Enantioselective, thiourea-catalyzed intermolecular addition of indoles to cyclic N-acyl iminium ions

Full text of DOI:10.1002/anie.200902420

Communications
DOI: 10.1002/anie.200902420
Organocatalysis
Enantioselective, Thiourea-Catalyzed Intermolecular Addition of
Indoles to Cyclic N-Acyl Iminium Ions**
Emily A. Peterson and Eric N. Jacobsen*
The discovery that chiral hydrogen-bond donors effectively
Table 1: Catalyst optimization studies.[a]
promote highly enantioselective reactions of cationic inter-
mediates has opened a new direction within the field of
organocatalysis.[1,2] For example, the development of thio-
urea-catalyzed enantioselective acyl-Pictet–Spengler-type
cyclizations has helped bring N-acyl iminium ions into the
realm of viable substrates for asymmetric catalysis.[2a–d,f,3] The
harnessing of N-acyl iminium ions for the enantioselective
intermolecular addition of indoles [e.g., Eq. (1)] would enable
Entry Catalyst R1
R2
R3
R4
R5
ee [%]
1
2
3
4
5
6
7
8
9
3
–
Me
H
Me
Me
Me
Me
Me
–
–
–
–
À14
55
35
13
21
40
23
65
75
80
89
93
4a
4b
4c
4d
4e
4 f
4g
4h
4i
H
H
H
H
H
H
H
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Me
SiEt3 tBu
SiEt3 tBu
SiEt3 tBu
tBu
tBu
NO2
OTIPS
Cl
tBu
Me Me (S)
Me Me (R) tBu
Me Me (R) CH2Ph SiEt3 tBu
10
11
12
4j
5
direct access to functionalized indole frameworks with
established biological activity[4] and also provide useful
precursors to more complex alkaloid natural product tar-
gets.[5] Intermolecular asymmetric catalytic addition reactions
of indoles to acyclic imines have been reported.[6] In most
cases, the electrophilic partners have been limited to sub-
stituted benzaldehyde derivatives, although Deng and co-
workers also identified successful reactions with a variety of
acyclic aliphatic imines.[6c] Herein we report highly enantio-
selective intermolecular additions of indoles to hydroxylac-
tam-derived cyclic N-acyl iminium ions under the catalysis of
a new thiourea Schiff base derivative.
[a] Bn=benzyl, TIPS=triisopropylsilyl, TMS=trimethylsilyl.
We selected as a model reaction the addition of indole to
the succinimide-derived hydroxylactam 1, a bench-stable,
storable compound that was prepared readily and could be
handled without difficulty.[7] A variety of thiourea and urea
catalyst frameworks were evaluated as potential catalysts
under conditions similar to those developed for the related
intramolecular acyl-Pictet–Spengler cyclization (Table 1).[2c]
A promising lead result was obtained in the reaction
promoted by Schiff base 4a[8] in tert-butylmethyl ether
(TBME) at À308C, with adduct 2a generated with 55% ee
and in 30% yield (Table 1, entry 2). No background reactivity
was observed under these conditions in the absence of a
catalyst. Interestingly, pyrrole derivative 3, the optimal
catalyst identified for the intramolecular acyl-Pictet–Spengler
reaction,[2c] afforded the opposite enantiomer with low
enantioselectivity (Table 1, entry 1).
Systematic variation of the catalyst structure around the
basic framework of 4 led to substantial improvements in
reaction enantioselectivity (Table 1). Diaminocyclohexane-
derived catalysts containing different Schiff base, amide, and
amino acid side-chain components were examined. The
primary amine resulting from hydrolysis of Schiff base 4a
[*] Dr. E. A. Peterson, Prof. Dr. E. N. Jacobsen
Department of Chemistry and Chemical Biology
Harvard University
12 Oxford Street, Cambridge, MA 02138 (USA)
Fax: (+1)617-496-1880
E-mail: jacobsen@chemistry.harvard.edu
[**] This research was supported by the NIH NIGMS (PO1 GM-69721)
and by an NIH NRSA grant to E.A.P.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902420.
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Chemie
was found to be catalytically active, but afforded the racemic
product. Thus, we recognized that it would be essential to
maintain the integrity of the Schiff base throughout the
reaction to observe high enantioselectivity. After extensive
experimentation, it was found that catalyst 4g, in which R4 is a
triethylsilyl group and R5 is a tert-butyl group, promoted the
formation of 2a with slightly higher enantioselectivity than
that observed with catalyst 4a (65 versus 55% ee).
No reaction was observed in the absence of TMSCl or
another acidic additive, and the comparison of different TMS-
X reagents revealed that the chloride counteranion was
uniquely effective for the promotion of high enantioselectiv-
ity.[13,14] The use of BCl3 as an additive in place of TMSCl led
to complete substrate conversion after only 8 hours, albeit
with slightly diminished enantioselectivity (91 versus
93% ee).
The introduction of a stereochemical element at the
benzylic position of the amide led to a further improvement in
enantioselectivity: the catalyst 4i, in which R2 is a methyl
group and the adjacent stereogenic center has the R configu-
ration, provided 2a with 80% ee (Table 1, entry 10). Whereas
the majority of effective thiourea catalysts identified to date
contain a tert-leucine backbone (R3 = tBu),[9] catalyst 4j
derived from phenylalanine proved substantially more enan-
tioselective than the tert-leucine analogue 4i (89 versus
80% ee; Table 1, entry 11). Finally, the constraint of the
chiral amide component in a cyclic framework, as in catalyst
5, led to additional improvement in enantioselectivity, with
the generation of 2a with 93% ee (Table 1, entry 12).[10–12]
Despite the high enantioselectivity observed with catalyst
5, the efficiency of product formation with hydroxylactam 1
was quite modest (30–40% conversion with 10 mol% cata-
lyst). This low conversion was attributable, at least in part, to
the poor solubility of 1 under the reaction conditions;
therefore, several derivatives of the hydroxylactam substrate
were prepared with the aim of discovering a more suitable N-
acyl iminium ion precursor. The acetyl derivative 6a,
prepared by acylation of 1, displayed improved solubility
and underwent conversion into 2a with 93% ee and in 71%
yield (Table 2).
The presence of controlled amounts of added water in the
TMSCl-promoted reactions also had a pronounced beneficial
effect on reactivity.[15] The best results were obtained when
the reaction was carried out with catalyst 5 (5 mol%), TMSCl
(2 equiv), and water (8 mol%) in anhydrous TBME at À308C
for 24 hours. Under these conditions, adduct 2 was generated
reproducibly with 93% ee and isolated in 84% yield. The
synergistic effect of TMSCl and catalytic H2O[16] suggests that
acetoxylactam 6 reacts with HCl generated in situ to form
chlorolactam 7, and that this equilibrium is driven by trapping
of the acetic acid by-product with TMSCl.[17] We propose that
the racemic chlorolactam 7 is the actual substrate in the
alkylation, and that the reaction proceeds through an SN1-
type anion-binding mechanism analogous to that proposed
for related thiourea-catalyzed acyl-Pictet–Spengler and oxo-
carbenium-ion-alkylation reactions (Scheme 1).[2c–e]
Table 2: Alkylation of electron-rich indole substrates.[a]
Entry
R
6
t [h]
Product
Yield [%][b]
ee [%]
1[c]
2
3
4
5
6
7
8
9
H
H
6a
6c
6a
6a
6a
6a
6d
6b
6b
6b
6b
6b
24
24
24
24
24
24
48
48
48
48
48
48
2a
2b
2c
2d
2e
2 f
2g
2h
2i
90
93
86
79
82
80
60
70
86
93
92
76
93 (99)[d]
86
4-Me
5-Me
5-CH CH2
6-OMe
H
H
5-OMe
5-Me
95
90 (91)[d]
Scheme 1. Proposed catalytic cycle.
=
90
80 (98)[d]
92
93
90
94
91
88
Having developed a reliable protocol, we investigated the
scope of the reaction. Under the optimized conditions, a
variety of electron-rich indoles underwent addition to both
succinimide- and glutarimide-derived electrophiles with high
enantioselectivity (Table 2).[18] Consistent results were
obtained upon a ten-fold increase in the scale of the reaction
(Table 2, entry 1). In several cases, we found that the
enantiomeric enrichment of the products could be increased
simply by trituration.[19]
10
11
12
2j
2k
2l
=
5-CH CH2
6-OMe
[a] Unless noted otherwise, reactions were carried out on a 0.3 mmol
scale. [b] Yield after chromatographic purification. [c] The reaction was
carried out on a 3 mmol scale. [d] The ee value of the product after
purification by trituration with Et2O is given in parentheses.
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the BCl3 protocol for electron-deficient indoles, are provided as
Supporting Information.
Encouraged by the scope of the addition with electron-
rich indoles, we also examined electron-deficient indoles.
Under the optimized conditions with TMSCl, these substrates
were converted into the corresponding adducts with high
enantioselectivity, but in low yield. In contrast, for halogen-
ated indole substrates, the use of BCl3 (10 mol%) in the
presence of 5 (10 mol%) led to the formation of products
2m–2u in useful yields and with high enantioselectivity
(Table 3).
Received: May 6, 2009
Published online: July 16, 2009
Keywords: N-acyl iminium ions · anion binding ·
.
asymmetric catalysis · indoles · thioureas
[1] For recent general reviews of chiral H-bond catalysts, see:
a) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550 –
1573; Angew. Chem. Int. Ed. 2006, 45, 1520 – 1543; b) A. G.
Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107, 5713 – 5743.
[2] a) M. S. Taylor, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126,
10558 – 10559; b) M. S. Taylor, N. Tokunaga, E. N. Jacobsen,
Angew. Chem. 2005, 117, 6858 – 6862; Angew. Chem. Int. Ed.
2005, 44, 6700 – 6704; c) I. T. Raheem, P. S. Thiara, E. A.
Peterson, E. N. Jacobsen, J. Am. Chem. Soc. 2007, 129, 13404 –
13405; d) I. T. Raheem, P. S. Thiara, E. N. Jacobsen, Org. Lett.
2008, 10, 1577 – 1580; e) S. E. Reisman, A. G. Doyle, E. N.
Jacobsen, J. Am. Chem. Soc. 2008, 130, 7198 – 7199; f) P. C. Pan,
B. List, Chem. Asian J. 2008, 3, 430 – 437; g) for a review of
anion-binding thiourea organocatalysis, see: Z. Zhang, P. R.
Schreiner, Chem. Soc. Rev. 2009, 38, 1187 – 1198.
[3] For seminal applications of N-acyl iminium ions in aluminum-
catalyzed Reissert reactions, see: a) M. Takamura, K. Funabashi,
M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2000, 122, 6327 –
6328; b) M. Takamura, K. Funabashi, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2001, 123, 6801 – 6808; c) K. Funabashi, H.
Ratni, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2001, 123,
10784 – 10785; d) E. Ichikawa, M. Suzuki, K. Yabu, M. Albert,
M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2004, 126, 11808 –
11809.
Table 3: Alkylation of electron-deficient indoles.
Entry
R
n
t [days]
Product
Yield [%][a]
ee [%]
1
2
3
4
5
6
7
8
9
4-F
4-Br
5-F
5-Br
6-F
6-Cl
4-Br
6-F
1
1
1
1
1
1
2
2
2
1.5
5
2
5
3
4
5
3
5
2m
2n
2o
2p
2q
2r
2s
2t
2u
57
47
87
80
75
81
12
75
40
96 (99)[b]
97
94
93
96
96
85
96
92
6-Cl
[a] Yield of the isolated product. [b] The ee value of the product after
purification by trituration from Et2O is given in parentheses.
In summary, we have developed a highly enantioselective
addition of indoles to cyclic N-acyl iminium ions with a chiral
thiourea Schiff base catalyst. Both electron-rich and electron-
poor indole nucleophiles can be used as substrates. The
products are synthetically useful intermediates that can be
elaborated readily: for example, cleavage of the benzyl
protecting group with Na/NH3 proceeds without erosion of
enantiomeric excess.[19] Efforts to apply anion-binding prin-
ciples to other reactions involving cationic intermediates are
underway.
[4] I. R. Baldwin, P. Bamborough, J. A. Christopher, J. K. Kerns, T.
Longstaff, D. D. Miller, WO 2005067923A1.
[5] a) B. Atta-ur-Rahman, Indole Alkaloids, Harwood Academic,
Chichester, 1998; b) M. Amat, S. Hadida, N. Llor, S. Sathyanar-
ayana, J. Bosch, J. Org. Chem. 1996, 61, 3878 – 3882; c) S.
Shimizu, K. Ohori, T. Arai, H. Sasai, M. Shibasaki, J. Org. Chem.
1998, 63, 7547 – 7551.
[6] a) M. Johannsen, Chem. Commun. 1999, 2233 – 2234; b) Y. X.
Jia, J. H. Xie, H. F. Duan, L. X. Wang, Q. L. Zhou, Org. Lett.
2006, 8, 1621 – 1624; c) Y. Q. Wang, J. Song, R. Hong, L. H.
Deng, J. Am. Chem. Soc. 2006, 128, 8156 – 8157; d) G. B.
Rowland, E. B. Rowland, Y. Liang, J. A. Perman, J. C. Antilla,
Org. Lett. 2007, 9, 2609 – 2611; e) Y.-X. Jia, J. Zhong, S.-F. Zhu,
C.-M. Zhang, Q.-L. Zhou, Angew. Chem. 2007, 119, 5661 – 5663;
Angew. Chem. Int. Ed. 2007, 46, 5565 – 5567; f) Q. Kang, Z.-A.
Zhao, S.-L. You, J. Am. Chem. Soc. 2007, 129, 1484 – 1485; g) M.
Terada, S. Yokoyama, K. Sorimachi, D. Uraguchi, Adv. Synth.
Catal. 2007, 349, 1863 – 1867; h) Q. Kang, X.-J. Zheng, S.-L. You,
Chem. Eur. J. 2008, 14, 3539 – 3542.
[7] J. C. Hubert, J. B. P. A. Wunberg, W. N. Speckamp, Tetrahedron
1975, 31, 1437 – 1441.
[8] A. G. Wenzel, E. N. Jacobsen, J. Am. Chem. Soc. 2002, 124,
12964 – 12965.
[9] For important exceptions, see: a) Y.-Q. Fang, E. N. Jacobsen, J.
Am. Chem. Soc. 2008, 130, 5660 – 5661; b) R. S. Klausen, E. N.
Jacobsen, Org. Lett. 2009, 11, 887 – 890.
[10] For an efficient asymmetric synthesis of 2-phenylpyrrolidines,
see: K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer, C.
Chen, J. Am. Chem. Soc. 2006, 128, 3538 – 3539.
Experimental Section
The indole (0.040 g, 0.343 mmol) and catalyst 5 (0.012 g, 0.017 mmol)
were placed in a 10 mL flame-dried round-bottomed flask, which was
then sealed with a rubber septum. The flask was flushed with N2, and
anhydrous TBME (1.6 mL) was added. The resulting yellow solution
was cooled to À788C, and a solution of acetoxylactam 6a in TBME
(0.65 mL, 0.34 mmol, 0.53m) was added. Next, solutions in TBME of
TMSCl (0.43 mL, 0.69 mmol, 1.6m) and H2O (0.20 mL, 0.03 mmol,
0.14m) were added sequentially, and the mixture was warmed to
À308C and stirred for 24 h. The heterogeneous reaction mixture was
quenched by the addition of a solution of NaOEt in EtOH (0.2 mL,
21 wt%), followed by the immediate addition of water (1 mL). The
mixture was allowed to warm to room temperature and was diluted
with EtOAc until all solids had dissolved (the amount of EtOAc
added (ca. 5–10 mL) depends on the product). The layers were
separated, and the organic layer was dried (Na2SO4) and concentrated
in vacuo. Purification procedures for individual products, as well as
[11] The diastereomer of catalyst 5, prepared from (R)-2-phenyl-
pyrrolidinone, d-phenylalanine, and (S),(S)-diaminocyclohex-
ane provided product 2 with À79% ee.
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[12] Thiourea catalysts derived from 2-aryl pyrrolidines were also
applied successfully to enantioselective alkylation reactions of
oxocarbenium ions; see reference [2e].
[13] Adduct 2 was obtained with 26% ee when TMSBr was used with
catalyst 4a, and as a racemate when TMSI was used.
[14] It has been established previously that thioureas interact much
more strongly with chloride than with bromide or iodide: a) S.
Kondo, M. Nagamine, Y. Tano, Tetrahedron Lett. 2003, 44, 8801 –
8804; b) S. Kondo, M. Sato, Tetrahedron 2006, 62, 4844 – 4850.
[15] Very poor reactivity was observed under strictly anhydrous
conditions. Elevated levels of added water (> 20 mol%) led to
diminished enantioselectivity.
[17] The conversion of 6a into chlorolactam 7 was established and
monitored by 1H NMR spectroscopy. Spectra (1H and 13C NMR)
of 7 and of related compounds are provided in the Supporting
Information.
[18] The absolute configuration of addition products was determined
by single-crystal X-ray analysis of the addition product 2s
(Table 3); the configuration of all other products was assigned by
analogy. CCDC 736017 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[16] Reactions carried out with HCl alone proceeded with compa-
rable enantioselectivity but were substantially slower.
[19] See the Supporting Information for complete details.
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