Enantioselective synthesis of 2-substituted alcohols using (+)-(1S,2S)-pseudoephedrine as chiral auxiliary

Article abstract of DOI:10.1055/s-2008-1000851

An improved method for the selective synthesis of enantiopure 2-substituted alcohols is described. Highly diastereoselective alkylation of pseudoephedrine-derived amides and subsequent oxidation of the hydroxyl group in the amide side chain, leads to oxoamides. These oxoamides can be purified by crystallization or preparative HPLC to obtain diastereomeric ratios of >99:1. The following reductive cleavage of the modified auxiliary allows the epimerization-free formation of enantiopure 2-substituted alcohols with up to 99.9% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1000851

PAPER
229
Enantioselective Synthesis of 2-Substituted Alcohols Using
(+)-(1S,2S)-Pseudoephedrine as Chiral Auxiliary
E
nantioselective
u
Synthesis
o
t
f
2-Sub
z
stituted AlcoholsF. Tietze,*a Christian Raith,a C. Christian Brazel,a Sören Hölsken,a Jörg Magullb
a
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstraße 2, 37077 Göttingen, Germany
Fax +49(551)399476; E-mail: ltietze@gwdg.de
b
Institut für Anorganische Chemie, Georg-August-Universität, Tammannstraße 4, 37077 Göttingen, Germany
Received 10 August 2007; revised 26 October 2007
of N-acyl pseudoephedrine derivatives, developed by
Myers,4 often fails to yield crystalline compounds amena-
ble to purification by recrystallization. In the case of non-
crystalline compounds, separation of the diastereomeric
Abstract: An improved method for the selective synthesis of enan-
tiopure 2-substituted alcohols is described. Highly diastereoselec-
tive alkylation of pseudoephedrine-derived amides and subsequent
oxidation of the hydroxyl group in the amide side chain, leads to
oxoamides. These oxoamides can be purified by crystallization or products by chromatography is seldom successful even
preparative HPLC to obtain diastereomeric ratios of >99:1. The fol-
using HPLC as we have observed. Nevertheless, the pro-
lowing reductive cleavage of the modified auxiliary allows the
cedure is very useful since, even in those cases where an
epimerization-free formation of enantiopure 2-substituted alcohols
enrichment is not possible, high selectivities can be ob-
with up to 99.9% ee.
tained with an ee of over 90% in most cases. However, we
have recently found that by a slight change of the proto-
col, the desired alkylated alcohols can be formed with up
Key words: alcohols, auxiliary, asymmetric synthesis, reduction,
alkylation
to 99.9% ee and, moreover, the liberation of the alcohols
is highly improved. Thus, before reductive cleavage to
Chiral alcohols with a stereogenic center in the 2-position
give the alcohols, we have incorporated an oxidation of
are versatile building blocks for natural product synthesis.
On the one hand, they can be transformed into chiral elec-
trophiles e.g. aldehydes, activated esters as triflates, tosy-
the primarily formed hydroxyamides 4 to give the corre-
sponding oxoamides 6, which are nearly always crystal-
line and can therefore be purified by recrystallization
lates or iodides and, on the other hand, they can be used as
(Scheme 1). Moreover, in almost all cases, the formed
nucleophiles. A variety of methods for the enantioselec-
diastereomers can also be separated by chromatography.
tive synthesis of 2-substituted alcohols has been devel-
For the total synthesis of polyoxygenated cembranoids,
oped,1 most of which are related to a diastereoselective
we needed alcohol (S)-5a.5 Alkylation of pseudoephe-
drine isovalerylamide (3) with 3-methylbut-3-enyl triflate
led to the formation of hydroxyamide 4a as an oil, which
could not be further purified. Reduction of 4a applying
lithium aminotrihydroborate (LAB) gave the alcohol 5a in
good yield (89%) but with an ee of only 90%, which was
alkylation of chiral enolates2 or enamines.3 A general
problem of these methods is the separation of the mixtures
of stereoisomers usually obtained to afford pure diastereo-
mers, which can then be converted into enantiopure alco-
hols. The well known and most widely applied alkylation
NH
LDA,
OH
LAB
(4.00 equiv)
LiCl,
RX
O
O
1
Et3N
+
HO
N
N
O
R
OH
R
OH
4a–f
3
5a–f
Cl
2
(COCl)2, DMSO, Et3N
enantiomeric
enrichment
O
purification by crystallization
or chromatography
LAB (6.00 equiv)
N
O
R
6a–f
Scheme 1 Comparison of the Myers procedure4 to the new oxoamide procedure
SYNTHESIS 2008, No. 2, pp 0229–0236
x
x
.
x
x
.2
0
0
8
Advanced online publication: 18.12.2008
DOI: 10.1055/s-2008-1000851; Art ID: T12807SS
© Georg Thieme Verlag Stuttgart · New York

230
L. F. Tietze et al.
PAPER
not sufficient for our synthesis.6 However, oxidation of
the hydroxyamide 4a led to the oxoamide 6a, which could
be purified by recrystallization and also chromatography.7
Reduction of 6a after crystallization using LAB, led to al-
cohol 5a in a comparable yield (89%) but with a highly in-
creased optical purity of 97% ee. After chromatographic
purification of 6a followed by reductive cleavage, the al-
cohol 5a was even obtained with 99.9% ee.
(COCl)2,
DMSO,
Et3N
LAB
(6.00 equiv)
O
4a–f
HO
N
R
O
R
6a–f
5a–f
Scheme 2 Synthesis of 2-substituted alcohols 5a–f via oxoamides
6a–f
In order to determine the scope and limitations of this
method, we prepared a range of 2-substituted alcohols.
For this investigation we used pseudoephedrine isovaleryl-
amide (3) as substrate, which was synthesized by N-acy-
lation of (+)-(1S,2S)-pseudoephedrine (1) with isovaleryl
chloride (2) in tetrahydrofuran in the presence of triethy-
lamine. Six different hydroxyamides 4a–f were synthe-
sized by diastereoselective alkylation of the lithium
enolate of 3 according to the protocol of Myers.4b The
alkylation reactions proceeded in good to excellent yields
(71–92%) and the hydroxyamides 4a–f were converted to
the 2-substituted alcohols by reductive cleavage with
LAB (Table 1).4b 4f was a crystalline solid, which after re-
crystallization and reduction with LAB, provided alcohol
5f in 80% yield (69% over two steps) and >99% ee as de-
termined by capillary GC on chiral stationary phases.
However, none of the remaining five hydroxyamides 4a–
e could be purified and the diastereomeric ratio of the
formed mixture of diastereomers could not be determined
using HPLC.8 In our experience, reduction of the hy-
droxyamides 4a–e with LAB is difficult and leads to the
alcohols 5a–e in low to moderate yields with selectivities
from 90% to 96% ee (Table 1). It can be assumed that the
ee values of the alcohols 5a–f correspond to the ratio of
the diastereomeric hydroxyamides 4a–e, since racemiza-
tion during the reductive cleavage seems not to occur; this
epimerization using triethylamine as base occurred and
the transformation was fast, simple and efficient.
Oxoamides 6a–b and 6d–f are crystalline solids with
melting points between 39 °C and 70 °C, but 6c was
formed as a yellow oil. The absolute configuration of 6a
was determined by X-ray diffraction considering the
known configuration of the amide side chain at the re-
maining 1′-position.11–13 The diastereomeric ratio could
be determined by HPLC using Daicel Chiralpak® IA and
IB analytical columns and n-hexane–2-propanol as mo-
bile phase. However, oxoamide 6d could not be separated
on these columns even using different mobile phases.14
Oxoamides 6a–c were purified using a preparative HPLC
Daicel Chiralpak® IA column, 6e was purified by using a
Daicel Chiralpak® IB colum. The resulting epimerically
enriched oxoamides were reduced with LAB to give the
desired alcohols 5a–c and 5e with highly increased enan-
tiopurity compared to the direct cleavage of the hydroxy-
amides 4. Moreover, since the liberation of the alcohols
was much easier, the yields for the three-step procedure
were improved (Table 2).
The described examples show that the original Myers pro-
cedure for the synthesis of 2-substituted chiral alcohols
Table 2 Oxidation of Hydroxyamides 4a–f and Reductive Cleavage
can be deduced from the reaction of 4f, which leads to of the Resulting Oxoamides to Alcohols 5a–f
enantiopure 5f.
Entry Alcohol
R
eea
Yield
Oxidation of 4a–f using 2-iodoxybenzoic acid, permanga-
nate or the Swern procedure, gave the oxoamides 6a–f,
which could then be purified by recrystallization or chro-
matography. We preferred the Swern protocol,10 as no
[three steps (%)]
90b
1
2
5a
5b
97c
58
70
>99.9d
96b
Table 1 Synthesis of 2-Substituted Alcohols 5a–f Starting from 3
using the Myers Protocol
>99.9d
90b
Entry Alcohol
R
ee
Yield
(%)a
[two steps9 (%)]
3
4
5
6
5c
5d
5e
5f
Me
Et
71
39
72
67
>99.9d
96b
1
2
5a
5b
90
96
63
56
95b
Pr
>99d
Bn
>99b
a The ee values of the alcohols 5a–f were determined by chiral capil-
lary GC. They correspond to the dr values of the oxoamides, which
were determined by HPLC on chiral stationary phases (Daicel Chiral-
pak® IA, IB).
3
4
5
6
5c
5d
5e
5f
Me
Et
90
96
43
26
37
69
Pr
94
b Without enrichment.
c After recrystallization from EtOH–H2O.
Bn
>98
d After preparative HPLC (entries 1–3, Daicel Chiralpak® IA; entry 5,
Daicel Chiralpak® IB).
a The ee values were determined by chiral capillary GC.
Synthesis 2008, No. 2, 229–236 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of 2-Substituted Alcohols
231
was stirred at –78 °C for 1 h, at 0 °C for 15 min and at r.t. for 5 min.
The alkylating agent (1.50 mmol) was added at 0 °C and the reac-
tion was stirred at this temperature, whilst monitoring the conver-
sion by TLC. The reaction was quenched with sat. aq NH4Cl
(16 mL). EtOAc (10 mL) was added, the organic phase was separat-
ed and the aqueous phase was extracted with EtOAc (3 × 10 mL).
The combined organic phases were dried with Na2SO4, concentrat-
ed in vacuo and the residue was purified by flash chromatography.
can be greatly improved in many cases by the intermedi-
ate oxidation of the hydroxyamide intermediate 4 to an
oxoamide 6, which can be purified either by crystalliza-
tion or chromatography before reductive cleavage to give
the desired chiral alcohols 5. The procedure works ex-
tremely well for compounds with longer and branched
side chains at the 2-position such as 5a and 5b.
(S)-2-Isopropyl-5-methylhex-5-enoic Acid N-[(1S,2S)-2-Hy-
droxy-1-methyl-2-phenylethyl]-N-methyl Amide (4a)
A solution of triflic anhydride (2.40 mmol) in CH2Cl2 (3 mL) was
added to a solution of 3-methylbut-3-en-1-ol (2.40 mmol) and pyri-
dine (2.88 mmol) in CH2Cl2 (3 mL) at –78 °C. The reaction mixture
was stirred for 2 h at 0 °C, poured on crushed ice, diluted with
CH2Cl2 (20 mL), extracted with cold aq HCl (1 M, 3 × 15 mL) and
washed with cold H2O (15 mL). The organic phase was dried over
MgSO4 and the solvent was removed in vacuo at 0 °C. The triflate
was obtained as a dark-purple liquid and used directly for the alky-
lation reaction.
All chemicals were obtained from commercial suppliers and used
without further purification. Melting points were determined with a
Mettler FP 61 apparatus and are uncorrected. Flash chromatography
was performed on silica gel 60 (Merck, 40–63 mm). Analytical
HPLC experiments were performed on Daicel Chiralpak® IA
(250 × 4.6 mm) and IB (250 × 4.6 mm) columns. Semi-preparative
HPLC separations were performed on semi-preparative Daicel
Chiralpak® IA (250 × 20 mm) and IB (250 × 10 mm) columns. For
chiral capillary GC analysis CP-Chirasil-Dex-CB and CP-Cyclo-
dextrin-B-2,2,6-M-19 columns were used. 1H and 13C NMR spectra
were measured on Mercury 300 and Unity 300 spectrometers
(300 MHz) with TMS as internal standard. IR spectra were mea-
sured on a Bruker Vector 22 spectrometer. Mass spectra were re-
corded with a Finnigan MAT 95 (EI), TSQ 7000 or LCQ (ESI). ESI-
HRMS were recorded on a Bruker APEX IV spectrometer. UV/Vis
spectra were measured using a Perkin–Elmer Lambda 2 spectrome-
ter.
To a stirred suspension of anhydrous LiCl (6.00 mmol) and diiso-
propyl amine (2.35 mmol) in THF (3 mL) at –78 °C, n-BuLi (2.5 M
in hexanes, 2.10 mmol) was added. The resulting suspension was
stirred at 0 °C for 5 min, cooled to –78 °C and treated with an ice-
cold solution of 3 (1.00 mmol) in THF (3 mL). The reaction mixture
was stirred at –78 °C for 1 h, at 0 °C for 15 min and at r.t. for 5 min.
The previously synthesized 3-methylbut-3-enyl triflate
(2.40 mmol) was added at –78 °C and the reaction mixture was al-
lowed to warm to –20 °C, while monitoring the conversion by TLC.
The reaction was quenched with sat. aq NH4Cl (16 mL). EtOAc
(10 mL) was added, the organic phase was separated and the aque-
ous phase was extracted with EtOAc (3 × 10 mL). The combined
organic phases were dried with Na2SO4, concentrated in vacuo and
the residue was purified by flash chromatography.
N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-3-N-dimethyl-
butyramide (3)
To
a solution of (+)-(1S,2S)-pseudoephedrine (1; 3.62 g,
21.9 mmol) and Et3N (3.60 g, 26.3 mmol) in THF (50 mL) at 0 °C,
a solution of isovaleryl chloride (2; 2.89 g, 2.94 mL, 24.0 mmol) in
THF (1 mL) was added within 15 min. After an additional 15 min,
the reaction mixture was quenched with H2O (10 mL). EtOAc
(50 mL) was added and the organic phase was separated, washed
with brine (2 × 40 mL) and dried with Na2SO4. The solvent was
evaporated in vacuo and the residue was purified by crystallization
from n-hexane to afford 3.
20
Yield: 83%; [a]D +85.2 (c 1.00, CHCl3); Rf = 0.2 (n-pentane–
Et2O, 1:1).
IR (film): 3385, 2963, 1616, 1452, 1051, 701 cm–1.
1H NMR (300 MHz, CDCl3): d (major rotamer) = 0.92 (d,
J = 6.6 Hz, 3 H, CH3CHCH3), 0.94 (d, J = 6.6 Hz, 3 H,
CH3CHCH3), 1.16 (d, J = 6.8 Hz, 3 H, CH3), 1.67 (s, 3 H,
C=CCH3), 1.59–1.95 (m, 5 H, CH3CHCH3, CH2CH2), 2.24–2.27
(m, 1 H, H-2), 2.86 (s, 3 H, NCH3), 4.38–4.54 (m, 1 H, NCH), 4.54
(s, 1 H, C=CHH), 4.61 (dd, J = 7.2, 7.2 Hz, 1 H, CHOH), 4.68 (s,
1 H, C=CHH), 4.85 (br s, 1 H, OH), 7.20–7.34 (m, 5 H); d (minor
rotamer) = 0.98 (d, J = 6.6 Hz, 3 H, CH3CHCH3), 2.92 (s, 3 H,
NCH3), 4.11 (q, J = 6.8 Hz, 1 H, NCH), 4.57 (m, 1 H, C=CHH),
4.72 (s, 1 H, C=CHH).
Yield: 5.30 g (97%); colorless crystals; mp 75–76 °C; [a]D20 +104.0
(c 1.00, CHCl3); Rf = 0.3 (Et2O).
IR (KBr): 3321, 2958, 2880, 1611 cm–1.
1H NMR (300 MHz, CDCl3): d (major rotamer) = 0.89–0.94 (m,
6 H, CH3CHCH3), 1.09 (d, J = 6.6 Hz, 3 H, CH3), 2.05–2.28 (m,
3 H, H-2, H-3), 2.78 (s, 3 H, NCH3), 4.41 (mc, 1 H, NCH), 4.56 (mc,
2 H, CHOH, OH), 7.20–7.36 (m, 5 H); d (minor rotamer) = 0.96 (d,
J = 3.3 Hz, 3 H, CH3), 2.88 (s, 3 H, NCH3), 3.99 (dq, J = 8.1,
6.6 Hz, 1 H, NCH).
13C NMR (75 MHz, CDCl3): d (major rotamer) = 14.5, 22.6, 22.7,
25.5, 33.3, 43.1, 58.8, 76.5, 126.3, 127.5, 128.3, 142.5, 175.0; d (mi-
nor rotamer) = 15.3, 26.7, 42.5, 58.3, 75.5, 126.9, 128.7, 141.1,
173.6.
13C NMR (75 MHz, DMSO-d6, 100 °C): d = 13.6, 18.7, 20.1, 21.4,
26.9, 29.6, 30.6, 34.6, 46.1, 54.0, 73.8, 109.2, 126.1, 126.3, 127.2,
143.2, 144.9, 147.3.
MS (DCI, NH3): m/z (%) = 318.5 (100) [M + H]+, 636.1 (23) [2 ×
M + H]+.
MS (DCI, NH3): m/z (%) = 250.3 (100) [M + H]+, 499.6 (19) [2 ×
M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C20H32NO2: 318.243; found:
HRMS-ESI: m/z [M + H]+ calcd for C15H24NO2: 250.1802; found:
318.243.
250.1802.
Anal. Calcd for C20H31NO2: C, 75.67; H, 9.84. Found: C, 75.41; H,
9.64.
UV/Vis (MeCN): lmax (log e) = 252 (2.34), 257 (2.41), 264 nm
(2.33).
(S)-2-Isopropyl-5-methylhex-4-enoic Acid N-[(1S,2S)-2-Hy-
droxy-1-methyl-2-phenylethyl]-N-methyl Amide (4b)
Amide 3 was alkylated with 3,3-dimethylallyl bromide.
Yield: 92%; [a]D20 +69.6 (c 0.50, CHCl3); Rf = 0.7 (Et2O).
Alkylation of 3, General Procedure
To a stirred suspension of anhydrous LiCl (6.00 mmol) and diiso-
propylamine (2.35 mmol) in THF (3 mL) at –78 °C, n-BuLi (2.5 M
in hexanes, 2.10 mmol) was added. The resulting suspension was
stirred at 0 °C for 5 min, cooled to –78 °C and treated with an ice-
cold solution of 3 (1.00 mmol) in THF (3 mL). The reaction mixture
IR (film): 3328, 2959, 2872, 1601, 1054, 754, 704 cm–1.
Synthesis 2008, No. 2, 229–236 © Thieme Stuttgart · New York

232
L. F. Tietze et al.
PAPER
1H NMR (300 MHz, CDCl3): d (major rotamer) = 0.88 (d,
J = 6.8 Hz, 3 H, CH3CHCH3), 0.94 (d, J = 6.8 Hz, 3 H,
CH3CHCH3), 1.07 (d, J = 6.6 Hz, 3 H, CH3), 1.58 (mc, 3 H,
C=CCH3), 1.61 (mc, 3 H, C=CCH3), 1.81 (dqq, J = 7.5, 6.8, 6.8 Hz,
1 H, CH3CHCH3), 2.16–2.40 (m, 3 H, H-2, CH2), 2.80 (s, 3 H,
NCH3), 4.41 (mc, 1 H, NCH), 4.59 (mc, 1 H, CHOH), 4.93 (mc, 1 H,
HC=C), 7.20–7.39 (m, 5 H); d (minor rotamer) = 0.86 (d,
J = 7.0 Hz, 3 H, CH3CHCH3), 0.93 (d, J = 6.6 Hz, 3 H,
CH3CHCH3), 0.96 (d, J = 6.2 Hz, 3 H, CH3), 1.66 (s, 3 H,
C=CCH3), 1.68 (s, 3 H, C=CCH3), 2.61 (mc, 1 H, H-2), 2.86 (s, 3 H,
NCH3), 4.11 (dq, J = 9.2, 6.8 Hz, 1 H, NCH), 4.50 (dd, J = 9.2,
2.1 Hz, 1 H, CHOH), 5.22 (mc, 1 H, HC=C).
1 H, NCH), 4.60 (mc, 1 H, CHOH), 7.20–7.37 (m, 5 H); d (minor
rotamer) = 0.97 (d, J = 7.1 Hz, 3 H, CH3), 2.53 (mc, 1 H, H-2), 2.89
(s, 3 H, NCH3), 4.14 (dq, J = 9.0, 7.0 Hz, 1 H, NCH), 4.56 (mc, 1 H,
CHOH).
13C NMR (75 Hz, CDCl3): d (major rotamer) = 11.7, 14.7, 19.9,
21.3, 23.2, 30.7, 33.5, 50.7, 59.2, 76.3, 126.3, 127.4, 128.2, 142.5,
178.4; d (minor rotamer) = 12.4, 15.2, 19.6, 21.5, 22.5, 26.7, 49.3,
58.1, 75.3, 127.0, 128.6, 141.2, 176.8.
MS (DCI, NH3): m/z (%) = 278.0 (100) [M + H]+, 295.4 (10) [M +
NH4]+, 555.7 (36) [2 × M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C17H28NO2: 278.2115; found:
13C NMR (75 MHz, CDCl3): d (major rotamer) = 14.6, 17.6, 19.9,
21.2, 25.7, 29.0, 30.8, 33.6, 49.4, 59.1, 76.4, 121.7, 126.4, 127.5,
128.3, 132.9, 142.5, 178.2; d (minor rotamer) = 15.3, 17.7, 20.1,
21.3, 25.8, 26.8, 29.2, 48.2, 58.5, 75.2, 122.4, 127.5, 128.2, 128.6,
134.2, 141.0, 176.7.
278.2120.
UV/Vis (MeCN): lmax (log e) = 252 (2.31), 258 (2.33), 264 nm
(2.26).
(S)-2-Isopropylpentanoic Acid N-[(1S,2S)-2-Hydroxy-1-meth-
yl-2-phenylethyl]-N-methyl Amide (4e)
Amide 3 was alkylated with 1-iodopropane.
Yield: 85%; [a]D20 +92.8 (c 0.50, CHCl3); Rf = 0.6 (Et2O).
IR (film): 3383, 2459, 1616, 1454, 761 cm–1.
MS (DCI, NH3): m/z (%) = 318.4 (100) [M + H]+, 635.7 (24) [2 ×
M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C20H32NO2: 318.2428; found:
318.2428.
1H NMR (300 MHz, CDCl3): d (major rotamer) = 0.80 (t,
J = 7.2 Hz, 3 H, CH3), 0.87 (d, J = 6.8 Hz, 3 H, CH3CHCH3), 0.90
(d, J = 6.8 Hz, 3 Hz, CH3CHCH3), 0.93–1.09 (m, 2 H, CH2CH3),
1.11 (d, J = 7.0 Hz, 3 H, CH3), 1.35 (mc, 1 H, H-3), 1.49–1.63 (m,
1 H, H-3), 1.82 (dqq, J = 8.2, 6.8, 6.8 Hz, 1 H, CH3CHCH3), 2.28
(ddd, J = 8.2, 8.2, 3.5 Hz, 1 H, H-2), 2.84 (s, 3 H, NCH3), 4.43 (mc,
1 H, NCH), 4.58 (d, J = 7.3 Hz, 1 H, CHOH), 7.18–7.35 (m, 5 H);
d (minor rotamer) = 0.95 (d, J = 6.6 Hz, 3 H, CH3), 2.63 (mc, 1 H,
H-2), 2.86 (s, 3 H, NCH3), 4.12 (dq, J = 9.1, 6.6 Hz, 1 H, NCH),
4.53 (d, J = 9.1 Hz, 1 H, CHOH).
UV/Vis (MeCN): lmax (log e) = 192 (4.70), 248 (2.36), 254 (2.38),
258 nm (3.30).
(S)-N-[(1S,2S)-2-Hydroxy-1-methyl-2-phenylethyl]-2,3,N-tri-
methylbutyramide (4c)
Amide 3 was alkylated with iodomethane.
20
Yield: 92%; [a]D +143.0 (c 0.50, CHCl3); Rf = 0.3 (Et2O–n-pen-
tane, 5:1).
IR (film): 3379, 2965, 1611, 1453, 702 cm–1.
1H NMR (300 MHz, CDCl3): d (major rotamer) = 0.85 (d,
J = 6.6 Hz, 3 H, CH3CHCH3), 0.87 (d, J = 6.6 Hz, 3 H,
CH3CHCH3), 0.97 (d, J = 6.8 Hz, 3 H, CH3), 1.18 (d, J = 7.2 Hz,
3 H, CH3), 1.85 (dqq, J = 8.1, 6.6, 6.6 Hz, 1 H, CH3CHCH3), 2.26
(dq, J = 8.1, 6.8 Hz, 1 H, H-2), 2.75 (s, 3 H, NCH3), 4.25 (mc, 1 H,
NCH), 4.61 (dd, J = 7.0, 7.0 Hz, 1 H, CHOH), 5.01 (br s, 1 H, OH),
7.19–7.38 (m, 5 H); d (minor rotamer) = 0.98 (d, J = 7.2 Hz, 3 H,
CH3CHCH3), 1.06 (d, J = 6.6 Hz, 3 H, CH3), 2.53 (dq, J = 7.2,
7.2 Hz, 1 H, H-2), 2.88 (s, 3 H, NCH3), 4.10 (dq, J = 8.4, 7.2 Hz,
1 H, NCH), 4.54 (d, J = 8.4 Hz, 1 H, CHOH).
13C NMR (75 MHz, CDCl3): d (major rotamer) = 14.4, 14.8, 19.2,
21.4, 31.0, 34.4, 43.4, 60.2, 76.4, 126.1, 127.4, 128.1, 142.6, 179.1;
d (minor rotamer) = 15.5, 19.3, 21.5, 26.9, 31.4, 42.5, 58.1, 75.3,
126.8, 128.2, 128.6, 141.4, 178.0.
13C NMR (75 MHz, CDCl3): d (major rotamer) = 14.3, 14.6, 19.9,
20.6, 21.2, 31.0, 32.5, 34.5, 49.0, 59.5, 76.3, 126.2, 127.4, 128.2,
142.6, 178.6; d (minor rotamer) = 15.2, 19.6, 21.5, 26.8, 31.8, 47.8,
75.3, 127.0, 128.3, 128.6, 141.2, 177.0.
MS (DCI, NH3): m/z (%) = 292.4 (100) [M + H]+, 583.7 (22) [2 ×
M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C18H30NO2: 292.2271; found:
292.2271.
UV/Vis (MeCN): lmax (log e) = 252 (2.31), 258 (2.33), 264 nm
(2.26).
(S)-2-Benzyl-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-
3,N-dimethylbutyramide (4f)
Amide 3 was alkylated with benzyl bromide.
Yield: 85%; mp 121–122 °C; [a]D20 –35.0 (c 0.50, CHCl3); Rf = 0.6
(Et2O).
MS (DCI, NH3): m/z (%) = 264.3 (100) [M + H]+, 527.7 (32) [2 ×
M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C16H26NO2: 264.1958; found:
264.1958.
IR (KBr): 3332, 2965, 1611, 696 cm–1.
1H NMR (300 MHz, CDCl3): d (major rotamer) = 0.61 (d,
J = 6.6 Hz, 3 H, CH3), 0.95 (d, J = 6.3 Hz, 3 H, CH3CHCH3), 1.06
(d, J = 6.3 Hz, 3 H, CH3CHCH3), 2.00 (mc, 1 H, CH3CHCH3), 2.46
(s, 3 H, NCH3), 2.64 (mc, 1 H, H-2), 2.76–2.93 (m, 2 H, CH2), 3.69
(mc, 1 H, NCH), 4.38–4.48 (m, 2 H, CHOH, OH), 7.13–7.28 (m,
10 H); d (minor rotamer) = 0.86 (d, J = 6.9 Hz, 3 H, CH3), 2.72 (s,
3 H, NCH3), 3.85 (dq, J = 8.7, 6.6 Hz, 1 H, NCH), 4.13 (dd, J = 8.7,
3.6 Hz, 1 H, CHOH).
UV/Vis (MeCN): lmax (log e) = 248 (2.36), 254 (2.39), 258 (2.39),
264 nm (2.23).
(S)-2-Ethyl-N-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-
N,3-dimethylbutyramide (4d)
Amide 3 was alkylated with iodoethane.
20
Yield: 80%; [a]D +92.8 (c 0.50, CHCl3); Rf = 0.4 (Et2O–n-pen-
tane, 5:1).
13C NMR (75 MHz, CDCl3): d (major rotamer) = 14.2, 20.2, 21.3,
31.2, 31.5, 37.1, 52.2, 57.1, 76.5, 126.1, 126.5, 126.6, 126.9, 127.6,
128.2, 128.3, 128.5, 128.6, 128.9, 129.2, 140.2, 142.2, 177.7; d (mi-
nor rotamer) = 15.2, 26.9, 36.8, 51.1, 58.2, 74.9, 140.8.
IR (film): 3383, 2963, 2873, 1615, 1454, 701 cm–1.
1H NMR (300 MHz, CDCl3): d (major rotamer) = 0.72 (t,
J = 7.1 Hz, 3 H, CH2CH3), 0.89 (d, J = 7.1 Hz, 3 H, CH3CHCH3),
0.91 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 1.12 (d, J = 6.9 Hz, 3 H,
CH3), 1.55 (mc, 2 H, H-6), 1.86 (dqq, J = 8.1, 6.9, 6.9 Hz, 1 H,
CH3CHCH3), 2.24 (mc, 1 H, H-2), 2.86 (s, 3 H, NCH3), 4.48 (mc,
MS (DCI, NH3): m/z (%) = 340.3 (100) [M + H]+, 679.8 (18) [2 ×
M + H]+.
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Enantioselective Synthesis of 2-Substituted Alcohols
233
HRMS-ESI: m/z [M + H]+ calcd for C22H30NO2: 340.2271; found:
340.2271.
UV/Vis (MeCN): lmax (log e) = 196 (4.54), 241 (3.99), 322 nm
(4.15).
UV/Vis (MeCN): lmax (log e) = 192 (4.64), 252 (4.01), 258 (4.59),
264 nm (3.90).
HPLC (IA; flow 0.8 mL/min; n-hexane–2-propanol, 99:1; 245 nm):
tR [(2S)-6b] = 15.0 min, tR [(2R)-6b] = 21.7 min; dr >99:1.
Formation of Oxoamides 6a–f; General Procedure
(S)-2,3,N-Trimethyl-N-[(S)-1-methyl-2-oxo-2-phenylethyl]-N-
To a stirred solution of oxalyl chloride (938 mg, 7.24 mmol) in
CH2Cl2 (16 mL) at –78 °C, dimethyl sulfoxide (1.03 g, 14.5 mmol)
in CH2Cl2 (3 mL) was added. After 5 min, the hydroxyamide
(6.58 mmol) was added dropwise as a solution in CH2Cl2 (7 mL)
over a period of 5 min. The solution was stirred for 15 min and
Et3N (3.33 g, 32.9 mmol) was added dropwise. After 10 min, the re-
action mixture was warmed to r.t. and the reaction was quenched
with H2O (50 mL). The phases were separated and the organic
phase was extracted with CH2Cl2 (50 mL). The combined organic
phases were washed with aq HCl (2 N, 50 mL), aq NaOH (2 M,
50 mL), H2O (50 mL), brine (50 mL) and dried with Na2SO4. The
solvent was evaporated in vacuo and the residue was purified by
flash chromatography. Crystalline products were crystallized from
EtOH–H2O. 6a–c and 6e were purified by semi-preparative HPLC,
using Daicel Chiralpak® IA or IB columns.
butyramide (6c)
Yield: 90%; [a]D –195.7 (c 3.00, CHCl3); Rf = 0.3 (Et2O–n-pen-
tane, 1:2).
20
IR (film): 2963, 2348, 1690, 1640, 1449, 1237, 749 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.72 (d, J = 6.8 Hz, 3 H,
CH3CHCH3), 0.82 (d, J = 6.8 Hz, 3 H, CH3), 1.00 (d, J = 6.8 Hz,
3 H, CH3CHCH3), 1.30 (d, J = 7.1 Hz, 3 H, CH3), 1.77 (mc, 1 H,
CH3CHCH3), 2.31 (mc, 1 H, H-2), 2.76 (s, 3 H, NCH3), 6.12 (q,
J = 6.8 Hz, 1 H, NCH), 7.37 (mc, 2 H), 7.50 (mc, 1 H), 7.93 (mc,
2 H).
13C NMR (75 MHz, CDCl3): d = 12.9, 14.3, 19.0, 21.4, 30.6, 30.7,
42.4, 53.1, 128.4, 128.5, 133.2, 135.2, 176.2, 199.7.
MS (DCI, NH3): m/z (%) = 276.4 (100) [M + H]+, 551.8 (1) [2 ×
M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C16H24NO2: 262.1802; found:
262.1802.
(S)-2-Isopropyl-5-methylhex-5-enoic Acid N-[(S)-1-Methyl-2-
oxophenylethyl]-N-methyl Amide (6a)
Yield: 79%; mp 53–54 °C; [a]D –228.0 (c 1.00, CHCl3); Rf = 0.4
(Et2O–n-pentane, 1:2).
20
UV/Vis (MeCN): lmax (log e) = 197 (4.46), 240 (4.00), 324 nm
(2.19).
IR (KBr): 2963, 1692, 1625, 1448, 693 cm–1.
HPLC (IA; flow 0.8 mL/min; n-hexane–2-propanol, 99:1; 245 nm):
tR (2S)-6c = 18.9 min, tR (2R)-6c = 20.9 min; dr >99:1.
1H NMR (300 MHz, DMSO-d6): d = 0.81 (d, J = 6.6 Hz, 3 H,
CH3CHCH3), 0.87 (d, J = 6.6 Hz, 3 H, CH3CHCH3), 1.35 (d,
J = 6.7 Hz, 3 H, CH3), 1.42–1.71 (m, 5 H, CH2CH2, CH3CHCH3),
1.64 (s, 3 H, C=CCH3), 2.46 (mc, 1 H, H-2), 2.97 (s, 3 H, NCH3),
4.59 (s, 1 H, C=CHH), 4.69 (s, 1 H, C=CHH), 5.63 (q, J = 6.7 Hz,
1 H, NCH), 7.46–7.62 (m, 3 H), 7.87 (d, J = 7.2 Hz, 2 H).
(S)-2-Ethyl-3,N-dimethyl-N-[(S)-1-methyl-2-oxo-2-phenyleth-
yl]butyramide (6d)
Yield: 86%; mp 63–64 °C; [a]D –242.2 (c 5.00, CHCl3); Rf = 0.2
(Et2O–n-pentane. 1:5).
20
IR (KBr): 2968, 2871, 1685, 1624, 1324, 750 cm–1.
13C NMR (50 MHz, DMSO-d6): d = 12.1, 18.6, 19.8, 21.2, 26.6,
29.6, 31.7, 34.3, 45.5, 55.1, 109.2, 127.1, 127.7, 131.8, 136.0,
144.7, 173.7, 198.2.
1H NMR (300 MHz, CDCl3): d = 0.70 (d, J = 6.8 Hz, 3 H,
CH3CHCH3), 0.84 (d, J = 6.8 Hz, 3 H, CH3CHCH3), 0.78 (t,
J = 7.3 Hz, 3 H, CH3), 1.34 (d, J = 6.8 Hz, 3 H, CH3), 1.47–1.69 (m,
2 H, CH2), 1.79 (mc, 1 H, CH3CHCH3), 2.27 (ddd, J = 7.7, 7.7,
4.0 Hz, 1 H, H-2), 2.81 (s, 3 H, NCH3), 6.21 (q, J = 6.8 Hz, 1 H,
NCH), 7.40 (mc, 2 H), 7.52 (mc, 1 H), 7.96 (mc, 2 H).
MS (ESI): m/z (%) = 338.2 (16) [M + Na]+, 653.1 (100) [2 × M +
Na]+.
HRMS-ESI: m/z [M + Na]+ calcd for C20H29NNaO2: 338.210;
found: 338.209.
13C NMR (75 MHz, CDCl3): d = 11.8, 13.3, 19.7, 21.1, 23.1, 30.7,
31.0, 49.6, 53.2, 128.4, 128.5, 133.2, 135.3, 175.6, 199.8.
UV/Vis (MeCN): lmax (log e) = 196 (4.55), 240 nm (4.04).
HPLC (IA; flow 0.8 mL/min; n-hexane–2-propanol, 99:1; 245 nm):
tR [(2S)-6a] = 18.9 min, tR [(2R)-6a] = 20.9 min; dr >99:1.
MS (DCI, NH3): m/z (%) = 267.4 (100) [M + H]+, 551.8 (1) [2 ×
M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C17H26NO2: 276.1958; found:
276.1958.
(S)-2-Isopropyl-5-methylhex-4-enoic Acid N-[(S)-1-Methyl-2-
oxo-2-phenylethyl]-N-methyl Amide (6b)
Yield: 80%; mp 39–40 °C; [a]D –175.3 (c 4.00, CHCl3); Rf = 0.3
(Et2O–n-pentane, 1:5).
20
UV/Vis (MeCN): lmax (log e) = 198 (4.49), 240 (4.01), 322 nm
(2.23).
IR (KBr): 2962, 1684, 1639, 1449, 702 cm–1.
(S)-2-Isopropylpentanoic Acid N-[(S)-1-Methyl-2-oxo-2-phe-
nylethyl]-N-methyl Amide (6e)
Yield: 92%; mp 64–65 °C; [a]D –224.0 (c 4.00, CHCl3); Rf = 0.3
(Et2O–n-pentane, 1:5).
1H NMR (300 MHz, CDCl3): d = 0.66 (d, J = 6.8 Hz, 3 H,
CH3CHCH3), 0.85 (d, J = 6.8 Hz, 3 H, CH3CHCH3), 1.25 (d,
J = 6.6 Hz, 3 H, CH3), 1.58 (s, 3 H, C=CCH3), 1.61 (s, 3 H,
C=CCH3), 1.83 (mc, 1 H, CH3CHCH3), 2.15–2.35 (m, 3 H, H-2, H-
6), 2.70 (s, 3 H, NCH3), 4.97 (mc, 1 H, HC=C), 6.20 (q, J = 6.7 Hz,
1 H, NCH), 7.37 (mc, 2 H), 7.49 (mc, 1 H), 7.95 (mc, 2 H).
13C NMR (75 MHz, CDCl3): d = 12.9, 17.6, 19.9, 21.0, 25.7, 29.3,
30.8, 30.9, 48.3, 52.9, 121.4, 128.4, 128.5, 133.2, 133.3, 135.2,
175.5, 199.8.
20
IR (KBr): 2959, 2872, 1691, 1638, 1449, 1237, 813 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.68 (d, J = 6.9 Hz, 3 H,
CH3CHCH3), 0.82 (d, J = 6.6 Hz, 3 H, CH3CHCH3), 0.83 (t,
J = 7.1 Hz, 3 H, CH3), 0.98–1.23 (m, 2 H, CH2), 1.32 (d, J = 6.9 Hz,
3 H, CH3), 1.34–1.43 (m, 1 H, H-6), 1.50–1.64 (m, 1 H, H-6), 1.73
(mc, 1 H, CH3CHCH3), 2.31 (ddd, J = 7.6, 7.3, 3.5 Hz, 1 H, H-2),
2.80 (s, 3 H, NCH3), 6.14 (q, J = 6.8 Hz, 1 H, NCH), 7.38 (mc, 2 H),
7.50 (mc, 1 H), 7.94 (mc, 2 H).
MS (EI, 70 eV): m/z (%) = 125.2 (8), 210.3 (24), 272.3 (6), 315.4
(8) [M]+.
HRMS-ESI: m/z [M + H]+ calcd for C20H30NO2: 316.2271; found:
316.2271.
13C NMR (75 MHz, CDCl3): d = 13.2, 14.4, 19.7, 20.8, 21.0, 30.8,
31.1, 32.3, 47.9, 53.3, 128.4, 128.5, 133.2, 135.4, 175.7, 199.8.
Synthesis 2008, No. 2, 229–236 © Thieme Stuttgart · New York

234
L. F. Tietze et al.
PAPER
MS (DCI, NH3): m/z (%) = 290.2 (100) [M + H]+, 581.4 (1) [2 ×
MS (EI, 70 eV): m/z (%) = 69 (100), 156 (10) [M]+.
HRMS-EI: m/z [M]+ calcd for C10H20O: 156.151; found: 156.151.
M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C18H28NO2: 290.2115; found:
290.2115.
UV/Vis (MeCN): lmax (log e) = 192 nm (3.90).
GC [120 °C; p(H2) = 3 psi; n-hexane]: tR [(S)-5a] = 16.29 min,
tR [(R)-5a] = 16.66 min; ≥ 99.9% ee.
UV/Vis (MeCN): lmax (log e) = 198 (4.48), 239 (4.02), 318 nm
(3.36).
HPLC (IB; flow 0.8 mL/min; n-hexane–2-propanol, 99:1; 245 nm):
tR [(2S)-6e] = 5.7 min, tR [(2R)-6e] = 6.4 min; dr >99:1.
(S)-2-Isopropyl-5-methylhex-4-en-1-ol (5b)
Yield: 95%; [a]D20 –7.5 (c 1.00, CHCl3); Rf = 0.4 (Et2O–n-pentane,
1:2).
(S)-2-Benzyl-3,N-dimethyl-N-[(S)-1-methyl-2-oxomethyl-2-
IR (film): 3356, 2954, 1451, 1378, 1042 cm–1.
phenylethyl]butyramide (6f)
Yield: 82%; mp 70–71 °C; [a]D –210.6 (c 5.00, CHCl3); Rf = 0.2
(Et2O–n-pentane, 5:1).
1H NMR (300 MHz, CDCl3): d = 0.88 (d, J = 6.9 Hz, 3 H,
CH3CHCH3), 0.89 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 1.31–1.42 (m,
1 H, H-2), 1.60 (s, 3 H, C=CCH3), 1.68 (s, 3 H, C=CCH3), 1.77
(dqq, J = 6.9, 6.9, 5.0 Hz, 1 H, CH3CHCH3), 1.89–2.08 (m, 2 H,
CH2), 3.56 (mc, 2 H, CH2OH), 5.14 (mc, 1 H, HC=C).
13C NMR (75 MHz, CDCl3): d = 17.7, 19.4, 19.9, 25.8, 26.8, 28.0,
47.3, 64.2, 123.4, 132.6.
20
IR (KBr): 2962, 1691, 1627, 1454, 963.3, 750.0, 521 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.70 (d, J = 6.7 Hz, 3 H,
CH3CHCH3), 0.91 (d, J = 6.8 Hz, 3 H, CH3), 0.99 (d, J = 6.7 Hz,
3 H, CH3CHCH3), 1.95 (dqq, J = 8.2, 6.8, 6.8 Hz, 1 H,
CH3CHCH3), 2.31 (s, 3 H, NCH3), 2.60 (mc, 1 H, H-2), 2.87 (mc,
2 H, CH2), 6.15 (q, J = 6.8 Hz, 1 H, NCH), 7.15–7.27 (m, 5 H), 7.39
(mc, 2 H), 7.51 (mc, 1 H), 7.96 (mc, 2 H).
MS (EI, 70 eV): m/z (%) = 69.1 (100), 82.1 (40), 156.3 (22) [M]+.
HRMS-ESI: m/z [M + H]+ calcd for C12H21O: 157.1587; found:
13C NMR (75 MHz, CDCl3): d = 12.6, 20.2, 20.9, 30.2, 31.3, 37.1,
51.1, 52.4, 126.2, 128.2, 128.5, 128.6, 129.0, 133.3, 135.2, 140.0,
174.9, 199.7.
157.1587.
UV/Vis (MeCN): lmax (log e) = 192 nm (3.90).
GC [120 °C; p(H2) = 3 psi; n-hexane]: tR [(S)-5b] = 16.29 min,
tR [(R)-5b] = 16.74 min; ≥ 99.9% ee.
MS (DCI, NH3): m/z (%) = 338.4 (100) [M + H]+, 675.7 (1) [2 ×
M + H]+.
HRMS-ESI: m/z [M + H]+ calcd for C22H28NO2: 338.2115; found:
338.2115.
(S)-2,3-Dimethylbutan-1-ol (5c)
20
Yield: 85%; [a]D +4.6 (c 1.00, CHCl3) [lit.16 [a]D20 +5.0 (c 3.0,
CH2Cl2)]; Rf = 0.4 (Et2O–n-pentane, 1:2).
IR (film): 3345, 2959, 2876, 1464, 1036 cm–1.
UV/Vis (MeCN): lmax (log e) = 192 (4.80), 242 (4.04), 323 nm
(2.21).
1H NMR (300 MHz, CDCl3): d = 0.79 (d, J = 7.2 Hz, 3 H,
CH3CHCH3), 0.82 (d, J = 7.0 Hz, 3 H, CH3), 0.87 (d, J = 6.9 Hz,
3 H, CH3CHCH3), 1.46 (mc, 1 H, H-2), 1.66 (dqq, J = 6.9, 6.9,
5.1 Hz, 1 H, CH3CHCH3), 1.83 (br s, 1 H, OH), 3.39 (dd, J = 10.5,
6.9 Hz, 1 H, H-1), 3.54 (dd, J = 10.5, 6.0 Hz, 1 H, H-1).
HPLC (IA; flow 0.8 mL/min; n-hexane–2-propanol, 99:1; 245 nm):
tR [(2S)-6f] = 20.9 min, tR [(2R)-6f] = 33.8 min; dr >99:1.
Synthesis of 2-Substituted Alcohols 5a–f; General Procedure
To a solution of diisopropylamine (306 mg, 3.02 mmol, 6.30 equiv)
in THF (4 mL) at –78 °C, n-BuLi (2.5 M in hexanes, 1.1 mL, 2.81
mmol, 5.85 equiv) was added. The solution was stirred for 10 min
at –78 °C and for another 10 min at 0 °C. Borane-ammonia com-
plex (90%, 98.8 mg, 2.88 mmol, 6.00 equiv) was added at 0 °C and
the resulting suspension was stirred at 0 °C for 15 min and at r.t. for
15 min. The mixture was cooled to 0 °C and a solution of the oxo-
amide (0.480 mmol, 1.00 equiv) in THF (1 mL) was added drop-
wise over a period of 3 min. The resulting mixture was stirred at r.t.
and the conversion was monitored by TLC. The reaction was
quenched by addition of aq HCl (2 M, 10 mL) and then stirred for
30 min. The organic phase was separated and the aqueous phase
was extracted with Et2O (3 × 10 mL). The combined organic phases
were washed with aq HCl (2 M, 10 mL), aq NaOH (2 M, 10 mL),
brine (10 mL) and dried with Na2SO4. The solvent was evaporated
in vacuo (200 mbar) and the product was purified by flash chroma-
tography.
13C NMR (75 MHz, CDCl3): d = 12.4, 17.9, 20.6, 28.8, 41.3, 66.4.
MS (DCI, NH3): m/z (%) = 120.2 (84) [M + NH4]+, 137.2 (24) [M +
NH3 + NH4]+.
HRMS-ESI: m/z [M + H]+ calcd for C6H15O: 103.1117; found:
103.1117.
UV/Vis (MeCN): lmax (log e) = 255 nm (1.45).
GC [80 °C; p(H2) = 3 psi; n-hexane]: tR [(S)-5c] = 22.58 min,
tR [(R)-5c] = 23.05 min; ≥ 99.9% ee.
(S)-2-Ethyl-3-methylbutan-1-ol (5d)
Yield: 57%; [a]D20 –5.8 (c 1.00, CHCl3) [lit.17 [a]D20 –9.47 (neat)];
Rf = 0.4 (Et2O–n-pentane, 1:2).
IR (film): 3345, 2960, 2876, 1466, 1035 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.84 (d, J = 6.9 Hz, 3 H,
CH3CHCH3), 0.85 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.87 (t,
J = 7.2 Hz, 3 H, CH3), 1.13–1.45 (m, 3 H, H-2, CH2), 1.76 (dqq,
J = 9.0, 6.9, 6.9 Hz, 1 H, CH3CHCH3), 1.82 (br s, 1 H, OH), 3.55
(mc, 2 H, CH2OH).
13C NMR (75 MHz, CDCl3): d = 12.1, 19.3, 19.7, 20.3, 27.5, 48.2,
63.2.
(S)-2-Isopropyl-5-methylhex-5-en-1-ol (5a)
Yield: 89%; [a]D20 –11.8 (c 1.00, CHCl3); [lit.15 (R)-5a: [a]D24 +9.04
(c 1.2, CHCl3)]; Rf = 0.4 (Et2O–n-pentane, 2:1).
IR (film): 3344, 2958, 1650, 1454, 1370, 1036 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.91 (d, J = 6.9 Hz, 3 H,
CH3CHCH3), 0.92 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 1.21–2.15 (m,
3 H, H-2, CHCH2), 1.74 (s, 3 H, C=CCH3), 1.78–1.89 (m, 1 H,
CH3CHCH3), 1.97–2.15 (m, 2 H, CH2C=C), 3.62 (mc, 2 H, CH2O),
4.70 (s, 1 H, C = CHH), 4.71 (s, 1 H, C = CHH).
13C NMR (75 MHz, CDCl3): d = 19.3, 19.8, 22.4, 25.7, 27.9, 36.0,
46.1, 63.6, 109.9, 146.
MS (DCI, NH3): m/z (%) = 134.2 (100) [M + NH4]+, 151.3 (32)
[M + NH3 + NH4]+, 205.5 (1) [2 × M + NH4]+.
HRMS-ESI: m/z [M + H]+ calcd for C7H17O: 117.1274; found:
117.1274.
UV/Vis (MeCN): lmax (log e) = 215 nm (2.27).
Synthesis 2008, No. 2, 229–236 © Thieme Stuttgart · New York

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Enantioselective Synthesis of 2-Substituted Alcohols
235
GC [80 °C; p(H2) = 3 psi; n-hexane]: tR [(S)-5d] = 23.65 min,
tR [(R)-5d] = 24.41 min; 96% ee.
(2) (a) Frater, G. In Houben-Weyl, 4th ed., Vol. E21; Helmchen,
G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.;
Thieme: Stuttgart, 1996, 723. (b) Högberg, H.-E. In
Houben-Weyl, 4th ed., Vol. E21; Helmchen, G.; Hoffmann,
R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme: Stuttgart,
1996, 791. (c) Caine, D. In Comprehensive Organic
Synthesis, Vol. 3; Trost, B. M.; Fleming, I., Eds.; Pergamon
Press: Oxford, 1991, Chap. 1.1. (d) Norin, T. In Houben-
Weyl, 4th ed., Vol. E21; Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E., Eds.; Thieme: Stuttgart, 1996,
697. (e) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980,
21, 4233. (f) Schmierer, R.; Grotemeier, G.; Helmchen, G.;
Selim, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 207.
(g) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett.
1989, 30, 5603. (h) Kawanami, Y.; Ito, Y.; Kitagawa, T.;
Taniguchi, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron
Lett. 1984, 25, 857. (i) Larcheveque, M.; Ignatova, E.;
Cuvigny, T. Tetrahedron Lett. 1978, 19, 3961.
(S)-2-Isopropylpentan-1-ol (5e)
Yield: 92%; Rf = 0.4 (Et2O–n-pentane, 1:2).
IR (film): 3345, 2959, 1466, 1040 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.84 (d, J = 7.1 Hz, 3 H,
CH3CHCH3), 0.87 (d, J = 6.9 Hz, 3 H, CH3CHCH3), 0.88 (t,
J = 6.5 Hz, 3 H, CH3), 1.13–1.38 (m, 5 H, H-2, CH2CH2), 1.77 (mc,
1 H, CH3CHCH3), 2.46 (br s, 1 H, OH), 3.53 (mc, 2 H, CH2OH).
13C NMR (75 MHz, CDCl3): d = 14.4, 19.0, 19.7, 20.9, 27.7, 29.9,
46.2, 63.6.
MS (DCI, NH3): m/z (%) = 148.2 (100) [M + NH4]+, 165.3 (52)
[M + NH3 + NH4]+, 278.5 (2) [2 × M + NH4]+.
HRMS-ESI: m/z [M + H]+ calcd for C8H19O: 131.1430; found:
131.1430.
(j) Larcheveque, M.; Ignatova, E.; Cuvigny, T. J.
Organomet. Chem. 1979, 177, 5. (k) Sonnet, P. E.; Heath,
R. R. J. Org. Chem. 1980, 45, 3137.
GC [90 °C; p(H2) = 3 psi; n-hexane]: tR [(S)-5e] = 19.51 min,
tR [(R)-5e] = 20.50 min; >99% ee.
(3) (a) Fey, P. In Houben-Weyl, 4th ed., Vol. E21; Helmchen,
G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.;
Thieme: Stuttgart, 1996, 973. (b) Fey, P. In Houben-Weyl,
4th ed., Vol. E21; Helmchen, G.; Hoffmann, R. W.; Mulzer,
J.; Schaumann, E., Eds.; Thieme: Stuttgart, 1996, 994.
(4) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. J.
Am. Chem. Soc. 1994, 116, 9361. (b) Myers, A. G.; Yang,
B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J.
L. J. Am. Chem. Soc. 1997, 119, 6496.
(5) The desired S-configuration for alcohol 5a originates in the
alkylation reaction. According to Myers,4b the newly
introduced alkyl chain is attached from the side which
comprises the methyl substituent of the pseudoephedrine
side chain. We measured the optical rotation for (S)-5a to be
[a]D20 –11.8 (c 1.00, CHCl3). In the literature the value for
the enantiomer (R)-5a was published as [a]D24 +9.04 (c 1.2,
CHCl3).15 The opposite signs illustrate that these compounds
are enantiomers and the higher value for our compound is
due to its higher optical purity. Additionally, the absolute
configuration of the oxoamide precursor (–)-(2S),1¢S)-6a,
which was converted into alcohol (S)-5a, was determined by
X-ray diffraction.11
(6) For determination of ee values by chiral capillary GC or
chiral HPLC, racemic mixtures of the alcohols were used as
standards. These were synthesized by alkylation of
isovaleric acid enolates and reduction of the resulting
2-substituted carboxylic acids by LiAlH4.
(7) The oxoamide 6a was recrystallized from EtOH–H2O.
Daicel Chiralpak® IA columns (n-hexane–2-propanol, 99:1)
were used for the analytical and semi-preparative HPLC
separation.
(S)-2-Benzyl-3-methylbutan-1-ol (5f)
Yield: 78%; [a]D20 –11.8 (c 1.00, CHCl3); Rf = 0.3 (Et2O–n-pentane,
1:2).
IR (film): 3355, 2458, 1451, 1039, 733.7 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.94 (d, J = 6.8 Hz, 3 H,
CH3CHCH3), 0.96 (d, J = 6.8 Hz, 3 H, CH3CHCH3), 1.47 (br s, 1 H,
OH), 1.65 (mc, 1 H, H-2), 1.85 (dqq, J = 9.1, 6.8, 6.8 Hz, 1 H,
CH3CHCH3), 2.50 (dd, J = 13.8, 9.2 Hz, 1 H, CH2), 2.69 (dd,
J = 13.7, 5.5 Hz, 1 H, CH2), 3.52 (d, J = 5.7 Hz, 2 H, CH2OH),
7.14–7.29 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 19.4, 19.6, 27.6, 34.3, 48.7, 62.8,
125.7, 128.3, 129.0, 141.4.
MS (EI, 70 eV): m/z (%) = 43.1 (100), 58.1 (55), 91.1 (48), 178.3
(16) [M]+.
HRMS-ESI: m/z [M + H]+ calcd for C12H19O: 179.1430; found:
179.1430.
UV/Vis (MeCN): lmax (log e) = 194 (4.45), 207 (3.92), 209 (3.91),
262 (2.36), 269 nm (2.25).
HPLC [IA; flow 0.8 mL/min; n-hexane–2-propanol, 97:3; 210 nm]:
tR [(R)-5f] = 13.27 min, tR [(S)-5f] = 17.12 min; ≥ 99% ee.
Acknowledgment
We thank BASF, Bayer and Degussa for gifts of chemicals. C.R.
thanks the Fonds der Chemischen Industrie for the granting of a
scholarship.
(8) HPLC experiments were performed on Jasco Kromasil®
RP-18 (MeCN–H2O and MeOH–H2O) and Daicel
Chiralpak® IA and IB (n-hexane–2-propanol and n-hexane–
CH2Cl2) columns. Epimeric mixtures of the hydroxyamides
were used as standards; they were synthesized from racemic
2-substituted carboxylic acids, activated as acid chlorides,
and reacted with (+)-(1S,2S)-pseudoephedrine.
(9) Yields for the alkylation correspond to those published in the
experimental section. The yields for the reduction of
hydroxyamides 4a–f directly to the alcohols originate in
unpublished results (L. F. Tietze, C. Raith).
References
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L. F. Tietze et al.
PAPER
(13) Sheldrick, G. M., SHELXS-97, Programm for Crystal
Structure Refinement, Göttingen (Germany), 1997.
(14) Mixtures of n-hexane–2-propanol and n-hexane–CH2Cl2 in
different compositions were tried. Epimeric mixtures of the
oxoamides were used as standards for HPLC separation.
These mixtures were obtained from oxidation of the
epimeric mixtures of the corresponding hydroxyamides.
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monochromated Mo-Ka radiation (l = 0.71073 Å). The
structure was solved by direct methods using SHELXS-9712
and refined against P21 on all data by full-matrix least-
squares with SHELXS-97.13 All non-hydrogen atoms were
refined anisotropically. All hydrogen atoms were included in
the model. CCDC-664393 [(–)-(2S,1¢S)-6a] contains the
supplementary crystallographic data for this article. These
data can be obtained free of charge from The Cambridge
Cyrstallographic Data Centre via www.ccdc.ac.uk/
data_request/cif.
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Synthesis 2008, No. 2, 229–236 © Thieme Stuttgart · New York