Asymmetric Organocatalytic Synthesis of Highly Substituted Cyclohexenols by Domino Double-Michael Reactions of 1-Hydroxy-1,4-dien-3-ones and 2-Alkylidenemalononitriles

FULL PAPER

Asymmetric organocatalytic synthesis of highly substituted cyclohexenols via

domino double Michael reactions of 1-hydroxy-1,4-dien-3-ones and 2-alkylidene

malononitriles

Yeong-Jiunn Jang,

_{Yu-Shan Chen,}

_{Chia-Jui Lee,}

_{Chi-Han Chen,}

_Ganapuram

Madhusudhan Reddy,

_{Chi-Ting Ko}

_{and Wenwei Lin*}

Keywords: Domino reactions / Michael addition / Cinchona alkaloids / Enones / Carbocycles

A facile asymmetric synthetic protocol to afford 4-hydroxy-3-keto-2,6-disubstituted-cyclohex-3-ene-1,1-dicarbonitriles has been developed through domino double Michael addition of 1-hydroxy-1,5-disubstituted-1,4-dien-3-ones to 2-alkylidene malononitriles using quinine as the catalyst. This simple organocatalytic domino

process provides access to various highly functionalized chiral 4-hydroxy-3-keto-cyclohex-3-enes, which are the rarely reported chiral diketo cyclohexane analogues, in moderate to good yields and enantioselectivities with excellent diastereoselectivities (> 25:1 dr).

____________

[a] Department of Chemistry, National Taiwan Normal University, No. 88, Sec. 4, Tingchow Road, Taipei, Taiwan 11677, R.O.C.

E-mail: wenweilin@ntnu.edu.tw

[b] School of Pharmacy, College of Pharmacy, China Medical University, No. 91 Hsueh-Shih Road, Taichung, Taiwan 40402, R.O.C.; Chinese Medicine Research and Development Center, China Medical University Hospital, No. 2 Yuh-Der Road, Taichung, Taiwan 40447, R.O.C.

[c] Y.-J. Jang and Y.-S. Chen made equal contributions to this work. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.

Introduction

The 1,3-dicarbonyl moieties and their derivatives have

been paid much attention for a long while as they are known

to act as the HIV integrase (IN) inhibitors and are

considered the key structures which interact with the metal

ion (Mg

_{) in the IN active site.}

_{Thus, some of the}

analogous compounds, such as curcumin

_{and S-1360}

_{, have}

already been thoroughly investigated in pharmacological

field.

_{Although few modifications of 1,3-dicarbonyls have}

been attempted,

_{there is still a major scope for further}

development in this area.

On the other hand, the 6-membered nonbenzenoid

carbocycles, related cyclohexanones and isomeric

cyclohexenols are the common core structures found in

biologically active natural products and drugs.

_Different

synthetic strategies and asymmetric protocols such as

cyclization

via

palladium-catalyzed intramolecular

hydroalkylation,

_{carbo [3+3] cycloaddition reaction via}

domino Michael/Knoevenagel condensation,

phosphine-catalyzed [4+2] annulation,

_vinylogous

Mukaiyama-Michael reaction,

_{conjugate addition of β-ketoesters to}

α,β-unsaturated ketones,

_{proline catalyzed Robinson}

annulation,

_{addition of ɛ-nitro-α,β-unsaturated esters to}

conjugated cyanosulfones,

_{addition of malanonitrile to}

1,5-disubstituted pentadien-3-ones

_{etc. have been reported for}

the generation of highly functionalized cyclohexanone

derivatives. The extensive use of nazarov-type reagents has

also been well documented to gain access to such

carbocycles.

_{In continuation of our earlier work on the}

synthesis of highly diastereoselective polysubstituted

4-hydroxy-3-keto-cyclohex-3-enes,

_{we herein report its}

organocatalytic enantioselective version for the synthesis of

such cyclohexanone derivatives.

Figure 1. Structure of beta-diketo acid derivatives.

In the present work, we tried to exploit one of the most

common organocatalysts, quinine, to initiate our asymmetric

domino double Michael reaction of

1-hydroxy-1,4-dien-3-ones and 2-alkylidene malononitriles. Using this protocol,

different

4-hydroxy-3-keto-2,6-disubstituted-cyclohex-3-ene-1,1-dicarbonitriles were obtained in good yields with

high diastereoselectivities and good enantiomeric excesses.

Results and Discussion

To begin with, our first concern was to identify the type

of organocatalyst suitable to initiate the pro-nucleophile,

1-hydroxy-1,4-dien-3-one. Based on our earlier work,

_we

could envisage that a tertiary amine was most suitable to

activate the pro-nucleophile. Hence, we selected the

cinchona category of alkaloids (I-XII) for our preliminary

study (Table 1) of the asymmetric domino double Michael

reaction of 2-alkylidene malanonitrile 1a and 1,3-diketone

2aa. While the cinchona catalysts with unsubstituted aryl

group resulted in low enantioselectivities of 21% and 2%

(entries 2 & 7), the methoxy substituted cinchona derivative

displayed better enantioselectivities, 63% and 51% (entries

1 & 6). Few other modifications of the cinchona catalyst

such as reduction of alkene, transformation of the hydroxyl

group to an amine, combination of thiourea or protection

with aroyl group (entries 3-5 & 8-10) failed to give better

results. The significantly different results with catalysts I

and V indicated that the free hydroxyl center was a key

function for the reaction to proceed smoothly (entries 1 &

3). It not only controlled the activity of reactants but also

demonstrated

its significance for

the

better

enantioselectivity: the NMR yield was merely 9% with a

racemic result when the hydroxyl group was masked (entry

3). In addition, the well-known diphenylprolinol silyl ether

catalyst (XIII) and the Takemoto-type catalyst (XIV & XV)

also failed to deliver better results (entries 11-13).

Table 1. Catalyst screening of asymmetric domino double Michael reaction of malanonitrile 1aanddiketone2aa.[a]

Entry Cat. Time (d) Product/SM[c] _{ee (%)}[d]

1 I 29 h 93/0 63 2 II 29 h 96/0 21 3 V 29 h 9/81 -4 VI 5 28/47 34 5 VII 5 40/32 23 6 VIII 29 h 92/0 51[e] 7 IX 29 h 91/0 2[e] 8 X 3 89/0 53[e] 9 XI 5 58/20 45[e] 10 XII 5 58/28 17 11 XIII 5 38/28 14 12 XIV 2 0/100 -13 XV 2 14/77 20

[a] Unless otherwise specified, all the reactions were carried out using 1a (0.12 mmol, 1.2 equiv) and 2aa (0.1 mmol) with 20 mol % of catalyst in CH2Cl2 (0.8 mL) and stirred at room temperature (30 °C). [b]

Diastereomeric ratio was determined by the 1_{H NMR analysis of crude}

reaction mixture. [c] NMR yield. [d] Determined by HPLC analysis on a chiral stationary phase. [e] Enantiometric excess of ent-3aaa.

The importance of hydroxyl group on quinine

demonstrates that the reaction was facilitated by the

hydrogen bonding interactions between the reagent and

cinchona catalyst. These interactions would be further

affected by the solvent selected. So we screened a series of

solvents to analyze their effect on the reaction (Table 2) and

it was evident that the reaction in the polar solvents such as

THF and EA (entries 2 & 3) resulted in lower

enantioselectivities, 37% and 46%, than in non-polar

solvents. Although using other solvents such as chloroform

and 1, 2-dichloroethane gave better yields, the enantiomeric

excess values of the products were not impressive (entries 1

& 5). Carrying out the reaction in non-polar solvents had the

better consequence with good yields and ee values with

xylenes being the best of the lot (entries 6-9). Decreasing the

reaction temperature to either 0 or -20

_{C did not yield any}

better results (entries 10 & 11). Later on, we tried to

evaluate the importance of methoxy substitution by carrying

out the reaction of malanonitrile 1a and

diketone 2aa in

xylenes using the isopropyl substituted quinine catalyst III.

Although increasing the steric hindrance on the quinoline

group slightly enhanced the enantioselectivity, the reactivity

dropped considerably (entry 12). Further, when diketone

2aa was reacted with other 2-alkylidene malononitriles such

as 1d in presence of III, the enantioselectivity decreased

dramatically. Conversely, when the cinchona catalyst (IV)

with hydroxy substituted aryl group was used to carry out

the reaction of 1a

and

2aa in xylenes, both the yield and

enantioselectvity of the reaction were low (entry 13).

Table 2. Solvent screening and optimization of asymmetric domino double Michael reaction of malanonitrile 1aanddiketone

2aa.[a]

Entry Solv. Time (d) Product/SM[c] _{ee (%)}[d]

1 CHCl3 3 91/0 58 2 THF 3 76/8 37 3 EA 1 77/8 46 4 Dioxane 2 1/83 -5 _{dichloroethane}1,2- 2 100/0 62 6 Toluene 3 85/6 75 7 Mesitylene 2 54/31 70 8 Benzene 2 83/2 74 9 Xylenes 2 84/3 77 10[e] _{Xylenes 2 66/22 77} 11[f] _{Xylenes 2 4/84 79} 12[g] _{Xylenes 2 75/14 80} 13[h] _{Xylenes 2 23/64 26}[i]

[a] Unless otherwise specified, all the reactions were carried out using 1a (0.12 mmol, 1.2 equiv) and 2aa (0.1 mmol) with 20 mol % of catalyst I in the solvent (0.8 mL) and stirred at room temperature (30 °C). [b] Diastereomeric ratio was determined by the 1_{H NMR analysis of crude}

reaction mixture. [c] NMR yield. [d] Determined by HPLC analysis on a chiral stationary phase. [e] 0 °C. [f] -20 °C. [g] 20 mol% of catalyst III was used. [h] 20 mol% of catalyst IV was used. [i] Enantiometric excess of

ent-3aaa.

After discovering that quinine and xylenes were the most

suitable catalyst and solvent respectively to carry out this

reaction, we tried to test whether the phase transfer catalysts

(PTCs) derived from quinine would afford even better

results. So, we screened certain PTCs (XVI-XIX) derived

from quinine for the asymmetric domino double Michael

reaction of malanonitrile 1a

and

diketone 2aa in presence

of a base in different solvents and the results are presented

in table 3. The use of PTCs (XVI-XIX) to carry out the

reaction did not seem to work as good as quinine and the

comparitive yields and enantiomeric excesses of the

products were lower. The best result while using a PTC was

obtained using the catalyst XVII in presence of 1.5 equiv of

K

CO

at 0 °C yielding the opposite enantiomer ent-3aaa in

69% ee (entry 14) which was lower than that obtained while

using quinine as catalyst.

Table 3. Screening of asymmetric domino double Michael reaction of malanonitrile 1aanddiketone2aa using PTCs.[a]

Entry Cat. Solv. Product/SM[c] _{ee (%)}[d]

1 XVI Xylenes 78/6 38

2 XVII Xylenes 52/26 58

3 XIX Xylenes 69/16 46

4[e] _{XVII Xylenes 60/17 44}

5[f] _{XVII Xylenes 52/21 32} 6[g] _{XVII Xylenes 64/19 59} 7[g] _{XVIII Xylenes 68/17 47} 8[h] _{XVII Xylenes 65/23 54} 9[g] _{XVII DCM 85/0 22} 10[g] _{XVII CHCl} 3 80/0 32 11[g] _{XVII THF 70/0 41} 12[g] _{XVII Toluene 80/0 55} 13[g] _{XVII Mesitylene 40/50 64}

14[g,i] _{XVII Toluene 53/23 69}

[a] Unless otherwise specified, all the reactions were carried out using 1a (0.12 mmol, 1.2 equiv), 2aa (0.1 mmol) and K2CO3 (0.3 mmol, 3.0 equiv)

with 20 mol % of phase transfer catalyst in the solvent (0.8 mL) and stirred at room temperature (30 °C). [b] Diastereomeric ratio was determined by the 1_{H NMR analysis of crude reaction mixture. [c] NMR yield. [d]}

Determined by HPLC analysis on a chiral stationary phase. [e] Cs2CO3 was

used as base. [f] K3PO4 was used as base. [g] K2CO3 (0.15 mmol, 1.5 equiv)

was used. [h] K2CO3 (0.02 mmol, 20 mol%) was used. [i] 0 °C.

In an attempt to enhance the hydrogen bonding

interactions in the transition state, the effect of common

additives has also been investigated in this reaction (please

see the supporting information). But the use of either the

acidic or the basic additives did not seem to enhance the

yields or enantiomeric excesses of the resulting products.

Based on the above investigations, we could conclude that

the optimized conditions to carry out this domino double

Michael reaction are as depicted in entry 9 (Table 2),

utilizing malanonitrile 1a (1.2 equiv) and diketone 2aa (0.1

mmol) with 20 mol % of quinine in xylenes (0.8 mL) at

room temperature (30 °C) in the absence of any additive.

Under the optimized conditions, the extensive scope of

the asymmetric domino double Michael reaction was

explored using different 2-alkylidene malononitriles 1

(Table 4). Although the phenyl, 1-naphthyl or 2-naphthyl

groups showed no obvious steric hindrance and did not

affect the enantioselectivity (entries 1-3), there was a

notable decrease in the yield of the product in case of

2-naphthyl substitution.

When compared to the unsubstituted phenyl group in

malanonitrile 1 (entry 1), the halide substituted ones (entries

4-7) displayed slightly better stereocontrol with ee ranging

between 76-86% without any extensive drop in their

respective yields. Surprisingly, the reaction of 2aa with the

malanonitrile substituted with a stronger electron

withdrawing group such as 4-nitro group resulted in reduced

stereocontrol although the reactivity was slightly better

(entry 12). Introducing an electron-donating methoxy group

on to the aromatic ring of malanonitrile 1 not only required

different ratios of diketone 2aa (1.2 equiv) and malanonitrile

1 (1 equiv) but also prolonged the reaction time to 15 days

(entry 8) to furnish the product in 68% yield and 77% ee.

Heteroaryl R

_{substituents were also examined for their}

reactivity: 2-thienyl, 2-furyl or 3-pyridinyl substituents

resulted in moderate yields of 58-75% with a reaction time

of 10 days (entries 9-11). Although the 3-pyridinyl

substitution in malanonitrile 1 facilitated a smooth reaction,

the enantioselectivity decreased to 62% ee. Surprisingly,

2-thienyl substituted malanonitrile 1 resulted in the product

with higher enantiomeric excess value of 92% (entry 9). The

aliphatic R

_{substitution such as ethyl group on}

malanonitrile 1 showed the decomposition of the starting

material (and may be also the product) and the expected

product could not be isolated, while 70% of diketone 2aa

could be recovered.

Table 4. Asymmetric domino double Michael reaction of R1

-substituted malanonitrile 1anddiketone2aa.[a]

Entry R1 _{(1) Time (d) Yield (%)}[c] _{ee (%)}[d]

1 Ph (1a) 3 3aaa, 76 77 2 1-Naphthyl (1b) 3.5 3baa, 80 76 3 2-Naphthyl (1c) 3.5 3caa, 62 72 4 4-ClC6H4 (1d) 2.5 3daa, 74 86 5 4-BrC6H4 (1e) 2.5 3eaa, 75 78 6 2-ClC6H4 (1f) 2 3faa, 72 76 7 2-BrC6H4 (1g) 22 h 3gaa, 86 81 8[e] _4-MeOC 6H4 (1h) 15 3haa, 68 77

9 2-Thienyl (1i) 10 3iaa, 58 92 10 2-Furyl (1j) 10 3jaa, 73 82 11 3-Pyridinyl (1k) 10 3kaa, 75 62

12 4-NO2C6H4(1l) 2.5 3laa, 80 50

[a] Unless otherwise specified, all the reactions were carried out using 1 (0.3 mmol, 1.2 equiv) and 2aa (0.25 mmol) in the presence of quinine (20 mol%) in xylenes (2 mL) at 30 o_{C. [b] Diastereomeric ratio was determined by the} 1_{H NMR analysis of crude reaction mixture. [c] Isolated yield. [d]}

Determined by HPLC analysis on a chiral stationary phase. [e] The reactions were carried out using 2aa (1.2 equiv) and 1h (0.25 mmol) in the presence of quinine (20 mol%) in xylenes (2 mL) at 30 o_C.

The asymmetric domino double Michael reaction was

then investigated using different R

_{substituents in diketone}

2 which could be obtained from benzilideneacetone and

corresponding acid chlorides.

_{The results are depicted in}

table 5. The varying substituents displayed a notable

impact on the yields of the products with a slight variation

in their enantiomeric excesses. The 4-chloro- and

4-bromo-phenyl substitution of R

_{showed similar results with an ee}

of 76 or 77% respectively (entries 1 & 2), though the

reaction time of 4-bromo phenyl substitution had to be

prolonged to 10 days. We then tried to compare the results

with a more electron withdrawing moeity such as 4-nitro

group, but the starting material was insoluble in xylenes

and could be recovered completely. Heteroaryl substitution

on R

_{, involving 2-thienyl or 2-furyl groups, seemed to}

display no significant influence on the enantioselectivity

but showed a considerable difference in the yields of the

respective products (entries 3 & 4). Next, the impact of

different degrees of aliphatic substitutions (ethyl, i-propyl

and t-butyl groups) on R

_{of diketone 2 were also}

examined. It showed a clear impact not only on the yield

but also on the enantioselectivity. (78-86% ee, entries 5-7).

Interestingly, the t-butyl substituted R

_{had the same}

impact in the achiral protocol, with the keto-form of the

product appearing as the major isomer 3aha-keto (70%)

and the enolic form being 25% (3aha-enol).

Table 5. Asymmetric domino double Michael reaction of malanonitrile 1a and R2_{-substituted diketone2.}[a]

Entry R2 _{(2) Time (d) Yield (%)}[c] _{ee (%)}[d]

1 4-ClC6H4 (2ba) 4 3aba, 76 76

2 4-BrC6H4 (2ca) 10 3aca, 81 77

3 2-Thienyl (2da) 2 3ada, 64 78 4 2-Furyl (2ea) 16 h 3aea, 80 78

5 n-Ethyl (2fa) 16 h 3afa, 94 78

6 i-Propyl (2ga) 22 h 3aga, 92 85

7 t-Butyl (2ha) 4 3aha-enol, 25 86

3aha-keto, 70 82

[a] Unless otherwise stated, all the reactions were carried out using 1a (0.3 mmol, 1.2 equiv) and 2 (0.25 mmol) in the presence of quinine (20 mol%) in xylenes (2 mL) at 30 °C. [b] Diastereomeric ratio was determined by the

1_{H NMR analysis of crude reaction mixture. [c] Isolated yield. [d]}

Determined by HPLC analysis on a chiral stationary phase.

Finally, the effect of varying R

_{substituents on diketone}

2 were studied (Table 6). The 4-chloro and 4-bromo

substituted diketone 2 resulted in similar yields, 77 and 78%

respectively, with good enantioselectivity (entries 1 & 2).

Similarly, neither the electron-withdrawing bromo group nor

the electron-donating methoxy group seemed to show any

influence on the reactivity and selectivity (entries 1 & 3).

The heteroaryl R

_{groups such as 2-thienyl, 2-furyl and}

3-pyridinyl, were also tolerated but with a considerable

decrease in the yield and selectivity (entries 4-6). The

product obtained with an aliphatic R

_{substitution such as}

ethyl group was not stable and decomposed while trying to

purify by column chromatography

.

Table 6. Asymmetric domino double Michael reaction of malanonitrile 1a and R3_{-substituted diketone2.}[a]

Entry R3 _{(2) Time (d) Yield (%)}[c] _{ee (%)}[d]

1 4-ClC6H4 (2ab) 5 3aab, 77 79

2 4-BrC6H4 (2ac) 4 3aac, 78 83

3 4-MeOC6H4 (2ad) 5 3aad, 80 80

4 2-Thienyl (2ae) 5 3aae, 76 73 5 2-Furyl (2af) 6 3aaf, 64 69 6 3-Pyridinyl (2ag) 5 3aag, 69 57 [a] Unless otherwise stated, all the reactions were carried out using 1a (0.3 mmol, 1.2 equiv) and 2 (0.25 mmol) in the presence of quinine (20 mol%) in xylenes (2 mL) at 30 °C. [b] Diastereomeric ratio was determined by the 1_{H and} 13_{C NMR analysis of isolated products. [c]}

Isolated yield. [d] Determined by HPLC analysis on a chiral stationary phase.

The absolute configuration of 3gaa was established by

single crystal X-ray data analysis and that of others was

assigned by analogy.

_{Based on the combination of the}

experimental data, catagory of catalysts screened and the

X-ray diffraction analysis, the plausible transition state is

presented in Figure 2. The highly acidic diketo group of

diketone 2 is induced by the tertiary amine of quinine while

the hydroxyl group on the 9 position of quinine is a key

function which coordinates with the dicyano substituted

electrophile 1 via hydrogen bonding. The methoxy

substitution on the quinoline also plays an important role in

enhancing the enanioselectivity (Table 1, entries 1 & 2). The

heteroaryl R

_{-substitution on diketone 2 has the repulsion}

with methoxyl group in quinine which destroys the

transition state. As a result, enantioselectivity is decreased

(Table 6, entries 4-6).

Figure 2. The stereochemical model predicting the asymmetric induction in domino double Michael reaction of malanonitrile 1g and diketone2aa.

Conclusions

In summary, we have successfully demonstrated the

asymmetric domino double Michael reaction of

malanonitrile 1 with diketone 2. The rarely constructed

chiral diketo cyclohexane derivatives,

4-hydroxy-3-keto-2,6-disubstituted-cyclohex-3-ene-1,1-dicarbonitriles, could

be effectively synthesized using this protocol. The simple

and mild reaction conditions provide moderate to good

yields and enantioselectivities of the desired adducts which

are highly potential targets for study in the pharmacological

field.

Experimental Section

General Procedure for the Synthesis of 3. In a glass vial equipped with a

magnetic stir bar, malanonitrile 1 (0.30 mmol, 1.2 equiv), diketone 2 (0.25 mmol) and quinine (20 mol %, 0.05 mmol) were dissolved in 2.0 mL of Xylenes and stirred at 30 °C. After the completion of the reaction, the mixture was directly subjected to flash column chromatography on silica gel to purify the corresponding product 3.

3-benzoyl-4-hydroxy-2,6-diphenylcyclohex-3-ene-1,1-dicarbonitrile (3aaa): White solid, 76.8 mg, yield 76%, Rf 0.21 (DCM/hexanes: 2/3); [α]D30 = -54.89 (c = 0.5 in CHCl3); 77% ee, determined by HPLC analysis

[Daicel chiralpak OD-H, n-hexane/i-PrOH = 80/20, 1.0 mL/min, λ = 298 nm, t (major) = 7.90 min, t (minor) = 45.10 min]; mp 241-242 °C; 1

H-NMR (400 MHz, CDCl3) δ/ppm: 16.41 (s, 1H), 7.44-7.34 (m, 7H),

7.34-7.29 (m, 2H), 7.30 (t, 1H, J = 7.6 Hz), 7.16-7.09 (m, 2H), 7.01 (d, 2H, J = 7.9 Hz), 4.52 (s, 1H), 3.47 (dd, 1H, J = 11.7, 6.2 Hz), 3.32 (dd, 1H, J = 19.7, 11.7 Hz), 3.10 (dd, 1H, J = 19.6, 6.2 Hz). 13_{C-NMR (100 MHz,}

129.3, 129.2, 128.9, 128.32, 128.3, 126.1, 114.4, 113.1, 105.4, 49.1, 44.4, 40.2, 34.7. HRMS (APCI-TOF) for C27H20N2O2Na, [M+Na]+ (427.1422)

found: 427.1415.

3-Benzoyl-4-hydroxy-2-(naphthalen-1-yl)-6-phenylcyclohex-3-ene-1,1-dicarbonitrile (3baa): White solid, 90.9 mg, yield 80%, Rf 0.18 (DCM/hexanes: 2/3); [α]D30 = -104.70 (c = 0.5 in CHCl3); 76% ee,

determined by HPLC analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 70/30, 1.0 mL/min, λ = 298 nm, t (major) = 10.34 min, t (minor) = 80.27 min]; mp 207-208 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.21 (s, 1H), 7.87 (d, 1H, J = 8.3 Hz), 7.79 (d, 1H, J = 8.2 Hz), 7.60 (d, 1H, J = 8.6 Hz), 7.50 (t, 1H, J = 7.7 Hz), 7.42-7.37 (m, 2H), 7.35-7.29 (m, 6H), 7.07 (t, 1H, J = 7.4 Hz), 6.92 (t, 2H, J = 7.7 Hz), 6.82 (d, 2H, J = 7.4 Hz), 5.55 (s, 1H), 3.72 (dd, 1H, J = 11.7, 6.4 Hz), 3.38 (dd, 1H, J = 19.8, 11.9 Hz), 3.14 (dd, 1H, J = 19.8, 6.1 Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 197.3, 180.5, 136.6, 135.0, 133.7, 132.7, 131.7, 130.3, 130.0, 129.4, 129.1, 128.8, 128.7, 128.4, 128.1, 126.4, 126.3, 125.5, 124.5, 122.8, 114.8, 112.9, 106.8, 43.2, 43.1, 40.4, 34.2. HRMS (ESI-TOF) for C31H22N2O2Na, [M+Na]+

(477.1579) found: 477.1581.

3-Benzoyl-4-hydroxy-2-(naphthalen-2-yl)-6-phenylcyclohex-3-ene-1,1-dicarbonitrile (3caa): Yellow solid, 70.5 mg, yield 62%, Rf 0.41 (DCM/hexanes: 1/1); [α]D30 = -76.07 (c = 0.5 in CHCl3); 72% ee,

determined by HPLC analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 70/30, 1.0 mL/min, λ = 298 nm, t (major) = 7.66 min, t (minor) = 88.40 min]; mp 182-183 °C; 1_{H-NMR (500 MHz, CDCl} 3) δ/ppm: 16.54 (s, 1H), 7.87 (d, 1H, J = 8.8 Hz), 7.83 (d, 2H, J = 8.6 Hz), 7.61 (s, 1H), 7.58-7.52 (m, 2H), 7.39-7.30 (m, 4H), 7.28-7.23 (m, 2H), 7.23-7.17 (m, 3H), 7.00 (d, 2H, J = 7.5 Hz), 4.70 (s, 1H), 3.53 (dd, 1H, J = 11.8, 6.4 Hz), 3.36 (dd, 1H, J = 20.0, 11.7 Hz), 3.16 (dd, 1H, J = 20.0, 6.3 Hz). 13_{C-NMR (125 MHz,} CDCl3) δ/ppm: 196.5, 182.6, 136.4, 134.9, 133.5, 133.3, 132.9, 130.7, 129.9, 129.4, 129.1, 128.7, 128.31, 128.29, 128.2, 127.7, 127.19, 127.16, 126.9, 126.1, 114.4, 113.2, 105.5, 49.2, 44.4, 40.3, 34.8. HRMS (ESI-TOF) for C31H21N2O2, [M-H]- (453.1603) found: 453.1594. 3-Benzoyl-2-(4-chlorophenyl)-4-hydroxy-6-phenylcyclohex-3-ene-1,1-dicarbonitrile (3daa): White solid, 81.2 mg, yield 74%, Rf 0.43 (DCM/hexanes: 1/1); [1α]D30 = -42.52 (c = 0.5 in CHCl3); 86% ee,

determined by HPLC analysis [Daicel chiralpak AD-H, n-hexane/i-PrOH = 95/5, 1.0 mL/min, λ = 298 nm, t (minor) = 11.54 min, t (major) = 13.59 min]; mp 182-183 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.35 (s, 1H), 7.45-7.37 (m, 4H), 7.37-7.28 (m, 6H), 7.04 (dd, 4H, J = 12.6, 8.4 Hz), 4.51 (s, 1H), 3.42-3.27 (m, 2H), 3.10 (dd, 1H, J = 18.4, 4.9 Hz). 13_{C-NMR (100} MHz, CDCl3) δ/ppm: 196.9, 182.0, 136.5, 135.6, 134.7, 134.5, 131.4, 130.8, 129.6, 129.3, 129.1, 128.5, 128.3, 126.0, 114.2, 113.1, 105.2, 48.6, 44.3, 40.3, 34.6. HRMS (ESI-TOF) for C27H18N2O2Cl, [M-H]- (437.1057) found: 437.1063. 3-Benzoyl-2-(4-bromophenyl)-4-hydroxy-6-phenylcyclohex-3-ene-1,1-dicarbonitrile (3eaa): White solid, 90.6 mg, yield 75%, Rf 0.56 (DCM/hexanes: 1/1); [α]D30 = -54.17 (c = 0.5 in CHCl3); 78% ee,

determined by HPLC analysis [Daicel chiralpak AD-H, n-hexane/i-PrOH = 95/5, 1.0 mL/min, λ = 298 nm, t (minor) = 12.77 min, t (major) = 15.51 min]; mp 244-245 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.35 (s, 1H), 7.50 (d, 2H, J = 8.2 Hz), 7.46-7.36 (m, 4H), 7.36-7.27 (m, 4H), 7.00 (d, 2H, J = 7.6 Hz), 6.99 (d, 2H, J = 8.2 Hz), 4.50 (s, 1H), 3.42-3.26 (m, 2H), 3.09 (dd, 1H, J = 18.3, 4.8 Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 196.8, 182.0, 136.4, 135.1, 134.7, 132.1, 131.7, 130.8, 129.6, 129.3, 128.5, 128.3, 126.0, 123.8, 114.2, 113.0, 105.1, 48.6, 44.2, 40.3, 34.6. HRMS (ESI-TOF) for C27H18N2O2Br, [M-H]- (481.0552) found: 481.0545. 3-Benzoyl-2-(2-chlorophenyl)-4-hydroxy-6-phenylcyclohex-3-ene-1,1-dicarbonitrile (3faa): White solid, 79.0 mg, yield 72%, Rf 0.57 (DCM/hexanes: 1/1); [α]D30 = -59.39 (c = 0.5 in CHCl3); 76% ee,

determined by HPLC analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 80/20, 1.0 mL/min, λ = 298 nm, t (major) = 13.12 min, t (minor) = 36.64 min]; mp 187-189 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.15 (s, 1H), 7.46-7.32 (m, 7H), 7.32-7.21 (m, 5H) , 6.96 (d, 2H, J = 7.4 Hz), 5.28 (s, 1H), 3.54 (dd, 1H, J = 12.0, 5.8 Hz), 3.36 (dd, 1H, J = 19.5, 12.0 Hz), 3.09 (dd, 1H, J = 19.6, 5.8Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 198.5, 180.5, 136.7, 136.3, 134.7, 134.1, 131.1, 130.44, 130.42, 129.6, 129.3, 128.6, 128.5, 127.0, 125.4, 114.3, 112.3, 105.8, 44.6, 42.8, 40.5, 34.1.

HRMS (ESI-TOF) for C27H18N2O2Cl, [M-H]- (437.1057) found: 437.1055.

3-Benzoyl-2-(2-bromophenyl)-4-hydroxy-6-phenylcyclohex-3-ene-1,1-dicarbonitrile (3gaa): White solid, 103.9 mg, yield 86%, Rf 0.57 (DCM/hexanes: 1/1); [α]D30 = -85.10 (c = 0.5 in CHCl3); 81% ee,

determined by HPLC analysis [Daicel chiralpak IB, n-hexane/i-PrOH = 70/30, 1.0 mL/min, λ = 220 nm, t (major) = 9.28 min, t (minor) = 55.93 min]; mp 193-194 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.12 (s, 1H), 7.44 (d, 1H, J = 8.0 Hz), 7.42-7.32 (m, 7H), 7.29 (t, 2H, J = 7.6 Hz), 7.25-7.15 (m, 2H), 6.95 (d, 2H, J = 7.2 Hz), 5.25 (s, 1H), 3.53 (dd, 1H, J = 12.0, 5.8 Hz), 3.35 (dd, 1H, J = 19.6, 12.0 Hz), 3.08 (dd, 1H, J = 19.6, 5.8 Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 198.7, 180.3, 136.8, 135.5, 134.7, 133.8, 131.2, 130.5, 130.4, 129.6, 129.2, 128.7, 128.4, 127.6, 127.4, 125.4, 114.2, 112.3, 105.9, 47.0, 42.7, 40.4, 34.0. HRMS (ESI-TOF) for C27H18N2O2Br, [M-H]- (481.0552) found: 481.0555. 3-Benzoyl-4-hydroxy-2-(4-methoxyphenyl)-6-phenylcyclohex-3-ene-1,1-dicarbonitrile (3haa): White solid, 73.9 mg, yield 68%, Rf 0.28 (DCM/hexanes: 1/1); [α]D30 = -39.67 (c = 0.5 in CHCl3); 77% ee,

determined by HPLC analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 70/30, 1.0 mL/min, λ = 290 nm, t (major) = 7.62 min, t (minor) = 49.34 min]; mp 144-145 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.42 (s, 1H), 7.42-7.34 (m, 4H), 7.34-7.24 (m, 4H), 7.08-7.00 (m, 4H), 6.88 (d, 2H, J = 8.7 Hz), 4.48 (s, 1H), 3.82 (s, 3H), 3.44 (dd, 1H, J = 11.8, 6.2 Hz), 3.29 (dd, 1H, J = 19.6, 11.8 Hz), 3.07 (dd, 1H, J = 19.7, 6.2 Hz). 13_{C-NMR (100} MHz, CDCl3) δ/ppm: 196.7, 182.0, 160.1, 136.5, 135.1, 131.3, 130.6, 129.4, 129.2, 128.3, 127.8, 126.1, 114.5, 114.2, 113.3, 105.7, 55.3, 48.5, 44.5, 40.1, 34.6. HRMS (ESI-TOF) for C28H21N2O3, [M-H]- (433.1552) found: 433.1551. 3-Benzoyl-4-hydroxy-6-phenyl-2-(thiophen-2-yl)cyclohex-3-ene-1,1-dicarbonitrile (3iaa): Yellow solid, 59.5 mg, yield 58%, Rf 0.59 (DCM/hexanes: 1/1); [α]D30 = -64.98 (c = 0.5 in CHCl3); 92% ee,

determined by HPLC analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 290 nm, t (major) = 9.19 min, t (minor) = 41.80 min]; mp 106-107 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.41 (s, 1H), 7.48-7.32 (m, 9H), 7.15 (d, 2H, J = 7.8 Hz), 7.05 (dd, 1H, J = 5.2, 3.6 Hz), 6.95 (d, 1H, J = 3.7 Hz), 4.83 (s, 1H), 3.59 (dd, 1H, J = 11.8, 6.4 Hz), 3.29 (dd, 1H, J = 19.7, 11.8 Hz), 3.07 (dd, 1H, J = 19.7, 6.4 Hz).13_{C-NMR (100} MHz, CDCl3) δ/ppm: 196.4, 182.2, 140.5, 136.3, 135.1, 130.9, 129.6, 129.3, 128.6, 128.3, 128.2, 127.7, 126.2, 114.0, 113.5, 107.1, 44.9, 44.6,

40.8, 34.6. HRMS (ESI-TOF) for C25H17N2O2S, [M-H]- (409.1011) found:

409.1007.

3-Benzoyl-2-(furan-2-yl)-4-hydroxy-6-phenylcyclohex-3-ene-1,1-dicarbonitrile (3jaa): Yellow solid, 72.0 mg, yield 73%, Rf 0.45 (DCM/hexanes: 1/1); [α]D30 = -39.76 (c = 0.5 in CHCl3); 82% ee,

determined by HPLC analysis [Daicel chiralpak IB, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 297 nm, t (major) = 8.21 min, t (minor) = 26.49 min]; mp 226-227 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.44 (s, 1H), 7.48 (t, 2H, J = 7.5 Hz), 7.44-7.35 (m, 7H), 7.16 (d, 2H, J = 7.4 Hz), 6.41 (dd, 1H, J = 3.2, 2.0 Hz), 6.21 (d, 1H, J = 3.3 Hz), 4.66 (s, 1H), 3.53 (dd, 1H, J = 11.8, 6.4 Hz), 3.27 (dd, 1H, J = 19.7, 11.8 Hz), 3.06 (dd, 1H, J = 19.6, 6.4 Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 195.3, 183.6, 149.3, 144.2, 136.1, 135.1, 131.0, 129.6, 129.3, 128.6, 128.3, 126.2, 113.7, 113.1, 112.4, 111.2, 103.7, 43.7, 43.5, 41.6, 34.9. HRMS (ESI-TOF) for C25H17N2O3, [M-H]- (393.1239) found: 393.1239. 3-Benzoyl-4-hydroxy-6-phenyl-2-(pyridin-3-yl)cyclohex-3-ene-1,1-dicarbonitrile (3kaa): White solid, 76.0 mg, yield 75%, Rf 0.62 (ethyl acetate /hexanes: 1/1); [α]D30 = -31.26 (c = 0.5 in CHCl3); 62% ee,

determined by HPLC analysis [Daicel chiralpak AD-H, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 210 nm, t (minor) = 13.44 min, t (major) = 24.10 min]; mp 251-252 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.28 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 7.47-7.38 (m, 5H), 7.37-7.27 (m, 5H), 7.02 (d, 2H, J = 7.5 Hz), 4.59 (s, 1H), 3.44-3.30 (m, 2H), 3.22-3.08 (m, 1H). 13 C-NMR (125 MHz, CDCl3) δ/ppm: 196.9, 181.8, 150.4, 149.9, 138.2, 136.4, 134.3, 132.3, 130.9, 129.8, 129.4, 128.6, 128.2, 125.8, 123.6, 113.9, 112.8, 104.3, 47.1, 44.1, 40.4, 34.4. HRMS (ESI-TOF) for C26H18N3O2, [M-H] -(404.1399) found: 404.1400. 3-Benzoyl-2-(4-nitrophenyl)-4-hydroxy-6-phenylcyclohex-3-ene-1,1-dicarbonitrile(3laa): White solid, 94.4 mg, yield 84%, Rf 0.28 (ethyl acetate /hexanes: 1/5); [α]D30 = -50.79 (c = 0.5 in CHCl3); 50% ee,

determined by HPLC analysis [Daicel chiralpak AD-H, n-hexane/i-PrOH = 95/5, 0.8 mL/min, λ = 284 nm, t (minor) = 52.72 min, t (major) = 61.14 min]; mp 147-148.1 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.29 (s, 1H), 8.20 (d, 2H, J = 8.56), 7.44-7.40 (m, 4H), 7.34-7.27 (m, 5H), 7.00 (d, 2H, J = 7.72), 4.66 (s, 1H), 3.42-3.33 (m, 2H), 3.22-3.13 (m, 1H). 13_{C-NMR (100} MHz, CDCl3) δ/ppm: 197.1, 181.7, 148.2, 143.0, 136.3, 134.2, 131.1, 131.0, 129.9, 129.4, 128.7, 128.2, 125.8, 123.9, 113.8, 112.8, 104.7, 48.7, 44.0, 40.5, 34.3. HRMS (ESI-TOF) for C27H19N3O4, [M+H]+ (450.1448) found: 450.1409. 3-(4-Chlorobenzoyl)-4-hydroxy-2,6-diphenylcyclohex-3-ene-1,1-dicarbonitrile (3aba): White solid, 83.4 mg, yield 76%, Rf 0.59 (DCM/hexanes: 1/1); [α]D30 = -38.90 (c = 0.5 in CHCl3); 76% ee,

determined by HPLC analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 70/30, 1.0 mL/min, λ = 298 nm, t (major) = 6.93 min, t (minor) = 37.30 min]; mp 147-148.1 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.38 (s, 1H), 7.46-7.35 (m, 6H), 7.34-7.28 (m, 2H), 7.28-7.23 (m, 2H), 7.16 (t, 2H, J = 3.6 Hz), 6.96 (d, 2H, J = 3.6 Hz), 4.46 (s, 1H), 3.46 (dd, 1H, J = 11.6, 6.3 Hz), 3.32 (dd, 1H, J = 19.6, 11.6 Hz), 3.11 (dd, 1H, J = 19.7, 6.2 Hz). 13 C-NMR (100 MHz, CDCl3) δ/ppm: 195.4, 182.7, 137.1, 135.8, 134.9, 134.8, 130.2, 129.54, 129.48, 129.3, 129.0, 128.7, 128.3, 127.7, 114.3, 113.0, 105.4, 49.1, 44.4, 40.2, 34.7. HRMS (ESI-TOF) for C27H18N2O2Cl, [M-H] -(437.1057) found: 437.1057. 3-(4-Bromobenzoyl)-4-hydroxy-2,6-diphenylcyclohex-3-ene-1,1-dicarbonitrile (3aca): White solid, 97.9 mg, yield 81%, Rf 0.57 (DCM/hexanes: 1/1); [α]D30 = -23.16 (c = 0.5 in CHCl3); 77% ee,

determined by HPLC analysis [Daicel chiralpak IB, n-hexane/i-PrOH = 75/25, 1.0 mL/min, λ = 295 nm, t (major) = 6.65 min, t (minor) = 24.66 min]; mp 242-243 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.37 (s, 1H), 7.44-7.34 (m, 8H), 7.33-7.27 (m, 2H), 7.18-7.12 (m, 2H), 6.88 (d, 2H, J = 8.4 Hz), 4.46 (s, 1H), 3.45 (dd, 1H, J = 11.6, 6.3 Hz), 3.31 (dd, 1H, J = 19.7, 11.6 Hz), 3.10 (dd, 1H, J = 19.7, 6.3 Hz). 13_{C-NMR (100 MHz,} CDCl3) δ/ppm: 195.3, 182.7, 135.8, 135.2, 134.9, 131.6, 130.2, 129.51, 129.45, 129.2, 129.0, 128.3, 127.8, 125.4, 114.3, 113.0, 105.4, 49.0, 44.3, 40.2, 34.7. HRMS (ESI-TOF) for C27H18N2O2Br, [M-H]- (481.0552) found: 481.0558. 4-Hydroxy-2,6-diphenyl-3-(thiophene-2-carbonyl)cyclohex-3-ene-1,1-dicarbonitrile (3ada): White solid, 65.7 mg, yield 64%, Rf 0.31 (DCM/hexanes: 1/1); [α]D30 = -19.21 (c = 0.5 in CHCl3); 78% ee,

determined by HPLC analysis [Daicel chiralpak AD-H, n-hexane/i-PrOH = 90:10, 1.0 mL/min, λ = 298 nm, t (major) = 11.95 min, t (minor) = 15.04 min]; mp 184-185 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 17.51 (s, 1H), 7.60 (d, 1H, J = 5.0 Hz), 7.54-7.43 (m, 5H), 7.41-7.35 (m, 3H), 7.34-7.27 (m, 3H), 7.00 (t, 1H, J = 4.4 Hz), 5.01 (s, 1H), 3.41 (dd, 1H, J = 11.7, 6.0 Hz), 3.32 (dd, 1H, J = 19.2, 11.7), 3.11 (dd, 1H, J = 19.2, 6.0 Hz). 13 C-NMR (100 MHz, CDCl3) δ/ppm: 184.8, 184.5, 139.6, 135.4, 135.1, 133.5, 132.2, 130.4, 129.7, 129.5, 129.2, 128.3, 128.1, 114.3, 113.4, 103.7, 48.5, 44.8, 40.1, 35.5. HRMS (ESI-TOF) for C25H17N2O2S, [M-H]- (409.1011) found: 409.1012. 3-(Furan-2-carbonyl)-4-hydroxy-2,6-diphenylcyclohex-3-ene-1,1-dicarbonitrile (3aea): Yellow solid, 78.9 mg, yield 80%, Rf 0.34 (DCM/hexanes: 1/1); [α]D30 = -31.28 (c = 0.5 in CHCl3); 78% ee,

determined by HPLC analysis [Daicel chiralpak AD-H, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 298 nm, t (major) = 11.58 min, t (minor) = 13.43 min]; mp 242-243 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 17.37 (s, 1H), 7.51 (s, 1H), 7.47-7.34 (m, 8H), 7.34-7.28 (m, 2H), 7.25 (d, 1H, J = 3.6 Hz), 6.47 (dd, 1H, J = 3.6, 1.6 Hz), 5.47 (s, 1H), 3.47 (dd, 1H, J = 12.2, 6.1 Hz), 3.33 (dd, 1H, J = 19.6, 12.1 Hz), 3.07 (dd, 1H, J = 19.5, 6.1 Hz). 13 C-NMR (100 MHz, CDCl3) δ/ppm: 184.2, 178.7, 150.4, 146.7, 136.5, 135.2, 130.2, 129.4, 129.2, 129.1, 128.6, 128.3, 120.4, 114.6, 113.4, 112.6, 103.4, 47.5, 44.6, 39.5, 35.3. HRMS (ESI-TOF) for C25H17N2O3, [M-H] -(393.1239) found: 393.1238. 4-Hydroxy-2,6-diphenyl-3-propionylcyclohex-3-ene-1,1-dicarbonitrile (3afa): White solid, 83.8 mg, yield 94%, Rf 0.45 (DCM/hexanes: 1/1); [α]D30 = -82.40 (c = 0.5 in CHCl3); 78% ee, determined by HPLC analysis

[Daicel chiralpak AD-H, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 298 nm, t (major) = 8.75 min, t (minor) = 11.15 min]; mp 174-175 °C; 1

H-NMR (400 MHz, CDCl3) δ/ppm: 16.14 (s, 1H), 7.51-7.44 (m, 3H), 7.41-7.34 (m, 5H), 7.33-7.27 (m, 2H), 4.58 (s, 1H), 3.41 (dd, 1H, J = 12.4, 5.9 Hz), 3.24 (dd, 1H, J = 19.5, 12.4 Hz), 2.95 (dd, 1H, J = 19.4, 5.9 Hz), 2.47 (dq, 1H, J = 17.6, 5.9 Hz), 1.95 (dq, 1H, J = 17.7, 5.9 Hz), 0.95 (t, 3H, J =7.2 Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 203.8, 176.6, 135.4, 135.0, 130.1, 129.6, 129.4, 129.2, 129.1, 128.2, 114.5, 113.1, 104.9, 48.6, 44.4, 39.7, 33.5, 30.9, 7.6. HRMS (ESI-TOF) for C23H19N2O2, [M-H] -(355.1447) found: 355.1448.

4-Hydroxy-2,6-diphenyl-3-isobutyrylcyclohex-3-ene-1,1-dicarbonitrile (3aga): White solid, 85.2 mg, yield 92%, Rf 0.51 (DCM/hexanes: 1/1); [α]D30 = -80.34 (c = 0.5 in CHCl3); 85% ee, determined by HPLC analysis

[Daicel chiralpak AD-H, n-hexane/i-PrOH = 97/3, 1.0 mL/min, λ = 298 nm, t (minor) = 14.83 min, t (major) = 17.35 min]; mp 196-197 °C; 1_H-NMR

(400 MHz, CDCl3) δ/ppm: 16.64 (s, 1H), 7.52-7.43 (m, 3H), 7.42-7.34 (m, 5H), 7.34-7.27 (m, 2H), 4.63 (s, 1H), 3.42 (dd, 1H, J = 12.3, 5.9 Hz), 3.25 (dd, 1H, J = 19.5, 12.3 Hz), 2.97 (dd, 1H, J = 19.5, 5.9 Hz), 2.57 (sept, 1H, J = 6.7 Hz), 1.16 (d, 3H, J = 6.8 Hz), 0.64 (d, 3H, J = 6.5 Hz). 13_C-NMR (100 MHz, CDCl3) δ/ppm: 206.9, 179.4, 135.7, 135.1, 130.3, 129.6, 129.4, 129.2, 129.1, 128.2, 114.4, 113.2, 104.1, 48.7, 44.5, 39.7, 34.1, 33.9, 19.7, 17.9. HRMS (ESI-TOF) for C24H21N2O2, [M-H]- (369.1603) found:

369.1599.

4-Hydroxy-2,6-diphenyl-3-pivaloylcyclohex-3-ene-1,1-dicarbonitrile (3aha-enol): White solid, 24.0 mg, yield 25%, Rf 0.49 (DCM/hexanes: 1/1); [α]D30 = +5.06 (c = 0.5 in CHCl3); 86% ee, determined by HPLC

analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 227 nm, t (major) = 6.88 min, t (minor) = 44.90 min]; mp 140-141 °C;

1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 17.20 (s, 1H), 7.49-7.41 (m, 3H), 7.40-7.32 (m, 5H), 7.31-7.25 (m, 2H), 5.05 (s, 1H), 3.31-3.15 (m, 2H), 3.07-2.93 (m, 1H), 1.15 (s, 9H). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 207.2, 181.0, 135.8, 135.2, 130.3, 129.4, 129.3, 129.2, 129.0, 128.3, 114.3, 113.8, 104.5, 47.7, 44.3, 43.1, 40.0, 34.7, 27.8. HRMS (FAB-magnetic sector) for C25H25N2O2, [M+H]+ (385.1916) found: 385.1917.

4-oxo-2,6-diphenyl-3-pivaloylcyclohexane-1,1-dicarbonitrile(3aha-keto): White solid, 67.3 mg, yield 70%, Rf 0.33 (DCM/hexanes: 1/1); [α]D30

= -49.10 (c = 0.5 in CHCl3); 82% ee, determined by HPLC analysis [Daicel

chiralpak OD-H, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 227 nm, t (minor) = 10.23 min, t (major) = 11.83 min]; mp 166-167 °C; 1_H-NMR

(400 MHz, CDCl3) δ/ppm: 7.53-7.43 (m, 3H), 7.42-7.28 (m, 7H), 4.74 (d,

1H, J = 12.5 Hz), 4.14-4.03 (m, 2H), 3.41 (dd, 1H, J = 16.7, 7.2 Hz), 3.02 (dd, 1H, J = 17.0, 1.6 Hz), 0.89 (s, 9H). 13_{C-NMR (100 MHz, CDCl}

3)

δ/ppm: 210.6, 203.5, 134.7, 134.1, 129.8, 129.7, 129.3, 129.1, 115.4, 112.8,

59.2, 48.2, 45.8, 45.0, 44.1, 42.4, 25.7. HRMS (FAB-magnetic sector) for

C25H25N2O2, [M+H]+ (385.1916) found: 385.1915.

3-Benzoyl-6-(4-chlorophenyl)-4-hydroxy-2-phenylcyclohex-3-ene-1,1-dicarbonitrile (3aab): White solid, 84.5 mg, yield 77%, Rf 0.27 (DCM/hexanes: 1/1); [α]D30 = -54.82 (c = 0.5 in CHCl3); 79% ee,

determined by HPLC analysis [Daicel chiralpak IB, n-hexane/i-PrOH = 70/30, 1.0 mL/min, λ = 298 nm, t (major) = 6.16 min, t (minor) = 20.13 min]; mp 166-167 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.43 (s, 1H), 7.45-7.33 (m, 6H), 7.29-7.23 (m, 4H), 7.12 (d, 1H, J = 6.9 Hz), 7.11 (d, 1H, J = 7.9 Hz), 7.04-6.97 (m, 2H), 4.52 (s, 1H), 3.45 (dd, 1H, J = 11.7, 6.4 Hz), 3.26 (dd, 1H, J = 19.6, 11.7 Hz), 3.09 (dd, 1H, J = 19.6, 6.4 Hz). 13 C-NMR (100 MHz, CDCl3) δ/ppm: 196.6, 181.9, 136.4, 135.8, 135.7, 133.5, 130.8, 130.2, 129.7, 129.5, 129.4, 129.0, 128.4, 126.1, 114.2, 113.0, 105.4, 49.0, 44.3, 39.8, 34.6. HRMS (EI-magnetic sector) for C27H19N2O2Cl, [M]+

(438.1135) found: 438.1137.

3-Benzoyl-6-(4-bromophenyl)-4-hydroxy-2-phenylcyclohex-3-ene-1,1-dicarbonitrile (3aac): White solid, 94.3 mg, yield 78%, Rf 0.25 (DCM/hexanes: 1/1); [α]D30 = -58.84 (c = 0.5 in CHCl3); 83% ee,

determined by HPLC analysis [Daicel chiralpak IB, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 298 nm, t (major) = 12.28 min, t (minor) = 92.09

min]; mp 198.6-199.4 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.43 (s, 1H), 7.50 (d, 2H, J = 8.4 Hz), 7.44-7.34 (m, 4H), 7.27 (t, 2H, J = 7.5 Hz), 7.19 (d, 2H, J = 8.4 Hz), 7.14-7.08 (m, 2H), 7.00 (d, 2H, J = 7.8 Hz), 4.52 (s, 1H), 3.43 (dd, 1H, J = 11.7, 6.4 Hz), 3.25 (dd, 1H, J = 19.7, 11.7 Hz), 3.08 (dd, 1H, J = 19.7, 6.4 Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 196.6, 181.9, 136.3, 135.8, 134.0, 132.4, 130.7, 130.1, 129.9, 129.4, 128.9, 128.4, 126.1, 123.8, 114.1, 113.0, 105.3, 49.0, 44.2, 39.8, 34.5. HRMS (ESI-TOF) for C27H18N2O2Br, [M-H]- (481.0552) found: 481.0546.

3-Benzoyl-4-hydroxy-6-(4-methoxyphenyl)-2-phenylcyclohex-3-ene-1,1-dicarbonitrile (3aad): White solid, 86.9 mg, yield 80%, Rf 0.47 (DCM/hexanes: 1/1); [α]D30 = -59.63 (c = 0.5 in CHCl3); 80% ee,

determined by HPLC analysis [Daicel chiralpak IB, n-hexane/i-PrOH = 85/15, 1.0 mL/min, λ = 298 nm, t (major) = 12.56 min, t (minor) = 42.75 min]; mp 183-184 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.43 (s, 1H), 7.42-7.33 (m, 4H), 7.20-7.30 (m, 4H), 7.15-7.08 (m, 2H), 7.03-6.97 (m, 2H), 6.88 (d, 2H, J = 8.8 Hz), 4.50 (s, 1H), 3.78 (s, 3H), 3.43 (dd, 1H, J = 11.6, 6.3 Hz), 3.28 (dd, 1H, J = 19.6, 11.6 Hz), 3.07 (dd, 1H, J = 19.6, 6.3 Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 196.6, 182.4, 160.3, 136.5, 136.0, 130.6, 130.2, 129.5, 129.2, 128.8, 128.3, 126.9, 126.1, 114.55, 114.47, 113.3, 105.5, 55.3, 49.0, 44.8, 39.5, 34.8. HRMS (ESI-TOF) for C28H21N2O3, [M-H]- (433.1552) found: 433.1556. 3-Benzoyl-4-hydroxy-2-phenyl-6-(thiophen-2-yl)cyclohex-3-ene-1,1-dicarbonitrile (3aae): White solid, 78.0 mg, yield 76%, Rf 0.32 (DCM/hexanes: 1/1); [α]D30 = -46.20 (c = 0.5 in CHCl3); 73% ee,

determined by HPLC analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 298 nm, t (major) = 14.35 min, t (minor) = 30.42 min]; mp 199-200 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.34 (s, 1H), 7.43-7.30 (m, 5H), 7.30-7.24 (m, 2H), 7.14-7.05 (m, 3H), 7.04-6.95 (m, 3H), 4.52 (s, 1H), 3.82 (t, 1H, J = 8.8 Hz), 3.25 (d, 2H, J = 8.8 Hz). 13 C-NMR (100 MHz, CDCl3) δ/ppm: 196.7, 181.2, 137.5, 136.5, 135.8, 130.7, 130.1, 129.3, 128.9, 128.3, 127.8, 127.4, 126.3, 126.0, 114.1, 113.1, 105.4, 48.7, 45.3, 36.5, 36.4. HRMS (ESI-TOF) for C25H17N2O2S, [M-H] -(409.1011) found: 409.1017. 3-Benzoyl-6-(furan-2-yl)-4-hydroxy-2-phenylcyclohex-3-ene-1,1-dicarbonitrile (3aaf): Yellow solid, 63.1 mg, yield 64%, Rf 0.36 (DCM/hexanes: 1/1); [α]D30 = -63.66 (c = 0.5 in CHCl3); 69% ee,

determined by HPLC analysis [Daicel chiralpak OD-H, n-hexane/i-PrOH = 90/10, 1.0 mL/min, λ = 295 nm, t (major) = 10.09 min, t (minor) = 13.18 min]; mp 172-173 °C; 1_{H-NMR (400 MHz, CDCl} 3) δ/ppm: 16.40 (s, 1H), 7.47-7.34 (m, 5H), 7.27 (t, 2H, J = 7.7 Hz), 7.15-7.07 (m, 2H), 7.00 (d, 2H, J = 7.3 Hz), 6.45-6.34 (d, 2H), 4.49 (s, 1H), 3.67 (dd, 1H, J = 11.3, 6.5 Hz), 3.30 (dd, 1H, J = 19.8, 11.4 Hz), 3.12 (dd, 1H, J = 19.8, 6.5 Hz). 13_C-NMR (100 MHz, CDCl3) δ/ppm: 196.5, 181.7, 148.5, 143.7, 136.4, 135.8, 130.8, 130.1, 129.4, 129.0, 128.4, 126.2, 113.9, 113.2, 110.9, 109.7, 105.4, 48.6, 43.1, 34.9, 33.2. HRMS (ESI-TOF) for C25H17N2O3, [M-H]- (393.1239) found: 393.1244. 3-Benzoyl-4-hydroxy-2-phenyl-6-(pyridin-3-yl)cyclohex-3-ene-1,1-dicarbonitrile (3aag): Yellow solid, 69.9 mg, yield 69%, Rf 0.24 (DCM/ethyl acetate/hexanes: 1/2/3); [α]D30 = -21.62 (c = 0.5 in CHCl3);

57% ee, determined by HPLC analysis [Daicel chiralpak AS-H, n-hexane/i-PrOH = 80/20, 1.0 mL/min, λ = 295 nm, t (minor) = 22.49 min, t (major) = 36.06 min]; mp 197-198 °C; 1_{H-NMR (400 MHz, CDCl}

3) δ/ppm: 16.45 (s,

7.28 (t, 2H, J = 7.9 Hz), 7.18-7.10 (m, 2H), 7.05-6.97 (m, 2H), 4.55 (s, 1H), 3.53 (dd, 1H, J = 11.6, 6.4 Hz), 3.29 (dd, 1H, J = 19.7, 11.7 Hz), 3.12 (dd, 1H, J = 19.7, 6.4 Hz). 13_{C-NMR (100 MHz, CDCl} 3) δ/ppm: 196.5, 181.5, 150.5, 149.7, 136.2, 135.62, 135.58, 130.8, 130.1, 129.6, 129.1, 128.4, 126.1, 124.1, 114.0, 112.8, 105.3, 48.9, 44.0, 38.1, 34.3. HRMS (EI-magnetic sector) for C26H19N3O2, [M]+ (405.1477) found: 405.1469.

Supporting Information (see footnote on the first page of this article): 1_H

and 13_{C NMR spectra and X-ray crystallographic data for all new}

compounds.

Acknowledgments

We thank the Ministry of Science and Technology of the Republic of China (MOST 103-2113-M-003-009-MY3) and National Taiwan Normal University (NTNU 100-D-06) for financial support.

____________

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Received: ((will be filled in by the editorial staff)) Published online: ((will be filled in by the editorial staff))

Layout 2:

((Key Topic))

Yeong-Jiunn Jang, Yu-Shan Chen, Chia-Jui Lee, Chi-Han Chen, Ganapuram Madhusudhan Reddy, Chi-Ting Ko and Wenwei Lin* ...1 – 8.

Asymmetric organocatalytic synthesis of highly substituted cyclohexenols via domino double Michael reactions of 1-hydroxy-1,4-dien-3-ones and 2-alkylidene malononitriles

Keywords: Domino reactions / Michael

addition / Cinchona alkaloids / Enones / Carbocycles

An effective asymmetric organocatalytic version for the synthesis of polysubstituted cyclohexenes from 1-hydroxy-1,4-dien-3-one and 2-alkylidene malononitriles via a domino double

Michael reaction sequence using quinine as the catalyst is achieved. The products were obtained in moderate to good yields (up to 96%) and enantioselectivities (up to 92% ee).