Catalytic asymmetric Pictet-Spengler reactions via sulfenyliminium ions

Article abstract of DOI:10.1002/anie.200701808

(Chemical Equation Presented) From cations to chiral products: β-Carbo-lines can be synthesized with good enantioselectivity by the title reaction catalyzed by a chiral binol-derived Bronsted acid (see scheme, BHT = 3,5-di(tert-butyl)-4-hydroxytoluene). T

Full text of DOI:10.1002/anie.200701808

Angewandte
Chemie
DOI: 10.1002/anie.200701808
Organocatalysis
Catalytic Asymmetric Pictet–Spengler Reactions via Sulfenyliminium
Ions**
Martin J. Wanner, Richard N. S. van der Haas, Kimberly R. de Cuba, Jan H. van Maarseveen,
and Henk Hiemstra*
The Pictet–Spengler condensation of tryptamine (or a sub-
stituted analogue) with an aldehyde, usually in the presence of
an excess of a Brønsted acid,[1] is the reaction of choice for the
preparation of tetrahydro-b-carbolines (for example, 1), a
structural moiety present in many alkaloids and related
biologically active molecules.[2]
harsh reductive conditions. Lower selectivity is observed with
the second method, but the diastereomers are readily
separable, and the sulfinyl auxiliary can be cleaved easily by
mild hydrolysis.
The first example of a reagent-controlled enantioselective
Pictet–Spengler-type cyclization was reported by Nakagawa
and co-workers.[5] They described the ring closure of nitrone 4
with up to 90% ee under the influence of a chiral borane
(ca. 2 equiv) as a Lewis acid. Two examples of catalytic
asymmetric Pictet–Spengler reactions have been reported
recently: Taylor and Jacobsen described the cyclization of the
N-acyliminium ion 5 with up to 95% ee under the catalysis of
an enantiomerically pure thiourea,[6a] and List and co-workers
disclosed the cyclization of the iminium diester 6 with up to
96% ee under the catalysis of an enantiomerically pure
phosphoric acid derived from binaphthol.[6b] Although both
methods are impressive examples of the power of asymmetric
organocatalysis, the former has the disadvantage that the N-
acetyl group is difficult to remove, and the latter is clearly
limited in scope by the requirement of two ester function-
alities.
Several strategies have been applied to the synthesis of
tetrahydro-b-carbolines in enantiomerically pure form. It is
possible to start with an enantiomerically pure chiral trypt-
amine, such as a tryptophan derivative, or aldehyde; alter-
natively, the use of a chiral auxiliary attached to the nitrogen
atom has been successful. Two remarkable examples are the
cyclization of the N-acyliminium ion 2, in which an a-N,N-
Within our research program on the development of
asymmetric reactions of iminium ions catalyzed by chiral
Brønsted acids, we considered the use of N-sulfenyliminium
ions as intermediates in the Pictet–Spengler condensation.[7]
The sulfenyl substituent was expected to stabilize the
intermediate iminium ion and thus favor Pictet–Spengler
cyclization over undesired enamine formation.[8] Another
advantage of the sulfenyl group is that its ready removal after
the cyclization is ensured. Herein, we demonstrate the
powerful combination of chiral phosphoric acids and N-
sulfenyl tryptamines as a useful method for catalytic asym-
metric Pictet–Spengler reactions.
The use of phosphoric acids derived from binaphthol as
chiral catalysts in asymmetric synthesis was shown recently by
two Japanese research groups to be highly successful for the
addition of carbon-centered nucleophiles to prochiral imi-
nium intermediates.[9,10] We set out to use such chiral acids as
catalysts for the generation in situ and cyclization of N-
sulfenyliminium ions derived from tryptamine.
phthaloylamino acid is used as a chiral auxiliary,[3] and the
cyclization of the N-sulfinyliminium ion 3, with the use of
menthyl p-toluenesulfinate as a chiral reagent.[4] The former
procedure proceeds with very high diastereoselectivity, but
the chiral auxiliary can be removed only under relatively
[*] M. J. Wanner, Dr. R. N. S. van der Haas, K. R. de Cuba,
Dr. J. H. van Maarseveen, Prof. Dr. H. Hiemstra
Van’t Hoff Institute for Molecular Sciences
University of Amsterdam
The Pictet–Spengler precursors 7 and 8 were prepared
readily by the treatment of tryptamine with the appropriate
commercially available sulfenyl chlorides in the presence of a
base. When the N-(o-nitrophenyl)sulfenyltryptamine 7 was
Nieuwe Achtergracht 129, 1018 WS Amsterdam (The Netherlands)
Fax: (+31)20-525-5670
E-mail: hiemstra@science.uva.nl
[**] This research was supported financially by the National Research
School Combination Catalysis (NRSC-C). We thank R. Z. Boerleider
and P. Hauwert for their help in the synthesis of the catalysts.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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stirred with n-hexanal (1.5 equiv) in chloroform in the
presence of the (R)-binaphthylphosphoric acid 9a (2 mol%)
lower temperatures had only a marginal effect on the
enantioselectivity of the reaction. Importantly, the addition
of powdered 3-Š molecular sieves to remove the water
released during the formation of the iminium salt led to an
improvement in both the yield and the enantioselectivity. The
chiral Brønsted acids 9a–g were screened under these
optimized conditions. The best result was again obtained
with catalyst 9d, in the presence of which 11 was formed with
a satisfactory 88% ee (Table 1).
To avoid the isolation of the labile N-tritylsulfenyl product
11, a one-pot procedure for the synthesis of the tetrahydro-b-
carboline 1a was developed. Thus, the molecular sieves were
removed by filtration after the completion of the reaction.
First thiophenol (1.2 equiv) and then HCl (4 equiv) in
dioxane (4m) were added to the filtrate, and the resulting
mixture was stirred overnight to give the hydrochloride salt of
the pure tetrahydro-b-carboline as a precipitate. This salt was
collected by filtration and then neutralized to provide pure 1a
in 87% yield and with 84% ee (Table 2). Comparison of the
sign of the specific rotation of the product with literature
at room temperature, the tetrahydro-b-carboline 10 was
obtained (Table 1). The reaction was attempted with a
range of chiral phosphoric acid catalysts, 9b–9g. In all cases
excellent yields were observed (92–98%), which underscores
the power of N-sulfenyliminiums to facilitate Pictet–Spengler
reactions. However, the enantioselectivities for the cycliza-
tion step were still unsatisfactory: In the best case, the use of
catalyst 9d led to 10 with a modest 31% ee.
Table 2: Scope of the reaction with respect to the aldehyde substrate.[a]
Product
R
t [h]
Yield [%][b]
87
ee [%][c]
Table 1: Screening of catalysts for the asymmetric Pictet–Spengler
reaction.
1a
2
84
1b
24
77
78
1c
1
88
81
30
72
Catalyst
Substrate 7[a]
10: ee [%]
Substrate 8[b]
11: ee [%]
t [h][c]
t [h][c]
1d[d]
24
9a
9b
9c
9d
9e
9 f
9g
1
1
42
1
56
56
56
5
12
22
31
15
4
1
4
42
2
42
20
42
À8
41
34
88
45
74
33
1e
1 f
0.5
4
88
90
76
87
26
1g[d]
1h[d]
24
24
77
78
82
82
[a] Reaction conditions:
7 (0.10 mmol), n-hexanal (1.5 equiv), 9
(2 mol%), chloroform (1.0 mL), room temperature. [b] Reaction con-
ditions: 8 (0.10 mmol), n-hexanal (3.0 equiv), 9 (5 mol%), BHT (5 mg),
3-Š MS (150 mg), toluene (1.0 mL), 08C. [c] The reaction was continued
until >95% conversion. MS=molecular sieves.
[a] Reaction conditions:
8 (0.10 mmol), aldehyde (3.0 equiv), 9d
(5 mol%), BHT (5 mg), powdered 3-Š MS (150 mg), toluene (1 mL).
[b] Yield of the isolated product after two steps. [c] Determined by
1H NMR spectroscopy with (R)-1-(9-anthryl)-2,2,2-trifluoroethanol.[11] [d]
9d: 10 mol%.
We then turned our attention to the bulkier N-tritylsul-
fenyl-substituted tryptamine substrate 8. The Pictet–Spengler
reaction of 8 with n-hexanal required careful optimization.
The N-tritylsulfenyltetrahydro-b-carboline 11 appeared to be
rather unstable, possibly as a result of homolytic cleavage of
the trityl–sulfur bond. The addition of 3,5-di(tert-butyl)-4-
hydroxytoluene (BHT) to the reaction mixture as a radical
scavenger prevented the problems associated with the
decomposition of the product. Further improvements
included a solvent change from chloroform to toluene and a
lowering of the reaction temperature to 08C. The use of even
data[3] indicated that (S)-1a was formed as the major
enantiomer when (R)-9d was used as the catalyst.
Next, the scope of the reaction with respect to the
aldehyde substrate was investigated. Fast reactions with fair
enantioselectivities occurred with a-unbranched aldehydes,
except in the case of acetaldehyde (Table 2). The best result
was obtained with phenylacetaldehyde, the reaction of which
led to the b-carboline 1 f in 90% yield and with 87% ee. The
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Bhattacharjee, T. M. John, D. Haynes-Johnson, S. Lundeen, Z.
aromatic aldehydes tested reacted more slowly; nevertheless,
the corresponding products 1g and 1h were furnished in
satisfactory yields and with satisfactory ee values.
As an indication of the scalability of the procedure, 1a was
formed with the same ee value of 84% and in comparable
yield when the reaction was carried out on a 3-g scale. When
the catalyst loading was lowered to 1.0 mol%, the Pictet–
Spengler reaction still gave 1a with 84% ee, but took 18 h to
reach completion.
In conclusion, an efficient catalytic asymmetric synthesis
of tetrahydro-b-carbolines[12] has been developed on the basis
of the Pictet–Spengler condensation of N-sulfenyltryptamines
with a wide range of aldehydes. The ease of both the
introduction of the sulfenyl substituent and its acid-mediated
removal make this method attractive. Present studies are
directed towards the improvement of the enantioselectivity of
the reaction by further fine-tuning of the sulfenyl substituent
and chiral phosphoric acid catalyst.
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[7] The use of N-sulfenyl substituents as protecting groups is known
in peptide synthesis; see a) L. Zervas, D. Borovas, E. Gazis,
J. Am. Chem. Soc. 1963, 85, 3660 – 3666; for reviews on
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Chem. Rev. 1989, 89, 689 – 712; d) I. V. Koval, Russ. Chem. Rev.
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[8] List and co-workers showed that the treatment of tryptamine
with propionaldehyde and substoichiometric trifluoroacetic acid
leads to the formation of aldol-condensation products (see
Ref. [6b]).
Received: April 24, 2007
Published online: August 14, 2007
[9] a) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126, 5356 –
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Keywords: asymmetric catalysis · chiral phosphoric acids ·
enantioselectivity · Pictet–Spengler reaction · sulfenamides
.
[10] For recent reviews on catalysis by chiral Brønsted acids, see
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b) T. Akiyama, J. Itoh, K. Fuchibe, Adv. Synth. Catal. 2006, 348,
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118, 1550 – 1573; Angew. Chem. Int. Ed. 2006, 45, 1520 – 1543.
[11] a) M. S. C. Pedras, M. Hossain, M. G. Sarwar, S. Montaut,
Bioorg. Med. Chem. Lett. 2004, 14, 5469 – 5471; b) W. H.
Pirkle, D. J. Hoover, Top. Stereochem. 1982, 13, 263 – 331.
[12] The extension of this method with N-sulfenyliminium ions to
isoquinoline synthesis is presently under investigation.
[1] a) A. Pictet, T. Spengler, Ber. Dtsch. Chem. Ges. 1911, 44, 2030 –
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Kaufmann in New Methods in the Asymmetric Synthesis of
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Trivandrum, India, 2005, chap. 4, pp. 99 – 147.
[2] For recent literature on biologically active tetrahydro-b-carbo-
lines, see a) K. Gudmundsson, WO 2007002051, 2007; b) W.
Jiang, J. Guan, M. J. Macielag, S. Zhang, Y. Qiu, P. Kraft, S.
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