Steric tuning of C2-symmetric chiral N-heterocyclic carbene in gold-catalyzed asymmetric cyclization of 1,6-enynes

Article abstract of DOI:10.1016/j.tet.2012.03.107

Steric tuning of C₂-symmetric chiral N-heterocyclic carbene (NHC) was performed in Au(I)-catalyzed asymmetric cyclization of 1,6-enyne. Higher enantioselectivity was realized when chiral NHC-AuCl/AgSbF₆ catalysts whose N-substituent on the NHC overlays the Au-Cl bond was utilized.

Full text of DOI:10.1016/j.tet.2012.03.107

Tetrahedron 68 (2012) 4159e4165
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Steric tuning of C2-symmetric chiral N-heterocyclic carbene in gold-catalyzed
asymmetric cyclization of 1,6-enynes
,
a
b
c
c,
*
Ken-ichi Yamada a , Yasumasa Matsumoto , Khalid B. Selim , Yasutomo Yamamoto , Kiyoshi Tomioka
*
a Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
b Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
c Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe 610-0395, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Steric tuning of C2-symmetric chiral N-heterocyclic carbene (NHC) was performed in Au(I)-catalyzed
asymmetric cyclization of 1,6-enyne. Higher enantioselectivity was realized when chiral NHCeAuCl/
AgSbF6 catalysts whose N-substituent on the NHC overlays the AueCl bond was utilized.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 27 January 2012
Received in revised form 14 March 2012
Accepted 27 March 2012
Available online 30 March 2012
1. Introduction
high isolated yields; however, the enantioselectivity of the reaction
was strongly dependent on the substituents on the NHC nitrogen
Gold(I) complexes with phosphanes or N-heterocyclic carbenes
(NHCs)1 have emerged as attractive homogeneous catalysts that
activate CeC multiple bonds.2 Chiral phosphaneegold(I) complexes
have been developed to catalyze asymmetric coupling of aldehydes
with isocyanoacetate esters,3 1,6-enyne cyclization,4 nucleophilic
addition to allenes5 and alkynes,6 and cyclopropanation of
alkenes.7 In turn, NHCs are a growing class of ligands for transition
atom (Table 1, entries 1e3). While complex 1a, bearing diphe-
nylmethyl groups, exhibited poor stereocontrolling ability (8% ee;
entry 1), complex 1b, bearing bis(2-methylphenyl)methyl groups,
provided 3a with 36% ee (entry 2). Furthermore, complex 1c, having
bis(2,5-dimethylphenyl)methyl groups, showed the best perfor-
mance, and 3a was obtained with 56% ee (entry 3). We speculated
that one each of the aryl groups of the two N-substituents overlays
the goldechlorine bond, and the bulkiest 2,5-dimethylphenyl
group of 1c created the most effective chiral environment around
the gold(I) coordination site among the complexes. We describe
herein the correlation between the structure of the C2-symmetric
chiral NHCegold(I) complex and enantioselectivity in the catalytic
asymmetric cyclization of 1,6-enynes as well as the X-ray structures
of the complexes, which validate our speculation. Additional in-
formation concerning effects of substituents on 1,6-enynes is also
described.
metals, characterized by strong
s-donor and poor p-acceptor
abilities, and have advantageous properties over phosphanes, such
as tolerance to air.8 Recently, we showed potential of a chiral
NHCegold(I) complex as a chiral catalyst for the first time,9 ap-
plying a C2-symmetric chiral NHC10 as a chiral ligand for gold(I) and
achieved moderate enantioselectivity in 1,6-enyne cyclization.11
Although several chiral NHCegold(I) complexes have been de-
veloped since then,12 reactions catalyzed by chiral NHCegold(I)
complexes generally proceed with low to moderate enantiose-
lectivity.2e,13 To date, there is only one example of highly enantio-
selective transformation catalyzed by a carbeneegold(I) complex,14
and thus development of a chiral NHCegold(I) catalyzed asym-
metric reaction is still important and challenging.
Ph
Ph
1a Ar = Ph
1e Ar = 2,3-Me2C6H3
1f Ar = 3,5-Me2C6H3
Ar
N
N
Ar
1b Ar = 2-MeC6H4
1c Ar = 2,5-Me2C6H3 1g Ar = 2-Me-5-PhC6H3
1d Ar = 2,4-Me2C6H3 1h Ar = 3,5-t-Bu2C6H3
In our preliminary communication,11 chiral NHCegold(I) com-
plexes 1aec (Fig. 1) were employed in asymmetric cyclization of
1,6-enyne.15 All the cationic chiral NHCegold(I) complexes, gener-
ated in situ from 1aec and silver hexafluoroantimonate, efficiently
catalyzed cyclization of enyne 2a in methanol at rt and gave 3a16 in
Ar
Ar
Au
Cl
Fig. 1. C2-Symmetric chiral NHCeAuCl catalysts 1.
2. Results and discussion
First, X-ray crystal analysis of 1aec was performed to gain
structural information of the NHCegold(I) complexes (Fig. 2). In
complex 1a, one of the phenyl groups of the N-substituents is
overlapping the phenyl group of the ethylenediamine moiety,
* Corresponding authors. Tel.: þ81 (0) 75 753 4573; fax: þ81 (0) 75 753 4604
(K.-i.Y.); tel.: þ81 (0) 774 65 8676; fax: þ81 (0) 774 65 8658 (K.T.); e-mail
addresses: yamak@pharm.kyoto-u.ac.jp (K.-ichi Yamada), tomioka@pharm.kyoto-u.
ac.jp (K. Tomioka).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.107

4160
K.-ichi Yamada et al. / Tetrahedron 68 (2012) 4159e4165
Table 1
3,5-disubstituted phenyl group seemed to be the best aryl group for
chiral environment around the gold(I) coordination site.
Chiral NHCeAu(I) 1-catalyzed cyclization of enyne 2a
Ph
Ph
Next, complex 1g, in which the 5-methyl group of 1c was
substituted by a bulkier phenyl group, was tested in the reaction.
The enantioselectivity was, however, almost the same level (54%
ee) as 1c (56% ee) though 3a was obtained in quantitative yield
(entry 7). Replacing the methyl groups of 1f by bulkier tert-butyl
groups dramatically decreased the enantioselectivity; the enan-
tiomer of 3a with 16% ee was quantitatively obtained when 1h,
bearing 3,5-di-tert-butylphenyl groups, was used as a catalyst
precursor (entry 8). Thus, newly developed complexes 1f and 1g
were found to have comparable stereocontrolling ability to that
of 1c.
Among the new complexes 1deh, crystals suitable for X-ray
analysis were obtained for 1e and 1g (Fig. 2). The relatively high
enantioselectivities observed in the reactions of 2a with 1e and 1g
are explainable with the X-ray structures, in which the stereo-
controlling groups, the aryl substituents are overlying the AueCl
bond. These observations support our aforementioned speculation.
In the X-ray structure of 1g, the space occupied by the phenyl
substituents of the diarylmethyl groups is far from the AueCl bond.
This would be the reason why 1g and 1c showed almost the same
stereocontrolling ability.
Ar
Ar
Ar
Ar
N
N
1
/AgSbF
AuCl
6
MeO2C
MeO2C
MeO2C
MeO2C
6 mol %
MeOH
rt, 1 h
OMe
2a
3a
Entry
NHCeAuCl 1
Yield (%)
ee (%)
1a
2a
3a
4
5
6
1a
1b
1c
1d
1e
1f
95
95
95
90
95
98
99
99
8
32
56
13
47
53
54
16b
7
8
1g
1h
a
Ref. 11.
The antipode was obtained.
b
The effects of substituents on 1,6-enynes was further in-
vestigated using NHCegold(I) complex 1c (Table 2) in addition to
the previously reported results (entries 1e3). First, enyne 2d,
bearing bissulfone and a phenylacetylene moiety, was applied to
the reaction because high enantioselectivity (94% ee) was reported
only for this particular substrate using a tol-BINAPegold(I) com-
plex, despite moderate enantioselectivity (2e53% ee) for other
substrates.4a Although solubility of 2d in methanol was quite low,
the reaction proceeded smoothly in a 10:3 mixture of methanol
and dichloromethane and produced 3d with 49% ee in 61% yield
(entry 4). The observed specific rotation value of 3d, ½a D25
þ105
ꢀ
(c 0.59, CHCl3), was significantly larger than that reported for the
antipode with 94% ee, ½a D25
ꢀ
ꢁ75.3 (c 0.6, CHCl3)4a and smaller than
that reported for 78% ee, ½a D22
ꢀ
ꢁ218.1 (c 1.05, CHCl3).4d Thus, the
specific rotation was confirmed by measuring again after enan-
tiomer enrichment by trituration in ether, and a reasonable value,
½
a 2D5
ꢀ
þ162 (c 0.65, CHCl3), was also observed for 73% ee.17 The low
yield of 3d was attributed to intramolecular FriedeleCrafts re-
action of the cationic intermediate of the enyne cyclization, for
byproduct 4 with 17% ee was isolated in 37% yield. The reaction
was then applied to 2e, with expectation that the bulky ester
moieties would improve the enantioselectivity. Although 3e was
formed in 95% yield within 1 h, the enantioselectivity was still
moderate (42% ee; entry 5). Apparently, the bulkiness of the R1
substituents of 2 has negative effect on enantioselectivity of the
reaction (entries 1, 3, and 5).
Fig. 2. Chem3D perspective view of X-ray structures of 1aec, 1e, and 1g. H atoms and
solvent molecules (Et2O, hexane, and THF for 1a, 1c, and 1g, respectively) were omitted
for clarity.
probably due to favorable
pep interaction, and the other phenyl
group is almost perpendicular to the AueCl bond. Accordingly, the
poor enantioselectivity observed using 1a is attributable to the
absence of a stereocontrolling group along with the AueCl bond. In
complexes 1b and 1c, the aryl substituents of the N-substituents are
overlying the AueCl bonds, and therefore, the stereocontrolling
groups, the aryl substituents are close to the gold(I) coordination
sites.
On the basis of these observations, complexes 1cef, bearing
regioisomeric bis(dimethylphenyl)methyl groups as N-sub-
stituents, were compared in the reaction of 2a to elucidate the best
substitution positions on the phenyl groups (Table 1, entries 3e6).
Although moderately good enantioselectivity (56% ee) was realized
using 2,5-dimethylphenyl isomer 1c (entry 3),11 the selectivity was
decreased to 13% ee with 2,4-dimethylphenyl isomer 1d (entry 4).
In contrast, 2,3-dimethylphenyl isomer 1e showed comparable
stereocontrolling ability to 1c and gave 3a with 47% ee in 95% yield
(entry 5), and almost the same level of enantioselectivity (53% ee)
as that with 1c was observed when 3,5-dimethylphenyl isomer 1f
was used as a catalyst precursor (entry 6). Consequently, a 2,5- or
3. Conclusion
The C2-symmetric chiral NHCegold(I) catalyst 1c, bearing
N-bis(2,5-dimethylphenyl)methyl substituents to endow chiral
environment around gold(I), showed the best selectivity in the
1,6-enyne cyclization among those tested, and 1f and 1g, bea-
ring N-bis(3,5-dimethylphenyl)methyl substituents and N-bis(4-
methylbiphenyl-3-yl)methyl substituents, respectively, also had
comparable stereocontrolling ability. The X-ray crystal structures
verified that the relatively high enantioselectivity was observed in
the reaction with the NHCegold (I) complexes whose N-sub-
stituents overlay the AueCl bond in the X-ray structures. Although
X-ray structures do not directly reflect the reacting structures, these
results would provide a basis for the design of much more efficient
chiral NHCegold(I) catalysts.

K.-ichi Yamada et al. / Tetrahedron 68 (2012) 4159e4165
4161
Table 2
as 5g. Recrystallization from hexane gave the titled compound as
colorless blocks (4.5 g, 84%) of mp 80e82 ꢂC. 1H NMR: 2.30 (12H, s),
6.15 (1H, s), 6.90 (2H, s), 7.07 (4H, s). 13C NMR: 21.2 (CH3), 56.1 (CH),
126.2 (CH), 129.8 (CH), 138.1 (C), 141.1 (C). IR: 2916, 1597, 1458, 1178,
856, 727. EIMS m/z: 303 (Mþ). Anal. Calcd for C17H19Br$0.25H2O: C,
66.35; H, 6.39. Found: C, 66.56; H, 6.29.
Cyclization of enynes 2 catalyzed by NHCeAu(I) 1c
R4
R1
R4
R3
6 mol % 1c
R1
R1
R1
6 mol % AgSbF6
R3
MeOH
rt, time
H
OMe
R2
2
3
R2
4.2.1.3. 5,50-(Bromomethylene)bis(1,3-di-tert-butylbenzene)
(5h). Synthesized from 3,5-t-Bu2C6H3MgBr by the same procedure
as 5g. Recrystallization from hexane gave the titled compound as
colorless powder (5.8 g, 68%) of mp 108e110 ꢂC. 1H NMR: 1.31 (36H,
s), 6.33 (1H, s), 7.33 (6H, s). 13C NMR: 31.4 (CH3), 34.9 (C), 57.6 (CH),
122.1 (CH), 123.1 (CH), 140.3 (C), 150.8 (C). IR: 2954, 1597, 1364, 725.
EIMS m/z: 391 (MꢁBr). Anal. Calcd for C29H43Br: C, 73.86; H, 9.19.
Found: C, 73.91; H, 9.25.
Entry
2
R1
R2, R3
R4
Time/h
Yield (%)
ee (%)
1a
2a
3a
4b
5
2a
2b
2c
2d
2e
CO2Me
CO2Me
SO2Ph
SO2Ph
Me, Me
H, Ph
Me, Me
Me, Me
Me, Me
H
H
H
Ph
H
1
11
1
3
1
95
91
56
59
52
93
61c
95
49
CO2CH (i-Pr)2
42d
PhO2S
PhO2S
H
4
4.2.2. Synthesis of diamines.
a
Ref. 11.
4.2.2.1. (1S,2S)-N,N0-Bis(bis(4-methylbiphenyl-3-yl)methyl)-1,2-
diphenylethane-1,2-diamine (6g). Prepared by an analogous pro-
cedure to that reported.25 A mixture of (1S,2S)-1,2-diphenylethane-
1,2-diamine (1.1 g, 5.2 mmol), 5g (4.7 g, 11 mmol), and Na2CO3
(2.1 g, 20 mmol) in DMPU (15 mL) was stirred for 2 h at 120 ꢂC, and
then 50 mL of water was added. The whole was extracted with
EtOAc (3ꢃ30 mL). The combined organic layers were washed with
water (2ꢃ50 mL) and brine (2ꢃ50 mL), dried over Na2SO4, and then
concentrated to give pale yellow oil. Column chromatography
(hexane/EtOAc¼15/1) gave the titled compound as pale yellow
b
c
Solvent was MeOH/CH2Cl2 (10:3).
Enyne cyclization-FriedeleCrafts product 4 with 17% ee was also obtained in
37% yield.
d
The ee was determined after conversion to diol with LiAlH4 reduction.
4. Experimental section
4.1. General
All melting points are uncorrected. Column chromatography
was performed using silica gel. NMR (500 MHz for 1H and 125 MHz
for 13C) was measured in CDCl3 unless otherwise mentioned, and
chemical shifts and coupling constants are presented in parts per
amorphous solid (1.6 g, 54%) of mp 108e110 ꢂC and ½a D25
ꢁ30.4 (c
ꢀ
1.02, CHCl3). 1H NMR: 1.85 (6H, s), 2.05 (6H, s), 2.79 (2H, s), 3.98 (2H,
s), 4.97 (2H, s), 7.00e7.02 (4H, m), 7.07e7.13 (10H, m), 7.17e7.20
(8H, m), 7.22e7.25 (4H, m), 7.32e7.34 (6H, m), 7.37e7.39 (2H, m),
7.43e7.47 (6H, m), 7.91 (2H, s). 13C NMR: 18.8 (CH3), 56.8 (CH), 65.9
(CH), 125.1 (CH), 125.4 (CH), 126.1 (CH), 126.67 (CH), 126.72 (CH),
126.75 (CH), 126.81 (CH), 127.1 (CH), 127.3 (CH), 127.9 (CH), 128.5
(CH), 128.6 (CH), 128.7 (CH), 131.0 (CH), 131.2 (CH), 135.6 (C), 135.7
(C), 138.5 (C), 138.6 (C), 140.0 (C), 141.0 (C), 141.1 (C), 141.3 (C). IR:
3325, 3024, 1481, 1450, 756, 694. EIMS m/z: 452 (M/2). Anal. Calcd
for C68H60N2: C, 90.22; H, 6.68; N, 3.09. Found: C, 90.22; H, 6.86; N,
3.03.
million d relative to Me4Si and hertz, respectively. Abbreviations are
as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad.
13C peak multiplicity assignments were made based on DEPT data.
IR spectroscopy of oil and solid samples were measured as neat
liquid films and KBr pellets, respectively. The wave numbers of
maximum absorption peaks of IR spectroscopy are presented
in cmꢁ1. Enynes 2a,18,19 2b,19 2c,20,21 and 2d22 were prepared
according to the reported procedures. (1S,2S)-1,2-Diphenylethane-
1,2-diamine was purchased and used as received. MeOH was dis-
tilled from CaH2 before use. All the reactions were performed under
argon atmosphere unless otherwise mentioned.
4.2.2.2. (1S,2S)-N,N0-Bis(bis(3,5-dimethylphenyl)methyl)-1,2-
diphenylethane-1,2-diamine (6f). Synthesized from 5f by the same
procedure as 6g. Column chromatography (hexane/EtOAc¼20/1)
gave the titled compound as colorless amorphous solid (2.5 g, 62%)
4.2. Synthesis of AueNHC complexes
4.2.1. Synthesis of diarylmethylbromides.23,24
of mp 75e76 ꢂC and ½a D25
ꢀ
þ23.2 (c 1.04, CHCl3). 1H NMR: 2.22 (12H,
4.2.1.1. 3,30-(Bromomethylene)bis(4-methylbiphenyl) (5g). A 1.0 M
solution of (4-methylbiphenyl-3-yl)magnesium bromide in THF
(50 mL, 50 mmol) was slowly added to a solution of HCO2Et (1.6 g,
22 mmol) in THF (44 mL) at 0 ꢂC. After 1 h, the reaction was
quenched with satd NH4Cl (50 mL), and then the whole was
extracted with EtOAc (3ꢃ20 mL). The combined organic layers were
washed with brine (2ꢃ20 mL), dried over Na2SO4, and then con-
centrated to give white solid. AcBr (7.1 mL, 97 mmol) was dropwise
added to a solution of the white solid in benzene (41 mL) at 0 ꢂC.
After 3 h, the mixture was concentrated to give brown solids,
whose recrystallization from hexane gave the titled compound as
pale brown powder (3.5 g, 68%) of mp 122e124 ꢂC. 1H NMR: 2.38
(6H, s), 6.68 (1H, s), 7.22e7.24 (2H, m), 7.30e7.33 (2H, m), 7.38e7.45
(6H, m), 7.53e7.55 (4H, m), 7.81e7.83 (2H, m). 13C NMR: 18.8 (CH3),
50.9 (CH), 126.9 (CH), 127.0 (CH), 127.3 (CH), 128.4 (CH), 128.9 (CH),
131.1 (CH), 134.3 (C), 138.8 (C), 139.4 (C), 140.8 (C). IR: 3024, 1481,
1172, 756, 694. EIMS m/z: 347 (MꢁBr). Anal. Calcd for C27H23Br: C,
75.88; H, 5.42. Found: C, 75.74; H, 5.49.
s), 2.25 (12H, s), 2.67 (2H, s), 3.62 (2H, s), 4.38 (2H, s), 6.77 (4H, s),
6.80e6.82 (4H, m), 6.91 (4H, s), 6.97e7.01 (4H, m), 7.10e7.16 (6H,
m). 13C NMR: 21.35 (CH3), 21.37 (CH3), 63.2 (CH), 65.9 (CH), 124.9
(CH),125.5 (CH),126.8 (CH),127.8 (CH),128.2 (CH),128.4 (CH),128.5
(CH), 137.66 (C), 137.68 (C), 141.5 (C), 143.5 (C), 145.3 (C). IR: 3313,
2916, 1599, 1452, 853, 702. EIMS m/z: 328 (M/2). Anal. Calcd for
C48H52N2: C, 87.76; H, 7.98; N, 4.26. Found: C, 87.79; H, 8.04; N, 4.05.
4.2.2.3. (1S,2S)-N,N0-Bis(bis(3,5-di-tert-butylphenyl)methyl)-1,2-
diphenylethane-1,2-diamine (6h). Synthesized from 5h by the same
procedure as 6g. Column chromatography (hexane/EtOAc¼40/1)
gave the titled compound as colorless amorphous solid (505 mg,
25
405
51%) of mp 84e86 ꢂC and ½
a
ꢀ
ꢁ14.1 (c 0.97, CHCl3). 1H NMR: 1.16
(36H, s), 1.23 (36H, s), 2.67 (2H, s), 3.64 (2H, s), 4.45 (2H, s),
6.97e6.99 (4H, m), 7.01e7.06 (8H, m), 7.15e7.19 (10H, m). 13C NMR:
31.42 (CH3), 31.44 (CH3), 34.6 (C), 34.7 (C), 64.9 (CH), 65.9 (CH),
120.2 (CH), 120.6 (CH), 122.0 (CH), 122.3 (CH), 126.7 (CH), 127.7
(CH), 128.6 (CH), 141.8 (C), 142.0 (C), 144.3 (C), 150.1 (C), 150.2 (C).
IR: 3336, 2951, 1599, 1477, 1248, 877, 698. EIMS m/z: 496 (M/2).
Anal. Calcd for C72H100N2: C, 87.04; H, 10.14; N, 2.82. Found: C,
86.97; H, 10.15; N, 2.78.
4.2.1.2. 5,50-(Bromomethylene)bis(1,3-dimethylbenzene)
(5f). Synthesized from 3,5-Me2C6H3MgBr by the same procedure

4162
K.-ichi Yamada et al. / Tetrahedron 68 (2012) 4159e4165
4.2.3. Synthesis of imidazolinium salts.
4.2.4.2. (4S,5S)-1,3-Bis(di-o-tolylmethyl)-4,5-diphenylimidazolidin-
2-ylidenegold(I) chloride (1b). Prepared from the corresponding imi-
dazolinium tetrafluoroborate10c by the same procedure as 1a. Col-
umn chromatography (benzene) gave the titled compound as
4.2.3.1. (4S,5S)-1,3-Bis(bis(4-methylbiphenyl-3-yl)methyl)-4,5-
diphenylimidazolinium tetrafluoroborate (7g). Prepared from 6g by
the reported procedure.26 Column chromatography (CHCl3 then
CHCl3/EtOH¼9/1) gave the titled compound as colorless amor-
colorless amorphous solid (112 mg, 63%) of mp 91e93 ꢂC and ½a D25
ꢀ
phous solid (701 mg, 64% yield) of mp 280e282 ꢂC and ½a D25
ꢀ
ꢁ318 (c
ꢁ182 (c 0.56, CHCl3). 1H NMR: 1.88 (6H, s), 2.14 (6H, s), 4.80 (2H, s),
5.95 (2H, s), 6.84e6.86 (2H, m), 7.02e7.07 (8H, m), 7.10e7.12 (2H, m),
7.20e7.25 (6H, m), 7.28e7.33 (6H, m), 7.47 (2H, m). 13C NMR: 18.8
(CH3), 19.8 (CH3), 60.6 (CH), 74.0 (CH), 126.38 (CH), 126.42 (CH), 127.8
(CH), 128.2 (CH), 128.45 (CH), 128.50 (CH), 128.8 (CH), 129.4 (CH),
130.2 (CH), 130.8 (CH), 131.1 (CH), 135.2 (C), 136.1 (C), 136.3 (C), 136.6
(C), 136.8 (C), 193.4 (C). IR: 3511, 2923, 1458, 1265, 748. FABMS m/z:
1650 (2MþHeCl). Anal. Calcd for C45H42AuClN2$1.5H2O: C, 62.10; H,
5.21; N, 3.22. Found: C, 62.02; H, 5.09; N, 3.13. Single crystals suitable
for X-ray diffraction were grown by placing a microtube of a THF
solution of 1b in a closed tube filled with hexane. The CIF file of the
crystal structure (CCDC 864359) was deposited at the Cambridge
Crystallographic Data Centre.
1.04, CHCl3). 1H NMR: 1.91 (6H, s), 2.06 (6H, s), 5.26 (2H, s), 6.07 (2H,
s), 7.12e7.19 (14H, m), 7.28e7.31 (6H, m), 7.32e7.38 (8H, m), 7.41
(1H, s), 7.43e7.46 (2H, m), 7.48e7.52 (6H, m), 7.61e7.63 (6H, m). 13C
NMR: 18.22 (CH3), 18.26 (CH3), 58.5 (CH), 73.3 (CH), 125.2 (CH),
126.8 (CH), 126.9 (CH), 127.0 (CH), 127.7 (CH), 127.9 (CH), 128.0 (CH),
128.1 (CH),128.5 (CH), 128.9 (CH),129.3 (CH),129.9 (CH), 131.0 (CH),
132.2 (C), 132.4 (CH), 132.5 (C), 132.8 (CH), 133.5 (C), 135.8 (C), 136.0
(C), 139.7 (C), 139.9 (C), 140.0 (C), 140.1 (C), 155.2 (CH). IR: 3031,
1643, 1481, 1057, 702. FABMS m/z: 916 (MþHeBF4). Anal. Calcd for
C69H59BF4N2: C, 82.62; H, 5.93; N, 2.79. Found: C, 82.50; H, 6.07; N,
2.78.
4.2.3.2. (4S,5S)-1,3-Bis(bis(3,5-dimethylphenyl)methyl)-4,5-
diphenylimidazolinium tetrafluoroborate (7f). Prepared from 6f by
the same procedure as 7g. Recrystallization from EtOH gave the
titled compound as colorless needles (1.0 g, 75%) of mp
4.2.4.3. (4S,5S)-1,3-Bis(bis(2,5-dimethylphenyl)methyl)-4,5-
diphenylimidazolidin-2-ylidenegold(I) chloride (1c). Prepared from
the corresponding imidazolinium tetrafluoroborate10d by the same
procedure as 1a. Column chromatography (benzene) gave the ti-
tled compound as colorless amorphous solid (176 mg, 72%) of mp
260e262 ꢂC and ½a 2D5
ꢀ
ꢁ267 (c 0.50, CHCl3). 1H NMR: 2.25 (12H, s),
2.27 (12H, s), 4.97 (2H, s), 5.54 (2H, s), 6.82e6.84 (8H, m), 6.90 (4H,
s), 7.18e7.20 (4H, m), 7.40e7.48 (6H, m), 7.52 (1H, s). 13C NMR:
21.10 (CH3), 21.15 (CH3), 65.5 (CH), 73.8 (CH), 125.7 (CH), 126.3
(CH), 127.3 (CH), 129.9 (CH), 130.1 (CH), 130.7 (CH), 130.9 (CH),
134.3 (C), 135.1 (C), 135.2 (C), 139.1 (C), 139.4 (C), 156.4 (CH). IR:
2920, 1605, 1458, 1035, 719. FABMS m/z: 668 (MþHeBF4). Anal.
Calcd for C49H51BF4N2: C, 77.98; H, 6.81; N, 3.71. Found: C, 77.70; H,
6.95; N, 3.75.
135e138 ꢂC and ½a 2D5
ꢀ
ꢁ236 (c 0.96, CHCl3). 1H NMR: 1.82 (6H, s),
2.06 (6H, s), 2.14 (6H, s), 2.47 (6H, s), 4.77 (2H, s), 5.86 (2H, s), 6.58
(2H, s), 6.97e7.10 (12H, m), 7.27e7.35 (8H, m). 13C NMR: 18.2
(CH3), 19.3 (CH3), 21.28 (CH3), 21.31 (CH3), 60.7 (CH), 73.7 (CH),
128.0 (CH), 128.7 (CH), 129.1 (CH), 129.4 (CH), 130.5 (CH), 131.1
(CH), 131.2 (CH), 133.5 (C), 133.6 (C), 135.2 (C), 135.5 (C), 135.6 (C),
136.0 (C), 136.6 (C), 192.9 (C). IR: 3495, 2916, 1450, 1211, 810.
FABMS m/z: 1762 (2MþHeCl). Anal. Calcd for C49H50AuClN2: C,
65.44; H, 5.60; N, 3.11. Found: C, 65.26; H, 5.67; N, 3.16. Single
crystals suitable for X-ray diffraction were grown by adding
a benzene solution of 1c to hexane. The CIF file of the crystal
structure (CCDC 864360) was deposited at the Cambridge Crys-
tallographic Data Centre.
4.2.3.3. (4S,5S)-1,3-Bis(bis(3,5-di-tert-butylphenyl)methyl)-4,5-
diphenylimidazolinium tetrafluoroborate (7h). Prepared from 6h by
the same procedure as 7g. Column chromatography (hexane/
EtOAc¼2/1) gave the titled compound as colorless amorphous solid
(1.0 g, 94%) of mp 233e236 ꢂC and ½a D25
ꢀ
ꢁ243 (c 1.03, CHCl3). 1H
NMR: 1.19 (36H, s), 1.31 (36H, s), 4.98 (2H, s), 5.55 (2H, s), 7.00e7.02
(8H, m), 7.13e7.15 (4H, m), 7.30 (2H, s), 7.35 (1H, s), 7.41e7.50 (8H,
m). 13C NMR: 31.2 (CH3), 31.3 (CH3), 34.8 (C), 34.9 (C), 66.6 (CH),
73.9 (CH), 122.2 (CH), 122.9 (CH), 123.2 (CH), 123.6 (CH), 127.6 (CH),
130.0 (CH), 130.7 (CH), 133.3 (C), 133.9 (C), 134.7 (C), 152.3 (C), 152.4
(C), 154.1 (CH). IR: 2964, 1628, 1213, 1064, 698. FABMS m/z: 1004
(MþHeBF4). Anal. Calcd for C73H99BF4N2$0.5H2O: C, 79.68; H, 9.16;
N, 2.55. Found: C, 79.41; H, 9.11; N, 2.55.
4.2.4.4. (4S,5S)-1,3-Bis(bis(2,4-dimethylphenyl)methyl)-4,5-
diphenylimidazolidin-2-ylidenegold(I) chloride (1d). Prepared from
the corresponding imidazolinium tetrafluoroborate10d by the same
procedure as 1a. Column chromatography (benzene) gave the titled
compound as colorless amorphous solid (157 mg, 65%) of mp
146e148 ꢂC and ½a 2D5
ꢀ
ꢁ171 (c 0.96, CHCl3). 1H NMR: 1.81 (6H, s),
2.10 (6H, s), 2.27 (6H, s), 2.31 (6H, s), 4.75 (2H, s), 5.88 (2H, s), 6.70
(2H, m), 6.82e6.85 (4H, m), 6.94 (2H, s), 7.01e7.03 (4H, m), 7.09 (2H,
m), 7.24e7.32 (8H, m). 13C NMR: 18.7 (CH3), 19.7 (CH3), 20.9 (CH3),
21.0 (CH3), 60.2 (CH), 73.9 (CH), 127.0 (CH), 127.1 (CH), 127.8 (CH),
128.4 (CH), 128.7 (CH), 129.2 (CH), 130.0 (CH), 131.6 (CH), 131.8 (CH),
132.3 (C), 133.4 (C), 136.3 (C), 136.5 (C), 136.6 (C), 137.7 (C), 138.4 (C),
194.7 (C). IR: 3517, 2916, 1450, 1265, 702. FABMS m/z: 1762
(2MþHeCl). Anal. Calcd for C49H50AuClN2$0.5H2O: C, 64.79; H,
5.66; N, 3.08. Found: C, 64.55; H, 5.59; N, 3.08.
4.2.4. Synthesis of AueCarbene complexes.
4.2.4.1. (4S,5S)-1,3-Dibenzhydryl-4,5-diphenylimidazolidin-2-
ylidenegold(I) chloride (1a). A mixture of the corresponding imi-
dazolinium tetrafluoroborate10c (300 mg, 0.47 mmol), NaOt-Bu
(46 mg, 0.47 mmol), and Me2S$AuCl (156 mg, 0.53 mmol) in THF
(12 mL) was stirred at rt for 4.5 h and filtrated. The filtrate was
concentrated, and the resulting residue was purified by column
chromatography (hexane/EtOAc¼3/1) to give the titled compound
as colorless amorphous solid (200 mg, 54%) of mp 257e259 ꢂC (dec)
4.2.4.5. (4S,5S)-1,3-Bis(bis(2,3-dimethylphenyl)methyl)-4,5-
diphenylimidazolidin-2-ylidenegold(I) chloride (1e). Prepared from
the corresponding imidazolinium tetrafluoroborate10d by the same
procedure as 1a. Column chromatography (benzene) gave the titled
compound as colorless amorphous solid (192 mg, 79%) of mp
and ½a 2D5
ꢀ
ꢁ188 (c 0.44, CHCl3). 1H NMR: 4.58 (2H, s), 5.84 (2H, s),
7.00e7.02 (4H, m), 7.08e7.10 (4H, m), 7.28e7.40 (22H, m). 13C NMR:
66.5 (CH), 74.0 (CH), 127.4 (CH), 128.2 (CH), 128.4 (CH), 128.7 (CH),
128.8 (CH), 129.00 (CH), 129.04 (CH), 129.2 (CH), 129.3 (CH), 136.3
(C), 138.1 (C), 138.5 (C), 193.4 (C). IR: 3433, 3030, 1452, 1261, 750.
FABMS m/z: 751 (MꢁCl). Anal. Calcd for C41H34AuClN2$1.25H2O: C,
60.82; H, 4.54; N, 3.46. Found: C, 60.63; H, 4.27; N, 3.43. Single
crystals suitable for X-ray diffraction were grown by placing
a microtube of a THF solution of 1a in a closed tube filled with Et2O.
The CIF file of the crystal structure (CCDC 864358) was deposited at
the Cambridge Crystallographic Data Centre.
146e149 ꢂC and ½a 2D5
ꢀ
ꢁ87.1 (c 0.98, CHCl3). 1H NMR: 1.89 (6H, s),
1.99 (6H, s), 2.10 (6H, s), 2.22 (6H, s), 4.79 (2H, s), 6.40 (2H, s), 6.88
(2H, m), 6.94e7.00 (8H, m), 7.05 (2H, m), 7.11 (2H, m), 7.16 (2H, m),
7.19e7.24 (6H, m). 13C NMR: 14.8 (CH3), 15.1 (CH3), 20.5 (CH3), 20.8
(CH3), 61.5 (CH), 74.3 (CH), 125.3 (CH), 125.6 (CH), 126.4 (CH), 127.2
(CH),127.8 (CH), 128.4 (CH),128.8 (CH),129.8 (CH),129.9 (CH),134.9
(C), 135.2 (C), 135.6 (C), 137.2 (C), 137.27 (C), 137.28 (C), 137.8 (C),

K.-ichi Yamada et al. / Tetrahedron 68 (2012) 4159e4165
4163
194.9 (C). IR: 3511, 2918, 1450, 1267, 731. FABMS m/z: 1762
(2MþHeCl). Anal. Calcd for C49H50AuClN2: C, 65.44; H, 5.60; N, 3.11.
Found: C, 65.21; H, 5.78; N, 3.06. Single crystals suitable for X-ray
diffraction were grown by placing a microtube of a THF solution of
1e in a closed tube filled with hexane. The CIF file of the crystal
structure (CCDC 864361) was deposited at the Cambridge Crystal-
lographic Data Centre.
compound as colorless oil (14.1 g, 52%). 1H NMR: 0.88 (12H, d,
J¼6.8), 0.90 (12H, d, J¼7.0), 1.91 (4H, m), 3.43 (2H, s), 4.66 (2H, t,
J¼6.1). 13C NMR: 17.1 (CH3), 19.4 (CH3), 29.3 (CH), 41.7 (CH2), 84.1
(CH), 166.9 (C). IR: 2970, 1736, 1265. FABMS m/z: 301 (MþH).
HRMSeFAB (m/z): [MþH]þ calcd for C17H33O4, 301.2379; found,
301.2378.
4.3.2. Bis(1-isopropyl-2-methylpropyl)-2-(3-methylbut-2-enyl)-2-
(prop-2-ynyl)malonate (2e). Prepared by an analogous procedure to
that reported.19 To a suspension of NaH (60% in mineral oil, 133 mg,
3.3 mmol) in DMF (6 mL), was added a solution of malonate 8 (1.0 g,
3.3 mmol) in DMF (6 mL) and then prenyl bromide (0.40 mL,
3.3 mmol) at 0 ꢂC. The mixture was stirred for 12 h at rt. The re-
action was quenched by addition of H2O (30 mL). After separation
of the organic phase, the aqueous phase was extracted with EtOAc
(3ꢃ20 mL). The combined organic layers were washed with brine
(5ꢃ10 mL), dried over Na2SO4, and concentrated to give pale yellow
oil (1.5 g). Column chromatography (Et2O/hexane¼1/19) gave pale
yellow oil (1.1 g). To a suspension of NaH (60% in mineral oil,
125 mg, 3.0 mmol) in DMF (18 mL) was added a solution of the
above oil (1.1 g) in DMF (8 mL) and then propargyl bromide
(0.25 mL, 3.3 mmol) at 0 ꢂC. The mixture was stirred for 13 h at rt.
The reaction was quenched by addition of H2O (30 mL). After sep-
aration of the organic phase, the aqueous phase was extracted with
EtOAc (3ꢃ20 mL). The combined organic layers were washed with
brine (6ꢃ10 mL), dried over Na2SO4, and concentrated to give or-
ange oil (1.1 g). Column chromatography (EtOAc/hexane¼1/30)
gave colorless solids (1.1 g). Distillation (122 ꢂC/0.3 mmHg) gave the
titled compound as colorless cubes (830 mg, 60% in two steps) of
mp 40e42 ꢂC. 1H NMR: 0.87e0.91 (24H, m), 1.68 (6H, s), 1.87e1.95
(4H, m), 1.98 (1H, t, J¼2.5), 2.81e2.89 (4H, m), 4.66 (2H, dd, J¼5.8,
6.1), 5.03 (1H, m). 13C NMR: 17.2 (CH3), 17.4 (CH3), 18.1 (CH3), 19.5
(CH3), 19.6 (CH3), 22.9 (CH2), 26.0 (CH3), 29.4 (CH), 29.6 (CH), 31.3
(CH2), 58.3 (C), 71.5 (CH), 80.2 (C), 84.8 (CH), 118.0 (CH), 136.2 (C),
170.4 (C). IR: 2970, 1728, 1226. FABMS m/z: 407 (MþH). HRMSeFAB
(m/z): [MþH]þ calcd for C25H43O4: 407.3161; found, 407.3145.
4.2.4.6. (4S,5S)-1,3-Bis(bis(3,5-dimethylphenyl)methyl)-4,5-
diphenylimidazolidin-2-ylidenegold(I) chloride (1f). Prepared from
7f by the same procedure as 1a. Column chromatography (benzene)
gave the titled compound as colorless amorphous solid (208 mg,
86%) of mp 99e102 ꢂC and ½a D25
ꢀ
ꢁ86.6 (c 0.43, CHCl3). 1H NMR: 2.20
(12H, s), 2.25 (12H, s), 4.57 (2H, s), 6.07 (2H, s), 6.73 (4H, s), 6.79
(2H, s), 6.84 (4H, s), 6.92 (2H, s), 7.01e7.04 (4H, m), 7.26e7.29 (6H,
m). 13C NMR: 21.2 (CH3), 21.4 (CH3), 67.1 (CH), 73.9 (CH), 126.7 (CH),
127.07 (CH), 127.08 (CH), 128.7 (CH), 128.9 (CH), 129.7 (CH), 136.6
(C), 137.9 (C), 138.1 (C), 138.9 (C), 139.1 (C), 194.7 (C). IR: 3529, 2916,
1602, 1458, 1265, 700. FABMS m/z: 1762 (2MþHeCl). Anal. Calcd for
C49H50AuClN2: C, 65.44; H, 5.60; N, 3.11. Found: C, 65.71; H, 5.69; N,
3.03.
4.2.4.7. (4S,5S)-1,3-Bis(bis(4-methylbiphenyl-3-yl)methyl)-4,5-
diphenylimidazolidin-2-ylidenegold(I) chloride (1g). Prepared from
7g by the same procedure as 1a. Column chromatography (ben-
zene) gave the titled compound as colorless amorphous solid
(128 mg, 56%) of mp 154e156 ꢂC and ½a D25
ꢀ
ꢁ143 (c 0.92, CHCl3). 1H
NMR: 1.95 (6H, s), 2.03 (6H, s), 4.78 (2H, s), 6.22 (2H, s), 6.85e6.91
(8H, m), 6.99 (2H, m), 7.13 (2H, m), 7.19 (2H, m), 7.28 (2H, m),
7.32e7.49 (20H, m), 7.54e7.56 (4H, m), 7.68 (2H, m). 13C NMR: 18.6
(CH3), 19.5 (CH3), 61.1 (CH), 74.8 (CH), 126.8 (CH), 127.0 (CH), 127.4
(CH), 127.6 (CH), 128.0 (CH), 128.4 (CH), 128.5 (CH), 128.7 (CH),
129.0 (CH), 131.4 (CH), 131.6 (CH), 135.2 (C), 135.8 (C), 136.1 (C),
137.2 (C), 137.3 (C), 139.2 (C), 139.6 (C), 140.7 (C), 141.6 (C), 194.5
(C). IR: 3488, 3032, 1481, 1265, 756. FABMS m/z: 2258 (2MþHeCl).
Anal. Calcd for C69H58AuClN2: C, 72.21; H, 5.09; N, 2.44. Found: C,
72.04; H, 5.25; N, 2.44. Single crystals suitable for X-ray diffraction
were grown by placing a microtube of a THF solution of 1g in
a closed tube filled with hexane. The CIF file of the crystal struc-
ture (CCDC 864362) was deposited at the Cambridge Crystallo-
graphic Data Centre.
4.4. Asymmetric cyclization of 1,6-enynes
4.4.1. Dimethyl
(S)-3-(1-methoxy-1-methylethyl)-4-methylenecy-
clopentane-1,1-dicarboxylate (3a) (Table 2, entry 1). A mixture of 1c
(27 mg, 0.03 mmol) and AgSbF6 (10 mg, 0.03 mmol) in MeOH
(2.5 mL) was stirred at rt for 15 min. To the mixture, was added
enyne 2a (119 mg, 0.5 mmol) in MeOH (2.5 mL) via cannula, and the
whole mixture was stirred for 1 h at rt. The mixture was filtered
through a Celite pad and concentrated. The resulting residue was
purified by column chromatography (EtOAc/hexane¼1/15) to give
4.2.4.8. (4S,5S)-1,3-Bis(bis(3,5-di-tert-butylphenyl)methyl)-4,5-
diphenylimidazolidin-2-ylidenegold(I) chloride (1h). Prepared from
7h by the same procedure as 1a. Column chromatography (ben-
zene) gave the titled compound as colorless amorphous solid
(129 mg, 55%) of mp 106e109 ꢂC and ½a D25
ꢀ
ꢁ62.6 (c 1.03, CHCl3). 1H
NMR: 1.20 (36H, s),1.25 (36H, s), 4.63 (2H, s), 6.15 (2H, s), 6.86e6.89
(4H, m), 7.08e7.09 (4H, m), 7.14e7.21 (12H, m), 7.31e7.33 (2H, m).
13C NMR: 31.39 (CH3), 31.44 (CH3), 34.70 (C), 34.77 (C), 68.8 (CH),
74.2 (CH), 121.90 (CH), 122.00 (CH), 123.4 (CH), 123.8 (CH), 126.8
(CH), 128.5 (CH), 129.0 (CH), 136.1 (C), 138.5 (C), 139.8 (C), 150.6 (C),
150.7 (C), 195.0 (C). IR: 2962, 1597, 1473, 1250, 702. FABMS m/z:
1234 (Mþ). HRMSeFAB m/z: [M]þ calcd for C73H98N2AuCl,
1234.7084; found, 1234.7058.
the titled compound16 as colorless oil (128 mg, 95%) of ½a 2D5
ꢁ13.4
ꢀ
(c 1.39, CHCl3) with 56% ee (lit.28
½
a 2D2
ꢀ
þ18.5 (c 0.14, CHCl3) for the
antipode with 50% ee). 1H NMR: 1.12 (3H, s), 1.18 (3H, s), 2.00 (1H,
dd, J¼9.5, 13.5), 2.51 (1H, ddd, J¼1.8, 8.5, 13.5), 2.83e2.93 (3H, m),
3.19 (3H, s), 3.72 (3H, s), 3.73 (3H, s), 4.98 (1H, s), 5.04 (1H, br s). 13C
NMR: 22.1 (CH3), 22.6 (CH3), 35.9 (CH2), 43.3 (CH2), 48.97 (CH3),
49.05 (CH), 52.64 (CH3), 52.68 (CH3), 58.5 (C), 76.7 (C), 110.5 (CH2),
148.2 (C), 172.0 (C), 172.1 (C). IR: 2978, 1736, 1434, 1234. FABMS m/z:
271 (MþH). Enantiomeric excess was determined by HPLC (DAICEL
ChiralPack AD, i-PrOH/hexane¼1/19, 0.5 mL/min, 220 nm, 9.0 min
and 10.0 min for S and R, respectively).4a The absolute configuration
was determined by the specific rotation.
4.3. Preparation of 2e
4.3.1. Bis(1-isopropyl-2-methylpropyl)malonate (8). Prepared by an
analogous procedure to that reported.27 A mixture of malonic
acid (9.4 g, 90 mmol), 2,4-dimethyl-3-pentanol (44 g,
380 mmol), and p-TsOH$H2O (1.7 g, 9.0 mmol) in toluene
(180 mL) was stirred under reflux with a DeaneStark trap for
14 h. The whole was washed with satd NaHCO3 (3ꢃ30 mL) and
brine (2ꢃ50 mL), dried over Na2SO4, and concentrated to give
yellow oil (18 g). Distillation (122 ꢂC/0.3 mmHg) gave the titled
4 . 4 . 2 . D i m e t h y l - 3 - ( m e t h o x y ( p h e n y l ) m e t h y l ) - 4 -
methylenecyclopentane-1,1-dicarboxylate (3b) (Table 2, entry
2).16 Colorless oil (145 mg, 91%) of ½a 2D5
ꢁ51.4 (c 1.0, CHCl3) with
ꢀ
59% ee. 1H NMR: 2.34 (1H, dd, J¼8.8, 13.4), 2.43 (1H, dd, J¼8.8, 13.4),
2.88e3.00 (3H, m), 3.20 (3H, s), 3.67 (3H, s), 3.74 (3H, s), 4.17 (1H, d,
J¼5.8), 4.51 (1H, s), 4.93 (1H, s), 7.26e7.35 (5H, m). 13C NMR: 35.3

4164
K.-ichi Yamada et al. / Tetrahedron 68 (2012) 4159e4165
(CH2), 42.0 (CH2), 49.3 (CH), 52.6 (CH3), 57.2 (CH3), 58.6 (C), 85.7
(CH), 108.5 (CH2), 127.3 (CH), 127.6 (CH), 128.3 (CH), 140.7 (C), 148.6
(C),172.1 (C),172.2 (C). IR: 2954,1735,1265. FABMS m/z: 319 (MþH).
Enantiomeric excess was determined by HPLC (DAICEL ChiralPack
AD-H, i-PrOH/hexane¼1/30, 0.5 mL/min, 254 nm, 11.7 min and
13.0 min for major and minor, respectively). Relative configuration
was determined by the comparison of spectra with those repor-
ted.16 The absolute configuration was tentatively assigned by
analogy.
1H NMR: 0.87e0.90 (24H, m),1.13 (3H, s), 1.19 (3H, s),1.85e1.94 (4H,
m), 2.04 (1H, dd, J¼9.8, 13.4), 2.61 (1H, m), 2.88e2.95 (3H, m), 3.19
(3H, s), 4.62e4.67 (2H, m), 4.99 (1H, s), 5.04 (1H, s). 13C NMR: 17.0
(CH3), 17.1 (CH3), 17.3 (CH3), 17.5 (CH3), 19.47 (CH3), 19.52 (CH3),
19.59 (CH3), 22.1 (CH3), 22.7 (CH3), 29.4 (CH), 29.5 (CH), 29.6 (CH),
36.6 (CH2), 44.0 (CH2), 48.89 (CH), 48.95 (CH3), 59.9 (C), 76.9 (C),
84.0 (CH), 84.2 (CH), 110.6 (CH2), 148.6 (C), 171.8 (C). IR: 2970, 1736,
1466, 1234. FABMS m/z: 439 (MþH). HRMSeFAB (m/z): [MþH]þ
calcd for C26H47O5, 439.3423; found, 439.3452. The absolute con-
figuration and enantiomeric excess were determined at the stage of
the corresponding diol by comparison of specific rotation and gas
chromatography with those of the authentic sample prepared from
(S)-3a (see below).
4.4.3. (S)-1,1-Bis(phenylsulfonyl)-3-(1-methoxy-1-methylethyl)-4-
methylenecyclopentane (3c) (Table 2, entry 3).16,29 Colorless powder
(202 mg, 93%) of mp 70e73 ꢂC and ½a D25
ꢁ20.5 (c 0.97, CHCl3) with
ꢀ
52% ee (lit.4a
½
a 25
ꢀ
þ21.2 (c 0.4, CHCl3) for the antipode with 53% ee).
1H NMR:1.10 (3H, s),1.19 (3H, s), 2.65(1H, m), 2.70e2.79 (2H, m), 3.02
(1H, m), 3.14 (3H, s), 3.46 (1H, m), 4.99 (1H, s), 5.01 (1H, s), 7.56e7.62
(4H, m), 7.70e7.73 (2H, m), 8.04e8.08 (4H, m). 13C NMR: 22.1 (CH3),
22.4 (CH3), 33.2 (CH2), 40.5 (CH2), 49.1 (CH3), 50.2 (CH), 76.7 (C), 91.8
(C), 111.1 (CH2), 128.66 (CH), 128.71 (CH), 131.1 (CH), 134.47 (CH),
134.65 (CH), 136.0 (C), 137.2 (C), 146.5 (C). IR: 2939, 1327, 1150, 756.
FABMS m/z: 435 (MþH). Enantiomeric excess was determined by
HPLC (DAICEL ChiralPack AD, i-PrOH/hexane¼1/9, 0.7 mL/min,
254 nm, 28.3 min and 34.9 min for major and minor, respectively).4a
The absolute configuration was determined by the specific rotation.
4.5. Determination of ee and absolute configuration of 3e
4.5.1. 3-(1-Methoxy-1-methylethyl)-4-methylenecyclopentane-1,1-
dimethanol (9). From (S)-3e. To a suspension of LiAlH4 (20 mg,
0.54 mmol) in Et2O (1 mL), was added a solution of (S)-3e (40 mg,
0.09 mmol) in Et2O (1 mL) at rt and stirred for 1 h. Then to the
reaction mixture, cooled in an ice-water bath, were added 0.5 mL of
H2O, 0.5 mL of 15% NaOH, and then 1.5 mL of H2O. The whole
mixture was extracted with Et2O (3ꢃ5 mL). The combined organic
layers were dried over Na2SO4, and concentrated. The resulting
residue was purified by column chromatography (EtOAc/
hexane¼2/1) to give the titled compound with 42% ee as colorless
4.4.4. (S)-(Z)-1,1-Bis(phenylsulfonyl)-4-(1-methoxy-1-methylethyl)-3-
phenylmethylidenecyclopentane (3d) (Table 2, entry 4).16,29 Colorless
oil (18 mg, 93%) of ½a D25
ꢀ
ꢁ34.5 (c 0.85, CHCl3): 1H NMR: 1.12 (3H, s),
powder (156 mg, 61%) of mp 162e164 ꢂC and ½a D25
þ105 (c 0.59,
ꢀ
1.18 (3H, s), 1.45 (1H, dd, J¼8.9, 13.7), 1.79 (1H, dd, J¼9.3, 13.7),
2.15e2.19 (3H, m), 2.28 (1H, d, J¼15.3), 2.75 (1H, dd, J¼8.9, 9.3), 3.20
(3H, s), 3.56 (2H, d, J¼4.5), 3.71 (2H, d, J¼4.3), 4.99 (1H, s), 5.02 (1H,
s). 13C NMR: 22.1 (CH3), 22.6 (CH3), 33.2 (CH2), 41.3 (CH2), 46.3 (C),
48.88 (CH3), 48.92 (CH), 67.4 (CH2), 71.2 (CH2), 77.2 (C), 110.3 (CH2),
150.7 (C). IR: 3379, 2939, 1381, 1041. FABMS m/z: 215 (MþH).
HRMSeFAB (m/z): [MþH]þ calcd for C12H23O3, 215.1647; found,
215.1638. Enantiomeric excess was determined by gas chroma-
tography (BETA DEXTM 120; 150 ꢂC for 30 min, then 3 ꢂC/min to
220 ꢂC; 42.2 min and 42.5 min for major and minor, respectively).
CHCl3) with 49% ee (lit. ½a D25
ꢀ
ꢁ75.3 (c 0.6, CHCl3)4a and ½a D22
ꢁ218.1 (c
ꢀ
1.05, CHCl3)4d for the antipode with 94 and 78% ee, respectively). 1H
NMR: 0.80 (3H, s), 0.89 (3H, s), 2.55 (1H, d, J¼15.9), 2.78 (1H, m), 2.87
(1H, m), 2.94 (3H, s), 3.67 (1H, m), 3.76 (1H, m), 6.41 (1H, s), 7.22 (1H,
m), 7.31e7.34 (4H, m), 7.53e7.57 (2H, m), 7.60e7.63 (2H, m),
7.67e7.73 (2H, m), 8.10e8.14 (4H, m). 13C NMR: 22.4 (CH3), 23.7
(CH3), 32.4 (CH2), 42.1 (CH2), 47.1 (CH), 49.1 (CH3), 78.2 (C), 91.8 (C),
126.3 (CH), 126.8 (CH), 128.3 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH),
131.1 (CH),131.2 (CH),134.4 (CH),134.6 (CH),135.9 (C),137.4 (C),138.6
(C), 140.6 (C). IR: 2977, 1319, 1150. FABMS m/z: 511 (MþH). Enantio-
meric excess was determined by HPLC (DAICEL ChiralPack AS-H, i-
PrOH/hexane¼1/20, 1 mL/min, 254 nm, 34.9 min and 50.0 min for
minor and major, respectively).4a The absolute configuration was
determined by the specific rotation. Trituration of the obtained
powder in Et2O followed by filtration gave enantiomerically enriched
4.5.2. From (S)-3a with 34% ee. The same procedure above was
followed using LiAlH4 (19 mg, 0.51 mmol) and (S)-3a (23 mg,
0.085 mmol, 34% ee) to give the titled compound as colorless oil
(17 mg, 93%) of ½a D25
ꢁ26.1 (c 0.85, CHCl3). The enantiomeric excess
ꢀ
was verified to be 38% ee by gas chromatography (see above).
3d (73% ee) as colorless powder with ½a D25
þ162 (c 0.65, CHCl3).
ꢀ
Acknowledgements
4.4.5. 4,4-Dimethyl-2,2-bis(phenylsulfonyl)-2,3,3a,4-tetrahydro-1H-
cyclopenta[b]naphthalene (4) (Table 2, entry 4). Colorless powder
This research was partially supported by a Grant-in-Aid for
Scientific Research (A), a Grant-in-Aid for Young Scientists (B), and
the Targeted Proteins Research Program of the Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan.
(90 mg, 37%) of mp 210e214 ꢂC (dec) and ½a D25
þ1.76 (c 0.54,
ꢀ
CD2Cl2). 1H NMR (CD2Cl2): 0.84 (3H, s), 1.34 (3H, s), 2.53 (1H, dd,
J¼8.3, 14.7), 2.77 (1H, dd, J¼12.2, 14.7), 2.93 (1H, m), 3.47 (1H, d,
J¼19.9), 3.55 (1H, ddd, J¼2.5, 2.8, 19.9), 6.36 (1H, m), 7.02 (1H, m),
7.13e7.18 (2H, m), 7.27 (1H, m), 7.59e7.67 (4H, m), 7.73e7.78 (2H,
m), 8.02e8.08 (4H, m). 13C NMR (CD2Cl2): 21.1 (CH3), 24.9 (CH3),
32.0 (CH2), 36.3 (CH2), 36.6 (C), 48.8 (CH), 92.2 (C), 119.7 (CH), 123.2
(CH), 126.1 (CH), 126.2 (CH), 127.1 (CH), 128.60 (CH), 128.64 (CH),
130.75 (CH), 130.79 (CH), 133.1 (C), 134.4 (CH), 134.6 (CH), 135.8 (C),
136.8 (C), 140.5 (C), 143.3 (C). IR: 2962, 1327, 1150. FABMS m/z: 479
(MþH). HRMSeFAB (m/z): [MþH]þ calcd for C27H27O4S2, 479.1351;
found, 479.1347. Enantiomeric excess was determined to be 17% by
HPLC (DAICEL ChiralPack AD-H, i-PrOH/hexane¼1/10, 1 mL/min,
254 nm, 41.8 min and 45.9 min for minor and major, respectively).
The absolute configuration was tentatively assigned by analogy.
Supplementary data
NMR spectra of the new compounds, and HPLC or GC traces for
the determination of the enantiomeric excesses. Supplementary
data related to this article can be found online at doi:10.1016/
j.tet.2012.03.107.
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