A new C2-symmetric chiral diphosphine ligand: Palladium-catalyzed enantioselective allylic alkylation of cycloalkenyl substrate

Article abstract of DOI:10.1016/S0957-4166(99)00100-7

A novel C₂-symmetric chiral diphosphine ligand 1 was developed using (2S)-2-amino-1-(diphenylphosphino)-3-methylbutane 2 which was derived from L- valine as in the previous work for the chiral amidine ligand, VALAP. Ligand 1 demonstrated extrem

Full text of DOI:10.1016/S0957-4166(99)00100-7

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1025–1028
A new C2-symmetric chiral diphosphine ligand:
palladium-catalyzed enantioselective allylic alkylation of
cycloalkenyl substrate
Akihito Saitoh, Mie Misawa and Toshiaki Morimoto∗
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka-shi, 422-8526, Japan
Received 23 February 1999; accepted 15 March 1999
Abstract
A novel C2-symmetric chiral diphosphine ligand 1 was developed using (2S)-2-amino-1-(diphenylphosphino)-
3-methylbutane 2 which was derived from L-valine as in the previous work for the chiral amidine ligand, VALAP.
Ligand 1 demonstrated extremely high levels of asymmetric induction, over 99% ee in palladium-catalyzed allylic
alkylations of 2-cyclohexen-1-yl pivalate 5. © 1999 Elsevier Science Ltd. All rights reserved.
Palladium-mediated allylic reactions have been attracting much attention as an efficient synthetic tool
for C–C bond formation that can be applied to intramolecular cyclization reactions and the production
of various kinds of natural products.1 The great demand for stereoselective transformations in the
applied science led to the development of chiral auxiliaries which could create a chiral environment
for asymmetric induction along with efficient transformations of substrates.2 In this field, we have
been developing the new chiral amidine ligand 3, VALAP3 derived from L-valine in which a variety
of modifications and further extensions of the ligand system4 are envisioned.
Based on our point of view to overcome the limitation with respect to reaction types,3a we have
been investigating palladium-catalyzed asymmetric allylic transformation of sterically less demanding
substrates. Among the various kinds of enantioselective allylic reactions, the asymmetric induction of
cyclic allyl compounds has proven to be the most difficult so that only a few examples concerning high
enantioselective induction beyond 90% ee have been reported.5 Chiral phosphanyldihydrooxazoles, P–N
hybrid ligands which are being investigated by numerous research groups, are effective for asymmetric
allylations of acyclic substrates, however the use of cyclic allyl substrates leads to low enantioselectivities
except for phosphanyldihydrooxazoles with fine tuning by a cymantrene unit.5c,6 On the other hand,
chiral diphosphine ligands with a large bite angle induced remarkably high enantioselectivities for
cycloalkenyl substrates.5a,d Optically active diphosphine ligands with C2-symmetry have been found
to possess effective chiral environments for substrates and nucleophiles.7 All assignable to this class
∗
Corresponding author. E-mail: morimtt@ys2.u-shizuoka-ken.ac.jp
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00100-7

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of ligands have been used for a variety of transition metal-catalyzed reactions. Hence we designed a
new C2-symmetric diphosphine ligand 1 as an extension of our concept for VALAP. Herein we wish
to demonstrate the development of the chiral diphosphine ligand 1 on the basis of α-amino acid and
remarkable levels of asymmetric induction in palladium-catalyzed allylic alkylations of 2-cyclohexen-1-
yl pivalate 5.
The new ligand 1 was prepared in one step from the precursor of VALAP 23a which was easily
accessible from L-valine. Two equivalents of 2 were treated with phthaloyl chloride in the presence
of diisopropylethylamine in toluene at reflux. The desirable product was isolated by silica gel column
chromatography as a white solid in 53% yield (Scheme 1).8
Scheme 1.
The new ligand thus prepared was subjected to palladium-catalyzed allylic alkylations of 2-
cyclohexen-1-yl pivalate 5 with an anionic soft nucleophile derived from dimethyl malonate/BSA/AcOLi
(Scheme 2).9 As listed in Table 1, the present ligand demonstrated remarkably high asymmetric
induction, giving (S)-610 in over 99% ee. The use of halogenated hydrocarbon solvents appeared to
be appropriate for the reactivity (entries 1 and 3) so that switching to THF resulted in a decrease of
catalytic activity (entry 4). However, no influence of solvent was observed in terms of enantioselectivity.
The reduction of the catalyst amount resulted in somewhat lower asymmetric induction (entry 2). In
the current chiral auxiliary, the combination of C2-symmetry, rigidity of the amide skeleton to fix the
two arms extending from the benzene ring, and the influence of the isopropyl groups on the stereogenic
carbons on the conformation of the phenyl rings on the phosphorus atoms would serve as a favorable
chiral binding site. All the present observations of this remarkable asymmetric induction suggest an
appropriate chelate coordination of diphosphine 1 to the metal, thus providing the effective chiral
environment.11
Scheme 2.
In summary, we extended our ligand concept for VALAP to the development of new C2-symmetric
chiral diphosphine ligand 1 which possessed remarkably high enantioselectivities in the palladium-
catalyzed allylic reactions of a cyclohexenyl substrate. The present ligand system will be extended by
employing other acid chlorides in which different chiral environments can be constructed by various
bite angles of ligands around the palladium atom. Further efforts including the optimization of ligand

A. Saitoh et al. / Tetrahedron: Asymmetry 10 (1999) 1025–1028
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Table 1
Asymmetric allylic alkylations of 5 catalyzed by a palladium–1 complexa
synthesis, application to other asymmetric reactions, and mechanistic considerations12,13 are being
currently pursued.
References
1. (a) Tsuji, J. Transition Metals in Organic Synthesis; Kagaku Dojin: Japan, 1997. (b) Tsuji, J. Palladium Reagents and
Catalysts, Innovations in Organic Synthesis; John Wiley: New York, 1995; p. 290.
2. (a) Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089. (b) Hayashi, T. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed. VCH: New York, 1993; Vol. 1, p. 325. (c) Trost, B. M.; van Vranken, D. L. Chem.
Rev. 1996, 96, 395.
3. (a) Saitoh, A.; Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1997, 8, 3567. (b) Saitoh, A.; Achiwa, K.; Morimoto,
T. Tetrahedron: Asymmetry 1998, 9, 741.
4. As one of the strategies, we derived chiral P–N hybrid ligands 4 consisting of imino groups with diverse phenyl substituents
from the precursor of VALAP, (2S)-2-amino-1-(diphenylphosphino)-3-methylbutane 2,3a in which the drastic improvement
of catalytic performance by electronic tuning for the ligands was demonstrated in palladium-catalyzed asymmetric
allylations. Saitoh, A.; Misawa, M.; Morimoto, T. Synlett, in press.
5. (a) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089. (b) Knühl, G.; Sennhenn, P.; Helmchen, G. J. Chem.
Soc., Chem. Commun. 1995, 1845. (c) Kudis, S.; Helmchen, G. Angew. Chem., Int. Ed. Engl. 1998, 37, 3047. (d) Dierkes,
P.; Ramdeehul, S.; Barloy. L.; Cian, A. D.; Fischer, J.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Osborn, J. A. Angew.
Chem., Int. Ed. Engl. 1998, 37, 3116.
6. Asymmetric allylations of cycloalkenyl substrates by phosphanyldihydrooxazoles, see: (a) Sennhenn, P.; Gabler, B.;
Helmchen, G. Tetrahedron Lett. 1994, 35, 8595. For other P–N hybrid ligands, see: (b) Brown, J. M.; Hulmes, D. I.;
Guiry, P. Tetrahedron 1994, 50, 4493. (c) Bourghida, M.; Widhalm, M. Tetrahedron: Asymmetry 1998, 9, 1073.
7. Whitesell, J. K. Chem. Rev. 1989, 89, 1581.
8. Analytical data for the ligand 1 isolated as a white solid: mp=57–59°C; [α]D24 +21.3 (c 0.5, CHCl3); 1H NMR (270 MHz,
CDCl3) δ: 0.90 (d, 6H, J=6.6 Hz), 0.92 (d, 6H, J=6.6 Hz), 2.00–2.12 (m, 2H), 2.26–2.41 (m, 4H), 4.03–4.17 (m, 2H),
6.78 (d, 2H, J=8.9 Hz), 7.26–7.47 (m, 24H); 31P{1H} NMR (161.7 MHz, CDCl3, H3PO4) δ: −22.74; FAB-MS: m/z 673
(MH+); IR (KBr): 1643 cm−1 (C_O), 3256 cm−1 (NH).
9. Typical procedure for asymmetric reactions (entry 1): A solution of [Pd(η3-C3H5)Cl]2 (4 mg, 0.0109 mmol) and 1 (17.6
mg, 0.0262 mmol) in 1 ml of CH2Cl2 (dry and oxygen free) was stirred at room temperature under Ar, followed by
adding compound 5 (79.4 mg, 0.436 mmol) in 1 ml of CH2Cl2. To the mixture was added a nucleophile solution prepared
in another flask by mixing dimethyl malonate (173 mg, 1.31 mmol) and BSA (266 mg, 1.31 mmol) in the presence of
lithium acetate (1.4 mg, 0.0218 mmol) in 2 ml of the solvent. After stirring at room temperature for 24 h and checking
the reaction by gas chromatography, the volatiles were removed in vacuo. The residue was purified by preparative TLC
1
(toluene:AcOEt=20:1). (S)-Dimethyl cyclohex-2-enylmalonate 6: H NMR (270 MHz, CDCl3) δ: 1.31–1.81 (m, 4H),

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1.96–2.06 (m, 2H), 2.86–2.95 (m, 1H), 3.29 (d, 1H, J=9.2 Hz), 3.74 (s, 3H), 3.75 (s, 3H), 5.52 (dd, 1H, J=2.3, 10.2 Hz),
5.74–5.82 (m, 1H).
10. The absolute configuration was determined on the basis of specific rotation.6a
11. A 31P NMR spectrum of the catalyst solution which was prepared by mixing [Pd(η3-C3H5)Cl]2 and 1 in CDCl3 was
measured as a preliminary study for the conformation of the Pd–1 complex. Two doublet peaks with the same coupling
constant were observed, suggesting a bidentate P–Pd–P bond and incompletely symmetrical chelation. 31P{1H} NMR
(161.7 MHz, CDCl3, H3PO4) δ: 6.43 (d, 2JP,P =34.8 Hz), 9.46 (d, 2JP,P =34.8 Hz).
12. In recent work Osborn et al.5d proposed a concept that nucleophilic attack on a π-allyl complex and the subsequent
rotation to a Pd–olefin complex are controlled by chiral ligands where it is essential for the π-allyl complex to avoid steric
repulsion in the late transition state (product-like). We have been considering the rotational mechanism concerning the
stereo-determining step by the combination with the P/M chirality concept13 in which the positioning array of the four
phenyl rings of diphosphine ligands established by X-ray analysis data closely correlates with the absolute configuration
of asymmetric hydrogenation products. In the asymmetric allylic alkylation of 5 using (S)-BINAP with M-chirality13 as
a representative diphosphine ligand, (S)-6 was produced in 34% ee under the same condition as that of entry 1. The
predominant S-selectivity was speculated upon by correlating the rotational concept with the M-chirality as depicted
in Scheme 3. According to the absolute configuration of the products, a similar path may be considered in the present
reactions using 1. Studies regarding the correlation of enantioselectivity with the P/M chirality are in progress.
Scheme 3.
13. Sakuraba, S.; Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1991, 2, 597.