Zirconium-BINOLate-catalyzed, enantioselective aldol-Tishchenko reactions of aromatic ketone aldols

Article abstract of DOI:10.1016/j.tetasy.2006.10.019

3,3′-Substituted BINOL's have been identified as suitable chiral ligands for the zirconium-catalyzed aldol-Tishchenko reaction of aromatic ketone aldols with aliphatic aldehydes. 1,3-anti-Diol monoesters were obtained in excellent yields, complete anti-diastereocontrol, and enantioselectivities of up to 60% ee.

Full text of DOI:10.1016/j.tetasy.2006.10.019

Tetrahedron: Asymmetry 17 (2006) 2738–2742
Zirconium–BINOLate-catalyzed, enantioselective
aldol-Tishchenko reactions of aromatic ketone aldols
Christoph Schneider,* Markus Hansch and Pankajakshan Sreekumar
Institut fu¨r Organische Chemie, Universita¨t Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
Received 24 July 2006; accepted 16 October 2006
Abstract—3,30-Substituted BINOL’s have been identified as suitable chiral ligands for the zirconium-catalyzed aldol-Tishchenko reaction
of aromatic ketone aldols with aliphatic aldehydes. 1,3-anti-Diol monoesters were obtained in excellent yields, complete anti-diastereo-
control, and enantioselectivities of up to 60% ee.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tinct limitation in all of these processes is the necessity to
employ aromatic aldehydes as coupling partners because
aliphatic aldehydes compete with the ketones in the enoli-
zation event.
The aldol-Tishchenko reaction has a long history in the
direct, one-step synthesis of 1,3-dioxygenated compounds.1
Much of the appeal of this transformation is based upon
the domino-type pathway which does not require isolation
or purification of the intermediate aldol product.2 In recent
years, a number of reports from different groups3–9 have
addressed the issue of relative and absolute stereocontrol
in this reaction culminating in the first catalytic, enantio-
selective aldol-Tishchenko reaction of isobutyraldehyde
and aromatic aldehydes reported by Morken et al.10 Subse-
quently, Shibasaki et al.11 established the first highly enan-
tioselective aldol-Tishchenko reaction of alkyl aryl ketones
and aromatic aldehydes catalyzed by a heterobimetallic
complex. Mlynarski et al.12 utilized chiral ytterbium cata-
lysts for reactions of dialkyl ketones whereas Mahrwald
et al.13 employed Ti(OtBu)4/cinchona alkaloid-combina-
tions for stoichiometric aldol-Tishchenko reactions. A dis-
We14 and Nevalainen et al.15 have independently devised a
conceptually different strategy. We found that ketone aldol
adducts such as diacetone alcohol 1a are excellent precur-
sors for the in situ-generation of metal enolates through
a retro-aldol process upon treatment with either Zr- or
Al-based catalysts, respectively. When for example 1a
and isobutyraldehyde 2a (2 equiv) were treated with
Zr(OtBu)4 (10 mol %) in CH2Cl2 at 0 ꢁC for 2 h, a 11:1-
mixture of differentiated 1,3-anti-diol monoesters 3a/3a0
was obtained in high yield (Scheme 1).14
Apparently, 3a/3a0 were formed via an initial aldol reaction
of the presumed acetone enolate followed by a highly
anti-diastereoselective Tishchenko reduction of the result-
O
OH
O
O
O
OH
OH
O
O
Zr(OtBu)4
+
+
H
CH2Cl2, 0 ºC
84% (11:1)
2a
1a
3a
3a'
Scheme 1. The Zr-catalyzed aldol-Tishchenko reaction of ketone aldols.
*
Corresponding author. Tel.: +49 341 9736559; fax: +49 341 9736599; e-mail: schneider@chemie.uni-leipzig.de
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.019

C. Schneider et al. / Tetrahedron: Asymmetry 17 (2006) 2738–2742
2739
ing b-hydroxy ketone with a second equivalent of the alde-
hyde. The small amount of regioisomer 3a0 resulted from
unselective Zr-catalyzed acyl migration. Subsequently, we
reported the first catalytic, enantioselective aldol-Tish-
chenko reaction of ketone aldols which employed Zr–
TADDOLate-complexes as chiral catalysts.16
(OtBu)4 (10 mol % each) in CH2Cl2 which was found to
be the solvent of choice.
As is evident from inspection of Table 1, all reactions pro-
ceeded in high yield and complete 1,3-anti-diastereocontrol
as expected but furnished the product 6a with varying
enantioselectivities. The most promising levels of enantio-
selectivity were obtained with aromatic substituents in the
3- and 30-positions of the BINOL backbone carrying a che-
lating ortho-methoxy group. Thus, when Zr(OtBu)4 and
3,30-di-o-anisyl-2-20-binaphthol 5c18 (10 mol % each) were
mixed in CH2Cl2 prior to the addition of 2a (3 equiv)
and 4a, the aldol-Tishchenko product 6a was formed in
90% yield and with 60% ee (Table 1, entry 3). In addition,
no acyl migration occurred and 6a was formed as a single
regioisomer. The absolute configuration of 6a was esta-
blished through conversion into aldol product 7 via hydro-
lysis (KOH, MeOH) and chemoselective oxidation of the
aryl carbinol with PDC19 and comparison of the specific
rotation value with the literature data.20
In our preliminary experiments we could not achieve a sat-
isfactory reaction with the catalyst Zr(OtBu)4/(R)-BINOL
in terms of yield and enantioselectivity which we attributed
to the formation of oligomeric zirconium species with this
rather small diol ligand. We speculated that substitution of
the binaphthol backbone in the 3- and 30-position, would
lead to more reactive and possibly more enantioselective
zirconium catalysts on the basis of the increased steric bulk
in the backbone of the ligand. In this communication we
show that 3,30-substituted 2,20-binaphthols with additional
chelating groups are indeed selective chiral ligands for the
zirconium-catalyzed aldol-Tishchenko reaction of aromatic
ketone aldols.
OH
O
2. Results and discussion
7
As a model reaction we selected the reaction of aceto-
phenone-based ketone aldol 4a and isobutyraldehyde (2a)
(3 equiv) in CH2Cl2 at 0 ꢁC since this transformation
constantly gave rise to very low enantioselectivity with
the Zr–TADDOLates (Table 1).16 Various 3,30-substituted
2,20-binaphthols 5a–g which were easily available through
cross-coupling chemistry according to the Snieckus proto-
col17 were screened as chiral ligands together with Zr-
Additional alkyl and alkoxy substituents on the phenyl ring
of the ligand did not alter the enantioselectivity signifi-
cantly except for a bulky 3-substituent which presumably
affected the coordination ability of the methoxy group (en-
try 5). Replacing the ortho-methoxy group with an ethyl
group of similar steric size resulted in a complete loss
of enantioselectivity (entry 6).When the ortho-methoxy
Table 1. The Zr–BINOLate-catalyzed aldol-Tishchenko reaction of ketone aldol 4a and isobutyraldehyde 2a with various (R)-BINOL-ligands 5a–g
10 mol-%
Zr(OtBu) /( )-BINOL
O
OH
O
O
O
OH
5
R
4
+
H
º
CH2Cl2, 0 , 2 h
C
exclusively 1,3-
anti
2a
4a
6a
Ar
5a
: Ar = Ph
5b: Ar = 4-tBu-Ph
5c: Ar = 2-MeO-Ph
5d: Ar = 2,4-(MeO)2-Ph
OH
OH
OH OMe
OH OMe
5e: Ar = 2-MeO-3,5-(tBu)2-Ph
5g
5f
: Ar = 2-Et-Ph
Ar
Entry
Ligand
Ar
eea (%)
Yieldb (%)
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
Ph
4-tBu–Ph
2-MeO–Ph
2,4-(MeO)2–Ph
2-MeO–3,5-(tBu)2–Ph
2-Et–Ph
11
26
60
57
7
89
88
90
75
95
91
71
0
8
5g
CH2–2-(MeO)–Ph
a Determined by HPLC-analysis of the crude product on a Chiracel-OD-phase with hexane/iPrOH 97:3.
b Isolated yield of the purified material.

2740
C. Schneider et al. / Tetrahedron: Asymmetry 17 (2006) 2738–2742
phenyl groups in the 3,30-positions of the BINOL back-
bone were changed to ortho-methoxy benzyl groups, the
enantioselectivity again dropped sharply suggesting a strict
requirement for 7-membered chelates (entry 7). From these
experiments it appears likely that intramolecular coordina-
tion of at least one of the ortho-methoxy groups to the
Lewis acidic zirconium atom occurs with a beneficial effect
on the enantioselectivity of the aldol-Tishchenko reaction.
Pu et al.21 and Jorgensen et al.22 have observed similar phe-
nomena in Et2Zn-addition to aldehydes and Al–BINOLate
catalyzed hetero Diels–Alder reactions, respectively.
4. Experimental
4.1. General
All reactions were performed in flame–dried glassware
under a dry nitrogen atmosphere. The solvents used for
the reactions were distilled from appropriate drying agents
prior to use. Diethyl ether, petroleum ether, and pentane
for chromatography were of technical grade and distilled
from KOH before use. All reactions were followed by
TLC on precoated silica gel SIL G/UV 254 plates (Mach-
ery, Nagel & Co.). Flash column chromatography was per-
formed by using Merck silica gel 60 230–400 mesh.
Zr(OtBu)4 was purchased from Strem Chemical Co. as
99.99% PURATREM quality, packed in ampules. The
ketone aldols were prepared according to literature proce-
dure.14 All other chemicals were used as received from
The catalyst combination Zr(OtBu)4/5c (10 mol %) was
subsequently employed in aldol-Tishchenko reactions of
various aromatic ketone aldols 4a–d and aliphatic alde-
hydes (Table 2). The product 1,3-diol monoesters 6a–i were
generally obtained in good to excellent yields, complete 1,3-
anti-diastereoselectivity and with enantiomeric excesses of
up to 60% ee. As a general trend, a-branched aldehydes
gave rise to more enantioselective reactions than straight-
chain aldehydes, whereas variations within the ketone aldol
component did not appear to have significant effects on the
selectivity. The anti-diastereoselectivity of the Tishchenko
step may best be explained through the model first put
forth by Evans and Hoveyda in their samarium-catalyzed
Tishchenko reduction.23 Use of chiral ligand 5c with differ-
ent enantiopurities revealed a linear correlation between
the ee of the product and that of the ligand suggesting a
monomeric catalyst species.24
1
commercial suppliers. H and 13C spectra were recorded
with 200 MHz (Gemini 2000), 300 MHz (Mercury 300) or
400 MHz (Mercury 400) varian systems in CDCl3 at
25 ꢁC with TMS as internal standard. IR spectra were
recorded with a Bruker avatar 360 FT-IR instrument.
Mass spectra were measured with electron spray ionization
(ESI) technique using an FT-ICR-MS Bruker Daltronics
APEX II instrument or with a 70 eV EI Masscom MAT
8230 instrument. The enantiomeric excess (ee) was deter-
mined with a Jasco 2080 HPLC instrument with a CHI-
RALCEL OD column and hexane/isopropanol 97:3 as
eluent. The optical rotations were measured using
(Schmidt + Haensch) Polartronic-D digital polarimeter.
3. Conclusion
4.2. General procedure for the catalytic, enantioselective
aldol-Tishchenko reaction
In conclusion, we have devised a novel chiral catalyst
system for the enantioselective aldol-Tishchenko reaction
between ketone aldols as enol equivalents and aliphatic
aldehydes which comprise a 3,30-substituted 2,20-dihydroxy
binaphthyl backbone with ortho-anisyl groups as chelating
groups for the zirconium center. Current studies are direc-
ted at improving the enantioselectivity of the reaction.
Zr(OtBu)4, (40 lL, 0.10 mmol) and the respective (R)-BI-
NOL ligand 5 (0.10 mmol)17,18 were dissolved in 4 mL of
dry dichloromethane in a flame-dried round bottom flask
at room temperature, stirred for 45 min and cooled to
0 ꢁC. Ketone aldol 4 (1.00 mmol) and the aldehyde
(3.00 mmol) were added and the reaction mixture was stir-
Table 2. The Zr–BINOLate 5c-catalyzed aldol-Tishchenko reaction of ketone aldols 4a–d and aldehydes 2
R1
10 mol-%
O
OH
O
O
O
OH
R2
Zr(OtBu) /( )-BINOL 5c
R
4
+
R1
H
R2
R1
º
C, 2 h
CH2Cl2, 0
4a-d
6a-i
2
Entry
Ketone aldol
R1
R2
Product
eea,b (%)
Yieldc (%)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4b
4b
4c
4d
4d
i-Pr
Ph
Ph
Ph
Ph
6a
6b
6c
6d
6e
6f
60
54
41
42
50
56
60
49
53
90
87
82
89
50
81
71
68
85
c-Hex
n-Hex
i-Bu
i-Pr
4-Me–Ph
4-Me–Ph
4-MeO–Ph
3-Me–Ph
3-Me–Ph
c-Hex
c-Hex
2-Et–Pr
c-Hex
6g
6h
6i
a Determined by HPLC-analysis of the crude product on a Chiracel-OD-phase.
b Absolute configuration of products was assigned by analogy to 6a assuming a unified reaction mechanism.
c Isolated yield of purified material.

C. Schneider et al. / Tetrahedron: Asymmetry 17 (2006) 2738–2742
2741
red at 0 ꢁC for 2 h. The reaction was quenched with 0.5 M
4.6. (1S,3R)-1-Hydroxy-5-methyl-1-phenylhexan-3-yl
3-methylbutanoate 6d
HCl (4 mL). The layers were separated and the aqueous
layer was extracted with ether (5 · 15 mL). The combined
organic layers were dried over MgSO4, filtered, and the sol-
vents were removed under reduced pressure. The crude
product was purified by flash column chromatography over
silica gel using ether/pentane.
20
Yield: 89% of colorless oil; 42% ee (HPLC); ½aꢀD ¼ ꢁ4:5 (c
1
1.2, CHCl3); H NMR (300 MHz, CDCl3): d = 7.34–7.25
(m, 5H, Ar–H), 5.34–5.24 (m, 1H, CHOCOR), 4.59 (ddd,
J = 9.0, 5.0, 4.0 Hz, 1H, CHOH), 3.38 (d, J = 4.0 Hz,
1H, OH), 2.24 (dd, J = 7.8, 2.5 Hz, 2H, OCOCH2CH-
(CH3)2), 2.20–2.14 (m, 1H, OCOCH2CH(CH3)2), 1.89–
1.83 (m, 2H, CH2), 1.72–1.61 (m, 2H, CH2CH(CH3)2),
1.34–1.28 (m, 1H, CH2CH(CH3)2), 1.00 (d, J = 6.5 Hz,
6H, CH(CH3)2), 0.93 (d, J = 7.0 Hz, 3H, CH(CH3)2),
0.90 (d, J = 7.0 Hz, 3H, CH(CH3)2); 13C NMR (75 MHz,
CDCl3): d = 174.5, 144.0, 128.5, 127.4, 125.6, 70.14,
70.13, 45.69, 44.05, 43.60, 25.79, 24.69, 23.36, 22.57,
21.94; IR (film): m = 3063, 2958, 2871, 1731, 1711, 1603,
1494, 1466, 1431, 1385, 1369, 1295, 1256, 1194, 1140,
1093, 933, 757, 700, 627 cmꢁ1; MS (EI): m/z = 292 (2)
[M+] 209 (37) [M+ꢁ2C3H7], 107 (75) [PhCO+], 85 (25)
[C5H8O+], 58 (50) [C3H5O+], 43 (100) ½C3H þꢀ. Anal. Calcd
for. C19H26O3: C, 73.93; H, 9.65. Found: C7, 73.61; H, 9.85.
4.3. (1S,3S)-1-Hydroxy-4-methyl-1-phenylpentan-3-yl
isobutyrate 6a
20
Yield: 90% of colorless oil; 60% ee (HPLC); ½aꢀD ¼ ꢁ5:7 (c
1
1.0, CHCl3); H NMR (200 MHz, CDCl3): d = 7.40–7.25
(m, 5H, Ar–H), 5.05 (dt, J = 8.0, 5.5 Hz, 1H, CHOCOR),
4.54 (dd, J = 7.5, 5.5 Hz, 1H, CHOH), 3.30 (br s, 1H, OH),
2.65 (sept, J = 7.0 Hz, 1H, OCOCH(CH3)2), 1.98–1.75 (m,
3H, CH2, CH(CH3)2), 1.23 (d, J = 7.0 Hz, 6H, CH(CH3)2),
0.94 (d, J = 7.0 Hz, 3H, CH(CH3)2), 0.93 (d, J = 7.0 Hz,
3H, CH(CH3)2); 13C NMR (50 MHz, CDCl3): d = 178.5,
144.0, 128.4, 127.3, 125.5, 75.36, 69.82, 42.14, 34.39,
32.16, 19.23, 19.18, 18.72, 17.50; IR (film): m = 3489,
3063, 3029, 2968, 2877, 1731, 1470, 1389, 1269, 1201,
1162, 1052, 758, 701 cmꢁ1; MS (DCI/NH3): m/z = 810
(1) ([3M+NHþ4 ]), 546 (20) [2M+NHþ4 ], 282 (50)
[M+NHþ4 ], 247 (100) [M+ꢁOH]. Anal. Calcd for
C16H24O3: C, 72.69; H, 9.15. Found: C, 72.68; H, 8.92.
4.7. (1S,3S)-1-Hydroxy-4-methyl-1-p-tolylpentan-3-yl
isobutyrate 6e
20
Yield: 50% of colorless oil; 50% ee (HPLC); ½aꢀD ¼ ꢁ14:8
1
(c 1.2, CHCl3); H NMR (300 MHz, CDCl3): d = 7.24 (d,
4.4. (1S,3S)-1-Cyclohexyl-3-hydroxy-3-phenylpropyl
cyclohexanecarboxylate 6b
J = 8.7 Hz, 2H, Ar–H), 7.14 (d, J = 7.0 Hz, 2H, ArH),
5.05 (dt, J = 9.3, 5.3 Hz, 1H, CHOCOR), 4.50 (ddd,
J = 9.0, 5.0, 3.0 Hz, 1H, CHOH), 3.21 (d, J = 3.0 Hz,
1H, OH), 2.68–2.59 (m, 1H, OCOCH(CH3)2), 2.34 (s,
3H, Ar–CH3), 1.92–1.82 (m, 3H, CH2, CH(CH3)2), 1.23
(d, J = 7.0 Hz, 6H, CH(CH3)2), 0.95 (d, J = 7.0 Hz, 3H,
CH(CH3)2), 0.91 (d, J = 7.0 Hz, 3H, CH(CH3)2); 13C
NMR (75 MHz, CDCl3): d = 178.5, 141.2, 137.0, 129.0,
125.6, 75.52, 69.82, 42.29, 34.50, 32.15, 21.22, 19.38,
18.87, 17.67; IR (film): m = 3416, 2966, 1730, 1613, 1513,
1429, 1385, 1264, 1198, 1089, 877, 815, 627 cmꢁ1; MS
(ESI + Na-formate): m/z = 579.4 (100) [2M+Na]+, 301.2
(9) [M+Na]+. Anal. Calcd for C17H26O3: C, 73.34; H,
9.41. Found: C, 73.01; H, 8.87.
20
Yield: 87% of colorless oil; 54% ee (HPLC); ½aꢀD ¼ ꢁ17:3 (c
1
1.1, CHCl3); H NMR (400 MHz, CDCl3): d = 7.34–7.21
(m, 5H, Ar–H), 5.04 (m, 1H, CHOCOR), 4.50 (ddd,
J = 7.6, 6.0, 4.0 Hz, 1H, CHOH), 3.40 (d, J = 6.0 Hz, 1H,
OH), 2.42–2.35 (m, 1H, OCOCHR), 1.98–0.98 (m, 23H);
13C NMR (75 MHz, CDCl3): d = 177.4, 144.1, 128.3,
127.2, 125.4, 74.75, 69.80, 43.82, 43.58, 42.26, 29.31,
27.82, 26.96, 25.79, 25.52; IR (film): m = 3429, 3028, 2927,
1727, 1708, 1603, 1449, 1384, 1278, 1195, 1172, 1091, 931,
894, 754 cmꢁ1; MS (ESI + Na-formate): m/z = 739 (100)
[2M+Na]+), 381 (8) [M+Na+]. Anal. Calcd for C22H32O3:
C, 76.70; H, 9.36. Found: C, 76.74; H, 9.29.
4.5. (1S,3R)-1-Hydroxy-1-phenylnonan-3-yl heptanoate 6c
4.8. (1S,3S)-1-Cyclohexyl-3-hydroxy-3-p-tolylpropyl
cyclohexanecarboxylate 6f
20
Yield: 82% of colorless oil; 41% ee (HPLC); ½aꢀD ¼ ꢁ3:0 (c
20
1
0.5, CHCl3); H NMR (200 MHz, CDCl3): d = 7.25–7.40
Yield: 81% of colorless oil; 56% ee (HPLC); ½aꢀD ¼ ꢁ15:7
1
(m, 5H, Ar–H), 5.26–5.17 (m, 1H, CHOCOR), 4.59 (dd,
J = 8.8, 4.5 Hz, 1H, CHOH), 3.36 (br s, 1H, OH), 2.36
(t, J = 7.5 Hz, 2H, OCOCH2–), 1.92–1.85 (m, 2H,
CH2CHOH), 1.18–1.11 (m, 18H, CH2 of n-heptyl), 0.98–
0.79 (m, 6H, CH3 of n-heptyl); 13C NMR (75 MHz,
CDCl3): d = 175.1, 143.8, 128.3, 127.3, 125.5, 71.53,
69.82, 44.90, 34.79, 34.53, 31.65, 31.42, 28.97, 28.82,
25.32, 25.07, 22.48, 22.45, 14.00; IR (film): m = 3455,
3063, 3030, 2930, 2859, 1732, 1455, 1379, 1174, 1060,
(c 1.1, CHCl3); H NMR (400 MHz, CDCl3): d = 7.23 (d,
J = 8.8 Hz, 2H, Ar–H), 7.14 (d, J = 7.6 Hz, 2H, Ar–H),
5.06–5.02 (m, 1H, CHOCOR), 4.47 (dd, J = 9.2, 5.2 Hz,
1H, CHOH), 3.25 (br s, 1H, OH), 2.33 (s, 3H, Ar–CH3),
2.42–2.36 (m, 1H, OCOCHR), 1.97–0.99 (m, 23H); 13C
NMR (75 MHz, CDCl3): d = 177.4, 141.2, 136.9, 129.1,
125.6, 74.82, 69.74, 65.92, 43.63, 42.24, 42.09, 29.36,
29.33, 29.25, 28.17, 26.46, 26.1; IR (film): m = 3435, 2927,
2853, 1728, 1614, 1449, 1384, 1313, 1278, 1248, 1195,
1090, 941, 894, 814, 656 cmꢁ1; MS (EI): m/z = 358 (12)
758, 700 cmꢁ1
;
MS (DCI/NH3): m/z = 714 (48)
[2M+NHþ4 ], 366 (69) [M+NHþ4 ], 331 (100) [M+ꢁOH].
Anal. Calcd for C22H36O3: C, 75.82; H, 10.41. Found: C,
75.48; H, 10.14.
[M+], 121 (30) [Ar–CH3–CO+], 43 (100) ½C3H þꢀ. Anal.
7
Calcd for C23H34O3: C, 76.82; H, 9.56. Found: C, 76.53;
H, 9.27.

2742
C. Schneider et al. / Tetrahedron: Asymmetry 17 (2006) 2738–2742
4.9. (1S,3S)-1-Cyclohexyl-3-hydroxy-3-(4-methoxyphenyl)-
propyl cyclohexanecarboxylate 6g
to yield aldol product 7 in 56% yield. The specific rotation
20
of this material, ½aꢀD ¼ ꢁ42:0 (c 1.2, CHCl3) for 60% ee,
was in good correlation with the reported value for the
20
20
Yield: 71% of colorless oil; 60% ee (HPLC); ½aꢀD ¼ ꢁ9:3 (c
enantiomer, ½aꢀD ¼ þ77:8 (c 1, CHCl3).20 All other abso-
1
1.1, CHCl3); H NMR (200 MHz, CDCl3): d = 7.24 (dd,
lute configurations were assigned by analogy.
J = 6.0, 2.2 Hz, 2H, Ar–H), 6.86 (dd, J = 6.8, 1.8 Hz, 2H,
Ar–H), 5.05–4.96 (m, 1H, CHOCOCy), 4.44 (dd, J = 8.6,
4.0 Hz, 1H, CHOH), 3.70 (s, 3H, OMe), 3.25 (s, 1H,
OH), 2.42–2.29 (m, 1H, OCOCHR), 2.00–0.92 (m, 23H);
13C NMR (75 MHz, CDCl3): d = 177.5, 158.9, 136.4,
126.8, 113.8, 74.87, 69.50, 55.30, 43.66, 42.05, 29.39,
28.19, 26.48, 26.24, 26.03, 25.47; IR (film): m = 3436,
2928, 2853, 1726, 1612, 1586, 1512, 1449, 1384, 1312,
1247, 1172, 1133, 1036, 830 cmꢁ1; MS (ESI + Na+-form-
ate): m/z = 1145 (100) [3M+Na+], 771 (100) [2M+ Na+],
397 (8) [M+Na]+. Anal. Calcd for C23H34O4: C, 73.76;
H, 9.15. Found: C, 73.58; H, 8.92.
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft (Schn 441/4-1) and the Fonds der Chemis-
chen Industrie. We thank Wacker AG for a generous
donation of TBDMSCl.
References
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4.10. (1S,3S)-4-Ethyl-1-hydroxy-1-m-tolylhexan-3-yl
2-ethylbutanoate 6h
20
Yield: 68% of colorless oil; 49% ee (HPLC); ½aꢀD ¼ ꢁ10:4
1
(c 1.2, CHCl3); H NMR (300 MHz, CDCl3): d = 7.25–
7.06 (m, 4H, Ar–H), 5.30 (dt, J = 10.5, 2.7 Hz, 1H, CHO-
COR), 4.50 (dt, J = 10.5, 3.2 Hz, 1H, CHOH), 3.30 (d,
J = 3.2 Hz, 1H, OH), 2.35 (s, 3H, Ar–CH3), 2.33–2.28
(m, 1H, OCOCHR), 1.99–0.89 (m, 23H); 13C NMR
(75 MHz, CDCl3): d = 177.7, 144.1, 138.2, 128.4, 128.2,
126.2, 122.6, 77.57, 77.08, 76.63, 72.56, 69.98, 49.56,
45.41, 42.00, 25.20, 22.59, 22.32, 21.69, 12.24, 11.88; IR
(film): m = 3458, 2968, 2934, 2877, 1712, 1597, 1489, 1469,
1387, 1370, 1341, 1268, 1200, 1161, 1090, 1014, 961, 855,
828, 558 cmꢁ1; MS (ESI + Na+-formate): m/z = 669 (100)
[2M+H+], 464, 357 (2) [M+Na+]. Anal. Calcd for
C21H34O3: C, 75.41; H, 10.25. Found: C, 75.43, H, 10.33.
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4.11. (1S,3S)-1-Cyclohexyl-3-hydroxy-3-m-tolylpropyl
cyclohexanecarboxylate 6i
12. Mlynarski, J.; Mitura, M. Tetrahedron Lett. 2004, 45, 7549;
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20
Yield: 85% of colorless oil; 53% ee (HPLC); ½aꢀD ¼ ꢁ11:3
1
(c 1.1, CHCl3); H NMR (300 MHz, CDCl3): d = 7.25–
7.05 (m, 4H, Ar–H), 5.00 (dt, J = 13.5, 3.5 Hz, 1H, CHOC-
OCy), 4.47 (dd, J = 9.0, 4.2 Hz, 1H, CHOH), 3.27 (s, 1H,
OH), 2.37 (m, 1H, OCOCHR), 2.35 (s, 3H, Ar–CH3),
1.99–1.00 (m, 23H); 13C NMR (75 MHz, CDCl3):
d = 177.4, 144.1, 138.0, 128.3, 128.0, 126.3, 122.7, 74.83,
69.84, 43.64, 42.3, 42.29, 42.09, 29.3, 29.36, 29.34, 29.26,
28.18, 27.00, 26.45, 26.18, 26.12, 25.83, 25.57, 25.55,
21.52; IR (film): m = 3443, 3024, 2927, 2853, 1709, 1608,
1590, 1449, 1383, 1312, 1278, 1248, 1173, 1133, 1038,
972, 938, 910, 894, 784, 441 cmꢁ1; MS (ESI + Na+-form-
ate): m/z = 1097 (100) [3M+Na+], 739 (55) [2M+Na+],
381 (6) [M+Na+]. Anal. Calcd for C23H34O3: C, 77.05;
H, 9.86. Found: C, 76.93, H, 10.09.
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4.12. Determination of absolute configuration of
aldol-Tishchenko product 6a
23. Evans, D. A.; Hoveyda, A. H. J. Am. Chem. Soc. 1990, 112,
6447.
24. Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1998, 37,
2922.
Aldol-Tishchenko product 6a was hydrolyzed (KOH,
MeOH) quantitatively to the corresponding 1,3-anti diol
and subsequently oxidized with pyridinium dichromate19