of intermediate 137 would generate an indole-

nine (not depicted) that would then be engaged by the

phenylalanine amide, rather than the tryptophan amide, provid-

ing the R-carboline 132. For this pathway, it is difﬁcult to

rationalize the selectivity observed on the basis of examination

of the substrate, as both the tryptophan and phenylalanine amides

are sterically and electronically similar. If this pathway does

proceed, the preferential formation of a six-membered ring could

only be the result of subtle conformational effects. Not surpris-

ingly, such imine intermediates are neither isolated nor observed,

as is frequently the case for indolenine species due to their

relative instability.

A third mechanistic postulate would involve ring closure of

137 to afford intermediate 138, which then participates in

macrocyclization. This pathway allows for a clear explanation

for the observed selectivity via a Curtin-Hammett scenario:

an equilibrium between 136 and 138 and rapid amidation of

the primary amine 138 over the secondary amine 136 results in

a predominance of the desired product. Both the second and

(68) Although no base is added, either DMF or trace dimethylamine may

act as a base in this peptide coupling reaction.

(69) Products 124 and 132 had R_fvalues of 0.58 and 0.43, respectively

(4:1 EtOAc/hexanes).

(70) Bodanszky, M.; Bodanszky, A. The Practice of Peptide Synthesis;

Springer-Verlag: Berlin, 1993.

(71) Carpino, L. A.; El-Faham, A. J. Org. Chem. 1994, 59, 695.

9

J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010 7135

A R T I C L E S

Newhouse et al.

Scheme 16. Completion of Kapakahines F (2) and B (3)^a

^aReagents and conditions: (a) LiOH, THF/H₂O/MeOH (40:2:1), 1 h; (b) HATU (4.0 equiv); (c) 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); (e) 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).

It was found that the presence of trace HOBt or other coupling

agents during the Boc removal with TFA was causing an

increase in the amount of hydrolyzed product.

well as HPLC co-injection conﬁrmed the structure of the natural

product and proved that 2 was also correctly synthesized.

Preliminary Biological Evaluation

After several aqueous washes and checking the crude

1

With access to large quantities of these rare natural products

(1-3), biological testing could be undertaken. Synthetic kapa-

kahines B and F did not possess signiﬁcant cytotoxicity in the

NCI 60-cell line. However, kapakahine B had an IC₅₀of 11.7

µM for breast cancer cell line DU4475.⁷³Psychotrimine did

show activity in the NCI screen and was submitted to a ﬁve-

dose GI₅₀study and had a broad spectrum of activity between

1.3 and 40 µM for the 60-cell line⁷⁴(see Supporting Information

for details). In addition to the NCI, large quantities of 1-3 have

been donated to Bristol-Myers Squibb and samples are freely

available from our laboratory on request.

intermediate for coupling agents by LC-MS and H NMR, the

trace impurities isolated together with 133 still caused unac-

ceptable levels of hydrolysis. The only solution was to exclude

nucleophilic peptide-coupling reagents during imidazolone

formation. Thus, treatment with oxalyl chloride and triethyl-

amine led to clean conversion to the imidazolone with starting

1

material absent by H NMR and LC-MS (Scheme 16). Con-

centration of the reaction in Vacuo to drive off excess oxalyl

chloride and several washes with NaHCO₃and NaOH to remove

salts gave large quantities of Boc-kapakahine F (133). Exposure

of Boc-kapakahine F (133) to TFA provided kapakahine F (2)

with excellent efﬁciency and purity (64% isolated yield, three

steps, >1 g synthesized) and without imidazolone hydrolysis

(139). HPLC co-injection of natural and synthetic kapakahine

Conclusion

This full account has traced the inspiration, design, develop-

ment, mechanistic study, and application of a new reaction for

the direct merger of anilines with tryptamines and related

species. This oxidative coupling reaction is believed to proceed

via a nitrenium ion generated from an aniline followed by

nucleophilic capture at C3 of the tryptamine. This powerfully

simplifying reaction has enabled the gram-scale synthesis of

three complex alkaloids: psychotrimine and kapakahines F and

B. It is worth mentioning that this work culminated from an

adherence to a set of guidelines at the outset of the planning

stages of this work.⁷⁵Aside from the invention of the direct

coupling of anilines to tryptamines, notable aspects of the total

1

F co-eluted perfectly; however, the kapakahine F H NMR

spectra obtained did not precisely match the literature spectra.⁷²

The conversion of kapakahine F (2) to kapakahine B (3) was

undertaken to secure our structural assignment. The overall yield

of 2 is 13.1% over 12 steps from serine.

This conversion proved uneventful, and surprisingly the use

of EDC and HOBt followed by Boc deprotection with TFA did

not hydrolyze the imidazolone. The basis for the difference in

stability between 133 and Boc-3 remains elusive. A comparison

of NMR spectra (¹H and ¹³C) for natural and synthetic 3 as

(73) Assays performed by Bristol-Myers Squibb.

(74) Assays performed by the NCI.

(75) (a) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446,

404. (b) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Acc. Chem. Res.

2009, 42, 530. (c) Hendrickson, J. B. J. Am. Chem. Soc. 1975, 97,

5784.

1

(72) For a comparison of synthetic kapakahine F (2) H NMR to that of

the natural source, please see ref 13b. For HMQC, HMBC, and

ROESY NMR data for kapakahine F (2), please see the Supporting

Information.

9

7136 J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010

Total Syntheses of Psychotrimine and Kapakahines B and F

A R T I C L E S

1-3 and to Yoichi Nakao for providing HPLC samples of 2 and

3. Drs. D. H. Huang and L. Pasternack are acknowledged for NMR

spectroscopic assistance, particularly with the direct injection

experiments. Drs. Arnold L. Rheingold and Antonio DiPasquale

are thanked for X-ray crystallographic analysis. Funding for this

work was provided by the NIH/NCI (CA134785), the Skaggs

Institute for Chemical Biology, Bristol-Myers Squibb (unrestricted

grant and graduate fellowship to T.N.), and the Canadian Institutes

of Health Research (postdoctoral fellowship to C.A.L.).

syntheses of the 1-3 include (1) absence of protecting group

chemistry and excellent redox economy in the synthesis of 1,

(2) chemoselective indole arylation using a Buchwald-Goldberg-

Ullmann reaction (109 f 107), (3) chemoselective Larock

indole syntheses in highly complex settings (98 f 107, 101f

109, 102b f 123, 127 f 124), and (4) a remarkable late-stage

architectural shift from a pyrroloindoline to an R-carboline ring

system (123 f132).⁷⁶

Acknowledgment. Dedicated to Prof. Albert Eschenmoser on

the occasion of his 85th birthday. We are grateful to the NCI and

Bristol-Myers Squibb (Dr. Percy Carter) for biological testing of

Supporting Information Available: Detailed experimental

procedures, copies of all spectral data, and full characterization

(PDF, CIF). This material is available free of charge via the

Internet at http://pubs.acs.org.

(76) During the review of this manuscript, a synthesis of kapakahine F

was reported that proceeded in 19 linear steps and 6.8% overall yield

(23 mg produced) from tryptophan: Espejo, V. R.; Rainier, J. D. Org.

Lett. 2010, 12, DOI: 10.1021/ol100672z (published ASAP online Mar

26, 2010).

JA1009458

9

J. AM. CHEM. SOC. VOL. 132, NO. 20, 2010 7137

Article Doi

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

DOI: 10.1021/ja1009458

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Article abstract of DOI:10.1021/ja1009458

Full text of DOI:10.1021/ja1009458

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