Ligand substituent effects on asymmetric induction. Effect of structural variations of the DIOP ligand on the Rh-catalyzed asymmetric hydrogenation of enamides

Article abstract of DOI:10.1021/ol006591f

(equation presented) Substituent changes in the ligand (L*) backbone and the chelating phosphorus atoms of the classical DIOP ligand result in dramatic changes in the enantioselectivity of Rh⁺L*-catalyzed enamide hydrogenations.

Full text of DOI:10.1021/ol006591f

ORGANIC
LETTERS
2000
Vol. 2, No. 26
4137-4140
Ligand Substituent Effects on
Asymmetric Induction. Effect of
Structural Variations of the DIOP Ligand
on the Rh-Catalyzed Asymmetric
Hydrogenation of Enamides
Yuan-Yong Yan and T. V. RajanBabu*
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received September 14, 2000
ABSTRACT
Substituent changes in the ligand (L*) backbone and the chelating phosphorus atoms of the classical DIOP ligand result in dramatic changes
in the enantioselectivity of Rh+L*-catalyzed enamide hydrogenations.
A select few prototypical transformations such as Rh-
catalyzed hydrogenation of R-acylaminoacrylic acid deriva-
tives1 and Pd-catalyzed alkylation of stabilized carbanions2
are used as benchmark reactions for evaluating new phos-
phine ligands. A large number of diverse, often structurally
unrelated, ligand scaffoldings have been successfully em-
ployed for these reactions, and newer ones continue to
emerge. Yet, there is a dearth of information on the effect
of systematic, deep-seated structural variations within a
specific ligand frame, the recent advances in combinatorial
approaches to ligand design notwithstanding.3,4 Such infor-
mation would be immensely valuable in developing working
models for the asymmetric induction process and, eventually,
for the de novo design of highly selective catalysts. In an
earlier paper,5a we reported a modest effort to make structural
changes in the well-known DIOP [1, (2,2-dimethyl-1,3-
dioxolane-4,5-diylbis-methylene)bisdiphenylphosphine], which,
as the first chelating phosphorus ligand to be used in
(3) Shimizu, K. D.; Snapper, M. L.; Hoveyda, A. H. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; p 1389. Burgess, K.; Porte, A. M. In AdVances in
Catalytic Processes; Doyle, M., Ed.; JAI Press: Greenwich, 1998; p 69.
(4) For notable exceptions, see the following. (a) Salen complexes for
epoxidation and epoxide opening reactions: Jaobsen, E. N.; Wu, M. H. In
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: Berlin, 1999; p 649, 1309. (b) Sugar phosphinite
ligands for hydrocyanation and hydrogenation reactions: RajanBabu, T.
V.; Casalnuovo, A. L.; Ayers, T. A. In AdVances in Catalytic Processes;
Doyle, M., Ed.; JAI Press: Greenwich, 1998; p 1.
(1) Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; p 121. (b) Burk,
M. J.; Gross, M. F.; Harper, T. G. P.; Kalberg, C. S.; Lee, J. R.; Martinez,
J. P. Pure Appl. Chem. 1996, 68, 37, and references therein. (c) Takaya,
H.; Ohta, T.; Noyori, R. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.;
VCH Publishers: New York, 1993; p 1.
(2) (a) Pfaltz, A.; Lautens, M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
p 833. (b) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395.
(5) (a) Yan, Y.-Y.; RajanBabu, T. V. J. Org. Chem. 2000, 65, 900. (b)
Yan, Y.-Y.; RajanBabu, T. V. Org. Lett. 2000, 2, 199.
10.1021/ol006591f CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/01/2000

asymmetric catalysis, occupies a historic place in organic
chemistry.6 A report on the use of these ligands for the Pd-
catalyzed allylation of dimethyl malonate with 1,3-diphen-
ylallyl acetate followed.5b Since then we have completed the
synthesis of a number of additional analogues, including a
few that would permit an evaluation of electronic effects on
enantioselectivity of a given reaction. In this paper we present
our recent findings on the synthesis and use of these ligands
for the Rh-catalyzed asymmetric hydrogenation of R-
arylenamides, a reaction that has attracted considerable
attention recently.7
prepared by dialkylcuprate opening of the known epoxide
13, mesylation, and formation of the C-P bonds by SN2
displacements.12
Scheme 1. Synthesis of Ligands 6-9
The ligands involved in this study are shown in Figure 1.
Of these, 1 ((RR)-DIOP) is commercially available, the
Hydrogenation of a prototypical substrate, N-(1-phenyl-
vinyl)acetamide, was examined in detail, and the results are
shown in Table 1. Reactions were carried out using isolated
cationic Rh complexes prepared by reacting stoichiometric
amounts of the ligand with Rh+(COD)2 X- where X ) BF4,
SbF6, or PF6.13 In each case, quantitative yield of the
hydrogenation product was obtained with ee’s approaching
99% in several instances. In our hands, use of BF4, SbF6, or
PF6 salt in CH2Cl2 appears to be the method of choice for
carrying out this reaction.14 This is a surprising finding in
view of the fact that CH2Cl2 has been reported to have a
delirious effect on the selectivity of this reaction when a [Rh-
(COD)2Cl]2 precursor was used.7f Use of the isolated cationic
salts in a noncoordinating solvent permits the reaction to be
conducted under milder conditions (20 psi/10 h vs 140 psi
and 48-60 h7f) with consistently high enantioselectivities.
Figure 1. Derivations of DIOP used for enamide hydrogenations.
synthesis of 2 was originally described by Kagan,8 and we
reported the synthesis of 5.5a,9 Syntheses of ligands 3 and 4
starting with the corresponding alcohols (10 and 11)10 are
shown in eq 1. Ligands 6, 7, and 8 were prepared by simple
(11) Syntheses of the diarylphosphines were accomplished by LAH
reduction of the corresponding chlorophosphine11a according to a published
procedure.11b (a) Casalnuovo, A. L.; RajanBabu, T. V.; Ayers, T. A.; Warren,
T. H. J. Am. Chem. Soc. 1994, 116, 9869. (b) Casey, C. P.; Paulsen, E. L.;
Beuttenmueller, W.; Proft, B. R.; Petrovich, L. M.; Matter, B. A.; Powell,
D. R. J. Am. Chem. Soc. 1997, 119, 11817.
SN2 reaction of the mesylate 12 with the corresponding
lithium diarylphosphide (Scheme 1).11,12 Ligand 9 was
(6) (a) Kagan, H. B. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; p 9. (b)
Kagan, H. B.; Dang, T. P. J. Am. Chem. Soc. 1972, 94, 6429.
(7) (a) Burk, M. J.; Wang, Y.; M.; Lee, J. R. J. Am. Chem. Soc. 1996,
118, 5142, and references therein. (b) Burk, M. J.; Casy, G.; Johnson, N.
B. J. Org. Chem. 1998, 63, 6084. (c) Zhang, F.-Y.; Pai, C.-C.; Chan, A. S.
C. J. Am. Chem. Soc. 1998, 120, 5808. (d) Zhu, G.; Zhang, X. J. Org.
Chem. 1998, 63, 9590. (e) Xiao, D.; Zhang, Z.; Zhang, X. Org. Lett. 1999,
1, 1679. (f) Li, W.; Zhang, X. J. Org. Chem. 2000, 65, 5871.
(8) Kagan, H. B.; Fiaud, J. C.; Hoornaert, C.; Meyer, D.; Poulin, J. C.
Bull. Soc. Chim. Belg. 1979, 88, 923.
(12) See Supporting Information for details of experimental procedure
and full characterization of the compounds.
(13) The hydrogenation reactions were carried out as follows. In a drybox,
a Fisher-Porter tube was charged with the enamide substrate (0.1 mmol),
the appropriate solvent (2 mL), and preformed Rh+L*(COD) X- (1 mol
%). After sealing, the tube was removed from the drybox and placed behind
proper shielding. After five vacuum-refilling cycles with hydrogen, the tube
was brought to the appropriate pressure (20 or 40 psi) of H2 and the mixture
was vigorously stirred for 10 h. After removing the catalyst on a plug of
silica gel, the ee’s of the products were determined by chiral GC (Chirasil-
L-Val on WCOT fused silica 25 m × 0.25 mm).
(9) While our paper was being readied for publication, Zhang reported
an alternate synthesis of 5 and its use in enamide reduction.7f The analytically
pure 5 is a white solid.
(14) For other results, see: Sinou, D.; Kagan, H. B. J. Organomet. Chem.
1976, 114, 325, and ref 7f.
(10) We thank Dr. M. J. Burk (Chirotecch) for the gift of these alcohols.
4138
Org. Lett., Vol. 2, No. 26, 2000

tions.4a,15 No report of ligand electronic effects have been
recorded for the Rh-catalyzed enamide reductions. Entries
6, 13, 14, and 15 in Table 1 address this issue in the context
of the “best” DIOP derivative (5). Our synthetic strategy
allows for the preparation of an electron-deficient ligand, 7,
and two electron-rich ones, 6 and 8. The data clearly show
the dramatic effect of an electron-deficient phosphorus on
the selectivity. As with the Rh-catalyzed hydrogenation of
R-acetamidoacrylic acid derivatives,15c the ee drops off
precipitously with electron-withdrawing ligand 7.
Table 1. Hydrogenation of R-Acetamidostyrene (eq 2)a
entry
ligand/X/solvent
pressure
% eeb (confign)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1/BF4/CH2Cl2
2/SbF6/CH2Cl2
3/BF4/CH2Cl2
4/BF4/CH2Cl2
5/BF4/MeOH
5/BF4/CH2Cl2
5/BF4/CH2Cl2
5/BF4/PhCH3
5/SbF6/MeOH
5/SbF6/THF
5/SbF6/CH2Cl2
5/PF6/CH2Cl2
6/BF4/CH2Cl2
7/BF4/CH2Cl2
8/BF4/CH2Cl2
9/BF4/CH2Cl2
20
20
20
20
40
20
40
40
20
20
20
20
40
40
20
20
53 (S)
20 (S)
91 (R)
95 (S)
94 (R)
98 (R)
98 (R)
86 (R)c
88 (R)
92 (R)
98 (R)
98 (R)
82 (R)
∼4 (R)
97 (R)
99 (R)
Data in Table 2 show how the new ligands affect the
enantioselectivity of other Rh-catalyzed enamide hydrogena-
tions. The selectivity for the 4-methylphenyl and 4-fluo-
Table 2. Hydrogenation of Enamides Using DIOP Analogsa
substrates (% ee,b configuration)
no.
1
L
X ) Me (eq 2) X ) F (eq 2) Z + E enamide (eq 3)
1
68 (S)
57 (S)c
∼0
71 (S)
50 (S)c
11 (S)
97 (R)
94 (S)
98 (R)
88 (R)
92 (S)
87 (S)c
6 (R)
96 (R)
77 (S)
96 (R)
76 (R)
a See footnote 13 and Supporting Information for details. b Determined
by GC. c 74% conversion.
2
3
4
5
6
2
3
4
5d
93 (R)
93 (S)
99 (R)
81 (R)
74 (R)c
4 (R)
Under our reaction conditions, (RR)-DIOP (1) gave 53%
ee (S) of the hydrogenation product N-acetyl-1-phenylethyl-
amine.14 The (SSSS)-dimethyl analogue 28 is a poorer ligand,
giving only 20% ee. Removal of the two oxygen atoms from
DIOP restores some of the selectivity as indicated by the
91% ee observed for 3 (entry 3). In the dideoxy analogues,
increasing the size of the R-substitituents improves the
selectivity (compare entries 3 and 4). The (RSSR)-dimethyl
analogue 5 is one of the best ligands for the asymmetric
reduction of an enamide, giving up to 98% ee in CH2Cl2
and slightly lower values in other solvents under our reaction
conditions (entries 5-12). The reaction appears to be slower
in a hydrocarbon solvent such as toluene. Comparison of
the sense of asymmetric induction imparted by ligands 2, 3,
4, and 5 shows that the chirality of the R-substituent (R to
the phosphorus atom) is the key control element in the
reaction. Since 3 is a better ligand than either 2 or 1, it is
reasonable to assume that the two oxygens in 2, by virtue of
their cis relationship to the methyl groups, contributes to
unfavorable interactions in the diasteromeric complexes
leading to the (S) product (vide infra). No such interactions
are present in the relevant intermediate leading to the (R)
product from 5 (the methyl groups and the dioxolane oxygens
are trans to each other). Thus, (RR)-3 and (RSSR)-5 give
high selectivities for the R product. Increasing the size of
the R-substituent in 5 has little impact on the selectivity or
reactivity. Thus, (RSSR)-9 gave 99% ee (entry 16) under the
standard conditions, not unlike (RSSR)-5.
6
7
8
9
7
8
9
2 (R)
96 (R)
99 (R)
6 (S)
98 (R)
98 (R)
98 (R)
99 (R)
a See footnote 13 and Supporting Information for details. In CH2Cl2 at
-
20 psi with BF4 as the counterion, unless otherwise specified. b ee
determined by GC. c In MeOH. d SbF6 and PF6 ions also gave comparable
ee’s.
rophenyl enamide derivatives16 (eq 2) parallels the behavior
of the unsubstituted compound for each of the ligands. Since
the preparation of isomerically pure E- or Z-enamides is
difficult, reduction of a mixture in high ee is of significant
practical interest. Indeed, a mixture of the Z- and E-enamides
(Z:E ) 1.0:2.4) is readily converted into the hydrogenation
products in excellent ee’s under the standard conditions (eq
3, Table 2, column 5). Gratifyingly, the dependence of
enantioselectivity on the structure of the ligand is entirely
predictable on the basis of studies of the prototypical system
(eq 2, Table 1). For all substrates, the electron-rich (RSSR)
ligand systems 5, 8, and 9 gave quantitative yields and
(15) For Rh-catalyzed reactions, see: (a) Inoguchi, K.; Sakuraba, S.;
Achiwa, K. Synlett 1992, 169. (b) Schnyder, A.; Hintermann, L.; Togni,
A. Angew. Chem., Int. Ed. Engl. 1995, 34, 931. (c) RajanBabu, T. V.; Ayers,
T. A.; Halliday, G. A.; You, K. K.; Calabrese, J. C. J. Org. Chem. 1997,
62, 6012. (d) RajanBabu, T. V.; Radetich, B.; You, K. K.; Ayers, T. A.;
Casalnuovo, A. L.; Calabrese, J. C. J. Org. Chem. 1999, 64, 3429.
Hydrocyanation reactions: Casalnuovo, A. L.; RajanBabu, T. V.; Ayers,
T. A.; Warren, T. H. J. Am. Chem. Soc. 1994, 116, 9869.
Electronic effects of ligands can have profound influence
on the rate and selectivity of asymmetric catalyzed reac-
(16) Prepared according to the procedure described by Burk et al.: Burk,
M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084.
Org. Lett., Vol. 2, No. 26, 2000
4139

excellent selectivities where as the (SSSS)-2 and the electron-
deficient (RSSR)-7 produced near-racemic products.
The striking deterioration of enantioselectivity in the case
of 7 (RSSR) as compared to 6 (RSSR) deserves further
comment. While 6 is one of the better ligands (highest ee,
88%), 7 uniformly gives low ee’s (<4%). Since the chirality
of the backbone is the same in both cases, and both aromatic
substituents have bulky groups in the m-positions (P[(3,5-
Me2-C6H3)]3 and P[3,5-(CF3)2-C6H3]3), one has to necessarily
invoke an electronic effect as the cause of this deterioration
of selectivity. The exact nature of this effect, whether it is a
consequence of equilibrium shifts among the diastereomeric
Rh-enamide complexes15d or of changes in kinetics of
oxidative addition of hydrogen to these complexes, remains
to be established. The latter assumes the Halpern mecha-
nism17 for enamide reduction, in which oxidative addition
of H2 to the initially formed diastereomeric complexes(s) is
the rate-determining step. In itaconate reduction, the ligand
electronic effects appear to alter the equilibrium between the
olefin-Rh complexes.15d
Figure 2. Effect of R-substitution in (SS)-DIOP ligand(s). The
λ-conformations are based on known X-ray structures of (SS)-DIOP
complexes.18
the key diastereomeric Rh-enamide complexes and ensuing
transition states. Unless there are huge differences in the rates
of oxidative addition of hydrogen between these diastereo-
mers, the reduction of the intrinsic differences in the energies
among these intermediates could result in a deterioration of
selectivity.
A very simple-minded explanation for the low selectivity
of 2 compared to that of 1 or 5 would start with an
examination of the ground state confirmation of the Rh+-
(L)(1) X-.18 The methyl groups in 5 (RSSR) are in a
quasiequatorial orientation and reinforce one stable ground
state conformation for the corresponding precatalyst (Figure
2). In 2 (SSSS), the quasiaxial orientation of the two methyl
groups destabilize this conformation, possibly resulting in
the intervention of others. Attendant effects would be felt in
In summary, we have evaluated the effect of various
electronic and steric parameters on the ability of DIOP to
function as a ligand in an important Rh-catalyzed asymmetric
hydrogenation reaction. Introduction of methyl or ethyl
groups, in an orientation where the conformational flexibility
of the precatalyst is diminished, seems to result in a dramatic
improvement (53 to 99% ee in a typical case) on the
enantioselectivity of the reaction. An electron-deficient
phosphorus, even on the best ligand scaffolding, leads to
nearly racemic products.
(17) Landis, C. R.; Halpern, J. J. Am. Chem. Soc. 1987, 109, 1746. For
a highly readable summary of the mechanism of Rh-catalyzed asymmetric
hydrogenation, see: Brown, J. M. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
p 121.
Acknowledgment. This work was supported by
EPA/NSF Program for Environmentally Benign Synthesis
(R826120-01-0) and NSF (CHE-9706766 and CHE-0079948).
(18) Based on X-ray structures of Rh+(DIOP)(norbornadiene)18a and Pd-
(DIOP)(ethylene).18b (a) Knowles, W. S.; Vineyard, B. D.; Sabacky, M. J.;
Stults, B. R. In Fundamental Research in Homogeneous Catalysis; Ishii,
Y.; Tsutsui, Eds.; Plenum: New York; Vol. 3, p 537. (b) Hodgson, M.;
Parker, D.; Taylor, R. J.; Ferguson, G. Organometallics 1988, 7, 1761. For
a discussion of a related conformational change due to an R-substituent in
an aminophosphine ligand, see: Pavlov, V. A.; Klabunovskii, E. I.;
Struchkov, Y. T.; Voloboev, A. A.; Yanovsky, A. I. J. Mol. Catal. 1988,
44, 217, especially pp 218-220.
Supporting Information Available: Details of the syn-
thesis of ligands 3, 4, 5, 6, 7, 8, and 9. Typical chromato-
grams of crude products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL006591F
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Org. Lett., Vol. 2, No. 26, 2000