A practical diastereoselective synthesis of syn-α- hydroxyaminonitriles

Article abstract of DOI:10.1055/s-2005-864838

An efficient and practical one pot two-step synthesis of syn-α-hydroxyaminonitriles through an acylation-diastereoselective reduction sequence from lithiated α-aminonitrile is achieved.

Full text of DOI:10.1055/s-2005-864838

LETTER
1033
A Practical Diastereoselective Synthesis of syn-a-Hydroxyaminonitriles
A
P
ractica
l
Sy
a
nthesis of
s
t
yn
-
a
-H
o
ydroxyamino
u
nitriles mia Abdillah, Loïc Almeras, Eric Leclerc, Pierre Mangeney,* Emmanuel Vrancken*
Laboratoire de Chimie Organique, UMR 7611, Université Pierre et Marie Curie, 4 place Jussieu, T. 44-45, 2° ét., bte 183,
75252 Paris Cedex 05, France
Fax +33(1)44277567; E-mail: mangeney@ccr.jussieu.fr; E-mail: vrancken@ccr.jussieu.fr
Received 31 January 2005
a-aminonitrile onto an aromatic ester in the presence of
Abstract: An efficient and practical one pot two-step synthesis of
syn-a-hydroxyaminonitriles through an acylation-diastereoselec-
tive reduction sequence from lithiated a-aminonitrile is achieved.
2.5 equivalents of NaHMDS at room temperature.6
In order to find a more general procedure, we examined
the addition of lithiated a-aminonitriles onto several eno-
lisable esters. a-Aminonitrile 1 was thus treated with 2
equivalents of LDA in THF at –78 °C, and then the ester
was added. The addition product bears an acidic proton,
therefore 2 equivalents of base are necessary to avoid con-
sumption of the lithiated a-aminonitrile (Table 1, entries
5 and 6). We attempted to characterise the keto-deriva-
Key words: amino alcohols, reduction, diastereoselectivity, acyl
cyanide, dynamic kinetic resolution
We have recently disclosed a diastereoselective aldolisa-
tion of a-aminonitriles1 leading to anti-a-hydroxyamino-
nitriles, which were valuable intermediates for the
preparation of syn,anti-b,g-diaminotriols.2 In the course
of our attempts in the preparation of all diastereoisomers
we turned our attention to a general, currently unavailable,
highly diastereoselective procedure for the synthesis of
syn-hydroxyaminonitriles3 from metallated a-amino-
nitriles.
1
tives (R = alkyl) obtained after hydrolysis through H
NMR spectroscopy, however, this failed probably due to
a fast keto 3b–d/enol 4b–d equilibrium. The only excep-
tion was observed for methyl benzoate, which gave main-
ly the stable enol 4a as a crystalline compound, which was
fully characterisable (Scheme 2).
As it had been shown by Carlier that the use of HMPA as
a co-solvent promoted the syn-selective aldol reaction of
arylacetonitriles with aromatic aldehydes,4 we first tried
to use these conditions for the aldolisation of the lithiated
species derived from a-aminonitrile 1 (Scheme 1). How-
ever, the selectivity of the reaction was poor and the
resulting a-hydroxyaminonitriles 2a and 2b were formed
as a mixture of syn/anti-isomers. Several attempts to im-
prove the syn-diastereoselectivity by changing the nature
of the nitrogen substituents were unsuccessful.
Bn
Bn
Bn
Bn
Bn
Bn
1. LDA (2 equiv),
–80 °C, THF
N
N
N
R
OH
2. RCOOR' (1.5 equiv)
–78 °C to r.t.
3. NH4Cl (aq)
NC
NC
NC
O
R
4a–e
1
3a–e
( )-
±
4a
R = Ph
3a
( )-
±
4b
4c
4d
4e
R = t-Bu
R = c-Hex
R = i-Pr
R = n-Bu
3b
3c
3d
3e
( )-
±
( )-
±
( )-
±
Scheme 2
1. LDA, –80 °C, THF
2. HMPA (6 equiv),
30 m, –78 °C
Bn
Bn
Bn
Bn
Nevertheless, the crude reaction mixtures were concen-
trated in vacuo, diluted with methanol and stirred for 20
hours in the presence of an excess of NaBH4/MgBr2 (2:1)
mixture.7 The use of the magnesium salts in the reduction
step was found to ensure a clean reaction and gave the best
yields. The results are summarised in Table 1.
Bn
Bn
N
N
N
+
R
R
NC
NC
3. RCHO, –78 °C
4. NH4Cl/NH4OH,
–78 °C to r.t.
NC
OH
OH
1
syn-2a,b
anti-2a,b
2a: R = Ph, 92% overall yield, dr syn/anti = 69:31 (50:50)a
2b: R = t-Bu, 89% overall yield, dr syn/anti = 50:50 (09:91)a
1. LDA (n equiv), –80 °C,
THF, 30 m
2. RCOX (1.5 equiv),
–78 °C to r.t.
a dr syn/anti observed in the absence of HMPA.
Bn
Bn
Bn
Bn
Bn
Bn
N
N
Scheme 1
N
+
R
R
3. MgBr2 (2 equiv),
NaBH4 (4 equiv)
MeOH, –20 °C to r.t. 20 h
4. NH4Cl aq
NC
NC
NC
We then followed an alternative strategy based on the well
documented syn-reduction of aminoketones5 and we de-
cided to study the reduction of the b-keto-a-aminonitrile
3. To our knowledge, only two preparations of such deriv-
atives have been reported. They involve the addition of an
OH
OH
1
syn-2a,e
anti-2a,e
Scheme 3
In all cases, the expected a-hydroxyaminonitriles syn-2a–
e were isolated in satisfactory yields and good diastereo-
selectivity (> 92% de). The syn-selectivity of the reduc-
tion can be explained by a very effective Felkin-type
SYNLETT 2005, No. 6, pp 1033–1035
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864838; Art ID: G04505ST
© Georg Thieme Verlag Stuttgart · New York
0
6.
0
4.
2
0
0
5

1034
F. Abdillah et al.
LETTER
Table 1 Stereoselective Synthesis of Hydroxyaminonitriles 2a–e
media. On the contrary, this colour change occurs imme-
diately at –78 °C when acyl cyanides are used. These ob-
servations seem to suggest that the addition to the acyl
cyanide is faster than the deprotonation of the addition
product, explaining why only one equivalent of base is re-
quired in this case.
Entry
LDA
(equiv)
RCOX
Product
Yield de
(%)a
88
87
80
68
38
85
68
68
68
(syn, %)b
1
2
3
4
5
6
7
8
9
2
2
2
2
1
2
2
1
1
PhCO2Me
syn-2a
syn-2b
syn-2c
syn-2d
syn-2e
syn-2e
syn-2c
syn-2c
syn-2e
>95
>95
92
t-BuCO2Me
c-HexCO2Me
i-PrCO2Et
Finally, we decided to take advantage of the fast keto/enol
equilibrium (Scheme 2) by performing an assymmetric
version of this reaction based on a kinetic dynamic reso-
lution. Therefore, a-aminonitrile 1 was added after metal-
lation to (R)-methylglycerate (R)-5 and the crude mixture
was treated with NaBH4 in methanol to give the corre-
sponding hydroxyaminonitrile as a mixture of only two
isomers 6a and 6b in a ratio of 60:40. Interestingly, the use
of MgBr2 in the reduction step resulted in a significant im-
provement of the above selectivity, 6a and 6b were thus
obtained in a 75:25 ratio.7 The syn,syn-relationship
(2S,3R,4R) of the major stereoisomer 6a was determined
by X-ray analysis (Figure 1).13
92
n-BuCO2Me
n-BuCO2Me
c-HexCOCN
c-HexCOCN
n-BuCOCN
92
92
92
92
92
a Isolated yield.
b Determined by 1H NMR spectroscopy of the crude mixture.1
control, even in the presence of a linear substituent such
as a nitrile group.8 It is interesting to note that the presence
of MgBr2 in the reaction did not affect the anti/syn ratio by
a possible Cram-chelated transition state involving a che-
lation with the dibenzylamino group.
As expected,9 the application of our two-step procedure to
the methylcrotonate according to Scheme 3 afforded
mainly the diastereomeric 1,4-addition products. In order
to increase the electrophilicity of the carbonyl moiety, the
methyl crotonate was replaced by the corresponding acyl
chloride. Unfortunately, only a trace amount of the
desired product was detected in the resulting complex
mixture.10 Nevertheless, the use of the acyl cyanide
derivative11 followed by a Luche reduction afforded
cleanly the amino alcohol syn-2f in 68% yield with the
same level of selectivity (92% de, Scheme 4).
Figure 1 ORTEP view of 6a.13
The selective formation of 6a might be rationalized by a
preferential Felkin-type reduction of the magnesium-che-
lated ketone 7a,14 which equilibrates quickly through the
enol 8 to the less reactive diastereoisomeric ketone 7b
(Scheme 5).
1. LDA (1.1 equiv), –80 °C,
THF, 30 min
2. C3H5COCN (1.5 equiv),
–78 °C, 30 min
Bn
Bn
Bn
Bn
N
N
3. CeCl3 (2 equiv), NaBH4 (4 equiv),
MeOH, –20 °C to r.t. 20 h
4. NH4Cl aq
NC
NC
68% yield,
92% de (syn)
OH
In conclusion, syn-hydroxyaminonitriles can be efficient-
ly prepared with high selectivity (up to >95% de) from the
easily available a-aminonitrile 1 by a practical one pot
acylation-reduction sequence. The use of acylcyanide al-
lows the synthetically valuable allylic hydroxy derivative
syn-2f to be obtained with the same level of selectivity.
When the (R)-methylglycerate 5 is used, a dynamic kinet-
ic resolution occurs during the reduction step to give the
hydroxyaminonitrile syn,syn-(2S,3R,4R)-6a in good yield
and selectivity. Development of an asymmetric version as
well as some synthetic applications will be reported in due
course.
1
syn-2f
Scheme 4
The generality of acyl cyanides12 in this reaction was then
addressed. As shown in Table 1 (entries 6–8) the syn-ami-
no alcohols were obtained in slightly lower yields than
when esters were employed. It is noteworthy that only one
equivalent of LDA is required to achieve such results
(compare entries 7 and 8 in Table 1). Moreover, it is inter-
esting to note that when esters are added the reaction tem-
perature must be increased from –78 °C to room
temperature to ensure a complete colour change of the
Synlett 2005, No. 6, 1033–1035 © Thieme Stuttgart · New York

LETTER
A Practical Diastereoselective Synthesis of syn-a-Hydroxyaminonitriles
1035
(5) Fraser, D. S.; Park, S. B.; Chong, J. M. Can. J. Chem. 2004,
82, 87; and references cited therein.
(6) (a) Takahashi, K.; Shibasaki, K.; Ogura, K.; Iida, H. Chem.
Lett. 1983, 859. (b) Yang, Z.; Zhang, Z.; Meanwell, N. A.;
Kadow, J. F.; Wang, T. Org. Lett. 2002, 4, 1103.
1. 1, LDA (2 equiv)
THF, –80 °C to r.t.
2. MgBr2 (2 equiv),
NaBH4 (4 equiv),
MeOH, –20 °C to r.t.
O
O
O
MeO
(7) Typical Procedure: To a cooled (–78 °C) solution of LDA
(2 mmol) in anhyd THF(10 mL), under an argon atmosphere,
was added dropwise a THF (3 mL) solution of N-dibenzyl-
aminoacetonitrile 1 (236 mg, 1 mmol). The reaction mixture
was warmed to –60 °C over 30 min, cooled to –78 °C and
ester (R)-5 was added dropwise over 5 min. The reaction
mixture was warmed to room temperature over 1 h,
quenched with MeOH (2 mL), and the solvents were
removed in vacuo. The resulting solid was dissolved in
MeOH (25 mL), MgBr2·Et2O (0.5 g, 2 mmol) was added and
the solution was cooled to –20 °C. NaBH4 (350 mg, 4 mmol)
was slowly added and the resulting suspension was allowed
to reach room temperature and stirred for 20 h. The solvents
were removed in vacuo, the resulting solid was dissolved in
CH2Cl2 (50 mL) and saturated NH4Cl (50 mL) were added.
After standard work-up, the crude product was purified by
column chromatography over silica gel (pentane–Et2O,
90:10) to yield pure 6a (216 mg, 59% yield) as colourless
crystals (mp 95 °C). [a]D20 = +73 (c 0.81, CH2Cl2). 1H NMR
(200 MHz): d = 7.40–7.30 (m, 10 H), 4.31–4.23 (m, 1 H),
4.04 (d, J = 13.4 Hz, 2 H), 4.02–3.97 (m, 1 H), 3.92–3.85 (m,
2 H), 3.80–3.72 (m, 1 H), 3052 (2, J = 13.4 Hz, 2 H), 3.21
(br s, 1 H), 1.31 (s, 3 H), 1.21 (s, 3 H). 13C (100 MHz): d =
136.8, 129.3, 128.9, 127.7, 115.2, 110.0, 74.8, 77.3, 68.9,
65.3, 57.3, 54.4, 26.6, 25.2. Anal. Calcd for C22H26N2O3: C,
72.11; H, 7.15; N, 7.14. Found: C, 72.19; H, 7.23; N, 7.35.
(8) Reetz, M. T. Chem. Rev. 1999, 1121.
(9) (a) Enders, D.; Gerdes, P.; Kipphardt, H. Angew. Chem., Int.
Ed. Engl. 1990, 29, 179. (b) Enders, D.; Mannes, D.; Raabe,
G. Synlett 1992, 837. (c) Enders, D.; Kirchhoff, J.;
Lausberg, V. Liebigs Ann. 1996, 1361. (d) Roux, M.-C.;
Wartski, L. Tetrahedron 1996, 52, 1083.
(10) Other attempts with alkyl (primary, secondary, and tertiary)
and aryl acyl chloride in the presence of two equivalents of
LDA led to the desired products but in lower yields (30–
60%) along with many side products. For a similar
observation see: Williams, D. R.; McClymont, E. L.
Tetrahedron Lett. 1993, 34, 7705.
(R)-5
O
Bn
Bn
Bn
Bn
O
MgBr2
O
Bn
N
O
O
N
N
Bn
NC
O
NC
O
CN
O
O
MgBr2
MgBr2
7a
8
7b
H
Bn
Bn
N
O
NBn2
O
O
H
O
NC
O
NC
OH
MgBr2
syn,syn-(2S,3R,4R)-6a
H
(59% yield)
Si attack
Scheme 5
Acknowledgment
We thank Aventis for financial support through a grant to E.L. We
also thank Prof. Jean Normant for many interesting discussions and
L.-M. Chamoreau and K. Boubekeur for the crystal structure deter-
mination.
References
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(11) All acyl cyanides were prepared according to the procedure
described by: Normant, J. F.; Piechucki, C. Bull. Soc. Chim.
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(13) Crystallographic data for the structural analysis have been
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Synlett 2005, No. 6, 1033–1035 © Thieme Stuttgart · New York