Stereocontrolled Reactions Mediated by a Remote Sulfoxide Group: Synthesis of Optically Pure anti-β-Amino Alcohols

Article abstract of DOI:10.1021/ol0358410

(Equation presented) A one-step synthesis of enantiomerically pure anti-1,2-amino alcohol derivatives has been achieved by reaction of prochiral oxygenated 2-p-tolylsulfinylbenzyl carbanions with N-sulfinylimines bearing the same configuration at sulfur.

Full text of DOI:10.1021/ol0358410

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4513-4516
Stereocontrolled Reactions Mediated by
a Remote Sulfoxide Group: Synthesis
of Optically Pure anti-â-Amino Alcohols
Jose´ L. Garc´ıa Ruano* and Jose´ Alema´n
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049-Madrid, Spain
joseluis.garcia.ruano@uam.es
Received September 23, 2003
ABSTRACT
A one-step synthesis of enantiomerically pure anti-1,2-amino alcohol derivatives has been achieved by reaction of prochiral oxygenated 2-p-
tolylsulfinylbenzyl carbanions with N-sulfinylimines bearing the same configuration at sulfur.
Enantiomerically pure â-amino alcohols are structural sub-
units of wide occurrence in natural products. These com-
pounds are of importance as key synthetic intermediates for
the synthesis of biologically active compounds1 and as
stationary phases in HPLC.2 However, the main interest in
these substrates is related to their use as chiral ligands or
auxiliaries in asymmetric reactions.3 There are a large number
of recent publications involved in the search for new and
efficient methods of synthesis. In addition to resolution
methods,4 the most common strategy for their preparation
involves sequential creation of both chiral centers starting
from compounds containing the R-imino carbonyl fragment
(OdC-CdN) or from functional groups (R-aminocarbonyls,
R-hydroxyimines or oximes, R-amino acids, etc.),5 which are
conveniently modified by reduction or nucleophilic addition.
These procedures are characterized by a sequential creation
of both chiral centers by the use of nonracemic chiral starting
compounds. Of special mention is the Sharpless asymmetric
dihydroxylation6 (followed by regioselective amination of
the resulting cyclic carbamates or cyclic sulfates) and
aminohydroxylation7 of olefins. The usefulness of these
methods is often restricted by regioselectivity problems,
similar to those observed in sequences that involve the ring
opening of oxiranes, that arise using different catalytic
systems.8 As a consequence, the synthesis of 1,2-diaryl
derivatives, with different aromatic residues, is very difficult
using asymmetric catalysis. Therefore, most of the 1,2-diaryl-
1,2-amino alcohols used as chiral ligands have identical
aromatic residues (usually phenyl).
(1) Relevant bioactive naturally occurring amino alcohols: (a) Nikolau,
K. C.; Mitchel, H. J.; van Delft, F. L.; Rubsam, F.; Rodriguez, R. M. Angew.
Chem., Int. Ed. 1998, 37, 1871. (b) Heightman, T. D.; Vasella, A. T. Angew.
Chem., Int. Ed. 1998, 38, 750. (c) Kolter, T.; Sandhoff, K. Angew. Chem.,
Int. Ed. 1998, 38, 1532. (d) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(2) Yuki, Y.; Saigo, K.; Tachibana, K.; Hasegava, M. Chem. Lett. 1986,
1347.
(3) Recent reviews: (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem.
ReV. 1996, 96, 835. (b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Reetz,
M. T. Chem. ReV. 1999, 99, 1121. (d) ComprehensiVe Asymmetric Catalyst;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin,
1999. (e) Ojima, I. Catalytic Asymmetric Synthesis, 2nd ed.; VCH: New
York, 2000. (f) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (g) Bonini,
C.; Righi, G. Tetrahedron 2002, 58, 4981. (h) Tang, Z.; Jiang, F.; Yu, L.-
T.; Xin, C.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem.
Soc. 2003, 125, 5262.
(5) Shimizu, M.; Tsukamoto, K.; Matsutani, T.; Fujisawa, T. Tetrahedron
1998, 54, 10265.
(6) (a) Sharpless, K. B.; Gao, Y. J. Am. Chem. Soc. 1988, 110, 7538.
(b) Sharpless, K. B.; Chang, H. T. Tetrahedron Lett. 1996, 37, 3129. (c)
Nicolaou, K. C.; Huang, X.; Zinder, S. C.; Rao, B. P.; Bella, M. V.; Reddy,
M. V. Angew. Chem., Int. Ed. 2002, 41, 834.
(7) (a) Li, G.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996, 35,
451-454. (b) Andrsson, M. A.; Epple R.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 472.
(8) (a) Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421. (b) Lane, B. S.;
Burgess, K. Chem. ReV. 2003, 103, 2457.
(4) Aoyagi, Y.; Agata, N.; Shibata, N.; Horiguchi, M.; Williams, R. M.
Tetrahedron Lett. 2000, 41, 10159.
10.1021/ol0358410 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/21/2003

Interestingly, the C-C bond disconnection represents the
most direct retrosynthetic route for simultaneously creating
both chiral carbon atoms of â-amino alcohols. An interesting
approach reported from the Uemura group9 is based on a
radical reductive cross-coupling of N-tosyl benzylideneamine
with chromium complexes of benzaldehydes mediated by
samarium iodide. Thus, this reaction gives syn-â-amino
alcohols in high optical purity (90-94% de). The coupling
reactions of R-metalloheteroatoms with aldehydes or imines
have also been used. The most common are those in which
the anion is generated adjacent to a nitrogen,1d but few are
efficient and only produce syn-amino alcohols.10 The reac-
tions of anions R to an oxygen are less popular (also yielding
the syn isomers), with imines11 perhaps due to the paucity
of suitable imines. In this sense, the use of N-sulfinylimines12
as electrophiles could provide a powerful method for 1,2-
amino alcohol preparation. However, their reactions with
R-oxygenated carbanions have never been reported.
Scheme 1
The synthesis of the enantiopure N-sulfinylimines 1a-j14
as well as alcohol (S)-213 has been previously reported. To
determine the role played by the sulfur configuration of each
reagent in controlling the newly created chiral centers, we
first studied the reaction of sulfoxide (S)-2 with (R)-1a, (S)-
1a, and the corresponding sulfone 1′a (Scheme 2). N-
Scheme 2
We have recently solved the problem regarding stereo-
selective benzylation of N-sulfinylimines by using benzyl-
carbanions stabilized by a p-tolylsulfinyl group at the ortho
position.13 This method efficiently achieved complete ste-
reocontrol in reactions forming two chiral centers simulta-
neously. Such results suggested an unusual configurational
stability of the benzylic carbanions, due to the stabilization
by the sulfinyl group. Taking into account the positive
influence of the oxygen on the configurational stability of
the carbanions, we reasoned that the reactions of the
N-sulfinylimines with the oxygenated carbanions also bearing
a p-tolylsulfinyl at the ortho position should provide 1,2-
amino alcohol derivatives. Moreover, as a similar stereo-
chemical course should be expected for both reactions, anti
products would be obtained (most of the reported methods
concern the syn isomers). This procedure would provide
access to diaryl derivatives with various aromatic residues,
which cannot be easily obtained by chiral catalysis. In this
paper we report the results obtained from the reaction of
different N-p-tolylsulfinylimines (1a-j), derived from ali-
phatic and aromatic aldehydes with the oxygenated carbanion
2, which produces anti-(1-alkyl or aryl)-2-aryl-1,2-amino
alcohol derivatives (Scheme 1).
sulfonylimine (1′a) yielded a 89:11 mixture of 3′ and 4′,
epimeric at C-2 (de 78%). This result demonstrates that the
sulfur configuration in (S)-2 completely controls the stereo-
selectivity at the benzylic position. It also exhibits a strong
influence on the configuration created at the electrophilic
center. A mixture of two compounds [(R)-3a and (R)-4a]
was also obtained starting from (R)-1a, but in this case, the
de was lower (50%) than that observed from the sulfone.
The reaction of (S)-2 with (S)-1a yielded the (S)-3a
compound as a single stereoisomer (de > 98%, Scheme 2).
These results indicate that changing the configuration at the
sulfur of 1a does not have any influence on the configuration
of the benzyl oxygenated carbon. The configuration is
completely controlled by the sulfinyl group of (S)-2. It is
remarkable that the chiral sulfur is more important than the
N-sulfinylimine in controlling the stereoselectivity at the
electrophilic center.
(9) (a) Tanaka, Y.; Taniguchi, N.; Uemura, M. Org. Lett. 2002, 4, 835-
838. (b) Tanaka, Y.; Taniguchi, N.; Kimura, T.; Uemura, M. J. Org. Chem.
2002, 67, 9227.
(10) (a) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett.
2002, 4, 2621. (b) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh,
N.; Shibasaki, M. J. Org. Chem. 1995, 60, 7388. (c) Horikawa, M.; Buch-
Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843.
(11) (a) Arrasate, S.; Lete, E.; Sotomayor, N. Tetrahedron: Asymmetry
2002, 13, 311. (b) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem. Soc.
1998, 120, 431.
(12) These compounds have shown their efficiency in controlling the
stereoselectivity of nucleophilic additions. The most significant contributions
are those from Davis’s group and Ellman’s group: (a) Davis, F. A.; Zhou,
P.; Chen, B. C. Chem. Soc. ReV. 1998, 27, 13. (b) Davis, F. A.; Wu, Y.;
Yan, H.; McCoull, W.; Prasad, K. R. J. Org. Chem. 2003, 68, 2410. (c)
Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y. Org. Lett. 2003, 5, 925.
(d) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35,
984. (e) Ellman, J. A. Pure Appl. Chem. 2003, 75, 39. (f) Weix, D. J.;
Ellman, J. A. Org. Lett. 2003, 5, 1317. (e) Schenkel, L. B.; Ellman, J. A.
Org. Lett. 2003, 5, 545.
In our reactions, the configuration of the imine only
modulates the stereocontrol exerted by the sulfinyl group in
(S)-2. In this sense, the stereochemical outcome of these
reactions is similar to that of a double-asymmetric induction
process where the matched pair is formed by reagents with
the same configuration at sulfur (S)-2 and (S)-1a. Another
significant fact concerns the comparison of the results
obtained from R-oxygenated carbanions (Scheme 2) and their
corresponding alkyl carbanions.14 The stereoselectivity of all
these reactions was higher with the oxygenated substrates,
in agreement with our initial analysis.
(13) Garc´ıa Ruano, J. L.; Aranda, M.; Carreno, M. C.; Toledo, M. A.
Angew. Chem., Int. Ed. 2000, 39, 2736.
(14) Garc´ıa Ruano, J. L.; Alema´n, J.; Soriano J. F. Org. Lett. 2003, 5,
677.
4514
Org. Lett., Vol. 5, No. 23, 2003

The stereochemical results shown in Scheme 2 can be
explained on the basis of the same model proposed for alkyl
benzyl carbanions.14 We assume the structure of the nucleo-
phile is (Li+-(S)-2) (Figure 1) where the benzyllithium is
Seven of them derive from arylaldimines (1a-g) containing
donor and electron-attracting groups due to the potential
interest of the 1,2-diaryl-1,2-amino alcohols with different
aromatic residues as chiral ligands. Alkylaldimines were also
studied. The NMR spectra of the crude reaction mixtures
show signals corresponding to only one diastereoisomer (3a-
j). This means that the de of the reaction is greater than 98%
in all of the cases studied, regardless the electronic character
of the aryl groups and the size of the alkyl ones. The isolated
yields were decreased, ranging from 68 to 81% (Table 1),
Table 1. Reactions of (S)-2 with N-Sulfinylimines (S)-1a-j
entry
products (R)
crude yield (%) yield (%) de (%)
1
2
3
4
5
6
7
8
9
(Ph) 3a
(o-BrC6H4) 3b
(p-MeOC6H4) 3c
(p-CNC6H4) 3d
(p-ClC6H4) 3e
(2-Py) 3f
>98
90
>98
>98
95
>98
>98
>98
>98
>98
81
71
78
74
76
77
68
74
72
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
(2-Napht) 3g
(n-Bu) 3h
Figure 1. Stereochemical model explaining the reactions of 2 and
with N-sulfinylimines.
(i-Pr) 3i
(t-Bu) 3j
10
see text
stabilized by the sulfinyl oxygen atom. The preferred
configuration of this intermediate is where the carbanion
adopts a pseudo axial arrangement with the p-tolyl and
OTIPS groups, thus avoiding allylic strain with the neighbor-
ing aromatic ortho protons.13 The complete stereoselective
control at the benzylic position observed in all the reactions
is consistent with the assumption that nucleophilic addition
to the CdN bond proceeds with total retention of stereo-
chemistry.
After association of the lone pair of electrons at the imine
nitrogen with the lithium metal, where an equatorial approach
is favored, two different four-membered ring transition states
(A and B in Figure 1) can be postulated. The minimized
steric interactions in TS-A (H/OTIPS + H/R) with respect
to TS-B (H/H + R/OTIPS) nicely explains the strong
influence of the sulfinyl group at (S)-2 on the stereoselectivity
at the electrophilic center. Compound 3 is the major product
regardless of the substituent group at nitrogen.15 The sulfur
configuration at (1) modifies the energetic difference between
TS-A and TS-B, and this becomes higher for (S)-1a (de >
98%) and lower for (R)-1a (de ) 50%).16
because the resulting amino alcohol derivatives are not
completely stable on silica gel.17 Configurational assignments
for compounds 3 were tentatively made from their NMR data
and later confirmed by X-ray analysis of compound 3i18 (see
Supporting Information). Chemical correlation of compound
3a with compound 919of known configuration was achieved
(Scheme 3).
Although the final aim of this work is the synthesis of
anti-1,2-amino alcohols, compounds 3a-i as well as their
partially deprotected derivate are also interesting in the field
of chiral ligands, because they contain additional coordination
centers. In particular, the ability of the sulfinyl group to
coordinate to several metals20 adds interest to the sulfinylated
amino alcohols. Eventually, these sulfoxides can be easily
transformed into thioethers, which have also been widely
(16) As the lone pair of electrons supported by the sulfur at sulfinylimine
group will be oriented toward the intermediate, thus minimizing steric
interactions, the relative stability of TS-A and TS-B will depend on the
configuration of 1 because the interaction (O/H)1,3-syndiaxial is lower than
(Tol/H)1,3-syndiaxial, thus making TS-BS and TS-AR less stable (see Figure
1).
(17) NMR spectra of the reaction crude are very clean and revealed the
almost quantitative conversion in all the cases, even starting from 1j. Indeed,
compound 3j was completely destroyed during chromatographic purification
(18) The authors have deposited atomic coordinates for 3i with the
Cambridge Crystallographic Data Centre (deposition number CCDC
208928). The coordinates can be obtained, on request, from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge Cb2
1EZ, UK.
With these results in hand, the reactions of (S)-2 with a
variety of (S)-N-p-tolylsulfinylimines (1a-j) were studied.
(15) The higher de observed from R-sylilated carbanions with respect
to their corresponding alkyl derivatives (see ref 13) could be explained with
this model by assuming the OTIPS group is larger than the Me one.
However, the competence between transition states such as TS-A with others
involving eight-membered rings cannot be disregarded and it is currently
under study with other electrophiles.
(19) Kanematsu, K.; Sasaki, T. J. Med. Chem. 1966, 847.
(20) Fernandez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651.
Org. Lett., Vol. 5, No. 23, 2003
4515

Scheme 3
used as coordinating centers.21 In this sense, an additional
In summary, the reaction between prochiral oxygenated
2-p-tolylsulfinylbenzyl carbanions with N-sulfinylimines
allows formation of the C-C bond to proceed with complete
stereoselective control at the two new stereogenic centers.
The method allows for a one-step synthesis of enantiomeri-
cally pure 1,2-diaryl anti-1,2-amino alcohols with identical
or different aromatic residues and 1-aryl-2-alkyl anti-1,2-
amino alcohol derivatives. The orthogonal deprotection of
the different functional groups yields a variety of structures
potentially useful as chiral ligands. Studies directed toward
adapting this procedure to the synthesis of the syn-1,2-amino
alcohols, as well as to probing the efficiency of the obtained
chiral ligands in asymmetric catalysis are in progress.
advantage of compounds 3 is the fact that their protecting
groups are orthogonal. Different approaches to the sequential
breaking in 3a of the N-S, O-Si, and C-S bonds, which
do not affect the configuration of the two newly created chiral
carbons, are illustrated in Scheme 3. The TIPS group can
be easily removed with Bu4NF or CsF without affecting the
other functions. Analogously, the N-S bond is easily broken
with TFA. Hydrogenolysis of the C-S bond with Ra-Ni
proceeds in higher yield with substrates containing a free
hydroxyl group. However, the use of the OTIPS derivative
can be more convenient in some cases in order to avoid
epimerization22 of the final benzylic alcohol, as was reported
in some cases.23
Acknowledgment. We thank CAICYT (Grant BQU2003-
04012) for financial support. J.A. thanks Spanish Ministerio
de Ciencia y Tecnolog´ıa for a predoctoral fellowship.
(21) Recent references about the use of sulfoxides as chiral ligands: (a)
Lai, C.-Y.; Mak, W.-L.; Chan, E. Y. Y.; Sau, Y.-K.; Zhang, Q.-F.; Lo, S.
M. F.; Williams, I. D.; Leung, W.-H. Inorg. Chem. 2003, 42, 5863. (b)
Ekegren, J. K.; Roth, P.; Kallstrom, K.; Tarnai, T.; Andersson, P. G. Org.
Biomol. Chem. 2003, 1, 358. (c) Rowlands, G. J. Synlett 2003, 236. (d)
Watanabe, K.; Hirasawa, T.; Hiroi, K. Chem. Pharm. Bull. 2002, 50, 372.
(e) Priego, J.; Mancheno, O.; Cabrera, S.; Carretero, J. C. J. Org. Chem.
2002, 67, 1346. Recent references about the use of thioethers as chiral
ligands: (f) Masdeu-Bulto, A. M.; Dieguez, M.; Martin, E.; Gomez, M.
Coord. Chem. ReV. 2003, 242, 159. (g) Verdaguer, X.; Pericas, M. A.; Riera,
A.; Maestro, M. A.; Mahia, J. Organometallics 2003, 22, 1868. (h) Dervisi,
A.; Jenkins, R. L.; Malik, K. M. A.; Hursthouse, M. B.; Coles, S. Dalton
Trans. 2003, 1133.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 3a-j and 5-9
and X-ray data for 3i. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0358410
(22) Partial epimerization was not observed in the reactions from 6 and
9 indicated in Scheme 3.
(23) Garc´ıa Ruano, J. L.; Paredes, C. G.; Hamdouchi, C. Tetrahedron:
Asymmetry 1999, 10, 2935 and references therein.
4516
Org. Lett., Vol. 5, No. 23, 2003