Catalytic asymmetric synthesis of 1,1-disubstituted tetrahydro-β- carbolines by phase-transfer catalyzed alkylations

Article abstract of DOI:10.1039/c0cc04447d

Efficient catalytic asymmetric synthesis of 1,1-disubstituted tetrahydro-β-carbolines has been achieved via asymmetric alkylation of 1-cyanotetrahydro-β-carbolines using a binaphthyl-modified N-spiro-type chiral phase-transfer catalyst. This is a valuable

Full text of DOI:10.1039/c0cc04447d

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Catalytic asymmetric synthesis of 1,1-disubstituted
tetrahydro-b-carbolines by phase-transfer catalyzed alkylationsw
Seiji Shirakawa, Kun Liu, Hironobu Ito and Keiji Maruoka*
Received 16th October 2010, Accepted 1st November 2010
DOI: 10.1039/c0cc04447d
Efficient catalytic asymmetric synthesis of 1,1-disubstituted
tetrahydro-b-carbolines has been achieved via asymmetric
alkylation of 1-cyanotetrahydro-b-carbolines using a binaphthyl-
modified N-spiro-type chiral phase-transfer catalyst. This is a
valuable example of hitherto difficult highly enantioselective
alkylations at a-carbon of the cyano group under phase-transfer
conditions.
alkylation product 3 can be transformed into various useful
functional groups. Although many examples of phase-transfer
catalyzed asymmetric alkylations at a-carbon of the carbonyl
group to create quaternary stereocenter via ammonium enolate
A (Scheme 2) are known,11,12 only limited examples of the
alkylations at a-carbon of the cyano group via intermediate B
(Scheme 2) have been reported14,15 despite the high synthetic
utility of this group. Here we wish to report highly
enantioselective alkylations of 1-cyanotetrahydro-b-carbolines
2 under mild phase-transfer conditions. The present reaction is
a valuable example of hitherto difficult highly enantioselective
a-alkylations of cyano compounds under these conditions.
As a key substrate for the asymmetric synthesis of 1,1-
disubstituted tetrahydro-b-carboline of type 1 under phase-
transfer conditions, 1-cyanotetrahydro-b-carboline 2a was
selected as a model substrate. An attempted reaction of
1-cyanotetrahydro-b-carboline 2a with benzyl bromide
(1.2 equiv.) in aqueous KOH/toluene under the influence of
N-spiro-type phase-transfer catalyst (S,S)-4a (2 mol%) at 0 1C
for 24 h afforded benzylation product 3a with 71% ee (Table 1,
entry 1). Switching the 3,30-aromatic substituent (Ar) of the
catalyst to a 3,5-bis(trifluoromethyl)phenyl group (4b) resulted
in improved enantioselectivity, and the product 3a was
obtained with high enantioselectivity (94% ee, entry 2).
Further screening of 3,30-aromatic substituent (Ar) of (S,S)-
416 did not improve the enantioselectivity (entries 3 and 4). The
use of phase-transfer catalyst (S)-5,17 which has one binaphthyl
unit, gave a product with moderate enantioselectivity (entry 5).
With optimal reaction conditions in hand, we further studied
the generality of the asymmetric alkylation of 1-cyanotetrahydro-
b-carboline 2a under the influence of chiral phase-transfer
catalyst (S,S)-4b, as shown in Table 2. A series of benzylic
bromides with different steric and electronic properties
The structure of 1-substituted tetrahydro-b-carboline appears
in many important natural products and biologically active
compounds, hence numerous synthetic efforts especially in
a stereoselective manner have been made to build up this
structure.1–5 Several efficient catalytic methods were developed
for the synthesis of these compounds via asymmetric hydro-
genations,3 Mannich-type reactions,4 and Pictet–Spengler
reactions.5 On the other hand, only two examples of the
catalytic asymmetric synthesis of 1,1-disubstituted tetrahydro-
b-carbolines of type 1 possessing a chiral quaternary carbon
center6 have been reported recently,7 despite the importance of
these compounds in natural product chemistry8 and medicinal
chemistry9 (Fig. 1). Notably, these two examples included
similar Pictet–Spengler-type intramolecular cyclizations, and
the structural motif of the obtained products was limited to a
tetracyclic lactam structure. For these reasons, the development
of novel catalytic asymmetric methods for the synthesis of
different types of 1,1-disubstituted tetrahydro-b-carbolines 1 is
highly desirable.10
Our strategy for the synthesis of 1,1-disubstituted tetrahydro-
b-carbolines of type 1 involves asymmetric phase-transfer
alkylation11,12 of racemic 1-cyanotetrahydro-b-carboline 2,
which can be prepared easily from 3,4-dihydro-b-carboline via
cyanation (Scheme 1).13 The electron-withdrawing nature of
the cyano group in compound 2 offers appropriate reactivity
for phase-transfer alkylations, and the cyano group of
Scheme 1 Synthetic scheme of 1,1-disubstituted tetrahydro-b-carboline.
Fig. 1 1,1-Disubstituted tetrahydro-b-carboline.
Laboratory of Synthetic Organic Chemistry and Special Laboratory
of Organocatalytic Chemistry, Department of Chemistry, Graduate
School of Science, Kyoto University, Sakyo, Kyoto, 606-8502, Japan.
E-mail: maruoka@kuchem.kyoto-u.ac.jp; Fax: +81-75-753-4041;
Tel: +81-75-753-4041
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for new compounds. CCDC 787177.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c0cc04447d
Scheme 2 Phase-transfer catalyzed alkylations.
Chem. Commun., 2011, 47, 1515–1517 1515
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Table 1 Screening of chiral phase-transfer catalystsa
Table 2 Asymmetric alkylation of a 1-cyanotetrahydro-b-carboline 2aa
Entry
RBr
Yieldb (%)
eec (%)
1
2
3
4
X = H
X = Me
X = F
72 (3a)
60 (3b)
88 (3c)
76 (3d)
94
92
95
96
X = Br
5
78 (3e)
94
Entry
PTC
Yieldb (%)
eec (%)
1
2
3
4
5
4a
4b
4c
4d
5
45
72
51
61
69
71
94
92
70
79
6
7
66 (3f)
75 (3g)
90
93
a
Reaction conditions: 2a (0.050 mmol) and benzyl bromide (0.060 mmol)
in the presence of 2 mol% of chiral phase-transfer catalyst (PTC)
in 50% aqueous KOH (0.25 mL)/toluene (0.50 mL) at 0 1C for
b
c
24 h. Yield of isolated products. Determined by chiral HPLC
analysis.
8
61 (3h)
86 (3i)
95
60
were tolerated, thus allowing the preparation of structurally
diverse, enantioenriched 1,1-disubstituted tetrahydro-b-carbolines
(90–96% ee, entries 1–7). The alkyl halide containing a hetero-
aromatic ring could also be applied to the reaction with high
enantioselectivity (95% ee, entry 8). The reaction with cinnamyl
bromide gave the product 3i in good yield with moderate
enantioselectivity (entry 9).18 The absolute configuration of 3d
was determined by X-ray diffraction analysis.19
9d
a
Reaction conditions: 2a (0.050 mmol) and alkyl halide (0.060 mmol)
in the presence of 2 mol% of (S,S)-4b in 50% aqueous KOH (0.25 mL)/
b
toluene (0.50 mL) at 0
c
products. Determined by chiral HPLC analysis. The reaction was
1C for 24 h. Yield of isolated
d
performed at ꢀ20 1C.
alkylations of cyano compounds to produce important
compounds are currently underway.
Other types of 1-cyanotetrahydro-b-carbolines 2 were found
to be employable for the reaction (Table 3). The introduction
of electron-donating and electron-withdrawing substituents on
the aromatic ring of tetrahydro-b-carboline core gave high
enantioselectivities (92–96% ee, entries 1 and 2). The use of N-
methyl and N-allyl substituted tetrahydro-b-carbolines also
gave high enantioselectivities (92–94% ee, entries 3 and 4).
The cyano group of the alkylation products 3 and 6 can be
readily transformed to other functional groups. For example,
the optically active alkylation product 3a was subjected to
alkaline hydrolysis to furnish amide derivative 7 possessing a
tetracyclic hydantoin structure (Scheme 3), which was observed
in biologically active compounds.20
This work was partially supported by a Grant-in-Aid for
Scientific Research from MEXT, Japan.
Table 3 Asymmetric benzylation of 1-cyanotetrahydro-b-carbolines 2a
Entry
X
R
Yieldb (%)
eec (%)
In summary, we have successfully developed the highly
enantioselective alkylation of 1-cyanotetrahydro-b-carbolines
for the synthesis of 1,1-disubstituted tetrahydro-b-carbolines
under mild phase-transfer conditions. The cyano group of the
products was easily transformed to other functional groups.
The present report illustrates a valuable example of hitherto
difficult highly enantioselective alkylations at a-carbon of
the cyano group under phase-transfer conditions. Further
investigations on the phase-transfer catalyzed asymmetric
1d
2
3
4
MeO
Cl
H
PhCH2
PhCH2
Me
CH2QCHCH2
77 (6a)
87 (6b)
89 (6c)
84 (6d)
92
96
92
94
H
a
Reaction conditions: 2 (0.050 mmol) and benzyl bromide (0.060 mmol)
in the presence of 2 mol% of (S,S)-4b in 50% aqueous KOH
b
(0.25 mL)/toluene (0.50 mL) at 0 1C for 24 h. Yield of isolated
products. Determined by chiral HPLC analysis. The reaction was
c
d
performed at ꢀ20 1C.
c
1516 Chem. Commun., 2011, 47, 1515–1517
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asymmetric synthesis of 1,1-disubstituted tetrahydro-b-carbolines
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Scheme 3 Transformation of the alkylation product 3a.
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c
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Chem. Commun., 2011, 47, 1515–1517 1517