Stereoselective alkylation-reduction of β-keto nitriles by the fungus Curvularia lunata

Article abstract of DOI:10.1016/S0957-4166(01)00269-5

The alkylation-reduction (AR) reaction of β-keto nitriles by growing cells of Curvularia lunata CECT 2130 has been explored. The reaction conditions for the ethylation of benzoylacetonitrile have been optimized in terms of both yield and stereoselectivity and the mechanism of this biotransformation was studied. The scope of this reaction has been extended to other alkylations (R = Et, Pr, Bu, iso-Bu) and to a series of aromatic and heteroaromatic substrates, yielding the corresponding optically active α-alkyl β-hydroxy nitriles. The yield (directly related to competing carbonyl reduction reaction) depends on the substrate bulk, whereas the enantiomeric and diastereomeric excesses (both up to 98%) seem to be dependent on several factors.

Full text of DOI:10.1016/S0957-4166(01)00269-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1485–1492
Stereoselective alkylation–reduction of b-keto nitriles by the
fungus Curvularia lunata
Juan R. Dehli and Vicente Gotor*
Departamento de Qu´ımica Orga´nica e Inorga´nica, Universidad de Oviedo, 33071 Oviedo, Spain
Received 10 May 2001; accepted 11 June 2001
Abstract—The alkylation–reduction (AR) reaction of b-keto nitriles by growing cells of Curvularia lunata CECT 2130 has been
explored. The reaction conditions for the ethylation of benzoylacetonitrile have been optimized in terms of both yield and
stereoselectivity and the mechanism of this biotransformation was studied. The scope of this reaction has been extended to other
alkylations (R=Et, Pr, Bu, iso-Bu) and to a series of aromatic and heteroaromatic substrates, yielding the corresponding optically
active a-alkyl b-hydroxy nitriles. The yield (directly related to competing carbonyl reduction reaction) depends on the substrate
bulk, whereas the enantiomeric and diastereomeric excesses (both up to 98%) seem to be dependent on several factors. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
out reduction of the ketone), due to the racemization of
the product in the reaction medium.8
Optically active a-alkyl b-hydroxy acid derivatives are
nowadays recognized as highly valuable chiral syn-
thons. Traditionally, most popular chemical1 and
enzymatic2,3 methods to obtain them consisted of the
stereoselective reduction of the corresponding a-alkyl
b-keto acid derivatives. In particular, a couple of exam-
ples concerning the bioreduction of acyclic4 and cyclic5
a-substituted b-keto nitriles have been reported.
In a preliminary communication, we have described
that the fungus Curvularia lunata CECT 2130 is able to
introduce short alkyl chains and reduce the carbonyl
group of benzoylacetonitrile, 1.9 Herein, continuing our
studies on the preparation of optically active amino
alcohols through chemoenzymatic transformations,
using isolated enzymes10,11 or microorganisms12 as bio-
catalysts, we provide full details of the AR process and
a study of its scope and limitations, by subjecting a
series of aliphatic, aromatic and heteroaromatic sub-
strates to the action of this fungal strain. The corre-
sponding a-alkyl b-hydroxy nitriles obtained are useful
precursors of new amino alcohols with potential appli-
cations in asymmetric synthesis13 and medicinal
chemistry.14
Several years ago, Itoh et al. described that during the
incubation of 3-oxobutyronitrile with baker’s yeast, an
ethyl group was incorporated at the a-position,
together with the carbonyl reduction.6 Unfortunately,
the process showed only very low diastereoselection,
although both epimers were virtually enantiopure.
Despite this elegant (and somewhat curious) means of
stereoselective CꢀC bond formation, no further exam-
ples of stereoselective alkylation–reduction (AR) reac-
tions with baker’s yeast have appeared in the literature.
Fuganti et al. proposed a mechanism for this reaction,
but they could not extend it to the structurally related
b-keto esters.7 Smallridge et al. showed that in the
presence of an excess of acetaldehyde, baker’s yeast was
able to mediate the non-stereoselective introduction of
an ethyl group in some aromatic b-keto nitriles (with-
2. Results and discussion
2.1. Optimization of the AR of benzoylacetonitrile
During our screening for a suitable strain to enantio-
selectively reduce benzoylacetonitrile, 1, we observed that
the fungus C. lunata produced an almost equimolar
mixture of the expected 3-hydroxy-3-phenylpropane-
nitrile,2,and2-(1-hydroxy-1-phenylmethyl)butanenitrile,
3a, in 22% yield, whose chiral chromatographic analysis
gave the promising values of 78% e.e. and 97% d.e. (see
Scheme 1).
* Corresponding author. Tel./fax: +34 985 10 34 48; e-mail: vgs@
sauron.quimica.uniovi.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00269-5

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J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 12 (2001) 1485–1492
O
OH
OH
C. lunata
CN
CN
CN
+
EtOH, 1%
1
2
3a
Scheme 1.
The mechanism for this quite unusual biotransforma-
tion was confirmed to be that proposed by Fuganti et
al.,7 and several clues for this have been already pre-
sented (biotransformation of a supposed intermediate,
modified pH conditions and isotopic labeling of the
co-solvent).9 The fact that AR does not occur with
similar b-keto esters (although extensively studied)
seems to be a consequence of their lower acidity,15
which might prevent the non-enzymatic condensation
with the acetaldehyde generated in the medium.
added as co-solvent) as the energy source. After 3 days,
we observed that no more glucose was left in the
culture medium and, therefore, the co-factor regenerat-
ing system oxidizes ethanol to acetaldehyde faster.
Afterwards, the enoate–reductase activity (responsible
of the irreversibility of the AR process) might decrease
faster than the alcohol deshydrogenase which yields 2.
Furthermore, the stereoselectivity of the process using
4-day-old growing cells increased to 96% d.e. and 98%
e.e. Therefore, these optimized conditions were adopted
as standard for the remaining experiments.
Our first interest was to minimize the competing simple
reduction, in order to obtain 3a in a synthetically useful
yield. The use of resting cells instead of growing cells
did not lead to considerable modifications in the pro-
portion of the two products. However, the use of
growing cells of different ages did produce a significant
change (see Fig. 1).
2.2. Introduction of different alkyl groups
An obvious challenge that would give this AR reaction
a higher value was to extend it to other alkyl groups
other than ethyl. Bearing this in mind, we carried out
the biotransformation of
1 using other primary
aliphatic alcohols (linear or not) as co-solvents.
Although MeOH clearly inhibited the AR,16 other short
chain alcohols behaved as ethanol and the correspond-
ing alkyl groups were incorporated at the a position
(see Scheme 2).
A plausible hypothesis for this behavior could be that
‘young’ cells use glucose (together with the ethanol
O
OH
C. lunata
CN
CN
ROH, 1%
R
1
3a-3d
Scheme 2.
As shown in Table 1, the longer the alkyl chain, the
lower the yield of the corresponding a-alkyl b-hydroxy
nitrile 3. The diastereomeric ratio (d.r.), as well as the
e.e. of the products were high to excellent, which makes
this AR reaction very attractive for the synthesis of
optically active compounds with two contiguous stereo-
genic centers.
Figure 1. Molar ratio between products 3a and 2 obtained in
the biotransformation of 1 with growing cells of C. lunata of
different ages.
Table 1. Biotransformations of benzoylacetonitrile with C. lunata in the presence of different alcohols
Alcohol
Product
R
Yield (%)a
D.r.b
E.e. (%)b,c
EtOH
PrOH
BuOH
iBuOH
3a
3b
3c
3d
Et
Pr
69
38
13
14
98:2
99:1
93:7
97:3
98
98
86
97
Bu
iBu
a Isolated yield, after flash chromatography.
b Determined by GC analysis of their MTPA derivatives.
c E.e. of the major diastereomer.

J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 12 (2001) 1485–1492
1487
Table 3. Biotransformations of heteroaromatic b-keto
nitriles with C. lunata in the presence of EtOH
2.3. AR reactions of other aromatic b-keto nitriles
As shown above, BY was only able to perform the AR
with one substrate.6 When bulkier substrates, such as 1,
were used, only alkylation, without reduction and the
introduction of chirality, occurred.8 In order to study
the scope and limitations of our AR reaction, and
taking into account this high substrate specificity shown
by BY, we subjected a series of benzoylacetonitrile
derivatives to the action of C. lunata, using EtOH as
co-solvent, due to the higher yield (as well as the very
satisfactory stereochemical outcome) obtained in the
case of product 3a (see Scheme 3).
Ar
Product
Yield (%)a
D.r.b
E.e. (%)b,c
2-Thienyl
2-Furyl
7a
8a
63
59
97:3
86:14
93
87
a Isolated yield, after flash chromatography.
b Determined by chiral GC.
c E.e. of the major diastereomer.
2.5. Biotransformations of aliphatic b-keto nitriles under
AR conditions
To complete our study, we also analyzed the ‘behavior’
of C. lunata towards aliphatic substrates. The results
obtained were, however, quite disappointing. The first
substrate tested, 3-oxobutyronitrile, had already been
subjected to AR with baker’s yeast.6 With C. lunata,
also a diastereomeric mixture (ca. 1:1) of syn and anti
2-ethyl-3-hydroxybutyronitrile, was obtained. But con-
trary to that example, low e.e. values were obtained (ca.
75% for the syn and 25% for the anti ). In the reactions
of 4,4-dimethyl-3-oxopentanenitrile and 3-cyclohexyl-3-
oxopropanenitrile no appreciable amounts of the corre-
sponding a-ethyl b-hydroxy nitriles were observed. In
the first case, steric hindrance may be invoked, but the
cause for the failed reaction in the latter case is not
clear. At this time, we do not have a conclusive expla-
nation for this. In both cases, only carbonyl reduction
took place, but the e.e. values of the products were
lower than those previously reported using methanol as
co-solvent.16
O
OH
C. lunata
CN
CN
Ar
Ar
EtOH, 1%
1
3a-8a
Scheme 3.
As shown in Table 2, the AR reactions took place with
high chemoselectivities except in the case of m-methyl-
benzoylacetonitrile, where the competing reduction
decreased the chemical yield slightly down to 42%,
probably due to steric hindrance. In the case of para
substituted compounds, the yields were similar to that
obtained with 3a, but both diastereo- and enan-
tiodiscrimination were lower.
Table 2. Biotransformations of aromatic b-keto nitriles
with C. lunata in the presence of EtOH
2.6. Assignment of the absolute configuration. Synthesis
of g-amino alcohols
Ar
Product
Yield (%)a
D.r.
E.e. (%)b
The absolute configuration of the carbinol atom in the
products 3a–d and 4a–8a was assigned by a compara-
C6H5
m-CH3-C6H4
p-CH3-C6H4
3a
4a
5a
69
42
64
58
98:2c
89:11d
96:4d
94:6d
98c
70d
83d
75d
1
tive study of the H NMR of their MTPA esters.18 In
all cases, the Dl values (lS-ester−lR-ester) were positive for
the aliphatic protons (both in the alcohol19 and in the
MTPA moiety20), and negative for the aromatic ones
(see Section 4), thus allowing us to tentatively assign
the absolute configuration for the C(1%) as (R).
p-CH3O-C6H4 6a
a Isolated yield, after flash chromatography.
b E.e. of the major diastereomer.
c Determined by GC analysis of its MTPA derivatives.
d Determined by chiral GC.
In order to establish the absolute configuration of the
C(2) stereogenic center, it was necessary to perform the
transformation outlined in Scheme 4: nitrile reduction21
with LiAlH4 of compounds 3–8, yielded the corre-
sponding g-amino alcohols which were directly†
cyclized using N,N%-carbonyldiimidazole (CDI) to
obtain the oxazinan-2-ones 10–18, six-membered rings
which allowed us to determine the relative configura-
tion of C(2) and C(1%) atoms by means of the coupling
constants (J) between the different protons (see Section
4).
2.4. AR of heteroaromatic b-keto nitriles
We also wanted to study the effect of having an het-
eroatom in the aromatic ring in the AR reaction. As
substrates, we chose 2-thenoylacetonitrile, due to the
well-known similarity between thienyl and phenyl
derivatives,17 and its oxygenated analogue, 2-
furoylacetonitrile.
Interestingly enough, the sulfurated a-ethyl b-hydroxy
nitrile 7a obtained had very high e.e. and d.e. However,
the furyl derivative 8a showed modest diastereodiscrim-
ination, although the e.e. of the major diastereomer was
quite high (see Table 3).
† The aminoalcohols 9a–c were purified and fully characterized (see
Section 4). The others were used for the in situ preparation of the
corresponding oxazinan-2-ones.

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J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 12 (2001) 1485–1492
O
OH
Hd
CN
O
Ha
O
O
NH
Ar
1. LiAlH4
2. CDI
Ar
R
R
Ar
N
H
Hb
Hc
R
3-8
10-18
Scheme 4.
In all cases (and after irradiation of the NH signal, in
order to simplify the spin system), we obtained a small
coupling constant (J) value between Hc and Hb (ca. 5
Hz) which corresponds to axial–equatorial coupling
and two large J values for the Ha–Hc (ca. 10 Hz) and
Hc–Hd (ca. 9 Hz) couplings, in accordance with axial–
axial arrangement, therefore leaving the Ar and the R
groups in the equatorial positions. This, in conjunction
with the Mosher analysis described above, corresponds
to (R,R) absolute configuration for the b-hydroxy
nitriles 3–8.
4.2. General procedures for cultures and
biotransformations
The fungus C. lunata was obtained from CECT (Colec-
cio´n Espan˜ola de Cultivos Tipo). It was precultured
and cultured as previously described.9 Afterwards, the
substrate (1 g L−1) and the alcohol used as co-solvent
(1% v/v) were added and the biotransformation contin-
ued until disappearance of the substrate (6–12 h, TLC
monitoring). The mycelium was then filtered off and
the fungal cake washed several times with aqueous
NaCl 0.8% until no further product was recovered. The
filtrate was continuously extracted with AcOEt for 12
h. After drying with Na2SO4, the solvent was evapo-
rated and the product purified by flash chromatography
3. Conclusions
(eluent: hexane–AcOEt, 5:1) as
diastereomers. The spectroscopic data given below cor-
respond to the major diastereomer.
a
mixture of
C. lunata has shown its ability to a-alkylate and con-
comitantly reduce aromatic and heteroaromatic b-keto
nitriles. After optimization of the conditions, in order
to minimize the competing simple reduction process,
this AR has allowed the creation of a CꢀC bond and
two stereogenic centers in moderate yields of up to 69%
and high stereoselectivities of up to 98% e.e. and d.e. in
most cases. Further work making use of these interest-
ing building blocks, as well as an extension of this
methodology to other substrates is currently in progress
in our laboratory.
4.2.1.
(2R,1%R)-2-(1-Hydroxy-1-phenylmethyl)butane-
nitrile 3a. White solid; yield 69%; mp 68–69°C; [h]2D0=
1
+16.8 (c 1.1, EtOH; e.e. 98%, d.r. 98:2); H NMR: l
(ppm) 1.05 (t, J=7.4, 3H, CH3), 1.4–1.7 (m, 2H, CH2),
2.65–2.75 (m, 1H, CH-Et), 3.34 (br s, 1H, OH), 4.73 (d,
J=6.4, 1H, CH-O), 7.36 (br s, 5H, Harom.); 13C NMR:
l (ppm) 11.3 (CH3), 22.0 (CH2), 42.3 (CH-Et), 73.0
(CH-O), 120.0 (CN), 125.9, 128.1, 128.3 (CHarom.),
140.3 (Carom.); IR (Nujol, cm−1): 2242, 3458; EI-MS:
m/z (relative intensity) 175 (M+, <1%), 107 (100%);
HRMS calcd for C11H13NO 175.0997, found 175.0999.
Anal. calcd for C11H13NO: C, 75.40; H, 7.48; N, 7.99.
Found: C, 75.26; H, 7.54; N, 7.92%. GC conditions for
the (R)-MTPA ester: column hp 19091s-436, 1 mL
min−1 He, 125°C, 0.1 min; 6.0°C min−1 until 280°C, tR
(min): 23.49 (two peaks), 23.72, 23.92 (major). Repre-
sentative Dl (Hz) of its MTPA esters: +8 (Me), +5
(CH-CN), −45 (arom.), +49 (MeO).
4. Experimental
4.1. General
Reagents were obtained from Aldrich Chemie or
Avocado. Solvents were distilled over an appropriate
desiccant and stored under nitrogen. Precoated TLC
plates of silica gel 60 F254 from Merck were used,
while for column chromatography, Merck silica gel
60/230–400 mesh was applied. Melting points were
taken using a Gallenkamp apparatus and are uncor-
rected. Optical rotations were measured using a Perkin
Elmer 343 polarimeter. IR spectra were recorded on a
4.2.2. (2R,1%R)-2-(1-Hydroxy-1-phenylmethyl)pentane-
nitrile 3b. Oil; yield 38%; [h]2D0=+12.8 (c 1.7, EtOH;
1
e.e. 98%, d.r. 99:1); H NMR: l (ppm) 0.92 (t, J=6.8,
3H, CH3), 1.35–1.7 (m, 4H, CH2CH2), 2.58 (br s, 1H,
OH), 2.8–2.9 (m, 1H, CH-Pr), 4.78 (d, J=6.1, 1H,
CH-O), 7.3–7.5 (m, 5H, Harom.); 13C NMR: l (ppm)
13.4 (CH3), 20.3 (CH2-Me), 30.9 (CH2-Et), 40.8 (CH-
Pr), 74.0 (CH-O), 120.1 (CN), 126.1, 128.6, 128.7
(CHarom.), 140.3 (Carom.); IR (neat, cm−1): 2247, 3421;
EI-MS: m/z (relative intensity) 189 (M+, 1%), 107
(100%); HRMS calcd for C12H15NO 189.1154, found
189.1161. Anal. calcd for C12H15NO: C, 76.16; H, 7.99;
N, 7.40. Found: C, 76.11; H, 8.02; N, 7.37%. GC
conditions for the (R)-MTPA ester: column hp 19091s-
436, 1 mL min−1 He, 125°C, 0.1 min; 6.0°C min−1 until
1
Mattson Genesis FT Infrared spectrometer. H and 13C
NMR spectra were carried out in CDCl3 using a Bruker
AC-300 (300 MHz for 1H and 75.5 MHz for 13C)
1
spectrometer or AC-200 (200 MHz for H and 50 MHz
for 13C) using TMS as internal standard. Mass spectra
were recorded on a Hewlett–Packard 5987 A spectrom-
eter using electronic impact procedures (75 eV) or on a
ESI-MSD (40 V). E.e. and d.r. values were determined
by GC analysis on a Hewlett–Packard 6890 Series II
chromatograph or by HPLC on a Shimadzu liquid
chromatograph.

J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 12 (2001) 1485–1492
1489
280°C, tR (min): 23.73, 23.92, 24.71, 24.89 (major).
Representative Dl (Hz) of its MTPA esters: +3 (Me),
+5 (CH-CN), −50 (arom.), +52 (MeO).
3H, CH3-Ar), 2.58 (br s, 1H, OH), 2.7–2.8 (m, 1H,
CH-Et), 4.73 (d, J=6.5, 1H, CH-O), 7.15–7.3 (m, 4H,
Harom.); 13C NMR: l (ppm) 11.6 (CH3-CH2), 21.1
(CH3-Ar), 22.4 (CH2), 42.6 (CH-Et), 73.7 (CH-O),
120.1 (CN), 126.0, 129.4 (CHarom.), 137.3, 138.5
(Carom.); IR (neat): 2242, 3452 cm−1; EI-MS: m/z (rela-
tive intensity) 189 (M+, 23%), 121 (100%); HRMS calcd
for C12H15NO 189.1154, found 189.1150. Anal. calcd
for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C,
76.12; H, 8.10; N, 7.29%; GC conditions: column Rt-
bDEXse, 1 mL min−1 N2, 130°C, 5 min; 1.0°C min−1
until 200°C, tR (min): 51.5, 52.4, 52.9 (major), 53.8.
Representative Dl (Hz) of its MTPA esters: +7 (CH3-
CH2), +5 (CH-Et), −6 (CH3-Ar), −38 (arom.), +50
(MeO).
4.2.3.
(2R,1%R)-2-(1-Hydroxy-1-phenylmethyl)hexane-
nitrile 3c. Oil; yield 13%; [h]2D0 +7.3 (c 2.8, EtOH; e.e.
1
86%, d.r. 93:7); H NMR: l (ppm) 0.90 (t, J=7.2, 3H,
CH3), 1.25–1.7 (m, 6H, CH2CH2CH2), 2.50 (br s, 1H,
OH), 2.75–2.9 (m, 1H, CH-Bu), 4.79 (d, J=6.1, 1H,
CH-O), 7.35–7.45 (m, 5H, Harom.); 13C NMR: l (ppm)
13.6 (CH3), 22.0 (CH2-Me), 28.6 (CH2-Et), 29.1 (CH2-
Pr), 41.0 (CH-Bu), 74.0 (CH-O), 120.2 (CN), 126.1,
128.6, 128.7 (CHarom.), 140.3 (Carom.); IR (neat, cm−1):
2241, 3446; EI-MS: m/z (relative intensity) 203 (M+,
<1%), 107 (100%), 79 (80%); HRMS calcd for
C13H17NO 203.1310, found 203.1296. Anal. calcd for
C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.73;
H, 8.48; N, 6.71%. GC conditions for the (R)-MTPA
ester: column hp 19091s-436, 1 mL min−1 He, 125°C,
0.1 min; 6.0°C min−1 until 280°C, tR (min): 25.64, 25.67,
25.89, 26.07 (major). Representative Dl (Hz) of its
MTPA esters: +3 (Me), +5 (CH-CN), −50 (arom.), +52
(MeO).
4.2.7.
(2R,1%R)-2-[1-Hydroxy-1-(4-methoxyphenyl)-
methyl]butanenitrile 6a. Oil; yield 58%; [h]2D0=+41.0 (c
1
1.0, CHCl3; e.e. 75%, d.r. 94:6); H NMR: l (ppm) 1.06
(t, J=7.4, 3H, CH3-CH2), 1.4–1.65 (m, 2H, CH2), 2.57
(br s, 1H, OH), 2.65–2.75 (m, 1H, CH-Et), 3.80 (s, 3H,
CH3O), 4.72 (d, J=6.8, 1H, CH-O), 6.90 (d, J=8.7,
2H, Harom.), 7.29 (d, J=8.7, 2H, Harom.); 13C NMR: l
(ppm) 11.6 (CH3-CH2), 22.4 (CH2), 42.7 (CH-Et), 55.2
(CH3-O), 73.5 (CH-O), 114.0 (CHarom.), 120.2 (CN),
127.4, (CHarom.), 132.4, 159.7 (Carom.); IR (neat, cm−1):
2246, 3441; EI-MS: m/z (relative intensity) 205 (M+,
2%), 187 (3%), 137 (100%); HRMS calcd for
C12H15NO2 205.1103, found 205.1101. Anal. calcd for
C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C,
70.01; H, 7.41; N, 6.69; GC conditions: column Rt-
bDEXse, 1 mL min−1 N2, 140°C, 5 min; 1.0°C min−1
until 200°C, tR (min): 52.0, 52.6, 53.6 (major), 54.1.
Representative Dl (Hz) of its MTPA esters: +8 (CH3-
CH2), +4 (CH-Et), −38, −22 (arom.), +54 (MeO).
4.2.4. (2R,1%R)-2-(1-Hydroxy-1-phenylmethyl)-4-methyl-
pentanenitrile 3d. Oil; yield 14%; [h]2D0=+6.3 (c 1.4,
1
EtOH; e.e. 97%, d.r. 97:3); H NMR: l (ppm) 0.89 (d,
J=6.4, 3H, CH3), 0.95 (d, J=6.4, 3H, CH3), 1.2–1.4
(m, 1H, CHMe2), 1.6–1.9 (m, 2H, CH2), 2.52 (br s, 1H,
OH), 2.85–2.95 (m, 1H, CH-iBu), 4.77 (d, J=5.9, 1H,
CH-O), 7.35–7.5 (m, 5H, Harom.); 13C NMR: l (ppm)
21.0, 23.0 (CH3), 26.0 (CHMe2), 37.7 (CH2), 39.1 (CH-
iBu), 74.2 (CH-O), 120.1 (CN), 126.1, 128.6, 128.7
(CHarom.), 140.3 (Carom.); IR (neat, cm−1): 2244, 3451;
ESI-MS: m/z 226 (M+Na)+. Anal. calcd for C13H17NO:
C, 76.81; H, 8.43; N, 6.89. Found: C, 76.79; H, 8.51; N,
6.71%; GC conditions for the (R)-MTPA ester: column
hp 19091s-436, 1 mL min−1 He, 125°C, 0.1 min; 6.0°C
min−1 until 280°C, tR (min): 24.80, 24.88, 25.08, 25.28
(major). Representative Dl (Hz) of its MTPA esters: +5
(CH-CN), −20 (arom.), +48 (MeO).
4.2.8. (2R,1%R)-2-[1-Hydroxy-1-(2-thienyl)methyl]butane-
nitrile 7a. Oil; yield 63%; [h]2D0=+27.0 (c 2.0, CHCl3;
1
e.e. 93%, d.r. 97:3); H NMR: l (ppm) 1.09 (t, J=7.5,
3H, CH3), 1.5–1.7 (m, 2H, CH2), 2.75–2.9 (m, 1H,
CH-Et), 3.07 (br s, 1H, OH), 5.03 (d, J=6.3, 1H,
CH-O), 6.95–7.0 (m, 1H, Harom.), 7.05–7.10 (m, 1H,
Harom.), 7.3–7.35 (m, 1H, Harom.); 13C NMR: l (ppm)
11.5 (CH3), 22.3 (CH2), 42.9 (CH-Et), 69.8 (CH-O),
119.8 (CN), 125.2, 125.7, 126.8 (CHarom.), 143.6
(Carom.); IR (neat, cm−1): 2240, 3448; ESI-MS: m/z 204
(M+Na)+. Anal. calcd for C9H11NOS: C, 59.64; H,
6.12; N, 7.73. Found: C, 59.48; H, 6.21; N, 6.55%;
HPLC conditions: column Chiralcel OD, eluent hexane:
propan-2-ol (95:5), 0.8 mL min−1; tR (min): 27.1, 28.9,
32.1, 33.9 (major). Representative Dl (Hz) of its MTPA
esters: +10 (CH3-CH2), +7 (CH-Et), +48 (MeO).
4.2.5. (2R,1%R)-2-[1-Hydroxy-1-(3-methylphenyl)methyl]-
butanenitrile 4a. Oil; yield 42%; [h]2D0=+31.7 (c 0.7,
1
CHCl3; e.e. 70%, d.r. 89:11); H NMR: l (ppm) 1.09 (t,
J=7.5, 3H, CH3-CH2), 1.35–1.7 (m, 2H, CH2), 2.37 (s,
3H, CH3-Ar), 2.47 (br s, 1H, OH), 2.7–2.8 (m, 1H,
CH-Et), 4.74 (d, J=6.5, 1H, CH-O), 7.15–7.3 (m, 4H,
H
arom.); 13C NMR: l (ppm) 11.6 (CH3-CH2), 21.4
(CH3-Ar), 22.5 (CH2), 42.6 (CH-Et), 73.9 (CH-O),
120.1 (CN), 123.2, 126.7, 128.6, 129.5 (CHarom.), 138.5,
140.2 (Carom.); IR (neat): 2241, 3446 cm−1; ESI-MS: m/z
212 (M+Na)+. Anal. calcd for C12H15NO: C, 76.16; H,
7.99; N, 7.40. Found: C, 76.27; H, 7.83; N, 7.28; GC
conditions: column Rt-bDEXse, 1 mL min−1 N2, 140°C,
5 min; 1.0°C min−1 until 200°C, tR (min): 43.1, 43.3,
44.3 (major), 44.8. Representative Dl (Hz) of its MTPA
esters: +6 (CH3-CH2), −24 (CH3-Ar), +61 (MeO).
4.2.9. (2R,1%R)-2-[1-(2-Furyl)-1-hydroxymethyl]butane-
nitrile 8a. Oil; yield 59%; [h]2D0=+45.3 (c 1.0, CHCl3;
1
e.e. 87%, d.r. 86:14); H NMR: l (ppm) 1.09 (t, J=7.4,
3H, CH3), 1.45–1.75 (m, 2H, CH2), 2.86 (d, J=5.4, 1H,
OH), 2.95–3.1 (m, 1H, CH-Et), 4.79 (dd, J=5.4, 6.6,
1H, CH-O), 6.3–6.5 (m, 1H, Harom.), 7.35–7.45 (m, 2H,
4.2.6. (2R,1%R)-2-[1-Hydroxy-1-(4-methylphenyl)methyl]-
butanenitrile 5a. Oil; yield 64%; [h]2D0=+43.1 (c 1.3,
H
arom.); 13C NMR: l (ppm) 11.5 (CH3), 22.3 (CH2),
1
CHCl3; e.e. 83%, d.r. 96:4); H NMR: l (ppm) 1.07 (t,
40.1 (CH-Et), 67.5 (CH-O), 108.0, 110.4 (CHarom.),
J=7.4, 3H, CH3-CH2), 1.45–1.65 (m, 2H, CH2), 2.35 (s,
119.8 (CN), 142.7 (CHarom.), 152.4 (Carom.); IR (neat,

1490
J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 12 (2001) 1485–1492
cm−1): 2243, 3455; EI-MS: m/z (relative intensity) 165
(M+, 3%), 147 (1%), 97 (100%); HRMS calcd for
C9H11NO2 165.0790, found 165.0788. Anal. calcd for
C9H11NO2: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.59;
H, 6.68; N, 8.58%; GC conditions: column Rt-bDEXse,
1 mL min−1 N2, 125°C, 5 min, 1°C min−1 until 200°C,
tR (min): 28.6 (two peaks), 29.1 (major), 29.8. Repre-
sentative Dl (Hz) of its MTPA esters: +7 (CH3-CH2),
+13 (CH-Et), −9, −16 (Fur), −20 (Ph), +52 (MeO).
J=12.6, 3.1, 1H, CHHN), 3.22 (br s, 3H, OH, NH2),
4.73 (d, J=6.1, 1H, CH-O), 7.2–7.5 (m, 5H, Harom.);
13C NMR: l (ppm) 13.9 (CH3), 22.8 (CH2-Me), 28.9
(CH2-Et), 29.2 (CH2-Pr), 43.5 (CH2-N), 44.9 (CH-Bu),
79.5 (CH-O), 126.4, 126.8, 128.0 (CHarom.), 144.9
(Carom.); IR (neat, cm−1): 3290 (br b); EI-MS: m/z
(relative intensity) 207 (M+, 8%), 190 (18%), 160 (37%),
77 (100%); HRMS calcd for C13H19O 189.1474, found
189.1475. Anal. calcd for C13H21NO: C, 75.32; H,
10.21; N, 6.76. Found: C, 75.19; H, 10.38; N, 6.61.
4.3. General procedure for the reduction of b-hydroxy
nitriles with lithium aluminium hydride
4.4. Synthesis of the 1,3-oxazinan-2-ones 10–18
N,N%-Carbonyldiimidazole (0.22 mmol) was added to a
solution of the corresponding aminoalcohol (0.2 mmol)
in CH2Cl2 at rt, and the resulting mixture was stirred
for 12 h. Then, the solvent was evaporated and the
residue solved in AcOEt and washed with aqueous HCl
(0.1 N) and water. After drying and elimination of the
solvent, the product was purified by flash chromatogra-
phy (eluent: hexane–AcOEt, 1:2).
To a solution of the corresponding a-alkyl b-hydroxy
nitrile 3–8 (0.3 mmol) in anhydrous THF (2 mL) at
0°C, an excess of LiAlH4 (3 mmol) was added and the
suspension was allowed to reach rt with stirring. After
3 h, the reaction was quenched with water (2 mL) and
extracted several times with Et2O. The combined
organic phases were dried and the solvent evaporated.
Compounds 9a–c were further purified by flash chro-
matography (eluent propan-2-ol:CH2Cl2:30% aq NH3,
2:2:0.1). In the other cases, the product was neither
isolated nor characterized, and the crude was directly
used for the next step (see below).
4.4.1. (5R,6R)-5-Ethyl-6-phenyl-1,3-oxazinan-2-one 10.
White solid; yield 75%; mp 137–138°C; [h]2D0=−1.0 (c
1
1.0, EtOH; e.e. 98%, d.r. 98:2); H NMR: l (ppm) 0.84
(t, J=7.4, 3H, CH3), 1.0–1.45 (m, 2H, CH2-Me), 1.9–
2.1 (m, 1H, CH-Et), 3.11 (m, J=9.5, 11.7, 1H,
CHHN), 3.46 (m, J=5.2, 11.7, 1H, CHHN), 4.97 (d,
J=8.7, 1H, CH-O), 6.46 (br s, 1H, NH), 7.2–7.5 (m,
5H, Harom.); 13C NMR: l (ppm) 10.9 (CH3), 22.1 (CH2),
38.6 (CH-Et), 43.6 (CH2-N), 83.7 (CH-O), 126.8, 128.5,
128.6 (CHarom.), 137.8 (Carom.), 154.6 (CO); IR (Nujol,
cm−1): 1698; EI-MS: m/z (relative intensity) 205 (M+,
5%), 107 (100%); HRMS calcd for C12H15NO2
205.1103, found 205.1108. Anal. calcd for C12H15NO2:
C, 70.22; H, 7.37; N, 6.82. Found: C, 70.15; H, 7.41; N,
6.71%.
4.3.1. (1R,2R)-2-(Aminomethyl)-1-phenylbutan-1-ol 9a.
Oil; yield 90%; [h]2D0=+17.9 (c 0.8, EtOH; e.e. 98%, d.r.
1
98:2); H NMR: l (ppm) 0.86 (t, J=7.4, 3H, CH3),
1.15–1.55 (m, 3H, CHCH2), 2.77 (dd, J=12.3, 7.0, 1H,
CHHN), 3.00 (dd, J=12.3, 2.8, 1H, CHHN), 3.28 (br
s, 3H, OH, NH2), 4.69 (d, J=6.5, 1H, CH-O), 7.2–7.45
(m, 5H, Harom.); 13C NMR: l (ppm) 11.4 (CH3), 21.9
(CH2-Me), 43.0 (CH2-N), 46.6 (CH-Et), 79.0 (CH-O),
126.3, 126.7, 127.9 (CHarom.), 144.7 (Carom.); IR (neat,
cm−1): 3300; EI-MS: m/z (relative intensity) 179 (M+,
4%), 132 (80%), 117 (100%); HRMS calcd for
C11H17NO 179.1310, found 179.1307. Anal. calcd for
C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.48;
H, 9.72; N, 7.63.
4.4.2. (5R,6R)-6-Phenyl-5-propyl-1,3-oxazinan-2-one 11.
White solid; yield 67%; mp 145–146°C; [h]2D0=−17.2 (c
1
1.5, EtOH; e.e. 98%, d.r. 99:1); H NMR: l (ppm) 0.81
(t, J=6.5, 3H, CH3), 1.1–1.35 (m, 4H, CH2CH2), 2.05–
2.2 (m, 1H, CH-Pr), 3.11 (m, J=9.5, 11.5, 1H,
CHHN), 3.45 (m, J=5.1, 11.5, 1H, CHHN), 4.96 (d,
J=8.7, 1H, CH-O), 6.18 (br s, 1H, NH), 7.2–7.5 (m,
5H, Harom.); 13C NMR: l (ppm) 13.9 (CH3), 19.6 (CH2-
Me), 31.2 (CH2-Et), 36.9 (CH-Pr), 44.1 (CH2-N), 83.8
(CH-O), 126.8, 128.5, 128.6 (CHarom.), 137.8 (Carom.),
154.3 (CO); IR (Nujol): 1692 cm−1; EI-MS: m/z (rela-
tive intensity) 219 (M+, 5%), 107 (100%); HRMS calcd
for C13H17NO2 219.1259, found 219.1262. Anal. calcd
for C13H17NO2: C, 71.21; H, 7.81; N, 6.39. Found: C,
71.04; H, 7.91; N, 6.25%.
4.3.2. (1R,2R)-2-(Aminomethyl)-1-phenylpentan-1-ol 9b.
Oil; yield 86%; [h]2D0 +10.6 (c 2.0, EtOH; e.e. 98%, d.r.
1
99:1); H NMR: l (ppm) 0.83 (t, J=6.1, 3H, CH3),
1.1–1.45 (m, 4H, CH2CH2), 1.6–1.7 (m, 1H, CH-Pr),
2.77 (dd, J=12.2, 6.5, 1H, CHHN), 2.99 (m, 1H,
CHHN), 3.47 (br s, 3H, OH, NH2), 4.68 (d, J=6.1,
1H, CH-O), 7.2–7.5 (m, 5H, Harom.); 13C NMR: l
(ppm) 14.1 (CH3), 20.0 (CH2-Me), 31.3 (CH2-Et), 43.3
(CH2-N), 44.6 (CH-Pr), 79.3 (CH-O), 126.3, 126.7,
127.9 (CHarom.), 144.7 (Carom.); IR (neat, cm−1): 3285;
EI-MS: m/z (relative intensity) 193 (M+, <1%), 176
(2%), 146 (14%), 77 (100%); HRMS calcd for C12H16O
176.1171, found 176.1174. Anal. calcd for C12H19NO:
C, 74.57; H, 9.91; N, 7.25. Found: C, 74.41; H, 10.14;
N, 7.11.
4.4.3. (5R,6R)-5-Butyl-6-phenyl-1,3-oxazinan-2-one 12.
White solid; yield 63%; mp 111–112°C; [h]2D0=−13.2 (c
1
0.5, EtOH; e.e. 86%, d.r. 93:7); H NMR: l (ppm) 0.81
(t, J=6.3, 3H, CH3), 1.1–1.35 (m, 6H, CH2CH2CH2),
2.0–2.15 (m, 1H, CH-Bu), 3.10 (m, J=9.4, 11.5, 1H,
CHHN), 3.46 (m, J=5.1, 11.5, 1H, CHHN), 4.97 (d,
J=8.7, 1H, CH-O), 6.15 (br s, 1H, NH), 7.2–7.5 (m,
5H, Harom.); 13C NMR: l (ppm) 13.7 (CH3), 22.4 (CH2-
Me), 28.5 (CH2-Et), 28.7 (CH2-Pr), 37.0 (CH-Bu), 44.0
4.3.3. (1R,2R)-2-(Aminomethyl)-1-phenylhexan-1-ol 9c.
Oil; yield 87%; [h]2D0 +14.5 (c 0.6, EtOH; e.e. 86%, d.r.
1
93:7); H NMR: l (ppm) 0.86 (t, J=5.9, 3H, CH3),
1.1–1.5 (m, 6H, CH2CH2CH2), 1.55–1.75 (m, 1H, CH-
Bu), 2.82 (dd, J=12.6, 6.7, 1H, CHHN), 3.04 (dd,

J. R. Dehli, V. Gotor / Tetrahedron: Asymmetry 12 (2001) 1485–1492
1491
(CH2-N), 83.0 (CH-O), 126.8, 128.5, 128.6 (CHarom.),
137.8 (Carom.), 154.4 (CO); IR (Nujol, cm−1): 1697;
EI-MS: m/z (relative intensity) 233 (M+, 1%), 107
(100%); HRMS calcd for C14H19NO2 233.1416, found
233.1420. Anal. calcd for C14H19NO2: C, 72.07; H, 8.21;
N, 6.00. Found: C, 71.91; H, 8.24; N, 6.05%.
Harom.), 7.25 (d, J=8.6, 2H, Harom.); 13C NMR: l (ppm)
10.9 (CH3), 22.1 (CH2-Me), 38.6 (CH-Et), 43.9 (CH2-
N), 55.2 (CH3O), 83.5 (CH-O), 113.8, 128.2 (CHarom.),
129.8 (Carom.), 154.5 (CO) 159.7 (Carom.-O); IR (Nujol):
1696 cm−1; ESI-MS: m/z 258 (M+Na)+. Anal. calcd for
C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.19; H, 7.41; N, 5.82%.
4.4.4. (5R,6R)-5-(2-Methylpropyl)-6-phenyl-1,3-oxazi-
nan-2-one 13. White solid; yield 58%; mp 125–126°C;
[h]2D0=−33.8 (c 0.5, CHCl3; e.e. 97%, d.r. 97:3); 1H
NMR: l (ppm) 0.78 (d, J=6.7, 3H, CH3), 0.84 (d,
J=6.4, 3H, CH3), 0.9–1.6 (m, 3H, CHCH2), 2.1–2.3 (m,
1H, CH-iBu), 3.08 (m, J=9.2, 11.5, 1H, CHHN), 3.44
(m, J=5.1, 11.5, 1H, CHHN), 4.96 (d, J=8.7, 1H,
CH-O), 6.22 (br s, 1H, NH), 7.3–7.5 (m, 5H, Harom.);
13C NMR: l (ppm) 21.2, 23.4 (CH3), 24.8 (CHMe2),
34.9 (CH-iBu), 38.1 (CH2-iPr), 44.1 (CH2-N), 84.0 (CH-
O), 126.8, 128.5, 128.6 (CHarom.), 137.7 (Carom.), 154.4
(CO); IR (Nujol, cm−1): 1695; EI-MS: m/z (relative
intensity) 233 (M+, 3%), 107 (100%); HRMS calcd for
C14H19NO2 233.1416, found 233.1411. Anal. calcd for
C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C,
71.98; H, 8.29; N, 5.83%.
4.4.8. (5R,6R)-5-Ethyl-6-(2-thienyl)-1,3-oxazinan-2-one
17. White solid; yield 58%; mp 137–138°C; [h]2D0=−15.0
1
(c 0.5, CHCl3; e.e. 93%, d.r. 97:3); H NMR: l (ppm)
0.89 (t, J=7.4, 3H, CH3), 1.1–1.6 (m, 2H, CH2-Me),
1.95–2.2 (m, 1H, CH-Et), 3.11 (m, J=9.5, 11.8, 1H,
CHHN), 3.51 (m, J=5.1, 11.8, 1H, CHHN), 5.27 (d,
J=9.0, 1H, CH-O), 6.53 (br s, 1H, NH), 7.01 (m, 1H,
Harom.), 7.08 (m, 1H, Harom.), 7.36 (m, 1H, Harom.); 13C
NMR: l (ppm) 10.8 (CH3), 22.3 (CH2-Me), 39.1 (CH-
Et), 43.5 (CH2-N), 79.3 (CH-O), 126.1, 126.4, 126.5
(CHarom.), 140.7 (Carom.), 154.0 (CO); IR (Nujol): 1698
cm−1; ESI-MS: m/z 234 (M+Na)+. Anal. calcd for
C10H13NO2S: C, 56.85; H, 6.20; N, 6.63. Found: C,
56.97; H, 6.35; N, 6.50%.
4.4.9. (5R,6R)-5-Ethyl-6-(2-furyl)-1,3-oxazinan-2-one 18.
White solid; yield 61%; mp 110–111°C; [h]2D0=−32.7 (c
4.4.5. (5R,6R)-5-Ethyl-6-(3-methylphenyl)-1,3-oxazinan-
2-one 14. White solid; yield 62%; mp 95–96°C; [h]2D0=
1
0.5, CHCl3; e.e. 87%, d.r. 86:14); H NMR: l (ppm)
1
+15.3 (c 0.6, CHCl3; e.e. 70%, d.r. 89:11); H NMR: l
0.87 (t, J=7.5, 3H, CH3), 1.1–1.5 (m, 2H, CH2-Me),
2.2–2.35 (m, 1H, CH-Et), 3.09 (m, J=9.5, 11.8, 1H,
CHHN), 3.49 (m, J=5.3, 11.8, 1H, CHHN), 5.03 (d,
J=9.1, 1H, CH-O), 6.24 (br s, 1H, NH), 6.35–6.4 (m,
2H, Harom.), 7.4 (m, 1H, Harom.); 13C NMR: l (ppm)
10.8 (CH3), 22.1 (CH2-Me), 35.7 (CH-Et), 43.5 (CH2-
N), 77.1 (CH-O), 109.6, 110.3, 142.9 (CHarom.), 150.1
(Carom.), 153.9 (CO); IR (Nujol): 1697 cm−1; ESI-MS:
m/z 218 (M+Na)+. Anal. calcd for C10H13NO3: C,
61.53; H, 6.71; N, 7.17. Found: C, 61.42; H, 6.82; N,
7.09%.
(ppm) 0.85 (t, J=7.4, 3H, CH3-CH2), 1.1–1.4 (m, 2H,
CH2-Me), 1.9–2.1 (m, 1H, CH-Et), 2.38 (s, 3H, CH3-
Ar), 3.11 (m, J=9.5, 11.5, 1H, CHHN), 3.47 (m,
J=5.1, 11.5, 1H, CHHN), 4.94 (d, J=8.7, 1H, CH-O),
6.20 (br s, 1H, NH), 7.1–7.35 (m, 4H, Harom.); 13C
NMR: l (ppm) 10.9 (CH3-CH2), 21.4 (CH3-Ar), 22.1
(CH2-Me), 38.6 (CH-Et), 43.7 (CH2-N), 83.7 (CH-O),
123.9, 127.3, 128.3, 129.3 (CHarom.), 137.7, 138.2
(Carom.), 154.5 (CO); IR (Nujol, cm−1): 1699; ESI-MS:
m/z 242 (M+Na)+. Anal. calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.04; H, 8.88; N,
6.15%.
Acknowledgements
4.4.6. (5R,6R)-5-Ethyl-6-(4-methylphenyl)-1,3-oxazinan-
2-one 15. White solid; yield 63%; mp 136–137°C; [h]2D0=
1
−3.3 (c 0.5, CHCl3; e.e. 83%, d.r. 96:4); H NMR: l
Financial support of this work by the CICYT (project
BIO 98-0770) is greatfully acknowledged. J.R.D. thanks
the Spanish Ministerio de Educacio´n y Cultura for a
predoctoral fellowship.
(ppm) 0.83 (t, J=7.4, 3H, CH3-CH2), 1.1–1.4 (m, 2H,
CH2-Me), 1.9–2.1 (m, 1H, CH-Et), 2.36 (s, 3H, CH3-
Ar), 3.11 (m, J=9.7, 11.5, 1H, CHHN), 3.47 (m,
J=5.1, 11.5, 1H, CHHN), 4.93 (d, J=8.8, 1H, CH-O),
5.77 (br s, 1H, NH), 7.1–7.2 (m, 4H, Harom.); 13C NMR:
l (ppm) 10.9 (CH3-CH2), 21.6 (CH3-Ar), 22.1 (CH2-
Me), 38.6 (CH-Et), 43.8 (CH2-N), 83.6 (CH-O), 126.7,
129.1 (CHarom.), 134.7, 138.4 (Carom.), 154.3 (CO); IR
(Nujol, cm−1): 1694; ESI-MS: m/z 242 (M+Na)+. Anal.
calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39.
Found: C, 70.99; H, 8.89; N, 6.25%.
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