Highly enantioselective pictet-spengler reactions with α-ketoamide- derived ketimines: Access to an unusual class of quaternary α-amino amides

Full text of DOI:10.1002/anie.200806110

Angewandte
Chemie
DOI: 10.1002/anie.200806110
Synthetic Methods
Highly Enantioselective Pictet–Spengler Reactions with a-Ketoamide-
Derived Ketimines: Access to an Unusual Class of Quaternary a-
Amino Amides**
Farhan R. Bou-Hamdan and James L. Leighton*
The Pictet–Spengler reaction[1] provides access to tetrahydro-
b-carbolines and tetrahydroisoquinolines, which are hetero-
cyclic ring systems of considerable importance to natural
products and medicinal chemistry. Asymmetric variants
would be expected to find utility, especially to the extent
that they reliably provide access to complex and highly
enantioenriched products from simple starting materials by
employing only straightforward experimental techniques.
While many Pictet–Spengler reactions controlled by chiral
auxiliaries have been reported,[2] it is only more recently that
the first reports of highly enantioselective variants (external
asymmetric induction) have appeared.[3] Notably, all of these
methods require prior modification of the amino group of the
tryptamine from which the active iminium species is prepar-
ed,[3a,d,e] or derivatization of the imine nitrogen prior to
cyclization,[3b] or the use of a substituted tryptamine precur-
sor.[3c] In terms of scope, most of these reports described the
reactions of aldimine derivatives; only very recently have
Jacobsen and co-workers reported the first examples of highly
enantioselective Pictet–Spengler reactions (and related reac-
tions with pyrroles) of ketimine derivatives.[4] Owing partly to
the fact that 1,1-disubstituted tetrahydro-b-carbolines appear
in important natural products (e.g. ecteinascidins 722 and
736)[5] and have been the subject of screening library
development,[6] and partly to the fundamental synthetic
challenge, the development of a highly enantioselective
ketimine Pictet–Spengler reaction—wherein tryptamine
itself and the ketone are simply condensed with no further
modification required—seemed a worthy goal.
NH group of imidazoles.[9] In a projected enantioselective
ketimine Pictet–Spengler reaction, the activating group
cannot be a part of the imine N-substituent (as in N-
acylhydrazones) and must therefore be a part of the ketone
from which the imine is derived. Carboxyl derivatives that
possess an acidic proton (e.g. carboxylic acid, secondary
amide) seemed attractive in this regard both because of their
general synthetic versatility and because the products would
represent an interesting class of quaternary a-amino acid
derivatives. Mechanistically, it was envisioned that O-silyla-
tion of compounds of the general structure 1 with silane (S,S)-
2
[7b,c,d] would give, by way of the illustrated complex, products
3 (Scheme 1). Owing to a resemblance to the “amide”
fragment of N-acylhydrazones, and to the expectation that
they would be readily electronically tunable, secondary N-
aryl amides became the subject of our exploratory studies
À
(X = N Ar).
As a proof of concept experiment, N-phenylglyoxamide-
derived imine 4a was prepared and treated with silane (S,S)-2
(Scheme 1). The desired product 5a was produced, but in only
trace quantities (< 10%). However, it was found that
electron-withdrawing groups on the N-aryl ring dramatically
enhanced the reaction rate. Among the aryl amides screened,
We have developed Lewis acidic chiral chlorosilanes for a
range of highly enantioselective imine addition reactions that
requires activation by protic nucleophiles within the imine
substrate. Effective activators include the NHCOR fragment
of N-acylhydrazones,[7] the OH group of phenols,[8] and the
[*] Dr. F. R. Bou-Hamdan, Prof. Dr. J. L. Leighton
Department of Chemistry, Columbia University
New York, NY 10027 (USA)
Fax: (+1)212-932-1289
E-mail: leighton@chem.columbia.edu
[**] This work was supported by a grant from the National Science
Foundation (CHE-08-09659). F.R.B.-H. was supported by a post-
doctoral fellowship from the MDS Research Foundation. We thank
Prof. Ged Parkin and Aaron Sattler for an X-ray crystal structure
analysis (see the Supporting Information), and the National Science
Foundation (CHE-0619638) is thanked for acquisition of an X-ray
diffractometer.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200806110.
Scheme 1. Reaction design, discovery, and optimization.
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the N-3-(trifluoromethyl)phenyl amide 4b provided superior
reactivity giving 5b in (an unoptimized) 65% yield and
48% ee. Having established the feasibility of the process, we
next prepared phenylketone-derived amide 6a and subjected
it to reactions with silane (S,S)-2. Although an elevated
reaction temperature and extended reaction time was
required, this reaction proceeded smoothly and gave 7a in
good yield and with an improved enantioselectivity relative to
5b. Optimization of the reaction conditions to maximize
efficiency and enantioselectivity was straightforward, and
using the illustrated conditions[10] 7a was isolated in 93%
yield and 93% ee.
Scheme 2. Optimization of the Pictet–Spengler reactions of ketimines
derived from alkyl ketones.
A series of N-3-(trifluoromethyl)phenyl amides 6 were
prepared and subjected to the Pictet–Spengler reaction with
silane (S,S)-2 (Table 1). As compared to parent substrate 6a
other aryl amides led to the discovery that the 2,6-difluoro-
phenyl group provided good results and upon optimization it
was found that treatment of imine 10a with 1.5 equivalents of
(S,S)-2 in toluene at 508C led to 11a in 89% ee. As toluene
proved to be an effective solvent for this reaction and is a
convenient and effective solvent for the imine formation, we
have developed a one-pot procedure wherein tryptamine and
the ketone are condensed in toluene at reflux (with a Dean–
Stark trap), and upon completion of the imine formation the
reaction mixture was cooled to 508C and the silane Lewis acid
was added. By using this convenient procedure, 11a may be
produced in 78% yield (from ketone 12a) and 89% ee.
The results of a brief survey of the scope and generality of
this one-pot process with tryptamines and alkyl ketones are
summarized in Table 2. As with the aryl ketone-derived
Table 1: Highly enantioselective Pictet–Spengler reactions of ketimines
derived from alkyl ketones.
Entry
R
Ar
Solvent t [h] Yield [%] ee [%]
1
2
3
4
5
6
7
8
H
Br
C6H5 (7a)
C6H5 (7b)
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
48
70
27
48
48
20
46
42
60
60
93
68
93
85
89
94
82
77
50
86
93
89
82
90
90
87
91
87
87
90
OMe C6H5 (7c)
H
H
H
H
H
H
H
p-BrC6H4 (7d)
p-CF3C6H4 (7e)
p-MeOC6H4 (7 f) CHCl3
2-naphthyl (7g)
3-pyridyl (7h)
1-naphthyl (7i)
2,4-Cl2C6H3 (7j)
CH2Cl2
CH2Cl2
DCE
Table 2: Highly enantioselective one-pot Pictet–Spengler reactions of
tryptamines and a-(alkyl)ketoamides.
9[a]
10[a]
DCE
[a] These reactions were performed with 2 equivalents of (S,S)-2.
(Table 1, entry 1), bromine substitution at the 5-position of
the indole (6b) resulted in a relatively sluggish reaction that
nevertheless produced 7b in 68% yield and 89% ee (Table 1,
entry 2), whereas the corresponding methoxy substitution
(6c) resulted in a highly efficient (93% yield), albeit less
selective (82% ee) reaction (Table 1, entry 3). Substitution of
the aryl group (Ar) was well tolerated (Table 1, entries 4–7),
as was the heteroaromatic (3-pyridyl) group (Table 1,
entry 8). While ortho substitution on the aryl group may be
tolerated (Table 1, entries 9 and 10), the reactions were
significantly more sluggish, and required both increased
loadings of the silane Lewis acid and higher reaction temper-
atures (1,2-dichloroethane (DCE) at reflux). Despite this, the
highly sterically hindered products 7h and 7i were obtained
with high levels of enantioselectivity (87 and 90% ee,
respectively).
Entry
R1
R2
T [8C]
t [h]
Yield [%]
ee [%]
1
2
3
4
5
H
Br
OMe
H
H
Me (11a)
Me (11b)
Me (11c)
iBu (11d)
iPr (11e)
50
75
50
50
55
36
48
48
26
25
78
67
86
81
83
89
86
81
90
94
substrates, 5-bromo and 5-methoxy substitution of the trypt-
amine are tolerated, albeit with a similar moderate drop in
enantioselectivity (compare Table 2, entry 1 with entries 2
and 3). Importantly, a significant degree of steric hindrance
may be tolerated, as demonstrated by the isobutyl and
isopropyl ketone substrates (Table 2, entries 4 and 5), and
indeed these reactions proceed with improved enantioselec-
tivity.
To establish greater generality and scope for the process
we next examined the performance of imines derived from
alkyl ketones (1, R = alkyl). Exploratory studies with pyru-
vate-derived amide 8 revealed that the 3-(trifluoromethyl)-
phenyl amide provided product 9 with insufficiently high
enantioselectivity (70% ee; Scheme 2). A brief survey of
To demonstrate that this process is readily scalable, the
reaction of 6a was carried out on a 5 mmol scale (with the
silane loading reduced to 1.3 equiv[11]). Tetrahydro-b-carbo-
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line 7a was isolated by recrystallization in 79% yield and
99% ee (Scheme 3). In addition, the pseudoephedrine was
quantitatively recovered by simple basification and extraction
Scheme 5. A plausible reaction mechanism and model for absolute
stereochemical induction. Ar=alkyl, aryl.
Scheme 3. Larger scale reaction without the need for chromatography
and quantitative recovery of the pseudoephedrine.
interaction with the relatively large phenyl group attached
to silicon, attacks the exposed front face as in structure 18,
which is consistent with the observed sense of induction.
We have developed a highly enantioselective Pictet–
Spengler reaction with ketimines derived from a-ketoamides
that provides access to an interesting and hitherto inaccessible
class of optically active quaternary a-amino acid derivatives.
The chiral silane Lewis acid (S,S)-2 is extraordinarily simple
to prepare and inexpensive, and the method—uniquely—does
not require any modification or derivatization of the trypt-
amine precursor or tryptamine-derived imines. Along the way
we have established a highly effective new activating group
for our silane Lewis acids (secondary N-aryl amides) that may
have implications in other reactions, and we have expanded
the list of reactions for which silane (S,S)-2 is a highly
effective and enantioselective promoter.
of the aqueous phase that was recovered from the work-up
procedure. Thus, neither the isolation of 7a nor the recovery
of the pseudoephedrine required any chromatography, and
despite the requirement for a stoichiometric amount of the
(extraordinarily simple to prepare in one step and inexpen-
sive) silane Lewis acid (S,S)-2, this is a process that may lay a
strong claim to a high degree of economic practicality and
scalability.
In principle, and as briefly discussed above, the amide
group of the products can serve as a versatile entry to many
other functional groups. In practice, however, attempts to
carry out alcoholysis and transamination reactions on amide
11a were unsuccessful. It was found, however, that treatment
of 11a with CS2 in the presence of pyridine and 4-dimethyl-
aminopyridine (DMAP) in a sealed tube at 908C led to 13 in
83% yield (Scheme 4). Compound 13 ably serves as an N-
protected active ester derivative as shown by the illustrated
alcoholysis and aminolysis reactions to give ester 14 and
amide 15 in 71% and 90% yields, respectively.
Received: December 15, 2008
Revised: January 23, 2009
Published online: February 16, 2009
Keywords: asymmetric synthesis · heterocycles · ketimines ·
.
Lewis acids · Pictet–Spengler reaction
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from attacking the back face of the imine by a steric
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[11] On this larger scale, the problem described in Ref. [10] is
mitigated, and the silane loading may be lowered with no loss in
enantioselectivity.
[12] Full details are provided in the Supporting Information file.
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