Diastereoselective hydrocyanation of chiral nitrones. Synthesis of novel α-(Hydroxyamino) nitriles

Full text of DOI:10.1021/jo961293a

9028
J . Org. Chem. 1996, 61, 9028-9032
Ch a r t 1
Dia ster eoselective Hyd r ocya n a tion of
Ch ir a l Nitr on es. Syn th esis of Novel
r-(Hyd r oxya m in o) Nitr iles
P. Merino,* A. Lanaspa, F. L. Merchan, and T. Tejero
Departamento de Quimica Organica, ICMA, Universidad de
Zaragoza, CSIC, E-50009 Zaragoza, Spain
Received J uly 9, 1996
The asymmetric hydrocyanation of carbonyl com-
pounds constitutes a useful transformation in organic
chemistry1 due to the utility of the resulting optically
active cyanohydrins as useful precursors of many impor-
tant classes of organic compounds.2 In particular, when
the reaction is conducted in the presence of either
ammonium chloride or salts of amines (Strecker synthe-
sis), R-amino nitriles, which are direct precursors of
R-amino acids, are obtained.3 In the asymmetric version
of the reaction a great number of alternative approaches
to the classical Strecker conditions have been described
in the past,4 the most popular being the addition of
cyanide to chiral imines.5 By contrast, other chiral
nonracemic substrates bearing a carbon-nitrogen double
bond have not been investigated. To our knowledge only
three reports concerning the nonasymmetric addition of
cyanide to oximes6 and nitrones7 have been described.
Nitrones are a particularly interesting class of com-
pounds by virtue of their utility in organic synthesis.
They are reactive starting materials in a large number
of 1,3-dipolar cycloadditions8 and can act as electrophiles
with a variety of both carbon9 and heteronucleophiles.10
In this context, we and Dondoni’s group have amply
demonstrated the synthetic utility of nitrones (readily
accessible from the parent carbonyl compounds11) for the
preparation of several nitrogen-containing compounds of
interest (i.e., aza- and aminosugars,12 amino acids,13
amino aldehydes,12 allyl amines,14 nucleoside antibi-
otics,15 and (aminomethyl)thiazoles16). Within our con-
tinuing interest in the application of the nucleophilic
addition to nitrones in organic synthesis, we have inves-
tigated the stereoselective hydrocyanation of R-alkoxy
and R-amino nitrones and herein we report our results.17
Resu lts
The results from the hydrocyanation of the various
nitrones 1-8 (Chart 1) are summarized in Table 1. The
obtained R-(hydroxyamino) nitriles 9-21 (Scheme 1) are
collected in Chart 2.
The nitrone 1 was studied as a prototypical probe of
stereoselective induction (entries 1-11, Table 1). The
reaction with various cyanide reagents proceeded highly
stereoselectively (entries 1, 2, 4, 7, 8, and 10, Table 1)
giving a mixture of syn-10a and anti-10b. In the case of
* To whom correspondence should be addressed. E-mail: pmerino@
msf.unizar.es.
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Wang, Z. Tetrahedron Lett. 1993, 34, 4001-4004. (d) Ohno, H.; Nitta,
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(12) Dondoni, A.; Franco, S.; J unquera, F.; Merchan, F. L.; Merino,
P.; Tejero, T.; Bertolasi, V. Chem. Eur. J . 1995, 1, 505-520.
(13) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino, P.; Tejero,
T. Synthesis 1994, 1450-1456.
(14) Merino, P.; Anoro, S.; Castillo, E.; Merchan, F. L.; Tejero, T.
Tetrahedron Asymmetry 1996, 7, 1887-1890.
(15) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino, P.; Tejero,
T. J . Chem. Soc., Chem. Commun. 1995, 2127-2128.
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1975, 331-334.
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Chem. 1991, 375-379. (b) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett.
1987, 28, 6469-6472.
(16) Merchan, F. L.; Merino, P.; Tejero, T.; Rojo, I.; Dondoni, A.
Tetrahedron: Asymmetry 1996, 7, 667-670.
(17) For a preliminary paper see: Merchan, F. L.; Merino, P.; Tejero,
T. Tetrahedron Lett. 1995, 6949-6952.
S0022-3263(96)01293-5 CCC: $12.00 © 1996 American Chemical Society

Notes
entry
J . Org. Chem., Vol. 61, No. 25, 1996 9029
Ta ble 1. Ster eoselective Ad d ition of Cya n id e Rea gen ts to Nitr on es 1-8
nitrone
cyanide reagent (equiv)
additivea
solvent
T (°C)
time (h)
syn:anti
yieldb (%)
adduct
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
3
3
4
4
4
5
5
5
5
6
6
6
7
7
7
7
8
8
Me3SiCN (5.0)
Me3SiCN (3.0)
Me3SiCN (1.1)
Et2AlCN (1.1)
Et2AlCN (5.0)
Et2AlCN (1.1)
Et2AlCN (1.1)
Bu4NCN (1.1)
Bu4NCN (1.1)
LiCN (1.1)
none
none
Et2AlCl
none
none
Me3SiCl
none
none
Et2AlCl
none
Et2AlCl
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
none
Et2AlCl
none
none
none
Et2AlCl
none
none
CH2Cl2
0
20
0
0
0
48
48
4
2
2
2
6
12
12
2
g95:5
81:19
g95:5
68:32
44:56
46:54
86:14
83:17
74:26
86:14
80:20
70:30
71:29
73:27
80:20
55:45
68:32
75:25
70:30
65:35
56:44
80:20
83:17
86:14
90:10
92:8
84
100
68
90
65
80
91
86
64
9
10
9
10
10
9
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
CH2Cl2
CH2Cl2
THF-CH2Cl2
THF-CH2Cl2
CH2Cl2
MeOH
THF
toluene
THF-CH2Cl2
CH2Cl2
THF
MeOH
THF
0
0
10
10
10
10
10
11
12
12
12
12
13
14
15
15
15
16
17
17
17
18
18
18
19
20
20
20
21
21
-60
-60
-60
-60
20
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
82
80
LiCN (1.1)
2
Me3SiCN (3.0)
Me3SiCN (3.0)
Et2AlCN (1.1)
Et2AlCN (1.1)
LiCN (1.1)
48
48
6
16
24
48
6
48
6
6
48
48
4
6
48
6
98c
100
100
96
20
-40
-80
-60
0
85
94
90
96
90
88
96
100
93
Me3SiCN (3.0)
Et2AlCN (1.1)
Me3SiCN (3.0)
Et2AlCN (1.1)
Et2AlCN (3.0)
Me3SiCN (3.0)
Me3SiCN (3.0)
Et2AlCN (1.1)
Et2AlCN (1.1)
Me3SiCN (3.0)
Et2AlCN (1.1)
Et2AlCN (1.1)
Me3SiCN (3.0)
Me3SiCN (3.0)
Et2AlCN (1.1)
Et2AlCN (1.1)
Me3SiCN (3.0)
Et2AlCN (1.1)
-40
0
-60
-60
0
THF
CH2Cl2
MeOH
THF
THF
MeOH
THF
0
0
-60
95
100
86
0
-60
-60
0
90:10
59:41
g95:5
g95:5
g95:5
g95:5
70:30
76:24
THF
6
89
CH2Cl2
MeOH
THF
THF
MeOH
THF
48
48
6
6
48
6
98c
100
96
0
-60
-60
0
98
100
96
-60
a
b
1.0 equiv was used. Isolated yield of the crude mixture of diastereomers.
Sch em e 1
Ch a r t 2
the reaction of 1 with trimethylsilyl cyanide in dichloro-
methane as a solvent (entry 1, Table 1) the corresponding
O-(trimethylsilyl) derivative syn-9a was obtained.18 In
this case only one diastereoisomer could be detected by
NMR. On the other hand, the lower selectivity was
observed with 1.1 equiv of diethylaluminum cyanide in
dichloromethane at 0 °C (entry 4, Table 1).19 At lower
temperatures (-60 °C) and using tetrahydrofuran as a
solvent, the diastereofacial selectivity was improved to
a ratio of 86:14 (entry 7, Table 1). In previous reports
from our laboratory we described the use of diethylalu-
minum chloride as an efficient precomplexing agent for
inducing the reversal of selectivity in nucleophilic addi-
tions to 1.12a,14,20 However, when 1 was treated with
diethylaluminum chloride and then trimethylsilyl cya-
nide (entry 3, Table 1) the same sense of diastereofacial
preference was observed as that in the absence of the
chelating agent. This behavior can be attributed to the
competitive reaction between diethylaluminum chloride
and trimethylsilyl cyanide to form diethylaluminum
cyanide and trimethylsilyl chloride.21 In fact, when
nitrone 1 was added to a mixture of diethylaluminum
cyanide and trimethylsilyl chloride the same stereochem-
ical result was obtained. Surprisingly, when the nitrone
(18) O-(Trimethylsilyl) derivatives can be readily transformed into
the R-(hydroxyamino) nitriles by treatment with 4% p/v methanolic
citric acid at room temperature.
(19) In our previous paper (see ref 17) we reported a reversed
selectivity for these conditions. After several repetitions we were unable
to obtain our previously reported result.
(20) (a) Dondoni, A.; Franco, S.; Merchan, F. L.; Merino, P.; Tejero,
T. Tetrahedron Lett. 1993, 34, 5475-5478. (b) Dondoni, A.; Franco,
S.; Merchan, F. L.; Merino, P.; Tejero, T. Tetrahedron Lett. 1993, 34,
5479-5482.
(21) The reaction of both reagents to give diethylaluminum cyanide
has been previously described. See: Imi, K.; Yanagihara, N.; Utimoto,
K. J . Org. Chem. 1987, 52, 1013-1016.

9030 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
1 was previously treated with trimethylsilyl chloride and
then diethylaluminum cyanide (entry 6, Table 1) a
complete lack of selectivity was observed and a 46:54
mixture of syn-9a and anti-9b was obtained. A similar
result was observed when the reaction was carried out
with an excess of diethylaluminum cyanide (entry 5,
Table 1). When the reaction was made with 1 equiv of
diethylaluminum cyanide in the presence of 1 equiv of
diethylaluminum chloride an identical lack of selectivity
was found. These results support the possibility of
diethylaluminum cyanide acting both as a cyanide equiva-
lent and as a chelating agent (see below). Precomplex-
ation of 1 with diethylaluminum chloride had little effect
upon the addition of other cyanide reagents like tetrabu-
tylammonium cyanide (entry 9, Table 1) or lithium
cyanide (entry 11, Table 1).
Since better and more interesting results were ob-
tained with trimethylsilyl cyanide and diethylaluminum
cyanide we examined them in greater detail with other
nitrones. In all the substrates tested thus far the syn
R-(hydroxyamino) nitriles were obtained as major ad-
ducts. When trimethylsilyl cyanide was used in dichlo-
romethane the corresponding O-(trimethylsilyl) deriva-
tives were obtained22 (entries 12, 17, 22, 29, Table 1).
Again, the use of diethylaluminum chloride as additive
(entry 28, Table 1) or an excess of diethylaluminum
cyanide (entry 21, Table 1) led to a considerable decrease
in the diastereoselectivity. For the L-serine-derived
nitrone 7, >95% diastereoselectivity toward the syn
adduct was achieved in all cases (entries 29-32, Table
1). It is notable that, regardless of the level of the
diastereofacial selectivity, excellent yields were consis-
tently observed for all nitrones tested.
F igu r e 1. Proposed model for the addition of cyanide reagents
to nitrones.
paper,17 the possibility that diethylaluminum cyanide can
act like both a cyanide transfer reagent and a chelating
agent, leading to internal and/or external cyanide deliv-
ery, respectively, makes the above interpretation rather
speculative, and other possibilities to explain the results
may exist.
In conclusion, we have described a stereoselective entry
to novel optically active R-(hydroxyamino) nitriles. The
addition of both trimethylsilyl cyanide and diethylalu-
minum cyanide to chiral nitrones proceeds with good to
excellent diastereoselectivity and very high yields (quan-
titative in some cases). Further studies on the synthetic
utility of the prepared R-(hydroxyamino) nitriles for their
use as starting materials in the preparation of R-amino
nitriles and R-(hydroxyamino) acids are ongoing and will
be published in due course.
The configurational assignment of syn and anti R-(hy-
droxyamino) nitriles 9-21 was based on X-ray structural
analyses of the adducts anti-10b anti-12b, anti-15b, and
syn-20a , which confirmed the stereochemical outcome of
the addition to nitrones 1, 2, 4, and 7, respectively.23 The
configurational assignments of the other adducts were
Exp er im en ta l Section
Gen er a l Meth od s. For general experimental information see
ref 27. Nitrones 1-8 were prepared as described.11b Trimeth-
ylsilyl cyanide was purchased from Aldrich (98%) and used
without further purification. Diethylaluminum cyanide was
prepared from diethylaluminum chloride (Aldrich) and trimeth-
ylsilyl cyanide as described,21 and accompanying trimethylsilyl
chloride was removed under reduced pressure in the absence of
moisture; in one case (Table 1, entry 15), diethylaluminum
cyanide was used in toluene from a 1.0 M commercial solution.
Tetrabutylaluminum cyanide was prepared by treating a solu-
tion of trimethylsilyl cyanide in dichloromethane with anhydrous
tetrabutylammonium fluoride. Lithium cyanide was prepared
by treating a solution of trimethylsilyl cyanide in dichlo-
romethane with a 1.6 M solution of butyllithium in hexanes.
P r ecom p lexa tion of Nitr on es. When trimethylsilyl chlo-
ride or diethylaluminum chloride was used as additive a solution
of the nitrone (1 mmol) in the corresponding solvent (Table 1)
was treated at ambient temperature with 1.0 equiv of the
additive. The resulting mixture was stirred for 5 min at ambient
temperature prior to the addition of the cyanide reagent.
Typ ica l P r oced u r e for th e Ad d ition of Cya n id e Re-
a gen ts to Nitr on es. To a solution of nitrone (1 mmol) in the
solvent (25 mL) and at the temperature indicated in Table 1
was added the corresponding cyanide reagent (see Table 1 for
equivalents). The reaction was kept at the indicated tempera-
ture for the given time (see Table 1). The reaction mixture was
then quenched by the addition of either 1 N NaOH (15 mL)
(when diethylaluminum cyanide or diethylaluminum chloride
was used) or brine (15 mL). Dichloromethane (10 mL) was
added, and the organic layer was separated. The aqueous layer
was extracted twice with dichloromethane (20 mL), and the
1
made on the basis of analogy, since the H and 13C NMR
data did not allow for general rules regarding the
configurational assignment. It is noteworthy that in all
cases the Rf value (TLC) of the major diastereomer (syn
adduct) was larger than that of the minor diastereomer
(anti adduct). Similar behavior has been previously
observed by Reetz and co-workers for amino alcohols and
diamines.5d
The observed sense of the diastereoselectivity conforms
to our previously proposed model12 A, similar to that
invoked by Houk for asymmetric addition to double
bonds.24 This model has been further supported for
R-alkoxy nitrones by semiempirical calculations made for
nitrone 1.25 In the case of R-amino nitrones 7 and 8 both
chemical and structural observations led to the same
model.26 However, as we pointed out in our preliminary
(22) Compounds 11 and 13 could not be separated, and they were
isolated and characterized as the corresponding R-(hydroxyamino)
nitriles 12 and 14, respectively. In addition, compounds anti-16b and
anti-17b could not be isolated as single diastereoisomers.
(23) The authors have deposited atomic coordinates, bond lengths,
and angles for structures anti-10b, anti-11b, anti-13b, and syn-18a
with the Cambridge Crystallographic Data Centre. The data can be
obtained, upon request, from the Director, Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
(24) Houk, K. N.; Paddon-Row, N. M.; Rondan, N. G.; Wu, Y. D.;
Brown, F. K.; Spellmeyer, D. C.; Metz, J . T.; Li, Y.; Loncharich, R. J .
Science 1986, 231, 1108-1117.
(26) Lanaspa, A.; Merchan, F. L.; Merino, P.; Tejero, T.; Dondoni,
A. Electronic Conference on Trends in Organic Chemistry (ECTOC-1)
[CD-ROM]; Rzepa, H. S., Goodman, J . G., Eds.; Royal Society of
Chemistry Publications: London, 1995.
(27) J unquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. Tetrahedron
1996, 52, 7045-7052.
(25) Merchan, F. L.; Merino, P.; Tejero, T. THEOCHEM 1996, in
press.

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9031
combined organic extracts were washed with brine, dried over
magnesium sulfate, and evaporated under reduced pressure to
yield the crude product, which was purified by column chroma-
tography. Both the diastereoselectivities (measured from the
isolated mixture of diastereomers by 1H NMR) and the chemical
yields are given in Table 1.
ane-diethyl ether, Rf 0.19): oil; [R]D -12.3° (c 0.33, CHCl3); 1H
NMR δ 0.10 (s, 3H), 0.15 (s, 3H), 0.90 (s, 9H), 1.24 (d, 3H, J )
6.3 Hz), 3.38 (d, 1H, J ) 8.6 Hz), 3.85 (d, 1H, J ) 12.7 Hz), 4.06
(dq, 1H, J ) 8.6, 6.3 Hz), 4.12 (d, 1H, J ) 12.7 Hz), 5.62 (bs, 1H,
ex. D2O), 7.30-7.38 (m, 5H); 13C NMR δ -6.7, -6.3, 21.1, 22.4,
25.5, 62.9, 66.0, 67.6, 116.0, 127.8, 128.4, 129.2, 135.5. Anal.
Calcd for C17H28N2O2Si: C, 63.71; H, 8.81; N, 8.74. Found: C,
63.54; H, 8.67; N, 8.65.
N-Ben zyl-1-cya n o-1-d eoxy-1-((t r im et h ylsiloxy)a m in o)-
2,3-O-isop r op ylid en e-D-th r eo-tr iitol (syn -9a ) (90:10 hexane-
diethyl ether, Rf 0.31): oil; [R]D -43.4° (c 1.1, CHCl3); 1H NMR
(55 °C) δ 0.21 (s, 9H), 1.29 (s, 3H), 1.31 (s, 3H), 3.76 (d, 1H, J )
5.6 Hz), 3.96 (d, 1H, J ) 12.7 Hz), 4.03 (dd, 1H, J ) 9.3, 6.1
Hz), 4.10 (dd, 1H, J ) 9.3, 6.1 Hz), 4.20 (d, 1H, J ) 12.7 Hz),
4.25 (pseudo q, 1H, J ) 6.1 Hz), 7.29-7.38 (m, 5H); 13C NMR
(55 °C) δ -0.2, 25.2, 26.4, 61.4, 63.6, 67.2, 74.2, 109.7, 114.7,
128.4, 128.8, 129.4, 134.7. Anal. Calcd for C17H26N2O3Si: C,
61.04; H, 7.84; N, 8.37. Found: C, 60.82; H, 8.09; N, 8.40.
N-Ben zyl-1-cya n o-1-d eoxy-1-((t r im et h ylsiloxy)a m in o)-
2,3-O-isop r op ylid en e-D-er yth r o-tr iitol (a n ti-9b) (90:10 hex-
ane-diethyl ether, Rf 0.22): oil; [R]D +35.9° (c 0.76, CHCl3); 1H
NMR (55 °C) δ 0.09 (s, 9H), 1.30 (s, 3H), 1.34 (s, 3H), 3.55 (d,
1H, J ) 8.1 Hz), 3.78 (dd, 1H, J ) 8.9, 4.2 Hz), 3.94 (d, 1H, J )
12.7 Hz), 3.95 (dd, 1H, 8.9, 5.9 Hz), 4.14 (d, 1H, J ) 12.7 Hz),
4.21 (ddd, 1H, J ) 8.1, 5.9, 4.2 Hz), 7.29-7.36 (m, 5H); 13C NMR
(55 °C) δ -0.4, 25.0, 26.9, 61.3, 64.0, 67.0, 72.5, 110.5, 115.2,
128.4, 128.8, 129.6, 134.8. Anal. Calcd for C17H26N2O3Si: C,
61.043; H, 7.84; N, 8.37. Found: C, 61.23; H, 7.95; N, 8.70.
N-Ben zyl-1-cya n o-1-d eoxy-1-(h yd r oxya m in o)-2,3-O-iso-
p r op ylid en e-D-th r eo-tr iitol (syn -10a ) (60:40 hexane-diethyl
ether, Rf 0.33): white solid; mp 116 °C; [R]D -34.8° (c 0.87,
CHCl3); 1H NMR δ 1.30 (s, 3H), 1.32 (s, 3H), 3.75 (d, 1H, J )
7.1 Hz), 3.91 (d, 1H, J ) 12.5 Hz), 4.02 (dd, 1H, J ) 9.5, 4.6
Hz), 4.12 (dd, 1H, J ) 9.5, 6.1 Hz), 4.19 (d, 1H, J ) 12.5 Hz),
4.42 (ddd, 1H, J ) 7.1, 6.1, 4.6 Hz), 6.26 (bs, 1H, ex. D2O), 7.33-
7.36 (m, 5H); 13C NMR δ 25.4, 26.5, 61.0, 63.3, 67.0, 74.0, 110.3,
114.4, 128.4, 128.8, 129.6, 134.7. Anal. Calcd for C14H18N2O3:
C, 64.11; H, 6.92; N, 10.68. Found: C, 64.34; H, 6.80; N, 10.42.
N-Ben zyl-1-cya n o-1-d eoxy-1-(h yd r oxya m in o)-2,3-O-iso-
p r op ylid en e-D-er yth r o-tr iitol (a n ti-10b) (60:40 hexane-di-
ethyl ether, Rf 0.26): transparent plates; mp 139 °C; [R]D +8.6°
(c 0.80, CHCl3); 1H NMR δ 1.33 (s, 3H), 1.43 (s, 3H), 3.58 (d,
1H, J ) 7.9 Hz), 3.84 (d, 1H, J ) 12.6 Hz), 3.94 (dd, 1H, J )
9.2, 4.0 Hz), 4.04 (dd, 1H, J ) 9.2, 5.9 Hz), 4.14 (d, 1H, J ) 12.6
Hz), 4.42 (ddd, 1H, J ) 7.9, 5.9, 4.0 Hz), 5.39 (bs, 1H, ex. D2O),
7.33 (bs, 5H); 13C NMR δ 25.1, 26.8, 61.9, 63.1, 67.0, 74.2, 110.8,
115.0, 128.2, 128.7, 129.5, 135.3. Anal. Calcd for C14H18N2O3:
C, 64.11; H, 6.92; N, 10.68. Found: C, 63.84; H, 7.11; N, 10.91.
N-Ben zyl-2-O-ben zyl-1-cyan o-1,3-dideoxy-1-(h ydr oxyam i-
n o)-L-th r eo-tr iitol (syn -12a ) (90:10 hexane-diethyl ether, Rf
0.18): oil; [R]D +5.3° (c 0.9, CHCl3); 1H NMR δ 1.37 (d, 3H, J )
6.3 Hz), 3.69 (d, 1H, J ) 6.5 Hz), 3.84 (d, 1H, J ) 12.8 Hz), 3.91
(pseudo quintuplet, 1H, J ) 6.4 Hz), 4.15 (d, 1H, J ) 12.8 Hz),
4.56 (d, 1H, J ) 11.7 Hz), 4.64 (d, 1H, J ) 11.7 Hz), 5.04 (bs,
1H, ex. D2O), 7.26-7.39 (m, 10H); 13C NMR δ 17.5, 62.7, 63.8,
71.7, 73.2, 115.2, 127.9, 127.9, 128.4, 128.6, 128.6, 129.3, 135.7,
137.6. Anal. Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45.
Found: C, 72.78; H, 6.68; N, 9.80.
3-O-Acetyl-N-ben zyl-5-cya n o-5-d eoxy-5-(h yd r oxya m in o)-
1,2-O-isop r op ylid en e-â-L-id o-1,4-p en tofu r a n osid e (syn -15a )
(40:60 hexane-diethyl ether, Rf 0.38): white solid; mp 94 °C;
[R]D -31.4° (c 1.60, CHCl3); 1H NMR δ 1.27 (s, 3H), 1.47 (s, 3H),
2.08 (s, 3H), 3.87 (d, 1H, J ) 12.7 Hz), 4.02 (d, 1H, J ) 8.0 Hz),
4.12 (d, 1H, J ) 12.7 Hz), 4.50 (d, 1H, J ) 3.7 Hz), 4.62 (dd, 1H,
J ) 5.9, 3.1 Hz), 5.12 (d, 1H, J ) 3.1 Hz), 5.62 (bs, 1H, ex. D2O),
5.89 (d, 1H, J ) 3.7 Hz), 7.29-7.38 (m, 5H); 13C NMR δ 20.4,
25.9, 26.4, 57.6, 62.9, 76.0, 76.3, 82.7, 104.6, 112.5, 113.8, 127.9,
128.4, 129.4, 135.1, 169.4. Anal. Calcd for C18H22N2O6: C,
59.66; H, 6.12; N, 7.63. Found: C, 59.60; H, 6.30; N, 7.94.
3-O-Acetyl-N-ben zyl-5-cya n o-5-d eoxy-5-(h yd r oxya m in o)-
1,2-O-isop r op ylid en e-r-D-glu co-1,4-p en tofu r a n osid e (a n ti-
15b) (40:60 hexane-diethyl ether, Rf 0.31): transparent blocks;
1
mp 136 °C; [R]D -67.8° (c 1.8, CHCl3); H NMR δ 1.27 (s, 3H),
1.49 (s, 3H), 1.80 (s, 3H), 3.85 (d, 1H, J ) 8.7 Hz), 3.90 (d, 1H,
J ) 12.5 Hz), 4.20 (d, 1H, J ) 12.5 Hz), 4.39 (d, 1H, J ) 3.6 Hz),
4.64 (dd, 1H, J ) 8.7, 2.9 Hz), 5.30 (d, 1H, J ) 2.9 Hz), 5.84 (bs,
1H, ex. D2O), 5.88 (d, 1H, J ) 3.6 Hz), 7.29-7.35 (m, 5H); 13C
NMR δ 20.6, 26.1, 26.62, 56.5, 63.1, 74.8, 77.0, 82.7, 104.9, 112.7,
114.6, 128.2, 128.8, 129.7, 134.8, 169.6. Anal. Calcd for
C
18H22N2O6: C, 59.66; H, 6.12; N, 7.63. Found: C, 59.62; H,
5.83; N, 7.89.
N-Ben zyl-4-O-b en zyl-1-cya n o-1-d eoxy-1-((t r im et h ylsil-
oxy)a m in o)-2,3-O-isop r op ylid en e-L-xylo-tetr itol (syn -16a )
(80:20 hexane-diethyl ether, Rf 0.39): oil; [R]D -27.6° (c 0.32,
1
CHCl3); H NMR (55 °C) δ -0.22 (s, 9H), 1.54 (s, 3H), 1.57 (s,
3H), 3.69 (dd, 1H, J ) 10.7, 4.8 Hz), 3.76 (dd, 1H, J ) 10.7, 3.1
Hz), 3.93 (d, 1H, J ) 13.1 Hz), 4.12-4.21 (m, 3H), 4.26 (d, 1H,
J ) 6.8 Hz), 4.61 (ABq, 2H, J ) 12.7 Hz, ∆δ ) 0.042), 7.20-
7.36 (m, 10H); 13C NMR (55 °C) δ -0.4, 27.0, 27.5, 62.4, 63.2,
70.2, 73.6, 74.4, 78.6, 110.5, 114.6, 127.6, 127.8, 128.1, 128.3,
128.5, 129.7, 135.5, 138.1. Anal. Calcd for C25H34N2O4Si: C,
66.0; H, 7.54; N, 6.16. Found: C, 66.34; H, 7.19; N, 6.38.
N-Ben zyl-4-O-ben zyl-1-cyan o-1-deoxy-1-(h ydr oxyam in o)-
2,3-O-isop r op ylid en e-L-xylo-tetr itol (syn -17a ) (80:20 hex-
ane-diethyl ether, Rf 0.14): oil; [R]D -14.3° (c 1.84, CHCl3); 1H
NMR δ 1.36 (s, 3H), 1.40 (s, 3H), 3.58 (dd, 1H, J ) 9.7, 6.9 Hz),
3.78 (dd, 1H, J ) 9.7, 5.9 Hz), 3.87 (d, 1H, J ) 12.7 Hz), 3.97 (d,
1H, J ) 5.1 Hz), 4.20 (d, 1H, J ) 12.7 Hz), 4.25 (dd, 1H, J )
6.6, 5.1 Hz), 4.48 (pseudo dt, 1H, J ) 6.8, 5.9 Hz), 4.57 (s, 2H),
6.90 (bs, 1H, ex. D2O), 7.30-7.40 (m, 10H); 13C NMR δ 26.9,
27.2, 61.4, 62.9, 71.2, 73.8, 76.6, 78.8, 110.1, 114.7, 127.9, 128.1,
128.6, 128.7, 129.3, 129.5, 135.4, 136.9. Anal. Calcd for
C
22H26N2O4: C, 69.09; H, 6.85; N, 7.32. Found: C, 68.97; H,
6.65; N, 7.26.
N-Ben zyl-4-O-(ter t-bu tyld im eth ylsilyl)-1-cya n o-1-d eoxy-
1-(h ydr oxyam in o)-2,3-O-isopr opyliden e-L-xylo-tetr itol (syn -
18a ) (80:20 hexane-diethyl ether, Rf 0.22): oil; [R]D -12.7° (c
N-Ben zyl-2-O-ben zyl-1-cyan o-1,3-dideoxy-1-(h ydr oxyam i-
n o)-L-er yth r o-tr iitol (a n ti-12b) (90:10 hexane-diethyl ether,
Rf 0.12): white crystals; mp 95 °C; [R]D -16.8° (c 1.10, CHCl3);
1H NMR δ 1.29 (d, 3H, J ) 6.2 Hz), 3.53 (d, 1H, J ) 8.4 Hz),
3.89 (d, 1H, J ) 12.7 Hz), 3.95 (dq, 1H, J ) 8.4, 6.2), 4.19 (d,
1H, J ) 12.7 Hz), 4.60 (d, 1H, J ) 11.2 Hz), 4.65 (d, 1H, J )
11.2 Hz), 4.99 (s, 1H, ex. D2O), 7.26-7.39 (m, 10H); 13C NMR δ
17.4, 63.1, 64.0, 72.1, 74.3, 115.7, 127.9, 128.0, 128.1, 128.5,
128.7, 129.4, 135.5, 137.5. Anal. Calcd for C18H20N2O2: C,
72.95; H, 6.80; N, 9.45. Found: C, 73.08; H, 7.08; N, 9.57.
N-Ben zyl-2-O-(ter t-bu tyld im eth ylsilyl)-1-cya n o-1,3-d id e-
oxy-1-(h yd r oxya m in o)-L-th r eo-tr iitol (syn -14a ) (95:5 hex-
1
2.10, CHCl3); H NMR δ 0.06 (s, 3H), 0.07 (s, 3H), 0.86 (s, 9H),
1.34 (s, 3H), 1.42 (s, 3H), 3.65 (dd, 1H, J ) 10.0, 8.2 Hz), 3.85
(d, 1H, J ) 12.6 Hz), 3.94 (dd, 1H, J ) 10.0, 4.0 Hz), 4.11 (d,
1H, J ) 4.6 Hz), 4.19 (d, 1H, J ) 12.6 Hz), 4.21 (dd, 1H, J )
6.6, 4.6 Hz), 4.48 (ddd, 1H, J ) 8.2, 6.6, 4.0 Hz), 7.09 (bs, 1H,
ex. D2O), 7.19-7.32 (m, 5H); 13C NMR δ -5.8, -5.8, 22.6, 25.7,
26.9, 27.2, 61.3, 62.7, 65.3, 77.3, 79.6, 109.8, 114.7, 127.98, 128.5,
129.5, 135.3. Anal. Calcd for C21H34N2O4Si: C, 62.03; H, 8.43;
N, 6.89. Found: C, 62.18; H, 8.24; N, 6.72.
N-Ben zyl-4-O-(ter t-bu tyld im eth ylsilyl)-1-cya n o-1-d eoxy-
1-(h ydr oxyam in o)-2,3-O-isopr opyliden e-L-lyxo-tetr itol (a n ti-
18b) (80:20 hexane-diethyl ether, Rf 0.19): oil; [R]D +3.7° (c
1
ane-diethyl ether, Rf 0.21): oil; [R]D +4.1° (c 0.21, CHCl3); H
1
NMR δ 0.07 (s, 3H), 0.11 (s, 3H), 0.88 (s, 9H), 1.31 (d, 3H, J )
6.3 Hz), 3.54 (d, 1H, J ) 5.2 Hz), 3.82 (d, 1H, J ) 12.7 Hz), 4.15
(dq, 1H, J ) 6.3, 5.2 Hz), 4.19 (d, 1H, J ) 12.7 Hz), 5.50 (bs, 1H,
ex. D2O), 7.28-7.40 (m, 5H); 13C NMR δ -6.5, -6.5, 20.8, 22.4,
25.5, 62.68, 54.6, 68.2, 115.7, 127.8, 128.4, 129.2, 135.5. Anal.
Calcd for C17H28N2O2Si: C, 63.71; H, 8.81; N, 8.74. Found: C,
63.78; H, 8.54; N, 8.99.
1.75, CHCl3); H NMR δ 0.03 (s, 3H), 0.05 (s, 3H), 0.85 (s, 9H),
1.37 (s, 3H), 1.44 (s, 3H), 3.70 (dd, 1H, J ) 10.0, 3.2 Hz), 3.73
(d, 1H, J ) 7.6 Hz), 3.89 (d, 1H, J ) 12.6 Hz), 3.98 (dd, 1H, J )
10.0, 3.4 Hz), 4.06 (pseudo dt, 1H, J ) 7.8, 3.3 Hz), 4.22 (d, 1H,
J ) 12.6 Hz), 4.38 (pseudo t, 1H, J ) 7.7 Hz), 6.40 (bs, 1H, ex.
D2O), 7.29-7.38 (m, 5H); 13C NMR δ -5.6, -5.5, 22.7, 25.8, 26.8,
27.1, 61.8, 61.9, 65.8, 78.5, 78.6, 110.4, 115.3, 128.37, 128.7,
129.4, 135.4. Anal. Calcd for C21H34N2O4Si: C, 62.03; H, 8.43;
N, 6.89. Found: C, 61.72; H, 8.53; N, 6.83.
N-Ben zyl-2-O-(ter t-bu tyld im eth ylsilyl)-1-cya n o-1,3-d id e-
oxy-1-(h yd r oxya m in o)-L-er yth r o-tr iitol (a n ti-14b) (95:5 hex-

9032 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
1,1-Dim eth yleth yl [R-(R)]-4-[(N-ben zyl-N-(tr im eth ylsil-
oxy)a m in o)cya n om et h yl]-2,2-d im et h yl-3-oxa zolid in eca r -
boxyla te (syn -19a ) (90:10 hexane-diethyl ether, Rf 0.19): white
solid; mp 48 °C; [R]D -8.2° (c 1.80, CHCl3); 1H NMR (DMSO-d6,
110 °C) δ 0.12 (s, 9H), 1.35 (s, 9H), 1.46 (s, 3H), 1.57 (s, 3H),
3.96 (d, 1H, J ) 13.0 Hz), 4.07-4.19 (m, 3H), 4.16 (d, 1H, J )
17.6, 28.3, 46.3, 61.3, 65.0, 80.8, 115.7, 127.6, 128.4, 128.7, 136.2,
157.3. Anal. Calcd for C16H23N3O3: C, 62.93; H, 7.59; N, 13.76.
Found: C, 62.63; H, 7.30; N, 13.73.
(2R,3S)-2-(N-Ben zyl-N-h yd r oxya m in o)-3-((ter t-b u t oxy-
ca r bon yl)a m in o)bu ta n en itr ile (a n ti-21b) (80:20 hexane-
diethyl ether, Rf 0.06): white solid; mp 187 °C; [R]D -86.5° (c
13.0 Hz), 4.24 (dd, 1H, J ) 8.7, 1.3 Hz), 7.28-7.35 (m, 5H); 13
C
1
0.33, CHCl3); H NMR δ 1.29 (d, 3H, J ) 6.8 Hz), 1.43 (s, 9H),
NMR (DMSO-d6, 90 °C) δ -0.3, 23.3, 26.6, 27.8, 58.2, 60.8, 63.2,
65.3, 80.4, 93.6, 115.3, 128.1, 128.5, 129.8, 135.1, 151.4. Anal.
Calcd for C22H35N3O4Si: C, 60.94; H, 8.15; N, 9.69. Found: C,
61.10; H, 8.43; N, 9.67.
3.54 (d, 1H, J ) 3.7 Hz), 3.85 (d, 1H, J ) 13.7 Hz), 4.30 (m, 1H),
4.33 (d, 1H, J ) 13.7 Hz), 4.75 (d, 1H, J ) 9.5 Hz), 7.01 (bs, 1H,
ex. D2O), 7.29-7.40 (m, 5H); 13C NMR δ 17.7, 46.3, 61.8, 65.0,
80.9, 115.9, 127.6, 128.3, 129.0, 136.3, 156.9. Anal. Calcd for
1,1-Dim eth yleth yl [R-(R)]-4-[1-(N-ben zyl-N-h yd r oxya m i-
n o)cya n om et h yl]-2,2-d im et h yl-3-oxa zolid in eca r b oxyla t e
(syn -20a ) (80:20 hexane-diethyl ether, Rf 0.23): transparent
blocks; mp 154 °C; [R]D +20.0° (c 0.99, CHCl3); 1H NMR (55 °C)
δ 1.29 (s, 3H), 1.47 (s, 3H), 1.52 (s, 9H), 3.56 (d, 1H, J ) 9.8
Hz), 3.85 (d, 1H, J ) 13.0 Hz), 3.92 (d, 1H, J ) 10.0 Hz), 4.00
(dd, 1H, J ) 10.0, 4.7 Hz), 4.25 (d, 1H, J ) 13.0 Hz), 4.40 (dd,
1H, J ) 9.8, 4.7 Hz), 7.25-7.39 (m, 5H), 7.69 (bs, 1H, ex. D2O);
13C NMR (55 °C) δ 24.5, 27.3, 28.3, 57.2, 61.1, 61.7, 65.2, 81.9,
95.0, 115.5, 127.8, 128.5, 129.0, 136.1, 154.2. Anal. Calcd for
C
16H23N3O3: C, 62.93; H, 7.59; N, 13.76. Found: C, 62.69; H,
7.53; N, 13.64.
Ack n ow led gm en t . Support from MEC (Project
PB94-0598, Madrid, Spain) is gratefully acknowledged.
A.L. thanks the DGA (Aragon, Spain) for a predoctoral
fellowship. The authors are also indebted to Dr. J . A.
Lopez (ICMA, Aragon) for his invaluable assistance in
obtaining X-ray data during some of this work.
C
19H27N3O4: C, 63.14; H, 7.53; N, 11.63. Found: C, 63.16; H,
7.74; N, 11.88.
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagrams
of anti-10b, anti-12b, anti-15b, and syn-20a (4 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
(2S,3S)-2-(N-Ben zyl-N-h yd r oxya m in o)-3-((ter t-b u t oxy-
ca r bon yl)a m in o)bu ta n en itr ile (syn -21a ) (80:20 hexane-
diethyl ether, Rf 0.12): white solid; mp 170 °C; [R]D +3.3° (c 1.23,
1
CHCl3); H NMR δ 1.34 (d, 3H, J ) 6.8 Hz), 1.46 (s, 9H), 3.15
(d, 1H, J ) 10.0 Hz), 3.84 (d, 1H, J ) 13.1 Hz), 4.10 (ddq, 1H, J
) 10.0, 9.3, 6.8 Hz), 4.21 (d, 1H, J ) 13.1 Hz), 4.41 (d, 1H, J )
9.3 Hz), 7.28-7.35 (m, 5H), 7.38 (bs, 1H, ex. D2O); 13C NMR δ
J O961293A