Stereoselective cyanosilylation of α-sulfinylketimines or its covalently stabilized enamine tautomers. Synthesis of enantiomerically pure α-sulfinylmethyl-α-amino nitriles

Article abstract of DOI:10.1016/S0040-4020(02)00234-X

α-Sulfinylketimines and β-sulfinylenamines undergo reaction with delivery cyanide reagents such as TMSCN or TBDMSCN in the presence of either stoichiometric excesses of ZnCl₂ or ZnBr₂, or catalytic amount of Yb(TfO)₃. The use of ZnCl₂ in alcohol solvents provides the best diastereoselectivity. It is mediated by a chelated transition state, the p-tolyl group driving the anti attack of the reagent. By using Yb(TfO)₃ poor diastereoselectivities but good yields are obtained. It seems that an iminium derivative originated by metal coordination with either the nitrogen or oxygen atom in the substrate is responsible for the observed results. Interestingly, β-sulfinylenamines provide analogous α-amino nitriles in the same reaction conditions. It allowed the cyanosilylation of the covalently stabilized enamines arising from unstable β-sulfinyl aldehydes.

Full text of DOI:10.1016/S0040-4020(02)00234-X

TETRAHEDRON
Pergamon
Tetrahedron 58 72002) 3217±3227
Stereoselective cyanosilylation of a-sul®nylketimines or its
covalently stabilized enamine tautomers. Synthesis of
enantiomerically pure a-sul®nylmethyl-a-amino nitriles
Hassan Acherki,a Carlos Alvarez-Ibarra,a,p Alfonso-de-Diosb and Maria L. Quirogaa
a
  Â
Facultad de Ciencias Quõmicas, Departamento de Quõmica Organica, Universidad Complutense,
Ciudad Universitaria, 28040 Madrid, Spain
Â
Eli Lilly & Co, Departamento de Investigacion Lilly S. A. Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain
b
Received 19October 2001; revised 31 January 2002; accepted 28 February 2002
AbstractÐa-Sul®nylketimines and b-sul®nylenamines undergo reaction with delivery cyanide reagents such as TMSCN or TBDMSCN in
the presence of either stoichiometric excesses of ZnCl2 or ZnBr2, or catalytic amount of Yb7TfO)3. The use of ZnCl2 in alcohol solvents
provides the best diastereoselectivity. It is mediated by a chelated transition state, the p-tolyl group driving the anti attack of the reagent. By
using Yb7TfO)3 poor diastereoselectivities but good yields are obtained. It seems that an iminium derivative originated by metal coordination
with either the nitrogen or oxygen atom in the substrate is responsible for the observed results. Interestingly, b-sul®nylenamines provide
analogous a-amino nitriles in the same reaction conditions. It allowed the cyanosilylation of the covalently stabilized enamines arising from
unstable b-sul®nyl aldehydes. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
benzylamine 7S-a-MBA) and NaCN, is a convenient
method for the synthesis of proteinogenous and non-
proteinogeneous a-amino acids.6 Since then, numerous
modi®cations of Harada's experimental protocol have
been described7 which can be classi®ed into the following
three categories:
Chiral a-sul®nylketimines have shown to be useful eno-
lizable synthons. The regio- and diastereoselectivity of the
addition reactions of its aza-enolates derivatives to b-substi-
tuted ene-esters are controlled by the chiral sul®nyl moiety.
The synthetic utility of these processes has been developed
by us to achieve 4,6-disubstituted 5-7p-tolylsul®nyl)-5,6-
dehydropiperidin-2-ones with high yields and entire dia-
stereoselectivity.1,2 The easy reductive ®ssion of the C±S
bond with Raney Nickel, and further in situ hydrogenation
of the CvC bond, originates enantiomerically pure
4,6-disubstituted d-lactams which display a high synthetic
utility.3,4 In a different way, the a-sul®nylketimines can be
turned into chiral a-sul®nylmethyl-a-amino nitriles with
different cyanation reagents as TMSCN or TBDMSCN in
the presence of Lewis acids as catalysts in a like-Strecker
reaction. The subsequent oxidative hydrolysis and reductive
®ssion of the C±S bond affords a-amino acid derivatives
7Scheme 1).
7i) The use of other suitable cyanide sources as TMSCN8
or diethyl phosphorocyanidate.9
7ii) The employment of the most widely applied chiral
auxiliary, a-MBA, as well as further arylalkylamines
like a-tertbutylbenzylamine, and a-ethylbenzylamine,10
a-phenylglycinol,11 N-benzylphenylglycinol,12 and aryl
sul®nimines.13
7iii) The introduction of chiral catalytic systems to
achieve high selectivities from metal salts and chiral
ligands.14
In this work, we have explored the application of the
methodology described by Garcia-Ruano et al.15 for the
In fact, the asymmetric Strecker synthesis that was
described for the ®rst time by Harada5 for the preparation
of l-alanine starting from acetaldehyde, 7S)-a-methyl-
Keywords: cyanosilylation; a-sul®nylketimines; b-sul®nylenamines; dia-
stereoselective synthesis; chiral sulfoxides; Lewis acid; Strecker reaction;
a-amino acids derivatives; b-sul®nyl-a-amino nitriles.
p
Corresponding author. Tel.: 134-91-394-4223; fax: 134-91-394-4103;
e-mail: caibarra@quim.ucm.es
Scheme 1.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020702)00234-X

3218
H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
Scheme 3.
Chart 1.
diastereoselective synthesis of a-cyanhydrins derived from
chiral b-ketosulfoxides to chiral a-sul®nylketimines 1 and 2
7Chart 1), in order to achieve chiral a-amino acids deriva-
tives with a quaternary asymmetric carbon 7Scheme 1).
Furthermore, the behavior of the chiral b-sul®nylenamine
3 derived from unstable aldimine 4 has been investigated
in the same reaction conditions. It will allow us to spread
out the experimental protocol to other unstable aldimines
which can be easily derivatized to b-sul®nylenamines to
accomplish its tautomeric stabilization.
fenylated derivative originated by reduction was the sole
isolated product.
Taking into account that the cyanide addition to imines is a
reversible process,20 the a-amino nitriles could be con-
®gurationally unstable in solution. Hence, some previous
experiments to ensure a kinetic control were performed.
Thus, the cyanosilylation reagents 7TMSCN and
TBDMSCN) in the presence of catalytic amounts of
Yb7TfO)3 or stoichiometric ones of ZnCl2 were used. The
most reliable results were achieved in CH2Cl2 as solvent by
using Yb7TfO3), whereas different solvents 7THF or ROH)
and relative excesses of cyanosilylation reagent and catalyst
had to be used for each substrate when ZnCl2 was used. By
mixing the reagents at 08C for 30 min, and leaving the
reaction mixture to stand at room temperature for 6±12 h,
the stereoselectivity appeared to be unchanged into the
limits that the conversion was modi®ed.
2. Results and discussion
The compound 1 was obtained from 1-phenylethyliden
74-methoxyphenyl) azane and 72)-7SS)-menthyl p-toluene-
sul®nate 5 7ee.98%) following the procedure described by
Garcia-Ruano et al.16 The compound 2 was prepared from
2-oxazoline 6 following a similar procedure 7Scheme 2).17
In both cases, the reaction occurs with an entire inversion of
the chiral sulfur con®guration.18
Additional experiments on the work up of the reactions were
also needed to make in order to prove the stability of the
adducts. Thus, hydrolysis of reaction mixture at 08C with
saturated NH4Cl solution showed to be the best method
when ZnCl2 was used. On the other hand, addition of a
saturated Na2CO3 solution to the reaction mixture obtained
in the presence of Yb7TfO)3 at 08C was the selected method.
The puri®cation of reaction mixtures was carried out by
¯ash chromatography on silica gel. The a-sul®nylmethyl-
a-amino nitriles become stables during their handling and
standing at 258C for two months. However, the derivati-
zation to a-sulfonylmethyl-a-amino carboxamides is
strongly recommended to prevent their decomposition
such as it has been made in one of the cases 7vide infra).
The compound 3 was accomplished from mesylate 8 and
dibenzylamine, whereas the derivative 8 was accessible
from 71)-7RS)-methyl p-tolylsulfoxide such as it is outlined
in Scheme 3.19 The intermediate compounds 7 and 8 were
transformed without previous isolating, and the compound 3
was obtained in a 58.5% overall yield.
The E-con®guration of the double bond of the compound
72)-3 was con®dently assigned from the observed vicinal
coupling constant for vinyl hydrogens 73Jˆ13.2 Hz).
Preliminary hydrocyanation essays with diethylaluminium
cyanide in the presence of ZnCl2 using the reaction con-
ditions previously described by Davis13c and by Garcia-
Ruano15a 7normal and inverse addition of the reagents,
respectively) on the compounds 1±3 were carried out. In
all the cases the results were unsuccessful since the sul-
2.1. Cyanosilylation reactions of compound &2)-1
The observed results in the cyanation reactions of 72)-1
with TMSCN and TBDMSCN in the presence of ZnCl2 or
Yb7TfO)3 710 mol%) have been collected in Table 1. The
mixtures of a-amino nitriles 9a and 9b were isolated by
¯ash chromatography on silica gel 7hexanes/ethyl acetate:
2:1) of the remaining a-sul®nylketimine 72)-1 and 7R)-[74-
methylphenyl)sul®nyl]-1-phenylethanone which was origi-
nated by hydrolysis of 72)-1. The separation of a-amino
nitriles 9a and 9b was carried out by ¯ash chromatography
on silica gel 7hexanes/ethyl acetate: 4:1±2:1) from enriched
mixtures of these isomers. Diastereomeric ratio was deter-
1
mined by H NMR analysis 7200 MHz) of the reaction
Scheme 2.

H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
Table 1. Cyanosilylation reactions of compound 72)-1
3219
Entry
XCN
Lewis acid 7L.A.)
1/XCN/L.A.
Solvent
Yield 7%)a
9a/9bb
1
2
3
4
TMSCN
ZnCl2
ZnCl2
Yb7TfO)3
Yb7TfO)3
1:1:1
1:1:2
1:1:0.1
1:1:0.1
i-PrOH
i-PrOH
CH2Cl2
CH2Cl2
60
25
80
51
86:14
83:17
63:37
64:36
TBDMSCN
TMSCN
TBDMSCN
All reactions were carried out by mixing the reagents at 08C for 30 min, next 12 h at rt.
Overall isolated yields.
a
b
Determined from 1H NMR spectra of the mixtures.
mixtures by integration of the AB systems 7CH2±SpO)
observed for 9a and 9b.
attack of the cyanation reagent with regard to the p-tolyl
group.
The best chemical yields were reached with TMSCN what-
ever that may be the Lewis acid 7ZnCl2 or Yb7TfO)3; Table
1; entries 1 versus 2 and 3 versus 4). On the other hand, the
diastereomeric ratio 9a/9b dropped signi®cantly when
Yb7TfO)3 was used instead ZnCl2 7Table 1; entries 1 versus
3 and 2 versus 4). The diastereoselectivity observed with
ZnCl2 must be con®dently related with the highest stereo-
differentiating effect of the sul®nyl group which could be
originated by a restricted rotation of CH2±SpO bond.
Because of the ability of this Lewis acid to provide chelated
complex with the nitrogen and oxygen atoms of the sul®nyl
group,21 a complex like 10 7Fig. 1) in a half-chair confor-
mation could be taken into account, the pseudo-equatorial
arrangement of the bulkiest p-tolyl group driving the facial
selectivity via a si approach 7anti attack) to afford 9a as
major diastereomer.
The assumption of this different behaviour for Yb7TfO)3 and
ZnCl2 must be related with the easily of the former to give
reactions of ligand substitution. Further, its catalytic role is
related to the ability to give transmetalated species as it has
been reported.22,23
The dual stereochemical behaviour of 72)-1 allows tenta-
tively to assign the 7RS,S) and 7RS,R) absolute con®gurations
to 9a and 9b, respectively. All attempts to achieve the
chemical correlation with l-phenylalanine were unsuccess-
ful by the dif®culty concerning to the deprotection of the
N±PMP substituted group with ceric ammonium nitrate.24
However, this assignment will be con®rmed later taking into
account the spectroscopic behaviour of 9a and 9b and that of
the other a-amino nitriles 7vide infra).
2.2. Cyanosilylation reactions of the compound &1)-2
On the contrary, the low observed diastereoselectivity in
the presence of Yb7TfO)3 can be explained on the basis of
opened transition states. Thus, an iminium derivative arising
from 1 via ligand substitution in the catalyst could be the
actual kinetic substrate 7Fig. 2). The selection of two confor-
mations 7A and B) in a fast interconversion equilibrium
would lead to two competitive reaction paths by an anti
The observed results in the cyanation reactions of 71)-2
with TMSCN and TBDMSCN in the presence of ZnCl2 or
Yb7TfO)3 710 mol%) have been collected in Table 2.
Firstly, an extensive decomposition of the compound 71)-2
occurred when excesses 75:1) of TMSCN or TBDMSCN
and ZnCl2 72:1) were used. It is probably due to the lability
Figure 1. Proposed stereochemical model for the cyanosilylation reactions
of 72)-1 with ZnCl2.
Figure 2. Proposed stereochemical pathways for the cyanosilylation reac-
tions of 72)-1 in the presence of Yb7TfO)3 as catalyst.

3220
H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
Table 2. Cyanosilylation reactions of the compound 71)-2
Entry
XCN
Lewis acid 7L.A.)
2/XCN/L.A.
Solvent
Yield 7%)a
11a/11bb
12a/12bb
13a/13bb
1
2
3
4
TMSCN
TMSCN
TMSCN
TBDMSCN
ZnCl2
1:2.2:1
1:3:0.1
1:5:0.1
1:5:0.1
i-PrOH
CH2Cl2
CH2Cl2
CH2Cl2
28
±
98
84
72:28
±
±
±
±
Yb7TfO)3
Yb7TfO)3
Yb7TfO)3
±
±
±
56:44
±
±
55:45
All reactions were carried out by mixing the reagents at 08C for 30 min, next 12 h at rt.
Overall isolated yields.
a
b
1
Determined from H NMR spectra of the mixtures.
of cyclic ketal against ZnCl2.22 Only in the reported reaction
conditions in Table 2 7entry 1), the reaction mixture was
clean although the yield was poor.
can be probably related with the superposition of other
differentiation effects such as the ring currents due to the
presence of the aryl groups in the epimers 9a and 9b. Other
spectroscopic data were irrelevant in order to establish the
con®gurational assignment although it will be de®nitively
On the other hand, the reactions of 71)-2 and TMSCN in the
presence of Yb7TfO)3 were unsuccessful when excesses of
reagent lower than 5:1 were used. However, good yields in
the dicyano derivatives 12a/12b or 13a/13b were achieved
by using a large excess 75 equiv.) of the cyanation reagent
7Table 2, entries 3 and 4) although the observed diastereo-
selectivity was very low.
1
established by H NMR analysis of the stereo analogous
a-amino nitriles 14a and 14b arising from cyanosilylation
of the compound 3 since the absolute con®guration of
14a and 14b was unequivocally established by chemical
correlation 7vide infra).
The stereochemical pathway of the reactions reported in
Table 2 is entirely similar to that observed for compound
1, although a generalized decrease of the stereoselectivity
was observed for the reactions of compound 2 and a light
inversion of diastereoselectivity occurred when Yb7TfO)3
was used as catalyst 7Table 2; entries 3 and 4). On the
other hand, the cyclic ketal is opened by attack of the
cyanide. It allows to suggest that the acid catalysis implies
to the ketal oxygen atom26 to give the epimeric N-cyclo-
hexylidene intermediates which are transformed in the
dicyano a-amino nitriles 12 or 13 by attack of a second
molecule of the reagent. A similar behavior has been
described in other nucleophilic reactions of the compound
2.17
In all the cases, each pair of diastereomeric a-amino nitriles
was separated from unreacted starting compound 71)-2 by a
¯ash chromatography on silica gel 7hexanes/ethyl acetate:
1:4) although their separation was unsuccessful in all tested
conditions. The structure of compounds 11±13 was con-
1
®dently assigned by elemental analysis and IR, H and 13C
NMR spectra. Diastereomeric ratios were determined by
integration of the key signals of 1H NMR spectra of reaction
mixtures.
Focussing our attention on the observed chemical shifts for
the methylenic hydrogens of the carbon bearing the sul®nyl
group 7AB system), the pairs 11a/11b, 12a/12b, 13a/13b
can be assembled in two groups: 11a, 12b, 13b and 11b,
12a, 13a. Thus, the isomers of the ®rst group display a larger
difference between dA and dB 7Dd.0.25 ppm) than the
isomers of the second group 7Dd,0.15 ppm). In addition,
the sense of the diastereoselectivity for the formation of the
pair 11a/11b 7Table 2, entry 1) must be the same than for the
pair 9a/9b 7Table 1; entry 1). Thus, the 7RS,R) and 7RS,S)
absolute con®gurations can be tentatively assigned to
compounds 11a, 12b, 13b and 11b, 12a, 13a, respectively
7notice that the priority of the groups attached to the new
stereogenic center is changed in the compounds 11±13 with
regard to 9).25 In fact, the compounds 9a and 9b display the
same difference for the chemical shifts of methylenic hydro-
gens 79a: Ddˆ0.357 ppm; 9b: Ddˆ0.350 ppm) although in
a lesser extent than the compounds 11±13. This decrease
2.3. Cyanosilylation reactions of compound &2)-3
The observed results in the cyanosilylation reactions of the
compound 72)-3 with TMSCN and TBDMSCN in the
presence of ZnBr2, ZnCl2 and Yb7TfO)3 710 mol%) have
been collected in Table 3.
Firstly, the in¯uence of the catalyst nature was tested in non-
protic solvents 7THF or CH2Cl2) by using TMSCN as
reagent 7entries 1, 2 and 7) and the best yield was achieved
with ZnBr2 or ZnCl2 7stoichiometric excess 2:1; entries 1
and 2). A scarcely increase of the diastereoselectivity was
observed by using a protic solvent 7i-PrOH, entry 3 versus 2)
while the highest selectivity was accomplished by

H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
Table 3. Cyanosilylation reactions of the compound 72)-3
3221
Entry
XCN
L.A.
ZnBr2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
Yb7TfO)3
Yb7TfO)3
3/XCN/L.A.
Solvent
Yield 7%)a
14a/14bb
1
2
3
4
5
6
7
TMSCN
TMSCN
TMSCN
TBDMSCN
TBDMSCN
TBDMSCN
TMSCN
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:2
1:1:0.1
1:1:0.1
1:5:0.1
THF
THF
95
95
76
95
88
75
55
24
85
59:41
60:40
65:35
63:37
72:28
67:33
55:45
51:49
52:48
i-PrOH
MeOH
i-PrOH
t-BuOH
CH2Cl2
CH2Cl2
CH2Cl2
8
9TBDMSCN
TBDMSCN
Yb7TfO)
3
All reactions were carried out by mixing the reagents at 08C for 30 min, next 12 h at rt.
Overall isolated yields.
a
b
Determined from 1H NMR spectra of the mixtures.
combining the stereodifferentiating effect of solvent, Lewis
acid and reagent 7TBDMS, entry 5). Attempts to increase
the stereodifferentiating effect of protic solvent 7MeOH or
t-BuOH; entries 4 and 6) were unsuccessful.
The major isomer 71)-14a was derivatized to the a-sul-
fonylcarboxamide 72)-15a by reaction with H2O2 730%
vol) and K2CO3 in DMSO 70±108C).27
The subsequent reductive ®ssion of the C±S bond of
71)-15a with Na7Hg) 7Na2HPO4, MeOH) at rt led to
2-[7N,N)-dibenzylamino]propanamide 72)-16a 7[a]Dˆ
238.3 7CDCl3, c 0.4)) 7Scheme 4).28
Newly, Yb7TfO)3 gave the lowest stereoselectivities and a
high drop in the yields 7entries 7 and 8) although the last
effect could be compensated by increasing the XCN excess
7entry 9).
Determination of the optical purity of 16a was done by a
1H NMR lanthanide induced shifts 7LIS) study using
71)-Eu7hfc)3 in CDCl3. Only a single enantiomer could be
detected and thus the sample is .97% ee.
The reaction mixtures were analyzed by 1H NMR
7200 MHz) and the diastereoselectivity determined by
3
integration of the signals at 4.324 7dd, 1H, Jˆ5.2, 10.4
2
Hz, H±Cp) and 3.623 7AB, 2H, Jˆ13.7 Hz, CH2Ph) of
2
the compound 14a and at 3.423 7AB, 2H, Jˆ13.3 Hz,
Furthermore, the compounds 16a and its enantiomer 16b
were independently obtained from enantiomerically pure
methyl lactates 7available from Aldrich Co.) using trans-
formations of proved stereochemistry 7Scheme 4).29,30
Both compounds 16a and 16b displayed a similar optical
purity to that of the problem sample 716a, ee.97%) such
2
3
CH2Ph) and 3.288 7dd, 1H, Jˆ13.2 Hz, Jˆ7.8 Hz, CH2±
Sp) of the compound 14b. Both epimers 14a and 14b were
separated by ¯ash chromatography on silica gel 7dichloro-
methane/ether: 10:1) and the overall yields 7Table 3) are
in isolated products. Structural characterization was
1
1
established from elemental analysis and their IR, H and
13C NMR spectroscopic data.
as it was established from a H NMR LIS study using
71)-Eu7hfc)3 in CDCl3 and the observed rotatory power.
Scheme 4.

3222
H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
each epimer with a signi®cant predominance of the con-
formations 18 and 20 for 7RS,R) and 7RS,S) isomers, respec-
tively 7Fig. 3). The other three conformations can be
clustered as 19 and 21 for each epimer taking into account
the relative arrangement of N,N-dibenzylamino and sul®nyl
groups.
Thus, the 7RS,R) epimer is conformationally more homo-
geneous than the 7RS,S) isomer. In the most stable confor-
mation for both epimers, the N,N-dibenzylamino and
sul®nyl groups adopt a relative synclinal arrangement
whereas in the other three conformations the relative orien-
tation of these groups is antiperiplanar. The selection of the
major conformations 18 and 20 can be due to a stabilizing
interaction between the lone pair of nitrogen and the
unoccupied d orbitals of the hypervalent sulfur.33 As the
0
relative arrangements of hydrogens H2/H3 and H2/H3 are
changed in the conformations of one and other isomer, the
vicinal coupling constants between the hydrogens H2 and
0
H3/H3 must be more averaged for 7RS,S) isomer than for
7RS,R) epimer. In accordance with the observed vicinal
coupling constants for compounds 14a 73Jˆ5.4 and 10.5
Hz) and 14b 73Jˆ7.8 Hz), the 7RS,R) and 7RS,S) absolute
con®gurations can be assigned to isomers 14a and 14b,
respectively, in accordance with the results of the chemical
correlation.
Figure 3. Conformational analysis of 7RS,R) and 7RS,S) epimers of
compound 18 and anisotropic effects of the cyano group on the chemical
0
shifts of hydrogens H3 and H3 . The 72) and 71) marks denote a deshielding
0
or shielding, respectively, of the hydrogens H3 and H3 . Dd is the absolute
difference between the observed chemical shifts of these hydrogens.
So, we assigned the 7S) and 7R) con®gurations to com-
pounds 72)-16a and 71)-16b obtained by us from enantio-
merically pure 7R) and 7S) methyl lactates. The comparison
of the rotatory power of synthetic samples with that of the
carboxamide 72)-16a obtained from 71)-14a allows to
assign the 7R) absolute con®guration to 71)-14a. The
opposed 7S) absolute con®guration can be assigned to the
epimer 72)-14b.
On the other hand, the observed differences for chemical
0
shifts of hydrogens H3 and H3 7Dd) can be justi®ed taking
into account the relative arrangement of the cyano group
and the referred hydrogens because the magnetic anisotropy
of the nitrile group can be the origin of those differences. In
accordance with the ®eld magnetic anisotropy of the cyano
group,34 the hydrogens H3 and H3 must be deshielded in the
0
On the other hand, the 1H NMR spectra of the epimers 14a
and 14b show some signi®cant differences. Thus, the minor
isomer 14b displays a larger difference for the chemical
shifts of the methylenic hydrogens of the carbon C3 7Ddˆ
0.215 ppm) than the major isomer 14a 7Ddˆ0.076 ppm).
Furthermore, the observed vicinal coupling constants for
major conformations 18 and 20 whereas in the clustered
conformations 19 and 21 one of these hydrogens is shielded
because there is an antiperiplanar arrangement between H3
0
or H3 and the cyano group. Then, the highest difference will
be observed for the epimer which displays the major relative
weight of the clustered conformations, that is the 7RS,S)
isomer. In accordance with the observed chemical shifts
0
0
hydrogens H2, H3 and H3 are very different for both
epimers. Thus, the isomer 14b shows two identical vicinal
0
for hydrogens H3 and H3 in the epimers 14a 7dH3
ˆ
coupling constants 73Jˆ7.8 Hz) for hydrogens H3 and H3
0
2.856 ppm, dH3 ˆ2.932 ppm, Ddˆ0.076 ppm) and 14b
whereas the isomer 14a displays two different couplings
73Jˆ5.2 and 10.4 Hz) for these hydrogens. These obser-
vations can be justi®ed regarding the deduced results from
the conformational analysis of the 7RS,R) and 7RS,S) epimers
of compound 14. The search of conformational space was
made with the Conformer utility of the molecular modeling
software package Chem3D31 and the energy of the selected
conformations was minimized by a PM3 semiempirical
calculation.32 In accordance with the results of this confor-
mational analysis, four conformations were selected for
0
7dH3ˆ3.073 ppm, dH3 ˆ3.288 ppm, Ddˆ0.215 ppm), the
7RS,R) and 7RS,S) absolute con®gurations can be assigned
to the isomers 14a and 14b, respectively. These relation-
ships are in accordance with the con®gurational assignment
established by chemical correlation 7vide supra).
By extension, this con®gurational assignment established
0
from observed chemical shifts for hydrogens H3 and H3
can be applied to the a-amino nitriles 9, 11±13. The results
of this approach have been collected in Table 4.
In accordance with the absolute con®gurational assignment
established for the a-amino nitriles 14a and 14b, an inverse
diastereoselectivity is observed for the cyanosilylation of
the b-sul®nylenamine 72)-3 with regard to that expected
from the a-sul®nylimine 4 7Chart 1) if the same stereo-
chemical model proposed to explain the cyanosilylation
reaction of a-sul®nylketimines is assumed 7vide supra).
It has a practical consequence since derivatizating the
ketimines to their covalently stabilized enamines, the
Table 4. Observed qualitative differences for chemical shifts 7Dd) of
methylenic hydrogens of the carbon bearing the sul®nyl group and con®gu-
rational assignment for epimers a and b of a-amino nitriles 9, 11±14
Isomers
Observed Dd
Major
Absolute con®guration
9a, 11a, 12b, 13b, 14b
9b, 11b, 12a, 13a, 14a
9a7S), 11a7R), 12b7R),
13b7R), 14b7S)
Minor
9b7R), 11b7S), 12a7S),
13a7S), 14a7R)

H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
3223
All reactions in non-aqueous media were carried out in
¯ame-dried glassware under argon atmosphere. Reagents
and solvents were handled by using standard syringe
techniques. Tetrahydrofuran 7THF) was distilled from
sodium and benzophenone, dimethylformamide 7DMF)
from calcium hydride and dichloromethane 7DCM) from
P2O5. In all other cases commercially available reagent-
grade solvents were employed without puri®cation. Ana-
lytical TLC was routinely used to monitor reactions. Plates
precoated with Merck silica gel 60 F254 of 0.25 mm
thickness were used, with UV light, either anisaldehyde:
sulfuric acid: ethanol 72:1:100) or 7% ethanolic phospho-
molibdic acid-heat as developing agents. Merck silica gel 60
7230±400 ASTM mesh) was employed for column chroma-
tography. Deactivated silica gel was performed by eluting
with 2% aqueous solution of NaHCO3/MeOH 75:95, v/v)
until the pH of eluents was basic, and then passing through
it dry acetone. Chemicals for reactions were used as
purchased from Aldrich Chemical Co. 74-Methoxyphenyl)
1-phenylethyliden azane,37 4-methyl-2,2-pentamethylene-
2,5-dihydrooxazol 617 and 7R)-7E)-2-7p-tolylsul®nyl)vinyl
methanesulfonate 819 were accomplished following the
reported procedures, their spectroscopic and analytical
data being in accordance with those described in the litera-
ture. 72)-Menthyl p-toluenesul®nate 5 was prepared using
Posner's organic synthesis procedure.38
Figure 4. Competitive transition states for the cyanosilylation reaction of
72)-3 in the presence of ZnX2 or Yb7TfO)3.
minor epimer which is obtained by cyanosilylation of
the former could be achieved in good yield.
In order to explain these results, a different stereochemical
model to that outlined in Fig. 1 must be proposed. Thus, the
actual kinetic substrate could be an iminium derivative
formed by coordination of sul®nyl group with the metal of
catalyst.35 Then, if a fast equilibrium conformational is
assumed 7Fig. 4; 22!23) to describe the nature of this
substrate in solution, the application of the Curtin±Hammett
principle36 to the two reaction pathways printed out in Fig. 4
722: re attack versus 23: si attack) affords a light stereo-
selectivity in accordance with the observed results ꢀkre $ ksi†:
3. Conclusions
4.2. Synthesis of a-sul®nyl ketimines 1 and 2. Typical
procedure
Diastereoselective synthesis of a-p-tolylsul®nylamino
nitriles bearing a quaternary chiral carbon have been accom-
plished by cyanosilylation reactions from enantiomerically
pure a-p-tolylsul®nylketimines. The TMSCN/ZnCl2 sys-
tem, in i-PrOH as solvent, seems to be the best one since
provides fairly yields compatibles with a high stereo-
selectivity, although the structural nature of the substrate
could become critical. In order to achieve the two diastereo-
meric amino nitriles, Yb7TfO)3 gives the highest yields.
Alternatively, b-sul®nylenamines can also be transformed
in the synthetical goals with delivery CN silyl reagents such
as TMSCN and ZnCl2 as mediator. Mechanistic pathways of
these reactions have been proposed to explain both the
nature of the products as well as the diastereoselectivity.
n-Butyl lithium 76 mmol) in hexane was added dropwised at
2408C to a stirred solution of diisopropylamine 76 mmol) in
THF 720 mL). The mixture was kept at 2108C for 30 min,
cooled to 2408C, and the imine 73 mmol) in THF 710 mL)
was added dropwise during ca. 45 min. The mixture was
kept at 2108C for 45±60 min, cooled to 2788C, and
72)-7S)-menthyl p-toluenesul®nate 5 73 mmol) in THF
710 mL) was added dropwise. After being stirred for 2 h at
2788C, the reaction mixture was quenched with a few drops
of methanol; the mixture was brought to rt and the solvents
evaporated off under reduced pressure at rt. The residue was
dissolved in DCM, the organic phase was washed with
brine, separated off, and dried on MgSO4. The solvent was
removed under reduced pressure at rt and the residue was
puri®ed by ¯ash chromatography.
4. Experimental
4.2.1. &R)-[1-Phenyl-2-&p-tolylsul®nyl)] &4-methoxyphenyl)-
ethyliden azane 1. 7Detectable small amounts of other
tautomeric forms 7,13%) were observed). From 74-meth-
oxyphenyl) 1-phenylethyliden azane: Rf 0.6 7Hex/EtOAc
3:1). 87% yield. Yellow solid: mp 778C 7hexane). [a]Dˆ
4.1. Methods and materials
Melting points were determined in a Gallemkamp apparatus
in open capillary tubes and are uncorrected. Optical rota-
tions were measured at room temperature 720±238C) using a
Perkin±Elmer 241 MC polarimeter 7concentration in
g/100 mL). Infrared spectra were recorded on a Perkin±
1
2161.8 7c 1.0, CHCl3). IR 7CHCl3): 1630, 1090 cm21. H
NMR d 2.397s, 3H, CH ), 3.81 7s, 3H, CH3O), 4.40, 4.10
3
7AB, 2H, Jˆ12.6 Hz, CH2Sp), 6.55 7dd, 2H, Jˆ8.8, 1.5 Hz,
H±PMP), 6.84 7dd, 2H, Jˆ7.2, 1.5 Hz, H±PMP), 7.23 7m,
4H, H±Tol), 7.48 7m, 3H, Ph), 7.95 7dd, 2H, Jˆ7.9, 1.7 Hz,
Ph). Calculated Analysis for C22H21NO2S % C 72.69, H
5.83, N 3.85. Found: C 72.61, H 5.72, N 3.85.
Elmer 781 IR Spectrophotometer. The H and 13C NMR
1
spectra were recorded at 200 and 50 MHz, respectively, in
a Bruker AC-200 spectrometer using CDCl3 and the
chemical shifts 7d) refer to TMS 71H) or deuterated chloro-
form 713C) signals. Coupling constants 7J) are reported in
hertz. Multiplicities in proton spectra are indicated as s
7singlet), d 7doublet), t 7triplet), q 7quartet), m 7multiplet)
and bs 7broad singlet). Elemental analyses were performed
with a Perkin±Elmer 2400 C, H, N analyzer.
4.2.2. &R)-2,2-Pentamethylene-4-&p-tolylsul®nyl)methyl-
2,5-dihydrooxazol 2. From 6: Rf 0.2 7Hex/EtOAc 2:1).
86% yield. Yellow oil. [a]Dˆ1170 7c 0.34, EtOH). IR
7CHCl3) 1720, 1090 cm21 1H NMR d 1.30±1.70 7m,
.

3224
H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
10H), 2.417 7s, 3H, CH3), 3.837 7s, 2H, CH2±Sp), 4.456,
4.521 7AB, 2H, 2Jˆ14.9Hz, CH 2O), 7.343 7d, 2H, Jˆ
8.1 Hz, Hortho), 7.523 7d, 2H, Jˆ8.1 Hz, Hortho). 13C NMR
d 21.41, 23.21, 25.03, 36.35, 36.43, 57.02, 75.38, 97.40,
110.75, 124.24, 130.01, 139.05, 142.14, 161.62. Calculated
Analysis for C16H21NO2S %: C 65.93, H 7.28, N 4.81.
Found: C 65.68, H 7.12, N 4.75.
4.4.2. Compound 9b. 7Hex/EtOAc: 2:1). Colorless oil.
[a]Dˆ214.5 7c 0.42, CHCl3). IR 7CHCl3): 3290, 2940,
2240 cm21 1H NMR d 2.416 7s, 3H, Me±Ar), 3.249,
.
3.599 7AB, 2H, 2Jˆ13.7 Hz, CH2±Sp), 3.699 7s, 3H,
OMe), 5.896 7s, 1H, NH), 6.52±6.57 7m, 2H, Hortho PMP),
6.69±6.73 7m, 2H, Hortho PMP), 7.35±7.48 7m, 7H, Ph),
7.69±7.70 7m, 2H, Hortho Tol). 13C NMR d 21.4, 55.5,
60.5, 68.5, 114.5, 117.3, 118.5, 124.1, 126.2, 129.4, 130.3,
136.5, 138.9, 142.7, 153.5. Calculated Analysis for
C23H22N2O2S %: C 70.73, H 5.69, N 7.17. Found: 70.70,
H 5.60, N 7.25.
4.3. Synthesis of &R)-&E)-N,N-dibenzyl-[2-&p-tolylsul®nyl)-
vinyl]amine 3
To 600 mg 72.3 mmol) of 8 in anhydrous DMF 710 mL)
were added 2.2 mL 711.5 mmol) of dibenzylamine and the
mixture was stirred at rt for 12 h. Next, water 75 mL) was
added and the aqueous phase was extracted with EtOAc
74£5 mL). The organic extracts were washed with brine,
dried over Na2SO4, and concentrated under reduced
pressure. The residue was then puri®ed by ¯ash chromato-
graphy on deactivated silica gel EtOAc/hexane: 3:1).
Obtained 770 mg of 3 792%) as white solid. Mp: 778C.
4.4.3. Compound 11a/11b. 7Hex/EtOAc: 1:4). Colorless
1
oil. IR 7CHCl3): 3290, 2960, 2252 cm21. H NMR 711a) d
1.4±1.97m, 10H, cyclohexyl), 2.427 7s, 3H, Me±Ar), 3.026
7bs, 1H, NH), 3.228, 3.481 7AB, 2H, 2Jˆ14.0 Hz, CH2±Sp),
2
3.993, 4.075 7AB, 2H, Jˆ11.8 Hz, CH2O), 7.30±7.50 7m,
2H, Tol), 7.55±7.65 7m, 2H, Tol). 1H NMR 711b) d 1.4±1.9
7m, 10H, cyclohexyl), 2.3897s, 3H, Me±Tol), 2.637 7bs, 1H,
2
NH), 3.346, 3.490 7AB, 2H, Jˆ13.8 Hz, CH2±Sp), 4.088,
2
4322 7AB, 2H, Jˆ12.1 Hz, CH2O), 7.30±7.50 7m, 2H,
1
[a]Dˆ2168.8 7c 1, CHCl3). H NMR d 2.38 7s, 3H, Me±
Tol), 7.55±7.65 7m, 2H, Tol). Calculated Analysis for
C17H22N2O2S %: C 64.11, H 6.98, N 8.80. Found: C
64.17, H 6.91, N 8.88.
2
Ar), 4.29, 4.28 7AB system, 4H, Jˆ15.0 Hz, 2£ CH2Ph),
3
5.30 7d, 1H, Jˆ13.2 Hz, vCHS7O)), 7.51±7.17 7m, 15H,
Ar, vCHS7O)). 13C NMR d 21.29, 55.8, 101.70, 124.66,
127.63, 127.95, 128.91, 129.46, 135.77, 139.78, 143.79,
150.13. Calculated Analysis for C23H23NOS %: C 76.41,
H 6.42, N 3.87. Found: C 76.45, H 6.34, N 3.90.
4.4.4. Compound 12a/12b. 7Hex/EtOAc: 1:4). Colorless
1
solid. IR 7CHCl3): 3292, 2864, 2245 cm21. H NMR 712a)
d 0.178 7s, 9H, SiMe3), 1.5±2.0 7m, 8H, cyclohexyl),
2.2±2.4 7m, 2H, cyclohexyl), 2.435 7s, 3H, Me±Tol),
3.110 7bs, 1H, NH), 3.295 7s, 2H, CH2±Sp), 4.100, 4.216
4.4. General procedure for cyanosilylation reactions
2
7AB, 2H, Jˆ10.3 Hz, CH2O), 7.30±7.397m, 2H, Tol),
7.53±7.62 7m, 2H, Tol). 13C NMR 712a) d 20.524, 21.41,
22.30, 22.38, 24.58, 37.16, 37.96, 54.47, 56.80, 61.13,
66.29, 118.17p, 121.68p, 123.89, 130.32, 139.92, 142.24p.
1H NMR 712b) d 0.228 7s, 9H, SiMe3), 1.5±2.0 7m, 8H,
cyclohexyl), 2.2±2.4 7m, 2H, cyclohexyl), 2.435 7s, 3H,
Me±Ar), 2.971, 3.381 7AB, 2H, 2Jˆ13.9Hz, CH 2±Sp),
To a solution of the imine 70.5 mmol) in 6 mL of solvent at
08C, either ZnCl2 71 M in Et2O; 1±2 mmol) or Yb7TfO)3
710 mol%) was added dropwise, and the solution was
stirred for 15 min at this temperature. Next, TMSCN or
TBDMSCN in the stoichiometric excess pointed out in
each case 7see Tables 1±3) was added in drops at 08C and
the reaction mixture was stirred for 30 min at this tempera-
ture, and further for 12 h at rt. Two different works up were
carried out:
2
3.214 7bs, 1H, NH), 3.681, 4.280 7AB, 2H, Jˆ10.3 Hz,
CH2O), 7.30±7.397m, 2H, Tol), 7.53±7.62 7m, 2H, Tol).
13C NMR 712b) d 20.574, 21.41, 22.50, 22.65, 24.58,
37.39, 38.12, 54.66, 57.67, 63.50, 66.70, 119.47p, 121.99p,
124.04, 130.24, 139.92, 142.35p 7pinterchangeable signals).
Calculated Analysis for C21H31N3O2SSi %: C 60.38, H 7.50,
N 10.06. Found: C 60.45, H 7.42, N 9.82.
The reaction mixtures arising from R3SiCN/ZnCl2 were
quenched with saturated aqueous solution of NH4Cl
75 mL), while those ones from R3SiCN/Yb7TfO)3 were
treated with saturated aqueous solution of Na2CO3, after
the solvent 7DCM) being evaporated in vacuum at rt. In
all the cases the aqueous phase was extracted with Et2O
73£5 mL) and the combined organic extracts were washed
with brine, separated off, and dried over Na2SO4. The
solvent was removed under reduced pressure at rt and the
reaction mixture was puri®ed by ¯ash chromatography
4.4.5. Compound 13a/13b. 7Hex/EtOAc: 1:4). Colorless
1
solid. IR 7CHCl3): 3292, 2858, 2250 cm21. H NMR 713a)
d 0.186 7s, 3H, Me±Si), 0.200 7s, 3H, Me±Si), 0.950 7s, 9H,
t-Bu), 1.4±1.97m, 10H, cyclohexyl), 2.434 7s, 3H, Me±Ar),
2
3.171 7bs, 1H, NH), 3.279, 3.340 7AB, 2H, Jˆ 13.6 Hz,
CH2±Sp), 4.149, 4.255 7AB, 2H, 2Jˆ10.3 Hz, CH2O), 7.30±
7.397m, 2H, Ar), 7.53±7.62 7m, 2H, Ar). 13C NMR 713a) d
25.48p, 25.39p, 18.15, 22.29, 22.54, 24.59, 37.17, 38.00,
54.43, 57.07, 61.90, 66.71, 118.77, 122.02, 123.89, 130.35,
139.86, 142.42 7pinterchangeable signals). 1H NMR 713b) d
0.137 7s, 3H, Me±Si), 0.147 7s, 3H, Me±Si), 0.920 7s, 9H,
t-Bu), 1.4±1.97m, 10H, cyclohexyl), 2.434 7s, 3H, Me±Ar),
4.4.1. Compound 9a. 7Hex/EtOAc: 4:1). Colorless oil.
[a]Dˆ1252.6 7c 0.66, CHCl3). IR 7CHCl3): 3290, 2940,
2253 cm21 1H NMR d 2.407 7s, 3H, Me±Ar), 2.933,
.
3.290 7AB, 2H, 2Jˆ13.6 Hz, CH2±Sp), 3.696 7s, 3H,
OMe), 6.422 7bs, 1H, NH), 6.50±6.56 7m, 2H, Hortho
PMP), 6.66±6.77 7m, 2H, Hortho PMP), 7.30±7.45 7m, 5H,
Ph), 7.55±7.70 7m, 4H, Hortho Tol). 13C NMR d 21.4, 55.5,
62.2, 68.2, 114.4, 117.9, 118.5, 123.9, 125.3, 129.3, 129.5,
130.4, 137.0, 138.6, 139.3, 142.8, 153.8. Calculated
Analysis for C23H22N2O2S %: C 70.73, H 5.69, N 7.17.
Found: C 70.65, H 5.73, N 7.07.
2
3.130 7bs, 1H, NH), 2.968, 3.414 7AB, 2H, Jˆ13.9Hz,
CH2±Sp), 3.715, 4.336 7AB, 2H, 2Jˆ10.3 Hz, CH2O),
7.30±7.397m, 2H, Ar), 7.53±7.62 7m, 2H, Ar). 13C NMR
713b) d 25.47p, 25.42p, 21.42, 22.39, 22.69, 25.72, 37.57,
38.09, 54.70, 57.61, 63.50, 67.19, 119.46, 121.63, 124.00,
130.25, 139.91, 142.19 7pinterchangeable signals).

H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
3225
1
3
Calculated Analysis for C24H37N3O2SSi %: C 62.69, H 8.13,
N 9.14. Found: C 62.84, H 8.21, N 9.24.
0.4, CHCl3). H NMR d 1.296 7d, 3H, Jˆ7.1 Hz, Me),
3
3.407 7q, 1H, Jˆ7.1 Hz, H±Cp), 3.416, 3.795 7AB, 2£2H,
2Jˆ13.2 Hz, 2£CH2Ph), 5.920 7bs, 1H, NH2), 7.135 7bs,
1H, NH2), 7.2±7.4 7m, 10H, Ph). 13C NMR d 7.06, 54.41,
57.34, 127.36, 128.22, 128.55, 138.80, 176.82. Calculated
Analysis for C17H20N2O %: C 76.07, H 7.53, N 10.44. Found
%: C 76.10, H 7.44, N 10.32.
4.4.6. Compound 14a. 7DCM/Et2O: 10:1). White solid. Mp
1248C, [a]Dˆ125.0 7c 3.9, CHCl3). IR 7KBr): 3290, 2857,
1
2250 cm21. H NMR d 2.383 7s, 3H, Me), 2.856 7dd, 1H,
2Jˆ13.4 Hz, 3Jˆ5.2 Hz, CH2±Sp), 2.932 7dd, 1H, 2Jˆ
3
13.4 Hz, Jˆ10.4 Hz, CH2±Sp), 3.623, 3.971 7AB, 2£2H,
2Jˆ13.7 Hz, CH2Ph), 4.324 7dd, 1H, 3Jˆ5.2 Hz, 10.4,
H±Cp), 7.15±7.55 7m, 14H, Ar). Calculated Analysis for
C24H24N2OS %: C 74.18, H 6.24, N 7.21. Found: C 73.86,
H 5.97, N 7.09.
4.7. Chemical sequence to establish the con®gurational
correlation of 16a29;30
To a stirred solution of 7R)-71)- or 7S)-72)-methyl lactate
71.040 g, 10.0 mmol) in DCM 720 mL) at 08C, was added
tri¯ic anhydride 71.90 mL, 11.0 mmol) followed by 2,6-luti-
dine 71.28 mL, 11.0 mmol). After stirring for 15 min,
dibenzylamine 76.00 mL, 31.0 mmol) in DCM 710 mL)
was added dropwise to the solution. The resulting mixture
was stirred for 2 h at rt and then concentrated by evaporation
in vacuum. The residue was dissolved in hexane 7150 mL),
passed through a short pad of silica gel, and concentrated
again to provide dibenzylamino ester 17a or 17b as a pale
yellow oil. This material was carried out on the next step
without further puri®cation.
4.4.7. Compound 14b. 7DCM/Et2O: 10:1). Colorless oil. IR
1
7CCl4): 3294, 2863, 2260 cm21. H NMR d 2.394 7s, 3H,
Me), 3.073 7dd, 1H, 2Jˆ13.2 Hz, 3Jˆ7.8 Hz, CH2±Sp),
2
3
3.288 7dd, 1H, Jˆ13.2 Hz, Jˆ7.8 Hz, CH2±Sp), 3.423,
3.965 7AB, 2£2H, 2Jˆ13.3 Hz, CH2Ph), 3.959 7t, 1H,
3Jˆ7.8 Hz, H±Cp), 7.15±7.55 7m, 14H, Ar). Calculated
Analysis for C24H24N2OS %: C 74.18, H 6.24, N 7.21.
Found: C 73.97, H 6.12, N 7.27.
4.5. Hydrolysis of sul®nylamino nitriles to sulfonylamino
amides38
A 2.5 M solution of AlMe3 70.8 mL, 2.0 mmol) in hexane
was slowly added at rt to a solution of 2.0 mmol of ammonia
in 5 mL of DCM. The mixture was stirred at rt for 15 min
and 17a or 17b 7566 mg, 2.0 mmol) was added. The mixture
was warmed up 25±408C until TLC analysis indicated that
the reaction had gone to completion. The reaction was care-
fully quenched with diluted HCl 72%) and extracted with
DCM 73£10 mL). The combined organic extracts were
dried 7Na2SO4) and concentrated in vacuum to afford the
carboxamide.
To a solution of sul®nylamino nitrile 70.181 mmol) in
DMSO 73 mL) cooled in an ice±water bath were added
K2CO3´1.5H2O 74 mg) and dropwise 30% H2O2 730 mL)
keeping the temperature at 108C. After stirring for 15 min,
water 70.6 mL) was added. A white solid forms, which was
®ltered, washed with water and dried in vacuum 70.1 torr) at
room temperature.
4.5.1.
&R)-2-&N,N-Dibenzylamino)-3-&p-tolylsulfonyl)-
propanamide 15a. Compound 15a was obtained from
14a in 91% yield after crystallization 7ethyl acetate/hexane).
MP 1408C 7white solid). [a]Dˆ251.4 7c 0.2, CHCl3). IR
4.7.1. Methyl &S)-2-&N,N-dibenzylamino)propanoate 17a.
Obtained 2.80 g from 7R)-71)-lactate 7100%). [a]Dˆ288.2
7c 2.2, CHCl3). 1H NMR d 1.32 7d, 3H, 3Jˆ6.5 Hz Me), 3.51
7q, 1H, 3Jˆ6.5 Hz, H±Cp), 3.59, 3.84 7AB, 2£2H, 2Jˆ 13.9
Hz, 2£CH2Ph), 3.73 7s, 3H, OMe), 7.40±7.35 7m, 10H, Ph).
Calculated Analysis for C18H21NO2 %: C 76.28, H 7.48, N
4.94. Found: C 76.35, H 7.40, N 4.86.
1
7KBr): 3462, 3352, 1691, 1147 cm21. H NMR d 2,331 7s,
3H, Me±Tol), 3.026 7dd, 1H, 3Jˆ5.6 Hz, 12.2, H±Cp),
2
3.432 7t, 1H, Jˆ3Jˆ12.2 Hz, CH2SO2), 3.478 7dd, 1H,
2Jˆ12.2 Hz, 3Jˆ5.6 Hz, CH2SO2), 3.567, 3.704 7AB,
2£2H, 2Jˆ13.6 Hz, 2£CH2Ph), 5.776 7bs, 1H, NH2),
6.492 7bs, 1H, NH2), 7.08±7.32 7m, 12H, H±Ar), 7.470
7d, 2H, Jˆ8.8 Hz, Hortho). Calculated Analysis for
C24H26N2O3S %: C 68.21, H 6.21, N 6.63. Found %: C
68.20, H 6.14, N 6.68.
4.7.2. Methyl &S)-2-&N,N-dibenzylamino)propanoate 17b.
Obtained 2.80 g from methyl 7S)-72)-lactate 7100%).
[a]Dˆ188.5 7c 2.2, CHCl3).
4.7.3. &R)-2-&N,N-Dibenzylamino)propanamide 16a.
Obtained 439mg. from 17a 782%). White solid. MP
1038C. [a]Dˆ238.5 7c 0.4, CHCl3).
4.6. Desulfuration of sulfonylamino amides
To a solution of sulfonylamino amide 70.28 mmol) in
MeOH 75 mL) at 2208C were added Na2HPO4 70.11
mmol) and 5% Na±Na´Hg 7668 mg, 1.45 mmol) keeping
the temperature at 208C. After stirring for 12 h saturated
aqueous solution of NH4Cl 76 mL) was added and the
aqueous phase was extracted with Et2O 73£10 mL). The
combined organic extracts were washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The
residue was puri®ed by ¯ash chromatography.
4.7.4. &S)-2-&N,N-Dibenzylamino)propanamide 16b.
Obtained 466 mg. from 17b 787%). White solid. MP
1038C. [a]Dˆ137.8 7c 0.4, CHCl3).
4.8. Optical yields determination
A lanthanide induced shifts 7LIS) study was carried out on
a sample of 12 mg of 16a 7arising from 15a) using
71)-Eu7hfc)3 70.5 equiv.) in CDCl3. In addition, samples
of 16a and 16b prepared from methyl esters 17a and 17b,
respectively, were also analyzed in these conditions. A
racemic sample was ®rst used to monitor the lanthanide
4.6.1. &S)-2-&N,N-Dibenzylamino)propanamide 16a.
Compound 16a was accomplished from 15a in 91.5%
yield. Flash chromatography 7hexane/EtOAc: 1:2, Rf
0.42). Isolated as white solid. MP 1038C. [a]Dˆ238.3 7c

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H. Acherki et al. / Tetrahedron 58 32002) 3217±3227
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Acknowledgements
We gratefully acknowledge the Spanish DGES 7MEC)
7Project: PB96-009) and DGI 7Ministerio de Ciencia y
Tecnologia) 7Project: BQU2000-0792 for support of
this research. H. A. is grateful to the Direction de
Â
l'Enseignement Superieur et de la Recherche Scienti®que
7Ministere de l'Education Nationale) of Morocco for his
Â
doctoral fellowship. We would also like to thank UCM for
its facilities of NMR and Elemental Analysis Services.
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