First chiral phosphoroamidite-phosphite ligands for highly enantioselective and versatile Pd-catalyzed asymmetric allylic substitution reactions

Article abstract of DOI:10.1021/ol0624631

(Chemical Equation Presented) A series of phosphite-phosphoroamidite ligands, derived from readily available D-xylose, has been successfully applied for the first time in the Pd-catalyzed allylic substitution of several substrates with different steric and electronic properties, with high enantioselectivities (ee's up to 98) and activities in standard conditions.

Full text of DOI:10.1021/ol0624631

ORGANIC
LETTERS
2007
Vol. 9, No. 1
49-52
First Chiral Phosphoroamidite-phosphite
Ligands for Highly Enantioselective and
Versatile Pd-Catalyzed Asymmetric
Allylic Substitution Reactions
Eva Raluy, Carmen Claver, Oscar Pa`mies,* and Montserrat Die´guez*
Departament de Qu´ımica F´ısica i Inorga`nica, UniVersitat RoVira i Virgili, C/ Marcel‚li
Domingo, s/n 43007 Tarragona, Spain
montserrat.dieguez@urV.cat; oscar.pamies@urV.cat
Received October 6, 2006
ABSTRACT
A series of phosphite-phosphoroamidite ligands, derived from readily available D-xylose, has been successfully applied for the first time in the
Pd-catalyzed allylic substitution of several substrates with different steric and electronic properties, with high enantioselectivities (ee’s up to
98) and activities in standard conditions.
One of the main goals of modern synthetic organic chemistry
is the catalytic enantioselective formation of C-C and
C-heteroatom bonds.1 In this respect, the asymmetric Pd-
catalyzed allylic substitution reaction is a powerful and highly
versatile procedure because it tolerates several functional
groups.1 A large number of chiral ligands, mainly P- and
N-containing ligands, which have either C2- or C1-symmetry,
have provided high enantiomeric excesses.1,2 However, one
disadvantage of using these ligands is that they are often
synthesized either from expensive chiral sources or in tedious
synthetic steps. Another common disadvantage for the most
successful ligand families developed for this process is that
they usually show low reaction rates and a high substrate
specificity (i.e., high ee’s are obtained in disubstituted linear
hindered substrates and low ee’s are obtained in cyclic and
unhindered linear substrates, or vice versa; Figure 1).1 These
limitations hamper their potential use in industrial scale.
Research into more versatile and efficient ligand systems
based on simple starting materials in this reaction is therefore
of great importance nowadays. For this purpose, carbohy-
drates are particularly advantageous thanks to their low price
and easy modular constructions.3 Although they have been
(2) See for example: (a) Pre´toˆt, R.; Pfaltz, A. Angew. Chem., Int. Ed.
1998, 37, 323. (b) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33,
336. (c) Evans, D. A.; Campos, J. R.; Tedrow, J. R.; Michael, F. E.; Gagne,
M. R. J. Am. Chem. Soc. 2000, 122, 7905. (d) Trost, B. M.; Oslob, J. D. J.
Am. Chem. Soc. 1999, 121, 3057. (e) Trost, B. M.; Bunt, R. C. J. Am.
Chem. Soc. 1994, 116, 4089. (f) Trost, B. M.; Krueger, A. C.; Bunt, R. C.;
Zambrano, J. J. Am. Chem. Soc. 1996, 118, 6520. (g) Pa`mies, O.; Die´guez,
M.; Claver, C. J. Am. Chem. Soc. 2005, 127, 3646. (h) Dierkes, P.;
Randechul, S.; Barloy, L.; De Cian, A.; Fischer, J.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Osborn, J. A. Angew. Chem. Int. Ed. 1998, 37,
3116. (i) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.; Dai, L.-X. J.
Am. Chem. Soc. 2001, 123, 7471. (j) Wiese, B.; Helmchen, G. Tetrahedron
Let. 1998, 39, 5727.
(1) For reviews, see for example: (a) Tsuji, J. Palladium Reagents and
Catalysis, InnoVations in Organic Synthesis; Wiley: New York, 1995. (b)
Trost, B. M.; van Vranken, D. L. Chem. ReV. 1996, 96, 395. (c) Johannsen,
M.; Jorgensen, K. A. Chem. ReV. 1998, 98, 1869. (d) Pfaltz, A.; Lautens,
M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol. 2, Chapter 24.
(e) Trost, B. M.; Crawley, M. L. Chem. ReV. 2003, 103, 2921.
(3) (a) Die´guez, M.; Pa`mies, O.; Claver, C. Chem. ReV. 2004, 104, 3189.
(b) Die´guez, M.; Pa`mies, O.; Ruiz, A.; D´ıaz, Y.; Castillo´n, S.; Claver, C.
Coord. Chem. ReV. 2004, 248, 2165. (c) Die´guez, M.; Ruiz, A.; Claver, C.
Dalton Trans. 2003, 2957.
10.1021/ol0624631 CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/13/2006

Because of the high enantioselectivity induced by mixed
bidentate donor ligands in the Pd-catalyzed allylic alkylation,1
we decided to use a new family of ligands based on 1 and
2 in which the phosphite group attached at C-5 is replaced
by a phosphoroamidite moiety (ligands 3 and 4, Scheme 1).
Scheme 1. Synthesis of Phosphite-phosphoroamidite Ligands
3 and 4
Figure 1. Summary of the best results with substrates S1-S4 with
three of the most representative ligand families developed for the
Pd-catalyzed allylic substitution reactions (reactions usually carried
out with 2-4 mol % Pd).
successfully used in other enantioselective reactions, they
have only very recently shown their huge potential as a
source of highly effective chiral ligands in this process.3,4
In this context, we have recently reported the use of xylo-
and ribo-furanoside diphosphite ligands 1 and 2 (Figure 2).5
Moreover, we expected to maintain the high activities
obtained with diphosphite ligands,6 because the phospho-
roamidite moiety is also a good π-acceptor group.7 Therefore,
this ligand design will overcome the drawback of low activity
usually observed for other successful ligand families. The
phosphite-phosphoroamidite ligands 3 and 4 also provide a
flexible ligand scaffold because they can be easily tuned in
different regions and their effect on catalytic performance
determined. As a result, the Pd-allylic substitution reactions
of several substrates with different electronic and steric
properties are reached.
The highly modular construction of these ligands makes
it easy for us to study three main effects on catalytic activity
and selectivity: (a) the effect of the configuration of the
stereocenter at carbon atom C-3 at the ligand bridge (ligands
3 vs 4), (b) the effect of the substituents in the biaryl groups
(ligands 3,4a vs 3,4b), and (c) the effect of the configuration
of the biaryl moieties groups (ligands 3,4c vs 3,4d). By
carefully selecting these elements, we achieved high enan-
tioselectivities and improved activities for several substrates.
We first tested the series of eight phosphite-phosphoro-
amidite ligands in the Pd-catalyzed allylic substitution of rac-
1,3-diphenyl-3-acetoxy-1-ene S1 with dimethyl malonate as
a model reaction using standard conditions (Table 1).
Figure 2. Xylo- and ribo-furanoside diphosphite ligands 1 and 2.
These ligands proved to be effective in the allylic substitution
of hindered substrate 1,3-diphenyl-3-acetoxyprop-1-ene S1
(ee’s up to 98%), but for unhindered linear S2 and cyclic
S3 substrates, their enantioselectivities were low (ee’s up to
59% and 34%, respectively).5
(4) See for example: (a) Yan, Y. Y.; RajanBabu, T. V. Org. Lett. 2000,
2, 199. (b) Liu, D.; Li, W.; Zhang, X. Org. Lett. 2002, 4, 4471. (c) Albinati,
A.; Pregosin, P. S.; Wick, K. Organometallics 1996, 15, 2419. (d) Guimet,
E.; Die´guez, M.; Ruiz, A.; Claver, C. Tetrahedron: Asymmetry 2005, 16,
959. (e) Yonehara, K.; Jashizume, T.; Mori, K.; Ohe, K.; Uemura, S. J.
Org. Chem. 1999, 64, 9374. (f) Boog-Wick, K.; Pregosin, P. S.; Trabesinger,
C. Organometallics 1998, 17, 3254. (g) Mata, Y.; Die´guez, M.; Pa`mies,
O.; Claver, C. AdV. Synth. Catal. 2005, 347, 1943.
(5) (a) Pa`mies, O.; van Strijdonck, G. P. F.; Die´guez, M.; Deerenberg,
S.; Net, G.; Ruiz, A.; Claver, C.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M. J. Org. Chem. 2001, 66, 8867. (b) Die´guez, M.; Pa`mies, O.; Claver, C.
AdV. Synth. Catal. 2005, 347, 1257.
(6) Diphosphite ligands have recently emerged as suitable ligands for
this process offering high activities; see for instance: (a) Reference 5b. (b)
Die´guez, M.; Pa`mies, O.; Claver, C. J. Org. Chem. 2005, 70, 3363.
(7) van Strijdonck, G. P. F.; Boele, M. D. K.; Kamer, P. C. J.; de Vries,
J. G.; van Leeuwen, P.W.N.M. Eur. J. Inorg. Chem. 1999, 1073.
50
Org. Lett., Vol. 9, No. 1, 2007

Scheme 2. Summary of Best Results Obtained in the
Pd-Catalyzed Allylic Substitution of S1-S6 Using
Phosphite-phosphoroamidite Ligands 3 and 4
Table 1. Pd-Catalyzed Allylic Alkylation of Substrate S1 using
Ligands 3 and 4a
entry
ligand
% conv (min)b
% eec
1
2
3
4
5
6
7
8
3a
3b
3c
3d
4a
4b
4c
4d
88 (15)
100 (15)
71 (30)
62 (S)
59 (S)
6 (S)
98 (S)
55 (S)
52 (S)
80 (S)
12 (S)
96 (30)d
64 (15)
83 (15)
12 (120)
15 (120)
a 0.5 mol % [Pd(π-C3H5)Cl]2, 1.1 mol % ligand, CH2Cl2 as solvent, BSA
(N,O-bis(trimethylsilyl)acetamide)/KOAc as base, room temperature. b Mea-
1
sured by H NMR. Reaction time in minutes shown in brackets. c Deter-
mined by HPLC on a Chiralcel-OD column. d 89% Isolated yield.
The results indicate that the catalytic performance (activity
and enantioselectivity) is highly affected by the configuration
of carbon atom C-3 of the tetrahydrofuran ring, the substit-
uents of the biphenyl moieties, and the configuration of the
binaphthyl groups. In general, ligands 3, with an S config-
uration on C-3, produced better activities and enantioselec-
tivies than ligands 4 (entries 1-4 vs 5-8). The presence of
methoxy groups in the para position of the biphenyl moieties
has a positive effect on activity but leads to lower enantio-
selectivities (entries 2 and 6 vs 1 and 5). We also observed
a cooperative effect between the configuration of the biaryl
moieties and the configuration of carbon atom C-3 (entries
3, 4, 7, and 8). The results indicated that the matched
combination is achieved with ligand 3d, which has an S
configuration at both carbon atom C-3 and in the biaryl
phosphite moieties (entry 4). In summary, the best enantio-
selectivity (ee’s up to 98%) was obtained with ligand 3d,
with an S configuration at carbon C-3 of the furanoside
backbone and two enantiopure binaphthyl moieties with S
configuration and bulky trimethylsilyl groups in the ortho
positions.
To study the potential of these readily available ligands
further, we also tested them in the allylic alkylation of
unhindered linear substrate S2, cyclic substrates S3 and S5,
and the monosubstituted linear substrates S4 and S6, as well
as the allylic amination of S1 (Scheme 2).
The enantioselectivity in unhindered linear S2 and cyclic
S3 and S5 substrates is usually more difficult to control than
in hindered substrate S1. Therefore, few catalytic systems
have provided good enantioselectivities.2e-h,j To achieve high
ee’s, it is crucial that ligands create a small chiral pocket (a
chiral cavity in which the allyl is embedded) around the metal
center, mainly because of the presence of less sterically syn
substituents.1 Although highly imposing enantioselective
catalyst families have been developed for these unhindered
substrates, they generally provide low enantiocontrol in such
hindered substrates as S1. The development of a enantio-
selective catalyst series for both hindered and unhindered
substrates is therefore still a challenge. Interestingly, for the
sterically undemanding substrates S2, S3, and S5, enantio-
selectivities were also high (84%, 85%, and 91%, respec-
tively) (Scheme 2). These results are among the best reported
for this type of unhindered substrates.2e-h,j It is also interest-
ing to note that, in contrast with substrate S1, ligands 4
provide better ee’s than ligands 3 in the alkylation of
sterically undemanding substrates S2, S3 and S5. This
indicates that the size of the chiral pocket is controlled by
the configuration of carbon atom C-3. Thus, ligands 4, with
R configuration at carbon C-3, lead to a smaller chiral pocket
than ligands 3 and, therefore, to higher enantioselectivities
for unhindered substrates (see Supporting Information). The
results obtained with linear substrate S2 and cyclic substrates
S3 and S5 also show that the biaryl moiety affects enenti-
oselectivity. Therefore, for linear substrate S2, ee’s are best
with ligand 4d, which contains a chiral binaphthyl moiety,
while for the cyclic substrates they are best with ligand 4a,
which contains atropoisomeric biphenyl groups. These
remarkable results clearly show the efficiency of using highly
modular scaffolds in the ligand design to increase their
versatility. In addition, comparing these excellent results with
the
poor
enantio-
selectivities obtained with ligands 1 and 2 (ee’s up to 59%)
in the alkylation of these unhindered substrates, we can
conclude that the introduction of a phosphoroamidite moiety
has been highly advantageous.
For substrates S4 and S6, as well as controlling the
enantioselectivity of the process, the regioselectivity is also
Org. Lett., Vol. 9, No. 1, 2007
51

a problem, because a mixture of regioisomers can be
obtained. Most Pd-catalysts developed to date favor the
formation of the achiral linear product rather than the desired
branched isomer.1 Therefore, the development of highly
regio- and enantioselective Pd-catalysts is still a challenge.
Under nonoptimized conditions, the catalytic system contain-
ing ligand 4c produced the desired branched isomer as the
major product with high enantioselectivity (90% ee). This
result is one of the best reported so far.2a,g,i Again, the
replacement of a phosphite moiety by a phosphoroamidite
group in the ligand design is seen to lead to higher regio-
and enantioselectivities than when ligands 1 and 2 are used
(% branched up to 29% and ee’s up to 33%).5b
Finally, we evaluated this ligand library in the allylic
amination process of S1 using benzylamine as nucleophile.
The results follow the same trend as in the allylic alkylation
of S1 (see Supporting Information), which is not unexpected
because the reactions have a similar mechanism.1 So enan-
tioselectivities were also high (ee’s up to 97%). Although
as expected the activities were lower than in the alkylation
reaction, they were again much higher than those obtained
with other successful ligands.1 The absolute stereochemistry
of the amination was the same as for the alkylation reaction,
though the CIP descriptor was inverted because of the change
in the priority of the groups.
moieties so that their effect on catalytic performance can be
explored. By carefully selecting the ligand components, we
obtained high activities and enantioselectivities in Pd-
catalyzed allylic substitution in substrates with different steric
and electronic properties under unoptimized reaction condi-
tions. Note also that these ligands afford higher activities
and substrate versatility than the corresponding diphosphite
analogues 1 and 2. So this is an exceptional ligand family
that competes with a few other ligand series that also provide
high ee’s for hindered and unhindered disubstituted and
monosubstituted substrates. These results open up a new class
of ligands for the highly active and enantioselective Pd-
catalyzed allylic substitution reactions of a wide range of
substrates. Mechanistic studies and further modifications in
both the sugar backbone and the biaryl moieties are currently
under way.
Acknowledgment. We are indebted to Prof. P. W. N.
M. van Leeuwen, University of Amsterdam, for his com-
ments and suggestions. We thank the Spanish Goverment
(Consolider Ingenio CSD2006-0003, CTQ2004-04412/BQU
and Ramon y Cajal fellowship to O.P.) and the Generalitat
de Catalunya (2005SGR007777 and Distinction to M.D.) for
financial support.
Supporting Information Available: Experimental pro-
cedures for the preparation of the ligands 3 and 4 and the
allylic substitution reactions, and the catalytic alkylation
results of S2-S6 and the amination of S1 using ligands 3
and 4. This material is available free of charge via the Internet
at http://pubs.acs.org.
In summary, we have described the first application of
phosphite-phosphoroamidite ligands for highly enantio-
selective and versatile asymmetric allylic substitution reac-
tions. These ligands have the advantage that they are easily
prepared in a few steps from commercial D-xylose, an
inexpensive natural chiral feedstock. In addition, they can
be easily tuned in the furanoside backbone and in the biaryl
OL0624631
52
Org. Lett., Vol. 9, No. 1, 2007