Convenient access to β-substituted chiral phenones

Article abstract of DOI:10.1002/hlca.200800375

A highly enantioselective approach towards the synthesis of β-substituted chiral ketones by utilizing Grignard reagents was achieved. The (R)- and (S)-antipodes of the target chiral ketones 2a-2k were obtained with up to 100% ee from chiral N-alkanoylcamp

Full text of DOI:10.1002/hlca.200800375

Helvetica Chimica Acta – Vol. 92 (2009)
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Convenient Access to b-Substituted Chiral Phenones
by Xiu-Fang Cao, Ming Hu, Fei Li, Wen-Chang Lu, Guang-Ao Yu, and Sheng-Hua Liu*
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan 430079, P. R. China (e-mail: chshliu@mail.ccnu.edu.cn)
A highly enantioselective approach towards the synthesis of b-substituted chiral ketones by utilizing
Grignard reagents was achieved. The (R)- and (S)-antipodes of the target chiral ketones 2a – 2k were
obtained with up to 100% ee from chiral N-alkanoylcamphorsultams 1 (Scheme, Table 2). This simple,
catalyst-free, direct procedure for the formation of chiral ketones is a fascinating method for the practical
syntheses of chiral synthons as valuable building blocks and important medicinal intermediates.
Introduction. – Optically active b-substituted ketones (b-chiral ketones) are
common subunits in biologically active molecules. They are used as excellent building
blocks, which have numerous applications in the enantioselective synthesis of natural
products and important medicinal intermediates [1 – 4]. In recent years, intensive
investigations on the synthesis of b-substituted chiral ketones have been reported. For
example, enantioselective metal-catalyzed types of the conjugate addition (CA) of
organometallic reagents to enones have been extensively studied with Grignard [5][6],
dialkylzinc [7 – 12], organocuprate, organoboron, alkyllithium, and silicon reagents
[13 – 18]. Most of these studies, however, involved the use of a catalytic or
stoichiometric amount of chiral ligands. Recently, a novel transformation method
from Weinreb amide to b-substituted chiral ketones has been developed [19 – 23].
Weinreb amide could be further alkylated with Grignard reagents to give various
ketone derivatives with C(b) as center of chirality. Simultaneously, Nagaoꢀs group
studied how active monothioester derivatives can be converted to chiral ketones when
treated with the Grignard reagent and metal-complex catalysts [24]. Furthermore,
enzymatic transformations to obtain chiral ketones have also been reported [25 – 28].
These include the hydrolysis of enol esters and baker-yeast-mediated asymmetric
reduction of a,b-unsaturated carbonyl compounds. Nevertheless, almost all of the
above-described synthetic methodologies for the synthesis of chiral ketones need
expensive chiral ligands and metal catalysts, and the reaction conditions are rigorous
(low temperature or long reaction time). Therefore, despite extensive research on the
synthesis of chiral ketones, a generally convenient method to obtain b-substituted chiral
ketones is still lacking. Recently, we have reported that the highly regioselective and
diastereoselective conjugate addition of a series of Ar-substituted a,b-unsaturated
carbonyl compounds with various Grignard reagents can be achieved by means of a
chiral auxiliary [29]. Therefore, in view of our interest in new methods to construct
chiral synthons, we would like to report herein a simple, catalyst-free, and direct
formation of b-substituted chiral phenones via a nucleophilic cleavage reaction of
corresponding N-alkanoylcamphorsultams with Ar-Grignard reagents (Scheme).
ꢁ 2009 Verlag Helvetica Chimica Acta AG, Zꢂrich

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Helvetica Chimica Acta – Vol. 92 (2009)
Results and Discussion. – The synthesis and reaction conditions of the b-substituted
chiral ketone derivatives 2a – 2k are outlined in the Scheme. The key chiral substrates 1
were prepared following the methods outlined in the literature, and their spectral and
analytical data were also identical to those stated in [29]. The chiral auxiliary attached
to the carbonyl moiety in substrates 1 was then nucleophilically substituted by the aryl
group on treatment with a Grignard reagent under optimized reaction conditions.
Scheme. Catalyst-Free Enantioselective Formation of b-Substituted Chiral Phenones 2a – 2k via Aryl-
Grignard Reagents (see Table 2 for Ar, Ar’, and R)
The reaction conditions were optimized with an investigation of the influence of
reaction temperature, reaction time, and the ratio of substrates on the yield and
enantioselectivity. At the outset of our study, we selected chiral substrate (ꢀ)-1a
bearing a propyl substituent as a typical substrate to examine the effectiveness of the
reaction conditions in the presence of THF (Table 1). The ratio of substrate (ꢀ)-1a to
the Grignard reagent Ar’MgBr (Ar’ ¼ 4-MeC6H4) was examined from 1:1 to 1:2,
establishing that the yield of target chiral ketone (ꢀ)-2a was relatively low (7 – 42%) at
the ratio 1:1 and moderate (54%) at the ratio 1:1.5. The highest enantioselectivity
(94%) was obtained at ꢀ 788, but the yield was the lowest, and the reaction required a
longer time for completion (Entry 5). Among the different reaction conditions, those
of Entry 6 gave the target (ꢀ)-2a in the best yield and with high enantioselectivity.
High enantioselectivity and convenient access to the b-substituted chiral ketone
(ꢀ)-2a under mild conditions prompted us to extend our investigation to obtain other
important chiral building blocks 2. To explore the generality of the above-described
direct transformation, differently b-alkyl-substituted substrates 1 with a variety of aryl
groups (Ar) bearing electron-withdrawing groups (such as halogen atoms) or electron-
donating substituents (Me and MeO) at the para-position were prepared and used as
substrates. As shown in Table 2, under optimized reaction conditions, the treatment of
these substrates 1 with a Grignard reagent Ar’MgBr afforded the desired b-chiral
phenones 2 with high enantioselectivity (up to 100% ee) in moderate yield. An obvious
increase in enantioselectivity for chiral substrates 1 with an unsubstituted phenyl (Ar)
and a shorter-chain alkyl group (Pr) at b-position was observed (Entries 1 – 4).

Helvetica Chimica Acta – Vol. 92 (2009)
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Table 1. Optimization of the Reaction Conditions for the Formation of b-Substituted Chiral Ketone (ꢀ)-2a
Entry
(ꢀ)-1a/Ar’MgBr
Temperature [8]
Time [h]
Yield [%]a)
ee of (ꢀ)-2ab)
1
2
3
4
5
6
7
8
1 : 1
1 : 1
1 : 1
1 : 1
0
0
ꢀ 40
ꢀ 60
ꢀ 78
0
1
1.5
4
6
10
1
32
33
42
11
7
54
54
52
91
91
92
92
94
91
91
91
1 : 1
1 : 1.5
1 : 1.5
1 : 2
0
0
1.5
1
a) Yield of isolated material. b) The ee values were determined by HPLC analysis with a chiral stationary
phase column (Daicel Chiralpak AD-H; hexane/i-PrOH 97: 3).
However, for substrates 1 with a weakly electron-withdrawing group (Cl) at the para-
position of Ar, the longer-chain alkyl group (Bu) led to an obvious increase in
enantioselectivity and relatively high yields (Entries 5 – 10). As a general trend, an
electron-donating group at the para-position of Ar provided excellent enantioselectiv-
ities (93 – 97% ee) (Entries 13 – 15). The reaction of chiral substrates 1 with PhMgBr
(Ar’ ¼ Ph) afforded the desired product with high enantioselectivity (up to 99%) but
the yields of the target chiral ketones 2 were lower (38 – 42%) (Entries 16 – 19).
Electron-donating groups at the para-position of Ar’ also provided excellent
enantioselectivity (up to 100% ee) and gave moderate yields (Entries 20 and 21).
Conclusion. – In summary, we have demonstrated that inexpensive and readily
available Grignard reagents can be used to provide b-substituted chiral ketones 2 with
excellent enantioselectivity. This simple, catalyst-free direct procedure for the
formation of chiral ketones is a fascinating method for the practical syntheses of
chiral synthons as valuable building blocks and important medicinal intermediates.
The authors acknowledge financial support from the National Natural Science Foundation of China
(Nos. 20572029 and 20772039), and the Science Foundation for the New Teacher at the University of China
(No. 20070511006).
Experimental Part
1. General. Unless otherwise noted, all materials were commercially available and were used directly
without further purification. HPLC: Agilent-1100 instrument; Chiralpak-AD-H column; hexane/i-PrOH
97:3, 1 ml/min; tR in min. M.p.: Bꢀchi B-545 melting-point apparatus; uncorrected. Optical rotations:
Jasco P-1010 polarimeter; enantiomer excesses (ee) by HPLC. 1H- and 13C-NMR Spectra: Mercury-Plus-

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Helvetica Chimica Acta – Vol. 92 (2009)
Table 2. Enantioselectivity for the Formation of b-Substituted Chiral Ketones 2a)
Entry Ar
Ar’
R
Product Yield [%]b) ee [%]c) Configurationd)e)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Pr
Pr
(ꢀ)-2a
(þ)-2a
54
53
51
48
46
48
48
52
60
56
46
48
45
52
64
40
42
38
41
45
50
91
95
86
78
93
89
80
87
97
95
79
82
97
96
93
99
81
93
88
80
100
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(R)
(S)
(R)
(S)
(R)
(S)
Bu (ꢀ)-2b
Bu (þ)-2b
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
4-MeOC6H4 4-MeC6H4
4-MeOC6H4 4-MeC6H4
4-MeC6H4
Ph
Et
Et
Pr
Pr
(ꢀ)-2c
(þ)-2c
(ꢀ)-2d
(þ)-2d
Bu (ꢀ)-2e
Bu (þ)-2e
Bu (ꢀ)-2f
Bu (þ)-2f
Bu (ꢀ)-2g
Bu (þ)-2g
4-MeC6H4
Et
Et
Et
Et
Et
(ꢀ)-2h
(ꢀ)-2i
(þ)-2i
(ꢀ)-2j
(þ)-2j
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeOC6H4 Bu (ꢀ)-2k
4-MeOC6H4 Bu (þ)-2k
a) All reactions were performed with 1 (1.0 mol-equiv.), and Ar’MgBr (1.5 mol-equiv.). b) Yield of
isolated material. c) The ee values were determined by HPLC analysis with a chiral stationary phase
column (Daicel Chiralpak AD-H; hexane/i-PrOH 97: 3). d) The absolute configuration was assigned by
e
chiroptical comparison with the published value. ) The configurations of compounds 2 were assigned via
the absolute configuration of compounds 1 [29].
400 spectrometer; in CDCl3 at 400 or 600 and 100 MHz, resp.; d in ppm rel. to Me4Si as internal standard,
J in Hz. MS: TraceMS-2000 organic mass spectrometer; in m/z (rel. %). Elemental analyses: Vario-EL-
III elemental analysis instrument.
2. Synthesis of 1: General Procedure. The key chiral intermediates (ꢀ)-1 and (þ)-1 were prepared
following the literature methods, and the spectral and anal. data of them, except those of (ꢀ)-1g and (þ)-
1g (see below), were in agreement with published data [29].
(ꢀ)-N-[(3R)-3-(4-Methoxyphenyl)heptanoyl]bornane-10,2-sultam (¼(ꢀ)-(3R)-3-(4-Methoxyphen-
yl)-1-[(3aS,6R,7aR)-tetrahydro-8,8-dimethyl-2,2-dioxido-3H-3a,b-methano-2,1-benzothiazol-1(4H)-yl]-
hexan-1-one; (ꢀ)-1g): White solid. M.p. 97 – 998. [a]2D4 ¼ ꢀ73.8 (c ¼ 1.0, CH2Cl2). H-NMR (400 MHz):
1
0.81 (t, J ¼ 7.2, 3 H); 0.96 (s, 3 H); 1.08 – 1.12 (m, 2 H); 1.16 (s, 3 H); 1.19 – 1.38 (m, 4 H); 1.53 – 1.61 (m,
2 H); 1.85 – 1.87 (m, 3 H); 2.0 – 2.02 (m, 2 H); 2.96 – 3.08 (m, 2 H); 3.15 – 3.17 (m, 1 H); 3.40 (d, J ¼ 14,
1 H); 3.49 (d, J ¼ 13.6, 1 H); 3.77 – 3.81 (m, 4 H); 6.77 – 6.83 (m, 2 H); 7.12 (d, J ¼ 8.8, 2 H). EI-MS: 433
(Mþ). Anal. calc. for C24H35NO4S: C 66.48, H 8.14, N 3.23, S 7.39; found: C 66.16, H 7.98, N 3.36, S 7.77.
(þ)-N-[(3S)-3-(4-Methoxyphenyl)heptanoyl]bornane-10,2-sultam (¼(þ)-(3S)-3-(4-Methoxyphen-
yl)-1-[(3aR,7S,7aS)-octahydro-8,8-dimethyl-2,2-dioxido-2,1-benzisothiazol-1(4H)-yl]heptan-1-one; (þ)-

Helvetica Chimica Acta – Vol. 92 (2009)
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1g): White solid. M.p. 97 – 998. [a]2D4 ¼ þ77.5 (c ¼ 1.0, CH2Cl2). Spectroscopic data: identical to those of
(ꢀ)-1g.
3. Synthesis of 2: General Procedure. To a soln. of 1 (10 mmol) in anh. THF (40 ml) under N2 at 08,
Ar’MgBr (15 ml, 15 mmol) was added dropwise. The mixture was stirred at 08 for 1 h, and was then
quenched with sat. aq. NH4Cl soln. and extracted with Et2O (2 ꢁ 100 ml). The combined org. phase was
washed with brine (100 ml), dried (MgSO4), and concentrated, and the residue purified by flash
chromatography (AcOEt/hexane 1:30): 2.
(ꢀ)-(3R)-1-(4-Methylphenyl)-3-phenylhexan-1-one ((ꢀ)-2a): White solid. M.p. 44 – 468. [a]D20
¼
1
ꢀ4.09 (c ¼ 1.0, CH2Cl2); 91% ee (HPLC: tR 8.96 (minor), 12.83 (major)). H-NMR (400 MHz): 0.84
(t, J ¼ 7.2, 3 H); 1.14 – 1.29 (m, 2 H); 1.58 – 1.70 (m, 2 H); 2.38 (s, 3 H); 3.21 – 3.23 (m, 2 H); 3.31 – 3.33 (m,
1 H); 7.15 – 7.29 (m, 7 H); 7.79 – 7.81 (m, 2 H). 13C-NMR (100 MHz): 14.0; 20.6; 21.6; 38.4; 41.0; 45.7;
126.1; 126.7; 127.5; 127.8; 128.1; 128.3; 128.6; 129.1; 129.3; 134.6; 143.6; 145.0; 198.8. EI-MS: 266 (Mþ).
Anal. calc. for C19H22O: C 85.67, H 8.32; found: C 85.75, H 8.19.
(þ)-(3S)-1-(4-Methylphenyl)-3-phenylhexan-1-one ((þ)-2a): White solid. M.p. 44 – 468. [a]D20
þ4.21 (c ¼ 0.51, CH2Cl2); 95% ee (HPLC: tR 9.09 (major), 13.33 (minor)).
¼
(ꢀ)-(3R)-1-(4-Methylphenyl)-3-phenylheptan-1-one ((ꢀ)-2b): [a]1D9 ¼ ꢀ9.55 (c ¼ 0.48, CH2Cl2);
1
86% ee (HPLC: tR 8.51 (minor), 11.90 (major)). H-NMR (400 MHz): 0.80 (t, J ¼ 7.2, 3 H); 1.09 – 1.26
(m, 4 H); 1.61 – 1.69 (m, 2 H); 2.35 (s, 3 H); 3.18 – 3.21 (m, 3 H); 7.10 – 7.27 (m, 7 H); 7.79 (d, J ¼ 8.4, 2 H).
13C-NMR (100 MHz): 13.9; 21.4; 22.5; 29.6; 35.9; 41.2; 45.7; 125.6; 125.9; 126.1; 127.5; 127.9; 128.3; 128.6;
129.0; 129.1; 134.6; 143.5; 145.0; 198.7. EI-MS: 280 (Mþ). Anal. calc. for C20H24O: C 85.67, H 8.63; found:
C 85.73, H 8.99.
(þ)-(3S)-1-(4-Methylphenyl)-3-phenylheptan-1-one ((þ)-2b): [a]1D9 ¼ þ9.79 (c ¼ 0.51, CH2Cl2); 78%
ee (HPLC: tR 8.45 (major), 11.91 (minor)).
(ꢀ)-(3R)-3-(4-Chlorophenyl)-1-(4-methylphenyl)pentan-1-one ((ꢀ)-2c): [a]1D9 ¼ ꢀ4.78 (c ¼ 0.9,
1
CH2Cl2); 93% ee (HPLC: tR 9.33 (minor), 18.33 (major)). H-NMR (400 MHz): 0.79 (t, J ¼ 7.2, 3 H);
1.59 – 1.61 (m, 1 H); 1.73 – 1.76 (m, 1 H); 2.39 (s, 3 H); 3.20 – 3.23 (m, 3 H); 7.13 – 7.27 (m, 6 H); 7.79 (d,
J ¼ 8.4, 2 H). 13C-NMR (100 MHz): 11.9; 21.6; 29.2; 42.4; 45.2; 128.0; 128.2; 128.4; 128.9; 129.1; 129.2;
131.7; 134.5; 143.1; 143.8; 198.4. EI-MS: 286 (Mþ). Anal. calc. for C18H19ClO: C 75.38, H 6.68; found: C
75.29, H 7.02.
(þ)-(3S)-3-(4-Chlorophenyl)-1-(4-methylphenyl)pentan-1-one ((þ)-2c): [a]1D9 ¼ þ11.78 (c ¼ 0.9,
CH2Cl2); 89% ee (HPLC: tR 9.25 (major), 18.52 (minor)).
(ꢀ)-(3R)-3-(4-Chlorophenyl)-1-(4-methylphenyl)hexan-1-one ((ꢀ)-2d): White solid. M.p. 45 – 468.
1
[a]2D0 ¼ ꢀ4.33 (c ¼ 0.9, CH2Cl2); 80% ee (HPLC: tR 9.35 (minor), 17.97 (major)). H-NMR (400 MHz):
0.84 (t, J ¼ 7.2, 3 H); 1.13 – 1.21 (m, 2 H); 1.55 – 1.67 (m, 2 H); 2.40 (s, 3 H); 3.18 – 3.20 (m, 2 H); 3.31 –
3.34 (m, 1 H); 7.11 – 7.27 (m, 6 H); 7.78 (d, J ¼ 8.4, 2 H). 13C-NMR (100 MHz): 13.9; 20.5; 21.5; 38.4;
40.4; 45.5; 125.8; 128.0; 128.1; 128.4; 128.8; 129.1; 129.2; 131.6; 134.5; 136.1; 143.4; 143.7; 198.3. EI-MS:
300 (Mþ). Anal. calc. for C19H21ClO: C 75.86, H 7.04; found: C 75.73, H 7.24.
(þ)-(3S)-3-(4-Chlorophenyl)-1-(4-methylphenyl)hexan-1-one ((þ)-2d): White solid. M.p. 45 – 468.
[a]2D0 ¼ þ3.56 (c ¼ 0.9, CH2Cl2); 87% ee (HPLC: tR 9.56 (major), 19.37 (minor)).
(ꢀ)-(3R)-3-(4-Chlorophenyl)-1-(4-methylphenyl)heptan-1-one ((ꢀ)-2e): White solid. M.p. 49 – 518.
[a]2D7 ¼ ꢀ5.92 (c ¼ 0.5, CH2Cl2); 97% ee (HPLC: tR 8.87 (minor), 16.47 (major)). 1H-NMR (400 MHz):
0.82 (t, J ¼ 7.2, 3 H); 1.08 – 1.30 (m, 4 H); 1.59 – 1.70 (m, 2 H); 2.39 (s, 3 H); 3.21 (d, J ¼ 6.4, 2 H); 3.29 (m,
1 H); 7.14 – 7.25 (m, 6 H); 7.79 (d, J ¼ 7.2, 2 H). 13C-NMR (100 MHz): 13.9; 21.5; 22.5; 29.5; 36.0; 40.6;
45.5; 128.1; 128.4; 128.9; 129.2; 131.7; 134.5; 143.5; 143.8; 198.4. EI-MS: 314 (Mþ). Anal. calc. for
C20H23ClO: C 76.29, H 7.36; found: C 76.18, H 7.48.
(þ)-(3S)-3-(4-Chlorophenyl)-1-(4-methylphenyl)heptan-1-one ((þ)-2e): White solid. M.p. 49 – 518.
[a]2D7 ¼ þ5.84 (c ¼ 0.5, CH2Cl2); 95% ee (HPLC: tR 8.83 (major), 16.99 (minor)).
(ꢀ)-(3R)-3-(4-Fluorophenyl)-1-(4-methylphenyl)heptan-1-one ((ꢀ)-2f): [a]1D9 ¼ ꢀ6.5 (c ¼ 0.48,
1
CH2Cl2); 79% ee (HPLC: tR 9.08 (minor), 14.38 (major)). H-NMR (400 MHz): 0.83 (t, J ¼ 7.2, 3 H);
1.06 – 1.30 (m, 4 H); 1.56 – 1.72 (m, 2 H); 2.39 (s, 3 H); 3.18 – 3.30 (m, 3 H); 6.91 – 6.97 (m, 2 H); 7.09 – 7.28
(m, 4 H); 7.79 (d, J ¼ 8, 2 H). 13C-NMR (100 MHz): 13.9; 21.5; 22.5; 29.5; 36.1; 40.6; 45.8; 115.1; 125.9;
128.0; 128.8; 129.1; 129.2; 134.6; 140.6; 143.7; 161.2; 198.6. EI-MS: 298 (Mþ). Anal. calc. for C20H23FO: C
80.50, H 7.77; found: C 80.51, H 7.81.

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Helvetica Chimica Acta – Vol. 92 (2009)
(þ)-(3S)-3-(4-Fluorophenyl)-1-(4-methylphenyl)heptan-1-one ((þ)-2f): [a]1D9 ¼ þ4.58 (c ¼ 0.46,
CH2Cl2); 82% ee (HPLC: tR 9.02 (major), 14.47 (minor)).
(ꢀ)-(3R)-3-(4-Methoxyphenyl)-1-(4-methylphenyl)heptan-1-one ((ꢀ)-2g): White solid. M.p. 46 –
488. [a]1D9 ¼ ꢀ4.45 (c ¼ 0.47, CH2Cl2); 97% ee (HPLC: tR 12.22 (minor), 22.16 (major)). 1H-NMR
(400 MHz): 0.81 (t, J ¼ 7.2, 3 H); 1.11 – 1.26 (m, 4 H); 1.59 – 1.70 (m, 2 H); 2.39 (s, 3 H); 3.16 – 3.19 (m,
3 H); 6.81 (d, J ¼ 8.8, 2 H); 7.13 (d, J ¼ 8.8, 2 H); 7.21 (d, J ¼ 8, 2 H); 7.79 (d, J ¼ 8, 2 H). 13C-NMR
(100 MHz): 13.9; 21.7; 22.5; 29.6; 36.1; 40.4; 46.0; 55.1; 113.6; 125.9; 127.9; 128.2; 128.3; 128.6; 129.0;
129.1; 134.7; 137.0; 143.5; 157.7; 198.9. EI-MS: 310 (Mþ). Anal. calc. for C21H26O2: C 81.25, H 8.44; found:
C 81.47, H 8.67.
(þ)-(3S)-3-(4-Methoxyphenyl)-1-(4-methylphenyl)heptan-1-one ((þ)-2g): White solid. M.p. 46 – 488.
[a]1D9 ¼ þ4.58 (c ¼ 0.48, CH2Cl2); 96% ee (HPLC: tR 11.71 (major), 21.35 (minor)).
(ꢀ)-(3R)-1,3-Bis(4-methylphenyl)pentan-1-one ((ꢀ)-2h): [a]1D9 ¼ ꢀ5.5 (c ¼ 1.2, CH2Cl2); 93% ee
(HPLC: tR 8.37 (minor), 15.42 (major)). 1H-NMR (400 MHz): 0.79 (t, J ¼ 7.2, 3 H); 1.58 – 1.63 (m, 1 H);
1.73 – 1.78 (m, 1 H); 2.26 – 2.34 (m, 1 H); 2.30 (s, 3 H); 2.39 (s, 3 H); 7.02 – 7.15 (m, 4 H); 7.21 – 7.28 (m,
2 H); 7.81 (d, J ¼ 8.4, 2 H). 13C-NMR (100 MHz): 12.0; 20.8; 21.5; 29.1; 42.5; 45.5; 125.5; 125.9; 127.4;
127.8; 128.1; 128.7; 129.0; 129.4; 134.7; 135.9; 141.6; 143.7; 198.9. EI-MS: 266 (Mþ). Anal. calc. for
C19H22O: C 85.67, H 8.32; found: C 85.79, H 8.21.
(ꢀ)-(3R)-1,3-Diphenylpentan-1-one ((ꢀ)-2i): [a]2D3 ¼ ꢀ5.6 (c ¼ 1.49, CH2Cl2) ([11]: [a]D25 ¼ ꢀ4.3
(c ¼ 1.35, EtOH)); 99% ee (HPLC: tR 6.74 (minor), 8.57 (major)). 1H-NMR (400 MHz): 0.80 (t, J ¼ 7.2,
3 H); 1.56 – 1.67 (m, 1 H); 1.76 – 1.78 (m, 1 H); 3.21 – 3.30 (m, 3 H); 7.15 – 7.26 (m, 5 H); 7.41 – 7.46 (m,
2 H); 7.89 – 7.91 (m, 2 H). Other spectral and anal. data: in good agreement with those reported in
[8][30 – 33].
(þ)-(3S)-1,3-Diphenylpentan-1-one ((þ)-2i): [a]2D4 ¼ þ5.2 (c ¼ 1.5, CH2Cl2) ([12]: [a]D22 ¼ þ4.6 (c ¼
1.26, EtOH)); 81% ee (HPLC: tR 6.70 (major), 8.55 (minor)).
(ꢀ)-(3R)-3-(4-Chlorophenyl)-1-phenylpentan-1-one ((ꢀ)-2j): [a]2D5 ¼ ꢀ4.7 (c ¼ 1.5, CH2Cl2) ([11]:
1
[a]2D5 ¼ ꢀ1.8 (c ¼ 1.97, EtOH)); 93% ee (HPLC: tR 7.32 (minor), 10.72 (major)). H-NMR (400 MHz):
0.80 (t, J ¼ 7.2, 3 H); 1.56 – 1.67 (m, 1 H); 1.76 – 1.78 (m, 1 H); 3.21 – 3.26 (m, 3 H); 7.14 – 7.26 (m, 4 H);
7.52 – 7.59 (m, 2 H); 7.88 (m, 2 H). Other spectral and anal. data: identical to those given in [31][33].
(þ)-(3S)-3-(4-Chlorophenyl)-1-phenylpentan-1-one ((þ)-2j): [a]2D5 ¼ þ3.8 (c ¼ 1.5, CH2Cl2) ([12]:
[a]2D4 ¼ þ1.5 (c ¼ 1.13, EtOH)); 88% ee (HPLC: tR 7.32 (major), 10.87 (minor)).
(ꢀ)-(3R)-3-(4-Chlorophenyl)-1-(4-methoxyphenyl)heptan-1-one ((ꢀ)-2k): [a]2D0 ¼ ꢀ9.6 (c ¼ 1.5,
1
CH2Cl2); 80% ee (HPLC: tR 9.02 (minor), 15.15 (major)). H-NMR (400 MHz): 0.82 (t, J ¼ 7.2, 3 H);
1.08 – 1.30 (br., 4 H); 1.57 – 1.73 (br., 2 H); 3.15 – 3.18 (m, 2 H); 3.27 – 3.31 (m, 1 H); 3.83 (s, 3 H); 6.89 (d,
J ¼ 8.8, 2 H); 7.15 (d, J ¼ 8, 2 H); 7.25 (d, J ¼ 8.8, 2 H); 7.87 (d, J ¼ 8.8, 2 H). 13C-NMR (100 MHz): 13.8;
22.5; 29.5; 35.9; 40.7; 45.3; 55.3; 113.6; 128.4; 128.8; 130.1; 130.2; 131.6; 143.5; 163.3; 197.2. EI-MS: 332
([M þ 2]þ). Anal. calc. for C20H23ClO2: C 72.61, H 7.01; found: C 72.79, H 7.08.
(þ)-(3S)-3-(4-Chlorophenyl)-1-(4-methoxyphenyl)heptan-1-one ((þ)-2k): [a]2D0 ¼ þ11.8 (c ¼ 1.5,
CH2Cl2); 100% ee (HPLC: tR 8.69 (major)).
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Received October 13, 2008