Asymmetric enamide hydrogenation using phosphinite thioglycosides: Synthesis of D- and L-aminoesters using D-sugars as catalyst precursors

Article abstract of DOI:10.1021/ol801301x

(Chemical Equation Presented) Diastereomerically pure cationic Rh(I) complexes derived from phosphinite thioglycosides I were used as catalysts in highly enantioselective hydrogenations of enamides. The conformational similarity of α-D-arabinopyranose wit

Full text of DOI:10.1021/ol801301x

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3697-3700
Asymmetric Enamide Hydrogenation
Using Phosphinite Thioglycosides:
Synthesis of D- and L-Aminoesters
Using D-Sugars as Catalyst Precursors
,†
†
†
†
´
Noureddine Khiar,* Raquel Navas, Bele´n Sua´rez, Eleuterio Alvarez, and
Inmaculada Ferna´ndez*,‡
Instituto de InVestigaciones Qu´ımicas, C.S.I.C-UniVersidad de SeVilla, c/. Ame´rico
Vespucio, 49, Isla de la Cartuja, 41092 SeVilla, Spain, and Departamento de Qu´ımica
Orga´nica y Farmace´utica, Facultad de Farmacia, UniVersidad de SeVilla,
41012 SeVilla, Spain
khiar@iiq.csic.es; inmaff@us.es
Received June 9, 2008
ABSTRACT
Diastereomerically pure cationic Rh(I) complexes derived from phosphinite thioglycosides I were used as catalysts in highly enantioselective
hydrogenations of enamides. The conformational similarity of r-D-arabinopyranose with ꢀ-L-galactopyranose allows the synthesis of both
enantiomers of r-amino acid derivatives such as D- and L-DOPA in excellent ee (97% and 98%), using derivatives of the former sugar as
catalyst precursors.
Asymmetric catalysis is the method of choice for the
synthesis of enantiopure compounds since it combines
efficiency and versatility with atom economy, and it is well-
matched for the “Green Chemistry” initiative.1 Commonly,
only one enantiomer is needed for a given activity, although
there are cases such as R-amino acids where both enanti-
omers are required in optically pure form. Alternating, for
instance, an even number of D- and L-amino acids in cyclic
peptides gives rise to supramolecular assemblies known as
peptide nanotubes, which are able to form artificial trans-
membrane channels for ion and glucose transport, as well
as exert antibacterial activity.2 D-Amino acids are constituents
of natural and synthetic cytotoxic peptides endowed with
important anticancer activities.3 Finally, with the increasing
importance of organocatalysis,4 there is a growing need for
structurally diverse amino acids in both enantiomeric forms
since they are among the best organocatalysts.5 As such,
(2) (a) Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.;
Khazanovich, N. Nature 1993, 366, 324. (b) Ghadiri, M. R.; Granja, J. R.;
Buehler, L. Nature 1994, 369, 301.
† C.S.I.C-Universidad de Sevilla.
‡ Facultad de Farmacia, Universidad de Sevilla.
(3) (a) Hamada, T.; Matsunaga, S.; Yano, G.; Fusetani, N. J. Am. Chem.
Soc. 2005, 127, 110. (b) Papo, N.; Brunstein, A.; Essahar, Z.; Shai, Y.
Cancer Res. 2004, 64, 5779.
(1) Recently, 2 Issues of the Proceedings of the National Academy of
Sciences of the USA were dedicated to the Special Feature of asymmetric
catalysis, see: Proc. Natl. Acad. Sci. U.S.A. 2004, 101 (15), 5311-5696
and Proc. Natl. Acad. Sci. U.S.A. 2004, 101 (16) 5697-6327.
(4) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(b) Pellissier, H. Tetrahedron 2007, 83, 9267.
10.1021/ol801301x CCC: $40.75
Published on Web 07/29/2008
2008 American Chemical Society

catalyst precursors are often derived from natural products,
and access to both enantiomers is not always possible. As a
part of our interest in chiral sulfur compounds,6 we have
recently started a research program directed toward the use
of sulfur-based ligands derived from carbohydrates in enan-
tioselective catalysis.7 Following the seminal work of Evans
on the use of mixed S/P ligands in asymmetric catalysis,8 in
the present paper we report our results on the Rh-catalyzed
asymmetric hydrogenation of enamides using our phosphinite
thioglycosides I as ligands. In light of the prohibitive price
of L-sugars, an important achievement of the present research
has been the synthesis of both enantiomers of R-amino acids
using natural D-sugars as catalyst precursors9 (Scheme 1).
respectively (see Supporting Information). Before conducting
the first catalytic study, we first synthesized an advanced
catalytic precursor with well-defined structure. Treatment of
the starting mixed S/P ligands with Rh(cod)2SbF6 in meth-
ylene chloride afforded the corresponding Rh(I) complexes
in variable yield (Scheme 2).10 In the case of ligands 2-5,
Scheme 2
Scheme 1
the corresponding Rh(I) complexes were obtained in excel-
lent yields, while the use of ligand 1 afforded a complex
mixture, most likely as a result of the 1,2-cis orientation of
the bulky SC(Me)3 and the OPPh2. One of the most salient
features of mixed ligands I is that, upon coordination to the
rhodium, the sulfur atom becomes stereogenic. Consequently,
highly enantioselective processes are expected with these
complexes, based on the close proximity of the chiral sulfur
atom to the coordination sphere of the transition metal,
provided that the low inversion barrier of the sulfur metal
To determine the structural features of the type I ligands
for optimal catalysis, compounds 1-5 derived from 2-diphe-
nylphosphinite-3,4-O-isopropyliden thiogalactoside were syn-
thesized (Figure 1).
bond can be surmounted.11 Interestingly, the H, 13C, and
1
31P NMR spectra indicated that complexes 6-9 were
obtained as a single diastereoisomer, highlighting the excel-
lent stereochemical control exerted by the sulfur substituent.
The preformed catalyst precursors 6-9 as well as the in
situ formed catalyst precursor derived from ligand 1 were
assayed in the hydrogenation of the model olefin methyl (Z)-
R-acetamido cinnamate 10, in various solvents and at
different hydrogen pressures using 1 mol % of the catalyst.
The results are summarized in Table 1.
As can be seen from Table 1, the R-thioglycoside ligand
1 is completely inactive in the hydrogenation of the model
olefin, as the starting material was obtained unchanged (Table
1, entry 1). The aromatic S/P complex 6 afforded the phenyl
alanine derivative 11 with low conversion and essentially
as a racemate, even though high hydrogen pressure was used
(Table 1, entry 2). Surprisingly, replacement of the aromatic
ring on the sulfur atom with a bulky alkyl group afforded
an excellent catalyst for the hydrogenation of methyl (Z)-
R-acetamido cinnamate 10. The use of 1 mol % of catalyst
7 at room temperature, and 4 atm of hydrogen pressure,
smoothly afforded the desired amino ester in quantitative
yield and 94% ee (Table 1, entry 3). Both catalysts 8 and 9
afforded the (S)-N-acetyl phenyl alanine methyl ester 11 in
92% ee, although 8 atm of hydrogen pressure was needed
for the reaction to reach completion (Table 1, entries 4 and
Figure 1. Structure of phosphinite thioglycosides 1-5 used as chiral
ligands in asymmetric enamide hydrogenation.
The new ligands 4 and 5 were evaluated to determine the
steric and electronic effects of the 6-hydroxyl group on the
catalytic behavior of those types of ligands. They were
obtained from 6-O-acetyl-2-diphenylphosphinite-3,4-O-iso-
propylidene thiogalactoside 3 in three and four steps,
(5) Inomata, K.; Barrague´, M.; Paquette, L. J. Org. Chem. 2005, 70,
533.
(6) Khiar, N.; Ferna´ndez, I. Chem. ReV. 2003, 103, 365.
(7) (a) Khiar, N.; Arau´jo, C. S.; Alvarez, E.; Ferna´ndez, I. Tetrahedron
Lett. 2003, 44, 3401. (b) Khiar, N.; Arau´jo, C. S.; Sua´rez, B.; Alvarez, E.;
Ferna´ndez, I. Chem. Commun. 2004, 714. (c) Khiar, N.; Sua´rez, B.; Valdivia,
V.; Ferna´ndez, I. Synlett 2005, 2963. (d) Khiar, N.; Sua´rez, B.; Ferna´ndez,
I. Inorg. Chem. Acta. 2006, 359, 3048.
(8) (a) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.;
Gagne, M. R J. Am. Chem. Soc. 2000, 122, 7905. (b) Evans, D. A.; Michael,
F. E.; Tedrow, J. S.; Campos, K. R. J. Am. Chem. Soc. 2003, 125, 3538.
(9) For a different approach using homodonor P/P ligands derived from
carbohydrates, see: (a) Rajanbabu, T. V.; Ayers, T. A.; Casalnuovo, A. L.
J. Am. Chem. Soc. 1994, 116, 4101. (b) Ayers, T. A.; RajanBabu, T. V.
U. S. Patent 5510507, 1996.
(10) Rajanbabu, T. V.; Ayers, T. A.; Halliday, G. A.; You, K. K.;
Calabrese, J. C. J. Org. Chem. 1997, 62, 6012.
(11) Inversion of the metal-sulfur barrier is low and around 15-20
kcal/mol: (a) Abel, E.; Bhargava, S. K.; Orrell, K. G. Prog. Inorg. Chem.
1984, 32, 1. (b) Abel, E.; Dormer, J.; Ellis, D.; Orrell, K. G.; Sik, V.;
Hursthouse, M. B.; Mazid, M. A. J. Chem. Soc., Dalton Trans. 1992, 1073.
3698
Org. Lett., Vol. 10, No. 17, 2008

15 with only 86% ee.12 Interestingly enough, while the
p-methoxy-phenylalanine derivative 16 was obtained in 88%
ee, the L-DOPA precursor 17 was obtained in an excellent
97% ee and quantitative yield.13 As stated in the introduction,
the main challenge when employing carbohydrates in asym-
metric catalysis is the access to both enantiomers of the
catalyst. As an illustration, while D-glucose is one of the less
expensive chiral compounds in the market (1.2 Eu/mol),
commercially available L-glucose is exceedingly expensive
(8690 Eu/mol). To solve this problem, we have recently made
use of the similarity between R-D-arabinose, a cheap com-
mercially available D-pentopyranose and ꢀ-L-galactose.
Treatment of arabinose-based mixed S/P ligand 18 with
[(cod)2Rh]SbF6 in methylene chloride at room temperature
afforded the cationic Rh(I) complex 19 in quantitative yield,
as a single diastereoisomer (Scheme 4). Fortunately, in this
Table 1. Enantioselective Hydrogenation of Methyl
(Z)-R-Acetamido Cinnamate 10 with Cationic Rh(I) Complexes
6-9a
P
(bar)
convn
(%)c
% ee
(conf)d
entrya
[L-Rh(cod)]SbF6
solv.
1
2
3
4
5
6
7
8
1b
6
7
8
9
7
7
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
4
35
4
8
8
1
4
18
0
20
-
8 (S)
100
100
100
100
100
100
94 (S)
92 (S)
92 (S)
94 (S)
92 (S)
90 (S)
THF
a All reactions were conducted in CH2Cl2 using 1 mol % of the catalyst.
b The reaction was conducted with the in situ generated catalyst. c Determined
Scheme 4
by H NMR after 24 h. d Determined by chiral HPLC using the Chiracel-
1
OJ column.
5). These results demonstrate that the key structural motifs
of the catalyst are the relative configurations at C1 and C2,
together with the nature of the substituent at the anomeric
sulfur atom. The best catalyst 7 was able to give the desired
product in 100% yield and 94% ee, using only 1 atm of
hydrogen pressure (Table 1, Entry 6).
case, we obtained adequate crystals for X-ray analysis (Figure
2). In the crystal form, the pentopyranose ring is in the C4
1
To determine the synthetic value of the process, aryl
enamides 12-14 were hydrogenated under the optimal
conditions, determined for 10, and the results are given in
Scheme 3.
Scheme 3
Figure 2. ORTEP plot for the cationic Rh(I) complex 19.
form while the six-membered metallacycle ring is in a twist-
boat conformation. Interestingly, the bulky tert-butyl group
is in a pseudoaxial disposition outlying from the pyranose
substituents, fixing the configuration of the sulfur atom as
R. The pseudoaxial disposition of the sulfur substituent is
actually well documented;14 though not fully understood, this
forces the aromatic rings of the phosphine to adopt an edge-
In all cases, the final amino esters were obtained in
quantitative yields and good to excellent ee’s, using simple
reaction conditions. It is worth mentioning that the 3-fluoro-
phenyl alanine derivative 15, which is obtained in 93% ee,
is currently being industrially produced by a chemoenzymatic
approach, where the first step is an asymmetric hydrogenation
of the enamide using DUPHOS as ligand. The latter produces
(13) (a) Knowles, W. In Asymmetric Catalysis on Industrial Scale:
Challenges, Approaches and Solutions; Blaser, H. U., Schmidt, E., Eds.;
Wiley-VCH: Weinheim; p 23. (b) Selke, R. In Asymmetric Catalysis on
Industrial Scale: Challenges, Approaches and Solutions; Blaser, H. U.,
Schmidt, E., Eds.; Wiley-VCH: Weinheim; p 39.
(14) Barbaro, P.; Currao, A.; Hermann, J.; Nesper, R.; Pregosin, P.;
Salzmann, R. Organometallics 1996, 15, 1879.
(12) Cobley, C. J.; Johnson, N. B.; Lennon, I. C. In Asymmetric Catalysis
on Industrial Scale: Challenges, Approaches and Solutions; Blaser, H. U.,
Schmidt, E., Eds.; Wiley-VCH: Weinheim; p 269.
Org. Lett., Vol. 10, No. 17, 2008
3699

on face-on conformation (Figure 2), which is suggested to
be of crucial importance in the enantiocontrol behavior of
C2-symmetric bisaryl phosphines.15
Table 2. Enantioselective Hydrogenation of Methyl Enamides
12-14 with the Cationic Rh(I) Complex 19
On the other hand, there is a large difference between the
bond lengths (around 0.1 Å) trans to the phosphorus
[Rh-C(29) ) 2.298 Å y Rh-C(30) ) 2.275 Å], compared
to those trans to the sulfur [Rh-C(25) ) 2.157 y Rh-C(26)
) 2.167 Å], highlighting the major trans influence of the
phosphorus atom compared to the sulfur atom.16 To compare
the performance of complex 19 with that derived from
galactose 7, the hydrogenation of the model substrate methyl
(Z)-R-acetamido cinnamate 10 was conducted under the same
conditions as before.
entrya
substrate
P (bar)
convn (%)b
% ee (conf)c
1
2
3
4
5
12
12
13
13
14
4
15
4
15
15
18
100
48
100
100
93 (R)
93 (R)
92 (R)
91 (R)
98 (R)
a All reactions were conducted in CH2Cl2 using 1 mol % of the catalyst.
b All the reactions were stopped after 24 h. c Determined by chiral HPLC
using the Chiracel-OJ column.
Employing 1 mol % of the complex 19, and 1 atm of
hydrogen, the desired phenyl alanine derivative 11 was
obtained in quantitative yield (Scheme 5). Interestingly, the
catalyst always gave higher enantioselectivities. This result
is of some importance as it indicates that, while flexibility
of the ligand has a negative effect on Pd-catalyzed allylic
substitution, in the case of asymmetric hydrogenation of
enamides it is helpful.17
Scheme 5
In conclusion, the results reported in this work illustrate
the high potential of phosphinite thioglycosides I in asym-
metric hydrogenation of enamides for the synthesis of
proteogenic and nonproteogenic R-amino acids in high
enantiomeric excesses. Using commercially accessible D-
sugars as catalyst precursors, we secured both enantiomers
of important proteogenic and nonproteogenic R-amino acid
derivatives such as D- and L-DOPA 17 in quantitative yields
with 97% and 98% ee’s, respectively. The tuning of other
parameters implemented in the synthetic design, such as the
electronic character of the phosphine moiety and the
conformation of the pyranose ring, may certainly lead to
more efficient catalysts. Work along these lines is under
active investigation in our group.
11R enantiomer, the opposite to that produced by the
galactose-derived catalyst 7, was obtained in 94% ee in both
methylene chloride and THF. To generalize the pseudoe-
nantiomeric behavior of catalyst 19 with that of 7, the
enamides 12-14 were hydrogenated as before, and the
results are summarized in Table 2.
As can be seen from Table 2, using 1 mol % of the catalyst
19, the final amino esters 15-17 were obtained with the R
absolute configuration, which is the opposite of the one
obtained with the galactose-derived catalyst 7. While higher
hydrogen pressures were needed (Table 2, entries 2, 4, and
5), the final amino esters were all obtained with high
enantiomeric excesses. Interestingly, and contrary to the
behavior of the starting ligands 3 and 18 in Pd-catalyzed
allyllic substitution, in the present case, the arabinose-based
Acknowledgment. We thank the Direccio´n General de
Investigacio´n Cient´ıfica y Te´cnica (grant No. CTQ2006-
15515-CO2-01 and CTQ2007-61185), la Junta de Andaluc´ıa
(grant P07-FQM-2774), and la Fundacio´n Ramo´n Areces for
financial support.
Supporting Information Available: Representative ex-
perimental procedures for the synthesis of compounds 4 and
5 and the Rh(I) complexes 6-9 and 19 and HPLC data for
the determination of enantiomeric excesses of 11 and 15-17.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Brown, J. M. Hydrogenation of Functionalized Carbon-Carbon
Double Bonds; Jacobsen, E. N., Pfaltz, A., Ymamoto, H., Eds.; Springer:
Berlin, 1999; Vol. 1, p 119. (b) Brown, J.; Evans, P. Tetrahedron 1988,
44, 4905.
(16) (a) Appleton, T. G.; Clarks, H. C.; Manzer, L. E. Coord. Chem.
ReV. 1973, 10, 335. (b) Murray, S.; Hartley, F. Chem. ReV. 1981, 81, 365.
(17) (a) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495. (b) Vargas, S.; Rubio,
M.; Sua´rez, A.; Pizzano, A. Tetrahedron Lett. 2005, 46, 2049.
OL801301X
3700
Org. Lett., Vol. 10, No. 17, 2008