Thiourea-Catalyzed Enantioselective Iso-Pictet– Spengler Reactions
Yunmi Lee, Rebekka S. Klausen, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138 jacobsen@chemistry.harvard.edu
Received Date (will be automatically inserted after manuscript is accepted)

ABSTRACT

A one-pot condensation of isotryptamines and aldehydes that affords enantiomerically enriched 4-substituted tetrahydro-γ-carbolines is reported. The reaction is induced by a chiral thiourea/benzoic acid dual catalyst system. Purification of the N-Boc-protected products by trituration or crystallization provides the optically pure tetrahydro-γcarboline derivatives in a scalable and highly practical procedure.

Natural and synthetic compounds containing the tetrahydro-β-carboline heterocyclic framework are endowed with an extraordinary range of important biological activities. 1 The closely related tetrahydro-γcarboline framework is unknown in natural product structures, but also holds considerable potential as a template for drug discovery. 2 In contrast to the rich
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assortment of known synthetic routes to chiral tetrahydroβ-carboline derivatives, 3 , 4 few methods have been indentified for the direct preparation of optically enriched tetrahydro-γ-carbolines. Reported strategies to the latter

(3) For reviews of Pictet−Spengler reactions, see: (a) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797−1842. (b) Lorenz, M.; van Linn, M. L.; Cook, J. M. Curr. Org. Synth. 2010, 7, 189−223. (c) Stockigt, J.; Antonchick, A. P.; Wu, F.; Waldmann, H. Angew. Chem. Int. Ed. 2011, 50, 8538−8564. For reductive approaches to enantioenriched tetrahydroβ-carbolines, see: (d) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5, 4301−4304. (e) Martin, S. F. Acc. Chem. Res. 2002, 35, 895−904. (f) Li, C.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 13208−13209. (g) Evanno, L.; Ormala, J.; Pihko, P. M. Chem. Eur. J. 2009, 15, 12963−12969. (h) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori. R. J. Am. Chem. Soc. 1996, 118, 4916−4917. (h) Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753−819. (4) For catalytic enantioselective Pictet−Spengler reactions, see: (a) Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2009, 11, 887−890. (b) Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder, R.; van Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405−6408. (c) Wanner, M. J.; vad der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem. Int. Ed. 2007, 46, 7485−7487. (d) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am, Chem. Soc. 2007, 129, 13404−13405. (e) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086−1087. (f) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 10558−10559.

class of compounds include classical resolution, 5 diastereoselective cyclization of chiral, substituted precursors, 6 and Pd-catalyzed enantioselective intramolecular allylic alkylation. 7 We describe here a straightforward and direct route to enantiomerically enriched 4-substituted tetrahydro-γ-carbolines through an enantioselective, catalytic “iso-Pictet Spengler reaction”, the one-pot condensation/cyclization of 2-substituted indolylethylamines (isotryptamines) and aldehydes (Scheme 1).8

Scheme 1. Synthesis of tetrahydro-β-carbolines and proposed route to tetrahydro-γ-carbolines co-catalyzed by chiral thioureas and BzOH

be more effective, affording 4am in 79% ee (entry 2). Substantially higher enantioselectivity was observed in the reaction of 2a and isobutyraldehyde 3n (89% ee). In all cases, it was found that the thiourea needed to be present at a concentration equal to or greater than that of the achiral carboxylic acid in order to prevent diminished enantioselectivities due to an acid-catalyzed racemic background reaction.10 This proved to a particular concern with iso-Pictet–Spengler reactions with aliphatic aldehydes, which may contain detectable levels of the corresponding aliphatic acids as received from commercial suppliers. Accordingly, for some aliphatic substrates, it was found that reducing the loading of BzOH led to measurable improvements in product ee (e.g., 91% ee vs. 89% ee for 4an, entries 3 and 4). Further optimization of the thiourea catalyst structure revealed that the highly sterically demanding derivative 5b bearing the 3,5-dimethylbenzhydryl group on the amide component afforded tetrahydro-γ-carboline 4an in 97% yield and 95% ee (entry 5).

Table 1. Optimization Pictet Spengler Reaction

of

the

Enantioselective

Iso-

Our approach drew directly on the recent discovery that the combination of chiral thioureas and carboxylic acid derivatives can serve as a highly effective co-catalyst system for enantioselective one-pot Pictet Spengler reactions of tryptamines and aldehydes (Scheme 1). 4a Under the conditions optimized for that reaction (thiourea 1/benzoic acid, 20 mol%), the model iso-Pictet–Spengler reaction between unsubstituted isotryptamine 2a and 4chlorobenzaldehyde 3m was found to proceed efficiently to the desired tetrahydro-γ-carboline 4am (>98% conversion within 1 h), and with 66% ee (entry 1, Table 1). Chiral thiourea 5a, which was identified previously as an effective catalyst for Strecker reactions,9 was found to
(5) Vecchietti, V; Clarke, G. D.; Colle, R.; Giardina, G.; Petrone, G.; Sbacchi, M. J. Med. Chem. 1991, 34, 2624−2633. (6) Sheng, Y-F.; Li, G-Q.; Kang, Q.; Zhang, A-J.; You, S-L. Chem. Eur. J. 2009, 15, 3351−3354. (7) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424−1425. (8) For the racemic variant, see: Molina, P.; Alcántara, J.; LópezLeonardo, C. Tetrahedron 1996, 52, 5833−5844. (9) (a) Zuend, S. J.; Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. Nature 2009, 461, 968−971. (b) Zuend, S. J.; Jacobsen, E. N. J. Am. Chem. Soc. 2009, 131, 15358−15374.

BzOH entry aldehyde thiourea (mol %)

product

yield (%)a

ee (%)b

1 3m 1 20 4am ndc 66 2 3m 5a 20 4am 95 79 3 3n 5a 20 4an 98 89 4 3n 5a 10 4an 97 91 5 3n 5b 10 4an 97 95 a Isolated yield after purification; >98% conversion in all cases. b Determined by HPLC analysis of the N-Boc derivative. c nd = not determined.

The thiourea/benzoic acid co-catalyzed isoPictet Spengler reaction was applied successfully to a variety of isotryptamine-aldehyde combinations, as illustrated in Table 2. In particular, high enantioselectivities were obtained in the cyclization of sterically demanding aliphatic or aromatic aldehydes with both electron-rich and electron deficient isotryptamine derivatives using thiourea 5b (entries 2-18). In contrast, aldehydes lacking branching at the α position proved less effective as substrates (entry 1, and discussion below).
(10) In the absence of thiourea, 20 mol % BzOH catalyzes isoPictet−Spengler reaction of 2a with 3n to 30% conversion in 0.5 h.

required no chromatographic purification steps and should be readily adaptable to preparative scale.
Table 2. Substrate Scope of the Thiourea-/BzOH-Co-Catalyzed Enantioselective Iso-Pictet Spengler Reaction Catalyzed by 5b Table 3. One-Pot Method for the Preparation of Optically Pure Tetrahydro-γ-Carboline Derivatives

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

isotryptamine (X) 2a (H) 2a 2a 2a 2a 2a 2b (5-F) 2c (6-F) 2d (5-MeO) 2e (6-MeO) 2f (5-Me) 2g (5-vinyl) 2d 2f 2b 2c 2b 2d

aldehyde (R) 3o (i-Bu) 3p (c-Hex) 3q (CH(Et)2) 3r (t-Bu) 3s (o-MeC6H4) 3t (1-naph) 3n 3n 3n 3n 3n 3n 3p 3p 3p 3q 3s 3s

BzOH time yield ee (mol %) (h) product (%)a (%)b 20 20 20 20 20 20 10 10 10 10 10 10 20 20 20 20 20 20 1 1 3 7d 1 2 1 1 1 1 1 1 1 1 1 5 2 1 4ao 4ap 4aq 4ar 4as 4at 4bn 4cn 4dn 4en 4fn 4gn 4dp 4fp 4bp 4cq 4bs 4ds 96 96 97 83c 99 96 98 97 96 94 95 97 98 93 99 96 96 93 79 91 95 87 92 86 94 94 94 94 95 95 91 93 90 93 88 91 entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 isotryptamine 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2c 2d 2g 2d 2b 2d aldehyde (R) 3u (n-pent) 3o (i-Bu)c 3n (i-Pr) 3p (c-Hex)c 3q (CH(Et)2) 3v (C6H5) 3w (p-FC6H4) 3m (p-ClC6H4) 3x (p-BrC6H4) 3s (o-MeC6H4 3n 3n 3n 3n c 3p 3s 3s time (h) product 1 1 1 1 5 1 1 1 1 2 1 1 1 1 1 2 2 6au 6ao 6an 6ap 6aq 6av 6aw 6am 6ax 6as 6bn 6cn 6dn 6gn 6dp 6bs 6ds ee (%)a >99 (61) >99 (74) >99 (88) 99 (91) >99 (90) >99 (70) >99 (74) >99 (76) >99 (75) >99 (86) >99 (88) >99 (89) 98 (85) >99 (92) >99 (92) >99 (79) 99 (87) yield (%)b 45 55 81 65 79 52 64 63 56 77 78 77 78 67 81 66 74

a Isolated yield after purification. b Determined by HPLC analysis of the N-Boc derivative. c 90% conversion.

a Determined by HPLC analysis. Numbers in parentheses correspond to the ee of 6 before trituration or recrystallization. For details on the trituration or recrystallization procedures, see the Supporting Information. b Isolated yield of product with upgraded ee. c 20 mol % 5a used.

Any variability in the enantioselectivity of the thioureacatalyzed iso-Pictet–Spengler reaction proved to be of only minor consequence, however, thanks to the identification of a remarkably straightforward protocol for upgrading the ee of the tetrahydro-γ-carboline products. As illustrated in Table 3, the crude products of the cyclization reaction were subjected to reaction with Boc2O at ambient temperature, and the enantiomeric composition of the resulting N-Boc tetrahydro-γ-carboline 6 could be upgraded to >99% ee in nearly all cases by direct crystallization or trituration. 11 This allowed use of reduced loadings of the less enantioselective but commercially available catalyst 5a,12 and extension of the method to substrates that undergo reaction with only moderate intrinsic enantioselectivity, such as unhindered aliphatic (entries 1-2) and aromatic (entries 6-9) aldehydes. This one-pot synthetic procedure for preparing enantiopure N-Boc tetrahydro-γ-carboline derivatives

Ketone substrates were also applied successfully to the iso-Pictet Spengler protocol. As depicted in Scheme 2, the ketoimine generated in situ from 2a and ketone 7 underwent enantioselective cyclization in the presence of 5a and benzoic acid to afford the tetrahydro-γ-carboline 8 in 95% yield and 76% ee. After N-Boc protection and trituration, 9 was isolated in 98% ee.

Scheme 2. Enantioselective Iso-Pictet Spengler Reaction of 2a and Ketone 7

(11) The absolute configuration of the products was assigned by Xray crystallographic analysis of compound 6ax. See Supporting Information for details. (12) Strem Chemicals, Newburyport, MA, USA.

Tetrahydro-β-carboline derivatives are the common biosynthetic precursors of the monoterpenoid indole alkaloid natural product family, which includes rearranged examples such as morphine. 13 We explored whether the tetrahydro-γ-carboline framework might undergo analogous transformations into structurally and stereochemically complex alkaloid scaffolds. In particular, we targeted the synthesis of a spirocyclic oxindole, a frequently observed structural motif in biologically active compounds. 14,15 Through the treatment of tetrahydro-γcarboline 6ao with NBS under acidic conditions, optically active spiro indoxyl 10 was isolated in 48% yield (Scheme 3).16 Oxidative rearrangement product 10 features contiguous nitrogen-bearing stereogenic centers, one of which is fully substituted.

Scheme 3. Synthesis of Spiro Indoxyl Derivative 10

In summary, we have developed an efficient method for the catalytic enantioselective synthesis of 4-substituted tetrahydro-γ-carbolines using a readily available chiral thiourea and BzOH. Optically pure products (98% to >99% ee) were obtained through a one-pot protocol of condensation, enantioselective cyclization, and Bocprotection, followed by trituration or recrystallization. The application of this methodology to new alkaloid-like scaffolds such as 10 is the subject of ongoing investigation. Acknowledgment. This work was supported by the NIGMS (PO1 GM-69721). We thank Dr. Shao-Liang Zheng for the X-ray data collection and structural determination. Supporting Information Available: Experimental procedures and characterization data for products and Xray crystallographic data of 6ax and 10. This material is available free of charge via the Internet at http://pubs.acs.org.

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