On the Effect of a Cation Binding Site in an Asymmetric Ligand for a Catalyzed Nucleophilic Substitution Reaction

Full text of DOI:10.1021/ja9706864

5962
J. Am. Chem. Soc. 1997, 119, 5962-5963
Scheme 1. Synthesis of Cation Channel Ligandsa
On the Effect of a Cation Binding Site in an
Asymmetric Ligand for a Catalyzed Nucleophilic
Substitution Reaction
Barry M. Trost* and Rumen Radinov
Department of Chemistry, Stanford UniVersity
Stanford, California 94305-5080
ReceiVed March 4, 1997
The development of an understanding of asymmetric induc-
tion in successful asymmetric catalytic reactions is important
to establish a basis for the rational design of new asymmetric
reactions. The complexity of the issues involved make such a
task particularly challenging. Consider the use of asymmetric
allylic alkylations catalyzed by palladium as illustrated in eq
1.1 Four motifs have been put forward to explain asymmetric
induction in such cases: (1) electronic desymmetrization of the
intermediate π-allylpalladium complex as in cases wherein the
binding atoms of the bidentate ligand are different,2,3 (2) steric
strain creating differential bonding between the two allylic
termini and palladium,4 (3) secondary interactions with the
incoming nucleophile by asymmetric attachment of an ion
binding group,5 or (4) a chiral pocket.6 For ligand 1 a model
involving the concept of a “chiral pocket” has been proposed,
but all attempts to obtain direct evidence such as X-ray
crystallography or NMR spectroscopy have proven fruitless.
While evidence disfavors electronic desymmetrization involving
coordination of an amide and a phosphine,7 metal ion coordina-
tion with the incoming nucleophile has some attractions. For
example, there is a strong metal ion effect as shown by the fact
that the enantiomeric excess (ee) increases in the order Na+ <
K+ < Rb+ < Cs+.8 However, since these results parallel a
cation effect seen with tetraalkylammonium salts in the order
(CH3)4N+ < (C2H5)4N+ < (n-C4H9)4N+ < (n-C6H13)4N+,9
specific ion binding effects are difficult to discern. It is par-
ticularly noteworthy that, in this case, the escort ion, the cation,
appears to play a much more significant role than the nucleo-
phile, the anion, even though the latter actually binds to the
allyl unit in the transition state of the enantiodiscriminating step.
Much interest has focused on the design, synthesis, and study
of synthetic ion channels to mimic natural transport proteins.10
One can conceive superimposing such a concept onto the
working model for the asymmetric induction of eq 1, which
invokes a “chiral pocket.” Modeling suggested that substituents
attached to the phenyl rings of the diphenylphosphino moiety
of 1 would project into the “chiral space” in which the reactants
a Key: (a) n-C4H9Li, ether, -75 °C, (C2H5)2NPCl2 then HCl, H2O,
CHCl3, 43%; (b) (Ph3P)4Pd, N-methylmorpholine, PhCH3, 120 °C, 69%;
(c) HCtCCH2CH2OTBDMS, (Ph3P)4Pd, CuBr, (C2H5)3N, 70 °C; (d)
TBAF, THF, 0 °C then MEM-Cl, (i-C3H7)2NC2H5, CH2Cl2, room
temperature (rt), 78% from 5; (e) HSiCl3, PhH, reflux, 47%; (f)
Ba(OH)2, H2O, CH3OH, rt, then HBTU, (C2H5)3N, CH2Cl2, 0 °C, 91%;
(g) i. Ba(OH)2, CH3OH, rt then HBTU, (C2H5)3N, CH2Cl2, 0 °C; ii.
2-(diphenylphosphino)benzoic acid, HBTU, (C2H5)3N. HBTU )
O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-
phosphate.
must reside. The unusual effects observed in eq 1 suggested
that incorporating cation binding sites to transport the counterion
of the nucleophile rather than the nucleophile itself may affect
both enantioselectivity and rate. Simple glyme-like units, as
depicted in ligands 2-4, were chosen for synthetic simplicity
and structural flexibility for the tentacle to reach out into solution
to coordinate and then to fold inward to deliver the ion pair.
(1) For reviews, see: Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996,
96, 395. Heumann, A.; Reglier, M. Tetrahedron 1995, 51, 975. Hayashi,
T. In Catalytic Asymmetric Synthesis; Ojima, I., Ed., VCH Publishers;
Inc.: New York, 1993. Fiaud, J. C. In Metal-Promoted SelectiVity in
Organic Synthesis; Graziani, M., Hubert, A. J., Noels, A. F., Eds.; Kluwer
Academic Publishers: Dordrecht, The Netherlands, 1991. Consiglio, G.;
Waymouth, R. M. Chem. Ber. 1989, 89, 257.
(2) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566.
Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coate, S. W. Tetrahedron
Lett. 1993, 34, 3149. Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993,
34, 1769. Baltzer, N.; Macko, L.; Schaffner, S.; Zehnder, M. HelV. Chem.
Acta 1996, 79, 803.
Ligands 2 and 3 have formal C2 symmetry; whereas, ligand 4
tests the importance of this symmetry element. Scheme 1, which
outlines the synthesis of 3 and 4, illustrates the facility by which
such ligands are accessible. Ligand 2 was obtained analogously
from 1,3,5-tribromobenzene.
The octopod ligand 2 proved unsuitable for allylic alkylations,
presumably because of steric hindrance. On the other hand,
the tetrapod ligand 3 and dipod ligand 4 generated active cata-
(3) Knu¨hl, G.; Sennhenn, P.; Helmchen, G. Chem. Commun. 1995, 1845.
Okada, Y.; Minami, T.; Umezu, Y.; Nishikawa, S.; Mori, R.; Nakayama,
Y. Tetrahedron: Asymmetry 1991, 2, 667.
(4) Mackenzie, P. B.; Whelan, J.; Bosnich, B. J. Am. Chem. Soc. 1985,
107, 2046. Pfaltz, A. Acc. Chem. Res. 1993, 26, 339. von Matt, P.; Lloyd-
Jones, G. C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neuberger, M.;
Zehnder, M.; Ru¨egger, H.; Pregosin, P. S. HelV. Chim. Acta 1995, 78, 265.
(5) Sawamura, M.; Ito, Y. Chem. ReV. 1992, 92, 857. For a leading
reference, see: Sawamura, M.; Nakayama, Y.; Tang, W.-M.; Ito, Y. J. Org.
Chem. 1996, 61, 9090.
(10) Sasaki, T.; Lieberman, M. In ComprehensiVe Supramolecular
Chemistry; Atwood, J. L., Davies, J. E. D., MacNirol, D. D., Vo¨gtle, F.,
Lehn, J. M., Murakami, Y., Eds.; Pergamon Press: Oxford, 1996; Vol. 4,
Chapter 5. Landini, D.; Maia, A.; Penso, M. In ComprehensiVe Supramo-
lecular Chemistry; Atwood, J. L., Davies, J. E. D., MacNirol, D. D., Vo¨gtle,
F., Lehn, J. M., Gokel, G. W., Eds.; Pergamon Press: Oxford, 1996; Vol.
1, Chapter 11. Lehn, J. M. Supramolecular Chemistry: Concepts and
PerspectiVes; VCH: Weinheim, 1995; Chapter 8.4. Pregel, M. J.; Jullien,
L.; Lehn, J. M. Angew. Chem., Int. Ed. Engl. 1992, 31, 1637.
(6) Trost, B. M. Acc. Chem. Res. 1996, 29, 355.
(7) Trost, B. M.; Breit, B.; Organ, M. G. Tetrahedron Lett. 1994, 35,
5817.
(8) Bunt, R. C., Ph.D. Thesis, Stanford University, 1995.
(9) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1994, 116, 4089.
S0002-7863(97)00686-0 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 25, 1997 5963
lysts. Performing reaction 1 with a catalyst derived from 0.2
mol % [η3-C3H5PdCl]2 and 0.6 mol % 3 with dibenzyl
sodiomalonate in methylene chloride at 40 °C gave a 90% yield
of alkylated product of 96% ee as determined by chiral HPLC.11
A similar reaction differing only in maintaining room temper-
ature with the dipod ligand 4 in the normally difficult acyclic
case (eq 2)12 gave a 68% yield of product 9 of 90% ee. Using
sodium benzenesulfinate as the nucleophile and (dba)3Pd2‚-
CHCl3 (dba ) dibenzylideneacetone) as the palladium source
in an aqueous methylene chloride two phase system gave an
81% yield of 10 of >99% ee.
see text
Figure 1. Cation effect with dipodal ligand 4.
+
or NH4 (>180 min). The tetrapodal ligand 3 shows similar
behavior to the dipodal ligand 4.
The dipodal and tetrapodal ligands 4 and 3 show that sodium
salts can give excellent ee values and simultaneously effect a
rate enhancement in contrast to our earlier studies with ligand
1. Furthermore, while the rate is cation dependent, the ee
became cation independent, being high in all cases. A consistent
explanation takes into account the dynamic structure that this
“chiral pocket” appears to exhibit, especially with the five-
membered ring substrate. By incorporating arms into the
“pocket,” either the relaxation of the “pocket” to provide the
symmetry necessary for high chiral recognition is enhanced or
the “pocket” already possesses the structure required for high
enantioselectivity. In either case, speeding up the rate of the
alkylation need not have a significant influence on the ee. The
enhanced rate undoubtedly derives from the metal binding effect
which would make the anion freer and thus more nucleophilic
as in polyethers. The cation specificity attests to this conclusion.
It is remarkable that simple unstructured glyme-like units show
such specific effects and that the more highly organized crown
structures are not required.15,16 Hayashi and Ito et al.5,17 have
developed a family of ligands wherein asymmetric interaction
of an arm directly with the incoming nucleophile is responsible
for molecular recognition. The fact that both the symmetrical
tetrapod and the unsymmetrical dipod ligands 3 and 4 gave the
same results suggests that such an asymmetric interaction with
the incoming nucleophile is not responsible for the molecular
recognition. Thus, it appears reasonable to conclude that in
this family of ligands, secondary interactions affect transport
of the nucleophile but not molecular recognition. The results
support the contention that molecular sculpting of the “chiral
pocket” in a somewhat rational fashion to elicit specific
selectivities may be possible and readily realized experimentally
by the strategy outlined herein.
Our earlier studies suggested that the cation effect leading to
high ee derived at least in part from a slower rate of alkylation
which permitted equilibration of the intermediate π-allylpalla-
dium complex so that it effectively symmetrized.13 On the other
hand, these reactions with ligands 3 and 4 appear to show
significant rate enhancements and still high ee. For example,
the time for complete consumption of starting material for the
cyclohexenyl substrate as shown in eq 3 dropped from 16 h at
40 °C with the malonate nucleophile using the standard ligand
1 to only 2 h with the tetrapod ligand 3 (99% yield, 99% ee).
see text
With sodium phthalimide as nucleophile, the standard ligand
required tetrahexylammonium bromide as a phase transfer
catalyst in an aqueous methylene chloride two-phase system
and led to completion after 18 h with 5 mol % catalyst. The
dipod ligand required no phase transfer agent, went to comple-
tion in 2 h with only 0.25 mol % catalyst, and provided 12 of
98% ee in 91% yield.
The reaction of the cyclohexenyl substrate with sodium
benzenesulfinate to give 1314 was explored in greater depth.
For these studies, the reaction conditions involved 0.13 mol %
(dba)3Pd2‚CHCl3 and 0.30 mol % ligand in a water/methylene
chloride two-phase mixture at 0 °C. A significant rate enhance-
ment was observed for the dipod ligand 4 compared to the
standard ligand 1 wherein 50% conversion occurred in less than
10 min in the former and less than 15% conversion occurred
even after 180 min in the latter. Furthermore, addition of 0.30
mol % 15-crown-5 with the standard ligand 3 saw the conversion
increase only to 40% after 180 min. As might be anticipated
for an ion channel effect, there is a dependence on the cation
as shown in Figure 1. Comparison of the times to reach 50%
conversion with the dipole ligand 4 showed a strong selectivity
for Na+ (<10 min) compared to Li+ (70 min), K+ (180 min),
Acknowledgment. We thank the National Science Foundation and
the National Institutes of Health, General Medical Sciences, for their
generous support of our programs. Mass spectra were provided by
the Mass Spectrometry Facility, University of San Francisco, supported
by the NIH Division of Research Resources.
Supporting Information Available: Characterization data and
experimental procedures for 3-8, summary table, and figure depicting
rate comparisons between standard and dipod ligands (9 pages). See
any current masthed page for ordering and Internet access instructions.
JA9706864
(11) Chiralpak AD column eluting with 90:10 heptane/2-propanol was
employed.
(15) For a review, see: Gokel, G. W.; Murillo, O. In ComprehensiVe
Supramolecular Chemistry; Atwood, J. L., Davies, J. E. D., MacNirol, D.
D., Vo¨gtle, F., Lehn, J. M., Gokel, G. W., Eds.; Pergamon Press: Oxford,
1996; Vol. 1, Chapter 1.
(12) Cf: Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J. J. Am.
Chem. Soc. 1996, 118, 6520.
(13) Trost, B. M.; Bunt, R. C. J. Am. Chem. Soc. 1996, 118, 235.
(14) Trost, B. M.; Organ, M. G.; O’Doherty, G. A. J. Am. Chem. Soc.
1995, 117, 9662.
(16) Cf.: Zaugg, H. E.; Ratajczyk, J. F.; Leonard, J. F.; Schaefer, A. D.
J. Org. Chem. 1972, 37, 2249.
(17) Hayashi, T. Pure Appl. Chem. 1988, 60, 7.