Direct and highly enantioselective iso-Pictet-Spengler reactions with α-ketoamides: Access to underexplored indole core structures

Article abstract of DOI:10.1021/ol300922b

Direct, one-pot, operationally simple, and highly enantioselective iso-Pictet-Spengler reactions are reported. The reactions involve the condensation of either (1H-indol-4-yl)methanamine or 2-(1H-Indol-1-yl)ethanamine with a variety of α-ketoamides, follo

Full text of DOI:10.1021/ol300922b

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2610–2613
Direct and Highly Enantioselective
Iso-PictetÀSpengler Reactions with
r-Ketoamides: Access to Underexplored
Indole Core Structures
€
Heike Schonherr and James L. Leighton*
Department of Chemistry, Columbia University, New York, New York 10027,
United States
leighton@chem.columbia.edu
Received April 10, 2012
ABSTRACT
Direct, one-pot, operationally simple, and highly enantioselective iso-PictetÀSpengler reactions are reported. The reactions involve the
condensation of either (1H-indol-4-yl)methanamine or 2-(1H-Indol-1-yl)ethanamine with a variety of r-ketoamides, followed by the addition of a
simple and commercially available chiral silicon Lewis acid. These reactions are the first asymmetric examples of these cyclization modes and
provide access to 3,3-disubstituted-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolines and 1,1-disubstituted-1,2,3,4-tetrahydropyrazino[1,2-a]-
indoles, respectively, two relatively underexplored indole-based core structure motifs in medicinal chemistry.
The indole version1 of the venerable PictetÀSpengler
reaction2 providesaccesstotetrahydro-β-carbolines, and it
is only recently that significant progress has been made
toward the development of enantioselective variants.3
Most notably, Jacobsen and co-workers have developed
a suite of asymmetric PictetÀSpengler reactions based on
the extraordinary and elegant concept of anion binding by
chiral thiourea catalysts.4 Despite these truly conceptually
pioneering advances, however, the asymmetric PictetÀ
Spengler reaction remains an at least partly, if not largely,
unsolved problem if success is defined as the ability to take
an unmodified tryptamine (directness), react it with any
aldehyde or ketone (scope) under operationally simple,
inexpensive, and otherwise practical reaction conditions
(practicality), and isolate the product in good yield and in
highly enantiomerically enriched form (generality and
applicability in complex settings). Such attributes are far
more directly correlated with widespread adoption of a
given asymmetric method than is, for example, the amount
of chiral inducer employed.5
(1) Tatsui, G. J. Pharm. Soc. Jpn. 1928, 48, 92.
(2) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
(b) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797. (c) Youn, S. W.
Org. Prep. Proced. Int. 2006, 38, 505.
(3) (a) Yamada, H.; Kawate, T.; Matsumizu, M.; Nishida, A.;
Yamaguchi, K.; Nakagawa, M. J. Org. Chem. 1998, 63, 6348. (b)
Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128, 1086.
(c) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van
Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46,
7485. (d) Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder,
R.; van Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405. (e)
Duce, S.; Pesciaioli, F.; Gramigna, L.; Bernardi, L.; Mazzanti, A.; Ricci,
A.; Bartoli, G.; Bencivenni, G. Adv. Synth. Catal. 2011, 353, 860. (f)
To that end, we reported in 2009 a direct asymmetric
PictetÀSpengler reaction with unmodified tryptamines
and R-ketoamides promoted by (S,S)-1,6 a simple, versatile,
and commercially available silicon Lewis acid7 (Figure 1a).
ꢀ
Badillo, J. J.; Silva-Garcia, A.; Shupe, B. H.; Fettinger, J. C.; Franz,
(5) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
A. K. Tetrahedron Lett. 2011, 52, 5550.
110, 3600.
(6) Bou-Hamdan, F. R.; Leighton, J. L. Angew. Chem., Int. Ed. 2009,
48, 2403.
(4) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N.
J. Am. Chem. Soc. 2007, 129, 13404. (c) Klausen, R. S.; Jacobsen, E. N.
Org. Lett. 2009, 11, 887.
(7) Leighton, J. L. Aldrichimica Acta 2010, 43, 3.
r
10.1021/ol300922b
Published on Web 04/27/2012
2012 American Chemical Society

This method remains the only general way to access a
variety of 1,1-disubstituted tetrahydro-β-carbolines8,9 in a
highly enantioselective fashion and at the same time is also
one of the only direct and one of the more practical
asymmetric PictetÀSpengler reactions reported to date.
Given that we had in hand an operationally simple and
practical method that can uniquely provide access to
potentially valuable products, we decided to investigate
whether the success of our method could be extended to
indole-based core structures other than tetrahydro-β-car-
bolines. Here too, Jacobsen has provided the seminal
contribution in the form of what was termed an “iso-
PictetÀSpengler reaction” that provides the first and only
enantioselective method to access tetrahydro-γ-carbolines.10
This is not the only possible iso-PictetÀSpengler reaction,
however, as at least two other variants, those employ-
ing amines 2 and 3, may be imagined (Figure 1b and c).
The only precedent at all for any asymmetric version
of either of these two cyclization modes is a very recent
report describing an enzymatic reaction between 3 and
secologanin.11 Because the hypothetical products of these
reactions might therefore represent potentially interesting
yet underexplored indole core structure space in medicinal
chemistry terms, we decided to examine whether our
asymmetric PictetÀSpengler methodology would be ap-
plicable in these contexts.
optimization of both efficiency and enantioselectivity and
2,6-difluorophenyl had proven to be one of the more
effective aryl groups in this regard (Scheme 1). Gratify-
ingly, we quickly found that the reaction was indeed
feasible and provided the desired product 6a with generally
high levels of enantioselectivity (g90% ee) depending on
solvent and reaction temperature. However, these explora-
tory reactions, which involved isolation of the imine 5a
prior to the cyclization step, were also characterized by
variable and generally low overall yields, a problem we
attributed to the instability of the imine 5a. We therefore
turned our attention to the development of a one-pot
procedure, and this proved straightforward and effective.
Thus, simply heating 2 and 4a in refluxing benzene with a
DeanÀStark trap and then adding silane 1 led to the
isolation of 6a in 63% yield and 92% ee.
Scheme 1. Development of a One-Pot Enantioselective Iso-
PictetÀSpengler Reaction with Amine 2 and R-Ketoamide 4a
The one-pot procedure proved generally effective for a
range of R-ketoamides as illustrated by the results de-
scribed in Table 1. Both aromatic (entries 1À3) and
aliphatic ketones (entries 4À8) generally reacted with
excellent levels of enantioselectivity, while the aliphatic
ketones generally provided higher yields. The only outlier
in terms of enantioselectivity was the 3-pyridyl ketone 4c
(entry 3), but this was not completely unexpected as we have
had prior indications that Lewis basic groups can interfere
with the smooth operation of the silane Lewis acid.13
(8) One of the Jacobsen variants (see ref 4b) and the Bernardi and
Bencivenni method (see ref 3e) allow the preparation of a limited set of
1,1-disubstituted tetrahydro-β-carbolines. Our claim to a greater degree
of generality is based upon both the fact that R (see Figure 1a) can be a
wide variety of both alkyl and aryl groups and the fact that the
carboxamide moiety may be readily converted into a variety of other
substituents.
(9) Maruoka has reported a non-PictetÀSpengler approach to the
enantioselective preparation of 1,1-disubstituted tetrahydro-β-carbo-
lines. See:Shirakawa, S.; Liu, K.; Ito, H.; Maruoka, K. Chem. Commun.
2011, 47, 1515.
Figure 1. (a) Enantioselective PictetÀSpengler reactions with
tryptamine and R-ketoamides. (b) A proposed iso-PictetÀSpen-
gler reaction to access 3,3-disubstituted-1,3,4,5-tetrahydropyr-
rolo[4,3,2-de]isoquinolines. (c) A proposed iso-PictetÀSpengler
reaction to access 1,1-disubstituted-1,2,3,4-tetrahydropyrazino-
[1,2-a]indoles.
(10) Lee, Y.; Klausen, R. S.; Jacobsen, E. N. Org. Lett. 2011, 13,
5564.
(11) Wu, F.; Zhu, H.; Sun, L.; Rajendran, C.; Wang, M.; Ren, X.;
€
Panjikar, S.; Cherkasov, A.; Zou, H.; Stockigt, J. J. Am. Chem. Soc.
2012, 134, 1498.
(12) Robaa, D.; Enzensperger, C.; Abul Azm, S. D.; El Khawass,
Our investigations began with (1H-indol-4-yl)metha-
namine 212 and R-ketoamide 4a (Ar = 2,6-diflourophenyl),
as prior experience alerted us to the fact that the choice of
the aryl group on the amide was critical to the successful
E. S.; El Sayed, O.; Lehmann, J. J. Med. Chem. 2010, 53, 2646.
Org. Lett., Vol. 14, No. 10, 2012
2611

Despite this reduced enantioselectivity, the reaction still
facilitates access to the product 6c with useful levels of
enantioselectivity, and it is likely that, should the need
arise, the enantiopurity of the product could be increased
by recrystallization.
the reaction described in Scheme 2 was an outlier (Table 2).
Thus, a variety of both aliphatic and aromatic ketones
generally provided good to excellent yields and enantios-
electivities (entries 1À7). It was also demonstrated in this
series that the corresponding 5-bromo derivative of 3
provided good results with 4d (entry 8), albeit with a drop
in reaction efficiency relative to that of entry 4.
Table 1. Scope of the Iso-PictetÀSpengler Reaction of 2 with
R-Ketoamides 4 Promoted by (S,S)-1
Table 2. Scope of the Iso-PictetÀSpengler Reaction with 2-(1H-
Indol-1-yl)ethanamine 3 and R-Ketoamides Promoted by (S,S)-1
entry R-ketoamide (R) time (h) product yield (%)a ee (%)b
entry R-ketoamide (R) time (h) product yield (%)a ee (%)b
1
2
3
4
5
6
7
8
4a (Ph)
24
24
24
8
6a
6b
6c
6d
6e
6f
63
67
66
83
86
87
77
70
92
96
82
98
98
98
94
90
4b (p-BrC6H4)
4c (3-pyridyl)
4d (n-Pr)
1
2
3
4
5
6
7
8c
4a (Ph)
30
30
30
8
7a
7b
7c
7d
7f
55
70
60
89
90
57
89
65
90
88
86
92
92
96
90
90
4b (p-BrC6H4)
4c (3-pyridyl)
4d (n-Pr)
4e (n-Hex)
4f (i-Bu)
10
8
4f (i-Bu)
10
24
5
4g (i-Pr)
24
24
6g
6h
4g (i-Pr)
7g
7i
8d
4h (c-Hex)
4i (CH3(CH2)13
)
a Isolated yield after purification. b Determined by chiral HPLC
analysis.
4d (n-Pr)
8
a Isolated yield after purification. b Determined by chiral HPLC
analysis. c 2-(5-Bromo-1H-indol-1-yl)ethanamine was used in this ex-
periment in place of 3. d The product of this reaction (8) is the 5-bromo
derivative of 7d. See the Supporting Information.
When we turned our attention to the use of (commercially
available) 2-(1H-indol-1-yl)ethanamine 3 in the iso-PictetÀ
Spengler reaction, we were gratified to find that the
reaction required almost no optimization. The only mod-
ification that proved necessary was to employ toluene as
the solvent instead of benzene, to allow for a necessary
increase in the reaction temperature due to the relative
sluggishness of the reaction. Thus, simply heating 3 and 4a
in refluxing toluene with a DeanÀStark trap and then
adding (S,S)-1 produced 7a in 55% yield and 90% ee
(Scheme 2). This is not the first time we have observed high
levels of enantioselectivity in refluxing toluene with this
family of silane Lewis acids,14 and this result stands as
another testament to their robustness. The lower rate of
reaction in this cyclization mode may presumably be
attributed to the lower nucleophilicity of the 2-position
of the indole.
Finally, in an effort to alleviate any concerns about the
use of 1.5 equiv of the silane Lewis acid,15 we have revisited
the reactions of 2 and 3 with 4d on a 10 and 8 mmol scale,
respectively, and with a reduced silane loading of 1.3 equiv
(Scheme 3). The products 6d and 7d were isolated by
recrystallization in 92% and 94% yields and 99% and
98% ee, respectively. Importantly, and as we have demon-
strated in other contexts,6,16 the pseudoephedrine was
recovered by simple extraction in both experiments. Thus,
by any objective measure, these reactions score very highly
for practicality, efficiency, atom-economy, and user-
friendliness, all while providing unique access to novel
and interesting enantiomerically highly enriched structures
that may be of use in medicinal chemistry applications.
We have devised two new asymmetric iso-PictetÀSpen-
gler reactions of aminoindoles 2 and 3 with a variety of
R-ketoamides promoted by the simple and commercially
Scheme 2. Optimization of an Iso-PictetÀSpengler Reaction
with 2-(1H-Indol-1-yl)ethanamine 3 and R-Ketoamide 4
(13) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc.
2003, 125, 9596.
(14) Rabbat, P. M. A.; Valdez, S. C.; Leighton, J. L. Org. Lett. 2006,
8, 6119.
(15) On the smaller scale (0.30 mmol of R-ketoamides 4) used for the
reactions described in Tables 1 and 2, we observed a small but noticeable
drop in enantioselectvity when we used less than 1.5 equiv of silane 1.
This problem is mitigated substantially as the scale of the reactions
increases.
(16) (a) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem. Soc. 2004,
126, 5686. (b) Shirakawa, S.; Berger, R.; Leighton, J. L. J. Am. Chem.
Soc. 2005, 127, 2858. (c) Shirakawa, S.; Lombardi, P. J.; Leighton, J. L.
J. Am. Chem. Soc. 2005, 127, 9974.
Anexamination ofthescope ofthe reactionwithamine 3
revealed that, for the most part, the moderate efficiency of
2612
Org. Lett., Vol. 14, No. 10, 2012

motifs (3,3-disubstituted-1,3,4,5-tetrahydropyrrolo[4,3,2-de]-
isoquinolines and 1,1-disubstituted-1,2,3,4-tetrahydro-
pyrazino[1,2-a]indoles) and provide additional examples
of the remarkable generality and versatility of silane 1.7
Scheme 3. “Large” Scale (8À10 mmol) Reactions with Product
Isolation by Recrystallization and Pseudoephedrine Recovery
by Extraction Demonstrate the Utility and Practicality of the
Iso-PictetÀSpengler Reactions
Acknowledgment. This work was supported by a grant
from the National Science Foundation (CHE-11-52949).
We thank the Deutsche Forschungsgemeinschaft for a
Postdoctoral Fellowship (SCHO 1403/1-1) to H.S. We
thank Professor Ged Parkin and Mr. Aaron Sattler
(Columbia University) for two X-ray structure analyses
(see Supporting Information), and the National Science
Foundation (CHE-0619638) is thanked for acquisition of
an X-ray diffractometer.
Supporting Information Available. Experimental pro-
cedures, characterization data, and stereochemical
proofs. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare the following competing financial interest(s):
Columbia University holds a patent on silane Lewis acid 1, and Columbia
has licensing deals in place with Sigma-Aldrich and Gelest, Inc. The authors
have no official relationship with either company otherwise and receive no
honoraria or fees of any kind from either of them.
available chiral silane Lewis acid 1. These operationally
simple, practical, and scalable reactions facilitate unique
access to two relatively underexplored indole core structure
Org. Lett., Vol. 14, No. 10, 2012
2613