Thiourea-catalyzed enantioselective iso-pictet-spengler reactions

Article abstract of DOI:10.1021/ol202300t

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-prot

Full text of DOI:10.1021/ol202300t

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5564–5567
Thiourea-Catalyzed Enantioselective
Iso-PictetÀSpengler Reactions
Yunmi Lee, Rebekka S. Klausen, and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street,
Cambridge, Massachusetts 02138, United States
jacobsen@chemistry.harvard.edu
Received August 24, 2011
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-γ-carboline derivatives in a scalable and highly practical procedure.
Natural and synthetic compounds containing the tetra-
hydro-β-carboline heterocyclic framework are endowed
with an extraordinary range of important biological activi-
ties.1 The closely related tetrahydro-γ-carboline framework
is unknown in natural product structures but holds con-
siderable potential as a template for drug discovery.2 In
contrast to the rich assortment of known synthetic routes
to chiral tetrahydro-β-carboline derivatives,3,4 few meth-
ods have been identified for the direct preparation of
optically enriched tetrahydro-γ-carbolines. Reported stra-
tegies to the latter class of compounds include classical
resolution,5 diastereoselective cyclization of chiral, sub-
stituted precursors,6 and Pd-catalyzed enantioselective
intramolecular allylic alkylation.7 We describe here a
straightforward and direct route to enantiomerically en-
riched 4-substituted tetrahydro-γ-carbolines through an
enantioselective, catalytic “iso-PictetÀSpengler reaction”,
the one-pot condensation/cyclization of 2-substituted
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Drug Discovery Dev. 2010, 13, 669–684.
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Y. U.; Sablin, S.; Zefirov, N. Ann. N.Y. Acad. Sci. 2001, 939, 425–435.
(3) For reviews of PictetÀSpengler 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 tetrahy-
dro-β-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. (i)
Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753–819.
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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)
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J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485–7487. (d)
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B. J. Am. Chem. Soc. 2006, 128, 1086–1087. (f) Taylor, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 2004, 126, 10558–10559.
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r
10.1021/ol202300t
Published on Web 09/15/2011
2011 American Chemical Society

indolylethylamines (isotryptamines) and aldehydes
(Scheme 1).8
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).
Scheme 1. Synthesis of Tetrahydro-β-carbolines and Proposed
Route to Tetrahydro-γ-carbolines Cocatalyzed by Chiral
Thioureas and BzOH
Table 1. Optimization of the Enantioselective Iso-PictetÀ-
Spengler Reaction
BzOH
yield
(%)a
ee
(%)b
entry aldehyde thiourea (mol %) product
1
2
3
4
5
3m
3m
3n
3n
3n
1
20
20
20
10
10
4am
4am
4an
4an
4an
ndc
95
98
97
97
66
79
89
91
95
5a
5a
5a
5b
Our approach drew directly on the recent discovery that
the combination of chiral thioureas and carboxylic acid
derivatives can serve as a highly effective cocatalyst system
for enantioselective one-pot PictetÀSpengler reactions of
tryptamines and aldehydes (Scheme 1).4a Under the con-
ditions optimized for that reaction (thiourea 1/benzoic
acid, 20 mol %), the model iso-PictetÀSpengler reaction
between unsubstituted isotryptamine 2a and 4-chloroben-
zaldehyde 3m was found to proceed efficiently to the
desired tetrahydro-γ-carboline 4am (>98% conversion
within 1 h), 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 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 be a particular concern with iso-PictetÀSpengler
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
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 cocatalyzed iso-PictetÀSpen-
gler reaction was applied successfully to a variety of
isotryptamineÀaldehyde combinations, as illustrated in
Table 2. In particular, high enantioselectivities were ob-
tained in the cyclization of sterically demanding aliphatic
or aromatic aldehydes with both electron-rich and -defi-
cient isotryptamine derivatives using thiourea 5b (entries
2À18). In contrast, aldehydes lacking branching at the R-
position proved less effective as substrates (entry 1, and
discussion below).
Any variability in the enantioselectivity of the thiourea-
catalyzed iso-PictetÀSpengler reaction proved to be of
only minor consequence, however, thanks to the identifi-
cation of a remarkably straightforward protocol for up-
grading 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 up-
graded to >99% ee in nearly all cases by direct crystal-
lization or trituration.11 This allowed use of reduced
loadings of the less enantioselective but commercially
ꢀ
(8) For the racemic variant, see: Molina, P.; Alcantara, J.; Lopez-
ꢀ
Leonardo, 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.
(10) In the absence of thiourea, 20 mol % BzOH catalyzes the iso-
PictetÀSpengler reaction of 2a with 3n to 30% conversion in 0.5 h.
(11) The absolute configuration of the products was assigned by
X-ray crystallographic analysis of compound 6ax. See Supporting
Information for details.
Org. Lett., Vol. 13, No. 20, 2011
5565

Table 2. Substrate Scope of the Thiourea-/BzOH-Cocatalyzed
Enantioselective Iso-PictetÀSpengler Reaction Catalyzed by 5b
Table 3. One-Pot Method for the Preparation of Optically Pure
Tetrahydro-γ-carboline Derivatives
isotryp-
isotryp-
aldehyde
(R)
time
ee
(%)a
yield
(%)b
tamine
(X)
aldehyde
(R)
BzOH time
yield ee
entry
(mol %) (h) product (%)a (%)b
entry tamine
(h) product
1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2g
2d
2b
2d
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
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
>99 (61)
>99 (74)
>99 (88)
99 (91)
45
55
81
65
79
52
64
63
56
77
78
77
78
67
81
66
74
1
2
3
4
5
2a (H)
3o (i-Bu)
3p (c-Hex)
3q (CH(Et)2)
3r (t-Bu)
3s
20
20
20
20
20
1
4ao
4ap
4aq
4ar
4as
96
96
97
79
91
95
2
2a
2a
2a
2a
1
3
3
7 d
1
83c 87
4
5
>99 (90)
>99 (70)
>99 (74)
>99 (76)
>99 (75)
>99 (86)
>99 (88)
>99 (89)
98 (85)
99
92
6
(o-MeC6H4)
3t (1-naph)
3n
7
6
7
8
9
2a
20
10
10
10
10
10
10
20
20
20
20
20
20
2
1
1
1
1
1
1
1
1
1
5
2
1
4at
96
98
97
96
94
95
97
98
93
99
96
96
93
86
94
94
94
94
95
95
91
93
90
93
88
91
8
2b (5-F)
2c (6-F)
4bn
4cn
4dn
4en
4fn
4gn
4dp
4fp
9
3n
10
11
12
13
14
15
16
17
2d (5-MeO) 3n
6bn
6cn
6dn
6gn
6dp
6bs
6ds
10 2e (6-MeO) 3n
11 2f (5-Me) 3n
12 2g (5-vinyl) 3n
3n
3n
3nc
>99 (92)
>99 (92)
>99 (79)
99 (87)
13 2d
14 2f
15 2b
16 2c
17 2b
18 2d
3p
3p
3p
3q
3s
3s
3p
3s
4bp
4cq
4bs
4ds
3s
a Determined by HPLC analysis. Numbers in parentheses corre-
spond to the ee of 6 before trituration or recrystallization. For details on
the trituration or recrystallization procedures, see the Supporting In-
formation. b Isolated yield of product with upgraded ee. c 20 mol % 5a
used.
a Isolated yield after purification. b Determined by HPLC analysis of
the N-Boc derivative. c 90% conversion.
available catalyst 5a12 and extension of the method to
substrates that undergo reaction with only moderate in-
trinsic enantioselectivity, such as unhindered aliphatic
(entries 1À2) and aromatic (entries 6À9) aldehydes. This
one-pot synthetic procedure for preparing enantiopure N-
Boc tetrahydro-γ-carboline derivatives required no chro-
matographic purification steps and should be readily
adaptable to preparative scale.
Scheme 2. Enantioselective Iso-PictetÀSpengler Reaction of 2a
and Ketone 7
Ketone substrates were also applied successfully to the
iso-PictetÀSpengler protocol. As depicted in Scheme 2, the
ketoimine generated in situ from 2a and ketone 7 under-
went 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.
Tetrahydro-β-carboline derivatives are the common
biosynthetic precursors of the monoterpenoid indole alka-
loid natural product family, which includes rearranged
examples such as morphine.13 We explored whether the
tetrahydro-γ-carboline framework might undergo analo-
gous transformations into structurally and stereochemi-
cally 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-γ-carboline 6ao with
NBS under acidic conditions, optically active spiro indoxyl
10 was isolated in 48% yield (Scheme 3).16 Oxidative
(14) (a) Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 7904–
7905. (b) Takayama, H.; Ishikawa, H.; Kurihara, M.; Kitajima, M.;
Aimi, N.; Ponglux, D.; Koyama, F.; Matsumoto, K.; Moriyama, T.;
Yamamoto, L. T.; Watanabe, K.; Murayama, T.; Horie, S. J. Med.
Chem. 2002, 45, 1949–1956. (c) Williams, R. M. Chem. Pharm. Bull.
2002, 50, 711–740.
(15) Badillo, J. J.; Hanhan, N. V.; Franz, A. K. Curr. Opin. Drug
Discovery Dev. 2010, 13, 758–776.
(16) (a) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003–3025.
(b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219.
(12) Strem Chemicals, Newburyport, MA, USA.
(13) O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532–547.
5566
Org. Lett., Vol. 13, No. 20, 2011

thiourea and BzOH. Optically pure products (98%
to >99% ee) were obtained through a one-pot protocol
of condensation, enantioselective cyclization, and Boc-
protection, followed by trituration or recrystallization.
The application of this methodology to new alkaloid-like
scaffolds such as 10 is the subject of ongoing investigation.
Scheme 3. Synthesis of Spiro Indoxyl Derivative 10
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 deter-
mination.
rearrangement product 10 features contiguous nitrogen-
bearing stereogenic centers, one of which is fully sub-
stituted.
In summary, we have developed an efficient method for
the catalytic enantioselective synthesis of 4-substituted
tetrahydro-γ-carbolines using a readily available chiral
Supporting Information Available. Experimental pro-
cedures and characterization data for products and X-ray
crystallographic data for 6ax and 10. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 13, No. 20, 2011
5567