Cobalt(II)-azabis(oxazoline)-catalyzed conjugate reduction of α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1002/adsc.200404295

Azabis(oxazolines) prove to be superior ligands for the enantioselective, cobalt(II)-catalyzed conjugate reduction of α,β-unsaturated carbonyl compounds with sodium borohydride. β-Trisubstituted α,β- unsaturated esters and amides as well as γ-butenolides are readily converted to their corresponding saturated counterparts with enantioselectivities up to 97% ee.

Full text of DOI:10.1002/adsc.200404295

FULL PAPERS
Cobalt(II)-Azabis(oxazoline)-Catalyzed Conjugate Reduction of
a,b-Unsaturated Carbonyl Compounds
Christian Geiger, Peter Kreitmeier, Oliver Reiser*
Institut fꢀr Organische Chemie, Universitꢁt Regensburg, Universitꢁtsstr. 31, 93053 Regensburg, Germany
Fax: (þ49)-941-943-4121, e-mail: oliver.reiser@chemie.uni-regensburg.de
Received: September 17, 2004; Accepted: December 10, 2004
Abstract: Azabis(oxazolines) prove to be superior li- turated counterparts with enantioselectivities up to
gands for the enantioselective, cobalt(II)-catalyzed 97% ee.
conjugate reduction of a,b-unsaturated carbonyl com-
pounds with sodium borohydride. b-Trisubstituted Keywords: azabis(oxazolines); cobalt; conjugate re-
a,b-unsaturated esters and amides as well as g-buten- duction; transition metals; a,b-unsaturated amides,
olides are readily converted to their corresponding sa- a,b-unsaturated esters
Introduction
gands for a wide range of catalytic asymmetric process-
es, and are readily accessible from amino acids in a broad
Enantioselective transfer of hydrogen to prochiral car- variety regarding the substituent R.[6] However, when
bon-carbon double bonds belongs to the most important we tested 4 for the reduction of 1a under the standard
catalytic asymmetric processes to date. In this context, conditions being reported, no reaction at all was ob-
the conjugate reduction of a,b-unsaturated carbonyl served.[7] These results suggested that a more electron-
compounds offers a valuable method for the construc- rich ligand might be a prerequisite for the title reaction.
tion of building blocks with a b-stereogenic center found
We recently introduced azabis(oxazolines) 7 (Scheme
in many natural products.[1] Recently, for this purpose a 2) as chiral ligands for asymmetric catalysis,[8] which are
very efficient system based on polyhydroxymethylsilane readily synthesized by condensation of 5 and 6, both of
(PMHS) as stoichiometric reducing agent using chiral which are conveniently available[9] from the chiral pool
Cu(I)/biarylphosphines[2] or Cu(I)/ferrocenyldiphos- in either enantiomeric form. Although these ligands
phines has been introduced.[3] Already in 1989 Pfaltz re- promote asymmetric reactions such as the Cu(I)-cata-
ported the use of semicorrin ligands such as 3 in combi- lyzed cyclopropanation in a similar way like bis(oxazo-
nation with CoCl2 to effect the conjugate reduction of lines), they are nevertheless considerably more elec-
a,b-unsaturated esters and amides by sodium borohy- tron-rich as reflected in their inferior activity for Lewis
dride with high enantioselectivities.[4] Despite the ease acid-catalyzed reactions such as [4þ2] cycloadditions,
of use and the remarkable results obtained by the latter their superior properties in ionic liquids[10] or for immo-
protocol, the limited availability of semicorrins from the bilization by ion exchange on nafion-silica hybrid mate-
chiral pool might have been prohibitive for its wider rec- rials or synthetic laponite clay as catalyst supports.[11]
ognition. Subsequently, aldiminatocobalt(II) com-
plexes[5] were examined in the 1,4-reduction of acryl-
amides, which gave generally lower selectivities as com-
pared to the semicorrins, but did also allow the control of
the a-stereocenter in this process.
Results and Discussion
Ligand Screening
An obvious alternative might have been the substitution
of the semicorrins 3 by the structurally related bis(oxa-
Scheme 1. Co(II)-catalyzed conjugate reduction of a,b-unsa-
zoline) ligands 4, which have proved to be superior li- turated esters.
Adv. Synth. Catal. 2005, 347, 249–254
DOI: 10.1002/adsc.200404295
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Christian Geiger et al.
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emic form in very low yield (entry 1). In distinct contrast,
with the N-methylated azabis(oxazoline) 8a greatly im-
proved yields (82%) and excellent enantioselectivity
(96% ee) were achieved (entry 2), which compares
well with the best catalysts described so far for this trans-
formation. Increasing the steric bulk by t-butyl substitu-
tion in the azabis(oxazoline) framework, resulting of-
ten[12] in even more selective catalysts is not tolerated
at all: no reaction was observed when 8b was employed
(entry 3). However, the phenyl-substituted ligand 8c
performs even slightly better than 8a with respect to
yield (entry 4), and was therefore used in subsequent re-
actions. Since 8a and 8c are pseudoenantiomeric to each
other, it was not surprising that 2a is obtained with oppo-
site stereochemistry with respect to these ligands. The
amount of catalyst could be reduced to 1 mol % with
only a small reduction in yield and selectivity, however,
further lowering the amount to 0.1 mol % was not toler-
ated well (entries 5 and 6).
Reduction of a,b-Unsaturated Esters and
g-Butyrolactones
Other esters were subsequently investigated in the con-
jugate reduction catalyzed by CoCl2 and 8c (Table 2).
Good yields and high enantioselectivities were ob-
tained with a number of aromatic and aliphatic sub-
strates. Especially, (Z)-1b gave rise to (R)-2b with 94%
ee (entry 4), which has been a problematic substrate
Scheme 2. Synthesis of azabis(oxazoline) ligands.
Based on the hypothesis that an electron-rich ligand with the semicorrin ligand 3.[13] Especially noteworthy
might be advantageous for the cobalt(II)-catalyzed is the smooth conversion of (E)-1d (entry 7), since the
conjugate reduction, we therefore wanted to investi- resulting (S)-2d can be converted after deprotection
gate azabis(oxazolines) for this process. An initial into the corresponding g-butyrolactone 10a,[14] thus pro-
screening using azabis(oxazoline) ligands 7a and 8a–c viding an alternative route to this important class of
in the reduction of 1a to 2a was therefore conducted compounds[15] with respect to the direct reduction of bu-
(Table 1).
tenolides 9. Indeed, 9 also proved to be suitable sub-
Under the basic conditions applied the azabis(oxazo- strates for the conjugate reduction catalyzed by CoCl2/
line) 7a should serve as an anionic ligand in close analo- 8c, however, yields and selectivities were somewhat low-
gy to semicorrin 3. However, the reduction of 1a pro- er than for the acyclic substrates described above
ceeded sluggishly, resulting in the formation of 2a in rac- (Scheme 3).
Table 1. Co(II)-catalyzed conjugate reduction of 1a in the presence of various azabis(oxazoline) ligands.[a]
Entry
Ligand
Yield of 2a [%]
Selectivity for 2a % ee
Configuration of 2a
1
2
3
7a
8a
8b
8c
8c
8c
12
82
0
86
81
22
0
96
–
96
94
49
–
S
–
R
R
R
4
5[b]
6[c]
[a]
Reagents and conditions: 2.5 mol % CoCl2 ·6 H2O, 2.8 mol % ligand, 2.5 equivs. NaBH4, EtOH/diglyme 1: 1, 24 h, room
temperature.
1 mol % CoCl2 ·6 H2O, 1.2 mol % 8c.
0.1 mol % CoCl2 ·6 H2O, 0.12 mol % 8c.
[b]
[c]
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Conjugate Reduction of a,b-Unsaturated Carbonyl Compounds
FULL PAPERS
Table 2. Conjugate reduction of a,b-unsaturated esters with
NaBH4 catalyzed by CoCl2/8c.[a]
Entry
1
R
Yield [%] ee [%]
2
(E)-1a 88
96
(R)-2a
2
3
(Z)-1a 87
(E)-1b 86
96
92
(S)-2a
(S)-2b
Scheme 4. Conjugate reduction of amides 11.
4
5
(Z)-1b 89
(E)-1c 86
94
93
(R)-2b
(R)-2c
a readily available and widely variable ligand system
for this process.
6
7
(Z)-1c 86
(E)-1d 85
97
95
(S)-2c
(S)-2d
[a]
Reagents and Conditions: 2.5 mol % CoCl2 ·6 H2O, Experimental Section
2.8 mol % 8c, 2.5 equivs. NaBH4, EtOH/diglyme 1: 1,
24 h, room temperature.
General Remarks
Infrared spectra were recorded on a Bio-Rad Excalibur Series
spectrometer. Optical rotations were measured on a Perkin-
Elmer 241 polarimeter at ambient temperature. NMR spectra
were recorded on a Bruker AC 250 or Avance 300 (1H:
250 MHz or 300 MHz, 13C: 75 MHz) spectrometer using TMS
as internal standard (d¼0) unless otherwise noted. Mass spec-
tra were measured on Varian MAT 311A and Finnigan MAT 95
spectrometers. Analytical thin layer chromatography was per-
formed on Merck TLC aluminium sheets silica gel 60 F254. For
liquid chromatography Merck silica gel 60 (230–400 mesh
ASTM) was used. GC and HPLC analyses were performed
as indicated. Racemic compounds analogous to the enantio-
merically enriched compounds described below were prepared
by reduction of the olefin substrates under a hydrogen atmos-
phere catalyzed by Pd/C. All reactions were carried out in
oven-dried glassware under a nitrogen atmosphere. Benzene
and diglyme were distilled from CaH2, methanol and ethanol
from Mg, diethyl ether from Na-alloy. Ethyl trans-b-methylcin-
namate was purchased from Aldrich. Other reagents were used
without purification unless otherwise noted.
Scheme 3. Conjugate reduction of butenolides 9
Reduction of a,b-Unsaturated Amides
Finally, N-methylamides instead of esters can be used in
the conjugate reduction with very good results as dem-
onstrated with 11 (Scheme 4). Under the same condi-
tions the reaction times were found to be longer in com-
parison to the corresponding ethyl esters, nevertheless,
both (E)- and (Z)-11 could be converted to (R)- and
(S)-12, respectively, in good yields with 93 and 95% ee,
respectively.
General Procedure A (GP A): Asymmetric Conjugate
Reduction of a,b-Unsaturated Esters
To CoCl2 ·6 H2O (0.013 mmol, 2.5 mol %) was added a solution
of 8c (0.014 mmol, 4.5 mg) in ethanol (0.5 mL) and the mixture
was stirred for 10 min until a deep blue solution resulted. A sol-
ution of the unsaturated ester (0.50 mmol) in ethanol (0.5 mL)
and diglyme (1.0 mL) was added, and the reaction mixture was
cooled to 08C. NaBH4 (1.25 mmol, 47.3 mg) was added in small
portions during which the solution turned pink. After complete
addition the mixture was stirred 24 h at room temperature. The
mixture was diluted with water (10 mL) and extracted with di-
Conclusion
We could demonstrate that appropriately functional-
ized aza(bisoxazolines) are highly efficient chiral pro-
moters of the Co(II)-catalyzed conjugate reduction of
a,b-unsaturated carbonyl compounds, thus, providing chloromethane (3ꢀ15 mL). The combined organic layers
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Christian Geiger et al.
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1
were washed 3 times with water (10 mL) and finally dried over
MgSO4. The solvent was evaporated and the residue was puri-
fied by column chromatography.
128C]; H NMR (300 MHz, CDCl3): d¼7.32–7.24 (m, 2H),
7.21–7.14 (m, 3H), 4.13 (q, J¼7.1 Hz, 2H), 2.74–2.53 (m,
2H), 2.35 (dd, J¼14.6, 6.0 Hz, 1H), 2.16 (dd, J¼ 14.6, 6.6 Hz,
1H), 2.10–1.94 (m, 1H), 1.74–1.60 (m, 1H), 1.56–1.44 (m,
1H), 1.25 (t, J¼7.1 Hz, 3H), 1.01 (d, J¼6.6 Hz, 3H); tR:
26.1 min (S), 28.9 min (R); [a]D: þ15.08 (c 1.0, CHCl3).
Ethyl (R)-Citronellate [(R)-2a][2a]
Ethyl (E)-geranate [(E)-1] was reacted following GPA. Purifi-
cation by column chromatography (hexanes/diethyl ether,
20:1) afforded (R)-2a as a clear oil; yield: 88 mg (0.44 mmol,
88%, 96% ee determined by chiral GC analysis [HP 5890 A,
Restek Rt-b DEX cst, oven 608C, inj.: split 2508C, det.: FID
Ethyl (S)-3-Methyl-5-phenylpentanoate [(S)-2c]
Ethyl (Z)-3-methyl-5-phenylpent-2-enoate [(Z)-1c] was react-
ed following GP A. Purification by column chromatography
(hexanes/ethyl acetate, 30:1) afforded (S)-2c as a clear oil;
yield: 95 mg (0.43 mmol, 86%, 97% ee determined by chiral
HPLC analysis); [a]D: ꢁ15.78 (c 1.0, CHCl3). NMR and GC
data were the same as reported in the previous example.
1
3008C, 150 kPa H2]); H NMR (300 MHz, CDCl3): d¼5.13–
5.04 (m, 1H), 4.12 (q, J¼7.1 Hz, 2H), 2.30, (dd, J¼14.5,
5.9 Hz, 1H), 2.10 (dd, J¼14.5, 8.2 Hz, 1H), 2.04–1.88 (m,
3H), 1.68 (s, 3H), 1.60 (s, 3H), 1.42–1.14 (m, 5H), 0.94 (d, J¼
6.6 Hz, 3H); tR: 66.4 min (R), 69.3 min (S); [a]D: þ4.98 (c 1.0,
CHCl3).
Ethyl (S)-Citronellate [(S)-2a]
(S)-4-(tert-Butyldimethylsilanyloxy)-3-methylbutyric
Acid Ethyl Ester [(S)-2d]
Ethyl (Z)-geranate [(Z)-1a] was reacted following GPA. Puri-
fication by column chromatography (hexanes/diethyl ether,
20:1) afforded the product (S)-2a as a clear oil; yield: 86 mg
(0.43 mmol, 87%, 96% ee); [a]D: ꢁ4.18 (c 1.0, CHCl3). NMR
and GC data were the same as reported in the previous exam-
ple.
(E)-4-(tert-butyldimethylsilanyloxy)-3-methylbut-2-enoic
acid ethyl ester [(E)-1d] was reacted following GPA. Purifica-
tion by column chromatography (hexanes/ethyl acetate, 30:1)
afforded (S)-2d as a clear oil; yield: 110 mg (0.42 mmol, 85%,
95% ee); 1H NMR (300 MHz, CDCl3 without TMS): d¼4.12
(q, J¼7.1 Hz, 2H), 3.49 (dd, J¼9.8, 5.4 Hz, 1H), 3.40 (dd,
J¼9.8, 6.3 Hz, 1H), 2.54–2.39 (m, 1H), 2.21–2.01 (m, 2H),
1.25 (t, J¼7.1 Hz, 3H), 0.93 (t, J¼6.6 Hz, 3H), 0.89 (s, 9 H),
0.03 (s, 6H); 13C NMR (75 Hz, CDCl3): d¼173.3, 67.4, 60.1,
38.2, 33.1, 25.9, 18.3, 16.5, 14.3, ꢁ5.4; IR (KBr): n¼2957,
Ethyl (S)-3-Phenylbutyrate [(S)-2b][2a]
Ethyl trans-b-methylcinnamate [(E)-1b] was reacted following
GP A. Purification by column chromatography (hexanes/di-
ethyl ether, 20:1) afforded (S)-2b as a clear oil; yield: 83 mg
(0.43 mmol, 86%, 92% ee determined by chiral GC analysis
[HP 5890 A, Restek Rt-b DEX cst, oven 558C, inj.: split
2930, 2858, 17.37, 1470 cmꢁ1
; HRMS: m/z calcd. for
[C13H28O3SiþHþ]: 261.1886; found: 261.1889; [a]D: ꢁ5.28
(c 1.0, CHCl3).
1
2608C, det.: FID 2508C, 151 kPa H2]); H NMR (300 MHz,
The enantioselectivity was determined by deprotection of
the alcohol followed by cyclization to the corresponding lac-
tone with p-TSA in MeOH. Chiral GC analysis (HP 5890 A,
Restek Rt-b DEX cst, oven 1208C, inj.: split 2508C, det.: FID
3008C, 150 kPa H2: tR: 14.2 min (R), 14.5 min (S); [a]D:
ꢁ22.28 (c 1.0, CHCl3).
CDCl3): d¼7.33–7.14 (m, 5H), 4.07 (q, J¼7.1 Hz, 2H),
3.35–3.21 (m, 1H), 2.61 (dd, J¼15.0, 7.0 Hz, 1H), 2.53 (dd,
J¼15.0, 8.2 Hz, 1H), 1.30 (d, J¼7.0 Hz, 3H), 1.18 (t, J¼
7.1 Hz, 3H);[1] tR: 182.6 min (S), 192.8 min (R); [a]D: þ24.18
(c 1.0, CHCl3).
Ethyl (R)-3-Phenylbutyrate [(R)-2b]
Ethyl cis-b-methylcinnamate [(Z)-1b] was reacted following
GP A. Purification by column chromatography (hexanes/di-
ethyl ether, 20:1) afforded (R)-2b as a clear oil; yield: 86 mg
(0.45 mmol, 89%, 94% ee); [a]D: ꢁ25.28 (c 1.0, CHCl3).
NMR and GC data were the same as reported in the previous
example.
General Procedure B (GP B): Asymmetric Conjugate
Reduction of Lactones
To CoCl2 ·6 H2O (2.5 mol %, 0.013 mmol) was added a solu-
tion of 8c (0.014 mmol, 4.5 mg) in ethanol (0.5 mL), and the
mixture was stirred for 10 min during which the solution turned
to a deep blue color. A solution of the unsaturated lactone
(0.50 mmol) in ethanol (0.5 mL) was added, and the reaction
mixture was cooled to 08C. NaBH4 (0.5 mmol, 18.9 mg) was
added and the reaction mixture was stirred at room tempera-
ture for the indicated time. The solution was quenched with
2 mL of 2 N HCl followed by addition of 5 mL of water. The
mixture was washed with dichloromethane (3ꢀ20 mL) and
the combined organic layers were dried over MgSO4. After re-
moving of the solvent the residue was purified by column chro-
matography.
Ethyl (R)-3-Methyl-5-phenylpentanoate [(R)-2c][2a]
Ethyl (E)-3-methyl-5-phenylpent-2-enoate [(E)-1c] was react-
ed following GP A. Purification by column chromatography
(hexanes/ethyl acetate, 30:1) afforded (R)-2c as a clear oil;
yield: 95 mg (0.43 mmol, 86%, 93% ee determined by chiral
HPLC analysis [Hewlett Packard HP1090M, Daicel Chiralcel
OB, ethanol/2-propanol, 99:1, 0.3 mL/min, UV 254 nm,
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Conjugate Reduction of a,b-Unsaturated Carbonyl Compounds
(R)-4-Methyldihydrofuran-2(3H)-one [(R)-10a][16]
FULL PAPERS
50 ml), acidified with 2 N HCl (pH 2) and extracted with dieth-
yl ether (3ꢀ100 ml). The combined organic layers were wash-
ed with brine (3ꢀ50 ml) and dried over MgSO4. The resulting
3-methyl-5-phenylpentanoic acid (0.189 mmol, 36.4 mg, 96%)
was dissolved in benzene (1 mL), then oxalyl chloride
(0.56 mmol, 71.2 mg), was added and the mixture was heated
to 808C for 2 h. The solvent was evaporated and diethyl ether
(1 mL) was added. (S)-Phenylethylamine (0.56 mmol,
67.9 mg), was added and the reaction mixture was stirred 2 h
at room temperature. The mixture was diluted with diethyl
ether (100 mL), washed with 2 N HCl (3ꢀ50 mL) and dried
over MgSO4. The organic layer was concentrated to yield
(R)-3-methyl-5-phenyl-N-[(S)-1-phenylethyl]pentanamide;
yield: 58 mg (quant.); chiral GC analysis (HP 5890 A, Phenom-
enex ZB-1a, oven 125–1308C, inj.: split 2508C, det.: FID
3008C, 150 kPa H2): tR: 81.3 (R), 83.7 min (S).
4-Methyl-2(5H)-furan-2-one (9a) was reacted for 24 h accord-
ing to GP B. Purification by column chromatography (hexanes/
ethyl acetate, 80:20) afforded (R)-10a as a clear oil; yield:
27 mg (0.27 mmol, 54%, 86% ee determined by chiral GC anal-
ysis [HP 5890 A, Restek Rt-b DEX cst, oven 1208C, inj.: split
1
2508C, det.: FID 3008C, 70 kPa H2]); H NMR (300 MHz,
CDCl3): d¼4.39 (dd, J¼8.8, 7.4 Hz, 1H), 3.85 (dd, J¼8.8,
6.4 Hz, 1H), 2.73–2.55 (m, 2H), 2.20–2.05 (m, 1H), 1.14 (d,
J¼6.6 Hz, 3H); tR: 14.4 min (R), 15.7 min (S); [a]D: þ18.98 (c
0.6, CHCl3).
(R)-4-Butyldihydrofuran-2(3H)-one [(R)-10b][17]
4-Butyl-2(5H)-furan-2-one (9b) was reacted for 4 h according
to GP B. Purification by column chromatography (hexanes/
ethyl acetate, 80:20) afforded (R)-10b as a clear oil; yield:
46 mg (0.32 mmol, 65%, 86% ee determined by chiral GC anal-
ysis [HP 5890 II, Restek Rt-b DEX cst, oven 1408C, inj.: split
(S)-N,3-Dimethyl-5-phenylpentanamide [(S)-12][4b]
(Z)-N,3-Dimethyl-5-phenylpent-2-enamide [(S)-11] was react-
ed according GP C. Purification by column chromatography
(hexanes/ethyl acetate, 1:5) afforded (S)-12 as a white solid;
yield: 90 mg (0.44 mmol, 88%, 95% ee); [a]D: ꢁ17.98 (c 1.0,
CHCl3). NMR data and melting point were the same as report-
ed in the previous example.
1
2508C, det.: FID 3508C, 150 kPa H2,]; H NMR (300 MHz,
CDCl3): d¼4.46–4.37 (m, 1H), 3.92, (dd, J¼9.0, 7.1 Hz, 1H),
2.68–2.45 (m, 2H), 2.27–2.10 (m, 1H), 1.53–1.42 (m, 2H),
1.38–1.21 (m, 4H), 0.90 (t, J¼6.8 Hz, 3H); tR: 25.7 (R), 27.5
(S); [a]D: þ5.68 (c 1.0, CHCl3).
General Procedure C (GP C): Asymmetric Conjugate
Reduction of a,b-Unsaturated Amides
Acknowledgements
This work was supported by the Fonds der Chemischen Indus-
trie and through generous chemical gifts by Degussa AG.
To CoCl2 ·6 H2O (2.5 mol %, 0.013 mmol) was added a solu-
tion of 8c (0.014 mmol, 4.5 mg) in 0.5 mL of ethanol and the
mixture was stirred for 10 min during which the solution turned
to a deep blue color. A solution of unsaturated amide (103 mg,
0.50 mmol) in 0.5 mL of ethanol and 1.0 mL of diglyme was
added, and the reaction mixture was cooled to 08C. NaBH4
(1.25 mmol, 47.3 mg) was added in small portions, and the mix-
ture was stirred 72 h at room temperature. Water (10 mL) was
added and the mixture was extracted with dichloromethane
(3ꢀ15 mL). The combined organic layers were washed with
ice water (10 mL), brine (3ꢀ10 mL) and dried over MgSO4.
After concentration the residue was purified by column chro-
matography to afford the product as a white solid.
References and Notes
[1] J. D. Connolly, R. A. Hill, Dictionary of Terpenoids,
Chapman and Hall, London, 1991, Vol. 1, pp. 476–541.
[2] a) D. H. Appella, Y. Moritani, R. Shintani, E. F. Ferreira,
S. L. Buchwald, J. Am. Chem. Soc. 1999, 121, 9473; b) G.
Hughes, M. Kimura, S. L. Buchwald, J. Am. Chem. Soc.
2003, 125, 11253.
[3] B. H. Lipshutz, J. M. Servesko, B. R. Taft, J. Am. Chem.
Soc. 2004, 126, 8352.
[4] a) U. Leutenegger, A. Madin, A. Pfaltz, Angew. Chem.
Int. Ed. Engl. 1989, 28, 60; b) P. v. Matt, A. Pfaltz, Tetra-
hedron: Asymmetry 1991, 2, 691; c) M. Misun, A. Pfaltz,
Helv. Chim. Acta 1996, 79, 961.
[5] a) T. Yamada, Y. Ohtsuka, T. Ikeo, Chem. Lett. 1998,
1129; b) Y. Ohtsuka, T. Ikeno, T. Yamada, Tetrahedron:
Asymmetry 2003, 14, 967.
[6] Recent review: H. A. McManus, P. J. Guiry, Chem. Rev.
2004, 104, 4151.
[7] Similar attempts to use various bis(oxazoline) ligands in
this reduction were also unsuccessful; a) A. Pfaltz, per-
sonal communication; b) D. A. Evans, personal commu-
nication.
[8] a) M. Glos, O. Reiser, Org. Lett. 2000, 2, 2045; b) H.
Werner, R. Vicha, A. Gissibl, O. Reiser, J. Org. Chem.
2003, 68, 10166.
(R)-N,3-Dimethyl-5-phenylpentanamide [(R)-12][4b]
(E)-N,3-Dimethyl-5-phenylpent-2-enamide [(E)-11] was re-
acted according to GP C. Purification by column chromatogra-
phy (hexanes/ethyl acetate, 1:5) afforded (R)-12 as a white sol-
id; yield: 83 mg (0.40 mmol, 81%, 93% ee); 1H NMR
(300 MHz, CDCl3): d¼7.31–7.23 (m, 2H), 7.21–7.13 (m,
3H), 5.6–5.2 (bs, 1H), 2.79 (d, J¼4.8 Hz, 3H), 2.75–2.50 (m,
2H), 2.28–2.13 (m, 1H), 2.10–1.91 (m, 2H), 1.75–1.60 (m,
1H), 1.55–1.40, (m, 1H), 1.00 (d, J¼6.4 Hz, 3H); [a]D:
þ17.38 (c 1.0, CHCl3); mp 68–708C.
The enantioselectivity was determined as follows. To the re-
duced amide (0.197 mmol, 40.4 mg) in a pressure vessel with
nitrogen inlet were added 2 mL of 25% aqueous sulfuric
acid. The mixture was degassed at 0.1 Torr and then heated
to 1408C for 36 h. The cooled reaction mixture was diluted
with 2 N NaOH (pH 14), washed with diethyl ether (3ꢀ
Adv. Synth. Catal. 2005, 347, 249–254
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254
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Adv. Synth. Catal. 2005, 347, 249–254