Catalytic enantioselective construction of β-quaternary carbons via a conjugate addition of cyanide to β,β-disubstituted α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/ja1035286

The first general catalytic enantioselective conjugate addition of cyanide to β, β-disubstituted α,β-unsaturated ketones and N-acylpyrroles was developed using a strontium catalyst derived from Sr(O ⁱPr)₂ and new chiral ligand 5. The reaction exhibited excellent enantioselectivity and a wide substrate scope using 0.5-10 mol % catalyst. 1,4-Adducts containing β-quaternary carbons were exclusively produced over 1,2-adducts. ESI-MS analysis of the strontium catalyst indicated that the active catalyst was a trimetallic Sr/5 = 3:5 complex. The exclusive 1,4-selectivity was partly due to the ability of the strontium complex to promote both a retro-cyanation reaction from the 1,2-adducts and highly enantioselective conjugate cyanation.

Full text of DOI:10.1021/ja1035286

Supporting Information
Catalytic Enantioselective Construction of -Quaternary Carbons via a Conjugate Addition
of Cyanide to ,-Disubstituted ,-Unsaturated Carbonyl Compounds
Yuta Tanaka, Motomu Kanai,* and Masakatsu Shibasaki*
Table of Contents
1
2
.
.
General Method··················································································································S1
General Procedure for the Catalytic Enantioselective Conjugate Addition of
Cyanide
to
,-Disubstituted
Enones
and
,-Disubstituted
,-Unsaturated N-acylpyrroles··························································································S2
3
4
5
6
.
.
.
.
Ligand Synthesis ················································································································S2
Substrate Synthesis·············································································································S8
Characterization of New Compounds················································································S11
Synthetically Useful Conversions of 10 and Determination of the Absolute
Configuration ···················································································································S25
Study of Catalytic Metals ·································································································S28
Ee vs Sr/ligand Ratio········································································································S28
Optimization of the Reaction Parameters ········································································S29
7
8
9
1
1
1
1
1
.
.
.
0. Catalytic Asymmetric Conjugate Cyanation Performed Using HCN ································S30
1. Crossover Experiment ····································································································S31
2. ESI-MS Studies················································································································S31
3. Proposed Catalytic Cycle··································································································S33
4. References for Catalytic Enantioseloective Conjugate Addition of Alkyl or
Aryl Groups in Quaternary Ketone Synthesis····································································S34
1
1
. General Method: H NMR spectra were recorded on a JEOL JNM-LA500 spectrometer, operating at
1
13
5
00 MHz for H NMR and 125.65 MHz for C NMR. Chemical shifts were reported downfield from
1
13
TMS ( = 0 ppm) for H NMR. For C NMR, chemical shifts were reported in the scale relative to the
solvent used as an internal reference. Optical rotations were measured on a JASCO P-1010 polarimeter.
ESI-TOF mass spectra were measured on JEOL JMS-T100LC. Column chromatographies were
performed with silica gel Merck 60 (230-400 mesh ASTM). The enantiomeric excess (ee) was
determined by HPLC or GC analysis. HPLC analysis was performed on JASCO HPLC systems
consisting of the following: pump, 880-PU or PU-980; detector, 875-UV, UV-970, or RI930, measured at
254 nm or RI; mobile phase, hexane2-propanol. GC analysis was performed Shimazu GC-14A with
Varian Chirasil DEX CB column (0.25 mm x 25 m). In general, reactions were carried out under an
i
argon atmosphere. Sr(O Pr)
2
was purchased from Kojundo Chemical Laboratory Co., Ltd. (Fax:
S-1

1
+
81-492-84-1351, sales@kojundo.co.jp). Chiral ligand 1 was prepared by reported methods.
2
. General Procedure for the Catalytic Enantioselective Conjugate Addition of Cyanide to

,-Disubstituted Enones and ,-Disubstituted ,-Unsaturated N-acylpyrroles (Table 2, entry 1):
i
Sr(OPr) (0.5 mol %)5 (0.8 mol %)
2
O
O
NC
TBSCN (2 equiv), 2,6-Dimethylphenol (2 equiv)
Ph
toluene, rt, 16 h
(E)-7a
100%, 97% ee
(R)-8a
i
To a solution of ligand 5 (3.9 mg, 8.3 mol) in THF (500 L), Sr(O Pr)
2
(0.10 M solution in THF, 50 µL, 5

mol) was added at room temperature. Then, the solvent was evaporated. After drying the resulting
pre-catalyst under reduced pressure (<5 mmHg) for 1 h, toluene (1 mL) was added, and the mixture was
stirred for 30 min at room temperature. 100 L of the catalyst solution was transferred to a reaction vessel
using a gas-tight syringe, and was used for the asymmetric cyanation reaction. To the catalyst solution,
(E)-7a (19.0 L, 18.8 mg, 0.10 mmol) was added. A solution prepared by mixing TBSCN (28.3 mg, 0.20
mmol) and 2,6-dimethylphenol (22.4 mg, 0.20 mmol) in toluene (0.1 mL) at room temperature for 20
minutes, was added to the reaction mixture. After stirring the reaction mixture at room temperature for 16 h,
the reaction mixture was directly loaded on column in a well-ventilated hood (caution! Highly toxic HCN is
generated), and purified by flash column chromatography (silica gel, AcOEt-hexane, 1:10) to afford the 8a
(22.3 mg, 0.104 mmol) in 100% yield as a colorless oil. The enantiomeric excess of the product was
determined by HPLC analysis to be 97% ee.
3
. Ligand Synthesis
(3-A) Synthesis of 2 and 3
t
(
1R,2R,6R)-2-(2’- Butyldimethylsilyloxyphenoxy)-7-oxabicyclo[4.1.0] heptane (13)
HO
TBSO
O
(
1.2 equiv)
O
O
PPh (1.2 equiv), DIAD (1.2 equiv)
3
OH
THF, rt, 3.5 h
TBSO
1
2
13
1
1
2 was prepared by reported methods (>99% ee). To a solution of PPh
3
(136 mg, 0.52 mmol, 1.2 equiv) and
2-t-butyldimethylsilyloxyphenol (117 mg, 0.52 mmol, 1.2 equiv) in THF (1.5 mL), DIAD (diisopropyl
azodicarboxylate, 102 μL, 0.52 mmol, 1.2 equiv) was added dropwise with cooling in an ice bath. Epoxy
alcohol 12 (49 mg, 0.43 mmol) in THF (0.5 mL) was added dropwise to the mixture, and the mixture was
warmed to room temperature. After stirring for 3.5 h, water was added, and the organic layer was separated.
The aqueous layer was extracted with EtOAc twice, and the combined organic layers were washed with brine,
and dried over Na
2
SO . The solvent was removed under reduced pressure, and the residue was purified by
4
flash column chromatography (silica gel, hexane-EtOAc, 200:1) to afford 13 (122 mg, 0.38 mmol) as a
1
Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.; Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M. Tetrahedron
2
007, 63, 5820.
S-2

1
colorless oil in 89% yield. H NMR (CDCl
3
): δ = 6.99-6.95 (m, 1Η), 6.92-6.81 (m, 3H), 4.46 (dd, J = 8.9, 5.5
Hz, 1H), 3.24 (brs, 1H), 3.21 (d, J = 3.7 Hz, 1H), 2.11-2.03 (m, 1H), 1.97-1.88 (m, 1H), 1.85-1.77 (m, 1H),
13
1
.58-1.40 (m, 2H), 1.34-1.24 (m, 1Η), 0.99 (s, 9H), 0.16 (s, 3H), 0.15 (s, 3H); C NMR (CDCl
3
): δ = 148.6,
1
45.8, 121.8, 121.6, 121.5, 115.5, 72.2, 53.8, 53.1, 26.7, 25.7, 24.2, 18.4, 14.7, 4.5; IR (neat): 3420, 2928,
-1
+
+
1
500 cm ; MS (ESI): m/z 343 [M+Na] ; HRMS (ESI): m/z calcd for C18
H
28
3
O SiNa [M+Na] 343.1705.
27
Found 343.1701; []
D
=  (c = 0.48, CHCl ) for 99% ee.
3
(1R,2R,6S)-6-Methoxycarbonyl-2-(2’-t-butyldimethylsilyloxyphenoxy)cyclohexanol (14) and
t
(
1R,2R,3R)-3 -(2’- Butyldimethylsilyloxyphenoxy)-2-hydroxycyclohexanecarbonitrile (15)
i
To a solution of 13 (7.24 g, 22.6 mmol) in THF (110 mL), Gd(O Pr)
3
(1.51 g, 4.52 mmol, 20 mol %) in THF
(22.6 mL) was added at rt. TMSCN (6.03 mL, 45.2 mmol, 2 equiv) was added to the reaction mixture, and
o
the mixture was warmed to 50 C. After stirring for 3.5 h, water was added, and the organic layer was
separated. The aqueous layer was extracted with EtOAc twice, and the combined organic layers were washed
with brine, and dried over Na
2
SO . The solvent was removed under reduced pressure. To the residue, HCl
4
solution in MeOH (4 M, prepared by mixing AcCl (10 mL) and MeOH (25 mL) on ice bath) was added at rt,
o
and the mixture was warmed to 100 C in the sealed tube. After stirring for 1.5 h, the reaction mixture was
poured into satd. NaHCO
3
. The aqueous layer was extracted with EtOAc three times, and the combined
organic layers were washed with brine, and dried over Na
2
SO . The solvent was removed under reduced
4
pressure. The residue was dissolved in DMF (100 mL), and imidazole (9.04 g, 46.9 mmol, 2.08 equiv) was
added to the mixture at rt. To the reaction mixture, TBSOTf (5.36 mL, 23.3 mmol, 1.03 equiv) was added
with cooling in an ice bath, and the mixture was warmed to rt. After stirring for 1.5 h, water was added, and
the organic layer was separated. The aqueous layer was extracted with EtOAc twice, and the combined
organic layers were washed with water. The organic layer was further washed with brine, and dried over
Na
2 4
SO . The solvent was removed under reduced pressure, and the residue was purified by flash column
chromatography (silica gel, hexane-Et
2
O, 4:1) to afford 14 (1.50 g, 3.94 mmol) as a colorless oil in 17%
yield and 15 (2.95 g, 8.50 mmol) as a colorless oil in 38% yield for 3 steps.
1
1
1
1
1
1
4
1
4: H NMR (CDCl
3
): δ = 6.97-6.93 (m, 1Η), 6.89-6.81 (m, 3H), 3.98-3.84 (m, 1H), 3.72 (s, 3H), 3.27 (s,
H), 2.48-2.40 (m 1H), 2.20-2.12 (m, 1H), 1.95-1.87 (m, 1H), 1.85-1.76 (m, 1H), 1.57-1.41 (m, 2H),
13
.39-1.28 (m, 1H), 0.99 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H); C NMR (CDCl
3
): δ = 174.2, 149.7, 146.5, 122.5,
22.1, 121.4, 118.1, 84.1, 74.5, 51.8, 49.1, 30.0, 28.0, 25.7, 23.1, 18.3, 4.4; IR (neat): 3484, 2950, 1740,
-
1
+
+
499, 1264 cm ; MS (ESI): m/z 403 [M+Na] ; HRMS (ESI): m/z calcd for C20
H
32
O SiNa [M+Na]
5
2
7
03.1917. Found 403.1899; []
D
=  (c = 3.10, CHCl ) for 99% ee.
3
1
5: H NMR (CDCl
3
): δ = 6.94-6.82 (m, 4Η), 3.79-3.70 (m, 3H), 2.53-2.46 (m, 1H), 2.21-2.16 (m, 1H),
S-3

2
0
3
3
.14-2.06 (m, 1H), 1.86-1.79 (m, 1H), 1.69-1.58 (m, 1H), 1.52-1.40 (m, 1H), 1.37-1.25 (m, 1H), 0.99 (s, 9H),
13
.20 (s, 3H), 0.17 (s, 3H); C NMR (CDCl ): δ = 149.4, 146.5, 123.2, 122.2, 121.4, 120.2, 118.9, 84.4, 74.0,
3
-1
4.8, 29.9, 28.3, 25.7, 22.7, 18.3, 4.3, 4.4; IR (neat): 3466, 2931, 2244, 1499, 1266 cm ; MS (ESI): m/z
+
+
27
70 [M+Na] ; HRMS (ESI): m/z calcd for C19
) for 99% ee.
5 can be converted to 14 by following procedure.
H
29NO
3
SiNa [M+Na] 370.1814. Found 370.1807; []
D
=

 (c = 5.42, CHCl
3
1
To 15 (2.95 g, 8.50 mmol), HCl solution in MeOH (4 M, prepared by mixing AcCl (10 mL) and MeOH (25
o
mL) on ice bath) was added at rt, and the mixture was warmed to 100 C in a sealed tube. After stirring for 3
h, the reaction mixture was poured into satd. NaHCO
3
. The aqueous layer was extracted with EtOAc three
times, and the combined organic layers were washed with brine, and dried over Na
2
SO . The solvent was
4
removed under reduced pressure. The residue was dissolved in DMF (40 mL), and imidazole (3.89 g, 20.2
mmol, 2.38 equiv) was added to the mixture at rt. To the reaction mixture, TBSOTf (2.32 mL, 10.1 mmol,
1
.19 equiv) was added with cooling in an ice bath, and the mixture was warmed to rt. After stirring for 1.5 h,
water was added, and the organic layer was separated. The aqueous layer was extracted with EtOAc twice,
and the combined organic layers were washed with water. The organic layer was further washed with brine,
and dried over Na
flash column chromatography (silica gel, hexane-Et
oil in 35% yield and 15 (1.50 g, 4.32 mmol) as a colorless oil in 51% yield for 2 steps.
2 4
SO . The solvent was removed under reduced pressure, and the residue was purified by
2
O, 4:1) to afford 14 (1.13 g, 2.97 mmol) as a colorless
(1R,2R,6S)-6-Diphenylhydroxymethyl-2-(2’-hydroxyphenoxy)cyclohexanol (2)
O
Ph Ph
HO
1
2
) TMSCl (1.5 equiv), NEt (4.5 equiv)
3
MeO
HO
CH Cl , rt, 1 h
2
2
) PhLi (3 equiv)
HO
o
o
THF, 78 C- 10 C, 2.5 h
O
O
3
) TBAF (2 equiv)
o
THF, 0 C, 10 min
TBSO
HO
14
2
To a solution of 14 (209 mg, 0.55 mmol) in CH
was added at rt. To the mixture, TMSCl (104 L, 0.82 mmol, 1.5 equiv) was added at rt. After stirring for 1 h,
water was added, and the organic layer was separated. The aqueous layer was extracted with CH Cl twice,
and the combined organic layers were washed with satd. NH Cl twice and brine. The organic layer was dried
Cl
2 2
(2.5 mL), triethylamine (341 L, 2.46 mmol, 4.5 equiv)
2
2
4
over Na
2 4
SO , and the solvent was removed under reduced pressure. The residue was dissolved in THF (2.5
o
mL), and PhLi (1.9 M solution in dibutylether, 0.87 mL, 1.65 mmol, 3 equiv) was added at 78 C. The
S-4

o
reaction mixture was gradually warmed to 10 C. After stirring for 2.5 h, satd. NH
4
Cl was added, and the
organic layer was separated. The aqueous layer was extracted with EtOAc twice, and the combined organic
layers were washed with brine, and dried over Na SO . The solvent was removed under reduced pressure.
The residue was dissolved in THF (2.5 mL), and TBAF (1 M solution in THF, 1.1 mL, 1.1 mmol, 2 equiv)
was added with cooling in an ice bath. After stirring for 10 min, satd. NH Cl was added and the organic layer
was separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were
washed with brine, and dried over Na SO . The solvent was removed under reduced pressure, and the residue
2
4
4
2
4
was purified by flash column chromatography (silica gel, hexane-EtOAc, 5:1) to afford 2 (170 mg, 0.44
1
mmol) as a white powder in 79% yield for 3 steps. H NMR (CDCl
3
): δ = 7.46-7.29 (m, 10H), 7.00-6.89 (m,
3
2
1
4
H), 6.74-6.69 (m, 1H), 5.62 (s, 1H), 3.69-3.62 (m, 1H), 3.56-3.49 (m, 1H), 3.00 (s, 1H), 2.71-2.64 (m ,1H),
13
.71-2.62 (m, 1H), 1.78-1.64 (m, 2H), 1.38-1.22 (m, 2H), 1.01-0.90 (m, 1H); C NMR (CDCl
3
): δ = 149.8,
45.9, 144.8, 141.3, 128.8, 128.2, 128.0, 127.7, 127.6, 127.4, 125.0, 121.9, 119.3, 116.8, 88.1, 83.5, 75.2,
-
1
+
9.2, 30.6, 27.6, 22.8; IR (neat): 3358, 2941, 1592, 1495, 1264 cm ; MS (ESI): m/z 413 [M+Na] ; HRMS
+
27
(
ESI): m/z calcd for C25
26
H O
4
Na [M+Na] 413.1729. Found 413.1710; []
D
=  (c = 0.55, CHCl ) for
3
9
9% ee.
(
1R,2R,6S)-6-Diphenylmethoxymethyl-2-(2’-hydroxyphenoxy)cyclohexanol (3)
Ph Ph
Ph Ph
HO
MeO
AcCl, MeOH
rt, 1 h
HO
HO
O
O
HO
HO
2
3
To 2 (128 mg, 0.33 mmol), HCl solution in MeOH (2 M, prepared by mixing AcCl (0.43 mL) and MeOH
2.57 mL) on ice bath) was added at rt. After stirring for 1 h, the reaction mixture was poured into satd.
NaHCO . The aqueous layer was extracted with EtOAc three times. The combined organic layers were
washed with brine, and dried over Na SO . The solvent was removed under reduced pressure, and the residue
(
3
2
4
was purified by flash column chromatography (silica gel, hexane-EtOAc, 10:1) to afford 3 (108 mg, 0.27
1
mmol) as a white powder in 81% yield. H NMR (CDCl
3
): δ = 9.27 (s, 1H), 7.47-7.32 (m, 10H), 7.01-6.93
(
(
m, 2H), 6.92-6.88 (m, 1H), 6.72-6.66 (m, 1H), 6.55 (s, 1H), 3.60-3.51 (m, 1H), 3.21 (t, J = 9.3 Hz, 1H), 2.86
13
s, 3H), 2.74-2.66 (m, 1H), 2.14-2.06 (m, 1H), 1.65-1.56 (m, 2H), 1.30-1.13 (m, 2H), 0.94-0.82 (m, 1H); C
3
NMR (CDCl ): δ = 150.3, 146.3, 137.9, 136.0, 129.5, 129.2, 128.5, 128.2, 127.7, 125.3, 122.9, 119.0, 117.0,
-
1
9
4
0.5, 88.9, 75.1, 51.9, 49.4, 30.5, 26.6, 22.7; IR (neat): 3391, 2941, 1590, 1495, 1266 cm ; MS (ESI): m/z
+
+
27
27 [M+Na] ; HRMS (ESI): m/z calcd for C26
1.00, CHCl ) for 99% ee.
3-B) Synthesis of 4 and 5
H O
28 4
Na [M+Na] 427.1885. Found 427.1870; []
D
= (c
=
3
(
(
1R,2R,6S)-6-Di-para-tolylhydroxymethyl-2-(2’-hydroxyphenoxy)cyclohexanol (16)
S-5

O
p-tol p-tol
1
) TMSCl (1.5 equiv), NEt (4.5 equiv)
3
MeO
HO
CH Cl , rt, 1 h
HO
2
2
n
2
) p-Bromotoluene (6 equiv), BuLi (4 equiv)
HO
O
o
o
THF, 78 C- 30 C, 2.5 h
O
3
) TBAF (2 equiv)
o
THF, 0 C, 10 min
TBSO
HO
14
16
To a solution of 14 (1.76 g, 4.63 mmol) in CH
was added at rt. To the mixture, TMSCl (882 L, 6.95 mmol, 1.5 equiv) was added at rt. After stirring for 1 h,
water was added, and the organic layer was separated. The aqueous layer was extracted with CH Cl twice,
and the combined organic layers were washed with satd. NH Cl twice and brine. The organic layer was dried
over Na SO , and the solvent was removed under reduced pressure. The residue was dissolved in THF (6
2
Cl
2
(23 mL), triethylamine (2.89 mL, 20.84 mmol, 4.5 equiv)
2
2
4
2
4
o
n
mL), and was added to a tolyllithium solution in THF at 78 C, prepared by adding BuLi (2.76 M solution
in hexane, 6.71 mL, 18.52 mmol, 4 equiv) to a solution of para-bromotoluene (3.42 mL, 27.78 mmol, 6
o
equiv) in THF (25 mL) at 78 C followed by stirring for 2 h. The reaction mixture was gradually warmed to
o

30 C. After stirring for 2.5 h, satd. NH
4
Cl was added, and the organic layer was separated. The aqueous
layer was extracted with EtOAc twice. The combined organic layers were washed with brine, and dried over
Na SO . The solvent was removed under reduced pressure. The residue was dissolved in THF (23 mL), and
TBAF (1 M solution in THF, 9.26 mL, 9.26 mmol, 2 equiv) was added with cooling in an ice bath. After
stirring for 10 min, satd. NH Cl was added, and the organic layer was separated. The aqueous layer was
extracted with EtOAc twice. The combined organic layers were washed with brine, and dried over Na SO
The solvent was removed under reduced pressure, and the residue was purified by flash column
2
4
4
2
4
.
chromatography (silica gel, CH
2
Cl ) to afford 16 (1.69 g, 4.03 mmol) as a white powder in 87% yield for 3
2
1
steps. H NMR (CDCl
3
): δ = 8.84 (s, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.2
Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 6.99-6.94 (m, 1H), 6.93-6.89 (m, 2H), 6.73-6.68 (m, 1H) 5.83 (s, 1H),
3
2
1
4
.64-3.57 (m, 1H), 3.50 (t, J = 9.3 Hz, 1H), 2.91 (s,1H), 2.66-2.58 (m, 1H), 2.38 (s, 3H), 2.32 (s, 3H),
13
.17-2.10 (m, 1H), 1.76-1.62 (m, 2H), 1.37-1.20 (m, 2H), 0.98-0.87 (m, 1H); C NMR (CDCl
3
): δ = 149.9,
46.0, 142.0, 138.2, 138.0, 137.2, 129.3, 128.3, 127.9, 127.3, 125.0, 122.2, 119.2, 116.8, 88.2, 83.3, 75.2,
-1
9.0, 30.6, 27.5, 22.7, 21.0, 21.0; IR (neat): 3344, 2943, 1591, 1495, 1264 cm ; MS (ESI): m/z 441
+
+
27
[
M+Na] ; HRMS (ESI): m/z calcd for C27
.97, CHCl ) for 99% ee.
1R,2R,6S)-6-Di-para-tolylmethoxymethyl-2-(2’-hydroxyphenoxy)cyclohexanol (4)
H
30
O
4
Na [M+Na] 441.2042. Found 441.2028; []
D
=  (c =
2
3
(
p-tol p-tol
p-tol p-tol
MeO
HO
AcCl, MeOH
rt, 1 h
HO
O
HO
O
HO
HO
16
4
To 16 (126 mg, 0.30 mmol), HCl solution in MeOH (2 M, 3mL) was added at rt. After stirring for 1 h, the
S-6

reaction mixture was poured into satd. NaHCO
3
. The aqueous layer was extracted with EtOAc three times.
The combined organic layers were washed with brine, and dried over Na
2
SO . The solvent was removed
4
under reduced pressure, and the residue was purified by flash column chromatography (silica gel,
1
hexane-EtOAc, 15:1) to afford 4 (104 mg, 0.24 mmol) as a white powder in 80% yield. H NMR (CDCl
3
): δ
=
9.31 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.27-7.21 (m, 4H), 7.16 (d, J = 8.1 Hz, 2H), 7.01-6.97 (m, 2H), 6.92-
6
2
0
1
1
4
.88 (m, 1H), 6.71-6.66 (m, 1H), 6.59 (s, 1H), 3.58-3.51 (m, 1H), 3.21 (t, J = 9.3 Hz, 1H), 2.85 (s, 3H),
.68-2.61 (m, 1H), 2.40 (s, 3H), 2.35 (s, 3H), 2.13-2.05 (m, 1H), 1.62-1.52 (m, 2H), 1.30-1.12 (m, 2H),
13
.90-0.80 (m, 1H); C NMR (CDCl
3
): δ = 150.3, 146.3, 138.2, 137.3, 135.0, 133.0, 129.4, 129.1, 128.8,
28.3, 125.3, 122.9, 119.0, 117.0, 90.4, 89.0, 75.1, 51.7, 49.4, 30.5, 26.6, 22.7, 21.0; IR (neat): 3236, 2941,
-1
+
+
590, 1495, 1266 cm ; MS (ESI): m/z 455 [M+Na] ; HRMS (ESI): m/z calcd for C28
H
32
O Na [M+Na]
4
2
7
55.2198. Found 455.2185; []
D
3
= (c = 1.60, CHCl ) for 99% ee.
(1R,2R,6S)-6-Di-para-tolyl(2’-methyl-1’-propyloxy)methyl-2-(2’-hydroxyphenoxy)cyclohexanol (5)
p-tol p-tol
p-tol p-tol
HO
O
iBuOH, TfOH
rt, 4 h
HO
O
HO
O
HO
HO
5
16
To a solution of 16 (126 mg, 0.30 mmol) in 2-methyl-1-propanol (6 mL), trifluoromethansulfonic acid (26
L, 0.3 mmol) was added at rt. After stirring for 4 h, satd. NaHCO was added, and the organic layer was
separated. The aqueous layer was extracted with EtOAc twice, and the combined organic layers were washed
with water. The organic layer was washed with brine and dried over Na SO . The solvent was removed

3
2
4
under reduced pressure, and the residue was purified by flash column chromatography (silica gel,
1
hexane-EtOAc, 50:1) to afford 5 (114 mg, 0.24 mmol) as a white powder in 80% yield. H NMR (CDCl
3
): δ
=
9.35 (s, 1H), 7.31 (d, J = 8.2Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz,
2
9
1
1
7
H), 7.00-6.93 (m, 1H), 6.91-6.88 (m, 1H), 6.81 (s, 1H), 6.71-6.66 (m, 1H), 3.59-3.52 (m, 1H), 3.25 (t, J =
.3Hz, 1H), 3.02 (dd, J = 8.9, 6.1 Hz, 1H), 2.71-2.63 (m, 1H), 2.39 (s, 3H), 2.37-2.34 (m, 4H), 2.11-2.04 (m,
13
H), 1.78-1.67 (m, 1H), 1.61-1.50 (m, 2H), 1.28-1.12 (m, 2H), 0.86-0.77 (m, 7H); C NMR (CDCl
3
): δ =
50.3, 146.2, 138.1, 137.2, 135.5, 133.4, 129.4, 129.2, 128.7, 128.2, 125.3, 122.9, 119.0, 117.0, 89.9, 88.8,
-1
5.1, 70.6, 49.4, 30.3, 28.5, 26.5, 22.7, 21.0, 19.6, 19.6; IR (neat): 3251, 2955, 1590, 1495, 1266 cm ; MS
+
+
(
[
(
ESI): m/z 497 [M+Na] ; HRMS (ESI): m/z calcd for C31
H
38
O Na [M+Na] 497.2668. Found 497.2665;
4
2
5
]
D
= (c = 1.27, CHCl
3
) for 99% ee.
1R,2R,6R)-6-Diphenylmethyl-2-(2’-hydroxyphenoxy)cyclohexanol (6)
Ph Ph
H
1
) Diphenylmethane(1.5 equiv)
O
nBuLi (1.25 equiv)
HO
THF, rt, 10 min
O
O
2
) TBAF (1 equiv)
o
TBSO
THF, 0 C, 10 min
HO
13
6
S-7

n
To a solution of diphenylmethane (388 L, 2.33 mmol, 1.5 equiv) in THF (8 mL), BuLi (2.76 M solution in
o
hexane, 703 L, 1.94 mmol, 1.25 equiv) was added at 78 C. The reaction mixture was warmed to rt, and
stirred for 1 h, followed by the addition of 13 (497 mg, 1.55 mmol) at rt. After stirring for 10 min, satd.
NH
The combined organic layers were washed with brine, and dried over Na
under reduced pressure. The residue was dissolved in THF (3.5 mL), and TBAF (1 M solution in THF, 1.55
mL, 1.55 mmol, 1 equiv) was added with cooling in an ice bath. After stirring for 10 min, satd. NH Cl was
added and the organic layer was separated. The aqueous layer was extracted with EtOAc twice. The
combined organic layers were washed with brine, and dried over Na SO . The solvent was removed under
4
Cl was added, and the organic layer was separated. The aqueous layer was extracted with EtOAc twice.
2
SO . The solvent was removed
4
4
2
4
reduced pressure, and the residue was purified by flash column chromatography (silica gel, hexane-EtOAc,
1
2
7
4
1
1
0:1) to afford 6 (228 mg, 0.61 mmol) as a white powder in 39% yield for 2 steps. H NMR (CDCl
3
): δ =
.74 (s, 1H), 7.37-7.26 (m, 8H), 7.23-7.18 (m, 2H), 6.98-6.93 (m, 2H), 6.92-6.87 (m, 1H), 6.77-6.71 (m, 1H),
.14 (d, J = 8.0 Hz, 1H), 3.69-3.60 (m, 2H), 2.48-2.37 (m, 1H), 2.22-2.16 (m, 2H), 1.75-1.64 (m, 2H),
13
.49-1.39 (m, 1H), 1.27-1.16 (m, 1H), 1.04-0.93 (m, 1H); C NMR (CDCl
3
): δ = 149.2, 145.5, 143.3, 142.4,
29.0, 128.9, 128.6, 128.2, 126.9, 126.6, 124.7, 120.9, 119.5, 116.4, 86.7, 77.6, 55.1, 46.4, 30.7, 28.9, 22.7;
-
1
+
IR (neat): 3405, 2939, 1594, 1496, 1262 cm ; MS (ESI): m/z 397 [M+Na] ; HRMS (ESI): m/z calcd for
+
25
C
25 26
H O
3
Na [M+Na] 397.1780. Found 397.1772; []
D
= (c = 2.64, CHCl ) for 99% ee.
3
4
. Substrate Synthesis
(4-A) General Procedure for the Synthesis of Enones 7a-7e, 7g, 7h (Synthesis of 7e)
N-Methoxy-N-methylcyclohexanecarboxamide (17)
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.9 g, 60 mmol, 1 equiv) in CH
2
Cl (120 mL),
2
triethylamine (17.6 mL, 126 mmol, 2.1 equiv) was added with cooling in an ice bath. To the mixture,
cyclohexanecarbonylchloride (8.0 mL, 60 mmol) was added and the mixture was warmed to rt. After stirring
for 17 h, water was added, and the organic layer was separated. The aqueous layer was extracted with
CH
over Na
colorless oil (ca. 93% yield), and crude 17 was used in the next reaction without purification.
2 2
Cl
twice. The combined organic layers were washed with 1 M HCl, satd. NaHCO
3
and brine, and dried
2
SO . The solvent was removed under reduced pressure to afford crude 17 (9.6 g, 56 mmol) as a
4
1-Cyclohexyl-2-butyn-1-one (18)
O
O
1
,2-Dibromopropane (1.1 equiv)
O
N
i
n
Pr NH (3.4 equiv), BuLi (3.5 equiv)
2
THF, rt, 18 h
17
1
8
n
To di-i-propylamine (26.7 mL, 190.4 mmol, 3.4 equiv), BuLi (1.59 M solution in hexane, 123 mL, 196
mmol, 3.5 equiv) was added with cooling in an ice bath. After stirring for 15 min, the mixture was cooled to
o

78 C, and THF (140 mL) was added. 1,2-Dibromopropane (6.41 mL, 61.6 mmol, 1.1 equiv) was added to
S-8

o
o
the mixture dropwise at 78 C, and the reaction mixture was warmed to 0 C. After stirring for 30 min, the
o
mixture was cooled to 78 C, and crude 17 (9.6 g, 56 mmol) was added. The mixture was gradually warmed
o
to rt. After stirring for 16 h, the mixture was cooled to 0 C, and 3 M HCl was added. The organic layer was
separated, and the aqueous layer was extracted with AcOEt twice. The combined organic layers were washed
successively with satd. NaHCO
3
and brine, and dried over Na
2 4
SO . The solvent was removed under reduced
pressure, and the residue was purified by flash column chromatography (silica gel, hexane-Et
2
O, 20:1) to
afford 18 (5.84 g, 38.9 mmol) as a colorless oil in 69% yield. Without further purification, 18 was used in the
next reaction.
(
E)-1-Cyclohexyl-3-methyl-2-hepten-1-one ((E)-7e) and
Z)-1-Cyclohexyl-3-methyl-2-hepten-1-one ((Z)-7e)
(
n
To a solution of CuCN (3.83 g, 42.8 mmol, 1.1 equiv) in THF (400 mL), BuLi (1.59 M solution in hexane,
o
2
6.9 mL, 42.8 mmol, 1.1 equiv) was added at 40 C. After stirring for 15 min, the mixture was cooled to
o

78 C, and 18 (5.84 g, 38.9 mmol) in THF (20 mL) was added. The reaction mixture was gradually warmed
o
to 40 C. After stirring for 3 h, satd. NH
4
Cl was added and the organic layer was separated. The aqueous
O twice. The combined organic layers were washed with brine, and dried over
. Solvent was removed under reduced pressure. The residue was passed through a short pad column
chromatography (silica gel, AcOEt), and the solvent was removed under reduced pressure. The residue
layer was extracted with Et
Na SO
2
2
4
(
mixture of E- and Z-isomers) was purified by Rover column (silica gel, Hexane-Et
2
O, 50:1) to afford (E)-7e
(3.23 g, 15.5 mmol) as a colorless oil in 40% yield and (Z)-7e (3.01 g, 14.4 mmol) as a colorless oil in 37%
yield.
1
(
E)-7e: H NMR (CDCl ): δ = 6.05 (s, 1H), 2.30-2.23 (m, 1H), 2.10-2.05 (m, 5H), 1.82-1.70 (m, 4H),
3
1
3
1
2
.66-1.59 (m, 1H), 1.45-1.38 (m, 2H), 1.33-1.10 (m, 7H), 0.87 (t, J = 7.3 Hz, 3H); C NMR (CDCl ): δ =
3
-1
04.3, 159.0, 122.2, 51.6, 41.0, 29.7, 28.6, 25.9, 25.8, 22.3, 19.2, 13.8; IR (neat): 2929, 1685, 1617 cm ; MS
+
+
(
ESI): m/z 231 [M+Na] ; HRMS (ESI): m/z calcd for C14H24ONa [M+Na] 231.1725. Found 231.1731.
1
(
Z)-7e: H NMR (CDCl
3
): δ = 6.03 (s, 1H), 2.52 (t, J = 7.7 Hz, 2H), 2.29-2.21 (m, 1H), 1.83 (s, 3H),
1
3
1
2
.81-1.71 (m, 4H), 1.67-1.58 (m, 1H), 1.41-1.10 (m, 9H), 0.87 (t, J = 6.6 Hz, 3H); C NMR (CDCl ): δ =
3
-1
03.8, 159.6, 122.9, 51.6, 33.3, 30.4, 28.6, 25.9, 25.8, 25.5, 22.9, 13.9; IR (neat): 2929, 1684, 1617 cm ; MS
+
+
(
ESI): m/z 231 [M+Na] ; HRMS (ESI): m/z calcd for C14
H
24ONa [M+Na] 231.1725. Found 231.1735.
Enones 7f and 7i were synthesized following the reported procedures.
4-B) General Procedure for the Synthesis of ,-Unsaturaned N-Acylpyrroles 9 (Synthesis of 9a)
2
3
(
3-Methyl-2-heptenoicacid 1,1-dimethylethylester (20)
2
-hexanone (1 equiv)
O
O
i
n
Pr NH (1.2 equiv), BuLi (1.2 equiv)
TMS
2
tBuO
tBuO
o
THF, 78 C- rt, 3 h
19
2
0
2
3
Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
Hudlicky, T.; Srnak, T. Tetrahedron Lett. 1981, 22, 3351.
S-9

4
1
9 was synthesized following reported procedure. To di-i-propylamine (3.36 mL, 24.0 mmol, 1.2 equiv),
n
BuLi (2.76 M solution in hexane, 8.70 mL, 24.0 mmol, 1.2 equiv) was added with cooling in an ice bath.
o
After stirring for 15 min, the mixture was cooled to 78 C, and THF (50 mL) was added. 19 (3.77 g, 20.0
o
mmol) was added to the mixture dropwise at 78 C. After stirring for 10 min, 2-hexanone (2.47 mL, 20.0
mmol, 1 equiv) was added and the reaction mixture was gradually warmed to rt. Aftrer stirring for 3 h, satd.
NH
The combined organic layers were washed with satd. NH
was removed under reduced pressure to afford a (E)- and (Z)-mixture of crude 20 (3.62 g, 18.3 mmol, E/Z =
4
Cl was added, and the organic layer was separated. The aqueous layer was extracted with EtOAc twice.
4
Cl and brine, and dried over Na SO . The solvent
2
4
1
/1) as a colorless oil (ca. 91% yield). Crude 20 was used in the next reaction without purification.
3-Methyl-2-heptenamide (21)
1
) TFA/CH Cl
rt, 10 min
2
2
O
O
2) Oxalyl chloride (2 equiv), DMF (cat.)
CH Cl , rt, 30 min
2
2
tBuO
; aq. NH OH, THF, rt, 10 min
H N
2
4
21
20
To a solution of crude 20 (3.62 g, 18.3 mmol) in CH
rt. After stirring for 10 min, water was added, and the organic layer was separated. The aqueous layer was
extracted with CH Cl twice. The combined organic layers were washed with brine, and dried over Na SO
The solvent was removed under reduced pressure. The residue was dissolved in CH Cl (75 mL), and oxalyl
2 2
Cl
(18 mL), trifluoroacetic acid (18 mL) was added at
2
2
2
4
.
2
2
chloride (2.84 mL, 36.6 mmol, 2 equiv) was added at rt. One drop of DMF was added to the reaction mixture
at rt. After stirring for 0.5 h, the mixture was evaporated, and the residue was dissolved in THF (30 mL). To
the mixture, aq. NH
separated. The aqueous layer was extracted with AcOEt twice. The combined organic layers were
successively washed with satd. NH Cl and brine, and dried over Na SO . The solvent was removed under
4
OH (30 % v/v, 18 mL) was added at rt. After stirring for 10 min, the organic layer was
4
2
4
reduced pressure to afford crude 21 (2.43 g, 15.1 mmol: ca. 83% yield). Crude 21 was used in the next
reaction without purification.
(
E)-3-Methyl-1-(pyrrol-1-yl)-2-hepten-1-one ((E)-9a) and
Z)-3-Methyl-1-(pyrrol-1-yl)-2-hepten-1-one ((Z)-9a)
(
To a solution of crude 21 (2.43 g, 15.1 mmol) in AcOH (60 mL), 2,5-dimethyltetrahydrofuran (2.9 mL, 22.7
o
mmol, 1.5 equiv) was added at rt, and the mixture was heated at 100 C. After stirring for 2.5 h, water and
AcOEt was added, and the organic layer was separated. The aqueous layer was extracted with AcOEt twice,
and the combined organic layers were washed with satd. NaHCO
washed with brine, and dried over Na SO . The solvent was removed under reduced pressure, and the residue
was purified by flash column chromatography (silica gel, hexane-CH Cl , 6:1) to afford (E)-9a (1.08 g, 5.7
3
five times. The organic layer was further
2
4
2
2
mmol) as a colorless oil in 37% yield and (Z)-9a (0.77 g, 4.0 mmol) as a colorless oil in 27% yield.
4
Ager, D. J. Organic Reactions, 1990, 38.
S-10

1
(
E)-9a: H NMR (CDCl ): δ = 7.33 (t, J = 2.3 Hz, 2H), 6.32-6.29 (m, 1H), 6.27 (t, J = 2.3 Hz, 2H), 2.24 (t, J
3
13
=
7.8 Hz, 2H), 2.19 (s, 3H), 1.55-1.47 (m, 2H), 1.39-1.30 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); C NMR
3
(CDCl ): δ = 163.3, 119.1, 114.3, 112.6, 41.1, 29.6, 22.3, 19.6, 13.9; IR (neat): 3381, 2957, 2931, 1696, 1631,
-1
+
+
1
467, 1277 cm ; MS (ESI): m/z 214 [M+Na] ; HRMS (ESI): m/z calcd for C12H17NONa [M+Na] 214.1208.
Found 214.1205.
1
(
Z)-9a: H NMR (CDCl
3
): δ = 7.33 (t, J = 2.1 Hz, 2H), 6.29 (s, 1H), 6.26 (t, J = 2.1 Hz, 2H), 2.62 (t, J = 7.8
13
Hz, 2H), 1.99 (s, 3H), 1.53-1.45 (m, 2H), 1.42-1.33 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); C NMR (CDCl
3
): δ =
1
1
63.8, 162.8, 119.1, 114.8, 112.6, 34.0, 30.3, 25.6, 22.9, 13.9; IR (neat): 3371, 2958, 2931, 1697, 1630, 1467,
-
1
+
+
274 cm ; MS (ESI): m/z 214 [M+Na] ; HRMS (ESI): m/z calcd for C12H17NONa [M+Na] 214.1208.
Found 214.1206.
(4-C) Synthesis of rac-11
(Z)-2,4-Dimethyl-2-hydroxy-3-octenenitrile (11)
i
1
) Gd(OPr) (5 mol %)
3
rac-FujiCAPO (7.5 mol %)
TMSCN (1.5 equiv)
THF, rt, 14 h
O
HO CN
2
) HF-pyridine/MeCN
o
rac-11
(Z)-7b
0 C, 10 min
1
To a solution of rac-FujiCAPO (153 mg, 0.375 mmol, 7.5 mol %) in THF (12.5 mL), a solution of
i
Gd(O Pr)
3
(83.8 mg, 0.25 mmol, 5 mol %) in THF (1.25 mL) was added at rt. The mixture was heated at 50
o
C. After stirring for 20 min, the mixture was cooled to rt, and (Z)-7b (815 L, 5 mmol) was added, followed
by the addition of TMSCN (1.0 mL, 7.5 mmol, 1.5 equiv). After stirring for 14 h, water was added, and the
organic layer was separated. The aqueous layer was extracted with AcOEt twice. The combined organic
layers were washed with brine, and dried over Na
2
SO . The solvent was removed under reduced pressure.
4
The residue was dissolved in MeCN (4 mL), and HF-pyridine (0.2 mL) was added with cooling in an ice
bath. After stirring for 10 min, water was added, and the organic layer was separated. The aqueous layer was
extracted with AcOEt twice. The combined organic layers were washed with brine, and dried over Na
2
SO .
4
The solvent was removed under reduced pressure, and the residue was purified by flash column
chromatography (silica gel, hexane-AcOEt, 20:1) to afford rac-11 (659 mg, 3.94 mmol) as a colorless oil in
1
7
3
6
9% yield. H NMR (CDCl
3
): δ = 5.26 (s, 1H), 2.83-2.77 (m, 1H), 2.40-2.27 (m, 2H), 1.73 (d, J = 1.6 Hz,
13
H), 1.67 (s, 3H), 1.50-1.31 (m, 4H), 0.91 (t, J = 7.3 Hz, 3H); C NMR (CDCl
3
): δ = 145.7, 125.0, 122.0,
-1
5.1, 32.5, 30.3, 29.7, 23.6, 22.8, 13.9; IR (neat): 3423, 2959, 2238, 1656, 1457, 1378, 1120 cm ; MS (ESI):
+
+
m/z 190 [M+Na] ; HRMS (ESI): m/z calcd for C10H17NONa [M+Na] 190.1208. Found 190.1201.
5
. Characterization of New Compounds
(E)-3,4-Dimethyl-1-phenyl-2-penten-1-one ((E)-7a)
1
H NMR (CDCl ): δ = 7.90 (d, J = 7.0 Hz, 2H), 7.50 (dd, J = 7.0, 7.0 Hz, 1H), 7.42 (dd, J = 7.0 Hz, 2H),
3
1
3
6
1
2
.72 (s, 1H), 2.51-2.42 (m, 1H), 2.15 (s, 3H), 1.13 (d, J = 6.7 Hz, 6H); C NMR (CDCl
3
): δ = 192.2, 165.4,
-
1
39.5, 132.2, 128.4, 128.1, 118.5, 38.5, 21.0, 17.3; IR (neat): 2964, 1661, 1609, 1239 cm ; MS (ESI): m/z
+
+
11 [M+Na] ; HRMS (ESI): m/z calcd for C13H16ONa [M+Na] 211.1099. Found 211.1103.
(Z)-3,4-Dimethyl-1-phenyl-2-penten-1-one ((Z)-7a)
S-11

1
H NMR (CDCl ): δ = 7.91 (d, J = 7.0 Hz, 2H), 7.50 (dd, J = 7.0, 7.0 Hz, 1H), 7.42 (dd, J = 7.0 Hz, 2H),
3
1
3
6
1
2
.59 (s, 1H), 3.80-3.71 (m, 1H), 1.90 (s, 3H), 1.06 (d, J = 6.7 Hz, 6H); C NMR (CDCl
3
): δ = 191.5, 164.8,
-
1
39.3, 132.3, 128.4, 128.3, 120.9, 30.1, 20.7, 19.7; IR (neat): 2924, 1660, 1609, 1239 cm ; MS (ESI): m/z
+
+
11 [M+Na] ; HRMS (ESI): m/z calcd for C13H16ONa [M+Na] 211.1099. Found 211.0954.
(E)-4-Methyl-3-octen-2-one ((E)-7b)
1
3
H NMR (CDCl ): δ = 6.02 (s, 1H), 2.13 (s, 3H), 2.09-2.05 (m, 5H), 1.45-1.37 (m, 2H), 1.32-1.23 (m, 2H),
13
0
.87 (t, J = 7.3 Hz, 3H); C NMR (CDCl
3
): δ = 198.8, 158.9, 123.4, 40.9, 31.7, 29.6, 22.3, 19.2, 13.8; IR
-
1
+
(
neat): 3412, 2932, 1688, 1617 cm ; MS (ESI): m/z 163 [M+Na] ; HRMS (ESI): m/z calcd for C
9
H16ONa
+
[
M+Na] 163.1099. Found 163.1095.
(Z)-4-Methyl-3-octen-2-one ((Z)-7b)
1
H NMR (CDCl ): δ = 6.01 (s, 1H), 2.53 (t, J = 7.6 Hz, 2H ), 2.11 (s, 3H), 1.82 (d, J = 1.6 Hz, 3H), 1.42-1.27
3
13
(
m, 4H), 0.87 (t, J = 7.3 Hz, 3H); C NMR (CDCl
3
): δ = 198.2, 159.6, 123.9, 33.3, 31.7, 30.3, 25.3, 22.8,
-
1
+
1
3.9; IR (neat): 3413, 2959, 1688, 1616 cm ; MS (ESI): m/z 163 [M+Na] ; HRMS (ESI): m/z calcd for
+
C
9
H
16ONa [M+Na] 163.1099. Found 163.1096.
(E)-4,5-Dimethyl-3-hexen-2-one ((E)-7c)
1
3
H NMR (CDCl ): δ = 6.04 (s, 1H), 2.34-2.25 (m, 1H), 2.15 (s, 3H), 2.06 (s, 3H), 1.03 (d, J = 7.0 Hz, 6H);
13
-1
C NMR (CDCl
3
): δ = 199.3, 164.0, 121.4, 38.2, 31.8, 20.9, 16.8; IR (neat): 3413, 2965, 1686, 1616 cm ;
+
+
MS (ESI): m/z 149 [M+Na] ; HRMS (ESI): m/z calcd for C H14ONa [M+Na] 149.0942. Found 149.0944.
8
(Z)-4,5-Dimethyl-3-hexen-2-one ((Z)-7c)
1
3
H NMR (CDCl ): δ = 5.95 (s, 1H), 3.92-3.82 (m, 1H), 2.11 (s, 3H), 1.75 (s, 3H), 0.97 (d, J = 7.0 Hz, 6H);
13
-1
C NMR (CDCl
3
): δ = 198.3, 164.2, 123.5, 31.9, 29.1, 20.9, 19.3; IR (neat): 3412, 2966, 1688, 1612 cm ;
+
+
MS (ESI): m/z 149 [M+Na] ; HRMS (ESI): m/z calcd for C H14ONa [M+Na] 149.0942. Found 149.0945.
8
(E)- 5-Methyl-1-phenyl-4-nonen-3-one ((E)-7d)
1
H NMR (CDCl
7.6 Hz, 2H), 2.13-2.08 (m, 5H), 1.46-1.38 (m, 2H), 1.33-1.26 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); C NMR
CDCl ): δ = 199.9, 159.2, 141.4, 128.3, 128.3, 125.9, 122.8, 45.8, 40.9, 30.1, 29.6, 22.3, 19.3, 13.8; IR
3
): δ = 7.27-7.23 (m, 2H), 7.19-7.14 (m, 3H), 6.02 (s, 1H), 2.90 (t, J = 7.6 Hz, 2H), 2.73 (t, J
13
=
(
(
[
3
-1
+
neat): 2930, 1686, 1617 cm ; MS (ESI): m/z 253 [M+Na] ; HRMS (ESI): m/z calcd for C16H22ONa
+
M+Na] 253.1568. Found 253.1555.
(Z)- 5-Methyl-1-phenyl-4-nonen-3-one ((Z)-7d)
1
H NMR (CDCl
7.7 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.85 (s, 3H), 1.44-1.30 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); C NMR
CDCl ): δ = 199.3, 159.9, 141.4, 128.3, 128.2, 125.8, 123.4, 45.8, 33.5, 30.3, 30.0, 25.4, 22.9, 13.9; IR
3
): δ = 7.27-7.23 (m, 2H), 7.19-7.14 (m, 3H), 6.01 (s, 1H), 2.89 (t, J = 7.7 Hz, 2H), 2.71 (t, J
13
=
(
(
[
3
-1
+
neat): 2929, 1686, 1616 cm ; MS (ESI): m/z 253 [M+Na] ; HRMS (ESI): m/z calcd for C16H22ONa
+
M+Na] 253.1568. Found 253.1555.
(E)-4-Phenyl-3-hexen-2-one ((E)-7h)
1
H NMR (CDCl ): δ = 7.46-7.41 (m, 2H), 7.39-7.33 (m, 3H), 6.36 (s, 1H), 3.03 (q, J = 7.6 Hz, 2H), 2.26 (s,
3
1
3
3
2
H), 1.04 (t, J = 7.6 Hz, 3H); C NMR (CDCl
3
): δ = 198.4, 160.4, 141.3, 128.9, 128.5, 126.8, 124.1, 32.2,
-
1
+
4.4, 13.5; IR (neat): 2968, 1682, 1597 cm ; MS (ESI): m/z 197 [M+Na] ; HRMS (ESI): m/z calcd for
+
C
12
H
14ONa [M+Na] 197.0942. Found 197.0936.
(Z)-4-Phenyl-3-hexen-2-one ((Z)-7h)
S-12

1
H NMR (CDCl ): δ = 7.38-7.30 (m, 3H), 7.16-7.12 (m, 2H), 6.06 (s, 1H), 2.45 (q, J = 7.3 Hz, 2H), 1.75 (s,
3
1
3
3
3
H), 1.03 (t, J = 7.3 Hz, 3H); C NMR (CDCl
3
): δ = 200.8, 158.5, 140.4, 128.4, 128.1, 127.4, 127.1, 33.5,
-1
+
0.2, 12.2; IR (neat): 2969, 1656 cm ; MS (ESI): m/z 197 [M+Na] ; HRMS (ESI): m/z calcd for C12
H14ONa
+
[
M+Na] 197.0942. Found 197.0954.
(R)-2-Methyl-2-(1-methylethyl)-4-oxo-4-phenylbutanenitrile (8a)
1
H NMR (CDCl ): δ = 7.95-7.90 (m, 2H), 7.60-7.54 (m, 1H), 7.46 (dd, J = 7.6, 7.6 Hz, 2H), 3.35 (d, J = 17.1
3
Hz, 1H) , 3.15 (d, J = 17.1 Hz, 1H), 2.19-2.09 (m, 1H), 1.45 (s, 3H), 1.11 (d, J = 6.7 Hz, 3H), 1.06 (d, J = 6.7
13
Hz, 3H); C NMR (CDCl
3
): δ = 195.6, 136.8, 133.6, 128.7, 128.0, 123.2, 43.7, 38.6, 34.6, 21.2, 18.3, 17.5;
-
1
+
IR (neat): 2971, 2233, 1690 cm ; MS (ESI): m/z 238 [M+Na] ; HRMS (ESI): m/z calcd for C14
H
17NONa
+
26
[
M+Na] 238.1208. Found 238.1194; []
D
=  (c = 1.09, CHCl ) for 97% ee; HPLC condition: Chiralpak
3
AS-H column, flow rate: 1.0 mL / min, n-hexane / i-PrOH = 4 / 1, t = 7.5 min (S, minor), 8.9 min (R, major).
λ= 254 nm.
HPLC chart of rac-8a
HPLC chart of (R)-8a
HPLC chart of (S)-8a
S-13

2-Butyl-2-methyl-4-oxo-pentanenitrile (8b)
1
3
H NMR (CDCl ): δ = 2.75 (d, J = 17.1 Hz, 1H) , 2.58 (d, J = 17.1 Hz, 1H), 2.18 (s, 3H), 1.72-1.65 (m, 1H),
13
1
.57-1.49 (m, 1H), 1.46-1.39 (m, 2H), 1.38 (s, 3H), 1.37-1.29 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H); C NMR
-
1
(
CDCl
3
): δ = 203.9, 123.6, 50.8, 38.9, 33.7, 30.8, 26.9, 24.0, 22.6, 13.8; IR (neat): 2959, 2234, 1720 cm ;
+
+
MS (ESI): m/z 190 [M+Na] ; HRMS (ESI): m/z calcd for C10
H
17NONa [M+Na] 190.1208. Found
2
6
1
o
90.1205; []
D
=  (c = 0.74, CHCl
3
) for 99% ee; GC condition: Chirasil DEX CB, injector temp. = 200
o
o
C, detector temp. = 250 C, column temp. = 95 C (isothermic), t = 16.6 min (major), 18.8 min (minor).
GC chart of rac-8b
GC chart of (+)-8b
S-14

HPLC chart of ()-8b
S-15

(S)-2-Methyl-2-(1-methylethyl)-4-oxo-pentanenitrile (8c)
1
H NMR (CDCl ): δ = 2.80 (d, J = 16.8 Hz, 1H) , 2.56 (d, J = 16.8 Hz, 1H), 2.20 (s, 3H), 2.01-1.92 (m, 1H),
3
13
1
.36 (s, 3H), 1.04 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H); C NMR (CDCl
3
): δ = 204.2, 123.0, 48.8,
-1
+
3
8.2, 34.7, 31.0, 20.8, 18.1, 17.4; IR (neat): 3428, 2922, 2233, 1720 cm ; MS (ESI): m/z 176 [M+Na] ;
+
25
HRMS (ESI): m/z calcd for C
9
H
15NONa [M+Na] 176.1051. Found 176.1056; []
D
=  (c = 0.56,
CHCl
0 / 1, t = 13.1 min (R, minor), 14.4min (S, major). RI detection.
HPLC chart of rac-8c
3
) for 99% ee; HPLC condition: Chiralpak AS-H column, flow rate: 1.0 mL / min, n-hexane / i-PrOH =
2
HPLC chart of (R)-8c
S-16

HPLC chart of (S)-8c
2-Butyl-2-methyl-4-oxo-6-phenylhexanenitrile (8d)
1
3
H NMR (CDCl ): δ = 7.26 (t, J = 7.5 Hz, 2H), 7.20-7.14 (m, 3H), 2.90 (t, J = 7.5 Hz, 2H), 2.78-2.72 (m,
2
H), 2.67 (d, J = 17.1 Hz, 1H) , 2.51 (d, J = 17.1 Hz, 1H), 1.69-1.61 (m, 1H), 1.53-1.45 (m, 1H), 1.42-1.28
13
(
m, 7H), 0.90 (t, J = 7.3 Hz, 3H); C NMR (CDCl ): δ = 205.4, 140.5, 128.5, 128.3, 126.2, 123.6, 50.2, 45.0,
3
-
1
+
3
8.9, 33.7, 29.6, 26.8, 24.0, 22.6, 13.8; IR (neat): 2933, 2234, 1719 cm ; MS (ESI): m/z 280 [M+Na] ;
+
26
HRMS (ESI): m/z calcd for C17
H
23NONa [M+Na] 280.1677. Found 280.1671; []
D
=  (c = 2.02,
CHCl
/ 1, t = 10.6 min (major), 13.7 min (minor). λ= 254 nm.
HPLC chart of rac-8d
3
) for 99% ee; HPLC condition: Chiralpak AS-H column, flow rate: 1.0 mL / min, n-hexane / i-PrOH =
9
HPLC chart of ()-8d
S-17

HPLC chart of ()-8d
2-Butyl-4-cyclohexyl-2-methyl-4-oxo-butanenitrile (8e)
1
H NMR (CDCl ): δ = 2.74 (d, J = 17.1 Hz, 1H) , 2.59 (d, J = 17.1 Hz, 1H), 2.34-2.26 (m, 1H), 1.84-1.60 (m,
3
1
3
6
5
H), 1.57-1.46 (m, 1H), 1.45-1.11 (m, 12H), 0.89 (t, J = 7.3 Hz, 3H); C NMR (CDCl
3
): δ = 209.4, 123.8,
-1
1.2, 47.8, 38.8, 33.7, 28.3, 28.1, 26.9, 25.7, 25.5, 25.4, 24.0, 22.6, 13.8; IR (neat): 2931, 2234, 1712 cm ;
+
+
MS (ESI): m/z 258 [M+Na] ; HRMS (ESI): m/z calcd for C15
H
25NONa [M+Na] 258.1834. Found
) for 99% ee; HPLC condition: Chiralpak AS-H column, flow rate:
.0 mL / min, n-hexane / i-PrOH = 99 / 1, t = 12.7min (major), 14.1 min (minor). RI detection.
25
2
1
58.1817; []
D
=  (c = 1.26, CHCl
3
HPLC chart of rac-8e
S-18

HPLC chart of ()-8e
HPLC chart of ()-8e
S-19

2-Methyl-4-oxo-2-phenylpentanenitrile (8f)
1
H NMR (CDCl ): δ = 7.45 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 8.0, 8.0 Hz, 2H), 7.29 (dd, J = 8.0, 8.0 Hz, 1H),
3
1
3
3
1
2
.12 (d, J = 17.0 Hz, 1H) , 3.01 (d, J = 17.0 Hz, 1H), 2.09 (s, 3H), 1.78 (s, 3H); C NMR (CDCl
3
): δ = 202.9,
-
1
39.6, 129.0, 128.0, 125.3, 122.7, 53.4, 38.7, 30.6, 27.3; IR (neat): 2983, 2238, 1719 cm ; MS (ESI): m/z
+
+
26
10 [M+Na] ; HRMS (ESI): m/z calcd for C12
0.60, CHCl
i-PrOH = 4 / 1, t = 10.2 min (major), 13.1 min (minor). λ= 254 nm.
H
13NONa [M+Na] 210.0895. Found 210.0893; []
D
=  (c
=
3
) for 99% ee; HPLC condition: Chiralpak AS-H column, flow rate: 1.0 mL / min, n-hexane /
2
,4-Diphenyl-2-methyl-4-oxobutanenitrile (8g)
1
3
H NMR (CDCl ): δ = 7.87 (d, J = 7.4 Hz, 2H), 7.58-7.50 (m, 3H), 7.43 (dd, J = 7.8, 7.8 Hz, 2H), 7.37 (dd, J
=
7.8, 7.8 Hz, 2H), 7.29 (dd, J = 7.4, 7.4 Hz, 1H), 3.72 (d, J = 17.7 Hz, 1H) , 3.56 (d, J = 17.7 Hz, 1H), 1.89
13
(
s, 3H); C NMR (CDCl ): δ = 194.2, 140.0, 136.1, 133.6, 129.0, 128.7, 127.9, 127.9, 125.4, 122.9, 48.7,
3
-
1
+
3
8.9, 27.6; IR (neat): 3061, 2238, 1689, 1448, 1225 cm ; MS (ESI): m/z 272 [M+Na] ; HRMS (ESI): m/z
+
25
calcd for C17
H
15NONa [M+Na] 272.1051. Found 272.1040; []
D
=  (c = 1.31, CHCl ) for 99% ee;
3
HPLC condition: Chiralpak AS-H column, flow rate: 1.0 mL / min, n-hexane / i-PrOH = 4 / 1, t = 12.1 min
major), 13.1 min (minor). λ= 254 nm.
(
2-Ethyl-4-oxo-2-phenylpentanenitrile (8h)
1
3
H NMR (CDCl ): δ = 7.40 (d, J = 7.8 Hz, 2H), 7.36 (dd, J = 7.8, 7.8 Hz, 2H), 7.28 (dd, J = 7.8 Hz, 1H),
3
0
3
C
.12 (d, J = 17.1 Hz, 1H) , 3.07 (d, J = 17.1 Hz, 1H), 2.19-2.09 (m, 1H), 2.05 (s, 3H), 1.95-1.87 (m, 1H),
13
.89 (t, J = 7.3 Hz, 3H); C NMR (CDCl ): δ = 202.9, 137.5, 128.9, 127.9, 125.9, 121.5, 52.5. 44.9, 33.8,
3
-
1
+
0.6, 9.3; IR (neat): 2973, 2237, 1718 cm ; MS (ESI): m/z 224 [M+Na] ; HRMS (ESI): m/z calcd for
+
26
13
H
15NONa [M+Na] 224.1051. Found 224.1051; []
D
=  (c = 0.57, CHCl ) for 89% ee; HPLC
3
condition: Chiralpak AS-H column, flow rate: 1.0 mL / min, n-hexane / i-PrOH = 20 / 1, t = 22.7min (major),
S-20

2
5.9 min (minor). λ= 254 nm.
HPLC chart of rac-8h
HPLC chart of ()-8h
HPLC chart of ()-8h
cis-2-Acetyl-1-methylcyclohexanecarbonitrile (8i)
1
3
H NMR (CDCl ): δ = 2.23 (dd, J = 12.5, 3.1 Hz, 1H), 2.18 (s, 3H), 2.02-1.86 (m, 3H), 1.77-1.59 (m, 3H),
13
1
.26-1.36 (m, 5H); C NMR (CDCl
3
): δ = 207.4, 122.5, 59.0, 38.7, 35.4, 28.9, 26.7, 25.2, 25.1, 22.7; IR
-
1
+
(
neat): 2935, 2232, 1712 cm ; MS (ESI): m/z 188 [M+Na] ; HRMS (ESI): m/z calcd for C10
H15NONa
+
26
[
M+Na] 188.1051. Found 188.1047; []
D
=  (c = 0.60, CHCl
3
) for 99% ee; GC condition: Chirasil
o
o
o
DEX CB, injector temp. = 200 C, detector temp. = 250 C, column temp. = 90 C (isothermic), t = 43.7 min
(
minor), 46.8 min (major).
(E)-3,4-Dimethyl-1-(pyrrol-1-yl)-2-penten-1-one ((E)-9b)
1
3
H NMR (CDCl ): δ = 7.33 (t, J = 2.3 Hz, 2H), 6.32 (s, 1H), 6.26 (t, J = 2.3 Hz, 2H), 2.51-2.42 (m, 1H), 2.16
1
3
(
(
s, 3H), 1.12 (d, J = 6.8 Hz, 6H); C NMR (CDCl
3
): δ = 168.1, 163.6, 119.1, 112.5, 38.4, 20.9, 17.2; IR
-1
+
neat): 2965, 1697, 1627, 1467, 1276 cm ; MS (ESI): m/z 200 [M+Na] ; HRMS (ESI): m/z calcd for
S-21

+
C
11
H
15NONa [M+Na] 200.1051. Found 200.1045.
(Z)-3,4-Dimethyl-1-(pyrrol-1-yl)-2-penten-1-one ((Z)-9b)
1
H NMR (CDCl ): δ = 7.32 (t, J = 2.5 Hz, 2H), 6.26 (t, J = 2.5 Hz, 2H), 6.19 (s, 1H), 3.79-3.68 (m, 1H), 1.91
3
13
(
d, J = 1.5 Hz, 3H), 1.07 (d, J = 6.7 Hz, 6H); C NMR (CDCl
3
): δ = 167.4, 162.9, 119.2, 114.4, 112.6, 30.3,
-1
+
2
0.6, 19.7; IR (neat): 2965, 1692, 1623, 1281 cm ; MS (ESI): m/z 200 [M+Na] ; HRMS (ESI): m/z calcd for
+
C
11
H
15NONa [M+Na] 200.1051. Found 200.1043.
(E)-3-phenyl-1-(pyrrol-1-yl)-2-buten-1-one ((E)-9c)
1
H NMR (CDCl ): δ = 7.33-7.21 (m, 7H), 6.45-6.43 (q, J = 1.6 Hz, 1H), 6.21 (t, J = 2.3 Hz, 2H), 2.30 (d, J =
3
13
1
.6 Hz, 3H); C NMR (CDCl ): δ = 163.5, 155.4, 139.9, 128.3, 128.2, 126.8, 119.3, 117.4, 112.8, 26.7; IR
3
-
1
+
(
neat): 3146, 3056, 2977, 1700, 1627, 1468, 1281 cm ; MS (ESI): m/z 234 [M+Na] ; HRMS (ESI): m/z
+
calcd for C14
H
13NONa [M+Na] 234.0895. Found 234.0908.
(Z)-3-phenyl-1-(pyrrol-1-yl)-2-buten-1-one ((Z)-9c)
1
H NMR (CDCl ): δ = 7.57-7.50 (m, 2H), 7.46-7.38 (m, 5H), 6.74 (s, 1H), 6.31 (t, J = 2.3 Hz, 2H), 2.61 (d, J
3
13
=
1.3 Hz, 3H); C NMR (CDCl ): δ = 163.3, 157.9, 142.0, 129.4, 128.7, 126.3, 119.2, 115.9, 112.9, 18.9; IR
3
-
1
+
(
neat): 3148, 3059, 1688, 1613, 1467, 1292, 1245 cm ; MS (ESI): m/z 234 [M+Na] ; HRMS (ESI): m/z
+
calcd for C14
H
13NONa [M+Na] 234.0895. Found 234.0891.
2-Butyl-2-methyl-4-oxo-4-(pyrrol-1-yl)butanenitrile (10a)
1
3
H NMR (CDCl ): δ = 7.32-7.23 (brs, 2H), 6.30 (t, J = 2.3 Hz, 2 H), 3.15 (d, J = 16.8 Hz, 1H) , 3.00 (d, J =
1
6.8 Hz, 1H), 1.89-1.81 (m, 1H), 1.69-1.62 (m, 1H), 1.53-1.44 (m, 5H), 1.41-1.33 (m, 2H), 0.92 (t, J = 7.3
13
Hz, 3H); C NMR (CDCl ): δ = 165.8, 123.1, 118.9, 113.7, 42.2, 38.9, 34.4, 27.0, 24.2, 22.6, 13.8; IR
3
-1
+
(
neat): 2959, 2236, 1722, 1470, 1366, 1278 cm ; MS (ESI): m/z 241 [M+Na] ; HRMS (ESI): m/z calcd for
+
25
C
13 18
H N
2
ONa [M+Na] 241.1317. Found 241.1298; []
D
=  (c = 1.09, CHCl ) for 98% ee; HPLC
3
condition: Chiralpak IC column, flow rate: 1.0 mL / min, n-hexane / i-PrOH = 20 / 1, t = 23.6 min (minor),
9.2 min (major). λ= 254 nm
HPLC chart of rac-10a
2
HPLC chart of ()-10a
S-22

HPLC chart of ()-10a
(R)-2-Methyl-2-(1-methylethyl)-4-oxo-4-(pyrrol-1-yl)butanenitrile (10b)
1
H NMR (CDCl
6.5 Hz, 1H), 2.19-2.10 (m, 1H), 1.49 (s, 3H), 1.11 (d, J = 6.7 Hz, 3H), 1.07 (d, J = 6.7 Hz, 3H); C NMR
CDCl ): δ = 166.1, 122.5, 118.9, 113.7, 40.2, 38.9, 34.6, 21.2, 18.3, 17.5; IR (neat): 2972, 2235, 1720, 1470,
3
): δ = 7.32-7.23 (brs, 2H), 6.30 (t, J = 2.3 Hz, 2 H), 3.19 (d, J = 16.5 Hz, 1H) , 2.99 (d, J =
13
1
(
3
-
1
+
+
1
2
363, 1277 cm ; MS (ESI): m/z 227 [M+Na] ; HRMS (ESI): m/z calcd for C12
16
H N
2
ONa [M+Na]
2
6
27.1160. Found 227.1163; []
D
=  (c = 0.92, CHCl
3
) for 95% ee; HPLC condition: Chiralpak AS-H
column, flow rate: 1.0 mL / min, n-hexane / i-PrOH = 9 / 1, t = 19.3 min (S, minor), 25.1 min (R, major). λ
254 nm
HPLC chart of rac-10b
=
HPLC chart of (R)-10b
S-23

HPLC chart of (S)-10b
2-Methyl-4-oxo-2-phenyl-4-(pyrrol-1-yl)butanenitrile (10c)
1
3
H NMR (CDCl ): δ = 7.51 (d, J = 7.6 Hz, 2H), 7.39 (dd, J = 7.6, 7.6 Hz, 2H), 7.32 (dd, J = 7.6 Hz, 1H),
7
3
.23-7.17 (brs, 2H), 6.26 (t, J = 2.4 Hz, 2 H), 3.51 (d, J = 16.8 Hz, 1H) , 3.41 (d, J = 16.8 Hz, 1H), 1.92 (s,
13
H); C NMR (CDCl ): δ = 165.2, 139.2, 129.1, 128.3, 125.3, 122.3, 118.8, 113.7, 45.1, 39.2, 27.3; IR
3
-1
+
(
neat): 3147, 2240, 1719, 1470, 1365, 1277 cm ; MS (ESI): m/z 261 [M+Na] ; HRMS (ESI): m/z calcd for
+
25
C
15 14
H N
2
ONa [M+Na] 261.1004. Found 261.0990; []
D
=  (c = 1.18, CHCl ) for 99% ee; HPLC
3
condition: Chiralpak AS-H column, flow rate: 1.0 mL / min, n-hexane / i-PrOH = 9 / 1, t = 24.9 min (major),
2.3 min (minor). λ= 254 nm
HPLC chart of rac-10c
3
HPLC chart of ()-10c
S-24

HPLC chart of ()-10c
6
. Synthetically Useful Conversions of 10 and Determination of the Absolute Configuration
O
CN
O
CN
O
NaOMe/MeOH
rt, 1 h
N
MeO
N
(Z)-9b
10b (97% ee)
22
Catalytic enantioselective conjugate addition
of cyanide to -unsaturated N-acylpyrrole
To a solution of 10b (97% ee, obtained from (Z)-9b, 46 mg, 0.225 mmol) in MeOH (2 mL), NaOMe (108 mg,
mmol) was added at rt. After stirring for 1 h, satd. NH Cl and AcOEt were added, and the organic layer
was separated. The aqueous layer was extracted with AcOEt twice, and the combined organic layers were
washed with brine. The organic layer was dried over Na SO , and the solvent was removed under reduced
2
4
2
4
pressure to afford crude 22 (36 mg, 0.190 mmol) as a colorless oil (ca. 85% yield). Crude 22 was used in the
next reaction without purification.
Crude 22 was dissolved in MeOH (1.5 mL), and conc. HCl (1.5 mL) was added at rt. The mixture was heated
o
at 120 C in a sealed tube. After stirring for 14 h, the reaction mixture was cooled in an ice bath, and water
and AcOEt were added. The organic layer was separated. The aqueous layer was extracted with AcOEt twice,
and the combined organic layers were washed with brine. The organic layer was dried over Na
2
SO , and the
4
solvent was removed under reduced pressure. The residue was dissolved in benzene (4 mL) and MeOH (1
mL). To the mixture, TMSdiazomethane (2 M in hexane, 138 L, 0.276 mmol, 1.5 equiv) was added at rt.
S-25

After stirring for 30 min, the solvent was removed under reduced pressure, and the residue was purified by
flash column chromatography (silica gel, hexane-AcOEt, 20:1) to afford (S)-23 (7.7 mg, 0.038 mmol) as a
2
3
colorless oil in 20% yield. []
D
=  (c = 0.72, CHCl
3
). The structure and the absolute configuration of
5
(
S)-23 was determined by referring to the reported data.
O
CN
1) NaOMe/MeOH
rt, 0.5 h
HN
N
O
2
) Pd/C, H2
MeOH, rt, 41 h
10b
24
To a solution of 10b (99% ee, obtained from (Z)-9b, 4.1 mg, 0.02 mmol) in MeOH (0.2 mL), NaOMe (11 mg,
.2 mmol) was added at rt. After stirring for 0.5 h, satd. NH Cl and AcOEt were added, and the organic layer
was separated. The aqueous layer was extracted with AcOEt twice, and the combined organic layers were
washed with brine. The organic layer was dried over Na SO , and the solvent was removed under reduced
0
4
2
4
pressure to afford crude 22 (3.4 mg, 0.02 mmol) as a colorless oil (ca. 100% yield). Crude 22 was used in the
next reaction without purification. Crude 22 was dissolved in MeOH (0.2 mL), and Pd/C (15 mg) was added.
Under H
under reduced pressure, and the residue was purified by flash column chromatography (silica gel,
hexane-AcOEt, 2:1, then, CH Cl -MeOH, 20:1) to afford (R)-24 (2.0 mg, 0.014 mmol) as a colorless crystal
in 71% yield. The enantiometric excess of the product was determined by GC analysis to be 99% ee.
2
atmosphere (1 atm) at rt, the mixture was stirred for 41 h. After filtration, the solvent was removed
2
2
(R)-4-Methyl-4-(1-methylethyl)-2-pyrrolidinone (24)
1
1
H NMR (CDCl
3
): H NMR (CDCl
3
): δ = 6.02-5.88 (brs, 1H), 3.18 (d, J = 9.5 Hz, 1H), 2.97 (d, J = 9.5 Hz,
1
3
H), 2.21 (d, J = 16.5 Hz, 1H), 1.98 (d, J = 16.5 Hz, 1H), 1.70-1.60 (m, 1H), 1.02 (s, 3H), 0.87 (d, J = 7.1 Hz,
13
H), 0.83 (d, J = 7.1 Hz, 3H); C NMR (CDCl
3
): δ = 177.9, 53.8, 43.5, 42.5, 36.7, 20.5, 18.0, 17.4; IR
-1
+
(
neat): 3189, 2956, 1668 cm ; MS (ESI): m/z 164 [M+Na] ; HRMS (ESI): m/z calcd for C
8
H15NONa
+
23
[
M+Na] 164.1051. Found 164.1053; []
D
=  (c = 0.07, CHCl
3
) for 99% ee; GC condition: Chirasil
o
o
o
DEX CB, injector temp. = 200 C, detector temp. = 250 C, column temp. = initial 20 min: 120 C, then the
o
o
temp. was elevated at the ratio 1 C/min. until 140 C, t = 35.6 min (minor), 36.7 min (major).
5
Kulkarni, M. V.; Eisenbraun, E. J. J. Org. Chem. 1968, 33, 1661.
S-26

O
O
N
Ph
(Z)-9b
(Z)-7a
Catalytic enantioselective conjugate addition
of cyanide to -unsaturated N-acylpyrrole
Catalytic enantioselective conjugate
addition of cyanide to enone
O
CN
O
CN
1
) PhMgBr (1.1 equiv)
N
o
o
THF, 0 C-50 C, 4 h
) DBU, CH Cl , rt, 1 h
Ph
S)-8a (99% ee)
To a solution of (S)-10b (99% ee, 10 mg, 0.05 mmol) in THF (0.5 mL), PhMgBr (1.08 M solution in THF, 51
2
2
2
(
(
S)-10b (99% ee)

L, 0.055 mmol, 1.1 equiv) was added with cooling in an ice bath, and the reaction mixture was warmed to
o
5
0 C. After stirring for 4 h, satd. NH
4
Cl was added, and the organic layer was separated. The aqueous layer
was extracted with AcOEt twice, and the combined organic layers were washed with brine. The organic layer
was dried over Na SO , and the solvent was removed under reduced pressure. The residue was dissolved in
CH Cl (1 mL), and one drop of DBU was added to the mixture at rt. After stirring for 1 h, satd. NH Cl was
added, and the organic layer was separated. The aqueous layer was extracted with EtOAc twice. The
combined organic layers were washed with brine, and dried over Na SO . The solvent was removed under
reduced pressure, and the residue was purified by flash column chromatography (silica gel, hexane-Et O,
0:1) to afford (S)-8a (4.1 mg, 0.019 mmol) as a colorless oil in 38% yield. The enantiometric excess of the
2
4
2
2
4
2
4
2
2
product was determined by HPLC analysis to be 99% ee.
O
O
N
(Z)-9b
(Z)-7c
Catalytic enantioselective conjugate addition
of cyanide to -unsaturated N-acylpyrrole
Catalytic enantioselective conjugate
addition of cyanide to enone
O
CN
O
(
CN
1
) MeMgBr (1.1 equiv)
N
o
THF, 0 C, 1.5 h
2) DBU, CH Cl , rt, 1 h
2
2
S)-8c
(
S)-10b (99% ee)
To a solution of (S)-10b (99% ee, 20 mg, 0.10 mmol) in THF (1 mL), MeMgBr (3 M solution in Et
.11 mmol, 1.1 equiv) was added with cooling in an ice bath. After stirring for 1.5 h, satd. NH Cl was added,
and the organic layer was separated. The aqueous layer was extracted with AcOEt twice, and the combined
organic layers were washed with brine. The organic layer was dried over Na SO , and the solvent was
removed under reduced pressure. The residue was dissolved in CH Cl (1 mL), and one drop of DBU was
Cl was added, and the organic layer was separated.
2
O, 37 L,
0
4
2
4
2
2
added to the mixture at rt. After stirring for 1 h, satd. NH
4
S-27

The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine,
and dried over Na SO . The solvent was removed under reduced pressure, and the residue was purified by
flash column chromatography (silica gel, hexane-EtOAc, 20:1) to afford (S)-8c (7.2 mg, 0.047 mmol) as a
2
4
2
5
colorless oil in 47% yield. []
D
=  (c = 0.52, CHCl ).
3
7
. Study of Catalytic Metals
Table S-1 Study of catalytic metals in combination with ligand 1
metal (X mol %)
1
(Y mol %)
O
O
TMSCN (2 equiv)
CN
2
,6-dimethylphenol (2 equiv)
THF
(
E)-7b
8b
entry
metal (X mol %)
1 (Y mol %)
temp
time (h)
15
yield (%) ee (%)
i
1
2
Ca(O Pr) (30 mol %)
30
30
30
rt
rt
rt
5
22
54
53
2
i
Sr(O Pr) (30 mol %)
15
82
90
2
Sr(HMDS) -2DME (30 mol %)
15
3
4
2
i
Ba(O Pr) (30 mol %)
30
40
rt
15
36
5
0
3
-
2
i
Ti(O Pr) (20 mol %)
rt-60 ºC
5
6
7
8
9
4
i
Zr(O Pr)4 (20 mol %)
40
40
30
30
30
15
rt-60 ºC
rt-60 ºC
rt-50 ºC
rt-50 ºC
rt-50 ºC
36
36
15
15
15
<5
<4
1
2
2
-
i
Hf(O Pr) (20 mol %)
4
i
Al(O Pr)3 (20 mol %)
trace
i
Ga(O Pr)3 (20 mol %)
0
0
0
i
In(O Pr) (20 mol %)
-
1
1
0
1
3
BEt (10 mol %)
rt-55 ºC
24
-
3
1
1
2
AlEt (10 mol %)
15
15
rt-55 ºC
rt
24
24
0
-
3
3a
4a
5a
Pr(O Pr) (10 mol %)
i
14
22
3
i
Nd(O Pr) (10 mol %)
15
15
15
rt
rt
rt
24
24
24
16
28
26
8
26
34
1
1
3
i
Sm(O Pr)3 (10 mol %)
6a
i
1
Gd(O Pr) (10 mol %)
3
a
TBSCN was used instead of TMSCN
8
. Ee vs Sr/ligand Ratio
Table S-2 Catalytic asymmetric conjugate cyanation of (E)-7a performed at different Sr/ligand ratio
S-28

i
Sr(O Pr) (10 mol %)
O
2
O NC
5
(X mol %)
TMSCN (2 equiv)
,6-Dimethylphenol (2 equiv)
THF, rt, 2 h
2
(E)-7a
8a
entry
ligand (X mol %)
metal : ligand ratio
yield (%)
100
ee (%)
1
2
3
4
10
15
20
25
1 : 1
2 : 3
1 : 2
2 : 5
96
98
98
98
100
100
100
The enantioselectivity was constantly high (>96% ee) regardless of the Sr:ligand ratio.
9
. Optimization of the Reaction Parameters
Table S-3 Catalytic asymmetric conjugate cyanation of (E)-7a performed using different solvents
i
O
Sr(O Pr) (2 mol %)
2
O
NC
5
(3 mol %)
TMSCN (2 equiv)
,6-dimethylphenol (2 equiv)
solvent, rt
2
(
E)-7a
8a
entry
solvent
time (h)
yield (%)
11
ee (%)
1
1
2
3
4
5
6
7
THF
18
18
1
dioxane
13
13
Et O
2
82
96.6
95.4
91.5
93.1
96.3
DME
MeCN
CH Cl
18
18
13
1
79
34
92
2
2
toluene
99
When the catalyst loading was reduced to 2 mol %, the use of THF gave significantly low yield and
enantioselectivity. On the other hand, by the use of toluene as a solvent, the catalyst loading could be reduced
to 2 mol % without any loss of yield nor enantioselectivity.
S-29

Table S-4 Catalytic asymmetric conjugate cyanation of (E)-7a performed using different silylcyanide
i
Sr(O Pr) (0.5 mol %)
O
2
O
NC
5
(0.8 mol %)
silylcyanide (2 equiv)
,6-dimethylphenol (2 equiv)
toluene, rt, 16 h
2
(
E)-7a
8a
entry
silylcyanide
TMSCN
yield (%)
ee (%)
50
1
2
11
TBSCN
100
97
When the catalyst loading was reduced to 0.5 mol %, the use of TMSCN gave significantly low yield and
enantioselectivity. On the other hand, by the use of TBSCN as a HCN source, the catalyst loading could be
reduced to 0.5 mol % without any loss of yield nor enantioselectivity.
1
0. Catalytic Asymmetric Conjugate Cyanation Performed Using HCN
Table S-5 Catalytic asymmetric conjugate cyanation of (E)-7a performed using HCN
i
O
Sr(O Pr)2 (10 mol %)
O
NC
5
(17 mol %)
cyanide source
o
(
E)-7a
THF, 40 C
8a
entry
cyanide source
time (h)
yield (%)
100
ee (%)
97
1
2
3
TMSCN (2 equiv) + 2,6-dimethylphenol (2 equiv)
TMSCN (2 equiv) + MeOH (2 equiv)
HCN (5M solution in toluene)
1
1
4
100
98
100
97
The use of HCN source other than silylcyanide + 2,6-dimethylphenol (entries 2 and 3) gave almost the same
yield and enantioselectivity. Therefore, we assume that HCN should be the stoichiometric cyanide source,
and silyl groups are not relevant to the catalytic cycle.
S-30