Weak Brønsted Acid–Thiourea Co-Catalysis: Enantioselective, Catalytic Protio-Pictet–Spengler Reactions

Abstract

The development of one-pot imine formation and asymmetric Pictet–Spengler reactions co-catalyzed by a chiral thiourea and benzoic acid is described. Optically active tetrahydro-β-carbolines, ubiquitous structural motifs in biologically active natural products, are obtained in high ee directly from tryptamine and aldehyde precursors.

The Pictet–Spengler reaction is an important biosynthetic and laboratory method for the synthesis of tetrahydroisoquinolines and tetrahydro-β-carbolines, structural motifs in a diverse array of biologically active natural and unnatural products.^{1, 2} Whereas synthetically valuable diastereoselective Pictet–Spengler reactions are well known,³ catalytic, enantioselective variants have only recently been developed.⁴ Chiral Lewis acids have not proven to be generally useful for the Pictet–Spengler reaction, a likely result of catalyst inhibition by the Lewis basic product.⁵ Greater success has been achieved with Brønsted acid or hydrogen bond-donor catalysts, albeit with specialized substrates.⁶ Thus, asymmetric catalysis of Pictet–Spengler-type reactions has been reported with N-acyliminium ions^4a or N-sulfenyliminium ions,^4b or with substrates biased towards cyclization and against competing aldol pathways by gem-disubstitution adjacent to the reactive imine.^4c An enantioselective, catalytic Pictet–Spengler protocol with broad substrate scope that affords unprotected tetrahydro-β-carboline products directly from simple tryptamine derivatives would represent a significant advance.

We have recently advanced a mechanistic model for asymmetric catalysis by thiourea derivatives in which substrate activation takes place via thiourea-mediated chloride abstraction to generate highly reactive N-acyliminium ions or oxocarbenium ions (Figure 1).⁷ This hypothesis suggests that a variety of other cationic intermediates, including protioiminium ions, could be activated towards enantioselective addition by analogous anion-binding mechanisms. In particular, we envisaged a catalytic cycle in which imine protonation is induced by a thiourea catalyst associated via H-bonding to the conjugate base of a weak Brønsted acid additive (Scheme 1).⁸ Cyclization of the highly reactive protioiminium ion followed by rearomatization would regenerate the Brønsted acid co-catalyst. Herein, we report that chiral thiourea derivatives in combination with benzoic acid promote catalytic asymmetric Pictet–Spengler reactions of electronically and sterically diverse imines, providing unprotected tetrahydro-β-carbolines in high ee and yield.

Figure 1.

Generation of N-acyliminium ion via anion-binding by a thiourea catalyst.

Scheme 1.

Brønsted acid and H-bond donor co-catalysis

We selected 6-methoxytryptamine derivative 2a as a model substrate. Methoxy-substituted tryptamine derivatives undergo cyclization in low enantioselectivity in the previously reported acyl-Pictet–Spengler reaction,⁹ a significant limitation given the prevalence of methoxyand hydroxy-substituted tetrahydro-β-carbolines in natural products.¹⁰ Moreover, elevated temperatures (> −30 °C) were required for acyl-Pictet–Spengler reactions of aryl imines, conditions under which the thiourea catalyst was subject to decomposition via rapid S-acetylation. We reasoned that greater generality in the imine component would be possible in a non-acylative reaction. Imine 2a was screened against a variety of representative thiourea catalysts¹¹ and achiral Brønsted acids. In combination with acetic acid (AcOH), catalysts 4a¹² and 7a¹³ provided tetrahydro-β-carboline 3a in high yield and 85% and −87% ee, respectively (Scheme 2). Notably, no product was observed in the absence of AcOH.

Scheme 2.

Screen of representative (thio)urea catalysts.

Yield determined by ¹H NMR on a 0.05 mmol scale. Enantioselectivity determined by chiral SFC analysis of the N-Boc derivative.

These initial results were obtained at room temperature, conditions under which imine formation is rapid. We therefore explored an operationally simpler protocol involving one-pot imine formation and thiourea-catalyzed Pictet–Spengler reaction. Treatment of tryptamine 9a and p-chlorobenzaldehyde with catalyst 4a in toluene provided product 3a in 88% ee and 54% yield (Table 1, entry 1). In contrast, sulfinamide 7a was a poor catalyst under in situ imine formation conditions, providing product in only 13% yield. A systematic evaluation of the influence of catalyst structure on both enantioselectivity and rate revealed that valine-derived catalyst 4b afforded optimal results (entry 2).¹⁴ This simple compound is prepared in 69% yield in three steps from commercially available N-methylbenzylamine and either (D)- or (L)-valine; only a single chromatographic purification is required. A screen of carboxylic acids revealed an increase in both enantioselectivity and rate with benzoic acid (PhCO₂H) (entry 2 vs. 4).¹⁵ Under the in situ imine-formation conditions, highest yields and enantioselectivities were obtained in reactions carried out at lower concentration (entries 4–6).

Table 1.

Optimization studies of the one-pot Pictet–Spengler reaction.

entry	catalyst	RCO2H	[9a]	yield (%)a	ee (%)b
1	4a	AcOH	0.05 M	54	88
2	4b	AcOH	0.05 M	48	92
3	7a	AcOH	0.05 M	13	−79
4	4b	PhCO2H	0.05 M	74	94
5	4b	PhCO2H	0.10 M	60	93
6	4b	PhCO2H	0.20 M	39	92

^aYield determined by ¹H NMR spectroscopy on a 0.05 mmol scale.

^bDetermined by chiral SFC analysis of the N-Boc derivative.

A variety of substituted benzaldehyde derivatives proved to be suitable substrates in combination with 9a, providing tetrahydro-β-carboline products 3a–3g in good-to-excellent ee's and yields (Table 2, entries 1–7). Substitution is tolerated at all ring positions of the aldehyde, with the shortest reaction times observed for ortho- and meta-substituted derivatives (entries 3–5). Less electron-rich tryptamines 9b and 9c also participated effectively in the condensation/cyclization reaction (89–99% ee), although elevated acid loadings and temperatures and extended reaction times were required to achieve useful product yields (entries 8–10).

Table 2.

Substrate scope of the thiourea and benzoic acid catalyzed Pictet–Spengler reaction.

entry	tryptamine	Ra	product	PhCO2H (mol%)	t (h)	yield (%)b	ee (%)c
1	9a	p-ClC6H4	3a	20	66	78	94
2	9a	p-FC6H4	3b	20	78	81	92
3	9a	p-BrC6H4	3c	20	74	79	94
4	9a	m-BrC6H4	3d	20	19	87	94
5	9a	o-BrC6H4	3e	20	11	74	95
6	9a	p-MeOC6H4	3f	20	91	78	85
7	9a	Ph	3g	20	70	94	86
8d	9b	p-ClC6H4	3h	40	14 d	73	89
9d	9b	o-BrC6H4	3i	40	87	82	99
10d	9c	o-BrC6H4	3j	100	10 d	45	95
11	9a	i-Pr	3k	20	4	60e	88
12	9a	i-Pr	3k	–	88	90	94
13	9a	CH(Et)2	3l	–	5 d	84	95
14	9a	n-pentyl	3m	–	18	74	86
15d	9b	i-Pr	3n	20	36	39	88

^aAll aldehydes were purified immediately prior to use. See the Supporting Information for details.

^bIsolated yield after column chromatography for 0.50 mmol-scale reactions, unless noted otherwise.

^cDetermined by chiral SFC analysis of the N-Boc derivative.

^dReaction carried out at 35 °C.

^eYield determined by ¹H NMR spectroscopy on a 0.05 mmol scale.

Aliphatic aldehydes displayed unexpected reactivity with tryptamine 9a in protio-Pictet–Spengler cyclizations catalyzed by 4b. Isobutyraldehyde underwent rapid reaction under the conditions optimized for aromatic aldehydes, affording product 3k in 60% conversion and 88% ee after 4 hours at room temperature (entry 11). In contrast to aryl substrates, however, cyclization was also observed in the absence of PhCO₂H. In fact, the enantioselectivity increased to 94% in the absence of acid additive, although much longer reaction times were required (entry 12). Both linear and α-branched aldehydes participated effectively in cyclizations with 9a (entries 12–14). In contrast, less nucleophilic tryptamines such as 9b and 9c were unreactive under neutral conditions. The basis for this intriguing difference in reactivity is not well understood at this stage. For substrates such as 9b, use of acidic additive was necessary (e.g., entry 15), with reactions proceeding in high ee and in modest yield due to the competitive aldol pathways.

We have identified a readily accessible chiral thiourea catalyst that promotes highly enantioselective Pictet–Spengler reactions for electronically and structurally diverse substrates under mild and operationally simple conditions. This method provides unprotected tetrahydro-β-carbolines in one step from tryptamine and aldehyde derivatives. Our current efforts are directed toward elucidation of the mechanism of co-catalysis by achiral Brønsted acids, and application of this principle to other enantioselective reactions of synthetic interest.