Additions of Enantiopure α-Sulfinyl Carbanions to (S)-N-Sulfinimines: Asymmetric Synthesis of β-Amino Sulfoxides and β-Amino Alcohols

Article abstract of DOI:10.1021/jo9903858

The addition of the lithium anions derived from (R)- and (S)-methyl and -ethyl p-tolyl sulfoxides to (S)-N-benzylidene-p-toluenesulfinamide provides an easy access route to enantiomerically pure β-(N-sulfinyl)amino sulfoxides. Stereoselectivity can be ach

Full text of DOI:10.1021/jo9903858

2856
J . Org. Chem. 2000, 65, 2856-2862
Ad d ition s of En a n tiop u r e r-Su lfin yl Ca r ba n ion s to
(S)-N-Su lfin im in es: Asym m etr ic Syn th esis of â-Am in o Su lfoxid es
a n d â-Αm in o Alcoh ols
J ose´ L. Garc´ıa Ruano,*,† Ana Alcudia,‡ Miriam del Prado,† David Barros,†
M. Carmen Maestro,† and Inmaculada Ferna´ndez*,‡
Departamento de Quı´mica Orga´nica, Universidad Auto´noma de Madrid, Cantoblanco,
28049 Madrid, Spain, and Departamento de Qu´ımica Orga´nica y Farmace´utica,
Facultad de Farmacia, Universidad de Sevilla, 41017 Sevilla, Spain
Received March 3, 1999
The addition of the lithium anions derived from (R)- and (S)-methyl and -ethyl p-tolyl sulfoxides to
(S)-N-benzylidene-p-toluenesulfinamide provides an easy access route to enantiomerically pure â-(N-
sulfinyl)amino sulfoxides. Stereoselectivity can be achieved when the configurations at the sulfur
atoms of the two reagents are opposite (matched pair), thus resulting in only one diastereoisomer,
even for the case in which two new chiral centers are created. The N-sulfinyl group primarily controls
the configuration of the carbon bonded to the nitrogen, whereas the configuration of the R-sulfinyl
carbanion seems to be responsible for the level of asymmetric induction, as well as for the
configuration of the new stereogenic C-SO carbon in the reactions with ethyl p-tolyl sulfoxides.
An efficient method for transforming the obtained â-(N-sulfinyl)amino sulfoxides into optically pure
â-amino alcohols, based on the stereoselective non-oxidative Pummerer reaction, is also reported.
Sch em e 1
In tr od u ction
The importance of enantiomerically pure â-amino
alcohols as chiral auxiliaries in asymmetric synthesis1
or as ligands in asymmetric catalysis2 is currently well
recognized, and thus, the search for new methods for the
asymmetric synthesis of these compounds is highly
interesting. Bravo et al.3 have recently reported that
certain fluorine-containing â-amino sulfoxides submitted
to Pummerer conditions (TFAA, sym-collidine) are con-
verted into the â-amino alcohols (Scheme 1) in high
optical purity, thereby showing the utility of amino
sulfoxides as chiral targets.
To extend this methodology as a general procedure for
the asymmetric synthesis of â-amino alcohols, it is
necessary to have an efficient method for preparing
enantiomerically pure â-amino sulfoxides, as well as for
determining whether the conditions reported by Bravo
et al. can be utilized with substrates lacking fluoroalkyl
substituents. Both questions have been investigated, and
the results are reported in this paper.
route to chiral amine derivatives. The sulfoxides have
proven to be efficient chiral auxiliaries when bonded to
either a nucleophile or an electrophile. Thus, the reaction
of achiral imines with enantiomerically pure R-sulfinyl
carbanions5 allows the asymmetric synthesis of â-amino
sulfoxides with moderate to high diastereomeric excess.
Diastereoselectivities range between 14 and 84% depend-
ing on factors such as the nature of the imine, the
substituent at the sulfur, and, particularly, the reaction
conditions (kinetically or thermodynamically controlled).
The best results were obtained in the reactions of
lithiomethyl p-tolyl sulfoxide with fluoroalkyl aldimines,3b
The nucleophilic addition of organometallic reagents
to the CdN double bond of imines4 provides an attractive
† Universidad Auto´noma de Madrid.
‡ Universidad de Sevilla.
(1) (a) Myers, G.; Yang, B. H.; Chen, H.; Mckinstry, L.; Kopecky, D.
J .; Gleason, J . L. J . Am. Chem. Soc. 1997, 119, 6496. (b) Shiori, Y.;
Hamada, Y. Heterocycles 1988, 27, 1035. (c) Barlow, C. B.; Bukhari,
S. T.; Guthrie, R. D.; Prior, A. M. Asymmetry in Carbohydrates; Marcel
Dekker: New York, 1979; pp 81-99.
(2) (a) Pfaltz, A. In Advances in Catalytic Processes; Doyle, M. P.,
Ed.; J AI Press: Greenwich, CT, 1995; pp 61-94. (b) Blaser, H.-U.
Chem. Rev. 1992, 92, 935. (c) Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483. (d) Denmark, S. E.;
Nakijima, N.; Nicaise, O. J . C.; Faucher, A. M.; Edwards, J . P. J . Org.
Chem. 1995, 60, 4884. (e) de Vries, A. H. M.; J ansen, J . F. G. A.;
Feringa, B. L. Tetrahedron 1994, 50, 4479.
(3) (a) Bravo, P.; Corradi, E.; Pesenti, C.; Vergani, B.; Viani, F.;
Volonterio, A.; Zanda, M. Tetrahedron: Asymmetry 1998, 9, 3731. (b)
Bravo, P.; Zanda, M.; Zappala, C. Tetrahedron Lett. 1996, 37, 6005.
(c) Bravo, P.; Farina, A.; Kukhar, V. P.; Markovsky, A. L.; Meille, S.
V.; Soloshonok, V. A.; Sorochinsky, A. E.; Viani, F.; Zanda, M.; Zappala,
C. J . Org. Chem. 1997, 62, 3424.
(4) (a) Volkmann, R. A. In Comprehensive Organic Synthesis;
Schreiber, S. L., Ed.; Pergamon Press: Oxford, 1991; Vol. 1, Chapter
1.12, p 355. (b) Risch, N.; Arend, M. In Stereoselective Synthesis
(Houben-Weyl); Helmechen, G., Hoffmann, R. W., Mulzer, J ., Schau-
mann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1995; E21b, D.1.4, p
1833. (c) Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8,
1895.
(5) (a) Tsuchihashi, G.; Iriuchijima, S.; Maniwa, K. Tetrahedron Lett.
1973, 3389. (b) Ronan, B.; Marchalin, S.; Samuel, O.; Kagan, H. B.
Tetrahedron Lett. 1988, 29, 6101. (c) Pyne, S. G.; Dikic, B. J . Chem.
Soc., Chem. Commun. 1989, 826. (d) Pyne, S. G.; Dikic, B. J . Org.
Chem. 1990, 55, 1932. (e) Pyne, S. G.; Boche, G. J . Org. Chem. 1989,
54, 2663.
10.1021/jo9903858 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/25/2000

Additions of Enantiopure R-Sulfinyl Carbanions
J . Org. Chem., Vol. 65, No. 10, 2000 2857
Sch em e 2
which proceeded with 84-88% de (diastereomeric excess).
Reactions with ketimines were much less satisfactory.6
Low reactivity and poor stereoselectivity, usually as-
sociated with the use of enantiopure imines, can be sub-
stantially improved by using enantiopure N-sulfinyl-
imines.7 Stereoselectivity of these reactions is high in a
few cases. Thus, the reaction of (S)-N-benzylidene-p-tolu-
enesulfinamide (1) with the lithium enolates of methyl
acetate provided high de (72-80%),8,9 which could be
increased by adding HMPA10 (96% de) or by using the
sodium enolates in THF (>98% de).10 Nevertheless, even
in these last optimal conditions, (R)-N-(3-pyridylmeth-
ylidene)-p-toluenesulfinamide provides lower stereose-
lectivity (76% de).11 The additions of phosphites,12 R-phos-
phonate carbanions,13 and sulfonium or oxosulfonium
ylides14 to N-sulfinimines take place with de’s ranging
between 70 and 97%, depending on the substrate. Finally,
the addition of Grignard reagents to N-sulfinimines and
N-sulfenimines derived from camphor15 gives high de only
in the cases of allylmagnesium bromide and tert-butyl-
magnesium bromide. Similar results were reported by
Hua.16 All of these results suggest a high efficiency of
the sulfinamidic sulfur configuration in controlling the
stereoselectivity of the addition of carbon nucleophiles.
Ta ble 1. Rea ction of (S)-1 w ith (R)- a n d (S)-Meth yl
p-Tolyl Su lfoxid e, 2
products
(relative ratio, %)
yield
(%)
entry
sulfoxide
T (°C)
de
80
66
>98
80
1
2
3
4
(S)-2
(S)-2
(R)-2
(R)-2
-78
0
3A (90) + 3B (10)
3A (83) + 3B (17)
4A
96
97
99
98
-78
0
4A (90) + 4B (10)
reported that reactions of the N-benzylidene-p-toluene-
sulfinamide 1 with ethyl butanoate anion yielded sig-
nificant amounts of the four possible diastereoisomers.
To control the stereoselectivity of these reactions and,
thus, achieve good stereoselectivity in the generation of
two new chiral centers, we decided to evaluate the
influence of incorporating the sulfinyl group in both the
electrophile and nucleophile. The additions of R-sulfinyl
carbanions derived from (R)- and (S)-methyl and -ethyl
p-tolyl sulfoxide, (R)-2, (S)-2, (R)-5, and (S)-5, to (S)-N-
benzylidene-p-toluenesulfinamide, 1, are reported in this
paper. Because inherent diastereofacial preferences of
chiral sulfoxide anions and N-sulfinylimines may rein-
force or oppose one another in the crossed condensation
(matched or mismatched pair), this study should provide
the proper combination (matched pair) for obtaining
optically pure â-(N-sulfinyl)amino sulfoxides.
The evolution of reactions with the simultaneous
formation of two new chiral centers, as a consequence of
the prochirality of the carbon nucleophile, has not been
extensively explored. To our knowledge, only reactions
of the enantiopure benzyl p-tolyl sulfoxide with achiral
fluoroalkyl aldimines have been reported.3b These reac-
tions are not highly stereoselective and give a mixture
of the four possible diastereoisomers. By contrast, the
behavior of enantiopure sulfinimines with enolates de-
rived from R-substituted esters, as well as that of
enantiopure alkyl sulfoxides (p-Tol-SO-R, R * Me) with
imines, has not been reported.17 In a recent paper,18 we
(6) Bravo, P.; Viani, F.; Zanda, P.; Fokina, N.; Kukhar, V. P.;
Soloshonok, V. A.; Sishkin, O. V.; Struchkov, Y. T. Gazz. Chim. Ital.
1996, 126, 645.
(7) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M.; Reddy, G. V.;
Portonovo, P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll,
P. J . J . Org. Chem. 1997, 62, 2555.
(8) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J . Org. Chem. 1992, 57,
6387.
(9) Fujisawa, T.; Kooriyama, Y.; Shimizu, M. Tetrahedron Lett. 1996,
37, 3881.
(10) Davis, F. A.; Reddy, R. E.; Szewczyk, J . M. J . Org. Chem. 1995,
60, 7037.
Resu lts a n d Discu ssion
Products formed in the reaction of N-sulfinylimine (S)-
1, easily prepared by the Davis method,14a with both
enantiomers of methyl p-tolyl sulfoxide, 2 (Scheme 2), are
shown in Table 1. Reaction with (S)-2 at -78 °C yielded
a 90:10 mixture of the two possible diastereoisomers 3A
and 3B (entry 1), whereas reaction with (R)-2, under
identical conditions, only afforded 4A (entry 3). When the
temperature was increased to 0 °C, the stereoselectivity
of both reactions eroded (compare entries 2 and 4 with
entries 1 and 3, respectively). At 0 °C, the reactions were
instantaneous, but a rapid decomposition of the products
was observed. To avoid this problem, the reactions were
immediately quenched once the addition of the anion had
finished. In this way, yields were almost quantitative in
all cases. Configuration assignments of the obtained
(11) Davis, F. A.; Szewczyk, J . M.; Reddy, R. E. J . Org. Chem. 1996,
61, 2222.
(12) Lefebvre, I. M.; Evans, S. A., J r. J . Org. Chem. 1997, 62, 7532.
(13) Mikolajczyk, M.; Lyzwa, P.; Drabowicz, J .; Wieczorek, M. W.;
Blaszczyk, J . J . Chem. Soc., Chem. Commun. 1996, 1503.
(14) (a) Garc´ıa Ruano, J . L.; Ferna´ndez, I.; Hamdouchi, C. Tetra-
hedron Lett. 1995, 36, 295. (b) Davis, F. A.; Zhou, P.; Liang, C. H.;
Reddy, R. E. Tetrahedron: Asymmetry 1995, 6, 1511. (c) Garc´ıa Ruano,
J . L.; Ferna´ndez, I.; del Prado Catalina, M.; Alcudia, A. Tetrahedron:
Asymmetry 1996, 7, 3407.
(15) Yang, T. K.; Chen, R. Y.; Lee, D. S.; Peng, W. S.; J iang, Y. Z.;
Mi, A. Q.; J ong, T. T. J . Org. Chem. 1994, 59, 914.
(16) Hua, D. H.; Lagneau, N.; Wang, H.; Chen, J . Tetrahedron:
Asymmetry 1995, 6, 349.
(17) Reactions of racemic benzyl tert-butyl sulfoxide with several
N-phenylimines are highly stereoselective (see ref 6e). A similar
behavior was observed in the synthesis of aziridines from racemic
R-halosulfoxides and imines (Satoh, T.; Oohara, T.; Yamakawa, K.
Tetrahedron Lett. 1988, 29, 4093). Racemic fluoromethyl phenyl
sulfoxide reacts with N-phenyl arylimines with moderate to very high
selectivity, depending on the nature of the aryl group (Mahidol, C.;
Reutrakul, V.; Prapansiri, V.; Panyanchotipun, C. Chem. Lett. 1984,
969).
1
â-amino sulfoxides were made by H NMR.
Diastereoisomers 3A and 4A, the major products in
these reactions, have identical configurations at the new
stereogenic carbons (R in both cases), despite the opposite
configuration of the sulfoxide used as the nucleophile in
each case. This fact reveals that the stereoselectivity is
primarily controlled by the sulfur configuration of the
starting electrophilic sulfinamide 1. However, the results
are rather surprising because the induced configuration
(18) Garc´ıa Ruano, J . L.; Ferna´ndez, I.; del Prado Catalina, M.;
Hermoso, J . A.; Sanz-Aparicio, J .; Mart´ınez-Ripoll, M. J . Org. Chem.
1998, 63, 7157.

2858 J . Org. Chem., Vol. 65, No. 10, 2000
Garc´ıa Ruano et al.
F igu r e 1. Reaction of (S)-1 with (R)-2 and (S)-2 lithium derivatives.
is the opposite of that obtained in reactions of 1 with ester
enolates8,9 and other nucleophiles.10-14 Therefore, the
reactions of compound (S)-1 with the sulfinyl carbanions
derived from (R)-2 and (S)-2 must proceed through a
stereochemical course different from that proposed for
the other reactions. The chelating ability of the lithium
cation could play an essential role in controlling product
stereochemistry. This result is just the opposite of that
found in reactions of (S)-1 with the lithium enolate
derived from ethyl acetate.10
We postulate that the R-sulfinyl carbanion acting as
the nucleophile could be stabilized by lithium because of
the presence of the sulfinyl oxygen, which allows the
formation of species such as IR and IS (Figure 1). The
association of the sulfinyl oxygen of the substrate (S)-1
with the lithium of the reagents I would yield species
able to suffer intramolecular nucleophilic attack of the
R-sulfinyl carbanion on the CdN bond. Taking into
account that this attack must take place from the plane
normal to that defined by the Ph-CdN-S grouping
(which contains the CdN bond), only the s-cis arrange-
ment of the N-sulfinyl oxygen is able to fix the attacking
carbanion at the suitable position, which will be the
position that is forming an angle close to 104° with the
CdN bond, as is required for CdO groups.
In the case of the matched pair [(S)-sulfinamide/(R)-
sulfoxide], TS1 is clearly favored with respect to TS2
(Figure 1), because the steric interactions of the two
sulfinyl groups destabilize the latter. This would justify
the high or complete stereoselectivity observed in these
reactions, with a favored attack of the (R)-sulfoxide from
the upper Si face of the imine. In contrast, stability
differences between the two possible transition states TS3
and TS4 for the mismatched pair [(S)-sulfinamide/(S)-
sulfoxide] must be significantly lower. The approach from
the Si face will be destabilized by the steric repulsion
between the phenyl group of the substrate and the p-tolyl
group of the reagent, whereas the attack from the Re face
will be hindered by the orientation of the p-tolyl group
at the substrate (Figure 1). The fact that the major
isomer obtained in the reaction of the mismatched pair
has the R configuration at the carbon indicates that the
favored approach takes place from the Si face, and,
therefore, TS3 must be more stable than TS4 (Figure 1).19
The results obtained in the reaction of (S)-1 with (R)-
and (S)-ethyl p-tolyl sulfoxide, 5 (Scheme 3), are shown
in Table 2.20 The reactions occurred in 15 min at -78
°C, and very high yields were obtained in all of the
conditions used. The addition of (S)-5 to (S)-1 yielded a
diastereoisomeric mixture containing three compounds,
6A, 6B, and 6C (entries 1 and 2), in different ratios
depending on the temperature. Starting from (R)-5, only
7A was obtained when the reaction took place at 0 °C
(entry 4), but a mixture of three diastereoisomers, 7A,
7B, and 7D, could be detected at -78 °C (entry 3).
Configurational assignments of compounds 6 and 7 were
made by 1H NMR and chemical correlation (as described
below). These results indicate that the matched pair is
formed by the reaction of the (R)-sulfoxide, (R)-5, and the
(S)-sulfinylimine, (S)-1, which yields only one diastereo-
isomer, 7A, in the optimal reaction conditions. Surpris-
ingly, the stereoselectivity of the reactions with both
enantiomers of compound 5 decreases when the temper-
ature is lowered (compare entries 2 and 4 with entries 1
and 3, respectively), and the most favorable product
(19) The interaction Tol/Ph, depicted in Figure 1 for TS3, seems to
be stronger than the interaction Tol/Li, depicted for TS4, thus sug-
gesting the lower stability of TS3. Nevertheless, we must take into
account that these reactions must be strongly exothermic. Thus,
according to the Hammond postulate, one must expect a reactant-like
transition state, involving a greater distance for the incipient new C-C
bond and thus resulting in a weaker repulsive interaction (Ph/Tol)
because of the long distance between the two groups.
(20) The behavior of ethyl p-tolyl sulfoxides, 5, was first studied on
the achiral N-phenylbenzylidene imine. The reaction of this imine with
(R)-5 yielded a mixture containing significant amounts of the four
possible diastereoisomeric â-amino sulfoxides. This result contrasted
with that obtained for the reaction of (R)-2 with the same imine, which
proceeded in an almost completely stereoselective manner (96% de)5
and which evidenced a strong decrease in the stereoselectivity of
reactions of achiral imines with alkyl p-tolyl sulfoxides.

Additions of Enantiopure R-Sulfinyl Carbanions
J . Org. Chem., Vol. 65, No. 10, 2000 2859
Sch em e 3
Sch em e 4
Sch em e 5
Ta ble 2. Rea ction of (S)-1 w ith (R)- a n d (S)-Eth yl p-Tolyl
Su lfoxid e, 5
products
(relative ratio, %)
yield
(%)
entry sulfoxide T (°C)
1
2
3
4
(S)-5
(S)-5
(R)-5
(R)-5
-78
0
6A (35) + 6B (57) + 6C (8)
6A (25) + 6B (63) + 6C (12)
7A (89) + 7B (3) + 7D (8)
7A
91
89
80
97
of these compounds, followed by the treatment of the
resulting ammonium salts with Dowex resin, afforded the
optically pure (R)-2-amino-2-phenylethanol, 14,21 and
(1R,2R)-1-amino-1-phenyl-2-propanol, 15.22 Two conclu-
sions can be drawn from these results. The first is that
the conditions reported by Bravo et al.3 for converting
â-amino sulfoxides, bearing fluoralkyl substituents, to
their corresponding â-amino alcohols can be successfully
applied to alkyl derivatives and, therefore, that the
presence of fluoroalkyl substituents is not strictly re-
quired. These reactions take place with complete inver-
sion of the configuration at the carbon supporting the
sulfinyl group, yielding optically pure â-amino alcohols.
The second conclusion concerns the configurational as-
signment of compound 7A. The chemical transformation
depicted in Scheme 4, connecting compound 7A with
(1R,2R)-1-amino-1-phenyl-2-propanol, 15, unequivocally
demonstrates that the starting aminosulfinyl derivative
must have a 1R,2S configuration at its chiral carbons,
as was also evidenced by its coupling constant values (as
discussed below).
Con figu r a tion a l Assign m en ts. The configurational
assignments of 3A and 4A, epimers at sulfur because
they were obtained as major components in reactions of
(S)-1 with (S)-2 and (R)-2, respectively, were established
as follows. The TFA hydrolysis of their N-sulfinyl moi-
eties yielded the corresponding free amines 16 and 8,
respectively (Scheme 5). The 1H NMR study of these
compounds revealed substantial differences between
them, primarily related to the relative values of their
-78
0
diastereoselection was observed under equilibrium-
controlled conditions. Additionally, when the reaction of
(R)-5 with (S)-1 was initiated at -78 °C and then the
mixture was allowed to warm to 0 °C, only 7A was
detected.
These stereochemical results suggest that the reaction
is thermodynamically controlled and that 7A is the
thermodynamically more stable product. The precise
reason for the thermodynamic preference of 7A over the
other diastereomers, however, is not clear.
Once the conditions for obtaining â-amino sulfoxides
with almost complete control of the stereoselectivity were
known, it was necessary to investigate the ability of the
obtained substrates to be transformed into â-amino
alcohols. In a first trial, compounds 4A and 7A were
treated with TFA and sym-collidine to determine whether
the NH-SOTol group could be transformed, as reported
by Bravo et al. for the corresponding carbamates,3 via a
stereoselective non-oxidative Pummerer reaction. Unfor-
tunately, the reaction gave a complex mixture of com-
pounds, suggesting that the N-sulfinyl group was not
stable to TFA. Therefore, compounds 4A and 7A were
first N-desulfinylated, by TFA hydrolysis, to afford
compounds 8 and 9, respectively, and then the amino
group was reprotected as N-BOC, yielding 10 and 11,
respectively. These compounds were transformed into the
corresponding hydroxycarbamates, 12 and 13, respec-
tively, by reaction with TFA and sym-collidine (Scheme
4). The deprotection of the N-tert-butoxycarbonyl group
(21) Dellaria, J . F.; Santarsieiro, B. D. Tetrahedron Lett. 1988, 29,
6079.
(22) Prelog, V.; Mutak, S. Helv. Chim. Acta 1983, 66, 2274.

2860 J . Org. Chem., Vol. 65, No. 10, 2000
Garc´ıa Ruano et al.
Ta ble 3. 1H NMR P a r a m eter s of 16 a n d 8 a n d Th eir S-Meth yl An a logu es 16′ a n d 8′ (Sch em e 5)
compd
solvent
J AX (Hz)
J BX (Hz)
δ
Α (ppm)
δ
Β (ppm)
δX (ppm)
16 (16′)a
CDCl3
DMSO-d6
CDCl3
8.4 (8.0)
7.4 (7.6)
9.2 (10.5)
10.5 (10.8)
4.9 (5.9)
6.8 (6.5)
4.1 (3.3)
3.3 (3.3)
3.15 (3.12)
3.10 (3.01)
3.02 (2.97)
3.15 (2.99)
2.86 (2.87)
2.95 (2.95)
2.94 (2.92)
2.82 (2.81)
4.52 (4.51)
4.15 (4.25)
4.52 (4.59)
4.25 (4.21)
8 (8′)a
DMSO-d6
a
Data from ref 24.
Sch em e 6
skeletons have proved to exhibit a behavior very similar
to that of their corresponding oxygenated compounds.24
In this sense, different series of erythro and threo
â-oxygenated sulfones derived from 1,2-diphenyl- and 1,2-
dimethylethane had been studied in detail.25 Such a
study demonstrated that erythro compounds exhibited a
low 3J value (<4 Hz), whereas the threo compounds
showed clearly higher values of such constants (3J > 8
Hz). By assuming that this behavior would be similar
for the nitrogenated compounds 17 and 18, we could
assign the erythro configuration (RS or SR) to 17 (3J CH,CH
) 2.9 Hz) and the threo configuration (RR or SS) to 18
(3J CH,CH ) 8.6 Hz). On the basis of Scheme 6, we can
deduce that sulfoxides 6A, 6C, and 7A have opposite
configurations at their chiral carbons (RS or SR), whereas
6B, 7B, and 7D have identical configurations there (RR
or SS).
vicinal coupling constants in different solvents (Table 3).
Similar differences had allowed for the configurational
assignment of diastereomeric sulfoxides 16′ and 8′, Ph-
CH(NH2)-CH2-SOMe,23 which differ from 16 and 8 only
in the nature of the group joined to sulfur (methyl instead
p-tolyl). A comparison of the 1H NMR parameters of both
pairs of compounds (Table 3) allowed us to unambigu-
ously assign the relative configurations of 16 and 8. The
latter would have identical configurations at its two
chiral centers (RR or SS), whereas the former must have
opposite configurations (RS or SR). As the configurations
at the sulfinyl sulfur of 3A and 4A were known to be S
and R, respectively, the absolute configuration of all of
these compounds could be assigned as indicated in Table
3.
The TFA hydrolysis of the N-sulfinyl groups of the
diastereoisomeric mixtures of 6 and 7, obtained according
to entries 1 and 3 of Table 2, afforded diastereoisomeric
mixtures of amino sulfoxides 19 and 9, respectively,
which are identical in composition to the starting N-
1
sulfinyl derivatives (Scheme 7). The H NMR spectra of
compounds 19A and 19B are respectively identical to
those of 9A and 9B (which is only possible if they are
enantiomers, because compounds 19 and 9 have different
configurations at the sulfur), but those of 19C and 9D
1
are clearly different. Significant H NMR parameters of
all of these compounds, obtained from the spectra of the
mixtures, are depicted in Scheme 7. A conformational
study of the four possible â-oxygenated (OH, OR, and
OAc) sulfoxides with 1,2-dimethyl- and 1,2-diphenyle-
thane skeletons revealed that erythro and threo sulfoxides
with different configurations at sulfur and C-â (the
carbon supporting the oxygenated function) show, re-
The configurational assignment of the different dias-
tereoisomers of 6 and 7 was deduced from the following
facts. The mixtures obtained under the conditions of
entries 2 and 3 of Table 2 were oxidized into the
corresponding N-sulfonyl sulfones (Scheme 6). Treatment
of the mixture 6A + 6B + 6C (25:63:12) with MCPBA
yielded a new mixture of only two sulfones, 17 and 18
(36:64). The relative proportion of the latter suggests that
6A and 6C have been transformed into enantiomeric
3
spectively, the lowest and highest J CH,CH values (see
Figure 2). Moreover, these coupling constants were barely
dependent on the solvent polarity,26 thus contrasting with
those of the erythro and threo sulfoxides with identical
configurations at sulfur and C-â, which are substantially
modified by the solvent. By assuming that our nitroge-
nated compounds 19 and 9 would exhibit a similar
behavior, their configurational assignment could be easily
completed, on the basis of their 3J values, as indicated
in Scheme 7, taking into account that they derive from
(S)-5 and (R)-5, respectively.
1
N-sulfonyl sulfones 17 (with identical H NMR spectra),
whereas the major component, 6B, has produced 18.
Oxidation of the mixture 7A + 7B + 7D (89:3:8) (entry
3, Table 3) with MCPBA yielded a mixture of the same
sulfones 17 and 18 (89:11) (Scheme 6). This suggests that
the relative configuration of the chiral carbons of 7A must
be correlated with that of 17, and similarly for 7B and
7C with 18.
1
(24) This similarity was established from a detailed conformational
study of compounds Ph-CHX-CH2-SOnMe (n ) 1 or 2). A comparison
of the oxygenated series with X ) OH and OMe (Alcudia, F.; Brunet,
E.; Garc´ıa Ruano, J . L.; Hoyos, M. A.; Prados, P.; Rodrı´guez, J . H. Org.
Magn. Reson. 1983, 21, 643) with the corresponding nitrogenated series
with X ) NHPh, NH2, and NR2 (Alcudia, F.; Brunet, E.; Carren˜o, M.
C.; Gallego, M.; Garc´ıa Ruano, J . L. J . Chem. Soc., Perkin Trans. 2
1983, 937) showed that the interactions controlling the conformational
behavior were similar in both series.
The H NMR study of compounds 17 and 18 reveals
very different values for their vicinal coupling constants
3J CH,CH (2.9 Hz for 17 and 8.6 Hz for 18). To our
knowledge, the conformational behavior of â-amino sulf-
oxides and â-amino sulfones with a 1-phenyl-2-methyl-
ethane skeleton has never been studied. However, simi-
larly functionalized substrates with 1-phenylethane
(25) Carretero, J . C.; Garc´ıa Ruano, J . L.; Mart´ınez, M. C.; Rod-
r´ıguez, J . H. Tetrahedron 1985, 41, 2419.
(23) Brunet, E.; Gallego, M. T.; Garc´ıa Ruano, J . L.; Alcudia, F.
Tetrahedron 1986, 42, 1423.
(26) ) A detailed discusion of the conformational behavior of these
substrates appears in ref 25.

Additions of Enantiopure R-Sulfinyl Carbanions
J . Org. Chem., Vol. 65, No. 10, 2000 2861
Sch em e 7a
a
1H NMR coupling constants in CDCl3 and DMSO-d6 (in parentheses).
almost quantitative yield and a very high control of the
stereoselectivity in all of the new stereogenic centers. It
emerges as one of the best methods for obtaining enan-
tiomerically pure â-amino sulfoxides. The accessibility of
the chiral reagents and the crystallinity of many of the
starting materials and products make the reported
procedure amenable to large-scale processes.
Exp er im en ta l Section
Ad d ition of En a n tiop u r e Alk yl p-Tolyl Su lfoxid e An -
ion s to N-Su lfin ylim in es. Gen er a l P r oced u r e. To a solu-
tion of diisopropylamine (3.43 mL, 24.3 mmol) in dry THF (100
mL) at -78 °C under argon was added a 2.4 M solution of
butyllithium in hexane (10.12 mL, 24.3 mmol). After 20 min,
a solution of the alkyl sulfoxide (24.3 mmol) in THF (120 mL)
was added dropwise. After the mixture was stirred for 30 min
at -78 °C, a solution of (+)-(S)-(E)-N-benzylidene-p-toluene-
sulfinamide (1) (2.77 g, 12.1 mmol) in THF (160 mL) was
added. After the reaction finished (15 min), a saturated
aqueous NH4Cl solution (50 mL) was added; the organic phase
was extracted with ethyl acetate (3 × 200 mL), dried over
anhydrous sodium sulfate, and evaporated in vacuo. The crude
product was treated with hot ethyl tert-butyl ether (5 × 25
mL) to eliminate the excess sulfoxide, affording the corre-
sponding N-(â-sulfinylalkyl)sulfinamide.
F igu r e 2. Coupling constants (3J CH,CH) of the erythro and threo
sulfoxides used as models for the configurational assignment
of the nitrogenated compound 9 and 19.
Con clu sion
In summary, we have developed a practical and ef-
ficient synthesis of enantiomerically pure â-amino alco-
hols from enantiopure N-sulfinylimines. The key steps
are the asymmetric addition of enantiopure alkyl p-tolyl
sulfoxide anions to compound (S)-1 and the stereospecific
non-oxidative Pummerer reaction of the resulting â-
amino sulfoxide. The first reaction is a double asymmetric
induction process, with the couple (R)-sulfoxide/(S)-
sulfinimine as the matched pair, which occurs with
(S)-N-[(2R,RS)-1-P h en yl-2-p-tolylsu lfin yleth yl]-p-tolu -
en esu lfin a m id e (4A). The product was obtained as a white
crystalline solid from (S)-1 and (R)-2: yield 98%; mp 161-

2862 J . Org. Chem., Vol. 65, No. 10, 2000
Garc´ıa Ruano et al.
162 °C; [R]25 ) +216.5 (c 0.9, acetone); 1H NMR (CDCl3) δ
ter t-Bu tyl N-[(1R,RS)-1-P h en yl-2-p-tolylsu lfin yleth yl]-
ca r ba m a te (10). The product was obtained as a white
D
2.30 (s, 3H), 2.37 (s, 3H), 3.23 (AB fragment of an ABX system,
2H, J ) 6.4, 8.2, 13.2 Hz, ∆ν ) 82 Hz), 4.93 (m, 1H), 5.26 (d,
1H, J ) 5.1 Hz), 7.13-7.56 (m, 13H); 13C NMR (CDCl3) δ 141.9,
141.2, 140.8, 140.5, 141.0, 130.0, 129.2, 128.7, 128.0, 127.0,
crystalline solid from 8: yield 91%; mp 132-134 °C; [R]25
)
D
+47.38 (c 0.5, methanol); 1H NMR (CDCl3) δ 1.39 (s, 9H), 2.38
(s, 3H), 3.14 (AB fragment of an ABX system, 2H, J ) 5.1,
9.6, 13.3 Hz, ∆ν ) 48.0 Hz), 5.01 (m, 1H), 5.49 (br s, 1H), 7.24-
7.40 (m, 9H); 13C NMR (CDCl3) δ 154.7, 141.4, 140.5, 139.9,
129.6, 128.3, 127.3, 126.0, 124.0, 79.0, 63.9, 50.6, 27.9, 21.0.
Anal. Calcd for C20H25NO3S: C, 66.82; H, 7.00; N, 3.89.
Found: C, 66.65; H, 7.28; N, 3.88.
125.7, 124.1, 64.9, 53.1, 21.4, 21.2. Anal. Calcd for C22H23
-
NO2S2: C, 66.46; H, 5.83; N, 3.52. Found: C, 66.37; H, 5.99;
N, 3.51. HRMS calcd for
397.1166 (0.8 ppm).
C22H23NO2S2, 397.1170; found,
(S)-N-[(1R,2S,RS)-1-P h en yl-2-p-tolylsu lfin ylp r op yl]-p-
tolu en esu lfin a m id e (7A). The product was obtained as a
ter t-Bu tyl N-[(1R,2R,RS)-1-P h en yl-2-p-tolylsu lfin ylp r o-
p yl]ca r ba m a te (11). The product was obtained as a white
white crystalline solid: yield 85%; mp 177-179 °C; [R]25
)
D
+154.4 (c 0.9, methanol); 1H NMR (CDCl3) δ 1.00 (d, 3H, J )
6.7 Hz), 2.32 (s, 6H), 2.36 (s, 1H), 3.12 (m, 1H), 4.53 (d, 1H, J
) 9.1 Hz), 7.51-6.93 (m, 13H); 13C NMR (CDCl3) δ 137.0,
136.9, 136.7, 134.9, 134.7, 125.4, 124.9, 124.1, 123.4, 122.7,
crystalline solid from 9A: yield 93%; mp 164-166 °C; [R]25
D
) +76.5 (c 0.6, methanol); 1H NMR (CDCl3) δ 1.05 (d, 3H, J )
7.0 Hz), 1.41 (s, 9H), 2.38 (s, 3H), 2.94 (m, 1H), 5.07 (m, 1H),
5.36 (d, 1H, J ) 7.7 Hz), 7.50-7.37 (m, 9H); 13C NMR (CDCl3)
δ 155.0, 141.4, 139.4, 129.8, 128.7, 127.7, 126.4, 124.5, 65.3,
55.6, 28.3, 21.4, 5.5. Anal. Calcd for C21H27NO3S: C, 67.53; H,
7.29; N, 3.75. Found: C, 67.42; H, 7.68; N, 3.69.
121.2, 120.0, 61.4, 54.1, 16.9, 16.8, 1.2. Anal. Calcd for C23H25
-
NO2S2: C, 67.12; H, 6.12; N, 3.40. Found: C, 67.00; H, 6.24;
N, 3.25.
Desu lfin ylation of N-(â-Su lfin ylalkyl)su lfin am ides. Gen -
er a l P r oced u r e. To a stirred solution of the N-(â-sulfinyl-
alkyl)sulfinamide (12.4 mmol) in methanol (124 mL) was
added TFA (4.7 mL, 61.8 mmol). After the mixture was stirred
for 15 h at room temperature, the solvent was evaporated, CH2-
Cl2 (100 mL) was added, and the organic phase was extracted
with a 10% HCl aqueous solution (3 × 150 mL). The aqueous
phase was neutralized, at 0 °C, with solid Na2CO3 and
extracted with CH2Cl2 (3 × 150 mL). The combined organic
extracts were dried over Na2SO4 and evaporated under vacuo
to yield the free â-amino sulfoxide.
P u m m er er Rea ction a n d Dep r otection of â-Su lfin yl-
ca r ba m a tes. Gen er a l P r oced u r e. To a stirred solution of
the â-sulfinylcarbamate (11.4 mmol, 1 equiv) and sym-collidine
(2.67 mL, 34.2 mmol, 3 equiv) in acetonitrile (50 mL) at 0 °C
was added TFAA (7.0 mL, 56.9 mmol, 5 equiv), dropwise. The
reaction mixture was maintained for 15 min at 0 °C under
stirring before the addition of water (5 mL) and solid K2CO3
until pH 7 was reached. The mixture was warmed to room
temperature; after 5 min, the reaction was quenched with
saturated NH4Cl aqueous solution (50 mL), and the organic
phase was extracted with ethyl acetate (5 × 100 mL). The
organic layers were treated with 10% HCl aqueous solution
(50 mL) to remove the excess sym-collidine, dried over Na2-
SO4, and evaporated under vacuo. The crude material was
treated with a mixture of 1 N HCl aqueous solution (25 mL)
and THF (4 mL). After 48 h of vigorous stirring, the crude
product was extracted with CH2Cl2 (20 mL), and the aqueous
layer was evaporated under vacuo. The residue was treated
with a Dowex 1X8-200 ion-exchange resin, affording the
corresponding â-amino alcohol.
(1R,RS)-1-P h en yl-2-p-tolylsu lfin yleth yla m in e (8). The
product was obtained as a yellow powder from 4A: yield 95%;
mp 46-48 °C; [R]25 ) +110.9 (c 0.6, methanol); 1H NMR
D
(CDCl3, D2O) δ 2.36 (s, 3H), 3.00 (AB fragment of an ABX
system, 2H, J ) 5.0, 8.4, 13.0 Hz, ∆ν ) 58.0 Hz), 4.5 (dd, 1H,
J ) 5.0, 8.4 Hz), 7.52-7.26 (m, 9H); 13C NMR (CDCl3) δ 143.4,
141.2, 140.5, 129.6, 128.4, 127.4, 126.0, 123.6, 66.1, 52.5, 21.0.
Anal. Calcd for C15H17NOS: C, 69.46; H, 6.60; N, 5.40.
Found: C, 69.39; H, 6.62; N, 5.36. HRMS calcd for C15H17NOS,
259.1030; found, 259.1037 (-2.5 ppm).
(1R,2S,RS)-1-P h en yl-2-p-tolylsu lfin ylp r op yla m in e (9A).
The product was obtained as a white crystalline solid from
(R)-2-Am in o-2-p h en yleth a n ol (14).22 This product was
obtained from 10: yield 94%; [R]25 ) -31 (c 0.76, 1 N HCl);
7A: yield 96%; mp 113-115 °C; [R]25 ) +110.0 (c 0.7,
D
D
1
1H NMR (CDCl3, D2O) δ 3.52 (AB fragment of an ABX system,
2H, J ) 4.6, 8.0, 10.7 Hz, ∆ν ) 32.0 Hz), 3.85 (dd, 1H, J ) 8.0,
4.6 Hz), 7.30-7.12 (m, 5H); 13C NMR (CDCl3) δ 143.4, 129.5,
128.3, 127.9, 68.9, 58.7.
methanol); H NMR (CDCl3, D2O) δ 1.02 (d, 3H, J ) 6.9 Hz),
2.34 (s, 3H), 2.69 (dq, 1H, J ) 5.1, 6.9 Hz), 4.50 (d, 1H, J )
5.1 Hz), 7.40-7.24 (m, 9H); 13C NMR (CDCl3) δ 142.9, 140.9,
139.0, 129.6, 128.5, 127.5, 126.5, 124.1, 66.5, 56.6, 21.2, 4.1.
Anal. Calcd for C16H19NOS: C, 70.29; H, 7.00; N, 5.12.
Found: C, 70.31; H, 7.12; N, 5.20. HRMS calcd for C16H19NOS,
273.1187; found, 273.1192 (-1.9 ppm).
(1R,2R)-1-Am in o-1-p h en ylp r op a n -2-ol (15). This product
was obtained from 11: yield 94%; 1H NMR (CDCl3, D2O) δ
0.82 (d, 3H, J ) 6.2 Hz), 3.45 (d, 1H, J ) 3.4 Hz), 3.63 (dq,
1H, J ) 3.4, 6.2 Hz), 7.28-7.11 (m, 5H); 13C NMR (CDCl3) δ
143.8, 129.5, 128.6, 127.8, 73.2, 64.2, 20.7. (1R,2R)-1-Am in o-
1-p h en ylp r op a n -2-ol h yd r och lor id e:23 mp 192-193 °C;
BOC P r otection of â-Su lfin yla m in es. Gen er a l P r oce-
d u r e. To a solution of the free â-amino sulfoxide (12 mmol) in
acetonitrile (180 mL) and Et3N (4.2 mL, 30 mmol) was added
(t-BuOCO)2O (3.4 g, 15.6 mmol). After the mixture was stirred
for 15 h at room temperature (the mixture turned brown), the
reaction was quenched with 10% HCl aqueous solution (20
mL), and the organic phase was extracted with ethyl acetate
(4 × 100 mL). The organic layer was dried over Na2SO4,
evaporated under vacuum, and purified by column chroma-
tography on silica gel (ether/hexane, 2:1) to give the corre-
sponding carbamate.
[R]25 ) -26 (c 0.9, water).
D
Ack n ow led gm en t. This work was supported by the
“Ministerio de Educacio´n y Ciencia” (Spain) under
DGICYT Grants PB95-210 and PB97-0731.
J O9903858