Organocatalytic kinetic resolution via intramolecular aldol reactions: Enantioselective synthesis of both enantiomers of chiral cyclohexenones

Article abstract of DOI:10.1039/b927343c

Kinetic resolution of 6-aryl-2,6-hexanediones was achieved with chiral secondary amine catalyzed intramolecular aldolization. The current kinetic resolution protocol enables the synthesis of both enantiomers of cyclohexenones with moderate to good enantioselectivity. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b927343c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalytic kinetic resolution via intramolecular aldol reactions:
Enantioselective synthesis of both enantiomers of chiral cyclohexenones†
Liujuan Chen, Sanzhong Luo,* Jiuyuan Li, Xin Li and Jin-Pei Cheng*
Received 7th January 2010, Accepted 17th March 2010
First published as an Advance Article on the web 1st April 2010
DOI: 10.1039/b927343c
Kinetic resolution of 6-aryl-2,6-hexanediones was achieved with chiral secondary amine catalyzed
intramolecular aldolization. The current kinetic resolution protocol enables the synthesis of both
enantiomers of cyclohexenones with moderate to good enantioselectivity.
desymmetrization processes, we presented herein organocatalytic
Introduction
kinetic resolutions of 6-aryl-2,6-hexanediones (e.g. R2 = Ar as
Chiral cyclohexenones are versatile chiral building blocks that
shown in Scheme 1) via intramolecular aldol condensation for
have been widely utilized in asymmetric natural product synthesis.1
Retrosynthetically, intramolecular aldol condensation reaction is
one of the most straightforward approaches for the synthesis
of chiral cyclohexenone skeletons (Scheme 1).2 One classical
example is the Hajos–Parrish–Eder–Sauer–Wiechert reaction3
which was developed in 1970 s for the synthesis of chiral Wieland–
Miescher ketones.4 Since this seminal work, a number of chiral
catalysts have been developed for this and similar reactions that
involve cyclohexenone-forming intramolecular aldol steps.5–8 For
example, based on Agami’s pioneering work with proline,5 Lerner
and Barbas6 have examined antibody 38C2 for the same aldol
cyclodehydrations with good activity but only low enantiose-
lectivity in the reactions of linear 2,6-heptanediones. Recently,
List7a and Akiyama7b reported respectively chiral primary amine
catalyst and chiral phosphoric acid catalyst for asymmetric
desymmetrization of 2,6-heptanediones via intramolecular aldol
condensation. Excellent catalytic activity and enantioselectivity
were achieved in both examples. In a manner distinctive to these
asymmetric synthesis of chiral cyclohexenones.8,9 After kinetic
resolution, the enantioenriched 6-aryl-2,6-hexanediones could be
transformed to the same cyclohexenones with opposite chiral
induction via a separate aldol condensation. Therefore, both
enantiomers of chiral cyclohexenones can be obtained from one
kinetic resolution (Scheme 1). To the best of our knowledge, such
a kinetic resolution via intramolecular aldol condensation has not
been reported so far.
Results and discussion
As a continuation to our efforts in developing chiral primary
aminocatalysis,10 we first tested a series of chiral primary amines
in the kinetic resolution of racemic 6-aryl-2,6-hexanediones 2.11
Though good activity was obtained with our previously developed
primary-tertiary diamine-Brønsted acid conjugates catalysts such
as 1b and 1c, the reactions only gave poor resolution as reflected
by the generally low s < 5 factors (Table 1, entries 2–3).12 Similar
results were obtained with chiral primary amine 1a (Table 1,
entry 1). In these reactions, only cyclodehydration product 3a
was observed. The use of other chiral primary amine catalyst
didn’t lead to any improvement, and in the cases of primary
Scheme
reaction.
1
Kinetic resolution via asymmetric intramolecular aldol
Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key
Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Science, Beijing, 100190, China. E-mail: luosz@
iccas.ac.cn; Fax: +86-10-62554449; Tel: +86-10-62554446
† Electronic supplementary information (ESI) available: Supplementary
spectra. See DOI: 10.1039/b927343c
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Table 1 Selected results of catalyst screening
Table 3 Reaction optimization
Entrya
Cat.
t/h
Conversion (%)b
ee (3a/2a,%)c
sd
Entry Condition
t/h Conversion (%)a ee (3a/2a,%)b sc
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
68
55
27
48
56
48
48
42
72
168
168
72
48
64
70
N.R
47
N.R
N.R
46
51
33
48/34
20/23
17/13
—
60/41
—
3
1
2
3
4
5
6
7
8
0.18 M/r.t.
0.18 M/r.t./4 A MS
72
72
60
36
24
42
51
43
57
56
41
47
46
72/66
62/86
76/66
57/93
60/93
80/63
75/80
78/73
43
29
30
35
19
39
48
28
˚
˚
1.5
1.2
—
4
—
—
6
10
0.8
6
0.38 M/r.t/4 A MS
˚
0.50 M/r.t./4 A MS
˚
0.75 M/r.t./4 A MS
0.38 M/4 ◦C/4 A MS 84
˚
—
0.50 M/4 ◦C/4 A MS 72
˚
36/37
63/70
39/23
54/27
67/63
0.75 M/4 ◦C/4 A MS 60
˚
9
10
11
12
1j
1k
1l
a Determined by H NMR of the reaction mixture. b From chiral HPLC
analysis. c Calculated by the formula s = ln(1 - c)(1 - eesm)/ln(1 -
c)(1 + eesm).
1
29
45
15
a Reaction concentration: 0.1875 M. b Determined by 1H NMR of the
reaction mixture. c From chiral HPLC analysis. d Calculated by the formula
s = ln(1 - c)(1 - eesm)/ln(1 - c)(1 + eesm), c: convertion, eesm: ee value of
starting material.
˚
accelerated by the addition of 4 A MS, albeit with a little sacrifice
of stereoselectivity (Table 3, entries 1 vs. 2). Finally, an optimal
s factor 48 was achieved using 0.5 M substrate at 4 ◦C in the
˚
presence of 4 A MS in CHCl3 (Table 3, entry 7).
amine-thioureas such as 1f and 1g and primary amine–amide 1d
there were even no reactions observed (Table 1, entries 4, 6–7).
After trials and errors, chiral secondary amines were found to be
the catalysts of choice for the current resolution and of a series
of chiral secondary amines examined catalyst 1i and 1l13 gave s
factors above 10 (Table 1, entries 9 and 12).
For practical kinetic processes, s factor >20 is generally
preferred. We therefore further optimized the reaction conditions
with the optimal catalysts 1i and 1l (Tables 2 and 3) in terms
of solvent, concentration, temperature and additive. Both highly
polar solvents such as DMSO and H2O and nonpolar solvents such
as toluene gave poor resolutions with s < 5 (Table 2). Chloroform
was found to be the optimal solvents for 1l-catalyzed reactions
with a s factor 43 (Table 2, entry 7). The reaction could be further
With optimal conditions established, we next investigated the
substrate scopes with different 6-aryl-2,6-hexanediones 2. In the
presence of 20 mol% 1l, all the examined reactions occurred
cleanly to afford the desired cyclohexenones products in 36–59%
isolated yields with moderate to good enantioselectivity and
the enantioenchriched starting material could be recovered with
36–49% isolated yields and 56–96% ee (Table 4).14 In all the
examined cases, only dehydrated cyclohexenones were obtained
and no aldol adducts have been observed.
The absolute configuration of 3a was determined to be S by
comparison of optical rotation with literature results (75% ee,
[a]2D0 = +20.0 (c = 0.5, CH2Cl2); lit.8a 99% ee, [a]2D3 = +36.9
(c = 2.0, CH2Cl2)). In accordance with previous reports on the
Table 4 Substrate scope
Table 2 Solvent screening
Entrya Cat Solvent t/h Conversion (%)b ee (3a/2a,%)c
sd
Entry R1
R2
t/h
3 (%) a
2 (%)b
ee (3/2,%)c
1
2
3
4
5
6
7
8
1i
1l
1i
1i
1i
1i
1l
1i
1i
1i
1i
CH2Cl2 72
CH2Cl2 72
51
45
11
25
53
35
42
10
81
61
25
63/70
67/63
64/rac
62/37
36/47
71/43
72/66
rac
10
15
—
27
4
14
43
—
3
1
2
3
4
5
6
7
8
H
H
4-Br
H
H
H
4-Br
H
H
H
H
72
124
72
124
96
72
124
124
124
72
144
48
3a/47d
3b/54
3c/59
3d/50
3e/39
3f/53
3g/43
3h/39
3i/59
3j/50
3k/50
3l/36
2a/50d
2b/41
2c/41
2d/43
2e/36
2f/43
2g/43
2h/35
2i/36
2j/45
2k/44
2l/49
75/80
46/90
35/80
70/87
70/90
32/90
75/91
82/76
66/96
55/85
66/75
70/56
3-Cl
2,4-(OMe)2
3-Cl
4-Ph
H
2-Br
4-Cl
4-OMe
2-Cl
H
NMP
DMF
PhCH3
CHCl3
CHCl3
H2O
72
72
72
50
72
82
26
9
10
11
MeOH
25/75
35/62
66/21
9
CH3CN 50
DMSO 72
4
5
10
11
12
4-Cl
4-Cl
4-Cl
a Reaction concentration: 0.18 M. b Determined by 1H NMR of the
reaction mixture. c From chiral HPLC analysis. d Calculated according to
s = ln(1 - c)(1 - eesm)/ln(1 - c)(1 + eesm).
a Isolated yield of 3. b Recovery of starting materials. c From chiral HPLC
analysis. d Determined by 1H NMR of the reaction mixture.
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similar reactions,5 cyclic chair-type transition states I and II are
proposed to account for the observed stereoselectivity (Scheme 2).
In this model, (R)-2a selectively forms (S)-3a via TS-I, whereas
the cyclic chair TS-II derived from (S)-2a is disfavored due to
the steric hindrance. The intramolecular aldol reaction of (S)-
2a is therefore kinetically slow and (S)-2a is enriched in the
resolution process. The enantioenriched (S)-2 compounds could
be readily transformed into the desired cyclohexenones (R)-3 with
quantitative yields and maintained enantioselectivity by simply
treatment with LiOH in methanol (Scheme 3).
intramolecular aldolization. The resolution reactions afforded
cleanly chiral cyclohexenones together with enantioenriched start-
ing hexanediones with moderate to high ee and excellent isolated
yields. Simple treatment of the recovered hexanediones with LiOH
produced the other enantiomers of cyclohexenones. Overall, the
current kinetic resolution protocol enables the synthesis of both
enantiomers of cyclohexenones by using a single chiral secondary
amine catalyst.
Experimental section
General
Commercial reagents were used as received, unless otherwise
1
stated. H and 13C NMR were recorded on a Bruker-DPX 300
spectrometer, and chemical shifts are reported in ppm relative
to tetramethylsilane with the solvent resonance as the internal
standard. The following abbreviations are used to designate
chemical shift mutiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, p = pentet, m = multiplet, br = broad. All first-order
splitting patterns were assigned on the basis of the appearance of
themultiplet. Splitting patterns that could not be easily interpreted
are designated as multiplet (m) or broad (br). Mass spectra were
obtained using a TOF or electrospray ionization (ESI) mass
spectrometer. Optical rotations were measured using a 1 mL cell
with a 1 dm path length on a Perkin-Elmer 341 digital polarimeter
and are reported as [a]2D0 values (c in g per 100 mL of solvent). IR
spectra were obtained from Jasco FT/IR-480 Plus instruments;
HPLC analysis was performed using Chiralcel OD-H, AS-H and
OJ-H columns purchased.
General procedure for the synthesis of catalyst 1l
Catalyst 1l: was synthesized following previous procedure.12 [a]D20 =
9.2 (c = 1.0, CHCl3), 1H NMR (300 MHz, CDCl3): d 1.60 (9 H, s),
2.03 (1H, q, J = 20.3 Hz), 2.29 (1H, s), 2.47 (2H, d, J = 6.1 Hz),
2.61–2.73 (4H, m), 3.15 (1H, dd, J = 3.1 Hz, J = 11.5 Hz), 3.15
(1H, d, J = 16.7 Hz), 3.40–3.49 (1H, m), 4.12 (1H, t, J = 8.1 Hz),
4.49 (2H, s), 7.25–7.36 (5H, m); 13C NMR (75 MHz, CDCl3): d
27.1, 28.2, 37.0, 52.1, 55.5, 55.9, 63.1, 69.9, 79.6, 127.6, 128.4,
138.5; IR (KBr): 3329, 2923, 2853, 1605, 1497, 1454, 1094, 734,
697 cm-1; HRMS for C18H28N2O (M+H+), calcd 289.2280, found
289.2267.
Scheme 2 Proposed transition states.
Representative procedure for synthesis of substrate 2
Synthesis of 2a. To the solution of chalcone (1.25 g, 6 mmol)
and I2 (30.4 mg, 1.2 mmol) in 60 ml CH2Cl2 at 0 ◦C, allyltrimethyl-
silane was added very slowly. The mixture was then allowed to
warm to room temperature and stirred overnight. Water was
added to quench the reaction and the solution was extracted with
CH2Cl2 3 times. The combined organic layer was washed with
15% solution of sodium thiosulfate and dried over anhydrous
Na2SO4. After concentrated in vacuo, the residue was purified by
column chromatography on silica gel to give the allylation product
(750 mg, 67% yield). To a three-necked round-bottom flask, PdCl2
(142 mg, 0.8 mmol), CuCl (391.6 mg, 4 mmol) and DMF–H2O
(6 ml/0.72 ml) was added and the solution was saturated with
oxygen. The above obtained allylic compound was then added
slowly and the resulted solution was stirred for 20 h under the
Scheme 3 Transformation of (S)-2 to 3 with LiOH.
Conclusion
In conclusion, we developed a novel kinetic resolution of 6-aryl-
2,6-hexanediones via chiral secondary amine, e.g. 1l, catalyzed
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oxygen atmosphere. After completion as indicated by TLC, the
reaction was quenched by the addition of water and the solution
was extracted by CH2Cl2 for 3 times. The combined organics were
washed with brine and dried over anhydrous Na2SO4. Purification
by column chromatography on silica gel gave known desired
product (520 mg, 70% yield).
2-propanol: hexane=20 : 80, 25 ◦C, 0.5 mL min-1, tR = 24.63 min
(minor), tR = 29.22 min (major)).
2d. The corresponding compound was obtained according to
above procedure in 40% yield. [a]2D0 = +2.4 (c = 0.5, CHCl3), 1H
NMR (300 MHz, CDCl3): d 2.10 (3H, s), 2.81 (1H, dd, J = 7.4 Hz,
J = 16.9 Hz), 2.93 (1H, dd, J = 6.6 Hz, J = 16.9 Hz), 3.25 (1H, dd,
J = 7.0 Hz, J = 16.8 Hz), 3.39 (1H, dd, J = 7.0 Hz, J = 16.8 Hz),
3.87 (1H, p, J = 6.9 Hz), 7.13–7.25 (4H, m), 7.42–7.47 (2H,
m), 7.53–7.58 (1H, m), 7.89–7.92 (2H, m); 13C NMR (75 MHz,
CDCl3): d 30.3, 36.3, 44.5, 49.3, 125.9, 126.9, 127.5, 128.1, 128.6,
129.9, 133.2, 134.4, 136.7, 145.9, 198.0, 206.6; IR(KBr): 1713,
1686, 1596, 1573, 1447, 782, 754, 693 cm-1. HRMS for C18H18ClO2
(M+H+), calcd. 301.0995, found 301.1007; enantioselective excess
was determined to be 87% by ◦chiral HPLC (Chiralpak AS-H,
2-propanol: hexane=20 : 80, 25 C, 0.5 mL min-1, tR = 23.34 min
(major), tR = 27.46 min (minor)).
General procedure for the intramolecular aldol reactions
To the mixture of racemic compound 2 (0.075 mmol), 1l
˚
(0.015 mmol) and 4 A MS (10 mg) was added chloroform 150 ml
◦
at rt and the resulted solution was stirred at 4 C. The reaction
was monitored by TLC or 1H NMR till ca. 50% conversion
of substrate 2. The reaction mixture was then directly loaded
onto a silica gel column to afford the desired product 3 (ethyl
acetate/petroleum ether = 1 : 8) and the remaining substrate 2
(ethyl acetate/petroleum ether = 1 : 4). Alternatively, the reaction
mixture was first treated with sat. NH4Cl to quench the reaction
and the organic layer was separated and purified by flash
chromatography after concentration.
2e. The corresponding compound was obtained according to
above procedure in 37% yield. [a]2D0 = +3.0 (c = 0.5, CHCl3), 1H
NMR (300 MHz, CDCl3): d 2.11 (3H, s), 2.89 (1H, dd, J = 7.5 Hz,
J = 16.7 Hz), 2.99 (1H, dd, J = 6.7 Hz, J = 16.7 Hz), 3.30–3.46
(2H, m), 3.97 (1H, p, J = 7.0 Hz), 7.30–7.35 (3H, m), 7.41 (2H, d,
J = 7.7 Hz), 7.46 (2H, d, J = 7.8 Hz), 7.50–7.57 (5H, m), 7.94 (2H,
d, J = 7.4 Hz); 13C NMR (75 MHz, CDCl3): d 30.4, 36.4, 44.8, 49.6,
127.0, 127.2, 127.4, 127.8, 128.1, 128.6, 128.7, 133.2, 136.8, 139.6,
140.8, 142.8, 198.5, 207.26; IR (KBr): 1710.6, 1686.4, 1594.8,
1580.4, 1486.9, 1449, 840, 766, 692 cm-1; HRMS for C24H23O2
(M+H+), calcd. 343.1698, found 343.1703; enantioselective excess
was determined to be 90% by ◦chiral HPLC (Chiralpak AS-H, 2-
propanol: hexane=20 : 80, 25 C, 0.5 mL min-1, tR = 25.34 min
(major), tR = 27.90 min (minor)).
General procedure for transformation of (S)-2 to 3 with LiOH
To the isolated unreacted (S)-2 in MeOH, was added LiOH (10%
in methanol, 150 ml) at 0 ◦C. The reaction was monitored by
TLC. When the reaction was completed, the reaction mixture
was directly loaded onto a silica gel column to afford the desired
product 3 (ethyl acetate/petroleum ether = 1 : 8) in quantitative
yield.
2a,15a 2i,15b 3a,8a 3h,15c 3i,15d 3k15e and 3l15c,15e are known
compounds.
2b. The corresponding compound was obtained according to
above procedure in 35% yield. [a]2D0 = +2.0 (c = 0.4, CHCl3), 1H
NMR (300 MHz, CDCl3): d 2.10 (3H, s), 2.80 (1H, dd, J = 7.1 Hz,
J = 17.1 Hz), 2.91 (1H, dd, J = 6.9 Hz, J = 17.1 Hz), 3.21 (1H,
dd, J = 7.2 Hz, J = 16.7 Hz), 3.32 (1H, dd, J = 6.7 Hz, J =
16.7 Hz), 3.84 (1H, p, J = 6.9 Hz), 7.11–7.28 (4H, m), 7.58 (2H,
d, J = 8.5 Hz), 7.77 (2H, d, J = 8.5 Hz); 13C NMR (75 MHz,
CDCl3): d 30.4, 36.2, 44.4, 49.27, 125.8, 127.0, 127.5, 128.5,
129.6, 129.9, 132.0, 134.4, 135.4, 145.7, 197.0, 206.6; IR (KBr):
1713, 1687, 1585, 812, 783, 696 cm-1. HRMS for C18H17BrClO2
(M+H+), calcd. 379.0100, found 379.0099; enantioselective excess
was determined to be 93% by chiral HPLC (Chiralpak OD-H,
2-propanol: hexane = 20 : 80, 25 ◦C, 0.5 mL min-1, tR = 9.67 min
(minor), tR = 11.60 min (major)).
2f. The corresponding compound was obtained according to
1
above procedure in 35% yield. [a]2D0 = -2.0 (c = 0.5, CHCl3), H
NMR (300 MHz, CDCl3): d 2.11 (3H, s), 2.82 (1H, dd, J = 6.8 Hz,
J = 13.9 Hz), 2.95 (1H, dd, J = 7.1 Hz, J = 16.8 Hz), 3.24 (1H,
dd, J = 7.1 Hz, J = 16.4 Hz), 3.35 (1H, dd, J = 6.9 Hz, J =
16.4 Hz), 3.87 (1H, p, J = 7.0 Hz), 7.17–7.23 (4H, m), 7.28–7.32
(1H, m), 7.57 (2H, dd, J = 2.2 Hz, J = 7.7 Hz), 7.77 (2H, dd,
J = 1.8 Hz, J = 8.6 Hz); 13C NMR (75 MHz, CDCl3): d 30.4,
36.8, 44.8, 49.6, 126.9, 127.3, 128.3, 128.7, 129.7, 131.9, 135.5,
143.4, 197.6, 207.2; IR (KBr): 1713, 1683, 1584, 1494, 1453, 813,
759, 700 cm-1; HRMS for C18H18BrO2 (M+H+), calcd. 345.0490,
found 345.0491; enantioselective excess was determined to be 90%
by chiral HPLC (Chiralpak OD-H, 2-propanol: hexane=20 : 80,
◦
25 C, 1.0 mL min-1, tR = 11.06 min (minor), tR = 12.89 min
2c. The corresponding compound was obtained according to
above procedure in 40% yield. [a]2D0 = +7.6 (c = 0.5, CHCl3),
1H NMR (300 MHz, CDCl3): d 2.10 (3H, s), 2.86 (1H, dd, J =
7.4 Hz, J = 16.3 Hz), 2.95 (1H, dd, J = 6.9 Hz, J = 16.3 Hz),
3.30 (2H, d, J = 7.0 Hz), 3.78 (3H, s), 3.79 (3H, s), 4.10 (1H, p,
J = 7.0 Hz), 6.40 (2H, dd, J = 2.4 Hz, J = 9.7 Hz), 7.07 (1H, d,
J = 8.7 Hz), 7.41–7.45 (2H, m), 7.51–7.56 (1H, m), 7.94 (2H, dd,
J = 1.5 Hz, J = 18.6 Hz); 13C NMR (75 MHz, CDCl3): d 30.1,
31.9, 43.5, 48.2, 55.3, 55.3, 98.9, 104.0, 123.6, 128.2, 128.2, 128.9,
132.9, 137.0, 157.9, 159.5, 199.3, 208.2; IR (KBr): 1711, 1679,
1611, 1587, 1504, 1449, 835, 755, 691 cm-1; HRMS for C20H22O4
(M+H+), calcd. 327.1596, found 327.1606; enantioselective excess
was determined to be 80% by chiral HPLC (Chiralpak AS-H,
(major)).
2g. The corresponding compound was obtained according to
above procedure in 37% yield. [a]2D0 = -22.4 (c = 0.5, CHCl3),
1H NMR (300 MHz, CDCl3): d 2.14 (3H, s), 2.84–3.01 (2H, m),
3.37 (2H, dd, J = 1.0 Hz, J = 6.6 Hz), 4.31–4.40 (1H, m), 7.03–
7.09 (1H, m), 7.24–7.27 (2H, m), 7.42–7.47 (2H, m), 7.53–7.57
(2H, m), 7.93–7.96 (2H, m); 13C NMR (75 MHz, CDCl3): d 30.0,
35.9, 43.1, 48.0, 124.4, 127.7, 128.0, 128.1, 128.6, 133.2, 133.4,
136.7, 142.3, 198.2, 207.1; IR (KBr): 1713, 1684, 1597, 1447, 752,
690 cm-1. HRMS for C18H18BrO2 (M+H+), calcd 345.0490, found
345.0508; enantioselective excess was determined to be 90% by
chiral HPLC (Chiralpak AS-H, 2-propanol: hexane = 20 : 80,
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◦
25 C, 0.5 mL min-1, tR = 21.09 min (minor), tR = 24.55 min
2-propanol: hexane = 20 : 80, 25 ◦C, 1.0 mL min-1, tR = 8.05 min
(minor), tR = 8.87 min (major)).
(major)).
3b. 1H NMR (300 MHz, CDCl3): d 2.63–2.81 (2H, m), 2.83–
3.04 (2H, m), 3.39–3.49 (1H, m), 6.49 (1H, d, J = 2.0 Hz), 7.17–
7.20 (1H, m), 7.28–7.34 (3H, m), 7.41 (2H, d, J = 8.6 Hz), 7.55
(2H, d, J = 8.6 Hz); 13C NMR (75 MHz, CDCl3): d 35.9, 40.7, 43.6,
124.7, 125.0, 125.4, 127.1, 127.4, 127.7, 130.2, 132.1, 134.7, 137.1,
145.0, 157.0, 198.3; IR (KBr): 1656, 1597, 1582, 1491, 1431, 1262,
805, 779 cm-1; HRMS for C18H15BrClO (M+H+), calcd. 360.9995,
found 360.9993; Enantioselective excess was determined to be 46%
by chiral HPLC (Chiralpak OD-H, 2-propanol: hexane = 20 : 80,
2h. The corresponding compound was obtained according to
above procedure in 40% yield. [a]2D0 = +2.0 (c = 0.5, CHCl3), 1H
NMR (300 MHz, CDCl3): d 2.11 (3H, s), 2.82 (1H, dd, J = 7.5 Hz,
J = 16.9 Hz), 2.94 (1H, dd, J = 6.7 Hz, J = 16.9 Hz), 3.26 (1H, dd,
J = 7.2 Hz, J = 16.7 Hz), 3.36 (1H, dd, J = 6.8 Hz, J = 16.7 Hz),
3.89 (1H, p, J = 7.0 Hz), 7.18–7.26 (4H, m), 7.43–7.48 (2H,
m), 7.55–7.60 (1H, m), 7.91–7.94 (2H, m); 13C NMR (75 MHz,
CDCl3): d 30.4, 36.0, 44.6, 49.5, 128.1, 128.6, 128.7, 128.8, 132.4,
133.3, 136.7, 142.2, 198.1, 206.8; IR (KBr): 1580, 1495, 1447, 813,
752, 689 cm-1; HRMS for C18H18ClO2 (M+H+), calcd. 301.0995,
found 301.1011; enantioselective excess was determined to be 76%
by chiral HPLC (Chiralpak OD-H, 2-propanol: hexane = 20 : 80,
◦
25 C, 1.0 mL min-1, tR = 19.48 min (major), tR = 22.65 min
(minor)).
3c. 1H NMR (300 MHz, CDCl3): d 2.67–2.86 (2H, m), 2.89–
3.08 (2H, m), 3.70–3.80 (1H, m), 3.84 (6H, s), 6.52 (3H, d, J =
2.5 Hz), 7.16 (1H, d, J = 9.1 Hz), 7.43 (3H, t, J = 6.4 Hz), 7.57–7.60
(2H, m); 13C NMR (75 MHz, CDCl3): d 34.7, 34.7, 42.9, 55.3, 55.4,
98.9, 104.1, 123.8, 125.0, 126.2, 127.5, 128.8, 130.0, 138.7, 158.2,
159.6, 159.8, 200.3; IR (KBr): 1655, 1612, 1587, 1506, 1446, 1263,
840, 690 cm-1; HRMS for C20H21O3 (M+H+), calcd. 309.1941,
found 309.1488; enantioselective excess was determined to be 35%
by chiral HPLC (Chiralpak AS-H, 2-propanol: hexane = 20 : 80,
◦
25 C, 0.5 mL min-1, tR = 15.37 min (major)), tR = 16.08 min
(minor)).
2j. The corresponding compound was obtained according to
above procedure in 38% yield. [a]2D0 = -11.2 (c = 0.5, CHCl3),
1H NMR (300 MHz, CDCl3): d 2.12 (3H, s), 2.84–3.01 (2H, m),
3.36–3.38 (2H, dd, J = 1.7 Hz, J = 7.1 Hz), 4.31–4.40 (1H, m),
7.10–7.22 (2H, m), 7.25–7.28 (1H, m), 7.35 (1H, dd, J = 1.5 Hz,
J = 7.7 Hz), 7.41–7.46 (2H, m), 7.52–7.57 (1H, m), 7.93 (2H, dd,
J = 1.6 Hz, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3): d 30.1,
33.4, 42.9, 47.8, 127.1, 127.9, 128.1, 128.3, 128.6, 130.1, 133.2,
133.6, 136.7, 140.6, 198.3, 207.1; IR (KBr): 1713, 1683, 1597, 1447,
751, 689 cm-1. HRMS for C19H21ClO3 (M+Na+), calcd. 319.1334,
found 319.1331; enantioselective excess was determined to be 85%
by chiral HPLC (Chiralpak OJ-H, 2-propanol: hexane = 20 : 80,
◦
25 C, 1.0 mL min-1, tR = 44.66 min (minor), tR = 64.70 min
(major)).
3d. 1H NMR (300 MHz, CDCl3): d 2.64–2.81 (2H, m), 2.86–
3.10 (2H, m), 3.39–3.50 (1H, m), 6.52 (1H, d, J = 2.2 Hz), 7.19 (1H,
dd, J = 1.8 Hz, J = 1.6 Hz), 7.27–7.34 (3H, m), 7.40–7.45 (3H, m),
7.54–7.57 (2H, m); 13C NMR (75 MHz, CDCl3): d 36.1, 40.7, 43.7,
125.0, 125.2, 126.2, 127.1 127.3, 128.9, 130.2, 130.3, 134.4, 138.2,
145.2, 158.5, 198.6; IR (KBr): 1662, 1605, 1573, 1496, 1446, 1256,
758, 694 cm-1; HRMS for C18H16ClO (M+H+), calcd. 283.0890,
found 283.0891; enantioselective excess was determined to be 70%
by chiral HPLC (Chiralpak AS-H, 2-propanol: hexane = 20 : 80,
◦
25 C, 1.0 mL min-1, tR = 17.19 min (minor), tR = 27.29 min
(major)).
2k. The corresponding compound was obtained according to
1
above procedure in 41% yield. H NMR (300 MHz, CDCl3): d
2.10 (3H, s), 2.85 (1H, dd, J = 7.1 Hz, J = 16.7 Hz), 2.95 (1H,
dd, J = 7.0 Hz, J = 16.8 Hz), 3.25 (1H, dd, J = 7.2 Hz, J =
16.4 Hz), 3.35 (1H, dd, J = 6.8 Hz, J = 16.4 Hz), 3.87 (1H, p,
J = 7.0 Hz), 7.18–7.32 (5H, m), 7.41 (2H, dd, J = 2.0 Hz, J =
8.7 Hz), 7.84–7.88 (2H, m); 13C NMR (75 MHz, CDCl3): d 30.4,
36.8, 44.8, 49.6, 126.8, 127.4, 128.7, 128.9, 129.6, 135.2, 139.5,
143.5, 197.3, 207.2; IR (KBr): 1714, 1684, 1589, 1494, 1453, 816,
761, 700 cm-1; HRMS for C18H18ClO2 (M+H+), calcd. 301.0995,
found 301.1006; enantioselective excess was determined to be 75%
by chiral HPLC (Chiralpak AS-H, 2-propanol: hexane = 20 : 80,
◦
25 C, 1.0 mL min-1, tR = 26.74 min (minor), tR = 39.87 min
(major)).
3e. 1H NMR (300 MHz, CDCl3): d 2.74–2.89 (2H, m), 2.95–
3.18 (2H, m), 3.49–3.60 (1H, m), 6.58 (1H, d, J = 2.1 Hz),
7.36–7.50 (8H, m), 7.59–7.65 (6H, m); 13C NMR (75 MHz,
CDCl3): d 36.4, 40.7, 44.0, 125.2, 126.2, 127.1, 127.3, 127.4, 127.6,
128.9, 128.9, 130.2, 138.4, 140.1, 140.7, 142.3, 158.8, 199.2; IR
(KBr): 1658, 1605, 1570, 1486, 1444, 1255, 832, 762, 694 cm-1.
HRMS for C24H21O (M+H+), calcd. 325.1592, found 325.1589.
Enantioselective excess was determined to be 70% by chiral
HPLC (Chiralpak AS-H, 2-propanol: hexane = 20 : 80, 25 ◦C,
1.0 mL min-1, tR = 36.60 min (minor), t R = 53.83 min (major)).
◦
25 C, 0.5 mL min-1, tR = 24.40 min (major), tR = 28.45 min
(minor)).
2l. The corresponding compound was obtained according to
1
above procedure in 42% yield. H NMR (300 MHz, CDCl3): d
3f. 1H NMR (300 MHz, CDCl3): d 2.67–2.83 (2H, m), 2.85–
3.05 (2H, m), 3.40–3.51 (1H, m), 6.49 (1H, d, J = 2.1 Hz), 7.30
(3H, d, J = 7.2 Hz), 7.36–7.43 (4H, m), 7.56 (2H, dd, J = 2.0 Hz,
J = 6.8 Hz); 13C NMR (75 MHz, CDCl3): d 36.2, 41.0, 43.9,
124.6, 125.4, 126.8, 127.2, 127.7, 128.9, 132.1, 137.3, 143.0, 157.3,
199.0; IR (KBr): 1657, 1604, 1586, 1491, 1454, 1263, 808, 766,
700 cm-1. HRMS for C18H16BrO (M+H+), calcd. 327.0385, found
327.0380. Enantioselective excess was determined to be 32% by
chiral HPLC (Chiralpak OD-H, 2-propanol: hexane = 20 : 80,
2.11 (3H, s), 2.81(1H, dd, J = 7.1 Hz, J = 17.0 Hz), 2.93 (1H,
dd, J = 6.9 Hz, J = 17.0 Hz), 3.21 (1H, dd, J = 7.4 Hz, J =
16.6 Hz), 3.34 (1H, dd, J = 6.6 Hz, J = 16.6 Hz), 3.85 (1H, p,
J = 7.0 Hz), 7.19 (2H, dd, J = 2.0 Hz, J = 7.5 Hz), 7.24–7.28
(2H, m), 7.43 (2H, dd, J = 1.7 Hz, J = 6.9 Hz), 7.86 (2H, d, J =
8.6 Hz); 13C NMR (75 MHz, CDCl3): d 30.4, 36.0, 44.5, 49.5, 128.8,
129.0, 129.4, 129.5, 132.5, 135.0, 139.7, 142.0, 197.0, 206.8; IR
(KBr): 1710, 1686, 1589, 1495, 811 cm-1; HRMS for C18H17Cl2O2
(M+H+), calcd. 335.0606, found 335.0606; enantioselective excess
was determined to be 56% by chiral HPLC (Chiralpak OD-H,
◦
25 C, 1.0 mL min-1, tR = 16.46 min (major), tR = 18.74 min
(minor)).
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3g. 1H NMR (300 MHz, CDCl3): d 2.60–2.72 (2H, m), 2.74–
2.81 (1H, m), 3.08 (1H, dd, J = 4.2 Hz, J = 17.6 Hz), 3.83–
3.94 (1H, m), 6.45 (1H, d, J = 2.2 Hz), 7.05–7.11 (1H, m),
7.25–7.31 (2H, m), 7.33–7.37 (3H, m), 7.46–7.55 (3H, m); 13C
NMR (75 MHz, CDCl3): d 34.8, 39.8, 42.7, 124.4, 125.2, 126.2,
127.3, 128.0, 128.6, 128.9, 130.3, 133.5, 138.3, 141.8, 158.7, 198.8;
IR (KBr): 1659, 1601, 1570, 1495, 1444, 1261, 756, 689 cm-1.
HRMS for C18H16BrO (M+H+), calcd. 327.0385, found 327.0380.
Enantioselective excess was determined to be 75% by chiral
HPLC (Chiralpak AS-H, 2-propanol: hexane = 20 : 80, 25 ◦C,
1.0 mL min-1, tR = 73.19 min (minor), tR = 77.66 min (major)).
3 (a) Z. G. Hajos and D. R. Parrish, Germany Patent DE 21022623,
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1385–1386; (b) C. Agami, N. Platzer and H. Sevestre, Bull. Soc. Chim.
Fr., 1987, 2, 358–360; (c) N. Harada, T. Sugioka, H. Uda and T.
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S. Swaminathan, Tetrahedron: Asymmetry, 1996, 7, 2189–2190; (e) T.
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3j. 1H NMR (300 MHz, CDCl3): d 2.68–2.77 (2H, m), 2.80–
2.91 (2H, m), 3.13 (1H, dd, J = 4.7 Hz, J = 17.6 Hz), 3.93–4.04
(1H, m), 6.52 (1H, d, J = 2.2 Hz), 7.19–7.35 (3H, m), 7.37–7.44
(4H, m), 7.54–7.57 (2H, m); 13C NMR (75 MHz, CDCl3): d 34.6,
37.2, 42.5, 125.2, 126.2, 127.2, 127.4, 128.3, 128.9, 130.1, 130.3,
133.7, 138.3, 140.2, 158.8, 198.9; IR (KBr): 1660, 1600, 1570, 1494,
1444, 1261, 755, 696 cm-1; HRMS for C18H16ClO (M+H+), calcd.
283.0890, found 283.0890; enantioselective excess was determined
to be 55% by chiral HPLC (Chiralpak OJ-H, 2-propanol: hexane =
20 : 80, 25 ◦C, 1.0 mL min-1, tR = 13.75 min (major), tR = 14.70 min
(minor)).
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Yamanaka and T. Akiyama, Angew. Chem. Int. Ed., 2009, 48, 9652–
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Thomson, Org. Biomol. Chem., 2007, 5, 3190–3200; (d) S. G. Davies,
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8 For other similar intramolecular aldol processes, see: (a) F.-Y. Zhang
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H.-F. Wang, M. X.-K. Chen, H.-F. Cui, C.-W. Zheng, H. Xiao, P. Li
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Acknowledgements
9 b-amino acid catalyzed dynamic kinetic resolution via an intermolec-
ular aldol reaction, see: J. Yang, T. Wang, Z. Ding, Z. Shen and Y.
Zhang, Org. Biomol. Chem., 2009, 7, 2208–2213.
We would likely to thank the Natural Science Foundation (NSFC
20632060 and 20702052), MOST (2008CB617501, 2009ZX09501-
018) and the Chinese Academy of Sciences for their supports.
10 (a) S. Luo, H. Xu, J. Li, L. Zhang and J.-P. Cheng, J. Am. Chem. Soc.,
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11 2 was synthesized according to the general procedures: (a) J. S. Yadav,
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Asami, Bull. Chem. Soc. Jpn., 1990, 63, 721–727; For chiral secondary
diamine catalysis, see: (b) S. Saito and H. Yamamoto, Acc. Chem. Res.,
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14 The recovered starting material 2 generally gave higher ee than the
one estimated based on the ee and conversion of product 3, suggesting
another enantio-enriched process, but unproductive by-pathway in the
resolution. Careful examination of the reaction mixture indicated a
minor uncharacterized byproduct.
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Notes and references
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2632 | Org. Biomol. Chem., 2010, 8, 2627–2632
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The Royal Society of Chemistry 2010
©