Regio- and Enantioselective Copper-Catalyzed 1,4-Conjugate Addition of Trimethylaluminium to Linear α,β,γ,δ-Unsaturated Alkyl Ketones

Article abstract of DOI:10.1002/adsc.201600375

A regio- and enantioselective copper-catalyzed 1,4-conjugate addition of trimethylaluminium to linear δ-aryl-substituted α,β,γ,δ-unsaturated alkyl ketones was developed. A series of γ,δ-unsaturated alkyl ketones were obtained in good yields with high regio- and enantioselectivity (up to 88% ee and 96:4 dr). Expansion of the reaction scope to substrates containing aromatic heterocycles also afforded good yields and enantioselectivities (up to 91% ee) with very high regioselectivities, exclusively providing the single 1,4-products. (Figure presented.).

Full text of DOI:10.1002/adsc.201600375

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DOI: 10.1002/adsc.201600375
Regio- and Enantioselective Copper-Catalyzed 1,4-Conjugate
Addition of Trimethylaluminium to Linear a,b,g,d-Unsaturated
Alkyl Ketones
Xiaoting Wu,a Fang Xie,a,* Zheng Ling,a Liang Tang,a and Wanbin Zhanga,*
a
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
Peopleꢀs Republic of China
Fax : (+86)-21-5474-3265; phone: (+86)-21-5474-3265; e-mail: xiefang@sjtu.edu.cn or wanbin@sjtu.edu.cn
Received: April 6, 2016; Revised: July 2, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600375.
Abstract: A regio- and enantioselective copper-cata- yields and enantioselectivities (up to 91% ee) with
lyzed 1,4-conjugate addition of trimethylaluminium very high regioselectivities, exclusively providing the
to linear d-aryl-substituted a,b,g,d-unsaturated alkyl single 1,4-products.
ketones was developed. A series of g,d-unsaturated
alkyl ketones were obtained in good yields with high Keywords: asymmetric catalysis; 1,4-conjugate addi-
regio- and enantioselectivity (up to 88% ee and 96:4 tion reaction; copper-catalyzed addition; linear
dr). Expansion of the reaction scope to substrates a,b,g,d-unsaturated alkyl ketones; organoaluminium
containing aromatic heterocycles also afforded good reagents
Introduction
larly methyl-substituted derivatives, are often found
in natural products and biologically active compounds
In asymmetric conjugate additions (ACA), excellent (Figure 2).[13–15] Therefore the ACA of methyl organo-
regio- and stereoselectivities have been achieved in metallic reagents represents a particularly important
reactions involving transition metal-catalyzed a,b-un- synthetic methodology.[16] Due to the importance of
saturated Michael acceptors, especially for copper-cat- this structural motif, significant resources have been
alyzed systems.[1] However, the use of a,b,g,d-unsatu- directed towards the development of efficient regio-
rated Michael acceptors[2–12] in ACA remains chal- and enantioselective procedures.
lenging because of the difficulties encountered in con-
trolling regioselectivity (preferential formation of 1,2- 1,4-ACA reactions have been reported by Alexa-
, 1,4-, and 1,6-products) and obtaining high enantiose-
kis[12a,b] and our group.[12c] These methodologies uti-
However, only three examples of copper-catalyzed
AHCTUNGTRENNUNG
lectivity, especially for reactions involving linear lized linear nitrodienes and nitroenynes, a,b,g,d-unsa-
a,b,g,d-unsaturated ketones. Since Hayashiꢀs pioneer-
ing work in 2004,[4a] several successful examples of
rhodium,[4] iridium,[5] and cobalt[6] catalyzed 1,6-ACA
with aryl organometallic reagents have been reported.
Copper-catalyzed 1,6-ACA with alkyl organometallic
reagents or silane reagents have also been realized by
Fillion,[7] Alexakis,[8] Feringa,[9] Hoveyda[10] and Cam-
pagne.[11]
The use of a,b,g,d-unsaturated Michael acceptors in
1,6-ACA reactions often leads to the formation of
1,6-adducts rather than the valuable 1,4-adducts. The
chiral products resulting from 1,4-ACA, especially
linear a,b,g,d-unsaturated ketones which contain a C=
C double bond, are versatile building blocks that can
be easily transformed into many other functional
groups (Figure 1). Such chiral intermediates, particu- Figure 1. Transformations of g,d-unsaturated alkyl ketones.
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eton of the 1,4-adducts, we herein report a copper-cat-
alyzed 1,4-ACA of trimethylaluminium to linear
a,b,g,d-unsaturated alkyl ketones with high regio- and
enantioselectivity, utilizing ligands bearing a D2-sym-
metric biphenyl backbone previously developed by
our group.[17]
Results and Discussion
In our previous research, a new highly regio- and
enantioselective copper-catalyzed asymmetric 1,4-con-
jugate addition of Grignard reagents to d-aryl-substi-
tuted a,b,g,d-unsaturated aryl ketones was developed,
utilizing 1,2-disubstituted planar ligands.[12c] However,
when linear d-aryl-substituted a,b,g,d-unsaturated
alkyl ketones were subjected to our reaction condi-
tions, only the 1,2-addition products were obtained,
and none of the desired 1,4-adducts were detected.
Figure 2. Representative chiral natural products and bioac-
tive compounds.
turated cyclic enones and linear a,b,g,d-unsaturated Based on previous reports and our research, it has
aryl ketones, all of which rely on specific structural been shown that the chiral catalyst affects not only
features of the substrates.
enantioselectivity but also regioselectivity. Firstly, 1,4-
Due to the importance of the methyl group in natu- conjugate additions of trimethylaluminium reagent
ral products and the importance of the structural skel- and dimethylzinc reagent (for comparison with
Table 1. Ligand and organometallic reagent screening.[a]
Entry
Ln
MR
Temperature [oC]
Conversion [%]
1,4/1,6[b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
–
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlEt3
À30
À30
À30
À30
À30
À30
À30
À30
r.t.
100
100
10
trace[d]
trace[d]
trace
88/12
88/12
96/4
87/13
82/18
0/100
5
5
À42
À68
78
87
À77
2
n.d.
–
–
89
100
100
100
48
trace
100
100
9
ZnMe2
MeMgBr
MeMgBr
10[e]
11[e,f]
À80
1,2-adduct
1,2-adduct
À80
[a]
The reaction of 1a (0.200 mmol) with MR (1.2 equiv.) was performed in THF for 12 h in the presence of the chiral com-
plex formed in situ from Cu(OAc)2·H2O (0.005 mmol, 2.5 mol%) and ligand (0.010 mmol, 5.0 mol%).
Determined by H NMR spectroscopy.
Determined by HPLC analysis.
Unknown components.
[b]
[c]
[d]
[e]
[f]
1
The reaction was performed in dichloromethane (DCM) for 15 h.
In the absence of Cu(OAc)2·H2O.
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Grignard reagents) to linear a,b,g,d-unsaturated alkyl amined (Table 2, entries 1–4). Cu(OAc)2·H2O provid-
ketones were screened using different chiral ligands ed the most satisfactory result considering regio- and
(Table 1).
enantioselectivity as well as yield (entry 4). A careful
Phosphoramidite ligands L1 and L2 possessing only screening of the solvent showed that THF was effec-
axial chirality were first used with trimethylaluminium tive and gave the best result (entries 4–6). Besides the
as nucleophile. The reaction proceeded to completion, copper salt and solvent, the optimal reaction tempera-
however only trace amounts of racemic 1,4- or/and ture was next investigated (entries 4 and 7–9). Excel-
1,6-conjugate addition products were obtained lent results were maintained when the temperature
(Table 1, entries 1 and 2). BINOL phosphoramidite li- was increased from À308C to À58C or room tempera-
gands L3 and L4 bearing chiral amine substituents ture (1,4:1,6=95:5) but enantioselectivity decreased
were next examined (entries 3 and 4). L4 provided (entry 4 vs. 7 and 8). Additionally, reducing the reac-
the desired 1,4-adduct as the main product with mod- tion temperature to À508C, was detrimental to the re-
erate enantioselectivity (entry 4). Ligands (L5–L7) action, which provided decreased regio- and enantio-
bearing a D2-symmetric biphenyl backbone were also selectivity with much lower reactivity (entry 4 vs. 9).
employed because they could be easily modified at Taking these factors into account, we chose À308C as
the 3,3’,5,5’-positions, and because of their excellent the optimal reaction temperature.
performance in previous 1,4-ACA reactions as report-
After the optimized conditions were identified, the
ed by our group (entries 5–7).[17] The substituents at scope of the 1,4-ACA for linear a,b,g,d-unsaturated
the 3,3’,5,5’-positions had an obvious effect on both alkyl ketones was then examined. The substrates can
regio- and enantioselectivity.[18] To our delight, the be easily prepared via an aldol reaction of commer-
1,4-adduct was obtained with excellent regioselectivity cially available unsaturated aldehydes with alkyl ke-
(96:4) and good enantioselectivity (87% ee) when L6 tones.[20] The reaction proceeded smoothly with
was used (entry 6). Then, triethylaluminium was a wide range of substrates (Scheme 1). The influence
tested under these conditions, the 1,4-adduct was ob- of the R1 group was first investigated. Increasing the
tained with good regioselectivity (82:18) but almost size of the R1 group (1a–c), led to a reduction in both
no enantioselectivity (2% ee) (entry 8). Subsequently, enantioselectivity and regioselectivity, and yield.
other organometallic reagents were investigated with When compound 1c was used, a sharp drop in reactiv-
this asymmetric catalytic system. Dimethylzinc gave ity was observed. When R1 was changed to a CF3
its corresponding 1,6-adduct with lower reactivity group, the 1,4-adduct 2d was obtained exclusively in
(entry 9) and methylmagnesium bromide afforded 71% yield but with much lower enantioselectivity
only the 1,2-adduct with complete conversion (en- (10% ee). When R1 was a methyl group, and R2 was
tries 9 and 10).
either a phenyl or substituted phenyl (1e–l), excellent
Optimization of this regio- and enantioselective re- regioselectivities (1,4:1,6=93:7–95:5), good enantio-
action was thus carried out using L6 as chiral ligand. selectivities (81–88% ee) and moderate to good yields
The influence of copper salts on the reaction was ex- (63–74%) were obtained (2e–l), irrespective of the
Table 2. Copper salts and temperature screening.[a]
o
Entry
Cu salt
Solvent
Temperature [ C]
Conversion [%]
1,4/1,6[b]
ee [%][c,d]
1
2
3
4
5
6
7
8
9
CuTC
Cu(OTf)2
Cu(OAc)2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
THF
THF
THF
THF
toluene
DCM
THF
THF
THF
À30
À30
À30
À30
À30
À30
r.t.
100
100
75
100
100
100
100
100
26
93/7
86/14
95/5
96/4
92/8
87/13
95/5
95/5
82/18
87
80
82
87
45
64
63
76
76
À5
À50
[a]
The reaction of 1a (0.200 mmol) with AlMe3 (1.2 equiv.) was performed for 12 h in the presence of the chiral complex
formed in situ from CuX (0.005 mmol, 2.5 mol%) and L6 (0.010 mmol, 5.0 mol%).
[b]
[c]
[d]
1
Determined by H NMR spectroscopy.
Determined by HPLC analysis.
The absolute configuration of 2a was determined as R according to ref.[19]
.
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Scheme 1. Substrate scope. The reactions of 1a–n (0.200 mmol) with AlMe3 (1.2 equiv.) were performed in THF at À308C
for 12 h in the presence of the chiral complex formed in situ from Cu(OAc)2·H2O (0.005 mmol, 2.5 mol%) and L6
(0.010 mmol, 5.0 mol%).
electronic properties or substitution pattern of the ar-
To demonstrate the potential utility of these chiral
omatic ring. However, when R2 was changed to an n- 1,4-adducts, linear a,b,g,d-unsaturated ketones con-
propyl group, a mixture of 1,2-, 1,4-, 1,6-adducts and taining a C=C double bond, transformations of 2a
unidentified products was obtained. Finally, the effect were carried out (Scheme 3): 2a could be reduced
of steric-hindrance on regio- and enantioselectivity into alcohol 4a with NaBH4 in 98% yield with 89% ee
was investigated (1m and 1n). As expected, the pres- and 1.2:1 dr and 2a could also be oxidized to epoxide
ence of a methyl group at the g-position provided 2m 5a by m-CPBA in 78% yield with high diasteroselec-
with improved excellent regioselectivity (1,4:1,6> tivity (25:1). These examples show the possible appli-
99:1) and 63% ee. A substrate bearing a methyl group cations of chiral 1,4-adducts.
at the a-position provided only the 1,2-addition prod-
uct (2n) with low reactivity. This result is similar to
copper-catalyzed 1,2-additions of Grignard reagents Conclusions
to a-methy-substituted a,b-unsaturated ketones[21]
.
In addition, the reaction scope was expanded to in- In summary, a copper-catalyzed 1,4-conjugate addi-
clude substrates bearing aromatic heterocycles such as tion of trimethylaluminium reagent to linear d-aryl-
thienyl and furyl rings systems (Scheme 2). The de- substituted a,b,g,d-unsaturated alkyl ketones with
sired products were obtained with good to excellent high regio- and enantioselectivies (up to 88% ee and
enantioselectivities (88–91% ee) and in good yields up to 96/4 for 1,4/1,6) has been developed. The reac-
(70–78%). To our delight, no 1,6-adducts were detect- tion conditions were also suitable for substrates bear-
ed.
ing heterocyclic ring systems, such as thienyl and furyl
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Scheme 2. Expansion of the reaction scope for aromatic heterocycles. The reactions of 1o–r (0.200 mmol) with AlMe3
(1.2 equiv.) were performed at À308C for 12 h in the presence of the chiral complex formed in situ from Cu(OAc)2·H2O
(0.005 mmol, 2.5 mol%) and L6 (0.010 mmol, 5.0 mol%).
(cas: 113388-19-5), 1k (cas:76594-51-9), 1l (cas: 76594-52-0),
1m (cas: 29622-02-4), 1n (cas: 19520-38-8), 1o (cas:113388-
26-4), 1p (cas: 90843–14–4).
(3E,5E)-6-(4-Bromophenyl)hexa-3,5-dien-2-one (1f): 72%
yield; yellow solid; mp 106–1088C; 1H NMR (400 MHz,
CDCl3): d=7.48 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H),
7.30–7.21 (m, 1H), 6.89–6.84 (m, 2H), 6.27 (d, J=15.2 Hz,
1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3): d=198.5,
143.1, 139.9, 135.0, 132.2, 131.1, 128.8, 127.4, 123.4, 27.3;
HR-MS (ESI): m/z=251.0077, calcd. for C12H11BrO [M+
H]+: 251.0072.
(3E,5E)-6-[4-(trifluoromethyl)phenyl]hexa-3,5-dien-2-one
(1g): 69% yield; yellow solid; mp 65–678C; 1H NMR
(400 MHz, CDCl3): d=7.25 (dd, J=8.4, 20.0 Hz, 4H), 7.31–
7.24 (m, 1H), 6.97–6.92 (m, 2H), 6.31 (d, J=15.6 Hz, 1H),
2.32 (s, 3H); 13C NMR (100 MHz, CDCl3): d=198.4, 142.6,
139.5, 139.3, 131.9, 130.8 (q, J=32.6 Hz), 129.2, 127.5, 125.9
(d, J=3.0 Hz), 122.8, 27.7; 19F NMR(376 MHz, CDCl3): d=
À62.72; HR-MS (ESI): m/z=241.0845, calcd. for C13H11F3O
[M+H]+: 241.0840.
Scheme 3. Transformations of 2a.
groups, giving the corresponding 1,4-adducts exclu-
sively in good yields (70–78%) and enantioselectivi-
ties (88–91% ee).
(3E,5E)-6-(2-Methylphenyl)hexa-3,5-dien-2-one
(1h):
1
71% yield; yellow oil; H NMR (400 MHz, CDCl3): d=7.55
(d, J=6.8 Hz, 1H), 7.32 (dd, J=10.8, 15.6 Hz, 1H), 7.26–
7.15 (m, 4H), 6.81 (dd, J=10.8, 15.6 Hz, 1H), 6.26 (d, J=
15.6 Hz, 1H), 2.40 (s, 3H), 2.32 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=198.7, 144.0, 139.0, 136.8, 134.9,
130.9, 130.5, 129.3, 127.8, 126.5, 125.8, 27.6, 20.0; HR-MS
(ESI): m/z=187.1121, calcd. for C13H14O [M+H]+:
187.1123.
Experimental Section
General
1H NMR (400 MHz), 13C NMR (100 MHz) and 19F NMR
(376 MHz) spectra were recorded on a Varian MERCURY
plus-400 spectrometer with TMS as an internal standard.
HR-MS was performed at the Analysis Center of Shanghai
Jiao Tong University. Enantioselectivity was measured by
a high performance liquid chromatography (HPLC) using
Daicel Chiralcel OD-H and AD-H columns with n-hexane/i-
PrOH as an eluent. Column chromatography was performed
using 100–200 mesh silica gel. Melting points were measured
with SGW X-4 micro melting point apparatus.
(3E,5E)-6-(3-Methylphenyl)hexa-3,5-dien-2-one (1i): 75%
1
yield; yellow oil; H NMR (400 MHz, CDCl3): d=7.32–7.22
(m, 4H), 7.14 (d, J=6.8 Hz, 1H), 6.95–6.83 (m, 2H), 6.24
(d, J=15.6 Hz, 1H), 2.36 (s, 3H), 2.31 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=198.6, 143.8, 141.7, 138.6, 136.3,
130.5, 130.3, 128.9, 128.1, 126.6, 124.7, 27.5, 21.6; HR-MS
(ESI): m/z=187.1125, calcd. for C13H14O [M+H]+:
187.1123.
(3E,5E)-6-(2-Naphthyl)hexa-3,5-dien-2-one (1l): 46%
yield; yellow solid; mp 98–1008C; 1H NMR (400 MHz,
CDCl3): d=7.86–7.79 (m, 4H), 7.66 (dd, J=1.6, 8.4 Hz,
Preparation of the Substrates 1
Dienones 1a (cas: 4173-44-8), 1b (cas: 75391-05-8), 1c (cas:
1654-02-0), 1d (cas: 17510-46-2), 1e (cas: 168211-22-1), 1f
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1H), 7.54–7.46 (m, 2H), 7.35 (dd, J=10.8, 15.6 Hz, 1H),
7.12 (d, J=15.6 Hz, 1H), 7.01 (dd, J=10.8, 15.6 Hz, 1H),
6.30 (d, J=15.6 Hz, 1H), 2.34 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=198.6, 143.7, 141.6, 133.9, 133.7, 130.7, 128.8,
128.5, 128.0, 127.2, 127.0, 126.9, 123.6, 27.6; HR-MS (ESI):
m/z=223.1124, calcd. for C16H14O [M+H]+: 223.1123.
(3E,5E)-6-(5-Chloro-2-thienyl)hexa-3,5-dien-2-one (1q):
(m, 1H), 2.57 (dd, J=6.8, 16.0 Hz, 1H), 2.46 (dd, J=7.2,
16.4 Hz, 1H), 2.14 (s, 3H), 1.11 (d, J=6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=207.9, 136.1, 135.4, 132.8,
128.8, 127.7, 127.5, 50.7, 33.0, 30.8, 20.3; HR-MS (ESI): m/
z=223.0975, calcd. for C13H15ClO [M+H]+: 223.0890;
HPLC (Chiralcel AD-H, n-hexane/i-PrOH=99:1, UV=
254 nm, flow rate=0.8 mLminÀ1): tR1 =15.56 min (minor)
and tR2 =18.28 min (major); ee=83%; [a]2D0: À29.5 (c 0.16,
CHCl3).
1
51% yield; yellow solid; mp 29–318C; H NMR (400 MHz,
CDCl3): d=7.18 (dd, J=11.2, 15.6 Hz, 1H), 6.94–6.82 (m,
3H), 6.53 (dd, J=11.2, 15.6 Hz, 1H), 6.22 (d, J=15.6 Hz,
1H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3): d=198.3,
142.6, 140.4, 133.1, 131.8, 130.5, 128.3, 127.4, 126.3, 27.8;
HR-MS (ESI): m/z=213.0146, calcd. for C10H9ClOS [M+
H]+: 213.0141.
(4R,5E)-4-Methyl-6-(4-bromophenyl)-5-hexaen-2-one
(2f): 65% yield (93/7, 1,4/1.6 mixture); colorless oil;
1H NMR (400 MHz, CDCl3): d=7.40 (d, J=8.4 Hz, 2H),
7.19 (d, J=8.4 Hz, 2H), 6.31 (d, J=16.0 Hz, 1H), 6.12 (dd,
J=7.6, 16.0 Hz, 1H), 2.94–2.82 (m, 1H), 2.56 (dd, J=6.8,
16.0 Hz, 1H), 2.46 (dd, J=7.2, 16.4 Hz, 1H), 2.14 (s, 3H),
1.11 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
207.9, 136.5, 135.6, 131.8, 127.9, 127.8, 121.0, 50.7, 33.0, 30.8,
20.3; HR-MS (ESI): m/z=267.0365, calcd. for C13H15BrO
[M+H]+: 267.0293; HPLC (Chiralcel AD-H, n-hexane/i-
(3E,5E)-6-(5-Methyl-2-thienyl)hexa-3,5-dien-2-one
(1r):
1
45% yield; yellow solid; mp 25–278C; H NMR (400 MHz,
CDCl3): d=7.21 (dd, J=10.8, 15.6 Hz, 1H), 6.98 (d, J=
15.2 Hz, 1H), 6.92 (d, J=3.6 Hz, 1H), 6.89–6.66 (m, 1H),
6.54 (dd, J=10.8, 15.6 Hz, 1H), 6.19 (d, J=15.2 Hz, 1H),
2.49 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
198.5, 143.6, 142.7, 139.7, 134.4, 129.5, 129.4, 126.6, 125.1,
27.6, 16.0; HR-MS (ESI): m/z=193.0688, calcd. for
C11H12OS [M+H]+: 193.0687.
PrOH=99:1, UV=254 nm, flow rate=0.8 mLminÀ1): tR1
=
17.05 min (minor) and tR2 =19.56 min (major); ee=84%;
[a]20: À18.5 (c 0.28, CHCl3).
(D4R,5E)-4-Methyl-6-(2-methylphenyl)-5-hexaen-2-one
(2h): 63% yield (94/6, 1,4/1.6 mixture); colorless oil;
1H NMR (400 MHz, CDCl3): d=7.40–7.35 (m, 1H), 7.18–
7.10 (m, 3H), 6.58 (d, J=15.6 Hz, 1H), 5.98 (dd, J=7.6,
16.0 Hz, 1H), 2.98–2.85 (m, 1H), 2.57 (dd, J=6.8, 15.6 Hz,
1H), 2.47 (dd, J=7.2, 16.0 Hz, 1H), 2.32 (s, 3H), 2.15(s,
3H), 1.13 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=208.1, 138.2, 137.6, 134.6, 128.9, 128.6, 128.1, 127.0, 123.5,
51.0, 33.2, 30.8, 21.6, 20.5; HR-MS (ESI): m/z=203.1443,
calcd. for C14H18O [M+H]+: 203.1436; HPLC (Chiralcel
OD-H, n-hexane/i-PrOH=98:2, UV=254 nm, flow rate=
General Procedure for Copper-Catalyzed
Enantioselective Conjugate Addition
A
flame-dried Schlenk tube was charged with
Cu(II)(OAc)2·H2O (0.005 mmol, 2.5 mol%) and 2.0 equiva-
lents of ligand (0.010 mmol) under nitrogen, and the mixture
was dissolved in dry THF (2.0 mL), resulting in a blue solu-
tion. The solution was stirred at room temperature for 2 h
and then cooled to À308C. The substrate 1 (0.200 mmol dis-
solved in 0.5 mL dry THF) was then added dropwise over
3 min. The solution was stirred for 5 min at À308C and
gradually turned to a light yellow color. AlMe3 (0.24 mmol,
0.24 mL of 1M solution in hexane) was added dropwise
over 3 min. The reaction mixture was stirred at À308C for
12 h and monitored by TLC until full conversion to the
product was observed. The reaction mixture was quenched
with aqueous saturated NH4Cl and extracted with ethyl ace-
tate (5.0 mLꢂ3). The organic extracts were combined, con-
centrated and the residue was purified by silica gel column
chromatography to afford the product. Enantiomeric excess
was determined by chiral HPLC.
0.8 mLminÀ1):
tR1 =8.89 min (minor) and tR2 =9.99 min
(major); ee=81%; [a]2D0: À18.3 (c 0.24, CHCl3).
(4R,5E)-4-Methyl-6-(3-methylphenyl)-5-hexaen-2-one
(2i): 67% yield (94/6, 1,4/1.6 mixture); colorless oil;
1H NMR (400 MHz, CDCl3): d=7.21–7.10 (m, 3H), 7.02 (d,
J=6.8 Hz, 1H), 6.35 (d, J=16.0 Hz, 1H), 6.12 (dd, J=7.6,
16.0 Hz, 1H), 2.90–2.82 (m, 1H), 2.56 (dd, J=6.8, 16.0 Hz,
1H), 2.46 (dd, J=7.2, 16.0 Hz, 1H), 2.33 (s, 3H), 2.14 (s,
3H), 1.12 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=208.1, 136.8, 136.2, 135.3, 130.4, 127.3, 126.9, 126.2, 125.7,
51.0, 33.5, 30.1, 20.7, 20.0; HR-MS (ESI): m/z=203.1445,
calcd. for C14H18O [M+H]+: 203.1447; HPLC (Chiralcel
OD-H, n-hexane/i-PrOH=98:2, UV=254 nm, flow rate=
(4R,5E)-1,1,1-Trifluoro-4-methyl-6-phenyl-5-hexaen-2-one
1
(2d): 71% yield; colorless oil; H NMR (400 MHz, CDCl3):
0.8 mLminÀ1):
tR1 =8.52 min (minor) and tR2 =10.24 min
d=7.38–7.19 (m, 5H), 6.44 (d, J=16.0 Hz, 1H), 6.11 (dd,
J=7.6, 16.0 Hz, 1H), 3.08–2.95 (m, 1H), 2.88 (dd, J=6.5,
18.0 Hz, 1H), 2.76 (dd, J=7.2, 18.0 Hz, 1H), 1.19 (d, J=
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=190.4 (q, J=
34.0 Hz), 137.19, 133.0, 130.0, 128.8, 127.6, 126.4, 115.7 (q,
J=291 Hz), 43.5, 32.2, 20.3; 19F NMR (376 MHz, CDCl3):
d=À79.55; HR-MS (ESI): m/z=243.0914, calcd. for
C13H13F3O [M+H]+: 243.0844; HPLC (Chiralcel OD-H, n-
(major); ee=86%; [a]2D0: À33.6 (c 0.24, CHCl3).
(4R,5E)-4-Methyl-6-(4-methylphenyl)-5-hexaen-2-one
(2j): 70% yield (93/7, 1,4/1.6 mixture); colorless oil;
1H NMR (400 MHz, CDCl3): d=7.23 (d, J=8.0 Hz, 2H),
7.10 (d, J=8.0 Hz, 2H), 6.35 (d, J=15.6 Hz, 1H), 6.07 (dd,
J=7.6, 16.0 Hz, 1H), 2.94–2.81 (m, 1H), 2.56 (dd, J=6.8,
16.0 Hz, 1H), 2.45 (dd, J=7.2, 16.0 Hz, 1H), 2.32 (s, 3H),
2.14 (s, 3H), 1.11 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=208.3, 137.1, 134.8, 133.7, 129.4, 128.7, 126.2,
51.0, 33.2, 30.8, 21.4, 20.5; HR-MS (ESI): m/z=203.1437,
calcd. for C14H18O [M+H]+: 203.1447; HPLC (Chiralcel
OD-H, n-hexane/i-PrOH=98:2, UV=254 nm, flow rate=
hexane/i-PrOH=98:2,
UV=210 nm,
flow
rate=
0.8 mLminÀ1):
tR1 =6.16 min (minor) and tR2 =38.85 min
(major); ee=10%; [a]2D0: À0.9 (c 0.42, CHCl3).
(4R,5E)-4-Methyl-6-(4-chlorophenyl)-5-hexaen-2-one
(2e): 64% yield (93/7, 1,4/1.6 mixture); colorless oil;
1H NMR (400 MHz, CDCl3): d=7.25 (s, 4H), 6.30 (dd, J=
1.2, 16.0 Hz, 1H), 6.10 (dd, J=7.2, 16.0 Hz, 1H), 2.94–2.82
0.8 mLminÀ1):
tR1 =8.08 min (minor) and tR2 =9.15 min
(major); ee=87%; [a]2D0: À38.6 (c 0.24, CHCl3).
Adv. Synth. Catal. 0000, 000, 0 – 0
6
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(4R,5E)-4-Methyl-6-(2-naphthyl)-5-hexaen-2-one
(2l):
209.1000; HPLC (Chiralcel OD-H, n-hexane/i-PrOH=98:2,
74% yield (94/6, 1,4/1.6 mixture); yellow solid; mp 47–498C;
1H NMR (400 MHz, CDCl3): d=7.80 (t, J=8.4 Hz, 3H),
7.71 (s, 1H), 7.59 (dd, J=1.6, 8.4 Hz, 1H), 7.50–7.40 (m,
2H), 6.58 (d, J=16.0 Hz, 1H), 6.29 (dd, J=7.6, 16.0 Hz,
1H), 3.03–2.93 (m, 1H), 2.64 (dd, J=6.8, 16.0 Hz, 1H), 2.53
(dd, J=6.8, 16.0 Hz, 1H), 2.19 (s, 3H), 1.19 (d, J=6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=207.9, 135.0, 134.8,
133.6, 132.7, 128.8, 128.1, 127.8, 127.6, 126.2, 125.7, 125.6,
123.5, 50.7, 33.0, 30.6, 20.3; HR-MS (ESI): m/z=239.1430,
calcd. for C17H18O [M+H]+: 239.1436; HPLC (Chiralcel
OD-H, n-hexane/i-PrOH=98:2, UV=254 nm, flow rate=
0.8 mLminÀ1): tR1 =15.26 min (minor) and tR2 =17.59 min
(major); ee=88%; [a]2D0: À24.4 (c 0.48, CHCl3).
UV=254 nm, flow rate=0.8 mLminÀ1):
tR1 =7.80 min
(minor) and tR2 =8.52 min (major); ee=91%; [a]2D0: À25.0 (c
0.40, CHCl3).
Transformations of 2a
A flame-dried flask equipped with a stir bar was backfilled
with N2 and 2a (0.1 mmol, 1.0 equiv., 82%ee) in anhydrous
MeOH (0.5 mL, 0.2M) was added before placing the flask
in an ice bath. NaBH4 (0.3 mmol, 3.0 equiv.) was added por-
tion-wise to control the evolution of H2 from the reaction
flask and the reaction mixture was allowed to stir at 08C for
1.0 h. The reaction was quenched with saturated NaHCO3
and extracted with DCM (3ꢂ10 mL), dried with MgSO4,
and concentrated under reduced pressure. The crude mix-
ture was purified by silica flash chromatography to afford
the product. The enantiomeric excess was determined by
chiral HPLC.
(4R,5E)-4-methyl-6-(2-furyl)-5-hexaen-2-one (2o): 72%
1
yield; colorless oil; H NMR (400 MHz, CDCl3): d=7.30 (d,
J=1.2 Hz, 1H), 6.34 (dd, J=1.6, 3.2 Hz, 1H), 6.21 (d, J=
16.0 Hz, 1H), 6.15 (d, J=3.2 Hz, 1H), 6.07 (dd, J=7.6,
16.0 Hz, 1H), 2.91–2.80 (m, 1H), 2.55 (dd, J=6.8, 16.4 Hz,
1H), 2.44 (dd, J=7.2, 16.4 Hz, 1H), 2.14 (s, 3H), 1.09 (d,
J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=208.0,
153.0, 141.7, 133.6, 117.6, 111.4, 107.0, 50.8, 32.8, 30.9, 20.3;
HR-MS (ESI): m/z=179.1072, calcd, for C11H14O2 [M+H]+:
179.1072; HPLC (Chiralcel OD-H, n-hexane/i-PrOH=98:2,
(4R,5E)-4-Methyl-6-phenyl-5-hexen-2-ol (4a): 98% yield
(18.6 mg); colorless oil; 1H NMR (400 MHz, CDCl3): d=
7.36–7.32 (m, 4H), 7.30–7.26 (m, 4H), 7.22–7.16 (m,2H),
6.40 (d, J=15.6 Hz, 1H), 6.38 (d, J=16.0 Hz, 1H), 6.12 (dd,
J=16.0, 8.4 Hz, 1H), 6.05 (dd, J=16.0, 8.4 Hz, 1H), 3.92–
3.79 (m, 2H), 2.61–2.50 (m, 1H), 2.49–2.39 (m, 1H), 1.78 (s,
2H), 1.65–1.52 (m, 2H), 1.48–1.42 (m, 2H), 1.20 (d, J=
6.4 Hz, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.11 (d, J=2.0 Hz,
3H), 1.09 (d, J=2.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=137.8 (d, J=6.2 Hz), 136.4 (d, J=51.6 Hz), 129.08 (s),
128.6 (d, J=18.2 Hz), 127.25 (s), 126.26 (s), 66.52 (d, J=
54.9 Hz), 46.77 (s), 34.82 (d, J=59.3 Hz), 24.12 (d, J=
45.8 Hz), 21.40 (d, J=56.3 Hz); HR-MS (ESI): m/z=
191.1433, calcd. for C13H19O [M+H]+: 191.1430; HPLC
(Chiralcel OD-H, n-hexane/i-PrOH=95:5, UV=254 nm,
UV=254 nm, flow rate=0.8 mLminÀ1):
tR1 =8.35 min
(minor) and tR2 =8.94 min (major); ee=89%; [a]2D0: À42.7 (c
0.22, CHCl3).
(4R,5E)-4-Methyl-6-(2-thienyl)-5-hexaen-2-one (2p): 78%
1
yield; colorless oil; H NMR (400 MHz, CDCl3): d=7.09 (d,
J=5.2 Hz, 1H), 6.93 (dd, J=3.6, 4.8 Hz, 1H), 6.88 (d, J=
3.2 Hz, 1H), 6.88 (d, J=15.2 Hz, 1H), 5.97 (dd, J=7.2,
15.6 Hz, 1H), 2.91–2.80 (m, 1H), 2.56 (dd, J=6.8, 16.4 Hz,
1H), 2.44 (dd, J=7.2, 16.4 Hz, 1H), 2.14 (s, 3H), 1.10 (d,
J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=208.0,
142.8, 134.6, 127.5, 125.1, 123.7, 122.2, 50.7, 32.9, 30.9, 20.3;
HR-MS (ESI): m/z=217.0687, calcd. for C11H14OS [M+
H]+: 217.0677; HPLC (Chiralcel OD-H, n-hexane/i-PrOH=
98:2, UV=254 nm, flow rate=0.8 mLminÀ1): tR1 =10.51 min
(minor) and tR2 =12.17 min (major); ee=90%; [a]2D0: À35.0
(c 0.52, CHCl3).
flow rate=0.9 mLminÀ1): tR2 =12.13 min (minor) and tR4
13.56 min (major), ee=89%; dr=1.2:1.
=
2a (0.1 mmol, 1.0 equiv., 63%ee) was dissolved in dry
CH2Cl2 (0.4 mL, 0.3M), and mCPBA (0.3 mmol, 3.0 equiv.,
75%), was added in small portions at 08C while stirring.
After 5 min, the mixture was allowed to warm to room tem-
perature and was stirred for another 0.5 h until complete
conversion as monitored by TLC. After addition of saturat-
ed. aqueous Na2S2O3 (1.5 mL) and NaHCO3 (1.5 mL), the
mixture was stirred for 15 min. Then the mixture was ex-
tracted with DCM (3ꢂ5 mL), dried with MgSO4, and the
solvent was removed on a rotary evaporator. The purifica-
tion of product was achieved using column chromatography.
(4S)-4-Methyl-5,6-epoxy-6-phenyl-2-hexanone (5a): 78%
(4R,5E)-4-Methyl-6-(5-chloro-2-thienyl)-5-hexaen-2-one
(2q): 70% yield; yellow oil; 1H NMR (400 MHz, CDCl3):
d=6.73 (d, J=4.0 Hz, 1H), 6.62 (d, J=4.0 Hz, 1H), 6.36 (d,
J=16.0 Hz, 1H), 5.84 (dd, J=8.0, 16.0 Hz, 1H), 2.89–2.77
(m, 1H), 2.53 (dd, J=8.0, 16.0 Hz, 1H), 2.43 (dd, J=8.0,
16.0 Hz, 1H), 2.13 (s, 3H), 1.08 (d, J=8.0 Hz, 3H);
13C NMR (100 MHz, CDCl3,): d=207.6, 141.6, 134.9, 128.0,
126.5, 124.3, 122.0, 50.6, 32.8, 30.8, 20.2; HR-MS (ESI): m/
z=229.0458, calcd. for C11H13ClOS [M+H]+: 229.0454;
HPLC (Chiralcel AD-H, n-hexane/i-PrOH=98:2, UV=
254 nm, flow rate=0.8 mLminÀ1): tR1 =8.43 min (minor) and
1
yield (15.9 mg); yellow oil; H NMR (400 MHz, CDCl3): d=
7.34–7.28 (m, 3H), 7.26–7.22 (m, 2H), 3.66 (d, J=2.0 Hz,
1H), 2.83 (dd, J=7.2, 2.0 Hz, 1H), 2.74 (dd, J=16.8, 4.8 Hz,
1H), 2.43 (dd, J=16.8, 8.4 Hz, 1H), 2.18 (s, 3H), 2.13–2.06
(m, 1H), 1.05 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=207.7, 137.7, 128.7, 128.4, 125.7, 66.6, 58.5, 47.5,
32.5, 30.7, 16.4; HR-MS (ESI): m/z=205.1223, calcd for
C13H17O2 [M+H]+: 205.1223; HPLC (Chiralcel AD-H, n-
t
R2 =11.02 min (major); ee=88%; [a]2D0: À37.5 (c 0.48,
CHCl3).
(4R,5E)-4-Methyl-6-(5-methyl-2-thienyl)-5-hexaen-2-one
1
(2r): 76% yield; yellow oil; H NMR (400 MHz, CDCl3): d=
6.64 (d, J=4.0 Hz, 1H), 6.56 (d, J=4.0 Hz, 1H), 6.41 (d, J=
16.0 Hz, 1H), 5.83 (dd, J=8.0, 16.0 Hz, 1H), 2.87–2.78 (m,
1H), 2.53 (dd, J=4.0, 16.0 Hz, 1H), 2.42 (dd, J=8.0,
16.0 Hz, 1H), 2.43 (s, 3H), 2.13 (s, 3H), 1.08 (d, J=8.0 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=207.9, 140.5, 138.2,
133.1, 125.3, 125.0, 122.4, 50.6, 32.7, 30.6, 20.2, 15.5; HR-MS
(ESI): m/z=209.1002, calcd. for C12H16OS [M+H]+:
hexane/i-PrOH=95:5,
UV=210 nm,
flow
rate=
0.8 mLminÀ1): tR1 =11.130 min (minor) and tR2 =14.184 min
(major), ee=80%; dr=25:1.
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[6] For one example of cobalt-catalyzed 1,6-addition reac-
Acknowledgements
tions, see: T. Sawano, A. Ashouri, T. Nishimura, T.
Hayashi, J. Am. Chem. Soc. 2012, 134, 18936–18939.
[7] For one example of copper-catalyzed asymmetric 1,6-
addition reactions of dialkylzinc reagents to Meldrumꢀs
acid acceptors, see: E. Fillion, A. Wilsily, E.-T. Liao,
Tetrahedron: Asymmetry 2006, 17, 2957–2959.
[8] For examples of copper-catalyzed asymmetric 1,6-addi-
tion reactions of dialkylzinc to dienones, see: a) H.
Henon, M. Mauduit, A. Alexakis, Angew. Chem. 2008,
120, 9262–9264; Angew. Chem. Int. Ed. 2008, 47, 9122–
9124; b) J. Wencel-Delord, A. Alexakis, C. Crꢆvisy, M.
Mauduit, Org. Lett. 2010, 12, 4335–4337; c) M. Magrez,
J. Wencel-Delord, A. Alexakis, C. Crꢆvisy, M. Mauduit,
Org. Lett. 2012, 14, 3576–3579; d) M. Magrez-Chiquet,
M.-S.-T. Morin, J. Wencel-Delord, S.-D. Amraoui, O.
Baslꢆ, A. Alexakis, C. Crꢆvisy, M. Mauduit, Chem. Eur.
J. 2013, 19, 13663–13667.
[9] For examples of copper-catalyzed asymmetric 1,6-addi-
tion reactions of Grignard reagents to linear a,b,g,d-un-
saturated esters or thioesters, see: a) T. den Hartog,
S. R. Harutyunyan, D. Font, A. J. Minnaard, B. L. Fer-
inga, Angew. Chem. 2008, 120, 404–407; Angew. Chem.
Int. Ed. 2008, 47, 398–401; b) T. den Hartog, D. J. van
Dijken, A. J. Minnaard, B. L. Feringa, Tetrahedron:
Asymmetry 2010, 21, 1574–1584.
[10] For one example of copper-catalyzed asymmetric 1,6-
addition reactions of a dimethylphenylsilanyl group to
cyclic a,b,g,d-dienones, see: K. Lee, A. H. Hoveyda, J.
Am. Chem. Soc. 2010, 132, 2898–2900.
This work was partially supported by the National Natural
Science Foundation of China (No. 21572129, 21472123 and
21232004), Program of Shanghai Subject Chief Scientists
(No.14XD1402300) and Shanghai Jiao Tong University
(SJTU) and the Instrumental Analysis Center of SJTU is
thanked for characterization data.
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