The direct asymmetric alkylation of α-amino aldehydes with 3-indolylmethanols by enamine catalysis

Article abstract of DOI:10.1021/ol503318c

This work describes an efficient α-alkylation reaction of α-amino aldehydes with 3-indolylmethanols. In the promotion of catalyst 3f, the target products were obtained in high yields (up to 99%), good diastereoselectivities (up to 88:12), and excellent en

Full text of DOI:10.1021/ol503318c

Letter
pubs.acs.org/OrgLett
The Direct Asymmetric Alkylation of α‑Amino Aldehydes with
3‑Indolylmethanols by Enamine Catalysis
Zhi-Lei Guo, Jia-Hui Xue, Li-Na Fu, Shun-En Zhang, and Qi-Xiang Guo*
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
S
* Supporting Information
ABSTRACT: This work describes an efficient α-alkylation
reaction of α-amino aldehydes with 3-indolylmethanols. In the
promotion of catalyst 3f, the target products were obtained in
high yields (up to 99%), good diastereoselectivities (up to
88:12), and excellent enantioselectivities (up to 96% ee). The
direct alkylation products can be readily converted into other tryptophan derivatives without the loss of stereoselectivities.
he catalytic asymmetric alkylation of carbonyl compounds
is an important C−C bond-forming strategy in organic
alkylation reaction of α-amino aldehydes with 3-indolylmetha-
nols by enamine catalysis. This method allowed for the
synthesis of a structurally diverse range of α,β-disubstituted
tryptophan12 precursors in good yields and excellent
enantioselectivities.
T
synthesis,1 and a diverse range of organocatalytic asymmetric
alkylation reactions have been developed during the course of
the past two decades for the construction of optically active
molecules.2 In 2009, Cozzi et al.3 reported the first asymmetric
alkylation of aldehydes, which used active biarylmethanols as
the alkylating agents by enamine catalysis. In the same year, we
reported the results of our pioneering study toward the
development of an alkylation reaction of emanides with 3-
indolylmethanols by Brønsted acid catalysis.4 Alcohols are ideal
reagents for the alkylation of carbonyl compounds because
water is produced as the only byproducts, making the
development of novel alkylation reactions between various
nucleophiles and active alcohols increasingly attractive from a
green chemistry perspective.2 Numerous carbonyl compounds
have been employed in asymmetric alkylation reactions of this
type, including aldehydes,5 ketones,6 and carbonyl derivatives,7
where they were alkylated with biarylmethanols. α-Amino
aldehydes, which are an important class of carbonyl
compounds, can be readily prepared from natural and unnatural
α-amino acids and α-amino nitriles,8 and these compounds can
be used as starting materials for the synthesis of novel optically
active α-amino aldehydes, α-amino acid, and amino alcohol
precursors. However, building blocks of this type are seldom
used in organocatalytic asymmetric synthesis and, to the best of
our knowledge, there have only been three examples reported
in the literature to date. The first of these reports involves the L-
proline catalyzed aldol addition of α-amino aldehydes to
aliphatic aldehydes,9 whereas the second involves the chiral
primary amine catalyzed Michael addition of α-amino
aldehydes to vinyl sulfones.8 Most recently, Maruoka et al.
reported an aldol reaction between α-amino acetaldehyde and a
series of different aldehydes.10 Given the limited number of
publications in this area, there is still plenty of scope for the
development of novel methodology involving the use of α-
amino aldehydes in organocatalytic asymmetric reactions. In
continuation of our work toward the development of new
strategies for the alkylation of carbonyl compounds with
biarylmethanols,4,11 we report herein the first direct asymmetric
This particular study started as an investigation of the L-
proline-catalyzed reaction13 between N-Boc protected α-amino
aldehyde 1a and 3-indolylmethanol 2a. Unfortunately, however,
the desired reaction did not take place in this case. The results
of our previous work indicated that chiral primary-amine-
thioureas are suitable organocatalysts for the direct α-alkylation
of aldehydes with 3-indolylmethanols. With this in mind,
catalyst 3a was added to the reaction of 1a and 2a and the
target product 4a was obtained in 82% yield with moderate
enantioselectivity (Table 1, entry 2). Based on the success of
this reaction, we proceeded to investigate the effectiveness of
catalysts 3b−e. Pleasingly, all four of these catalysts performed
well in this reaction to give the desired product 4a with a good
chiral induction, although the diastereoselectivities were very
poor (Table 1, entries 3−6). The use of catalyst 3f in the
reaction led to an increase in the enantioselectivity of the major
diastereoisomer of 4a to 92% ee, as well as a significant increase
in the diastereoselectivity (Table 1, entry 7). Catalyst 3g, which
was prepared from (1S,2R)-2-amino-1,2-diphenylethanol, was
then used to investigate the compatibility of these two chiral
units. Unfortunately, however, the use of this catalyst led to a
slight reduction in enantio- and diastereoselectivity of the
reaction, as well as a significant decrease in the yield of 4a
(Table 1, entry 8). Catalysts 3h and 3i, which were derived
from (1S,2S)-cyclohexane-1,2-diamine and 1,2-diphenylethane-
1,2-diamine, respectively, were also tested in this reaction, but
neither of these catalysts performed as well as 3f (Table 1,
entries 9 and 10). Catalysts 3j−m were also prepared and
evaluated in terms of their ability to promote the reaction
between 1a and 2a. Unfortunately, although catalysts 3j−l
promoted this reaction, they gave poor yields of the desired
Received: November 16, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503318c | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the acid additive was found to have a significant impact on the
outcome of the reaction (Table 2, entries 1−4), with p-
nitrobenzoic acid (PNBA) providing the best results of all of
the additives tested in the current study. The effect of the
solvent was also investigated and found to have a significant
impact on the yield and stereoselectivity of the reaction, and
dichloromethane (DCM) was identified as the best solvent for
this reaction (Table 2, entry 2). The effect of temperature was
also investigated, and it was found that the enantioselectivity of
the reaction increased slightly when the reaction was conducted
at low temperature, but this also led to a decrease in the yield
(Table 2, entries 8−9). The nature of the N-protecting group
used in 1 also had a significant impact on the outcome of this
reaction. For example, the reaction proceeded at a much greater
rate when α-amino aldehyde 1c was used as a donor, with
compound 4c being produced in excellent yield, with good
diastereoselectivity and excellent enantioselectivity over a short
reaction time (Table 2, entry 11).
Table 1. Screening of the Catalysts
a
b
c
entry
3
t (h)
y (%)
dr
ee
1
L-proline
3a
48
46
46
52
55
46
48
51
51
51
69
69
69
48
−
−
−
2
82
89
80
51
91
93
60
75
82
50
56
55
46:54
45:55
50:50
45:55
48:52
24:76
32:68
29:71
34:66
43:57
43:57
44:56
41/80
52/81
55/70
48/80
68/76
73/92
78/88
40/70
77/84
53/50
43/59
51/60
ND
3
3b
4
3c
5
3d
3e
With the optimal reaction conditions in hand, we proceeded
to explore the substrate scope for this reaction using a variety of
different 3-indolylmethanols (Table 3). The alkylation products
6
7
3f
8
3g
9
3h
3i
Table 3. Substrate Scope of 3-Indolylmethanols
10
11
12
13
14
3j
3k
3l
d
3m
trace
ND
a
b
Isolated yield of the two diastereoisomers. Determined by HPLC.
a
b
c
entry
Ar, R2
C6H5, H
5
t (h) y (%)
dr
ee (%)
c
d
Determined by chiral HPLC. ND = Not Determined.
1
4c
5a
5b
5c
5d
5e
5f
22
64
64
70
132
110
117
15
15
31
39
28
11
36
88
88
88
22
27
24
34
96
117
96
99
75
70
75
63
76
76
86
82
88
81
94
81
83
80
83
82
84
87
84
82
87
72
71
76:24
86:14
88:12
88:12
77:23
81:19
82:18
79:21
77:23
74:26
77:23
70:30
70:30
80:20
79:21
78:22
76:24
83:17
71:29
76:24
79:21
85:15
74:26
76:24
93
91
96
90
93
87
94
81
89
86
87
86
85
84
89
93
90
94
91
89
90
90
92
92
2
4-ClC6H4, H
4-FC6H4, H
3
product with low levels of enantio- and diastereoselectivity
(Table 1, entries 11−13). Notably, catalyst 3m, which has been
used extensively in organocatalysis,14 failed to promote this
reaction (Table 1, entry 14). Based on these results, catalyst 3f
was selected as the optimal catalyst to further optimize the
reaction conditions.
4
4-BrC6H4, H
4-CF3C6H4, H
3-ClC6H4, H
2-BrC6H4, H
4-MeOC6H4, H
4-MeC6H4, H
4-tBuC6H4, H
3-MeC6H4, H
3-MeOC6H4, H
2-MeOC6H4, H
2-Naphthyl, H
C6H5, 6-F
5
6
7
8
5g
5h
5i
9
With the optimal catalyst in hand, we proceeded to screen
some of the other reaction conditions (Table 2). The nature of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
5j
5k
5l
Table 2. Optimization of the Reaction Conditions
5m
5n
5o
5p
5q
5r
C6H5, 5-Cl
C6H5, 5-Br
4-FC6H4, 5-Me
4-FC6H4, 5-MeO
4-FC6H4, 6-Me
4-FC6H4, 7-Me
4-BrC6H4, 6-Me
2-BrC6H4, 7-Me
2-ClC6H4, 7-Me
a
b
c
entry
additives
solvent
y (%)
dr
ee (%)
5s
5t
1
BA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
PhCH3
THF
43
93
86
64
87
33
49:51
24:76
28:72
40:60
26:74
21:79
40/52
73/92
66/85
80/72
94/91
84/92
ND
2
PNBA
DNBA
o-FBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
PNBA
5u
5v
5w
3
4
5
a
b
Isolated yield of the two diastereoisomers. Determined by 1H NMR;
ee of the major diastereomers determined by chiral HPLC.
6
c
d
7
trace
80
ND
e
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
22:78
21:79
32:68
24:76
−/94
−/94
f
were converted to the corresponding amino alcohols using
NaBH4 and then submitted to NMR and chiral HPLC analysis.
A variety of different groups were introduced to the phenyl ring
of the 3-indolylmethanol substrate 2. The introduction of
electron-withdrawing groups led to a slight reduction in the rate
of the reaction, and extended reaction times were required to
obtain the corresponding products 5a−f in good yields (Table
9
48
g
10
11
87
69/87
h
99
72/-93
a
b
Isolated yield of the two diastereoisomers. Determined by HPLC.
c
d
e
f
Determined by chiral HPLC. ND = Not Determined. At 10 °C. At
g
h
0 °C. Using 1b as donor. Using 1c as donor.
B
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Organic Letters
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3, entries 2−7). Notably, however, 3-indolylmethanol sub-
strates bearing electron-withdrawing groups tended to afford
enhanced stereochemical outcomes. For example, the 3-
inolymethanol substrate bearing a 4-F-phenyl substituent gave
the corresponding alkylated product 5b in 88:12 dr and 96% ee
(Table 3, entry 3). In contrast, 3-indolylmethanols bearing an
electron-rich substituted phenyl group gave the corresponding
alkylation products in good yields and enantioselectivities, but
with only moderate diastereoselectivities (Table 3, entries 8−
13). The introduction of electron-rich phenyl substituents led
to a dramatic increase in the rate of the reaction, which was
attributed in part to their ability to rapidly form alkylidene-
indolenium intermediates during the course of the reaction
compared to that of the electron-deficient phenyl substituted 3-
indolylmethanols. The effects of placing different substituents
on the indole ring of the 3-indolylmethanol substrate were also
investigated. The results of these reactions revealed that
electron-donating and -withdrawing substituents were well
tolerated at the 5-, 6-, and 7-positions of the indole ring, with
the corresponding products 5o−w being formed in good yields
and diastereoselectivities with excellent enantioselectivities
(Table 3, entries 15−24).
Scheme 1. Alkylation of α-Amino Aldehyde 1c with
Biphenylmethanols
in the presence of trifluoroacetic acid with a slight decrease in
the enantioselectivity (Scheme 2, eq 1), albeit in a low yield of
Scheme 2. Synthesis of Novel Indoles from Compounds 4a
and 4d
This transformation was found to be particularly sensitive to
the nature of the substituents on the α-amino aldehyde. For
example, the use of bulky α-amino aldehydes such as ethyl (1-
oxobutan-2-yl) carbamate led to a significant decrease in the
yield and stereoselectivity, with the corresponding product 5x
being isolated in 60% yield and moderate stereoselectivities
(Table 4, entry 1). Further increasing the size of the α-
Table 4. Substrate Scope of the α-Amino Aldehydes
a
b
c
entry
R, Ar
5
y (%)
dr
ee (%)
1
2
3
Et, 4-BrC6H4
nPr, 4-ClC6H4
Bn, 4-BrC6H4
5x
5y
5z
60
52
41
75:25
67:33
34:66
79
31%. After successfully optimizing the reaction conditions, we
established that successive alkylation/cyclization reactions
could be conducted in a one-pot manner to give the polycyclic
product 7a in good yield and excellent enantioselectivity
(Scheme 2, eq 2). The alkylated indole products could also be
used to prepare α,β-disubstituted tryptophan derivatives. For
example, the oxidation of 4d with NaClO2 gave 8a in excellent
yield (Scheme 2, eq 3).15 The relative and absolute
configuration of 7b was determined by single crystal X-ray
analysis,16 and the stereochemistries of compounds 4, 5, and 8a
were assigned accordingly.
In conclusion, we have developed an efficient reaction for the
alkylation of α-amino aldehydes with 3-indolylmethanols. The
alkylated products were obtained in high yields, with good
diastereoselectivities and good to excellent enantioselectivities.
Furthermore, the products resulting from this reaction could be
converted into other indole derivatives without any discernible
impact on their stereoselectivities.
67
−55
a
b
Isolated yield of the two diastereoisomers. Determined by 1H NMR.
ee of the major diastereomers determined by chiral HPLC.
c
substituent led to further decreases in the yield and
stereoselectivity of the reaction, as exemplified by the n-propyl
and benzyl substituted α-amino aldehydes, which gave the
corresponding products 5y and 5z in 52% and 41% yields,
respectively, with poor enantio- and diastereoselectivities
(Table 4, entries 2 and 3). These results therefore suggest
that steric hindrance from the α-substituent was leading to the
observed decrease in the yield and stereoselectivity of these
reactions.
Biphenylmethanols have been used extensively as substrates
in alkylation reactions involving carbonyl compounds.5 With
this in mind, we also evaluated the use of biphenylmethanols in
the current reaction (Scheme 1). Although the alkylation
products 6a and 6b were obtained in high yields under the
optimized conditions, the enantio- and diastereoselectivities
were very poor.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterizations, and H NMR, 13C
■
S
1
The alkylated indole products described above could be
readily converted into a variety of novel indole compounds. For
example, aldehyde 4a was converted to cyclopenta[b]indole 7a
NMR, and HPLC spectra copies for all products as well as X-
ray crystallographic data for compound 7b. This material is
available free of charge via the Internet at http://pubs.acs.org.
C
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Organic Letters
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(14) (a) Bertelsen, S.; Jorgensen, K. A. Chem. Soc. Rev. 2009, 38,
2178. (b) Pellissier, H. Tetrahedron 2007, 63, 9267. (c) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.
AUTHOR INFORMATION
■
Corresponding Author
(15) Goto, T.; Natori, Y.; Takeda, K.; Nambu, H.; Hashimoto, S.
Tetrahedron: Asymmetry 2011, 22, 907.
(16) CCDC 1030822 (7b) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
*E-mail: qxguo@swu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from NSFC (21272002,
21472150), the Fundamental Research Funds for the Central
Universities (XDJK2013B028), and the Program for New
Century Excellent Talents in Universities (NCET-12-0929).
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