Synthesis and application of macrocyclic binaphthyl ligands with extended chiral bias

Article abstract of DOI:10.1016/S0957-4166(98)00375-9

Two macrocyclic and one non-cyclic chiral diphosphine ligand containing a 2,2'-bridged binaphthyl unit were synthesized in six steps from (R)-2,2'- dimethoxy-1,1'-binaphthyl in overall yields of 25 and 17%, respectively. The new ligands showed asymmetric inductions of up to 98% e.e. if used in palladium catalyzed allylic alkylation reactions.

Full text of DOI:10.1016/S0957-4166(98)00375-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3607–3610
Synthesis and application of macrocyclic binaphthyl ligands with
extended chiral bias
Yuan-Yong Yan and Michael Widhalm ∗
Institut für Organische Chemie, Universität Wien, Währingerstraße 38, A-1090 Vienna, Austria
Received 11 August 1998; accepted 15 September 1998
Abstract
Two macrocyclic and one non-cyclic chiral diphosphine ligand containing a 2,20-bridged binaphthyl unit were
synthesized in six steps from (R)-2,20-dimethoxy-1,10-binaphthyl in overall yields of 25 and 17%, respectively.
The new ligands showed asymmetric inductions of up to 98% e.e. if used in palladium catalyzed allylic alkylation
reactions. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The concepts of transition metal catalyzed asymmetric transformations have been extended to num-
erous reaction types.1 Among these, carbon–carbon bond-forming reactions have attracted particular
attention since the generation of a new stereogenic center and the construction of the carbon skeleton take
place in a single step. The variety of C–C coupling reactions, both in view of mechanism and diversity
of substrate structure make the successful modeling of catalyst reactivity and selectivity, especially in
asymmetric catalysis, a challenge of central importance. According to this it was evident that groups
of structurally related ligands exhibiting gradually different degrees of steric or electronic influence in
suitable proximity to the co-ordinated substrate are desired.
2. Results and discussion
Searching for suitable ligand structures for allylic alkylation reactions with soft nucleophiles prompted
us to investigate primarily ligands with ‘remote’ chiral interaction which are prone to envelope the
substrate co-ordination sites. If co-ordinating atoms and the chiral moiety in the ligand are connected
to each other through spacer groups, chiral macrocycles can be formed. Such an array seemed promising
∗
Corresponding author. E-mail: miwi@felix.orc.univie.ac.at
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00375-9

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in view of the proposed mechanism which requires ‘outer-sphere’ chiral control of the prochiral Pd–allyl
precursor.2 The outstanding broadness of scope and efficiency of 2,20-disubstituted 1,10-binaphthyls in
chiral auxiliaries has been amply demonstrated in a plenitude of stoichiometric and catalytic reactions.3
We recently reported the synthesis of macrocyclic binaphthyl ligands4 and their application in allylic
alkylation reactions.5 Among the structures investigated, 7a (Scheme 1) was found to be most effective in
allylic alkylation reactions with asymmetric inductions up to 86% e.e. To further improve the asymmetric
induction we tried to extend the area of chiral interaction by introducing aromatic substituents of different
size in positions 3 and 30 of the binaphthyl skeleton. A Suzuki coupling was chosen to construct the biaryl
moiety, using boronic acid 2 as a suitable precursor.6 A five step synthesis applying standard procedures
furnished (R)-6b and (R)-6c in an overall yield of 51 and 35%, respectively (from 2). The final cyclization
step proceeded highly stereoselectively to afford exclusively the C1-symmetrical diastereomer. For
comparative studies the non-cyclic analog 8 was also synthesized, albeit in low yield (24%).
Scheme 1. Reagents: i: 1. n-BuLi, 2. B(OCH3)3, ii: R0X/Pd(PPh3)4/Na2CO3/toluene/reflux, iii: BBr3/CH2Cl2/0°C-→rt, iv:
1. ClCH2CO2C2H5/KOtBu, 2. LiAlH4/THF, v: TsCl/Py/0°C, vi: 1,2-bis(phenylphosphinyl)benzene/n-BuLi/THF/reflux, vii:
LiPPh2/THF/0°C-→rt
Macrocycles 7a–c represent a set of chiral ligands with increasingly extended chiral bias which is ex-
pected to result in different chiral modeling of the reaction area.7 Nevertheless, the degree of actual steric
interaction is difficult to predict and will be governed by the preferred conformation of the macrocycle.
As test reactions we chose the Pd-catalyzed allylic alkylation reaction of 1,3-symmetrically disubsti-
tuted propenyl acetates with dimethyl malonate as the nucleophile (Scheme 2).8
The results are collected in Table 1. For Reaction (1) the presence of substituents in position 3 and 30 of
the ligand significantly improved the asymmetric induction from 86% e.e. 7a to 98% e.e. (7c in CH3CN).
A solvent change from CH2Cl2 to THF or CH3CN did not alter the enantioselectivity but the reaction
rate reached a maximum of approximately 100 turnovers per h in CH3CN. Generally, isolated yields
are high, exceeding 90% in nearly all cases. The use of sodium hydride instead of BSA/KOAc decreased
enantioselectivities to 81–91% e.e. (for 7a and 7c, respectively). In contrast to this, no improvement could

Y.-Y. Yan, M. Widhalm / Tetrahedron: Asymmetry 9 (1998) 3607–3610
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Scheme 2.
Table 1
Asymmetric induction in Pd-catalyzed in allylic alkylation reactionsa)
(a) Experiments were run in 1 ml of solvent with 1 mmol of substrate and 3 mmol of
dimethylmalonate and N,O-bis(trimethylsilyl)acetamide (BSA) each, a trace of KOAc, and
the catalyst prepared in situ from 0.5 mol% of [Pd(C3H5)Cl]2 and 2 mol% of ligand; for
experimental details see the literature.5
(b) NaH was used instead of BSA/KOAc.
(c) Instead of pentenyl acetate the corresponding carbonate was used as substrate.
(d) Figures refer to: e.e./configuration of product/isolated yield (in parentheses); e.e was
determined by HPLC (Reaction (1): Chiralcel-ODH, 250×4.6 mm, 2-PrOH/n-hexane, 2:98),
GC (Reaction (2): 50% of octakis(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodextrin, 0.25 mm×25
m, 0.5 bar H2, 55°C) or on the basis of specific rotation:9 Reaction (3): (S)-dimethyl 2-
(cyclopent-2-ene-1-yl)malonate [α]D20=−98.7 (c=2.27, CHCl3); Reaction (4): (S)-dimethyl 2-
(cyclohex-2-ene-1-yl)malonate [α]D20=−46.1 (c=2.85, CHCl3).
be attained for Reaction (2). Only 24% e.e. in the case of ligand 7c was observed using the corresponding
pentenyl carbonate as substrate, which is a lower selectivity than that obtained with the non-cyclic ligand
8 (28% e.e.). The asymmetric induction was also found to be low for cyclic substrates (Reactions (3) and
(4)) and did not show any dependence upon the steric bulk of the ligands.
3. Conclusions
New ligands 7b and 7c with extended chiral bias (compared with 7a) allow excellent enantioselectivity
in the allylic alkylation reactions of 1,3-diphenylpropenyl acetate but failed to induce considerable
asymmetric induction with aliphatic cyclic and non-cyclic substrates, a behavior frequently observed with

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Y.-Y. Yan, M. Widhalm / Tetrahedron: Asymmetry 9 (1998) 3607–3610
other ligands. From our findings we conclude that for alkyl-substituted substrates a more carefully tuned
steric interaction between substrate and ligand is required. In view of the so far incomplete understanding
of the mechanism10 the ‘tailoring’ of ligands will be an empirical procedure, preferably by varying steric
interaction in proximity to the P-co-ordination sites. Appropriate structural modifications of the ligand
are presently under progress.
Acknowledgements
Generous financial support by the Fonds zur Förderung der wissenschaftlichen Forschung (P11990-
CHE) is gratefully acknowledged. Y.Y. is grateful for a Lise Meitner grant (M00399-CHE).
References
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7. All new compounds gave analyses and spectroscopic data in agreement with the proposed structures; selected data: (R)-
7b: yield: 88%; white powder; mp: 143–146°C, [α]D20=+419 (c=1.0, CH2Cl2). 1H NMR (CDCl3) δ: 1.93–2.01 (m, 1H);
2.07–2.30 (m, 3H); 3.52–3.66 (m, 2H); 3.73–3.81 (m, 1H); 3.85–3.93 (m, 1H); 6.68–6.73 (m, 1H); 6.78–6.82 (m, 1H);
6.95–6.99 (m, 2H); 7.03–7.23 (m, 15H); 7.29–7.41 (m, 9H); 7.82 (s, 1H); 7.82 (d, J=7.8 Hz, 1H); 7.88 (d, J=7.3 Hz, 2H);
7.91 (d, J=7.8 Hz, 1H); 8.00 (s, 1H). 31P NMR δ: −27.13 (d, J=149.2 Hz); −28.93 (d, J=149.2 Hz). MS (FD, 230°C):
784.9 (M+, 100%). (R)-7c: Yield: 76%; white powder; mp: 149–152°C; [α]D20=+190 (c=1.0, CH2Cl2). 1H NMR (CDCl3)
δ: 2.00–2.16 (m, 3H); 2.30–2.38 (m, 1H); 3.58–3.72 (m, 2H); 3.74–3.82 (m, 1H); 4.02–4.10 (m, 1H); 6.46–6.50 (m, 1H);
6.80–6.84 (m, 7H); 6.99 (t, J=7.5 Hz, 3H); 7.04–7.11 (m, 2H); 7.18 (d, J=8.5 Hz, 2H); 7.25–7.31 (m, 2H); 7.34–7.45 (m,
5H); 7.54–7.58 (m, 3H); 7.68–7.70 (m, 1H); 7.77 (d×d, J=2.0, 8.5 Hz, 2H); 7.86–7.94 (m, 4H); 7.97 (t, J=4.0 Hz, 2H);
8.06 (brs, 1H); 8.09 (d×d, J=1.5, 8.5 Hz, 1H); 8.14 (s, 1H); 8.38 (s, 1H). 31P NMR δ: −26.00 (d, J=152.1 Hz); −29.85
(d, J=152.1 Hz). MS (FD, 280°C): 884 (M+, 100%).
8. High asymmetric inductions have been reported for Reaction (1), cf.: Andersson, P. G.; Harden, A.; Tanner, D.; Norby, P.
O. Chem. Eur. J. 1995, 1, 12; von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566; Dawson, G. J.; Frost, C.
G.; Williams, J. M. J.; Coates, S. W. Tetrahedron Lett. 1993, 34, 3149; Reaction (2) cf.: Trost, B. M.; Krueger, A. C.; Bunt,
R. C.; Zambrano, J. J. Am. Chem. Soc. 1996, 118, 6520; Reactions (3) and (4): Trost, B. M.; Bunt, R. C. J. Am. Chem.
Soc. 1994, 116, 4089; Helmchen, G.; Kudis, S.; Sennhenn, P.; Steinhagen, H. Pure Appl. Chem. 1997, 69, 513.
9. Sennhenn, P.; Gabler, B.; Helmchen, G. Tetrahedron Lett. 1994, 35, 8595.
10. Although palladium catalyzed allylic substitution reactions have been the subject of numerous mechanistic investigations
the origin of enantioselection is not completely understood; different mechanistic models have been presented and
arguments for both early and late transition states have been proposed for the nucleophile attack, the rate- and
configuration-determining step. In this context the role of an equilibrium between preceding diastereomeric π-allyl-
palladium(II) complexes was also discussed. See: Auburn, P. R.; Mackenzie, P. B.; Bosnich, B. J. Am. Chem. Soc. 1985,
107, 2033; Mackenzie, P. B.; Wehlan, J.; Bosnich, B. J. Am. Chem. Soc. 1985, 107, 2046; Brown, J. M.; Hulmes, D. I.;
Guiry, P. J. Tetrahedron 1994, 50, 4493; see also Helmchen, G. et al. in Ref. 8.