Facile construction of vicinal quaternary and tertiary stereocenters via regio- and stereoselective organocatalytic michael addition to nitrodienes

Article abstract of DOI:10.1002/adsc.201100618

A highly regio- and stereoselective protocol for the synthesis of vicinal quaternary and tertiary stereocenters has been developed. The 6′-OH Cinchona alkaloids (BnCPN or BnCPD) at low catalyst loading (0.5-5 mol%) catalyze the Michael addition of trisubstituted carbon nucleophiles to nitrodienes in good to excellent yield (up to >99), high enantioselectivity (up to 99% ee) and high diastereoselectivity (up to >99:1 dr) under mild reaction conditions. Copyright

Full text of DOI:10.1002/adsc.201100618

FULL PAPERS
DOI: 10.1002/adsc.201100618
Facile Construction of Vicinal Quaternary and Tertiary
Stereocenters via Regio- and Stereoselective Organocatalytic
Michael Addition to Nitrodienes
Pankaj Chauhana and Swapandeep Singh Chimnia,*
a
Department of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru Nanak Dev University, Amritsar –
143005, India
Fax : (+91)-183-225-8820; e-mail: sschimni@yahoo.com or sschimni.chem@gndu.ac.in
Received: August 3, 2011; Published online: November 17, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100618.
Abstract: A highly regio- and stereoselective proto- enantioselectivity (up to 99% ee) and high diastereo-
col for the synthesis of vicinal quaternary and terti- selectivity (up to >99:1 dr) under mild reaction con-
ary stereocenters has been developed. The 6’-OH ditions.
Cinchona alkaloids (BnCPN or BnCPD) at low cata-
lyst loading (0.5–5 mol%) catalyze the Michael addi-
tion of trisubstituted carbon nucleophiles to nitro- Keywords: Cinchona alkaloids; Michael addition; ni-
dienes in good to excellent yield (up to >99), high trodienes; organocatalysis; quaternary stereocenter
Introduction
co-workers have successfully extended the catalytic
application of chiral bifunctional guanidine catalysts
The asymmetric Michael addition to nitroalkenes has for the addition of tri-substituted b-keto esters to ni-
emerged as one of the most important carbon-carbon trodienes in order to obtain adjacent quaternary and
bond-forming reactions for the synthesis of valuable tertiary stereocenters.[4c]
chiral entities.[1] Nitro-olefins are considered as excel-
The vicinal quaternary and tertiary stereocenters
lent electrophiles for the catalytic asymmetric Mi- are present in many natural products and biologically
chael reaction, due to their high reactivity and the hy- important molecules. Significant progress have been
drogen bond accepting ability of the nitro functionali- made towards the asymmetric synthesis of adjacent
ty.[2] The corresponding nitroalkanes are synthetically quaternary and tertiary stereocenters.[5] Owing to
useful molecules, since the nitro group can be trans- steric encumbrance, the stereoselective construction
formed into other valuable functional groups. The of quaternary stereocenters is considered to be a syn-
synthetic utility of nitro-olefins can be enhanced by thetic challenge for organic chemists, requiring rela-
the introduction of a carbon-carbon double bond in tively harsh reaction conditions.[6]
conjugation with the nitro-olefinic double bond. The
On the other hand, for the synthesis of potentially
nitrodienes have an additional reactive site, i.e., a bioactive chiral molecules and their precursors, it is
double bond, that can be exploited widely for the imperative to synthesize both enantiomers of the
construction of synthetically valuable and potentially target molecules. In this regard Cinchona alkaloids
bioactive targets. Furthermore, in nitrodienes, there have emerged as valuable organocatalysts since by
exists the additional possibilty of d-attack rather than using the pseudoenantiomeric catalysts, both enantio-
b-attack due to the two conjugate double bonds. So mers of the product can be synthesized.[7,8]
far, only a little progress has been made for the devel-
During our current investigations on bifunctional
opment of asymmetric Michael reactions employing Cinchona alkaloids-catalyzed carbon-cabon bond for-
nitrodienes as acceptors.[3,4] Although the nitrodienes mation,[9] we envisaged that the quinuclidine nitrogen
have emerged as effective electrophiles in asymmetric of the Cinchona alkaloids activates the prochiral nu-
enamine catalysis,[3] there are limited examples of cleophile and the hydroxy group (9-OH/or 6’-OH
their use as Michael acceptor in non-covalent bifunc- group) of the catalyst activates and orients the nitro-
tional hydrogen bond catalysis[4]. Recently, Feng and diene through hydrogen bonding with the nitro group.
Adv. Synth. Catal. 2011, 353, 3203 – 3212
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Pankaj Chauhan and Swapandeep Singh Chimni
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Herein, we disclose the catalytic potential of bifunc- dition of the trisubstituted b-keto ester (6a) to nitro-
tional Cinchona-derived organocatalysts for the diene 7a in toluene at room temperature (Table 1).
highly regio- and stereoselective conjugate addition of All Cinchona alkaloids (Figure 1) provided very high
trisubstituted carbon nucleophiles to nitrodienes for yields of 8a in short reaction times, although the ste-
the construction of vicinal quaternary and tertiary ste- reoselectivity varied from catalyst to catalyst. The nat-
reocenters.
ural (QN, CD, CN and QD) and 9-OH protected Cin-
chona alkaloids (BnQN and AcQN) provided moder-
ate ee and high dr (Table 1, entries1–6). In order to
achieve better results in terms of enantioselectivity,
the 6’-OH Cinchona alkaloids were employed, as
Results and Discussion
Our initial experiments involved the screening of dif- these catalysts have shown great potential as bifunc-
ferent Cinchona alkaloid catalysts (10 mol%) for ad- tional organocatalysts for asymmetric conjugate addi-
tion reactions.[10,11] Cupreine (CPN) affords 8a with
Table 1. Catalyst screening and optimization.[a]
91% ee and dr of 91:9 (Table 1, entry 7). BnCPN pro-
vide the 1,4-adduct 8a with 97% ee and 91:9 dr
(Table 1, entry 8). The other 9-OH alkylated 6’-OH
Cinchona catalysts such as 1g and 1h provide similar
levels of stereoselectivity (Table 1, entries 9 and 10).
The esterified catalysts BzCPN and AcCPN also pro-
vide 8a in high enantioselectivity but with lower dia-
stereoselectivity (Table 1, entries 11 and 12). The
pseudoenantiomeric 6’-OH Cinchona alkaloid cata-
lysts derived from quinidine such as cupreidine
(CPD), BnCPD and b-ICPD provide the desired
product 8a with high enantioselectivity of opposite
enantiomer (Table 1, entries 13–15). The thiourea de-
rivatives of Cinchona alkaloids (CDT and QDT) re-
sulted in moderate ee and high dr of up to 95:5
(Table 1, entries 16 and 17).
Entry Catalyst [x
mol%]
Time
[h]
Yield
[%][b]
dr[c] ee
[%][d]
1
2
3
4
5
6
7
8
QN (10)
CD (10)
CN (10)
QD (10)
BnQN(10)
AcQN (10)
CPN (10)
BnCPN (10)
NpCPN (10)
C14H29CPN (10)
BzCPN (10)
AcCPN (10)
CPD (10)
6
6
6
6
10
10
5
5
5
5
5
5
5
5
5
5
5
98
99
98
99
96
97
99
98
99
98
97
97
98
99
98
98
99
97
96
97
98
99
97
97
72
38
90:10 À45
90:10 À61
90:10 60
90:10 40
91:9 46
91:9 44
91:9 91
91:9 97
91:9 95
91:9 97
82:18 97
83:17 96
91:9 À89
91:9 À94
91:9 À82
95:5 70
95:5 81
91:9 96
91:9 96
91:9 97
91:9 96
91:9 97
91:9 97
91:9 97
91:9 97
91:9 97
The effect of additives such as molecular sieves,
benzoic acid and thiouredic acid (5) on the stereose-
9
10
11
12
13
14
15
16
17
BnCPD (10)
b-ICPD (10)
CDT (10)
QNT (10)
18[e] BnCPN (10)
6
19[f]
20[g] BnCPN (10)
BnCPN(10)
10
10
6
10
15
24
81
120
21
22
23
24
25
26
BnCPN (5)
BnCPN (2)
BnCPN (1)
BnCPN (0.5)
BnCPN (0.25)
BnCPN (0.1)
[a]
Unless otherwise noted, reactions were carried out with
0.3 mmol of 6a and 0.2 mmol of 7a in 0.2 mL of toluene
with x mol% of catalyst at room temperature.
Yield refers to isolated yield after column chromatogra-
phy.
dr refers to diastereomeric ratio after short column chro-
matography.
ee refers to enantiomeric excess of major diastereomer.
4ꢁ molecular sieves (4ꢁ MS) were added.
10 mol% of PhCOOH was added.
[b]
[c]
[d]
[e]
[f]
Figure 1. Structures of organocatalysts and additive used.
[g]
10 mol% of 5 was used as additive .
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Facile Construction of Vicinal Quaternary and Tertiary Stereocenters
Table 2. Solvent screening.[a]
lectivity of the BnCPN-catalyzed reaction of 6a with
7a was evaluated. The additives slowed down the re-
action and did not show any improvement in the ee
and dr of the 8a (entries 18–20). On reducing the cat-
alyst loading from 10 mol% to 1 mol% stereoselectiv-
ity of 8a remained nearly the same (entries 21–23).
The 1 mol% of BnCPN provides 97% of 8a with 97%
ee and 91:9 dr in 15 h (Table 1, entry 23). Further low-
ering of the catalyst loading did not effect the stereo-
chemical outcome of the reaction although a decrease
in the reaction rate was observed (Table 1, entries 24–
26).
Entry Solvent
Time [h] Yield [%][b] dr[e] ee [%][d]
1
2
3
4
5
6
7
8
9
10
toluene
xylene
CHCl3
CH2Cl2
ClCH2CH2Cl 18
THF
MTBE
diethyl ether 12
DMF
MeOH
15
15
15
15
98
99
98
>99
97
99
98
99
26
66
91:9 97
91.9 97
90:10 96
94:6 97
94:6 96
93.7 96
93:7 97
92:8 90
91:9 84
89:11 66
18
16
36
36
A very small effect on the yield and stereoselectiv-
ity of adduct 8a was observed on screening different
solvents with 1 mol% of BnCPN (Table 2). Dichloro-
methane turns out to be the solvent of choice that
provides the product 8a in quantitative yield, 97% ee
and 94:6 dr after 15 h (Table 2, entry 4).
[a]
Reactions were carried out with 0.3 mmol of 6a and
0.2 mmol of 7a in 0.2 mL of solvent with 1 mol% of
BnCPN at room temperature.
Yield refers to isolated yield after column chromatogra-
phy.
dr refers to diastereomeric ratio after short column chro-
matography.
ee refers to enantiomeric excess of major diastereomer.
[b]
[c]
[d]
Table 3. BnCPN-catalyzed asymmetric Michael reaction of prochiral trisubstituted nucleophiles with nitrodienes.[a]
Entry
Nucleophile
Nitrodiene
Time [h]
Product
Yield [%][b]
dr[c]
ee [%][d]
1
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6d
6e
6f
6f
6g
6h
6i
7a
7b
7c
7d
7e
7f
7g
7h
7a
7a
7a
7e
7a
7a
7e
7a
7a
7a
15
24
24
48
48
36
96
36
18
60
72
96
48
72
96
96
15
60
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
>99
98
99
92
91
97
74
77
99
88
92
80
94
82
73
63
93
93
94:6
96:4
93:7
90: 10
89:11
93:7
>99:1
65:35
89:11
96:4
97:3
98:2
88:12
99:1
99:1
65:35
56:44
79:21
97
96
95
91
93
97
88
2[e]
3[e]
4
5
6
7[f]
8
91, 95[g]
90
93
97
98
95
9
10
11
12
13
14
15
16[f]
17[f]
18
99
98
96, 75[g]
93, 89[g]
90
[a]
Unless noted, reactions were carried out with 0.3 mmol of 6 and 0.2 mmol of 7 in 0.2 mL of CH2Cl2 with 1 mol% of 1f.
Yield refers to isolated yield after column chromatography.
dr refers to diastereomeric ratio after short column chromatography.
ee refers to enantiomeric excess of major diastereomer.
0.5 mol% of catalyst was used.
[b]
[c]
[d]
[e]
[f]
5 mol% of catalyst was used.
ee of minor diastereomer.
[g]
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After optimization, the substrate scope was evaluat- dicates a high turnover number for this transforma-
ed by screening different nitrodienes (7) and trisubsti- tion (Table 5). Generally, the turnover numbers of or-
tuted carbon nucleophiles (6) using BnCPN as cata- ganocatalytic reactions are lower than those of transi-
lyst in dichloromethane at room temperature tion metal-mediated processes. A high catalyst turn-
(Table 3). Initially, the screening was carried out with over renders this transformation ideal for industrial
6a as nucleophile with nitrodienes (7b and 7c) substi- applications. To demonstrate this, a gram scale reac-
tuted with electron-withdrawing groups in the aromat- tion was performed between 6a and 7a in the pres-
ic ring. The products (8b and 8c) were isolated in ex- ence of 0.5 mol% of BnCPN. The product 8a was iso-
cellent yield and high stereo-induction with 0.5 mol% lated in 98% yield and with same level of stereoselec-
of catalysts (Table 3, entries 2 and 3). The nitrodienes tivity (Scheme 1). The enantiopure catalyst was recov-
substituted with electron-releasing groups (7d, 7e and ered in 96% yield by simply washing the column with
7f) also provide good yield and high ee and dr of 1,4- methanol.
adducts (Table 3, entries 4–6). The nitrodiene bearing
The proposed mechanism for this transformation
an a-methyl group 7g also resulted in the formation can be elucidated as shown in Figure 2. BnCPN (or
of the desired adduct 8g in good yield and ee with BnCPD) acts as bifunctional organocatalyst, which
>99:1 dr in the presence of 5 mol% of the catalyst provides the synergic activation to both the react-
(Table 3, entry 7). Not only aromatic but also an ali-
ants.[5a] The proposed transition state involves a terna-
ACHTUNGTRENNUNG
phatic nitrodiene 7h resulted in the formation of Mi- ry complex of prochiral nucleophile, nitrodiene and
chael adduct 8h in good yield and enantioselectivity catalyst. The tertiary amine activates the nucleophile
although the diastereoselectivity was low (Table 3, by stabilizing the enol through hydrogen bonding and
entry 8).
the aromatic OH of the catalyst activate the nitro-
After successful screening of various nitrodiene de- diene and also orients the keto ester with the hydro-
rivatives, different cyclic b-keto esters were screened. gen bonding network.
The five-membered b-keto esters such as Me, i-Pr, t-
The synthetic utility of this transformation was
Bu and Bn esters react with nitrodiene to provide the demonstrated for the synthesis of chiral octahydroin-
respective adducts 8i–8m in good to high yield and dole derivative (10) (Scheme 2), since this octahy-
stereoselectivity (Table 3, entries 9–13). The absolute droindole is a common core in bioactive natural prod-
configuration of the Michael adducts obtained with ucts such as aeruginosin 298A, dysinosin A1, oscillar-
BnCPN can be assigned as 1S,2’R on comparision of in, etc.[12] The process involves the Zn/HCl-mediated
the specific rotation and HPLC chromatogram of the reductive cyclization of adduct 8n obtained with
adduct 8k with that reported in the literature.[4c]
BnCPN to imine 9. Reduction of imine (9) with
The six-membered cyclic b-keto ester (6f) also NaCNBH3 followed by Boc protection results in octa-
reacts with nitrodienes (7a and 7e) providing the de- hydroindole 9 in good overall yield and without race-
sired adducts (8n and 8o) in good yield and excellent mization.
stereoselectivity (Table 3, entries 14 and 15). 5 mol%
of BnCPN also catalyzes the Michael addition of acy-
clic trisubstituted b-keto ester 6g with 7a to provide Conclusions
the adduct 8p in 63% yield and 96% ee of the major
diastereomer, but the diastereoselectivity was poor In conclusion, we have established a highly stereose-
(Table 3, entry 16).
lective approach for the construction of vicinal qua-
The chlorinated quaternary stereocenter was ob- ternary and tertiary stereocenters via 6’-OH Cinchona
tained in high yield and low dr with a good level of ee alkaloids-catalyzed Michael addition of trisubstituted
for both the diastereomers in the presence of 5 mol% carbon nucleophiles to nitrodienes. This reaction is
of BnCPN (Table 3, entry 17). Not only b-keto esters applicable not only to a wide variety of carbon nucle-
but cyclic diketones (e.g., 6i) also resulted in the for- ophiles but also to a substantial range of nitrodienes
mation of Michael adduct 8r with moderate dr and as well. This asymmetric protocol expands the range
good ee (Table 3, entry 18).
of optically active molecules bearing adjacent tertiary
The substrate scope was also evaluated with and quaternary stereocenters that can be directly gen-
BnCPD as catalyst, which provides access to vicinal erated from readily available prochiral precursors.
quaternary and tertiary stereocenters in comparable The present method has several advantages such as
yield and stereoselectivity to that of BnCPN. The op- use of easily available pseudoenantiomeric organoca-
posite enantiomers with good to excellent yield and talysts, low catalyst loading, room temperature reac-
ee were obtained with 0.5–5 mol% of BnCPD tion, in combination with a high regio- and stereose-
(Table 4).
lectivity that is insensitive to reactant concentration
Remarkably, on the lowering of catalyst loading of and catalyst loading as well as to air and moisture.
BnCPN (1–0.05 mol%), the Michael adduct 7a was The present methodology has a high turnover number
isolated without the loss of ee and dr, these results in- that enables the scaling up of the reaction. The prod-
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Facile Construction of Vicinal Quaternary and Tertiary Stereocenters
Table 4. BnCPD-catalyzed asymmetric Michael reaction of trisubstituted carbon nucleophiles with nitrodienes.[a]
Entry
Nucleophile
Nitrodiene
Time [h]
Product
Yield [%][b]
dr[c]
ee [%][d]
1
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6d
6e
6f
6f
6g
6h
6i
7a
7b
7c
7d
7e
7f
7g
7h
7a
7a
7a
7e
7a
7a
7e
7a
7a
7a
15
24
24
48
48
36
96
36
18
60
72
96
48
72
96
96
15
60
8a’
8b’
8c’
8d’
8e’
8f’
8g’
8h’
8i’
8j’
8k’
8l’
8m’
8n’
8o’
8p’
8q’
8r’
99
97
97
91
92
96
71
73
99
85
91
78
92
84
76
57
89
94
94:6
95:5
92:8
90:10
88:12
93:7
>99:1
65:35
90:10
96:4
97:3
97:3
89:11
98:2
99:1
67:33
57:43
78:22
97
97
88
90
94
95
88
2[e]
3[e]
4
5
6
7[f]
8
90, 90[g]
89
96
96
97
93
9
10
11
12
13
14
15
16[f]
17[f]
18
97
99
88, 69[g]
94, 87[g]
89
[a]
Unless noted, reactions were carried out with 0.3 mmol of 6 and 0.2 mmol of 7 in 0.2 mL of CH2Cl2 with 1 mol% of 2f.
Yield refers to isolated yield after column chromatography.
dr refers to diastereomeric ratio after short column chromatography.
ee refers to enantiomeric excess of major diastereomer.
0.5 mol% of catalyst was used.
[b]
[c]
[d]
[e]
[f]
5 mol% of catalyst was used.
ee of minor diastereomer.
[g]
Table 5. Effect of catalyst loading.[a]
Entry
BnCPN [mol%]
Time [h]
Yield [%][b]
dr[c]
ee [%][d]
TON[e]
1
2
3
4
5
6
1
15
24
36
96
120
144
99
99
99
81
35
18
94:6
94:6
94:6
94:6
94:6
94:6
97
97
97
97
96
96
9,900
0.75
0.50
0.25
0.10
0.05
13,200
19,800
32,400
35,000
36,000
[a]
Reactions were carried out with 0.3 mmol of 6a and 0.2 mmol of 7a in 0.2 mL of CH2Cl2 with BnCPN as catalyst at room
temperature.
Yield refers to isolated yield after column chromatography.
dr refers to diastereomeric ratio after short column chromatography.
ee refers to enantiomeric excess of major diastereomer.
Turnover number (TON) was calculated as follows: TON=yield [%]ꢂmmol of 7a/mmol of BnCPN.
[b]
[c]
[d]
[e]
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Scheme 1. Gram-scale prepration of 8a having vicinal quaternary and tertiary stereocenters.
Scheme 2. Derivatization of Michael adducts 8n to octahydroindole-carboxylate analogue 10.
(silica gel 60–120 mesh) using hexane:ethyl acetate (8.5:1.5)
as eluent.
(E)-(S)-Ethyl
1-[(R)-1’-nitro-4’-phenylbut-3’-en-2’-yl]-2-
oxocyclopentanecarboxylate (8a): Colorless oil; yield:
>99%; dr 94:6; [a]2D0: +62.5 (c 1.0, CHCl3); ee 97%; HPLC
[Chiralpak AD-H, hexane/i-PrOH (95:5), 1 mLminÀ1,
210 nm]: tR =15.5 min (major) and tR =20.5 min (minor);
1H NMR (300 MHz, CDCl3): d=7.34–7.24 (m, 5H, ArH),
6.51 (d, J=15.6 Hz, 1H, CH), 6.13 (dd, J=14.1 and 9.5 Hz,
1H, CH), 5.00 (dd, J=12.6 and 3.6 Hz, 1H, CH2), 4.63 (dd,
J=12.6 and 10.5 Hz, 1H, CH2), 4.21 (q, J=6.9 Hz, 2H,
OCH2), 3.54–3.46 (m, 1H, CH), 2.50–2.42 (m, 2H, CH2)
2.37–2.31 (m, 1H, CH2), 2.13–2.00 (m, 3H, CH2), 1.28 (t, J=
7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=14.0,
19.4, 32.2, 38.0, 45.0, 61.1, 62.0, 76.2, 122.8, 126.6, 128.2,
128.3, 128.5, 128.6, 135.9, 136.5, 169.6, 212.9; MS (Q-TOF):
m/z=354.0989 (M+Na)+.
(E)-(S)-Ethyl 1-[(R)-1’-nitro-4’-(2’’-nitrophenyl)but-3’-en-
2’-yl]-2-oxocyclopentanecarboxylate (8b): Yellow oil; yield:
98%; dr 96:4; [a]2D0: +63.0 (c 1.0, CHCl3); ee 96%; HPLC
[Chiralpak AD-H, hexane/i-PrOH (97/3), 0.3 mLminÀ1,
235 nm]: tR =40.3 min (major) and tR =57.1 min (minor);
1H NMR (300 MHz, CDCl3): d=7.99–7.97 (m, 1H, ArH),
7.70–7.32 (m, 3H, ArH), 6.99 (d, J=15.6 Hz, 1H, CH), 6.14
(dd, J=15.6 and 9.3 Hz, 1H, CH), 5.10 (dd, J=12.6 and
3.3 Hz, 1H, CH2), 4.75 (dd, J=12.7 and 10.0 Hz, 1H, CH2),
4.20 (q, J=7.2 Hz, 2H, OCH2), 3.49–3.41 (m, 1H, CH),
2.56–1.97 (m, 6H, CH2), 1.27 (t, J=7.2 Hz, 3H, CH3);
13C NMR (75 MHz, CDCl3): d=14.0, 19.4, 33.2, 38.0, 38.6,
44.9, 60.7, 75.8, 124.5, 128.6, 128.8, 129.6, 132.3, 132.6, 133.5,
147.3, 169.8, 213.1; MS (Q-TOF): m/z=399.0722 (M+Na)+.
(E)-(S)-Ethyl 1-[(R)-1’-nitro-4’-(4’’-nitrophenyl)but-3’-en-
2’-yl]-2-oxocyclopentanecarboxylate (8c): Yellow oil; yield:
99%; dr 93:7; [a]2D0: +67.0 (c 0.5, CHCl3); ee 95%; HPLC
[Chiralpak AD-H, hexane/i-PrOH (90:10), 1.0 mLminÀ1,
286 nm]: tR =34.8 min (major) and tR =43.8 min (minor);
1H NMR (300 MHz, CDCl3): d=8.24–8.15 (m, 2H, ArH),
7.49–7.44 (m, 2H, ArH), 6.80–6.55 (m, 1H, CH), 6.42–5.84
(m, 1H, CH), 5.09–4.93(m, 1H, CH2), 4.70–4.52 (m, 1H,
CH2), 4.26–4.18 (m, 2H, OCH2), 3.92–3.46 (m, 1H, CH),
Figure 2. Plausible transition states: TS1 with BnCPN and
TS2 with BnCPD catalyst
uct can be readily converted into a chiral octahydroin-
dole analogue that, further enhances the utility of this
transformation for the synthesis of potentially valua-
ble chiral molecules.
Experimental Section
General Procedure for BnCPN-Catalyzed Michael
Addition Reaction
To a stirred solution of nitrodienes 7 (0.2 mmol) and catalyst
BnCPN (0.5–5 mol%) in 0.2 mL of CH2Cl2, b-keto ester 6
(0.3 mmol) was added. The reaction mixture was stirred at
room temperature and monitored with thin layer chroma-
tography. After the completion of the reaction the crude re-
action mixture was purified by column chromatography
3208
asc.wiley-vch.de
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3203 – 3212

Facile Construction of Vicinal Quaternary and Tertiary Stereocenters
2.53–2.17 (m, 3H, CH2), 2.15–1.95 (m, 3H, CH2), 1.31–1.24
(m, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=14.0, 19.4,
33.7, 38.0, 38.7, 45.1, 62.2, 75.8, 123.8, 124.0, 127.2, 128.0,
128.7, 129.2, 133.8, 134.4, 169.6, 212.8; MS (Q-TOF):
399.0734 (M+Na).
(E)-(S)-Ethyl 1-[(R)-4’-(2’’-methoxyphenyl)-1’-nitrobut-3’-
en-2’-yl]-2-oxocyclopentanecarboxylate (8d): Yellow oil;
yield: 92%; dr 90:10; [a]2D0: +62.0 (c 0.5, CHCl3); ee 91%;
1.29 (t, J=7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d=13.9, 15.2, 19.1, 32.2, 37.5, 50.5, 60.8, 62.1, 75.5, 127.0,
128.1, 128.9, 132.4, 132.7, 136.6, 169.0, 212.3; MS (Q-TOF):
m/z=368.1116 (M+Na)+.
(E)-(S)-Ethyl 1-[(R)-4,8-dimethyl-1-nitronona-3,7-dien-2-
yl]-2-oxocyclopentanecarboxylate (8h): Colorless oil; yield:
77%; dr 65:35; [a]2D0: +32.0 (c 1.0, CHCl3); ee 91% (95%);
HPLC [Chiralpak IB, hexane/i-PrOH (90:10), 0.5 mLminÀ1,
205 nm]: major diastereomer tR =7.0 min (major) and tR =
11.2 min (minor), minor diastereomer tR =6.9 min (major)
HPLC [Chiralpak
AD-H, hexane/i-PrOH (85:15),
0.5 mLminÀ1, 210 nm]: tR =18.3 min (major) and tR =
24.5 min (minor)]; 1H NMR (300 MHz, CDCl3): d=7.36–
7.34 (d, J=7.5 Hz, 1H, ArH), 7.26–7.20 (m, 1H, ArH),
6.91–6.78 (m, 3H, ArH and CH), 6.14 (dd, J=15.9 and
9.6 Hz, 1H, CH), 5.00 (dd, J=12.6 and 3.3 Hz, 1H, CH2),
4.68–4.60 (m, 1H, CH2), 4.20 (q, J=7.2 Hz, 2H, OCH2) 3.81
(s, 3H, OCH3), 3.54–3.47 (m, 1H, CH), 2.49–2.43 (m, 2H,
CH2), 2.37–2.26 (m, 1H, CH2), 2.18–1.99 (m, 3H, CH2), 1.28
(t, J=7.0 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=
14.0, 19.4, 32.3, 38.1, 45.4, 55.4, 61.2, 61.9, 76.4, 110.9, 120.5,
123.3, 124.9, 127.0, 129.2, 131.3, 156.8, 169.7, 213.1; MS (Q-
TOF): m/z=384.1051 (M+Na)+.
1
and tR =13.2 min (minor)]; H NMR (300 MHz,CDCl3): d=
5.13–4.99 (m, 2H, CH2), 4.91- 4.73 (m, 1H, CH), 4.44–4.35
(m, 1H, CH), 4.18 (q, J=6.9 Hz, 2H, OCH2), 3.89–3.68 (m,
1H, CH), 2.43–2.40 (m, 2H, CH2), 2.33–2.22 (m, 1H, CH2),
2.06–1.97 (m, 7H, CH2), 1.71–1.59 (m, 9H, 3ꢂCH3), 1.30–
1.25 (m, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=14.0,
16.4, 17.6, 19.6, 19.8, 23.4, 25.6, 26.2, 26.4, 32.1, 31.6, 32.1,
38.1, 39.3, 39.6, 39.9, 61.4, 61.6, 76.9, 77.2, 118.1, 118.7, 123.6,
123.8, 131.8, 143.7, 169.7, 212.7; MS (Q-TOF): m/z=
374.1732 (M+Na)+.
(E)-(S)-Methyl 1-[(R)-1’-nitro-4’-phenylbut-3’-en-2’-yl]-2-
oxocyclopentanecarboxylate (8i): Colorless oil; yield: 99%;
dr 89:11; [a]2D0: +58.0 (c 0 .5, CHCl3); ee 90%; HPLC [Chir-
alpak AD-H, hexane/i-PrOH (99/1), 1.3 mLminÀ1, 206 nm]:
tR =36.4 min (major) and tR =46.4 min (minor); 1H NMR
(300 MHz, CDCl3): d=7.34–7.24 (m, 5H, ArH), 6.50 (d, J=
15.9 Hz, 1H, CH), 6.11 (dd, J=16.5 and 9.3 Hz, 1H, CH),
5.00 (dd, J=9.3 and 3.6 Hz,1H, CH2), 4.63 (dd, J=12.6 and
10.5 Hz, 1H, CH2), 3.74 (s, 3H, CH3), 3.54–3.46 (m, 1H,
CH), 2.47–2.40 (m, 2H, CH2) 2.35–2.23 (m, 1H, CH2), 2.16–
1.96 (m, 3H, CH2); 13C NMR (75 MHz, CDCl3): d=19.8,
32.5, 38.4, 45.3, 53.2, 61.4, 76.6, 123.1, 126.9, 128.6, 128.9,
136.2, 136.9, 170.5, 213.2; MS (Q-TOF): m/z=340.0803
(M+Na)+.
(E)-(S)-Ethyl 1-[(R)-4’-(4’’-methoxyphenyl)-1’-nitrobut-3’-
en-2’-yl]-2-oxocyclopentanecarboxylate (8e): Yellow oil;
yield: 91%; dr 89:11; [a]2D0: +68.0 (c 0.5, CHCl3); ee 93%;
HPLC [Chiralpak
AD-H, hexane/i-PrOH (80:10),
0.5 mLminÀ1, 209 nm]: tR =25.7 mim (major) and tR =
1
35.4 min (minor); H NMR (300 MHz, CDCl3): d=7.26 (d,
J=5.1 Hz, 2H, ArH), 6.82 (d, J=8.4 Hz, 2H, ArH), 6.44 (d,
J=15.9 Hz, 1H, CH), 5.97 (dd, J=14.4 and 9.6 Hz, 1H,
CH), 4.99–4.88 (m, 1H, CH2), 4.65–4.58 (m, 1H, CH2), 4.20
(q, J=6.9 Hz, 2H, OCH2) 3.79 (s, 3H, OCH3), 3.50–3.45 (m,
1H, CH), 2.45–1.99 (m, 6H, 3CH2) 1.27 (t, J=6.9 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3): d=14.0, 19.4, 32.1, 38.0,
45.1, 55.2, 61.2, 62.0, 76.4, 113.9, 120.4, 127.8, 128.6, 135.9,
159.6, 169.6, 213.0; MS (Q-TOF): m/z=384.1082 (M+Na)+.
(E)-(S)-Ethyl 1-[(R)-4’-(4’’-acetoxy-3’’-methoxyphenyl)-1’-
(E)-(S)-iso-Propyl
1-[(R)-1’-nitro-4’-phenylbut-3’-en-2’-
yl]-2-oxocyclopentanecarboxylate (8j): Light yellow oil;
nitrobut-3’-en-2’-yl]-2-oxocyclopentanecarboxylate
(8f):
yield: 88%; dr 96:4; [a]2D0: +67.0 (c 1.0, CHCl3); ee 93%;
Yellow oil; yield: 97%; dr 93:7; [a]2D0: +52.5 (c 1.0, CHCl3);
ee 98%; HPLC [Chiralpak IB, hexane/i-PrOH (80:20),
0.5 mLminÀ1, 214 nm]: tR =35.5 mim (major) and tR =
40.6 min (minor)]; 1H NMR (300 MHz, CDCl3): d=6.98–
6.89 (m, 3H, ArH), 6.47 (d, J=15.9 Hz, 1H, CH), 6.09 (dd,
J=15.7 and 9.4 Hz, 1H, CH), 5.00 (dd, J=12.6 and 3.3 Hz,
1H, CH2), 4.67–4.59 (m, 1H, CH2), 4.21 (q, J=7.0 Hz, 2H,
OCH2) 3.84 (s, 3H, OCH3), 3.51–3.45 (m, 1H, CH), 2.53–
2.42 (m, 2H, CH2), 2.37–2.34 (m, 1H, CH2), 2.31 (s, 3H,
COCH3) 2.11–1.98 (m, 3H, CH2), 1.28 (t, J=6.9 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3): d=14.0, 19.5, 20.6, 32.3,
38.0, 45.0, 55.9, 61.0, 62.1, 76.2, 110.5, 119.1, 122.8, 123.2,
134.9, 135.9, 139.7, 151.1, 169.0, 169.6, 212.9; MS (Q-TOF):
m/z=442.1070 (M+Na)+.
HPLC
[Chiralpak
AD-H,
hexane/i-PrOH
(85/15),
0.5 mLminÀ1, 211 nm]: tR =15.2 min (major) and tR =
1
18.4 min (minor); H NMR (300 MHz, CDCl3): d=7.30–7.27
(m, 5H, ArH), 6.49 (d, J=15.6 Hz, 1H, CH), 6.13 (dd, J=
15.7 and 9.4 Hz, 1H, CH), 5.08–4.96 (m, 2H, CH2 and
OCH), 4.64–4.57 (m, 1H, CH2), 3.51–3.44 (m, 1H, CH),
2.50–2.39 (m, 2H, CH2), 2.33–2.21 (m, 1H, CH2), 2.12–1.97
(m, 3H, CH2) 1.26–1.23 (m, 6H, CH3); 13C NMR (75 MHz,
CDCl3): d=19.4, 21.5, 21.6, 32.3, 38.0, 45.0, 61.1, 69.9, 76.3,
122.9, 126.6 128.2, 128.5, 135.9, 136.4, 169.1, 213.0; MS (Q-
TOF): m/z=368.1078 (M+Na)+.
(E)-(S)-tert-Butyl-1-[(R)-1’-nitro-4’-phenylbut-3’-en-2’-yl]-
2-oxocyclopentanecarboxylate (8k): Light yellow oil; yield:
92%; dr 97:3; [a]2D0: +62.5 (c 1.0, CH2Cl2); ee 97%; HPLC
[Chiralpak AD-H, hexane/i-PrOH (90/10), 1.0 mLminÀ1,
208 nm]: tR =7.0 min (major) and tR =8.2 min (minor);
1H NMR (300 MHz, CDCl3): d=7.32–7.25 (m, 5H, ArH),
6.49 (d, J=15.9 Hz, 1H, CH), 6.15 (dd, J=15.7 and 9.4 Hz,
1H, CH), 5.07–4.97 (m, 1H, CH2), 4.63–4.56 (m, 1H, CH2),
3.49–3.43 (m, 1H, CH), 2.48–2.41 (m, 2H, CH2), 2.31–2.18
(m, 1H, CH2), 2.05–1.97 (m, 3H, CH2) 1.47 (s, 9H, 3ꢂCH3);
13C NMR (75 MHz, CDCl3): d=19.5, 27.9, 32.5, 38.0, 45.2,
61.6, 76.4, 83.3, 123.1, 126.6, 128.2, 128.6, 136.0, 136.3, 168.8,
213.4; MS (Q-TOF): 382.1190 (M+Na)+.
(E)-(S)-Ethyl 1-[(R)-3’-methyl-1’-nitro-4’-phenylbut-3’-en-
2’-yl]-2-oxocyclopentanecarboxylate (8g): Yellow oil; yield:
74%; dr>99:1; [a]2D0: +50.0 (c 1.0, CHCl3); ee 88%; HPLC
[Chiralpak AD-H, hexane/i-PrOH (85:15), 0.5 mLminÀ1,
207 nm]: tR =12.7 mim (major) and tR =14.4 min (minor);
1H NMR (300 MHz, CDCl3): d=7.39–7.29 (m, 2H, ArH),
7.26–6.22 (m, 1H, ArH), 7.18–7.16 (m, 2H, ArH), 6.42 (s,
1H), 5.21 (dd, J=13.0 and 3.1 Hz, 1H, CH2), 4.96 (dd, J=
12.9 and 11.1 Hz, 1H, CH2), 4.20 (q, J=7.2 Hz, 2H, OCH2),
3.35–3.31 (m, 1H, CH), 2.65–2.57 (m, 1H, CH2), 2.48–2.43
(m, 2H, CH2), 2.15–2.01 (m, 3H, CH2), 1.80 (s, 3H, CH3),
Adv. Synth. Catal. 2011, 353, 3203 – 3212
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
3209

Pankaj Chauhan and Swapandeep Singh Chimni
FULL PAPERS
(E)-(S)-tert-Butyl 1-[(R)-4’-(4’’-methoxyphenyl)-1’-nitro-
but-3’-en-2’-yl]-2- oxocyclohexanecarboxylate (8l): Yellow
oil; yield: 80%; dr 98:2; [a]20: +52.0 (c 0.5, CHCl3); ee 98%;
22.6 min (minor), minor diastereomer tR =16.6 min (major)
and tR =19.6 min (minor); H NMR (300 MHz, CDCl3): d=
1
7.28–7.23 (m, 5H, ArH), 6.54–6.47 (m, 1H, CH), 6.07–5.94
(m, 1H, CH), 4.72–4.66 (m, 1H, CH2), 4.61–4.49 (m, 1H,
CH2), 4.27–4.17 (m, 2H, OCH2), 3.70–3.75 (m, 1H, CH),
2.17 (s, 3H, CH3), 1.47 (m, 3H, CH3), 1.30–1.23 (m, 3H,
CH3); 13C NMR (75 MHz, CDCl3): d=14.0, 17.8, 27.0, 46.2,
61.4, 62.2, 76.8, 122.9, 126.6, 128.2, 128.5, 135.9, 136.5, 170.8,
204.4; MS (Q-TOF): m/z=342.1698 (M+Na)+.
(E)-Ethyl 2-acetyl-2-chloro-3-(nitromethyl)-5-phenylpent-
4-enoate (8q): Yellow oil; yield: 93%; dr 56:44; [a]2D0: + 25.0
(c 1.0, CHCl3); ee 93% (ee 89% minor diastereomer);
HPLC [Chiralpak
ADD-H, hexane/i-PrOH (90:10),
1 mLminÀ1, 265 nm]: tR =9.7 min (major) and tR =14.4 min
1
(minor); H NMR (300 MHz, CDCl3): d=7.27–7.24 (m, 2H,
ArH), 6.84–6.81 (m, 2H, ArH), 6.42 (d, J=15.9 Hz, 1H,
CH), 6.99 (dd, J=15.6 and 9.6 Hz, 1H, CH),5.01 (dd, J=
15.4 and 3.3 Hz, 1H, CH2), 4.57 (dd, J=17.7 and 10.6 Hz,
1H, CH2), 3.79 (s, 3H, OCH3), 3.47–3.49 (m, 1H, CH),
2.47–2.41 (m, 2H, CH2), 2.31–2.21 (m, 1H, CH2), 2.06–1.96
(m, 3H, CH2) 1.46 (s, 9H, 3ꢂCH3); 13C NMR (75 MHz,
CDCl3): d=19.5, 27.8, 32.4, 38.0, 45.2, 55.3, 61.7, 76.5, 83.2,
113.9, 120.7, 127.8, 128.8, 135.8, 159.6, 168.8, 213.3; MS (Q-
TOF): m/z=412.1213 (M+Na)+.
HPLC
[Chiralpak
OD-H,
hexane/i-PrOH
(90/10),
1.0 mLminÀ1, 210 nm]: major diastereomer tR =11.8 min
(major) and tR =13.9 min (minor), minor diastereomer tR =
8.7 min (major) and tR =10.2 min (minor); 1H NMR
(300 MHz, CDCl3): d=7.31–7.25 (m, 5H, ArH), 6.59 (d, J=
7.8 Hz, 1H, CH) diastereomer, 6.54 (d, J=7.8 Hz, 1H, CH),
6.13–6.01 (m, 1H, CH), 4.89–4.49 (m, 2H, CH2), 4.30–4.04
(m, 3H, CH and OCH2), 2.36 (s, 3H, CH3) diastereomer,
2.34 (s, 3H, CH3), 1.30–1.20 (m, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d=13.9, 25.5, 27.1, 46.4, 48.2, 63.7, 64.0,
76.2, 76.4, 120.7, 120.9, 126.7, 128.5, 128.6, 135.5, 137.5,
137.9, 165.0, 196.5; MS (Q-TOF): m/z=362.1164 (M+Na)+.
(E)-2-Acetyl-2-(1’-nitro-4’-phenylbut-3’-en-2’-yl)cyclopen-
tanone (8r): Yellow oil; yield: 92%; dr 72:28; [a]2D0: +38.0 (c
0.5, CHCl3); ee 92%; [Chiralpak AD-H, hexane/i-PrOH (90/
10), 0.1 mLminÀ1, 207 nm]: tR =24.9 min (major) and tR =
(E)-(S)-Benzyl 1-[(R)-1’-nitro-4’-phenylbut-3’-en-2’-yl]-2-
oxocyclopentanecarboxylate (8m): Colorless wax; yield:
94%; dr 88:12; [a]2D0: +64.0 (c 1.0, CHCl3); ee 95%; HPLC
[Chiralpak IB, hexane/i-PrOH (80/20), 0.5 mLminÀ1,
210 nm]: tR =20.4 min (major) and tR =26.0 min (minor);
1H NMR (300 MHz, CDCl3): d=7.38–7.25 (m, 10H, ArH),
6.54–6.46 (m, 1H, CH), 6.15–6.07 (m, 1H, CH), 5.20–5.18
(m, 2H, OCH2), 4.98–4.90 (m, 1H, CH2), 4.63–4.53 (m, 1H,
CH2), 3.54–3.51 (m, 1H, CH), 2.45–1.96 (m, 6H, CH2);
13C NMR (75 MHz, CDCl3): d=19.4, 32.2, 38.1, 45.1, 61.2,
67.7, 76.1, 122.6, 126.6, 128.2, 128.3, 128.6, 128.7, 134.9,
135.8, 136.6, 169.4, 212.7; MS (Q-TOF): 416.0997 (M+Na)+.
(E)-Ethyl 1-(1’-nitro-4’-phenylbut-3’-en-2’-yl)-2-oxocyclo-
hexanecarboxylate (8n): Colorless oil; yield: 82%; dr 99:1;
[a]2D0: À60.0 (c 0.5, CHCl3); ee 99%; HPLC [Chiralpak AD-
H, hexane/i-PrOH (90/10), 0.5 mLminÀ1, 210 nm]: tR =20.2
1
26.9 min (minor); H NMR (300 MHz, CDCl3): d=7.32–7.24
(m, 5H, ArH), 6.54 (d, J=14.4 Hz, 1H, CH), 6.02 (dd, J=
15.6 and 9.0 Hz, 1H, CH), 4.52–4.35 (m, 2H, OCH2), 3.84–
3.72 (m, 1H, CH), 2.58–2.32 (m, 3H, CH2), 2.29 (s, 3H,
CH3), 2.08–1.85 (m, 3H, 2ꢂCH2); 13C NMR (75 MHz,
CDCl3): d=19.5, 26.5, 28.1, 38.6, 45.0, 70.1, 76.1, 122.0,
126.6, 128.4, 128.6, 135.7, 136.7, 137.0, 202.9, 213.7; MS (Q-
TOF): m/z=324.0924 (M+Na)+.
1
min (major) and tR =28.2 min (minor); H NMR (300 MHz,
CDCl3): d=7.31–7.26 (m, 5H, ArH), 6.45 (d, J=15.9 Hz,
1H, CH), 6.08 (dd, J=15.7 and 10.0 Hz, 1H, CH), 4.80–4.76
(m, 1H, CH2), 4.45–4.38 (m, 1H, CH2), 4.27- 4.21 (m, 2H,
OCH2), 3.52–3.45 (m, 1H, CH), 2.46–2.52 (m, 3H, CH2),
2.05–2.00 (m, 1H, CH2), 1.85–1.81 (m, 1H, CH2), 1.66–1.60
(m, 3H, CH2), 1.31–1.25 (m, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=14.1, 22.3, 27.4, 38.3, 41.2, 46.4, 61.9, 62.5, 77.1,
123.5, 126.5, 126.6, 128.0, 128.5, 135.9, 136.0, 170.1, 207.1;
MS (Q-TOF): m/z=368.1018 (M+Na)+.
Procedure for the Synthesis of 9
The mixture of zinc powder (305.0 mg, 4.70 mmol), optically
pure 8n (110 mg, 0.32 mmol) and EtOH (3.0 mL) was stirred
in a 10-mL round-bottom flask at 358C for 10 min. After
which 2 mL of 4M aqueous HCl were added dropwise over
2 h and the resulting mixture was stirred at 358C for 24 h.
To maintain the pH of the mixture in the range of 0–1, addi-
tional 4M aqueous HCl was added. On completion of the
reaction (as monitored by TLC), the solvent was removed
under reduced pressure and aqueous 3M NaOH (6 mL) was
added, and the solution stirred for 5 min. Dichloromethane
(20 mL) was added to the mixture. The mixture was filtered
and the two layers were separated. The aqueous layer was
extracted with CH2Cl2 (3ꢂ10 mL), and the combined organ-
ic layers were washed with brine and dried over anhydrous
Na2SO4 and concentrated to obtain crude blackish oil. The
crude oil was purified by column chromatography on silica
gel (hexane:EtOAc=7:3) to afford the product 9; yield:
87 mg (91%).
(E)-Ethyl
1-[4’-(4’’-methoxyphenyl)-1’-nitrobut-3’-en-2’-
yl]-2-oxocyclohexanecarboxylate (8o): Light yellow oil;
yield: 73%; dr; 99:1; [a]20: À63.6 (c 0.5, CHCl3); ee 98%;
HPLC
[Chiralpak
ADD-H,
hexane/i-PrOH
(90/10),
0.5 mLminÀ1, 210 nm]: tR =29.1 min (major) and tR =
1
41.9 min (minor); H NMR (300 MHz, CDCl3): d=7.27–7.22
(m, 2H, ArH), 6.83–6.79 (m, 2H, ArH), 6.39 (d, J=15.6 Hz,
1H, CH), 5.92 (dd, J=15.7 and 10.0 Hz, 1H, CH), 4.75 (dd,
J=12.3 and 3.0 Hz, 1H, CH2), 4.40 (dd, J=12.4 and
10.3 Hz, 1H, CH2), 4.25–4.21 (m, 2H, OCH2), 3.79 (m, 3H,
CH3), 3.48–3.40 (m, 1H, CH), 2.57–2.44 (m, 3H, CH2), 2.03–
2.00 (m, 1H, CH2), 1.82–1.81 (m, 1H, CH2), 1.69–1.56 (m,
3H, CH2), 1.28 (t, J=7.2 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=14.1, 22.3, 27.4, 36.3, 41.2, 46.5, 55.3, 61.9, 62.6,
77.3, 113.9, 121.1, 127.8, 128.8, 128.9, 135.3, 139.0, 159.5,
170.1, 207.1; MS (Q-TOF): m/z=398.1033 (M+Na)+.
(E)-Ethyl 2-acetyl-2-methyl-3-(nitromethyl)-5-phenylpent-
4-enoate (8p): Yellow oil; yield: 63%; dr 65:35; [a]2D0: À7.3
(c 0.25, CHCl3); ee 96% (ee 75% minor diastereomer);
HPLC [Chiralpak IB, hexane/i-PrOH (90/10), 0.5 mLminÀ1,
204 nm]: major diastereomer tR =16.2 min (major) and tR=
(E)-Ethyl
3,3a,4,5,6,7-hexahydro-3-styryl-2H-indole-3a-
carboxylate (9): Brown oil; yield 91%; dr 99:1; [a]2D0: +108.5
(c 1.0, CHCl3); ee 99%; HPLC [Chiralpak OD-H, hexane/i-
PrOH (95/5), 1 mLminÀ1, 207 nm]: tR =12.3 min (minor)
1
and tR =20.2 min (major); H NMR(300 MHz, CDCl3): d=
3210
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3203 – 3212

Facile Construction of Vicinal Quaternary and Tertiary Stereocenters
7.30–7.22 (m, 5H, ArH), 6.47–6.41 (m,1H, CH), 6.05–5.96 References
(m, 1H, CH), 4.32–4.04 (m, 3H, CH2 and OCH2), 3.77–3.69
(m, 1H, CH2), 2.98–2.92 (m, 1H, CH), 2.77–2.67 (m, 2H,
CH2), 2.35–2.14 (m, 1H, CH2), 1.98–1.81 (m, 1H, CH2),
1.77–1.74 (m, 1H, CH2), 1.49–1.43 (m, 2H, CH2), 1.31–1.20
(m, 4H, CH3 and CH2); 13C NMR (75 MHz, CDCl3): d=
14.4, 23.3, 26.1, 31.4, 36.5, 54.6, 61.0, 63.7, 65.0, 126.2, 126.3,
127.5, 128.5, 132.8, 136.8, 170.5, 185.3; MS (Q-TOF): m/z=
320.1393 (M+Na)+.
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Procedure for the Synthesis of 10
A mixture of 60 mg (0.2 mmol) of 9, 200 mL AcOH, and
3 mL MeCN was stirred in a 25-mL round-bottom flsak.
The mixture was cooled to 08C for 10 min, Then 63 mg of
NaCNBH3 (1.0 mmol, 5 equiv.) were added in one portion.
The reaction mixture was stirred at room temperature for
24 h. After the completion of the reaction, MeCN was re-
moved under reduced pressure, aqueous 2M NaOH
(12 mL) was added, and then the solution was stirred for 5
min. The reaction mixture was diluted with 15 mL CH2Cl2
and the mixture was filtered and the two layers were sepa-
rated. The aqueous layer was extracted with CH2Cl2 (3ꢂ
10 mL) and then the combined organic layer was washed
with brine, dried over anhydrous Na2SO4, and concentrated.
The crude oil was diluted with 5 mL CH2Cl2. The reaction
mixture was cooled to 58C for 10 min, then (Boc)2O
(0.4 mmol, 2 equiv.) was added over 5 min. The contents
were stirred at room temperature for 2 h. After the reaction
was completed, aquous 2M NaOH (12 mL) was added, and
then the solution was stirred for 30 min. The reaction mix-
ture was diluted with 15 mL CH2Cl2 and two layers were
separated. The aqueous layer was extracted with CH2Cl2
(3ꢂ10 mL), and then the combined organic layer was
washed with brine, dried over anhydrous Na2SO4, and con-
centrated. The crude oil was purified by column chromatog-
raphy on silica gel (hexane:ethyl acetate=8:2) to afford the
10; yield: 53%.
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3a-Ethyl 1-tert-Butyl octahydro-3-styrylindole-1,3a-dicar-
boxylate (10): Dark brown oil; yield: 53%; [a]2D0: +28.5 (c
1.0, CHCl3); 99% ee; HPLC [Chiralpak ODH, hexane/i-
PrOH (95/5), 0.5 mLminÀ1, 250 nm]: tR =12.5 min (minor)
1
and tR =16.6 min (major); H NMR (300 MHz, CDCl3): d=
7.27–7.12 (m, 5H, ArH), 6.35 (d, J=15.6 Hz, 1H, CH),6.02
(dd, J=15.7 and 8.5 Hz, 1H, CH), 4.16–4.04 (m, 3H), 3.58–
3.51 (m, 1H), 3.42–3.36 (m, 1H), 3.04–2.96 (m, 1H), 1.99–
1.94 (m, 1H, CH2), 1.83–1.77 (m, 1H), 1.56–1.44 (m, 1H),
1.40 (s, 9H, CH3) 1.33–1.25 (3H, m), 1.21–1.12 (m, 5H);
13C NMR (75 MHz, CDCl3): d=12.3, 21.4, 22.2, 28.5, 32.0,
44.8, 58.3, 60.5, 61.5, 78.1, 79.2, 126.2, 126.7, 127.5, 128.5,
130.9, 132.9, 136.9, 137.0, 154.5, 173.9; MS (Q-TOF): m/z=
422.2775 (M+Na)+.
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Acknowledgements
The research was supported by funds from the research proj-
ect sanctioned to SSC by UGC, India. The financial support
of DST, India under FIST program and UGC, India, under
CAS-I is gratefully acknowledged.
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3212
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 3203 – 3212