Lewis Base-Catalyzed Enantioselective Conjugate Reduction of β,β-Disubstituted α,β-Unsaturated Ketones with Trichlorosilane: E/ Z-Isomerization, Regioselectivity, and Synthetic Applications

Article abstract of DOI:10.1021/acs.joc.9b01298

The chiral bisphosphine dioxide-catalyzed asymmetric conjugate reduction of acyclic β,β-disubstituted α,β-unsaturated ketones with trichlorosilane affords saturated ketones having a stereogenic carbon center at the carbonyl β-position with high enantioselectivities. Because the E/Z-isomerizations of enone substrates occur concomitantly, reduction products with the same absolute configurations are obtained from either (E)- or (Z)-enones. Conjugate reduction is accelerated in the presence of an electron-rich aryl group at the β-position of the enone owing to its carbocation-stabilizing ability. Computational studies were also conducted in order to elucidate the origin of the observed enantioselectivity. The regio- and enantioselective reductions of dienones were realized and applied to the syntheses of ar-turmerone, turmeronol A, mutisianthol, and jungianol, which are optically active sesquiterpenes.

Full text of DOI:10.1021/acs.joc.9b01298

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Article
Lewis Base-catalyzed Enantioselective Conjugate Reductions of
#,#-Disubstituted #,#-Unsaturated Ketones with Trichlorosilane:
E/Z Isomerization, Regioselectivity, and Synthetic Applications
Masaharu Sugiura, Yasuhiko Ashikari, Yuka Takahashi,
Koki Yamaguchi, Shunsuke Kotani, and Makoto Nakajima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01298 • Publication Date (Web): 26 Aug 2019
Downloaded from pubs.acs.org on August 27, 2019
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The Journal of Organic Chemistry
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Lewis Base-catalyzed Enantioselective Conjugate Reduction of -Disubstituted
-Unsaturated Ketones with Trichlorosilane: E/Z Isomerization, Regioselectivity,
and Synthetic Applications
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Masaharu Sugiura,*,† Yasuhiko Ashikari,‡ Yuka Takahashi,‡ Koki Yamaguchi,† Shunsuke Kotani,‡
and Makoto Nakajima‡
†Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan
‡Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-
0973, Japan
TOC GRAPHIC
ABSTRACT
The chiral bisphosphine dioxide-catalyzed asymmetric conjugate reduction of acyclic -disubstituted -
unsaturated ketones with trichlorosilane affords saturated ketones having a stereogenic carbon center at the
carbonyl -position with high enantioselectivities. Because the E/Z isomerizations of enone substrates occur
concomitantly, reduction products with the same absolute configurations are obtained from either (E)- or (Z)-
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enones. Conjugate reduction is accelerated in the presence of an electron-rich aryl group at the -position of the
enone owing to its carbocation-stabilizing ability. Computational studies were also conducted in order to
elucidate the origin of the observed enantioselectivity. The regio- and enantioselective reductions of dienones
were realized and applied to the syntheses of ar-turmerone, turmeronol A, mutisianthol, and jungianol, which
are optically active sesquiterpenes.
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Keywords: asymmetric catalysis, conjugate reduction, optically active sesquiterpene, phosphine oxide,
trichlorosilane
INTRODUCTION
The enantioselective conjugate reductions of -disubstituted -unsaturated ketones (referred to as enones
in this article) are powerful methods for the construction of stereogenic carbon centers at carbonyl -positions.
A hydride attacks the -carbon atom of the enone to generate an enolate intermediate, which then forms a
saturated ketone with -stereogenic center upon protonation. Although many transition metal-catalyzed
methods have been developed to achieve this outcome,1 2 organocatalytic methods, which offer several
,
advantages such as low toxicity and high catalyst reusability, have been limited.3 4 We reported that (S)-BINAP
,
dioxide [(BINAPO)], which is a chiral Lewis base, catalyzes the enantioselective conjugate reduction of enone
(E)-1a with trichlorosilane to give enantioenriched ketone 2a with high enantioselectivity (Scheme 1).5,6,7
A
hypervalent silicon complex8 generated from the Lewis base catalyst and trichlorosilane9 10 has been speculated
,
to reduce the enone to give a chiral ketone after workup. The exclusive formation of a (Z)-enolate intermediate
was confirmed by NMR spectroscopy during the reduction of benzalacetone, suggesting that the reaction
proceeds via a six-membered cyclic transition state. The resulting enolate intermediates were subsequently
applied in enantioselective aldol reactions with aldehydes.5,6b Herein, we report further investigations into the
conjugate reduction process. The concomitant E/Z isomerization of enone substrates, regioselective reduction
of dienones, and applications to the syntheses of optically active sesquiterpenes are disclosed.
Scheme 1. Enantioselective Conjugate Reductions of Enones Catalyzed by a Chiral Lewis Base.
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RESULTS & DISCUSSION
Reactions of 3-Alkyl-1,3-diarylprop-2-en-1-ones
To survey the substrate scope, we first investigated the reductions of several 3-alkyl-1,3-diarylprop-2-en-1-
ones 111 with (S)-BINAPO and trichlorosilane (Table 1). As shown in Scheme 1, the reaction of (E)-1,3-
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diphenylbut-2-en-1-one (1a) with trichlorosilane (2 equiv.) in the presence of (S)-BINAPO (10 mol%) at 0 °C for
20 h afforded (S)-1,3-diphenylbutan-1-one (2a) with high enantioselectivity (entry 1). Both electron-rich and -
poor aromatic rings (enones 1b and 1c, respectively) were tolerated in this reaction, providing similarly high
enantioselectivities as unsubstituted enone 1a (entries 2 and 3). To compare reactivities, the reactions of 1a−c
were terminated after 1 h; as a result, saturated ketones 2a–c were obtained in yields of 71%, 80%, and 16%,
respectively. Enones with electron-rich aromatic rings tended to be reduced faster than those with electron-
poor aromatic rings. This observation is discussed in more detail below (vide infra). Unexpectedly, the reactions
of geometrical isomers (Z)-1a−c furnished products 2a−c with the same absolute configurations and
enantioselectivities (96–97% ee) as those of their (E)-counterparts (entries 4−6).12 13 Similarly, the reactions of
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-ethyl-substituted enones (E)- and (Z)-1d provided the same product, namely (S)-2d, with a slightly lower but
nevertheless high enantioselectivity (93% ee) (entries 7 and 8) compared to 2a−c. These results suggest that
geometrical isomerization of the enone occurs concomitantly under the reaction conditions. In fact, TLC analysis
of the reaction of (Z)-1d after 15 min indicated the formation of (E)-1d as the major component of the
remaining enone substrate. In addition, enone 1d was recovered in 59% yield in a 88:12 E/Z ratio when the
reaction was conducted with 0.5 equivalents of trichlorosilane (entry 9). The same E/Z ratio was observed even
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when the reaction was quenched after 1 h, which indicates that geometrical isomerization proceeds rapidly
prior to reduction. The reaction of the -isopropyl-substituted enone (E)-1e led to a reversal of the enantiofacial
selectivity compared to the -methyl- or -ethyl-substituted enones 1a–d (entry 10). The reaction of (Z)-1e
afforded a slightly higher enantioselectivity than (E)-1e, indicating a slower E/Z isomerization process and a
preference for the (Z)-geometry during reduction (entry 11).
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Table 1. Reductions of 3-Alkyl-1,3-diarylprop-2-en-1-ones.
entry
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enone
(E)-1a
(E)-1b
(E)-1c
(Z)-1a
(Z)-1b
(Z)-1c
(E)-1d
(Z)-1d
(Z)-1d
(E)-1e
(Z)-1e
Ar
Ph
R
yield (%) ee (%)
Me
Me
Me
Me
Me
Me
Et
Et
Et
i-Pr
i-Pr
97
84
87
94
84
71
95
99
41
74
69
97 (S)
96
95
97 (S)
97
96
93 (S)
93 (S)
93 (S)
47 (S)
60 (S)
p-MeOC6H4
p-ClC6H4
Ph
p-MeOC6H4
p-ClC6H4
Ph
Ph
Ph
9b
10
11
Ph
Ph
aUnless otherwise noted, the reaction was performed using 1 (0.5 mmol), trichlorosilane (1.0 mmol), and (S)-
BINAPO (0.05 mmol, 10 mol%) in dichloromethane (2 mL) at 0 °C for 20–28 h. bWith HSiCl3 (0.5 equiv.); 1b (E/Z
= 88:12) was recovered in 59% yield.
Reaction of -Dialkyl-substituted Enone 1f
-Dialkyl-substituted enone 1f gave chlorinated product 3f along with the desired reduced product 2f when
reacted under the same conditions as those listed in Table 1 (Scheme 2). We hypothesized that hydrogen
chloride, generated in situ from trichlorosilane and adventitious water contamination, added to the enone.14
Hence, 2,6-lutidine (1.0 equiv.) was added to the reaction mixture to trap the hydrogen chloride. As a
consequence, formation of 3f was completely suppressed, which led to an improved yield and selectivity for the
reduced product 2f.
Scheme 2. The Effect of 2,6-Lutidine.
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Although no chlorinated products were obtained in the reactions of -alkyl--aryl-disubstituted enones 1a–e
(see Table 1),15 transient enone chlorination may be responsible for the observed E/Z isomerization. Therefore,
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to confirm whether or not this is the case, (E)- and (Z)-1b were reacted in the presence of 2,6-lutidine (1 equiv.).
As a result, slightly lower but nevertheless high enantioselectivities were observed (96% yield and 95% ee from
(E)-1b; 85% yield and 93% ee from (Z)-1b), which indicates that E/Z isomerization is rapid at 0 °C even in the
presence of 2,6-lutidine. We speculate that trichlorosilane, rather than hydrogen chloride, reversibly adds to
enones 1 to form the chlorinated trichlorosilyl enol ethers 4, which facilitates rapid E/Z isomerization (Scheme
3). To confirm if the presence of the Lewis base is required for the E/Z-isomerization, we conducted a control
experiment using (Z)-1d. On treatment of (Z)-1d with trichlorosilane and 2,6-lutidine (2.0 and 1.0 equivalents,
respectively) in dichloromethane at 0 °C, almost no isomerization proceeded.16 However, on addition of (S)-
BINAPO (10 mol%) to this mixture, a rapid E/Z-isomerization and relatively slow reduction were observed. The
workup with saturated aqueous NaHCO3 after 20 min at 0 °C afforded a 87:13 mixture of 1d (E/Z = 88:12) and
2d. This control experiment clearly shows that both the E/Z-isomerization and conjugate reduction are
catalyzed by BINAPO and that the E/Z-isomerization is much faster than the conjugate reduction.
Scheme 3. Possible E/Z-Isomerization Mechanism and Preference of the (E)-isomer in Conjugate Reduction.
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Reactions of Other Enones
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We recently reported a one-pot synthetic method for the preparation of -disubstituted -unsaturated
ketones that uses a TiCl4/Bu3N-promoted aldol reaction between simple ketones followed by base-promoted
elimination of the titanoxy group (Scheme 4).14 Among the bases tested for promoting the elimination step,
DMF, TMEDA, and pyridine gave good results. The formation of the enone products and the E/Z ratios are under
kinetic control in the presence of pyridine (5 equiv.), but under thermodynamic control with DMF (5 equiv.) or
TMEDA (1 equiv.); clearly the outcome depends on the basicity of the base and the amount used.
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Scheme 4. One-pot Synthesis of Enones.
The (S)-BINAPO-catalyzed conjugate reductions of other enones, prepared by the above-mentioned method,
were examined (Table 2). Firstly, the effect of the R2 group was investigated when R1 = Ph (entries 1−8), and
high enantioselectivities were obtained when R2 was an aryl group, including the 2-thienyl group (entries 1−5).
2,6-Lutidine was added to the reaction mixture to suppress undesired -chlorination for enones bearing alkyl
groups (R2 = alkyl; see Scheme 2), with higher enantioselectivities observed for systems bearing larger alkyl
groups (entries 6–8). The size of the R2 group appears to be important and must be differentiated from that of
the methyl group at the -position. Secondly, the effect of the R2 group was investigated when R1 = i-Pr (entries
9−11). Compared to the outcomes observed when R1 = Ph, lower reactivities and selectivities were observed
when R1 = i-Pr, with the R2 group observed to play a more important role, namely, higher reactivities were
observed with more electron-rich aromatic R2 groups. Thirdly, the effect of the R1 group was investigated when
R2 = Ph (entries 12−15). In contrast to the effect observed when the R2 group was varied, an electron-deficient
aryl group was more reactive than an electron-rich one (entries 12 and 13). In addition, smaller R1 alkyl groups
were observed to be more reactive than larger ones (entries 14, 15, and 9), while similar enantioselectivities
were observed in these cases.
Table 2. Various Enone Reductions.a
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entry
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enone
(E)-1a
(E)-1g
(E)-1h
(E)-1i
(E)-1j
R1
R2
Ph
product
2a
2g
2h
2i
2j
2k
2f
2l
2m
2n
2o
2p
2q
2r
yield (%)
ee (%)
97 (S)
96 (S)
97 (S)
97 (S)
95
40
68
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93 (S)
90 (S)
97 (S)
98 (S)
89
Ph
Ph
Ph
Ph
Ph
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76
90
p-MeOC6H4
p-ClC6H4
2-naphthyl
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c-Pr
i-Pr
t-Bu
Ph
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p-ClC6H4
Ph
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Ph
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7b
8d
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(E/Z)-1kc Ph
(E)-1f
(E)-1l
(E)-1m
(E)-1n
(E)-1o
(E)-1p
(E)-1q
(E)-1r
(E)-1s
Ph
Ph
i-Pr
i-Pr
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14
15
i-Pr
p-MeOC6H4
p-ClC6H4
c-Hex
c-Pr
Ph
1s
89
aUnless otherwise noted, the reaction was performed using 1 (0.5 mmol), trichlorosilane (1.0 mmol), and (S)-
b
BINAPO (0.05 mmol, 10 mol %) in dichloromethane (2 mL) at 0 °C for 20–24 h. With 2,6-lutidine (2.0 equiv.).
cE/Z = 58:42. dAt rt for 48 h.
Computational Study
We used computational methods to elucidate the origins of the observed enantioselectivities.17 As depicted in
Scheme 5, we speculate that a hexavalent silicon species (LB-HSiCl3 complex), generated by bidentate
coordination of the chiral bisphosphine dioxide (LB) to trichlorosilane, forms cationic complex A by accepting
(E)-enone 1a after dissociation of a chloride anion. Hydride transfer from the silicon atom to the enone -carbon
then occurs through either TSS or TSR, which are six-membered cyclic transition states, to give the (S,Z)- or
(R,Z)-silyl enol ether B, respectively (Scheme 5, right half). Similarly, (Z)-enone 1a produces (S,Z)- or (R,Z)-silyl
enol ether B via complex A’ and cyclic transition states TS’S or TS’R, respectively (Scheme 5, left half). These
structures were first optimized, vibrational frequencies calculated, and intrinsic reaction coordinate (IRC)
pathways calculated at the HF/6-31G(d) level of theory. Thermochemical properties were then calculated at the
ONIOM(M06-2X/6-311++G(3df,3pd):HF/6-31G(d)) level with the ONIOM-polarizable continuum model
(PCM)/X for dichloromethane applied.18 The binaphthyl backbone of (S)-BINAPO was simplified to an (S)-
configured axially chiral biphenyl unit in these calculations. The two electronegative chlorine atoms were
located at the trans apical positions to stabilize the hypervalent three-center four-electron bonding.8d Figure 1
summarizes the energy profile for the overall process, as well as the optimized structures of complex A, TSS, TSR,
complex A’, TS’S, TS’R, (S,Z)-B, and (R,Z)-B. The atoms treated with a high level of theory are represented as ball
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and stick models, while remaining atoms are shown as a tube model. TSS was calculated to be the most stable
among the transition states, which provides an enantioselectivity of 96.7% ee (S) at 0 °C assuming a Boltzmann
distribution, which is in good agreement with the experimental result [97% ee (S) using (S)-BINAPO]. The side
views of TSS and TSR (Figure 2) reveal steric repulsion between a phenyl group of the bisphosphine dioxide and
the phenyl ketone moiety of the enone in TSR, which is likely to be the origin of the observed enantioselectivity.
In addition, there is a weak edge-to-face -interaction19 between the -phenyl of the enone (ring A) and a P-
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phenyl of the catalyst (ring B) in TSs (Figure 3). The distance between the centroids of ring A and ring B is 5.35
Å. This interaction would favor the reduction of the enone having an aryl group at the β-position to give high
selectivity.
Scheme 5. Assumed Mechanism.
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TS’S
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TSR
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TSR
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14.17
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11.56
TSS
0.01
complex A’
0.00
complex A
TSS
TS’R
(R,Z)-B
–27.08
(R,Z)-B
–27.08
(R,Z)-B
–27.42
(S,Z)-B
–27.42
(S,Z)-B
(S,Z)-B
Reduction of (Z)-1a
Reduction of (E)-1a
Figure 1. ONIOM(M06-2X/6-311++G(3df,3pd):HF/6-31G(d))+ONIOM-PCM/X-calculated Energy Profile in
kcal/mol.
steric repulsion
TSS
TSR
Figure 2. Side Views of TSS and TSR.
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Figure 3. Edge-to-face -Interaction in TSS.
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The Lewis base catalyst (LB, bisphosphine dioxide) would be released from product (S,Z)-B via formation of
complex C by coordination of the chloride anion (Scheme 6). The released LB coordinates to HSiCl3 to form the
LB-HSiCl3 complex, which goes on to the next catalytic cycle. The catalyst resting state would be the LB-HSiCl3
complex, which was calculated to be more stable than complex C (see Supporting Information), presumably
because HSiCl3 has higher Lewis acidity than the trichlorosilyl enol ether product.
Scheme 6. Regeneration of the Lewis Base Catalyst (LB) and Formation of LB-HSiCl3.
Synthesis of ar-Turmerone
ar-Turmerone (Eq. 1) is an optically active sesquiterpene isolated from Curcuma longa (turmeric), with
several biological properties, such as antioxidant and antitumor activities, being reported.20 Recently, ar-
turmerone was reported to induce neural stem cell proliferation in vitro and in vivo.21 Due to its simple
structure, many synthetic studies have been reported; in most cases these studies aimed to test new asymmetric
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synthetic methods.22 We also planned to synthesize ar-turmerone through the conjugate reduction of ar-
atlantone (Eq. 1). Herewith, regioselectivity during reduction of the dienone presents an unavoidable issue.
Considering the stabilizing extended conjugation of the right-hand (as drawn) -aryl-substituted enone moiety,
the left-hand -dimethyl enone moiety is likely to be more reactive. However, the substituent effect noted in
Table 2 suggests selectivity for the reduction of the right-hand moiety.
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The starting material, ar-atlantone (1t) was synthesized from mesityl oxide and p-methylacetophenone by the
one-pot enone synthetic method in 86% yield and with 93% E-geometry (Eq. 2),14,23 and subjected to conjugate
reduction (Table 3), with 2,6-lutidine used to prevent chlorination of the left-hand moiety. To our delight, the
desired regioselectivity was observed, with ar-turmerone (2t) obtained in high yield with good
enantioselectivity (entry 1). Decreasing the temperature to −40 °C improved the enantioselectivity (entry 2). We
then screened a variety of chiral Lewis bases at −40 °C (entries 3−6 and Figure 4). Compared to a bulkier
catalyst (xylyl-BINAPO)24 or more Lewis basic catalysts (SEGPHOSO and p-tol-DIOPO25) (entries 3−5), 4,4’-
dibromo-BINAPO (Br2-BINAPO)26 provided higher regio- and enantioselectivities (entry 6). Both selectivities
were improved (to 99:1 regioselectivity and 92% ee) when the reaction temperature was further lowered to
−78 °C using Br2-BINAPO (entry 7). In addition, the catalyst loading could be reduced to 3 mol% without loss of
reactivity or selectivity (entry 8). After the product was obtained by column chromatography on silica gel
(hexane/CH2Cl2), the catalyst (Br2-BINAPO) was recovered by eluting with CH2Cl2/MeOH and reused after
recrystallization. A large-scale synthesis of ar-turmerone was also possible without decreasing the regio- and
enantioselectivities (entry 9).
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Table 3. The Synthesis of ar-Turmerone.a
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entry
catalyst
(S)-BINAPO
(S)-BINAPO
(S)-xylyl-BINAPO
(S)-SEGPHOSO
(R,R)-p-tol-DIOPO
(S)-Br2-BINAPO
(S)-Br2-BINAPO
(S)-Br2-BINAPOb
(R)-Br2-BINAPO
temp (°C)
0
yield (%)
93
84
80
94
78
94
93
91
ee (%)
67
81
63
75
−55
85
92
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2t/2t’
94:6
95:5
82:18
95:5
87:13
97:3
99:1
99:1
99:1
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−78
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aUnless otherwise noted, the reaction was performed using 1t (0.1 mmol), trichlorosilane (0.2 mmol), 2,6-
b
lutidine (0.1 mmol), and a catalyst (0.01 mmol, 10 mol%) in dichloromethane (0.4 mL) for 24 h. With 3 mol%
catalyst. A large scale synthesis of (R)-ar-turmerone using 1t (5.0 mmol, 1.072 g) and (R)-Br2-BINAPO (3
mol%).
c
Figure 4. Chiral Lewis Bases Tested.
Origin of the Observed Regioselectivity
Several control experiments were performed in order to clarify the origin of the high regioselectivity
observed in this study. Firstly, the cyclohexyl-bearing dienone 1u was reacted instead of the p-tolyl-bearing 1t
in order to evaluate the steric effect of the aryl group in ar-atlantone (1t) (Scheme 7a); this reaction was
conducted at 0 °C because of the low conversion observed at −40 °C. Interestingly, 1u exhibited the reverse
regioselectivity to 1t; the sterically less-hindered side was preferentially reduced to give 2u' as the major
product. Secondly, the -cyclohexyl-'-phenyl-substituted enone 1v was reduced in order to clarify the
electronic role played by the aryl group (Scheme 7b); this reaction proceeded regioselectively at the phenyl-
substituted terminus to give 2v as the major product, suggesting that the electronic properties of the aryl group
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controls the regioselectivity, rather than steric factors. Compared to the reduction of 1t (Table 3, entry 2), 1v
was reduced with significantly lower regioselectivity, indicating that the steric nature of the cyclohexyl group is
also influential. Finally, enones 1n and 1o were competitively reduced in order to evaluate the roles of
electronic factors, with the methoxy-bearing ketone 2n obtained with high chemoselectivity (Scheme 7c).
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Scheme 7. Control Experiments.
These results reveal that trichlorosilane selectively attacks -carbon atoms that are attached to carbocation-
stabilizing group(s). The development of positive charge at the -position to the carbonyl in the transition state
is stabilized by an electron-rich aromatic ring, such as p-tolyl and p-anisyl, which facilitates the high
regioselectivity observed during the reduction of ar-atlantone (Figure 5).27 Figure 6 reveals that the
ONIOM(M06-2X/6-311++G(3df,3pd):HF/6-31G(d))-calculated natural charges of selected atoms in transition
state TSS also support this hypothesis; positive charge is developed on carbon C3, with hydrogen H2 acting as
the hydride.
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Figure 5. Stabilizing the Transition State with an Electron-rich Aromatic Ring.
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Figure 6. ONIOM(M06-2X/6-311++G(3df,3pd):HF/6-31G(d))+ONIOM-PCM/X-calculated Natural Charges of
Selected Atoms in TSS.
Syntheses of Turmeronol A, Mutisianthol, and Jungianol
To extend the synthetic utility of the conjugate-reduction chemistry developed in this study, ar-turmerone
was further transformed into turmeronols A and B (Eq. 3). Turmeronol A and B are also isolated from turmeric
along with ar-turmerone, and are known to have antioxidant activities and soybean lipoxygenase inhibitory
activities.28 Despite their simple structures, only a limited number of asymmetric syntheses have been
reported.29 We planned to synthesize turmeronols A and B by the direct hydroxylation of the aromatic ring of
ar-turmerone.
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We first explored the use of Siegel’s aromatic hydroxylation protocol.30 Accordingly, ar-turmerone was
treated with phthaloyl peroxide (2 equiv.) in hexafluoroisopropanol (HFIP) at 50 °C for 48 h. After basic
hydrolysis to remove the phthaloyl group, turmeronols A and B were obtained in yields of 15% and 7%,
respectively, with most of the starting material recovered. Slight modifications (changing the amount of
phthaloyl peroxide (1.3-2.0), solvent (2,2,2-trifluoroethanol), temperature (40–50 °C), and time (24–72 h) were
unable to improve these yields. p-Cymene, a simplified model compound, was quantitatively oxidized under the
same conditions to give carvacrol and thymol in a 68:32 ratio (99% yield). However, the yield was reduced to
65% or 66% in the presence of mesityl oxide or acetone, respectively. These control experiments suggest that
the ketone moiety may inhibit the hydroxylation reaction; this effect is larger when the ketone moiety is present
in the same molecule.
We next examined a formylation/Dakin oxidation sequence (Scheme 8). Treatment of ar-turmerone with
31
TiCl4/MeOCHCl2 gave 4-formyl-ar-turmerone as the sole regioisomer. The use of excess amounts of reagent
was needed to obtain a good yield. Subsequent Dakin oxidation with m-CPBA32 followed by basic hydrolysis
furnished turmeronol A without loss of enantiomeric purity.
Scheme 8. Synthesis of Turmeronol A.
Mutisianthol and jungianol are phenolic sesquiterpenes isolated from Mutisia homoeantha and Juniga
malvaefolia, respectively. The former is known to exhibit antitumor activity;33 however, asymmetric syntheses
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have been limited.34 We planned to synthesize these two sesquiterpenes through sequences involving
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intramolecular Friedel–Crafts alkylations of the allylic alcohol derived from ent-turmeronol A (Scheme 9). The
conjugate reduction of ar-atlantone with trichlorosilane and (R)-Br2-BINAPO gave ent-ar-turmerone.
Subsequent formylation and Dakin oxidation, as shown in Scheme 8, afforded ent-turmeronol A with 92% ee.
Luche reduction35 of ent-turmeronol A gave allylic alcohol 5 with a dr of 6:4. Treatment of the diastereomeric
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mixture of 5 with a low concentration of anhydrous FeCl3 in dichloromethane36 afforded mutisianthol and
junginal as mixtures of epimers with a slight loss of optical purity. Although the regio- and stereoselectivities of
the Friedel–Crafts cyclization reactions require improvement, a short-step synthesis of these sesquiterpenes
was achieved.
Scheme 9. Synthesis of Mutisianthol and Jungianol.
CONCLUSIONS
Herein, we disclosed significant aspects of the enantioselective conjugate reductions of -disubstituted -
unsaturated ketones with trichlorosilane catalyzed by chiral bisphosphine dioxides. These reactions were
accompanied by the E/Z isomerization of enone substrates; consequently, reduction products of the same
absolute configurations were obtained from either (E)- or (Z)-enones. This conjugate reduction is accelerated by
the incorporation of an electron-rich aryl group at the -position of the enone owing to its ability to stabilize the
developing carbocation. The origin of the observed enantioselectivity is discussed on the basis of calculated
transition structures. The regioselective reductions of dienones were realized and applied to the synthesis of ar-
turmerone and other optically active sesquiterpenes.
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EXPERIMENTAL SECTION
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General Methods. Melting points (mp) were uncorrected. 1H and 13C{1H} NMR spectra were measured in CDCl3
with 400, 500, or 600 MHz spectrometer. Tetramethylsilane (TMS) ( = 0 ppm) and CDCl3 ( = 77.0 ppm) served
as internal standards for 1H and 13C{1H} NMR, respectively. Infrared spectra were recorded on an FT-IR
spectrometer. High-resolution mass spectra were recorded on an ESI-TOFMS spectrometer or a double-focusing
magnetic-sector mass analyzer operating in a FAB or EI mode. Thin-layer chromatography (TLC) was visualized
with UV light, phosphomolybdic acid and/or anisaldehyde. Column chromatography was performed using silica
gel (spherical, neutral, 63−210 nm). The reactions under anhydrous conditions were carried out using oven, and
heating gun-dried glassware with a rubber septum and a magnetic stirring bar under argon atmosphere.
Dichloromethane was dried over 4Å MS. Titanium(IV) chloride was distilled under reduced pressure and
used as a dichloromethane solution (ca. 3 M). Pyridine was distilled from CaH2 and stored over 4Å MS.
Trichlorosilane (>98%) was purchased from Tokyo Kasei Kogyo (TCI) and used as a dichloromethane solution
(ca. 3 M) prepared in a screw-top test tube with PTFE-lined screw cap. (S)-BINAPO, (S)-xylyl-BINAPO, and (S)-
SEGPHOSO were prepared by oxidation of the corresponding diphosphine with hydrogen peroxide in acetone. 37
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(R,R)-p-tolyl-DIOPO25 and (S)-Br2-BINAPO26 were prepared according to the literatures. Enones 1a–1c,11
1d−1e,2g 1f,14 1l–1s,14 and ar-atlantone (1t)14 were prepared according to the literatures. All other solvents and
chemicals were purified based on standard procedures.
General Procedure A: One-pot Synthesis of -Disubstituted Enone.14 To a stirred solution of a ketone
(aldol donor, 1.0 mmol) in CH2Cl2 (2.0 mL) cooled at –78 °C in a dry ice bath are successively added TiCl4 (ca. 3
M in CH2Cl2, 1.1 mmol) and Bu3N (0.29 mL, 1.2 mmol). After 30 min, another ketone (aldol acceptor, 1.0 mmol)
is added to the mixture at −78 °C. After 1 h, formation of the aldol product is detected by TLC analysis. Then
pyridine (0.40 mL, 5.0 mmol) is added at −78 °C and the dry ice bath is removed. After being stirred at rt for the
indicated time, the reaction mixture is diluted with Et2O (5 mL) and hexane (5 mL). The mixture was filtered
through a Celite pad with Et2O and the filtrate was concentrated. The residue is purified by column
chromatography on silica gel (hexane/AcOEt) to give enone 1. In most cases, the geometrical isomers are
separable.
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3-(4-Methoxyphenyl)-1-phenylbut-2-en-1-one (1g).38 According to General Procedure A, the reaction of
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acetophenone (120.2 mg) and p-methoxyacetophenone (150.1 mg) at rt for 2 h gave enone 1g as yellow oil
(134.5 mg, 53%, E/Z = 90:10). (E)-isomer: TLC Rf 0.44 (hexane/AcOEt = 7:1, stained red-orange with
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anisaldehyde). H NMR (400 MHz)  2.60 (s, 3H), 3.86 (s, 3H), 6.94 (d, J = 8.4 Hz, 2H), 7.16 (s, 1H), 7.47
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(apparent t, J = 7.3 Hz, 2H), 7.52-7.58 (m, 3H), 7.99 (apparent d, J = 7.6 Hz, 2H). (Z)-isomer: TLC Rf 0.36
(hexane/AcOEt = 7:1, stained red-orange with anisaldehyde). 1H NMR (400 MHz) representative signals:  2.29
(d, J =1.4 Hz, 3H), 3.75 (s, 3H), 6.62 (q, J = 1.4 Hz, 1H).
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3-(4-Chlorophenyl)-1-phenylbut-2-en-1-one (1h).38, According to General Procedure A, the reaction of
acetophenone (120.2 mg) and p-chloroacetophenone (154.6 mg) at rt for 2 h gave 1h as yellow oil (218.2 mg,
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85%, E/Z = 82:18). (E)-isomer: TLC Rf 0.61 (hexane/AcOEt = 7:1, stained yellow-green with anisaldehyde). H
NMR (400 MHz)  2.57 (d, J = 1.4 Hz, 3H), 7.14 (q, J = 1.4 Hz, 1H), 7.39 (apparent d, J = 8.2 Hz, 2H), 7.46-7.53 (m,
4H), 7.57 (apparent t, J = 7.3 Hz, 1H), 7.98 (apparent d, J = 6.8 Hz, 2H). (Z)-isomer: TLC Rf 0.50 (hexane/AcOEt =
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7:1, stained yellow-green with anisaldehyde). H NMR (400 MHz) representative signals:  2.29 (d, J =1.4 Hz,
3H), 6.74 (q, J = 1.4 Hz, 1H).
3-(Naphthalen-2-yl)-1-phenylbut-2-en-1-one (1i).39 According to general procedure A, the reaction of
acetophenone (120.2 mg) and 2’-acetonaphthone (170.2 mg) at rt for 2 h gave 1i as yellow oil (178.2 mg, 65%,
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E/Z = 79:21). (E)-isomer: TLC Rf 0.56 (hexane/AcOEt = 10:1, stained red-purple with anisaldehyde). H NMR
(400 MHz)  2.71 (d, J = 1.4 Hz, 3H), 7.32 (q, J = 1.4 Hz, 1H), 7.44-7.60 (m, 5H), 7.71 (dd, J = 8.7, 1.4 Hz, 1H), 7.84-
7.93 (m, 3H), 8.00-8.06 (m, 3H). (Z)-isomer: TLC Rf 0.44 (hexane/AcOEt = 10:1, stained dark green with
anisaldehyde). 1H NMR (400 MHz) representative signals:  2.40 (d, J =1.4 Hz, 3H), 6.80 (q, J = 1.4 Hz, 1H).
1-Phenyl 3-(thiophen-2-yl)but-2-en-1-one (1j).38 According to General Procedure A, the reaction of
acetophenone (134.1 mg) and 2-acetylthiophene (129.8 mg) at rt for 2 h gave 1j as yellow oil (147.8 mg, 51%,
E/Z = 94:6). (E)-isomer: TLC Rf 0.44 (hexane/AcOEt = 10:1, stained dark green with anisaldehyde). 1H NMR (500
MHz)  2.66 (d, J = 1.4 Hz, 3H), 7.10 (t, J = 4.3 Hz, 1H), 7.33 (q, J = 1.4 Hz, 1H), 7.38 (d, J = 5.2 Hz, 1H), 7.43 (d, J =
3.6 Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.56 (t, J = 6.9 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H). (Z)-isomer: TLC Rf 0.39
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(hexane/AcOEt = 10:1, stained dark green with anisaldehyde). 1H NMR (500 MHz) representative signals:  2.41
(d, J = 1.4 Hz, 3H), 6.57 (q, J = 1.4 Hz, 1H).
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3-Cyclopropyl-1-phenylbut-2-en-1-one (1k).40 According to General Procedure A, the reaction of
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acetophenone (237.6 mg) and cyclopropyl methyl ketone (176.0 mg) at rt for 1 h gave enone 1k as yellow oil
(348.7 mg, 94%, E/Z = 58:42). E/Z mixture: TLC Rf 0.58 (hexane/AcOEt = 7:1, stained purple with anisaldehyde).
1H NMR (400 MHz)  0.76-0.94 (m, 4H), 1.66 (d, J = 1.4 Hz, 1.26H (Z)), 1.67 (tt, J = 8.2, 5.0Hz, 0.58H (E)), 2.02 (d,
J = 1.4 Hz, 1.74H (E)), 3.26 (tt, J = 8.2, 5.0 Hz, 0.42H (Z)), 6.79 (brs, 0.42H (Z)), 6.82 (brs, 0.58H (E)), 7.42−7.54
(m, 3H), 7.91-7.96 (m, 2H).
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2-Cyclohexyl-6-methylhepta-2,5-dien-4-one (1u). According to General Procedure A, the reaction of mesityl
oxide (94.1 mg) and cyclohexyl methyl ketone (126.2 mg) at rt for 1 h gave dienone 1u as yellow oil (159.6 mg,
81%, E/Z = 88:12). (E)-isomer: TLC: Rf 0.49 (hexane/AcOEt = 10:1, stained purple with anisaldehyde). IR (ATR)
1
2925, 1672, 1621, 1604, 1446, 1380, 1215, 1108, 871 cm–1. H NMR (400 MHz)  1.10-1.36 (m, 5H), 1.65-1.85
(m, 5H), 1.88 (d, J = 1.4 Hz, 3H), 1.95 (tt, J = 7.4, 3.2 Hz, 1H), 2.14 (d, J = 1.4 Hz, 3H), 2.16 (d, J = 1.4 Hz, 3H), 6.02
(brs, 3H), 6.08 (brs, 3H). 13C{1H} NMR (100 MHz) δ 17.7, 20.5, 26.1, 26.4, 27.7, 31.4, 49.0, 123.8, 126.5, 153.9,
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162.8, 192.3. (Z)-isomer: TLC Rf 0.51 (hexane/AcOEt = 10:1, stained dark green with anisaldehyde). H NMR
(400 MHz)  1.08-1.47 (m, 7H), 1.56-1.65 (m, 2H), 1.65-1.78 (m, 3H), 1.80 (s, 3H), 1.88 (s, 3H), 2.17 (s, 3H), 3.56-
3.66 (m, 1H) 5.94 (s, 1H), 6.05 (s, 1H). 13C{1H} NMR (100 MHz)  20.5, 21.0, 26.2, 27.8, 29.7, 30.9, 40.1, 125.9,
126.4, 154.0, 162.9, 191.3. HRMS (EI+) Calcd for C14H22O (M+) 206.1671, found 206.1671.
2-Cyclohexyl-6-phenylhepta-2,5-dien-4-one (1v). According to General Procedure A, the reaction of (E)-4-
phenylpent-3-en-2-one (80.1 mg)41 and cyclohexyl methyl ketone (63.1 mg) at rt for 1 h gave dienone 1v as
yellow oil (112.2 mg, 84%, E/Z = 87:13). (E,E)-isomer: TLC: Rf 0.67 (hexane/AcOEt = 7:1, stained purple with
anisaldehyde). IR (ATR) 2924, 2851, 1663, 1606, 1445, 1104, 879, 759, 695. 1H NMR (400 MHz)  1.10-1.36 (m,
5H), 1.64-1.88 (m, 5H), 1.95-2.03 (m, 1H), 2.19 (d, J = 1.4 Hz, 3H), 2.56 (d, J = 1.4 Hz 3H), 6.17 (brs, 1H), 6.51
(brs, 1H), 7.32-7.40 (m, 3H), 7.46-7.52 (m, 2H). 13C{1H} NMR (100 MHz)  17.9, 18.1, 26.1, 26.4, 31.4, 49.0, 124.2,
126.4, 127.2, 128.4, 128.7, 142.9, 152.8, 163.6, 192.3. HRMS (EI+) Calcd for C19H24O (M+) 268.1827, found
268.1815.
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General Procedure B: Asymmetric Conjugate Reduction of Enone. Trichlorosilane (ca. 3.00 M CH2Cl2; 1
mmol) is added to a stirred solution of (S)-BINAPO (32.7 mg, 10 mol %), enone 1 (0.5 mmol), and 2,6-lutidine
(0.5 mmol, in the cases of -dialkyl--unsaturated ketones) in CH2Cl2 (2 mL) at 0 °C or rt. The mixture is
stirred at that temperature for the indicated time. The reaction is quenched with saturated NaHCO3 (5 mL). The
mixture was stirred for 1 h at rt, filtered through a Celite pad, and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered, and evaporated. The
residue was purified by silica gel column chromatography (hexane/CH2Cl2 or hexane/AcOEt) to give saturated
ketone 2. For the reduction of -dialkyl enones, 2,6-lutidine (0.5 mmol) is added to prevent unwanted chloride
addition.
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(S)-1,3-Diphenylbutan-1-one (2a).42 According to General Procedure B, the reaction of enone (E)-1a as
colorless needles (111.8 mg) and trichlorosilane (1.57 M CH2Cl2; 0.64 mL) with (S)-BINAPO (32.4 mg) in CH2Cl2
(2 mL) at 0 °C for 20 h gave (S)-2a (109.7 mg, 97% yield, 97% ee). TLC: Rf 0.33 (hexane/CH2Cl2 = 1:1, stained
1
purple with anisaldehyde). Mp: 50–51 °C. H NMR (400 MHz, CDCl3)  1.34 (d, J = 6.8 Hz, 3H), 3.18 (dd, J = 8.4,
16.8 Hz, 3H), 3.30 (dd, J = 6.0, 16.8 Hz, 3H), 3.51 (ddq, J = 6.0, 6.8, 8.4 Hz, 3H), 7.16-7.34 (m, 5H), 7.38-7.57 (m,
3H), 7.88-7.98 (m, 2H). HPLC (a combination of Chiralpak AD-H and AS-H, hexane/2-propanol = 9:1, 1.0
mL/min, 254 nm) tR = 14.4 min (S), 15.8 min (R). []23D +14.7 (c 1.005, CCl4) for 97% ee (S) [lit.2h []25D –13.5 (c
1.00, CCl4) for 82% ee (R)].
1,3-Bis(4-methoxyphenyl)butan-1-one (2b).43 According to General Procedure B, the reaction of enone (E)-
1b (141.5 mg) and trichlorosilane (2.98 M, 0.34 mL) with (S)-BINAPO (32.9 mg) in CH2Cl2 (2 mL) at 0 °C for 20 h
gave (S)-2b as colorless needles (119.8 mg, 84% yield, 97% ee). Mp 92-93 °C. IR (KBr, cm–1) 2962, 1674, 1601,
1514, 1250, 1176, 1030, 816. TLC Rf 0.08 (hexane/CH2Cl2 = 1:1, stained red-purple with anisaldehyde). 1H NMR
(400 MHz, CDCl3)  1.30 (d, J = 6.9 Hz, 3H), 3.09 (dd, J = 16.0, 8.3 Hz, 1H), 3.20 (dd, J = 16.0, 6.0 Hz, 1H), 3.44
(ddq, J = 8.3, 6.0, 6.9 Hz, 1H), 3.78 (s, 3H), 3.86 (s, 3H), 6.84 (apparent d, J = 8.7 Hz, 2H), 6.91 (apparent d, J = 8.7
Hz, 2H), 7.91 (apparent d, J = 8.7 Hz, 2H). HPLC (a combination of CHIRALPAK AD and AS-H, hexane/2-
propanol= 9:1, flow rate 1.0 mL/min, UV detection at 254 nm) tR = 23.1 min (S), 30.0 min (R). []31 –1.6 (c
D
1.005, CHCl3) for 96% ee.
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1,3-Bis(4-chlorophenyl)butan-1-one (2c).44 According to General Procedure B, the reaction of enone 1c
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(146.0 mg) and trichlorosilane (2.98 M, 0.34 mL) with (S)-BINAPO (32.9 mg) at 0 °C for 24 h gave 2c as colorless
needles (128.5 mg, 87%, 96% ee). TLC Rf 0.42 (hexane/CH2Cl2 = 1:1, stained purple with anisaldehyde). Mp: 58–
59 °C. 1H NMR (400 MHz, CDCl3)  1.32 (d, J = 6.9 Hz, 3H), 3.13 (dd, J = 16.9, 7.6 Hz, 1H), 3.23 (dd, J = 16.9, 6.4
Hz, 1H), 3.47 (ddq, J = 7.6, 6.4, 6.9, 1H), 7.19 (apparent d, J = 8.7 Hz, 2H), 7.26 (apparent d, J = 8.7 Hz, 2H), 7.41
(apparent d, J = 8.7 Hz, 2H), 7.84 (apparent d, J = 8.7 Hz, 2H). HPLC (a combination of Chiralpak AD-H and AS-H,
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hexane/2-propanol = 9/1, flow rate 1.0 mL/min, UV detection at 254 nm) tR = 11.3 min (S), 12.8 min (R). []28
–
D
11.4 (c 1.085, CHCl3) for 95% ee.
(S)-1,3-Diphenylpentan-1-one (2d).2h According to General Procedure B, the reaction of enone (E)-1d (117.1
mg) and trichlorosilane (2.89 M, 0.35 mL) with (S)-BINAPO (32.2 mg) in CH2Cl2 (2 mL) at 0 °C for 22 h gave 2d
as colorless needles (112.7 mg, 95% yield, 93% ee (S)).
According to General Procedure B, the reaction of enone (Z)-1d (117.8 mg) and trichlorosilane (2.89 M, 0.35
mL) with (S)-BINAPO (32.8 mg) in CH2Cl2 (2 mL) at 0 ℃ for 22h gave 2d as colorless needles (117.9 mg, 99%
yield, 93% ee (S)). TLC Rf 0.31 (hexane/CH2Cl2 = 1:1, stained yellow with anisaldehyde). Mp: 45–46 °C. 1H NMR
(400 MHz, CDCl3)  0.80 (t, J = 7.2 Hz, 3H), 1.59-1.71 (m, 1H), 1.73-1.85 (m, 1H), 3.19-3.34 (m, 3H), 7.15-7.34 (m,
5H), 7.43 (apparent t, J = 7.6 Hz, 2H), 7.53 (apparent t, J = 7.6 Hz, 1H), 7.92 (apparent d, J = 7.6 Hz, 2H). HPLC (a
combination of CHIRALPAK AY-3, hexane/2-propanol= 19/1, flow rate 1.0 mL/min, UV detection at 254 nm) tR =
7.3 min (S), 10.8 min (R). []20D +14.0 (c 1.320, EtOH) for 93% ee (S) [lit.45 []25D –4.3 (c 1.35, EtOH) for 80% ee
(R)].
(S)-4-Methyl-1,3-diphenylpentan-1-one (2e).2h According to General Procedure B, the reaction of enone (E)-
1e (124.9 mg, 0.5 mmol) and trichlorosilane (2.89 M, 0.35 mL) with (S)-BINAPO (32.6 mg, 0.05 mmol) in CH2Cl2
(2 mL) at 0 °C for 28 h gave 2e as colorless needles (92.8 mg, 74% yield, 47% ee). TLC Rf 0.28 (hexane/CH2Cl2 =
1
1:1, stained yellow with anisaldehyde). Mp: 40–43 °C. H NMR (400 MHz, CDCl3)  0.79 (d, J = 6.9 Hz, 3H), 0.98
(d, , J = 6.9 Hz 3H) , 1.88-2.00 (m, 1H), 3.17 (dt, J = 7.3, 6.9 Hz, 1H), 3.36 (d, J = 7.3 Hz 2H), 7.12-7.20 (m, 3H),
7.20-7.28 (m, 2H), 7.41 (apparent t, J = 7.6 Hz, 2H), 7.52 (apparent t, J = 7.3 Hz, 1H), 7.87 (apparent d, J = 8.2 Hz,
2H). HPLC (a combination of CHIRALPAK AD-H, hexane/2-propanol= 49/1, flow rate 1.0 mL/min, UV detection
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at 254 nm) tR = 8.8 min (R), 10.6 min (S). []20D −8.2 (c 1.015, CCl4) for 47% ee (S). [lit.46 []22 +13.2 (c 2.591,
D
1
2
3
CCl4) for 71% ee (R)].
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3,4-Dimethyl-1-phenylpentan-1-one (2f).47 According to General Procedure B, the reaction of enone 1f (57.3
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mg), 2,6-lutidine (35 L) and trichlorosilane (2.77 M, 0.22 mL) with (S)-BINAPO (20.3 mg) at 0 °C for 26 h gave
2f as colorless oil (50.7 mg, 89% yield, 68% ee). TLC Rf 0.42 (hexane/CH2Cl2 = 1:1, stained purple with
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anisaldehyde). H NMR (400 MHz, CDCl3)  0.88 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz,
3H), 1.61-1.71 (m, 1H), 2.04-2.16 (m, 1H), 2.71 (dd, J = 15.6 , 9.2 Hz, 1H), 2.99 (dd, J = 15.6, 4.6 Hz, 1H), 7.46
(apparent t, J = 8.0 Hz, 2H), 7.56 (apparent t, J = 7.4 Hz, 1H), 7.95 (apparent d, J = 8.0 Hz, 2H). HPLC (Chiralpak
AY-H, hexane/2-propanol = 49:1, flow rate 1.0 mL/min, UV detection at 220 nm) tR = 5.5 min (S), 6.0 min (R).
[]19D –17.7 (c 0.80, CHCl3) for 58% ee.
3-(4-Methoxyphenyl)-1-phenylbutan-1-one (2g).22g According to General Procedure B, the reaction of enone
1g (50.5 mg) and trichlorosilane (3.19 M, 0.13 mL) with (S)-BINAPO (13.1 mg) at 0 °C for 24 h gave 2g as
1
colorless oil (50.3 mg, 99%, 96% ee). TLC Rf 0.14 (hexane/CH2Cl2 = 1:1, stained purple with anisaldehyde). H
NMR (400 MHz, CDCl3)  1.31 (d, J = 6.9 Hz, 3H), 3.15 (dd, J = 16.3, 8.2 Hz, 1H), 3.24 (dd, J = 16.3, 6.0 Hz, 1H),
3.45 (ddq, J = 8.2, 6.0, 6.9 Hz,, 1H), 3.78 (s, 3H), 6.84 (apparent d, J = 8.5 Hz, 2H), 7.19 (apparent d, J = 8.5 Hz, 2H),
7.44 (apparent t, J = 7.8 Hz, 2H), 7.54 (apparent t, J = 7.4 Hz, 1H), 7.92 (apparent d, J = 7.3 Hz, 2H). HPLC (a
combination of Chiralpak AD-H and AS-H, hexane/2-propanol = 9:1, flow rate 1.0 mL/min, UV detection at 220
nm) tR = 14.9 min (S), 16.8 min (R). []20D +6.6 (c 1.01, CHCl3) for 92% ee (S) [lit.18d []31.4D –6.87 (c 1.39, CHCl3)
for >98% ee (R)].
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3-(4-Chlorophenyl)-1-phenylbutan-1-one (2h).22g,42, According to the typical procedure B, the reaction of
enone 1h (64.2 mg) and trichlorosilane (3.12 M, 0.19 mL) with (S)-BINAPO (19.4 mg) at 0 °C for 24 h gave 2h as
1
colorless oil (54.5 mg, 84%, 97% ee). TLC Rf 0.33 (hexane/CH2Cl2 = 1:1, stained orange with anisaldehyde). H
NMR (400 MHz, CDCl3)  1.32 (d, J = 6.9 Hz, 3H), 3.19 (dd, J = 16.5, 7.8 Hz, 1H), 3.24 (dd, J = 16.5, 6.4 Hz, 1H),
3.49 (ddq, J = 7.8, 6.4, 6.9 Hz, 1H), 7.20 (apparent d, J = 8.5 Hz, 2H), 7.26 (apparent d, J = 8.5 Hz, 2H), 7.45
(apparent t, J = 7.8 Hz, 1H), 7.56 (apparent t, J = 7.3 Hz, 1H), 7.91 (apparent d, J = 8.5 Hz, 2H). HPLC (Chiralpak
AD-H, hexane/2-propanol = 19:1, flow rate 1.0 mL/min, UV detection at 254 nm) tR = 5.7 min (S), 6.9 min (R).
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[]21D –1.5 (c 0.59, CHCl3) for 97% ee [lit.18d []24.0D +1.76 (c 1.30, CHCl3) for 95% ee].
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3-(Naphthalen-2-yl)-1-phenylbutan-1-one (2i).49 According to General Procedure B, the reaction of enone 1i
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(38.7 mg) and trichlorosilane (2.88 M, 0.10 mL) with (S)-BINAPO (9.1 mg) at 0 °C for 20 h gave 2i as colorless
needles (37.3 mg, 97%, 97% ee). TLC Rf 0.28 (hexane/CH2Cl2 = 1:1, stained purple with anisaldehyde). Mp: 59–
61 °C. 1H NMR (400 MHz, CDCl3)  1.43 (d, J = 6.8 Hz, 3H), 3.28 (dd, J = 16.5, 8.2 Hz, 1H), 3.41 (dd, J = 16.8, 5.6 Hz,
1H), 3.69 (ddq, J = 8.2, 5.6, 6.8 Hz, 1H), 7.39-7.49 (m, 5H), 7.55 (apparent t, J = 7.3 Hz, 1H), 7.70 (brs, 1H), 7.70-
7.83 (m, 3H), 7.95 (apparent d, J = 7.6 Hz, 2H). HPLC (a combination of Chiralpak AD-H and AS-H, hexane/2-
propanol = 39:1, flow rate 1.0 mL/min, UV detection at 254 nm) tR = 8.0 min (S), 9.3min (R). []20D +7.1 (c 1.02,
CHCl3) for 97% ee.
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3-(2-Thienyl)-1-phenylbutan-1-one (2j).50 According to General Procedure B, the reaction of enone 1j as
yellow oil (67.6 mg, 0.3 mmol) and trichlorosilane (2.91 M, 0.21 mL) with (S)-BINAPO (19.8 mg, 0.03 mmol) in
CH2Cl2 (1.2 mL) at 0 °C for 20 h gave 2j (55.1 mg, 80% yield, 95% ee). TLC Rf 0.33 (hexane/CH2Cl2 = 1:1, stained
1
blue-green with anisaldehyde). H NMR (400 MHz, CDCl3)  1.42 (d, J = 6.9 Hz, 3H), 3.20 (dd, J = 16.7, 8.0 Hz,
1H), 3.37 (dd, J = 16.7, 5.7 Hz, 1H), 3.85 (ddq, J = 8.0, 5.7, 6.9, 1H), 6.87 (d, J = 3.7 Hz, 1H), 6.92 (dd, J = 5.0, 3.8 Hz,
1H), 7.13 (brd, J = 5.0 Hz, 1H), 7.46 (apparent t, J = 7.8 Hz, 2H), 7.56 (apparent t, J = 7.3 Hz, 1H), 7.95 (apparent d,
J = 7.3 Hz, 2H). HPLC (a combination of CHIRALPAK AD-H and AS-H, hexane/2-propanol= 39:1, flow rate 1.0
mL/min, UV detection at 254 nm) tR = 5.4 min (S), 5.9 min (R). []20D +7.7 (c 1.09, EtOH) for 95% ee.
3-Cyclopropyl-1-phenylbutan-1-one (2k). According to General Procedure B, the reaction of enone 1k (18.6
mg), 2,6-lutidine (12 L) and trichlorosilane (3.19 M, 0.06 mL) with (S)-BINAPO (6.5 mg) at 0 °C for 24 h gave
2k as colorless oil (18.0 mg, 96% yield, 40% ee). TLC Rf 0.42 (hexane/CH2Cl2 = 1:1, stained purple with
1
anisaldehyde). IR (ATR) 2959, 1682, 1448, 1279, 1171, 1010, 753, 689 cm–1. H NMR (400 MHz, CDCl3)  0.04-
0.17 (m, 2H), 0.33-0.50 (m, 2H), 0.59-0.70 (m, 1H), 1.05 (d, J = 6.9 Hz, 3H), 1.33-1.48 (m, 1H), 2.92 (dd, J = 15.6,
8.2 Hz, 1H), 3.10 (dd, J = 15.6, 5.5 Hz, 1H), 7.46 (apparent t, J = 7.8 Hz, 2H), 7.55 (apparent t, J = 7.1 Hz, 1H), 7.96
(apparent d, J = 7.8 Hz, 2H). 13C{1H} NMR (100 MHz)  3.9, 4.4, 18.2, 20.1, 35.8, 46.1, 128.1, 128.5, 132.8, 137.5,
200.4. HRMS (ESI+) Calcd for C13H16NaO (M+Na+) 211.1093 found 211.1094. HPLC (Chiralpak AY-H, hexane/2-
propanol = 49:1, flow rate 1.0 mL/min, UV detection at 220 nm) tR = 11.9 min (S), 12.6 min (R). []21 –3.2 (c
D
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1.38, CHCl3) for 40% ee.
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4,4-Dimethyl-1,3-diphenylpentan-1-one (2l). According to General Procedure B, the reaction of enone 1l
(20.6 mg), 2,6-lutidine (12 L) and trichlorosilane (3.19 M, 0.063 mL) with (S)-BINAPO (6.6 mg) at rt for 48 h
gave 2l as colorless oil (18.5 mg, 89% yield, 93% ee). TLC Rf 0.17 (hexane/CH2Cl2 = 2:1, stained blue with
anisaldehyde). IR (ATR) 2959, 1683, 1448, 1365, 1288, 1214, 1178, 750, 689 cm–1. 1H NMR (400 MHz, CDCl3) 
0.88 (d, J = 6.9 Hz, 3H), 0.94 (s, 9H), 2.02 (ddq, J = 10.5, 2.8, 6.9 Hz, 1H), 2.64 (dd, J = 15.6, 10.5 Hz, 1H), 3.10 (dd,
J = 15.6, 2.8 Hz, 1H), 7.46 (apparent t, J = 7.6 Hz, 2H), 7.56 (apparent t, J = 7.3 Hz, 1H), 7.95 (apparent d, J = 7.3
Hz, 2H). 13C{1H} NMR (100 MHz)  15.1, 27.3, 33.0, 39.1, 41.5, 128.1, 128.5, 132.8, 137.5, 201.2. HRMS (EI+)
Calcd for C14H20O (M+) 204.1514, found 204.1520. HPLC (Chiralpak AY-H, hexane/2-propanol = 49:1, flow rate
1.0 mL/min, UV detection at 220 nm) tR = 5.7 min (S), 6.4 min (R). []17D –42.3 (c 1.71, CHCl3) for 93% ee (S).
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2-Methyl-5-phenylhexan-3-one (2m).51 According to General Procedure B, the reaction of enone 1m (37.6
mg) and trichlorosilane (3.13 M, 0.13 mL) with (S)-BINAPO (13.2 mg) at 0 °C for 24 h gave 2m as colorless oil
(31.6 mg, 83%, 92% ee). TLC Rf 0.54 (hexane/Et2O = 6:1, stained purple with anisaldehyde). 1H NMR (400 MHz,
CDCl3)  0.98 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 1.25 (d, J = 6.9 Hz, 3H), 2.48 (sept, J = 6.9 Hz, 1H), 2.67
(dd, J = 16.5, 8.2 Hz, 1H), 2.75 (dd, J = 16.5, 6.0 Hz, 1H), 3.34 (ddq, J = 8.2, 6.0, 6.9 Hz, 1H), 7.16-7.23 (m, 3H),
7.25-7.32 (m, 2H). HPLC (Chiralpak AD-H, hexane/2-propanol = 49:1, flow rate 1.0 mL/min, UV detection at 254
nm) tR = 4.3 min (S), 4.6 min (R). []20D +30.5 (c 1.00, CHCl3) for 92% ee (S) [lit.47 []25D +19.7 (c 1.00, CHCl3) for
65% ee (S)].
5-(4-Methoxyphenyl)-2-methylhexan-3-one (2n). According to General Procedure B, the reaction of enone
1n (43.7 mg) and trichlorosilane (3.19 M, 0.13 mL) with (S)-BINAPO (13.1 mg) at 0 °C for 20 h gave 2n as
colorless oil (43.6 mg, 99%, 93% ee). TLC Rf 0.16 (hexane/CH2Cl2 = 1:1, stained red-purple with anisaldehyde).
IR (ATR) 2965, 1708, 1512, 1244, 1034, 828, 551 cm–1. 1H NMR (600 MHz, CDCl3)  0.97 (d, J = 6.9 Hz, 3H), 1.03
(d, J = 6.9 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 2.47 (sept, J = 6.9 Hz, 1H), 2.63 (dd, J = 16.5, 7.8 Hz, 1H), 2.72 (dd, J =
16.5, 6.4 Hz, 1H), 3.29 (ddq, J = 7.8, 6.0, 6.9 Hz, 1H), 3.78 (s, 3H), 6.83 (apparent d, J = 8.7 Hz, 2H), 7.13 (apparent
d, J = 8.7 Hz, 2H). 13C{1H} NMR (100 MHz)  17.8, 17.9, 21.9, 34.4, 41.2, 49.1, 55.1, 113.7, 127.6, 138.5, 157.8,
213.6. LRMS (FAB+, CHCl3+NBA) m/z 220 (M + H+, 45), 135 (CH3CH+C6H4OMe, 100). HRMS (FAB+, CHCl3+NBA)
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Calcd for C14H20O2 (M + H+) 220.1463, found 220.1460. HPLC (Chiralpak AD-H, hexane/2-propanol = 49:1, flow
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rate 1.0 mL/min, UV detection at 220 nm) tR = 5.9 min (S), 6.7 min (R). []23D +31.8 (c 1.00, CHCl3) for 92% ee.
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5-(4-Chlorophenyl)-2-methylhexan-3-one (2o). According to General Procedure B, the reaction of enone 1o
(44.5 mg) and trichlorosilane (3.19 M, 0.13 mL) with (S)-BINAPO (13.1 mg) at 0 °C for 24 h gave 2o as colorless
oil (26.0 mg, 58%, 93% ee). TLC Rf 0.29 (hexane/CH2Cl2 = 1:1, stained purple with anisaldehyde). IR (ATR) 2968,
1710, 1683, 1601, 1492, 1093, 1011, 823, 534 cm–1. 1H NMR (400 MHz, CDCl3)  0.98 (d, J = 6.9 Hz, 3H), 1.04 (d, J
= 6.9 Hz, 3H), 1.23 (d, J = 6.9 Hz, 3H), 2.48 (sept, J = 6.9 Hz, 1H), 2.65 (dd, J = 16.5, 7.6 Hz, 1H), 2.73 (dd, J = 16.5,
6.9 Hz, 1H), 3.33 (ddq, J = 7.6, 6.9, 6.9 Hz, 1H), 7.15 (apparent d, J = 8.2 Hz, 2H), 7.25 (apparent d, J = 8.2 Hz, 2H).
13C{1H} NMR (100 MHz)  17.8, 18.0, 21.8, 34.5, 41.3, 48.7, 128.2, 128.5, 131.8, 144.9, 213.1. HRMS (ESI+) Calcd
for C13H17ClNaO (M+Na+) 247.0860 found 247.0860. HPLC (Chiralpak AD-H, hexane/2-propanol = 49:1, flow
rate 1.0 mL/min, UV detection at 220 nm) tR = 4.6 min (S), 5.1 min (R). []18D +33.2 (c 1.00, CHCl3) for 93% ee.
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1-(4-Methoxyphenyl)-3-phenylbutan-1-one (2p).48, According to General Procedure B, the reaction of
enone 1p (19.0 mg) and trichlorosilane (3.19 M, 0.05 mL) with (S)-BINAPO (4.9 mg) at 0 °C for 24 h gave 2p as
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colorless oil (13.3 mg, 70%, 97% ee). TLC Rf 0.11 (hexane/CH2Cl2 = 1:1, stained brown with anisaldehyde). H
NMR (400 MHz, CDCl3)  1.33 (d, J = 6.9 Hz, 3H), 3.13 (dd, J = 16.0, 8.5 Hz, 1H), 3.23 (dd, J = 16.0, 5.5 Hz, 1H),
3.49 (ddq, J = 8.5, 5.5, 6.9 Hz, 1H), 3.86 (s, 3H), 6.91 (apparent d, J = 8.9 Hz, 2H), 7.17-7.34 (m, 5H), 7.92
(apparent d, J = 8.9 Hz, 2H). HPLC (Chiralpak AS-H, hexane/2-propanol = 9/1, flow rate 1.0 mL/min, UV
detection at 254 nm) tR = 8.2 min (S), 9.0 min (R). []21D –8.8 (c 1.02, CHCl3) for 97% ee.
1-(4-chlorophenyl)-3-phenylbutan-1-one (2q).48 According to General Procedure B, the reaction of enone 1q
(13.9 mg) and trichlorosilane (3.19 M, 0.03 mL) with (S)-BINAPO (3.5 mg) at 0 °C for 24 h gave 2q as colorless
oil (12.2 mg, 87%, 98% ee). TLC Rf 0.31 (hexane/CH2Cl2 = 1:1, stained brown with anisaldehyde). 1H NMR (400
MHz, CDCl3)  1.34 (d, J = 6.9 Hz, 3H), 3.15 (dd, J = 16.5, 8.2 Hz, 1H), 3.27 (dd, J = 16.5, 6.0 Hz, 1H), 3.48 (ddq, J =
8.2, 6.0, 6.9 Hz, 1H), 7.17-7.34 (m, 5H), 7.41 (apparent d, J = 8.7 Hz, 2H), 7.86 (apparent d, J = 8.7 Hz, 2H). HPLC
(a combination of Chiralpak AD-H and AS-H, hexane/2-propanol = 39:1, flow rate 1.0 mL/min, UV detection at
254 nm) tR = 5.2 min (S), 5.6 min (R). []29D –5.5 (c 1.15, CHCl3) for 98% ee.
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1-Cyclohexyl-3-phenylbutan-1-one (2r). According to General Procedure B, the reaction of enone 1r (10.4
mg) and trichlorosilane (3.12 M, 0.03 mL) with (S)-BINAPO (3.0 mg) at 0 °C for 24 h gave 2r as colorless oil (8.1
mg, 76%, 89% ee). IR (ATR) 2919, 2853, 1705, 1348, 762, 698 cm–1. TLC Rf 0.26 (hexane/CH2Cl2 = 1:1, stained
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light blue with anisaldehyde). H NMR (400 MHz, CDCl3)  1.12-1.45 (m, 6H), 1.24 (d, J = 6.9 Hz, 3H), 1.58-1.85
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(m, 4H), 2.17-2.27 (m, 1H) 2.66 (dd, J = 16.5, 8.2 Hz, 1H), 2.69 (dd, J = 16.5, 6.4 Hz, 1H), 3.33 (ddq, J = 8.2, 6.4, 6.9
Hz, 1H), 7.15-7.23 (m, 3H), 7.25-7.31 (m, 2H). 13C{1H} NMR (100 MHz)  21.8, 25.7, 25.8, 28.1, 28.3, 35.1, 49.1,
51.2, 126.2, 126.8, 128.4, 146.6, 210.1. HRMS (ESI+) Calcd for C16H22NaO (M+Na+) 253.1563 found 253.1558.
HPLC (Chiralpak AD-H, hexane/2-propanol = 49:1, flow rate 1.0 mL/min, UV detection at 220 nm) tR = 5.3 min
(S), 5.7 min (R). []22D +22.9 (c 1.00, CHCl3) for 89% ee.
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1-Cyclopropyl-3-phenylbutan-1-one (2s). According to General Procedure B, the reaction of enone 1s (70.5
mg) and trichlorosilane (3.12 M, 0.24 mL) with (S)-BINAPO (24.9 mg) at 0 °C for 24 h gave 2s as colorless oil
(64.4 mg, 90%, 89% ee). TLC Rf 0.53 (hexane/AcOEt = 10:1, stained black with anisaldehyde). IR (ATR) 2963,
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1695, 1384, 1073, 1010, 762, 699 cm–1. H NMR (400 MHz, CDCl3)  0.74-0.86 (m, 2H), 0.91-1.01 (m, 2H), 1.28
(d, J = 6.9 Hz, 3H), 1.83-1.90 (m, 1H), 2.77 (dd, J = 16.0, 8.2 Hz, 1H), 2.87 (dd, J = 16.0, 6.4 Hz, 1H), 3.35 (ddq, J =
8.2, 6.4, 6.9 Hz, 1H), 7.15-7.33 (m, 5H). 13C{1H} NMR (100 MHz)  10.6, 10.7, 20.9, 21.9, 35.6, 51.9, 126.2, 126.8,
128.4, 146.3, 209.9. HRMS (ESI+) Calcd for C13H16NaO (M+Na+) 211.1093 found 211.1093. HPLC (Chiralpak AD-
H, hexane/2-propanol = 49:1, flow rate 1.0 mL/min, UV detection at 220 nm) tR = 5.4 min (S), 5.8 min (R). []21
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+44.8 (c 1.00, CHCl3) for 89% ee.
Asymmetric Conjugate Reduction of ar-Atlantone to ar-Turmerone. To a stirred solution of (S)-4,4’-Br2-
BINAPO (24.4 mg, 0.03 mmol), ar-atlantone (1t) (214.3 mg, 1.0 mmol) and 2,6-lutidine (0.12 mL, 1.0 mmol) in
CH2Cl2 (4.0 mL) was added trichlorosilane (3.19 M CH2Cl2; 0.63 mL) at –78 °C. The mixture was stirred at −78 °C
for 24 h. The reaction was quenched with saturated NaHCO3 (5 mL). The mixture was stirred for 1 h at rt,
filtered through a Celite pad and extracted with AcOEt (3 × 20 mL). The combined organic layers were washed
with brine, dried over anhydrous MgSO4, filtered, and evaporated. The residue was purified by silica gel column
chromatography (hexane/CH2Cl2 = 1:3) to give (S)-ar-turmerone (2t) (197.0 mg, 91% yield, 92% ee, 2t:2t' =
99:1).
The reaction of ar-atlantone (1t) (1.072 g, 5 mmol) with (R)-4,4’-Br2-BINAPO (121.9 mg, 0.03 equiv), 2,6-
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lutidine (0.58 mL) and trichlorosilane (3.12 M CH2Cl2; 3.13 mL) gave (R)-ar-turmerone (2t) as yellow oil (918.6
mg, 85%, 92% ee, 2t:2t' = 98:2).
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recovered quantitatively by eluting with CH2Cl2/MeOH (10:1) and reused after recrystallization.26
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ar-Turmerone (2t).22 TLC: Rf 0.45 (hexane/CH2Cl2 = 1:1, stained black with anisaldehyde); H NMR (400 MHz,
CDCl3)  1.24 (d, J = 6.8 Hz, 3H), 1.86 (d, J = 0.9 Hz, 3H), 2.11 (d, J = 1.4 Hz, 3H), 2.31 (s, 3H), 2.61 (dd, J = 15.6, 8.3
Hz, 1H), 2.71 (dd, J = 15.6, 6.0 Hz, 1H), 3.29 (ddq, J = 8.3, 6.0, 6.8 Hz, 1H), 6.03 (sept, J = 1.4 Hz, 1H), 7.07-7.13 (m,
4H). HPLC (Chiralpak AD-3, hexane/2-propanol = 29:1, 1.0 mL/min, 220 nm) tR = 4.5 min (S), 5.0 min (R). [α]24
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+56.4 (c 1.00, CHCl3) for 92% ee (S). With (R)-4,4’-Br2-BINAPO instead of (S)-catalyst: []22 –56.4 (c 1.00,
D
CHCl3) for 92% ee (R) [lit.18f []22D –60.6 (c 1.00, CHCl3) for 98% ee (R)].
(E)-6-Methyl-2-(p-tolyl)hept-2-en-4-one (2t').53 TLC: Rf 0.48 (hexane/CH2Cl2 = 1:1, stained dark green with
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anisaldehyde). H NMR (500 MHz)  0.96 (d, J = 6.3 Hz, 6H), 2.14-2.25 (m, 1H), 2.37 (s, 3H), 2.40 (d, J = 6.9 Hz,
2H), 2.53 (d, J = 1.4 Hz, 3H), 6.49 (d, J = 1.4 Hz, 1H), 7.18 (apparent d, J = 8.1 Hz, 2H), 7.39 (apparent d, J = 8.1 Hz,
2H). 13C{1H} NMR (125 MHz)  18.2, 21.2, 22.7, 25.3, 53.9, 123.8, 126.3, 129.2, 139.2, 139.6, 153.5, 201.5. HRMS
(ESI+) Calcd for C15H20NaO (M+Na+) 239.1406 found 239.1404.
Control Experiment 1: Regioselective Reduction of Dienone 1u. According to General Procedure B, the
reaction of 1u (20.6 mg, 0.10 mmol), HSiCl3 (3.33 M CH2Cl2; 0.06 mL), 2,6-lutidine (12 L, 0.10 mmol), and (S)-
BINAPO (6.5 mg, 0.01 mmol) at 0 °C for 21 h gave 2u as colorless oil (6.8 mg, 33% yield, 38% ee) and 2u' as
colorless oil (10.4 mg, 50% yield).
(S)-6-Cyclohexyl-2-methylhept-2-en-4-one (2u). TLC: Rf 0.52 (hexane/ CH2Cl2 = 1:1, stained yellow with
anisaldehyde). IR (ATR) 2924, 2852, 1686, 1615, 1448, 1378 cm–1. 1H NMR (400 MHz)  0.84 (d, J = 6.9 Hz, 3H),
0.89-1.31 (m, 5H), 1.58-1.68 (m, 3H), 1.68-1.78 (m, 2H), 1.88 (s, 3H), 1.84-1.96 (m, 1H), 2.14 (s, 3H), 2.15 (dd, J =
15.1, 9.2 Hz, 1H), 2.44 (dd, J = 15.1, 4.8 Hz, 3H), 6.06 (s, 1H). 13C{1H} NMR (100 MHz)  16.6, 20.6, 26.6, 26.7, 27.6,
29.1, 30.4, 34.7, 42.9, 49.1, 124.2, 154.2, 201.7. LRMS (EI+) m/z 208 (M+, 9), 125 (Me2C=CHCOCHC+Me, 51), 98
(Me2C=CHC(OH+)C=CH2, 99), 83 (Me2C=CHCO+, 100). HRMS (ESI+) Calcd for C14H24NaO (M+Na+) 231.1719
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found 231.1717. HPLC (Chiralpak AY-H, hexane/2-propanol= 99:1, 1.0 mL/min, 254 nm) tR = 5.7 min (S), 6.1
min (R). []20D +8.3 (c 0.31, CHCl3) for 86% ee (S).
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anisaldehyde). H NMR (400 MHz)  0.92 (d, J = 6.7 Hz, 6H), 1.11-1.36 (m, 5H), 1.66-1.84 (m, 5H), 1.94 (tt, J =
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11.0, 3.2 Hz, 11 H), 2.06-2.18 (m, 1H), 2.10 (d, J = 0.9 Hz, 3H), 2.29 (d, J = 6.9 Hz, 2H), 6.03 (s, 1H). 13C{1H} NMR
(100 MHz)  17.8, 22.7, 25.2, 26.1, 26.4, 31.4, 48.9, 53.6, 121.8, 163.0, 201.9.
Control Experiment 2: Regioselective Reduction of Dienone 1v. According to General Procedure B, the
reaction of 1v (17.1 mg, 0.064 mmol), HSiCl3 (2.64 M CH2Cl2; 0.05 mL), 2,6-lutidine (7.4 L, 0.064 mmol), and
(S)-BINAPO (4.2 mg, 0.0064 mmol) at –40 °C for 24 h gave 2v as yellow oil (13.3 mg, 77% yield, 86% ee) and 2v'
as yellow oil (3.8 mg, 22% yield).
(S,E)-2-Cyclohexyl-6-phenylhept-2-en-4-one (2v). TLC: Rf 0.45 (hexane/CH2Cl2 = 1:1, stained red with
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anisaldehyde). IR (ATR) 2924, 2852, 1731, 1686, 1608, 1450, 1261, 1119, 1073, 1014, 762, 699 cm–1. H NMR
(400 MHz)  1.08-1.35 (m, 5H), 1.27 (d, J = 6.9 Hz, 3H), 1.63-1.83 (m, 5H), 1.91 (tt, J = 11.4, 2.8 Hz, 1H), 2.06 (s,
3H), 2.65 (dd, 1H, J = 15.6, 8.2 Hz), 2.74 (dd, 1H, J = 15.6, 6.2 Hz), 3.31 (ddq, J = 18.2, 6.2, 6.9 Hz, 1H), 5.97 (s, 1H),
7.15-7.32 (m, 5H). 13C{1H} NMR (100 MHz)  17.9, 22.0, 26.1, 26.3, 31.3, 35.9, 48.9, 52.8, 121.7, 126.1, 126.8,
128.4, 146.7, 163.5, 200.5. HRMS (ESI+) Calcd for C19H26NaO (M+Na+) 293.1876 found 293.1869. HPLC
(Chiralpak AD-3, hexane/2-propanol = 29:1, 1.0 mL/min, 220 nm) tR = 10.8 min (S), 11.8 min (R). []22D +32.5 (c
0.57, CHCl3) for 86% ee (S).
(E)-6-Cyclohexyl-2-phenylhept-2-en-4-one (2v'). TLC: Rf 0.48 (hexane/CH2Cl2 = 1:1, stained yellow with
anisaldehyde). IR (ATR) 2922, 2851, 1682, 1599, 1447, 1376, 1056, 756, 696 cm–1. 1H NMR (400 MHz)  0.88 (d,
J = 6.9 Hz, 3H), 0.93-1.33 (m, 5H), 1.60-1.80 (m, 5H), 1.91-2.03 (m, 1H), 2.29 (dd, J = 15.1, 9.2 Hz, 1H), 2.55 (d, J =
1.4 Hz, 1H), 2.61 (dd, J = 15.1, 4.9 Hz, 1H), 6.49 (q, J = 1.4 Hz, 1H), 7.35-7.42 (m, 3H), 7.46-7.51 (m, 2H). 13C{1H}
NMR (100 MHz)  16.7, 18.3, 26.6, 26.7, 26.8, 29.1, 30.4, 34.9, 42.9, 49.7, 124.7, 126.5, 128.5, 129.0, 142.7, 153.3,
202.1. LRMS (EI+) m/z 270 (M +, 2), 187 (MeCH+CH2COCH=CMePh, 13), 160 (CH2=C(O+H)CH=CMePh, 59), 145
(+COCH=CMePh, 100). HRMS (EI+) Calcd for C19H26O (M +) 270.1984, found 270.1987. The enantiomeric excess
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