A general approach to high-yielding asymmetric synthesis of chiral 3-alkyl-4-nitromethylchromans via cascade Barbas-Michael and acetalization reactions

Article abstract of DOI:10.1039/c0ob00861c

A general approach to the high-yielding asymmetric synthesis of chiral 3-alkyl-4-nitromethylchromans as drug intermediates was achieved through cascade Barbas-Michael and acetalization (BMA) reactions on 2-(2-nitrovinyl)phenols with aldehydes in the prese

Full text of DOI:10.1039/c0ob00861c

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PAPER
A general approach to high-yielding asymmetric synthesis of chiral
3-alkyl-4-nitromethylchromans via cascade Barbas–Michael and acetalization
reactions†
Dhevalapally B. Ramachary,* M. Shiva Prasad and R. Madhavachary
Received 11th October 2010, Accepted 11th January 2011
DOI: 10.1039/c0ob00861c
A general approach to the high-yielding asymmetric synthesis of chiral 3-alkyl-4-nitromethylchromans
as drug intermediates was achieved through cascade Barbas–Michael and acetalization (BMA)
reactions on 2-(2-nitrovinyl)phenols with aldehydes in the presence of a catalytic amount of
(R)-DPPOTMS and PhCO2H. Herein, we have also demonstrated the application of chiral BMA
products in the synthesis of functionalized chromanes and chromenes in very good yields with high
optical purity, which are very useful compounds in medicinal chemistry.
4-nitromethylchroman-2-ones via cascade “Barbas–Michael and
Introduction
acetalization (BMA) reactions”.3
Chromanes and chromenes are important classes of the benzopy-
Recently Barbas et al. discovered the modern technology of
ran structural unit found in many natural products and are widely
amine-catalyzed Michael reactions of ketones/aldehydes with
used as drug intermediates and ingredients in pharmaceuticals.1
variety of active olefins to provide a variety of Michael adducts
Chiral benzopyran represents a privileged structural unit that is
in good yields with high enantioselectivity, which has become
the “Barbas–Michael reaction”.4 The advent of this bio-mimetic
enamine based technology triggered a burst of activity in the
synthesis of a huge variety of chiral pool of 1,4-adducts.4
available in a range of natural products and drug molecules with
vast biological applications. Thus, it is very much urgent to develop
sustainable asymmetric strategies to construct optically pure chro-
mans and chromenes.2 Interestingly, to the best of our knowledge
there is no report on the direct catalytic asymmetric method for
the synthesis of chiral 3-alkyl-4-nitromethylchromans. Herein, we
are reporting the metal-free approach to the asymmetric synthesis
of functionalized 3-alkyl-4-nitromethylchroman-2-ols and 3-alkyl-
However, the amine-catalyzed Michael reaction of aldehydes 1
with 2-(2-nitrovinyl)phenols 2 was not known and resulting prod-
ucts 5/6 have a wide range of uses in pharmaceutical chemistry (see
Scheme 1) and also there is no methodology available to prepare
even achiral compounds 5/6.5 Herein, we have reported a metal-
free technology for the asymmetric synthesis of substituted 3-alkyl-
4-nitromethylchroman-2-ols 5/6, 3-alkyl-4-nitromethylchroman-
2-ones 7/8 and 2-(3-hydroxy-2-alkyl-1-nitromethylpropyl)phenols
9/10 by using organocatalytic BMA, oxidation and reduction
reactions from easily available aldehydes 1, 2-(2-nitrovinyl)phenols
2, amines 3, acids 4, PCC or IBX and NaBH4 (Scheme 1).
School of Chemistry, University of Hyderabad, Hyderabad, -500 046, India.
E-mail: ramsc@uohyd.ernet.in; Fax: +91-40-23012460
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data (1H NMR, 13C NMR, HRMS and HPLC)
for all new compounds. CCDC reference number 795663. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00861c
In a continuation of our investigation for new reactive species
for the development of green asymmetric cascade reactions,6
Scheme 1 Direct organocatalytic asymmetric cascade BMA reactions.
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Table 1 Reaction optimization for the cascade BMA reaction of 1a and 2a
Entry
Catalyst 3/4 (20/20 mol%)
Solvent (0.25 M)
Time (h)
Product yield (%)a
ee (%)b
de (%)b
5aa
52
70
76
93
65
60
92
80
89
87
87
96
95
72
70
7aa
50
50
63
63
50
50
50
40
65
50
50
60
70
50
50
7aa
31
46
97
99
87
96.7
97
97.8
98
96.6
98
7aa
90
63
88
95
66
81
69
66
82
76
79
95
93
43
32
1
2
3
4
5
6
7
8
3a
DMSO
DCM
Hexane
Hexane
Et2O
Toluene
DCM
DCM
DCM
C6H5CH3
DCM
DCM
DCM
8
4
10
18
4
4
2
2
1
2
2
1
0.5
24
36
3b/PhCO2H 4a
3c
3c/4a
3c/4a
3c/4a
3c/MeCO2H 4b
3c/Ph2CHCO2H 4c
3c/4a
9
10
11
12
13c
14
15
3d/4a
3d/4a
3e/4a
-99.9
-99.9
-87
-85
3e/4a
3f/4a
3f/4a
DCM
C6H5CH3
a Yield refers to the column-purified product. b ee and de determined by CSP HPLC analysis. c Oxidation was carried out with 1.5 equiv. of IBX in CHCl3
at 65 ◦C for 15–24 h.
we decided to explore the 2-(2-nitrovinyl)phenols 2 as an active
olefin in an amine-catalyzed BMA reaction with aldehydes 1.
We thought that the reaction of 2-(2-nitrovinyl)phenols 2 with
in situ-generated enamine from aldehydes 1 would lead to 3-(2-
hydroxyphenyl)-2-alkyl-4-nitrobutyraldehydes. However, Michael
adducts were not detected and instead it has shown the completely
cyclized lactol product of 3-alkyl-4-nitromethylchroman-2-ols 5/6
under the standard reaction conditions. This interesting result
represents a novel tool for the preparation of chiral lactols 5/6
and a new reactivity for amine catalysts. Herein, we report our
findings regarding these new cascade asymmetric reactions.
and also for the clear HPLC separation, we transformed the crude
product 5aa/6aa into two easily separable products cis-7aa and
trans-8aa with 50% yield via PCC oxidation in DCM at 25 ◦C for
1–2 h (see Table 1). In a further optimization, reaction of 1a and
2a in DCM under 20 mol% of diamine/PhCO2H 3b/4a-catalysis
followed by PCC oxidation furnished the major product cis-(-)-
7aa in 50% yield with only 46% ee and 63% de (Table 1, entry 2).
Interestingly, reaction of 1a with 2a in hexane under 20 mol%
of (S)-a,a-diphenylprolinol trimethylsilyl ether (L-DPPOTMS)
3c-catalysis at 25 ◦C for 10 h furnished the lactols 5aa/6aa in
76% yield, which on further oxidation with PCC furnished the
major product cis-(-)-7aa in 63% yield with 97% ee and 88%
de (Table 1, entry 3). The same reaction under 20 mol% of L-
DPPOTMS/PhCO2H 3c/4a-catalysis in hexane for 18 h furnished
the lactols 5aa/6aa in 93% yield, which on further PCC oxidation
furnished the major product cis-(-)-7aa in 63% yield with 99% ee
and 95% de (Table 1, entry 4).
Results and discussion
Direct amine-catalyzed asymmetric cascade BMA reaction of
propionaldehyde with 2-methoxy-6-(2-nitrovinyl)phenol: reaction
optimization
To further improve the asymmetric BMA reaction, especially
for decreasing the reaction time to <1 h and increasing the ee/de
to >99.9%, we tested the BMA reaction of 1a and 2a catalyzed
by 3c and 3d with different acids 4a–c as co-catalysts in various
solvents. But none of these results are superior compared to entry
4 except in decreasing the reaction time (Table 1, entries 5–11).
Interestingly, cascade BMA reaction of 1a with 2a in DCM under
20 mol% of D-DPPOTMS/PhCO2H 3e/4a-catalysis at 25 ◦C for
1 h furnished the lactols 5aa/6aa in 96% yield, which on further
oxidation with PCC furnished the major product cis-(+)-7aa in
For the optimization of designed BMA reaction, we screened a
number of organocatalysts for the reaction of 2-methoxy-6-(2-
nitrovinyl)phenol 2a with 10 equiv. of propionaldehyde 1a and
some important results are shown in Table 1. Interestingly, reaction
of 2a with 10 equiv. of 1a in DMSO under 20 mol% of L-proline 3a-
catalysis furnished the 1 : 1 ratio of cis-lactol/trans-lactol of major
product syn-5aa in 52% yield with 31% ee and 90% de along with
minor isomer anti-6aa (see Scheme 1 and Table 1, entry 1). For the
clear understanding of diastereoselectivity between 5aa and 6aa;
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Table 2 High-yielding synthesis of chiral BMA products 5, 7 and 9abc
a Reactions were carried out in DCM (0.25 M) with 10 equiv. of 1a or 1.5 equiv. of 1b–f relative to the 2a–j (0.5 mmol) in the presence of 20 mol% of
catalyst 3e/4a. b Yield refers to the column-purified product. c ee and de were determined by CSP HPLC analysis (see SI†).
60% yield with 99.9% ee and 95% de (Table 1, entry 12). The yield
of the oxidation product cis-(+)-7aa was improved by treating
crude 5aa/6aa with 1.5 equiv. of IBX in CHCl3 at 65 ◦C for 15-24
h as shown in Table 1, entry 13. After successful results with chiral
D-DPPOTMS 3e as a catalyst, we were interested in screening
alkaloid based primary amines like 9-amino-9-deoxyepiquinine 3f
as the catalyst for the BMA reaction to monitor the outcome of
selectivity (Table 1, entries 14–15).7 Interestingly, BMA reaction
of 2a with 10 equiv. of 1a under 20 mol% of 3f/4a-catalysis in
DCM or toluene for 24/36 h, followed by oxidation, furnished
the major product cis-(+)-7aa in 50% yield with only 87/85% ee
and 43/32% de, respectively (Table 1, entries 14–15). Finally we
envisioned the optimized condition to be 25 ◦C in DCM under 20
mol% of D-DPPOTMS/PhCO2H 3e/4a-catalysis followed by IBX
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Scheme 2 Synthesis of chromanes with three contiguous stereocenters.
oxidation to furnish the highly substituted cascade BMA product
cis-(+)-7aa in 70% yield with 99.9% ee and 93–95% de (Table 1,
entry 13). Structure and absolute stereochemistry of cascade BMA
products 5aa/6aa and 7aa/8aa was confirmed by NMR analysis
and also finally confirmed by X-ray structure analysis on (-)-7aa
as shown in Figure S1 (see Supporting Information†).8
lactols 5 in the synthesis of functionalized chiral chromanes and
chromenes via acid-catalysis as shown in Schemes 2–4. Reaction of
pure lactol (+)-5ab with 20 mol% of p-TSA in polar protic solvent
of MeOH (a) at 0 ◦C for 0.5 h, and 25 ◦C for 3 h, furnished
the cyclized 2-methoxy-3-methyl-4-nitromethylchromane trans-
(-)-5aba in 63% yield with 98% ee and cis-(+)-5aba in 25% yield
with 99% ee as shown in Scheme 2. In a similar manner, reaction of
(+)-5ad with 40 mol% of p-TSA in MeOH (a) at 0 ◦C for 0.5 h, and
25 ◦C for 5 h, furnished the cyclized 6-chloro-2-methoxy-3-methyl-
4-nitromethylchromane trans-(-)-5ada in 65% yield with 81% ee
and cis-(+)-5ada in 21% yield with 90% ee as shown in Scheme
2. Interestingly, isomers of chiral chromanes cis-5aba–ada/trans-
5aba–ada containing three contiguous stereocenters are easily
separated from simple column chromatography and also diversity-
oriented synthesis of these chiral chromanes could be obtained
from sequential one-pot operation for synthetic applications.
Interestingly, a similar type cyclization reaction on cis-lactol
(+)-5aa with 5–10 mol% of p-TSA in nonpolar aprotic solvent
Diversity-oriented synthesis of chiral BMA products 5–9
With the optimized reaction conditions in hand, the scope of
the amine-catalyzed asymmetric cascade BMA reactions was
investigated.9 A series of substituted 2-(2-nitrovinyl)phenols 2a–j
were reacted with 10 equiv. of propionaldehyde 1a catalyzed by 20
◦
mol% of 3e/4a at 25 C in DCM, for 0.5–4 h, to furnish chiral
cascade BMA products 5aa–aj with very good yields, ee’s and de’s,
which on further oxidation with IBX or reduction with NaBH4,
furnished the products 7 and 9, respectively (Table 2).10 The chiral
cascade products 5aa–aj, 7aa–aj and 9aa–aj were obtained as
major isomers with excellent yields, ee’s and de’s. Without showing
much of electronic factors, neutral, electron-withdrawing and
electron-donating substituted 2-(2-nitrovinyl)phenols 2a–j gener-
ated expected products 5aa–aj, 7aa–aj and 9aa–aj with excellent
yields, ee’s and de’s (see Table 2). Fascinatingly, reaction of 2-
(2-nitrovinyl)phenol 2b with propionaldehyde 1a under 3e/4a-
catalysis furnished the cis-lactol (+)-5ab as the major product in
90% yield, which on further reduction with NaBH4 furnished the
diol (+)-9ab as the major product with >95% yield with 89% ee
and >99% de (Table 2, entry 2). In a similar manner, 2-methoxy-
6-(2-nitrovinyl)phenol 2a was reacted with a series of aldehydes
1b–f, catalyzed by 20 mol% of 3e/4a at 25 ◦C in DCM for 6–
9 h, to furnish chiral cascade BMA products 5ba–fa with very
good yields, ee’s and de’s, which on further oxidation with IBX
or reduction with NaBH4, furnished the products 7ba–fa and
9ba–fa, respectively (Table 2). Structure and stereochemistry of
BMA products 5aa–fa, 7aa–fa and 9aa–fa was confirmed by NMR
analysis.
◦
of toluene at 110 C for 1 h furnished the selectively cyclized 8-
methoxy-3-methyl-4-nitromethyl-4H-chromene (-)-11aa in 86%
yield with 99% ee as shown in Scheme 3. Hydrogenation of (-)-
11aa with 10% Pd/C in methanol at 25 ◦C for 4 h followed by base-
induced Boc2O protection furnished the partially hydrogenated
amine (-)-12aa in 75% yield with 81% ee. The same hydrogenation
on (-)-11aa for a longer reaction time (14 h) followed by base-
induced Boc2O protection furnished the completely hydrogenated
amine (+)-13aa in 75% yield with <5% de and each 93% ee as
shown in Scheme 3. In a similar manner, reaction of cis-lactol (+)-
5ab with 10 mol% of p-TSA in toluene at 110 ◦C for 1 h furnished
the selectively cyclized 3-methyl-4-nitromethyl-4H-chromene (-)-
11ab in 90% yield with 94% ee as shown in Scheme 3. Double
◦
hydrogenation of (-)-11ab with 10% Pd/C in methanol at 25 C
for 8 h followed by base-induced Boc2O protection furnished the
completely hydrogenated amine (+)-13ab in 85% yield with <5%
de and 94% ee as shown in Scheme 3.
As illustrated in Scheme 4, highly functionalized chromane
acetates containing three contiguous stereocenters could be
produced through cascade Wittig reaction followed by intra-
molecular oxa-Michael addition (W/OM) on the BMA com-
pound of (+)-5aa with Ph3P CHCO2Me. The two isomers cis-
14aa and trans-14aa were furnished in 26% yield with 99% ee
and 28% yield with 99% ee, respectively, as shown in Scheme 4.
Applications of chiral BMA products
Synthesis of functionalized chiral chromanes and chromenes
based on the BMA platform. With synthetic and pharmaceutical
applications in mind, we decided to explore the utilization of cis-
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Scheme 3 Synthesis of chiral chromenes and their applications.
Scheme 4 Synthesis of chiral chromane acetates via cascade W/OM reactions on BMA products.
Structure and stereochemistry of cascade W/OM products 14aa
was confirmed by NMR analysis and also finally confirmed by 1H–
1H COSY analysis on (+)-cis-14aa (see Supporting Information†).
Functionalized chiral methyl chromane acetates 14 could be
suitable starting materials for the synthesis of vitamin E analogues.
Compounds (-)-5ada, (-)-12aa and (+)-13aa are drug-like
molecules; these types of molecules are used for the treatment
of potent anti-ischemic property, anti-hypertensives, spasmolytics
for blood vessels and also as potassium channel blockers, which
emphasizes the value of this BMA approach to pharmaceuticals.1
In addition, the presently discovered cascade BMA technology
will be suitable to develop the substituted benzopyran structural
unit, which is found in many natural products and designed drug
molecules.2a
electrostatic interactions between the partially positive nitrogen
of the quinine and the partially negative nitro group, and also
between the partially positive phenolic OH and the partially
negative quinine OMe in the transition state (Fig. 1). The observed
stereochemistries of the products 5 could be explained by approach
of the 2a–j from the less hindered re-face to the re- or si-face of
enamine as shown in TS-2.
Conclusions
In summary, we have developed the D-DPPOTMS/PhCO2H
3e/4a-catalyzed asymmetric cascade BMA reaction of aldehydes
with 2-(2-nitrovinyl)phenols at ambient conditions. The cascade
asymmetric reaction proceeds in very good yields with high
selectivity using 3e/4a as the catalyst. Furthermore, we have
demonstrated the application of chiral lactol products 5 in the
synthesis of functionalized chromanes and chromenes, which are
very useful compounds in medicinal chemistry. Further work is
in progress to utilize chiral lactols 5 as intermediates for the bio-
active molecules synthesis.
Mechanistic insights
Although further studies are needed to firmly elucidate the mech-
anism of the phenol group involvement in an asymmetric BMA
reaction through 3e/4a- or 3f/4a-catalysis, the reaction most likely
proceeds via an enamine mechanism (see Fig. 1). In the case of the
addition of aldehydes 1a–f to substituted 2-(2-nitrovinyl)phenols
2a–j via D-DPPOTMS/PhCO2H 3e/4a-catalysis, we can rational-
ize the observed stereochemistries through a favoured transition
state where the less hindered re-face of 2a–j approaches the re-face
of enamine as shown in TS-1. In the case of 3f/4a-catalysis, the
observed similar enantioselectivity and poor diastereoselectivity
may be explained by model TS-2, in which there are favourable
Experimental
1
General methods. The H NMR and 13C NMR spectra were
recorded at 400 MHz and 100 MHz, respectively. The chemical
shifts are reported in ppm downfield to TMS (d = 0) for 1H
NMR and relative to the central CDCl3 resonance (d = 77.0)
for 13C NMR. In the13C NMR spectra, the nature of the carbons
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Fig. 1 Proposed transition states for the cascade BMA reactions.
(C, CH, CH2 or CH3) was determined by recording the DEPT-135
experiment, and is given in parentheses. The coupling constants J
are given in Hz. Column chromatography was performed using
Acme’s silica gel (particle size 0.063–0.200 mm). High-resolution
mass spectra were recorded on micromass ESI-TOF MS. GC-
MS mass spectrometry was performed on Shimadzu GCMS-
QP2010 mass spectrometer. Elemental analyses were recorded on
a Thermo Finnigan Flash EA 1112 analyzer. LC-MS mass spectra
were recorded on either a VG7070H mass spectrometer using
EI technique or a Shimadzu-LCMS-2010A mass spectrometer.
IR spectra were recorded on JASCO FT/IR-5300 and Thermo
Nicolet FT/IR-5700. The X-ray diffraction measurements were
carried out at 298 K on an automated Enraf-Nonious MACH
3 diffractometer using graphite monochromated, Mo-Ka (l =
1.5 equiv.). After stirring the reaction mixture at 65 ◦C for 15–24
h, it was brought to 25 ◦C and the crude reaction mixture was
passed through a pad of celite and concentrated to dryness. Pure
chiral products 7 were obtained by column chromatography (silica
gel, mixture of hexane–ethyl acetate).
General procedure for the reduction of cascade BMA products.
In an oven dried round bottom flask, to the lactol 5/6 (0.3 mmol),
dry MeOH (3.0 mL), and NaBH4 (0.45 mmol, 1.5 equiv.) was
added. After stirring the reaction mixture at 0 ◦C for 0.5 h,
it was brought to 25 ◦C and the crude reaction mixture was
worked up with aqueous NH4Cl solution. The aqueous layer
was extracted with dichloromethane (3 ¥ 10 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated. Pure
chiral products 9 were obtained by column chromatography (silica
gel, mixture of hexane–ethyl acetate).
˚
0.71073 A) radiation with CAD4 software, or the X-ray intensity
data were measured at 298 K on a Bruker SMART APEX CCD
area detector system equipped with a graphite monochromator
˚
and a Mo-Ka fine-focus sealed tube (l = 0.71073 A). For thin-
layer chromatography (TLC), silica gel plates Merck 60 F254 were
used and compounds were visualized by irradiation with UV light
and/or by treatment with a solution of p-anisaldehyde (23 mL),
conc. H2SO4 (35 mL), acetic acid (10 mL), and ethanol (900 mL)
followed by heating.
Brønsted acid-catalyzed hydrolysis of cascade BMA products.
In an oven dried round bottom flask, to the lactol 5/6 (0.3 mmol),
dry toluene (3.0 mL), and p-TSA·H2O (3.5 mg, 10 mol%) was
added. After heating the reaction mixture to 110 ◦C for 1 h,
it was brought to 25 ◦C and the crude reaction mixture was
worked up with aqueous NaHCO3 solution. The aqueous layer
was extracted with dichloromethane (3 ¥ 10 mL). The combined
organic layers were dried (Na2SO4), filtered and concentrated.
Pure chiral products 11 were obtained by column chromatography
(silica gel, mixture of hexane–ethyl acetate).
Materials. All solvents and commercially available chemicals
were used as received.
General experimental procedures for the cascade BMA reactions
General procedure for amine-catalyzed asymmetric cascade BMA
reaction of aldehydes 1 with 2-(2-nitrovinyl)phenols 2. In an
ordinary glass vial equipped with a magnetic stirring bar, to
a mixture of D-DPPOTMS 3e (0.1 mmol) and PhCO2H 4a
(0.1 mmol) in DCM (2.0 mL), was added propionaldehyde 1a
(5.0 mmol, 10 equiv.) or aldehydes 1b–f (0.75 mmol, 1.5 equiv.)
and 2-(2-nitrovinyl)phenols 2a–j (0.5 mmol). After stirring the
reaction mixture at 25 ◦C as shown in Tables 1–2, the crude
reaction mixture was worked up with aqueous NH4Cl solution and
the aqueous layer was extracted with ethyl acetate (3 ¥ 10 mL).
The combined organic layers were dried (Na2SO4), filtered and
concentrated. Pure chiral products 5/6 were obtained by column
chromatography (silica gel, mixture of hexane–ethyl acetate).
Hydrogenation followed by protection of nitro products. In an
oven dried round bottom flask, activated (10%) Pd/C (7 mg, 10
mol%) was taken with compound (-)-11aa (0.3 mmol), dissolved
in dry MeOH (3.0 mL) and stirred under H2 atmosphere at 25 ◦C
for 4 or 14 h. The reaction mixture was passed through a pad of
celite and concentrated to dryness. The crude mixture was taken
in a dry oven dried round bottom flask in dry DCM (3.0 mL) and
dry triethylamine (60 mL, 0.4 mmol) and di-tert-butyl carbonate
(86 mg, 0.4 mmol) was successively at 0 ◦C. The resulting mixture
was stirred at 25 ◦C for 2 h and then worked up with aqueous
NH4Cl. The aqueous layer was extracted with ethyl acetate (3 ¥
10 mL). The combined organic layers were dried (Na2SO4), filtered
and concentrated. Pure product (-)-12aa or (+)-13aa was obtained
by column chromatography (silica gel, mixture of hexane–ethyl
acetate).
General procedure for the oxidation of cascade BMA products
with IBX. In an oven dried round bottom flask, to the lactol
5/6 (0.3 mmol), added dry CHCl3 (3.0 mL), and IBX (0.45 mmol,
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5 For organocatalytic asymmetric sequential Michael-acetalization
(SMA) reactions of acetone with 2-(2-nitrovinyl)phenols and methanol,
see: D. B. Ramachary and R. Sakthidevi, Org. Biomol. Chem., 2010, 8,
4259–4265.
6 For selected recent papers on asymmetric cascade reactions from our
group, see: (a) D. B. Ramachary and M. Kishor, J. Org. Chem., 2007,
72, 5056–5068; (b) D. B. Ramachary and R. Sakthidevi, Org. Biomol.
Chem., 2008, 6, 2488–2492; (c) D. B. Ramachary and M. Kishor,
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Sakthidevi, Chem.–Eur. J., 2009, 15, 4516–4522; (e) D. B. Ramachary
and Y. V. Reddy, J. Org. Chem., 2010, 75, 74–85.
7 For selected recent papers on 9-amino-9-deoxyepiquinine 3f-catalyzed
asymmetric reactions, see: (a) C. M. Reisinger, X. Wang and B. List,
Angew. Chem., Int. Ed., 2008, 47, 8112–8115; (b) M. W. Paixao, N.
Holub, C. Vila, M. Nielsen and K. A. Jørgensen, Angew. Chem., Int.
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Biomol. Chem., 2010, 8, 2859–2867 and references therein.
8 CCDC-795663 for (-)-7aa contains the supplementary crystallo-
graphic data for this paper. This data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html or
from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; or
mailto:deposit@ccdc.cam.ac.uk. See supporting information for crys-
tal structure†.
9 For organocatalytic synthesis of substituted 2-(2-nitrovinyl)phenols2a–
j, see: D. B. Ramachary and R. Sakthidevi, Org. Biomol. Chem., 2010,
8, 4259–4265.
10 For organocatalytic high-yielding synthesis of racemic products 5aa–
fa, 7aa–fa and 9aa–fa from 1a–f and 2a–j through DL-proline-catalysis,
see Table S1 in Supporting Information-I.† For, the ee and de’s of minor
compounds 6/8/10, see Supporting Information-I and II†.
Acknowledgements
This work was made possible by a grant from the Department
of Science and Technology (DST), New Delhi [Grant No.:
DST/SR/S1/OC-65/2008]. MSP and RM thank Council of
Scientific and Industrial Research (CSIR), New Delhi for their
research fellowship. We thank Dr P. Raghavaiah for his help in
X-ray structural analysis.
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