Highly diastereoselective cyanation of methyl ketimines obtained from (R)-glyceraldehyde

Article abstract of DOI:10.1021/jo051592c

Addition of trimethylsilyl cyanide to ketimines derived from (R)-2,2-dimethyl-1,3-dioxolan-4-yl methyl ketone to generate a quaternary stereocenter has been achieved with high yields and excellent diastereoselectivity. The stereoselectivity was found to b

Full text of DOI:10.1021/jo051592c

years, several methods and strategies for the asymmetric
synthesis of quaternary stereocenters have been devel-
oped and published4 and the stereoselective Strecker
reaction of ketimines is one of the most direct and
practical methods for the synthesis of amino nitriles with
quaternary stereocenters.
Reactions involving ketimines remain a great challenge
because of their low reactivity and the difficulty in
controlling facial stereoselectivity, and in this context,
some research has been carried out in an attempt to
overcome these difficulties. These efforts have recently
culminated in efficient chiral catalysts for the cyanation
of ketimines,5 and these systems provide excellent enan-
tioselectivities for aromatic ketimines. Nevertheless, the
stereoselectivity is significantly lower when aliphatic
ketimines are used as starting materials. Moreover, the
cost and time involved in synthesizing these complex
catalysts constitute a serious drawback for their ap-
plicability.
Highly Diastereoselective Cyanation of
Methyl Ketimines Obtained from
(R)-Glyceraldehyde
Ramo´n Badorrey, Carlos Cativiela,
Mar´ıa D. D´ıaz-de-Villegas,* Roberto D´ıez,
Fabrizio Galbiati, and Jose´ A. Ga´lvez*
Departamento de Quı´mica Orga´nica, Instituto de Ciencia de
Materiales de Arago´n, Instituto Universitario de Cata´lisis
Homoge´nea, Universidad de Zaragoza-CSIC, E-50009
Zaragoza, Spain
loladiaz@unizar.es; jagl@unizar.es
Received July 29, 2005
Most of the reported methods for the asymmetric
cyanation of ketimines involve the use of stoichiometric
chiral auxiliaries or optically active starting materials.
Among the stoichiometric approaches, the addition of
cyanide to ketimines using amines as chiral auxiliaries
has already been investigated and applied to the stereo-
selective synthesis of R,R-dialkylamino acids.6,7
In contrast, Strecker-type reactions using ketimines in
which the chiral matrix is the carbonyl moiety have been
exploited to a much lesser extent. Indeed, most studies
have been based on the use of chiral cyclic ketimines
derived mainly from carbohydrates.8 Approaches using
acyclic ketimines derived from chiral ketones afford the
corresponding R-amino nitriles in acceptable yields but,
unfortunately, with modest or very low diastereoselec-
tivities.9
Addition of trimethylsilyl cyanide to ketimines derived from
(R)-2,2-dimethyl-1,3-dioxolan-4-yl methyl ketone to generate
a quaternary stereocenter has been achieved with high
yields and excellent diastereoselectivity. The stereoselectiv-
ity was found to be temperature and solvent dependent. The
â-hydroxy-R-amino nitrile of syn configuration was the major
compound in kinetically controlled reactions, whereas the
anti stereoisomer was obtained in excess in thermodynami-
cally controlled reactions. Double stereodifferentiation under
kinetic control conditions was successful, and the cyanation
reaction occurred with complete syn diastereoselectivity
using the matched pair. The versatility of the resulting
amino nitrile as a synthetic intermediate was tested by
performing the synthesis of orthogonally protected (R)-(2-
aminomethyl)alanine.
(4) For a recent review, see: Denissova, I.; Barriault, L. Tetrahedron
2003, 59, 10105-10146.
(5) For leading references, see: (a) Spino, C. Angew. Chem., Int. Ed.
2004, 43, 1764-1766 and references therein. (b) Gro¨ger, H. Chem. Rev.
2003, 103, 2795-2827 and references therein.
R-Amino nitriles have proven to be versatile intermedi-
ates for a large number of synthetic applications.1 In
historical terms, the most important use of R-amino
nitriles involves hydrolysis of the nitrile group to gener-
ate R-amino acids. It is also possible to reduce the nitrile
group to prepare 1,2-diamines, which are employed as
medicinal agents or chiral ligands.2 The cyanation of
imines offers a short route to R-amino nitriles, and there
has been great interest in developing an asymmetric
version of this process to obtain chiral R-amino nitriles
for use as intermediates in the production of optically
active R-amino acids. Of particular interest are nonpro-
teinogenic R-amino acids,3 which are often used as key
building blocks in pharmaceuticals. Moreover, in recent
(6) See, for example: (a) Warmuth, R.; Munsch, T. E.; Stalker, R.
A.; Li, B.; Beatty, A. Tetrahedron 2001, 57, 6383-6397. (b) Ma, D.;
Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120-125. (c) Meyer, U.;
Breitling, E.; Bisel, P.; Frahm, A. W. Tetrahedron: Asymmetry 2004,
15, 2029-2037. (d) Bisel, P.; Fondekar, K. P.; Volk, F.-J.; Frahm, A.
W. Tetrahedron 2004, 60, 10541-10545. (e) Truong, M.; Lecornue´, F.;
Fadel, A. Tetrahedron: Asymmetry 2003, 14, 1063-1072. (f) Zhou, P.;
Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003-8030. (g) Li,
B.-F.; Yuan, K.; Zhang, M.-J.; Wu, H.; Dai, L.-X.; Wang, Q. R.; Hou,
X.-L. J. Org. Chem. 2003, 68, 6264-6267. (h) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984-995. (i) Davis, F. A.;
Lee, S.; Zhang, H.; Fanelli, D. L. J. Org. Chem. 2000, 65, 8704-8708.
(j) Ohfune, Y.; Shinada, T. Bull. Chem. Soc. Jpn. 2003, 76, 1115-1129.
(k) Namba, K.; Kawasaki, M.; Takada, I.; Iwama, S.; Izumida, M.;
Shinada, T.; Ohfune, Y. Tetrahedron Lett. 2001, 42, 3733-3736.
(7) For leading references, see: (a) Williams, R. M. Synthesis of
Optically Active R-Amino Acids, 1st ed.; Pergamon Press: Oxford, 1989.
(b) Wirth, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225-227. (c)
Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998,
9, 3517-3599. (d) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2000, 11, 645-732 and references therein.
(1) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359-373.
(2) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
Engl. 1998, 37, 2580-2627.
(3) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539-1650. (b)
Williams, R. M. Synthesis of Optically Active R-Amino Acids. In
Organic Chemistry Series; Baldwin, J. E., Magnus, P. D., Eds.;
Pergamon: Oxford, 1989; Vol. 7.
(8) (a) Dom´ınguez, L.; Van Nhien, A. N.; Tomassi, C.; Len, C.; Postel,
D.; Marco-Contelles, J. J. Org. Chem. 2004, 69, 843-856. (b) Postel,
D.; Van Nhien, A. N.; Pillon, M.; Villa, P.; Ronco, G. Tetrahedron Lett.
2000, 41, 6403-6406. (c) Fadel, A.; Khesrani, A. Tetrahedron: Asym-
metry 1998, 9, 305-320. (d) Steiner, B.; Koo´s, M.; Langer, V.;
Gyepesova´, D.; Smrcok, L. Carbohydr. Res. 1998, 311, 1-9.
10.1021/jo051592c CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/27/2005
10102
J. Org. Chem. 2005, 70, 10102-10105

SCHEME 1
diastereoselectivity in favor of the amino nitrile of R
configuration on the newly formed stereogenic center
(relative configuration syn) (entry 1). In the presence of
a Lewis acid such as zinc chloride or through the use of
other cyanide sources such as diethylaluminum cyanide,
the starting ketimine rapidly decomposed and a complex
mixture of products that was difficult to purify was
obtained. Fortunately, the use of a larger excess of
trimethylsilyl cyanide (2 equiv) substantially improved
the yield of the cyanation reaction (entry 2). We pro-
ceeded to investigate the influence of temperature and
solvent on the reaction. By repeating the reaction at a
lower temperature in dichloromethane or by using other
aprotic solvents, we observed slight variations in chemi-
cal yield and diastereoselectivity (entries 3-8). The best
results were obtained at -20 °C in dichloromethane or
acetonitrile. On the other hand, the diastereofacial
selectivity was found to be very sensitive to temperature
changes by using the protic solvent 2-propanol (entries
9-11). For example, syn-2a was obtained preferentially
at -20 °C whereas the anti diastereoisomer was obtained
in excess at room temperature. Moreover, when the
reaction time was increased from 3 to 12 h, the syn/anti
ratio changed markedly to reach a maximum value of
34:66.
On the basis of the experimental data described above,
we reasoned that the addition of trimethylsilyl cyanide
to imine 1a proceeded under kinetic control at -20 °C in
CH2Cl2 and under thermodynamic control at room tem-
perature in 2-propanol in conjunction with longer reac-
tion times. In an effort to demonstrate this assumption,
diastereomerically pure amino nitriles syn-2a and anti-
2a, which were previously purified by column chroma-
tography, were dissolved in CH2Cl2 and 2-propanol,
respectively. The four resulting solutions were kept at
room temperature for several days, and the syn/anti ratio
was monitored by high-pressure liquid chromatography
(HPLC). After 2 days, products dissolved in CH2Cl2
remained unaltered whereas solutions of both syn-2a and
anti-2a in 2-propanol evolved to reach a thermodynamic
ratio (syn/anti ) 34:66).
Bearing in mind the important role that R,R-dialky-
lamino acids with aliphatic side chains can play in the
construction of novel peptidic sequences with tailor-made
enhanced properties,10 it is essential to carry out ad-
ditional studies on the asymmetric cyanation of aliphatic
acyclic ketimines.
We have previously reported the diastereoselective
addition of cyanide to aldimines derived from conve-
niently protected (R)-glyceraldehyde as a novel approach
to enantiomerically pure â-hydroxy-R-amino acids.11 We
wish to report here an extension of this methodology to
N-benzyl ketimines derived from (R)-2,2-dimethyl-1,3-
dioxolan-4-yl methyl ketone to afford dihydroxylated
R-amino nitriles bearing a quaternary stereogenic center
and a tertiary stereogenic center at consecutive positions.
These compounds can be regarded as useful new building
blocks because they have four possible points of deriva-
tization in contiguous positions, namely cyano and
amino groups at C2 and hydroxy groups at C3 and C4
(Scheme 1).
(R)-2,2-Dimethyl-1,3-dioxolan-4-yl methyl ketone was
easily obtained from (R)-2,3-O-isopropylideneglyceralde-
hyde following the procedure described by Leyes and
Poulter.12 Condensation of this ketone with benzylamines
promoted by TiCl413 yielded the N-benzyl ketimines 1a-c
employed in this study. The E stereochemistry of the Cd
N bond was assigned by selective ge-1D nuclear Over-
hauser enhancement spectroscopy (NOESY) experiments.
Crude ketimines were used in the subsequent cyana-
tion reaction (Scheme 1), and chromatographic purifica-
tion was not required. The results obtained in the
cyanation reactions of compounds 1a-c are collected in
Table 1.
The absolute configuration at the newly formed ste-
reogenic center in the cyanation reaction was unambigu-
ously determined by single-crystal X-ray diffraction
analysis of compound anti-2a.
Initially, ketimine 1a was allowed to react with tri-
methylsilyl cyanide (1.2 equiv) in dichloromethane at
room temperature to afford a mixture of the correspond-
ing amino nitriles 2a in moderate yield and with high
Finally, we studied the possibility of using ketimines
derived from chiral amines as starting compounds to
perform a double stereodifferentiation process. With this
aim in mind, ketimines 1b and 1c, derived from (R)- and
(S)-R-methylbenzylamines, respectively, were treated
with trimethylsilyl cyanide under the optimal kinetic
reaction conditions established previously, i.e., using
dichloromethane as the solvent at -20 °C. Under these
conditions, the corresponding cyanide addition products
were obtained in high yields (entries 12 and 13). Asym-
metric induction was not observed on starting with the
ketimine derived from (R)-R-methylbenzylamine, and an
almost equimolecular mixture of syn and anti adducts
was obtained (mismatched pair). On the other hand,
when the imine derived from (S)-R-methylbenzylamine
was used as the substrate, the syn diastereoisomer was
the only product detected by NMR (matched pair).
(9) (a) Acherki, H.; Alvarez-Ibarra, C.; Alfonso-de-Dios; Quiroga, M.
L. Tetrahedron 2002, 58, 3217-3227. (b) Micova´, J.; Steiner, B.; Koo´s,
M.; Langer, V.; Dur´ık, M.; Gyepesova´, D.; Smrcok, L. Carbohydr. Res.
2002, 337, 663-672.
(10) Some recent reviews: (a) Hruby, V. J.; Li, G.; Haskell-Luevano,
C.; Shenderovich, M. Biopolymers 1997, 43, 219-266. (b) Venkatra-
man, J.; Shankaramma, S. C.; Balaram, P. Chem. Rev. 2001, 101,
3131-3152 (c) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C.
Biopolymers (Pept. Sci.) 2001, 60, 396-419. (d) Hill, D. J.; Mio, M. J.;
Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893-
4011.
(11) (a) Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A. Tetra-
hedron Lett. 1995, 35, 2859-2860. (b) Cativiela, C.; D´ıaz-de-Villegas,
M. D.; Ga´lvez, J. A.; Garc´ıa, J. I. Tetrahedron 1996, 52, 9563-9574.
(c) Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A.
Tetrahedron: Asymmetry 2000, 11, 1015-1025.
(12) Leyes, A. E.; Poulter, C. D. Org. Lett. 1999, 1, 1067-1070.
(13) Palomo, C.; Aizpurua, J. M.; Garc´ıa, J. M.; Galarza, R.; Legido,
M.; Urchegui, R.; Roma´n, P.; Luque, A.; Server-Carrio´, J.; Linden, A.
J. Org. Chem. 1997, 62, 2070-2079.
J. Org. Chem, Vol. 70, No. 24, 2005 10103

TABLE 1. Stereoselective Addition of Cyanide to Ketimines 1a-c
reaction
time
[CN-] source
(equiv)
T
(°C)
yielda
(%)
drb
syn/anti
entry
ketimine
solvent
(h)
product
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
Me3SiCN (1.2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
Me3SiCN (2)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
MeCN
iPrOH
iPrOH
iPrOH
CH2Cl2
CH2Cl2
rt
3
3
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
44
79
84
84
72
77
69
89
47
73
61
79
82
84/16
83/17
81/19
87/13
79/21
84/16
85/15
86/14
82/18
41/59
34/66
50/50
>98/2
rt
3
0
3
4
-20
-40
-20
-20
-20
-20
rt
3
5
3
6
3
7
3
8
3
9
3
10
11
12
13
3
rt
-20
-20
12
3
3
a Isolated yield after chromatography on silica gel. b Ratio determined by 1H NMR analysis of the crude reaction mixtures using C6D6
as solvent.
SCHEME 2a
FIGURE 1.
We previously reported a model for the addition of
trimethylsilyl cyanide to N-benzylimines derived from
conveniently protected (R)-glyceraldehyde, and this model
was supported by ab initio calculations.11b According to
this model, the stereochemical course of the cyanation
reaction of ketimine 1c can be rationalized by assuming
(i) that the trimethylsilyl moiety coordinates to the imine
nitrogen, (ii) that the carbonyl moiety preferentially
adopts an anti-Felkin-Anh conformation in which the
R-C-OR bond is orthogonally oriented to the plane
containing the imine group, and (iii) that the N-(S)-R-
methylbenzyl group adopts a conformation in which the
allylic 1,3 strain is minimized.14 Attack of the cyanide
from the re side accounts for the observed preferential
production of the syn diastereoisomer (Figure 1).
a Reagents and conditions: (a) TMSCN, CH2Cl2, -20 °C, 6 h;
(b) LiAlH4, THF, 0 °C f room temperature, 3 h; (c) Ac2O, Et3N,
DMAP, CH2Cl2, room temperature, 2 h; (d) H2 20% Pd(OH)2/C,
Boc2O, EtOH, room temperature, 18 h; (e) CF3CO2H, 3:1 MeOH/
H2O, room temperature, 24 h; (f) NalO4, 2:2:3 CH3CN/CCl4/H2O,
room temperature, 5
presence of di-tert-butyl dicarbonate resulted in the
formation of orthogonally protected diamine 4 in high
yield. Deprotection of the acetal with trifluoroacetic acid
afforded diol 5, from which the (R)-(2-aminomethyl)-
alanine derivative 6 was obtained by oxidative cleavage
of the 1,2-diol moiety by treatment with excess sodium
periodate in the presence of ruthenium trichloride.15
Amino nitrile syn-2c can be used as a synthetic
intermediate to prepare a wide variety of nitrogen-
containing compounds with a chiral quaternary carbon
atom, including amino alcohols, diamines, R-methyl-R-
amino acids, etc., by the appropriate elaboration of the
amino, the 2,2-dimethyl-1,3-dioxolan-4-yl, and/or the
nitrile moieties. As an example, to demonstrate the
versatility of this intermediate, the synthesis of orthogo-
nally protected (R)-(2-aminomethyl)alanine was chosen.
In our strategy, which is outlined in Scheme 2, the 2,2-
dimethyl-1,3-dioxolan-4-yl moiety acts as the carboxylic
acid precursor and the aminomethyl group is obtained
from the nitrile group.
In summary, the optimal conditions to carry out the
cyanation of N-benzyl ketimines derived from (R)-2,2-
dimethyl-1,3-dioxolan-4-yl methyl ketone have been iden-
tified and involve the use of trimethylsilyl cyanide in the
absence of Lewis acid in dichloromethane at a low
temperature. Under these conditions, the addition of
cyanide to ketimines derived from (S)-R-methylbenzy-
lamine exhibits a double stereodifferentiation process and
the reaction takes place with complete control of stereo-
selectivity to afford the corresponding quaternary R-ami-
no nitrile with the syn relative configuration. The re-
sulting γ,â-dihydroxy-R-amino nitrile has four possible
points for further derivatization and can presumably be
used to prepare a wide variety of nitrogen-containing
Reduction of amino nitrile syn-2c with lithium alumi-
num hydride provided the desired amine, which was
isolated as the corresponding N-acetyl derivative 3.
Hydrogenolytic N-debenzylation of compound 3 in the
(15) Physical and spectral data of (R)-(2-aminomethyl)alanine ob-
tained by hydrolysis of compound 6 fully agreed with those described
in the literature. Obrecht, D.; Karajiannis, H.; Lahmann, C.; Scho¨n-
holzer, P.; Spiegler, C.; Mu¨ller, K. Helv. Chim. Acta 1995, 78, 703-
714.
(14) Badorrey, R.; Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J.
A. Tetrahedron 1999, 55, 7601-7612.
10104 J. Org. Chem., Vol. 70, No. 24, 2005

(R)-N-Acetyl-2-(tert-butoxycarbonylamino)-2-[(S)-2,2-di-
methyl-1,3-dioxolan-4-yl]-1-propylamine (4). To a solution
of compound 3 (6.4 mmol) and Boc2O (19.2 mmol) in absolute
ethanol (75 mL) was added 20% Pd(OH)2/C (300 mg), and the
mixture was hydrogenolysed with H2 at 1 atm with shaking at
room temperature for 18 h. After completion of the reaction, the
mixture was filtered through Celite and concentrated in vacuo.
The residue was purified by silica gel flash chromatography (1st
eluent ether/hexane 1:1; 2nd eluent AcOEt) to give pure 4 as a
compounds. As an example, the 2,2-dimethyl-1,3-diox-
olan-4-yl moiety has been transformed into a carboxylic
acid group and the nitrile group has been reduced to an
aminomethyl group to give a (R)-(2-aminomethyl)alanine
derivative. Substitution of methylmagnesium bromide by
different organomagnesium reagents16 in the synthesis
of the starting ketone would allow the preparation of a
variety of alkyl ketimines, and this would extend the
scope of the methodology described here. Research into
this area is underway and will be published in due
course.
colorless oil (1.85 g, 91%): [R]26 ) -11.7 (c 1.05, CHCl3); IR
D
absorption (pure) 3311, 1710, 1659 cm-1
;
1H NMR (400 MHz,
CDCl3) δ 6.59 (bs, 1H), 5.12 (bs, 1H), 4.19 (dd, 1H, J ) 6.4 Hz,
J ) 6.4 Hz), 4.02 (dd, 1H, J ) 9.2 Hz, J ) 6.4 Hz), 3.88 (dd, 1H,
J ) 9.2 Hz, J ) 6.4 Hz), 3.57 (dd, 1H, J ) 14.0 Hz, J ) 6.4 Hz),
3.40 (dd, 1H, J ) 14.0 Hz, J ) 5.6 Hz), 1.98 (s, 3H), 1.45 (s, 3H),
1.43 (s, 9H), 1.32 (s, 3H), 1.25 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 170.6, 155.8, 109.6, 79.7, 79.4, 65.0, 56.6, 45.7, 28.3,
26.2, 24.5, 23.3, 21.7; HRMS (FAB+) calcd for C15H29N2O5 (MH+)
317.2076, found 317.2081.
Experimental Section
(R)-2-[(S)-1-Phenylethylamino]-2-[(S)-2,2-dimethyl-1,3-
dioxolan-4-yl]propane Nitrile (syn-2c). TMSCN (36.10 mmol)
was added to a solution of crude imine 1c (18.03 mmol) in dry
CH2Cl2 (150 mL) at -20 °C under argon. The reaction mixture
was kept at this temperature for 6 h and then quenched by
adding saturated aqueous NH4Cl (40 mL) and water (40 mL).
The organic phase was washed successively with saturated
aqueous NaHCO3 and brine and then dried over anhydrous
MgSO4. Removal of the solvents in vacuo yielded 4.51 g of a
crude product containing the corresponding amino nitrile syn-
2c, which was used in the next step without further purification.
For characterization purposes, amino nitrile syn-2c was
purified by flash chromatography on a silica gel column using
(R)-4-Acetylamino-3-(tert-butoxycarbonylamino)-3-meth-
yl-1,2-butanediol (5). A solution of compound 4 (1.90 mmol)
in 3:1 MeOH/H2O (8 mL) was treated with CF3CO2H (0.96
mmol), and the mixture was stirred for 24 h at room tempera-
ture. The solvent was removed in vacuo, and the residue was
diluted with H2O (5 mL) and extracted with CH2Cl2. The
combined organic layers were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The residue was purified
by silica gel flash chromatography (AcOEt/EtOH 7:1) to give pure
5 as a white solid (481 mg, 92%): mp ) 131-132 °C; [R]24
)
D
hexane/ethyl acetate (3:1): [R]27 ) -104.9 (c 1.36, CHCl3); IR
D
+8.9 (c 1.0, CH3OH); IR absorption (KBr) 3535, 3442, 3327, 1710,
1684 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.46 (bs, 1H), 5.29 (bs,
1H), 3.72 (dd, 1H, J ) 11.2 Hz, J ) 3.2 Hz), 3.64 (dd, 1H, J )
14.0 Hz, J ) 6.8 Hz), 3.60 (dd, 1H, J ) 11.2 Hz, J ) 7.6 Hz),
3.51 (dd, 1H, J ) 7.6 Hz, J ) 3.2 Hz), 3.47 (dd, 1H, J ) 14.0 Hz,
J ) 6.4 Hz), 2.01 (s, 3H), 1.41 (s, 9H), 1.27 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 172.1, 156.3, 80.0, 74.5, 62.1, 57.6, 45.0,
28.3, 23.2, 20.3. Elemental Anal. Calcd (%) for C12H24N2O5: C,
52.16; H, 8.75; N, 10.14. Found: C, 52.58; H, 8.94; N, 10.23.
(R)-(2-Acetylaminomethyl)-N-(tert-butoxycarbonyl)ala-
nine (6). Small portions of NaIO4 (4.88 mmol) were added to a
stirred solution of compound 5 (1.12 mmol) in CH3CN/CCl4/H2O
(2:2:3, 30 mL). After being vigorously stirred for 5 min following
completion of the addition, the mixture was treated with RuCl3
(0.053 mmol) and stirring was continued for 2 h. CH2Cl2 was
added (30 mL). The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2. The combined organic
layers were dried over anhydrous MgSO4, and the solvent was
evaporated in vacuo. The residue was purified by silica gel flash
chromatography (AcOEt) to give pure product 6 as a colorless
1
absorption (pure) 3342, 2222 cm-1; H NMR (400 MHz, CDCl3)
δ 7.40-7.05 (m, 5H), 4.17 (dd, 1H, J ) 6.8 Hz, J ) 6.8 Hz), 4.12
(dd, 1H, J ) 8.0 Hz, J ) 6.8 Hz), 4.10 (q, 1H, J ) 6.8 Hz), 3.99
(dd, 1H, J ) 8.0 Hz, J ) 6.8 Hz), 1.95 (bs, 1H), 1.54 (s, 3H), 1.41
(s, 3H), 1.40 (d, 3H, J ) 6.8 Hz), 0.94 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 147.1, 128.4, 127.0, 126.3, 121.3, 110.5, 80.2, 64.3,
57.6, 54.7, 26.5, 26.1, 24.9, 21.9; HRMS (FAB+) calcd for C15H22
-
NO2 (M+ - CN) 248.1650, found 248.1645.
(R)-N-Acetyl-2-[(S)-1-phenylethylamino]-2-[(S)-2,2-di-
methyl-1,3-dioxolan-4-yl]-1-propylamine (3). A 1 M solution
of LiAlH4 in THF (66 mmol) was added dropwise to a solution
of the crude amino nitrile syn-2c (obtained in the previous step)
in dry THF (200 mL) at 0 °C. The reaction mixture was allowed
to warm to room temperature, stirred for 3 h, and then cooled
to 0 °C. After the addition of CH2Cl2 (100 mL), the reaction
mixture was carefully quenched with saturated aqueous NaH-
CO3 (50 mL) and filtered through Celite. The aqueous phase was
extracted with CH2Cl2. The combined organic layers were dried
over anhydrous MgSO4, and the solvents were removed in vacuo.
The residue was dissolved in dry CH2Cl2 (120 mL), and to the
solution was added successively Et3N (24.8 mmol), DMAP (0.86
mmol), and Ac2O (19.81 mmol). The reaction mixture was stirred
at room temperature for 2 h and then quenched with saturated
aqueous NaHCO3 (50 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2. The combined
organic layers were dried over anhydrous MgSO4, and after
removal of the solvent, the residue was chromatographed on
silica gel (AcOEt) to give pure product 3 as a colorless oil (3.82
oil (180 mg, 62%): [R]25 ) +40.5 (c 1.0, CHCl3); IR absorption
D
(KBr) 3500-2500, 1710, 1652 cm-1; 1H NMR (400 MHz, CDCl3)
δ 6.45 (bs, 1H), 6.27 (bs, 1H), 3.76 (dd, 1H, J ) 14.0 Hz, J ) 6.8
Hz), 3.54 (dd, 1H, J ) 14.0 Hz, J ) 5.6 Hz), 2.02 (s, 3H), 1.54 (s,
3H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.5, 172.4,
157.5, 81.7, 61.5, 46.4, 28.3, 22.9, 21.3; HRMS (FAB+) calcd for
C11H21N2O5 (MH+) 261.1450, found 261.1444.
Acknowledgment. This work was supported by the
Spanish MCYT and FEDER (Project CTQ2004-05358)
and the Diputacio´n General de Arago´n. R.D. was
supported by a Spanish MCYT Predoctoral Fellowship.
g, 66% from imine 1c): [R]26 ) -11.9 (c 0.96, CHCl3); IR
D
1
absorption (pure) 3309, 1653 cm-1; H NMR (400 MHz, CDCl3)
δ 7.42-7.15 (m, 5H), 6.20 (bs, 1H), 4.08 (dd, 1H, J ) 7.6 Hz, J
) 7.6 Hz), 4.00 (dd, 1H, J ) 6.4 Hz, J ) 6.4 Hz), 3.94 (q, 1H, J
) 6.8 Hz), 3.87 (dd, 1H, J ) 7.6 Hz, J ) 6.4 Hz), 3.80 (dd, 1H,
J ) 14.0 Hz, J ) 8.8 Hz), 2.79 (dd, 1H, J ) 14.0 Hz, J ) 2.4
Hz), 2.05 (bs, 1H), 1.94 (s, 3H), 1.50 (s, 3H), 1.38 (s, 3H), 1.27
(d, 3H, J ) 6.8 Hz), 0.64 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
169.8, 148.9, 128.2, 126.4, 126.2, 109.2, 82.3, 65.4, 55.7, 51.1,
44.9, 27.2, 26.3, 25.2, 23.3, 20.2; HRMS (FAB+) calcd for
Supporting Information Available: General statement
describing materials and methods, general experimental pro-
cedures, 1H NMR, and 13C NMR spectra for all compounds;
thermal ellipsoid plot for compound anti-2a; and X-ray crystal-
lographic data in CIF format for compound anti-2a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
C
18H29N2O3 (MH+) 321.2178, found 321.2187.
(16) Carda, M.; Rodr´ıguez, S.; Castillo, E.; Bellido, A.; D´ıaz-Oltra,
S.; Marco, J. A. Tetrahedron 2003, 59, 857-864.
JO051592C
J. Org. Chem, Vol. 70, No. 24, 2005 10105