Proline-catalyzed enantioselective synthesis of aza-quaternary carbon derivatives

Article abstract of DOI:10.1055/s-0030-1260773

2-Aryl-3H-indol-3-ones reacted with aldehydes or ketones in the presence of l-proline as a catalyst to give the corresponding aza-quaternary carbon addition product in good yield with moderate to excellent regioselectivity and enantioselectivity. The system was applied to the reaction of 2-(2-bromo-phenyl)-3H-indol-3-one and acetaldehyde to give 2-[2-(2-bromophenyl)- 3-oxoindolin-2-yl]acetaldehyde, which is a precursor for the synthesis of some alkaloids such as hinckdentine A. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260773

LETTER
1727
Proline-Catalyzed Enantioselective Synthesis of Aza-Quaternary Carbon
Derivatives
Synthesis of
A
z
i
a-Quat
q
ernary
C
arbo
i
n DerivativesLi, Manyi Han, Mingxing Xiao, Zhixiang Xie*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: xiezx@lzu.edu.cn
Received 13 March 2011
aldol reaction and Beckmann rearrangement sequence
which enable us to accomplish the asymmetric total syn-
thesis of (+)-(11R,12S)-mefloquine hydrochloride, an an-
Abstract: 2-Aryl-3H-indol-3-ones reacted with aldehydes or ke-
tones in the presence of L-proline as a catalyst to give the corre-
sponding aza-quaternary carbon addition product in good yield with
moderate to excellent regioselectivity and enantioselectivity. The
system was applied to the reaction of 2-(2-bromo-phenyl)-3H-in-
dol-3-one and acetaldehyde to give 2-[2-(2-bromophenyl)-3-oxoin-
dolin-2-yl]acetaldehyde, which is a precursor for the synthesis of
some alkaloids such as hinckdentine A.
H
O
N
O
NH
H
Br
OH
O
Br
Key words: aza-quaternary carbon, proline, Mannich reaction,
N
N
hinckdentine A
Br
hinckdentine A
OH
OH
N
O
isatisine A
Chiral amine synthesis is very important for pharmaceuti-
cal drugs and alkaloids as a vast majority of these com-
pounds contain chiral amine functional groups. With this
in mind, synthetic chemists have developed many general
and efficient methods to gain access to chiral amines.1
Asymmetric Mannich reaction is one of the most effective
strategies for the construction of chiral b-amino carbonyl
compounds2 which serve as versatile intermediates for the
synthesis of biologically active compounds and drug can-
didates. However, despite tremendous amount of works
and efforts devoted to the development of asymmetric
Mannich reactions, the structures of the product have been
mostly restricted to aza-tertiary carbon (secondary a-car-
bon). The preparation of aza-quaternary chiral carbon by
asymmetric Mannich reaction is still a difficult problem.
The challenge lies in the fact that the construction of the
aza-quaternary chiral carbon by asymmetric Mannich re-
action needs ketimines derived from ketones as electro-
philes, but ketimines are less reactive to nucleophilic
additions than aldimines owing to steric hindrance in the
C–C bond-forming step. Besides, acyclic ketimines can
easier adopt E- and Z-isomers, and these isomers often
lead to opposite enantiomers of the addition product,
thereby reducing enanioselectivity. Due to these difficul-
ties, only two successful examples have been reported in
the literature.3
Figure 1 Natural products containing aza-quaternary chiral carbon
Table 1 Optimization of Proline-Catalyzed Asymmetric Mannich
Reactiona
O
N
N
Ts
O
1a
1) conditions
2) NaBH4
N
Ts
+
O
CH2OH
N
H
2a
4a
Entry Solvent
Temp
Time
(h)
Yield
(%)b
dr
ee
(°C)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
15
(%)d
1
2
3
4
5
6
7
8
9
CH2Cl2
THF
74
23
23
4
67
70
72
76
84
87
–
nd
nd
nd
nd
nd
nd
–
nd
nd
nd
nd
nd
nd
–
dioxane
MeCN
DMF
4
DMSO
DMF
2
24
2
Proline is an abundant chiral molecule that is inexpensive
and available in both enantiomeric forms. As a commonly
used organocatalyst, proline has been extensively studied
in various reactions.4 We recently reported the synthesis
of chiral amines by proline-catalyzed asymmetric direct
DMF
30
93
95
>95:5c 99
>95:5c 99
DMSO
30
0.5
a Reaction conditions: 1a (0.075 mmol), propionaldehyde (2a, 0.113
mmol), L-proline (20%, 0.015 mmol), in solvent (1 mL) and then re-
duction by NaBH4.
SYNLETT 2011, No. 12, pp 1727–1730
x
x
.x
x
.2
0
1
1
b Yields were calculated after column chromatography.
c Only one diastereomer was observed by 1H NMR analysis.
d The ee was determined by HPLC analysis (OD-H column).
Advanced online publication: 21.06.2011
DOI: 10.1055/s-0030-1260773; Art ID: W06911ST
© Georg Thieme Verlag Stuttgart · New York

1728
L. Li et al.
LETTER
timalarial drug.5 In this letter, we want to report proline- ports on the use of proline-catalyzed asymmetric Mannich
catalyzed asymmetric Mannich reaction for the construc- reaction for the construction of optically active aza-qua-
tion of optically active aza-quaternary carbon derivatives. ternary carbon derivatives, which are ubiquitous in natu-
ral-occurring biologically active substances, such as
The applications of proline-catalyzed asymmetric Man-
isatisine A13 and hinckdentine A (Figure 1).14 Therefore,
nich reaction to the enantioselective synthesis of chiral
it is of great interest to develop new methods for the syn-
amines have been reported by many groups, such as List,6
thesis of optically active aza-quaternary carbon deriva-
Barbas,7 and others.8 In order to improve stereoselectivity
tives by using the proline-catalyzed asymmetric Mannich
and reduce reaction time, proline-catalyzed asymmetric
reaction.
Mannich reactions have been promoted by high pressure,9
microwave conditions,10 ionic liquids,11 and ultrasound.12
However, to the best of our knowledge there are no re-
Table 2 Enantioselective Mannich Reactions of Ketimines 1a and 1b, with Aldehyde or Ketonea
Entry
1
Ketimines
Nucleophile
Mannich product
Time (h)
Yield (%)b drc
eed
O
O
0.5
95
>95:5e
>99
NTs
CHO
NTs
N
N
CH2OH
H
1a
1a
4a
3b
O
2
3
12
76.3f
–
>99
>99
NTs
CHO
N
H
CHO
O
NTs
1a
1a
1
74
83
>95:5e
CHO
N
H
CHO
3c
O
O
NTs
O
4
12
–
94
N
H
3d
O
O
NTs
O
5
6
1a
6
96
79
>95:5e
>99
N
H
3e
3f
O
O
O
10g
4:1
64
CHO
N
N
H
Br
Br
1b
Synlett 2011, No. 12, 1727–1730 © Thieme Stuttgart · New York

LETTER
Synthesis of Aza-Quaternary Carbon Derivatives
1729
Table 2 Enantioselective Mannich Reactions of Ketimines 1a and 1b, with Aldehyde or Ketonea
Entry
7
Ketimines
Nucleophile
Mannich product
Time (h)
24g
Yield (%)b drc
eed
O
CHO
1b
86
98
3:2
66
82
CHO
N
H
Br
3g
O
8
1b
20g
–
CHO
N
Br
CHO
H
3h
a All reactions were carried out with 20 mol% L-proline.
b Isolated yields.
c Ratio was determined by 1H NMR analysis.
d The ee was determined by HPLC analysis (OD-H column).
e Only one diastereomer was observed by 1H NMR analysis.
f The yields were determined based on the recovered substrate.
g DMF was used as solvent.
In our initial studies, proline-catalyzed Mannich reactions phy, respectively (Figure 2).16 The Mannich product 3h
of 1a15 were examined. We envisioned that 1a should be could be readily further modified to achieve the enantiose-
high reactive towards a variety of nucleophiles due to the lective formal synthesis of hinckdentine A, which is a mo-
incorporation of (Z)-C-acylketimine in it. Treatment of 1a lecular target of synthetic interest.17 The total synthesis of
and propionaldehyde with 20 mol% L-proline in CH2Cl2 ( )-hinckdentine A has been reported recently.17e As
at ambient temprature for 74 hours afforded the desired shown in Scheme 1, compound 3h was converted into
Mannich product, which was then reduced by NaBH4 to benzylamine 5, which was then acetylated under standard
the correspording product 4a in 67% yield (Table 1, entry conditions to yield 6, a building block for enantioselective
1). In order to improve the yield and shorten the reaction synthesis of 8-desbromohinckdentine A.17c
time, other solvents were screened, and the results showed
that DMF and DMSO were the best solvents for this
Mannich reaction (Table 1, entries 5 and 6). As low tem-
perature often provide better regioselectivity and enanti-
oselectivity, the influence of the reaction temperature was
also examined. However, when the reaction was per-
formed at 15 °C, no reaction occurred. When the reaction
temperature was raised to 30 °C, the yields were improved
to 93% and 95%, respectively, with very good regioselec-
tivity and enantioselectivity.
Figure 2 The X-ray structure of 3c and 3i
Having optimized the reaction conditions, the substrate
scope was investigated. As shown in Table 2, 2-(2-indol)-
O
3H-indol-3-ones (1a) reacted with various aldehydes or
2,4-dimethoxybenzylamine,
ketones in the presence of 20 mol% L-proline to give the
AcOH, NaBH3CN,
corresponding aza-quaternary carbon addition product in
N
H
MeOH–THF, r.t.
10 h
Br
O
moderare to good yields with exellent regioselectivity and
enantioselectivity (Table 2, entries 1–5). When ketimine
2-(2-bromophenyl)-3H-indol-3-one (1b) reacted with al-
dehydes such as propionaldehyde and 3-methylbutanal,
the regioselectivity and enantioselectivity were both de-
creased (Table 2, entries 6 and 7). In those cases, better
yields were obtained in DMF. Using acetaldehyde (40%
in water) as nucleophilic reagent, the yield and enantio-
selectivity were both improved (Table 2, entry 8).
3h
O
DMBn
DMBn
HN
N
O
O
Ac2O
pyridine
N
N
H
H
Br
5
Br
6
The relative stereochemistry of 3c and the absolute stereo-
chemistry of 3h were determined by X-ray crystallogra-
Scheme 1 Application of the catalytic enantioselective Mannich
reaction to the synthesis of the key precursor 6 for hinckdentine A
Synlett 2011, No. 12, 1727–1730 © Thieme Stuttgart · New York

1730
L. Li et al.
LETTER
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In conclusion, we have developed a facile and effective
strategy for the construction of aza-quaternary carbon ad-
dition product in good yield with moderate to excellent re-
gioselectivity and enantioselectivity. The system was
applied to reaction of 2-(2-bromophenyl)-3H-indol-3-one
(1b) and acetaldehyde to give 2-[2-(2-bromophenyl)-3-
oxoindolin-2-yl]acetaldehyde, which is a precursor for the
synthesis of some alkaloids such as hinckdentine A. Syn-
thetic studies toward aza-quaternary carbon-containing
natural products employing this newly developed method
are under way in this laboratory.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. It includes
experimental procedures and NMR data for all new compounds.
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Acknowledgment
This work is financially supported by 973 Program (Grant
2010CB833203), the National Natural Science Foundation of China
(Grant Nos. 20772050 and 21072083), and the Fundamental Re-
search Funds for the Central Universities (Grant No. lzujbky-2009-
75). We sincerely thank Dr. Wei Yu (Lanzhou University) for help-
ful discussions.
(11) Chowdari, N. S.; Ramachary, D. B.; Barbas, C. F. III. Synlett
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contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/deposit [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax +44 (1223)336033; email:
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