Regioselective substitution of fluorine in F8BINOL as a versatile route to new ligands with axial chirality

Article abstract of DOI:10.1021/ol006428k

(Equation Presented) Nucleophilic substitution of aromatic fluorine in F₈BINOL offers the possibility of selectively introducing a variety of substituents at the 6, 6′, 7, and 7′ positions. The configurational integrity of the homochiral precur

Full text of DOI:10.1021/ol006428k

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3433-3436
Regioselective Substitution of Fluorine
in F8BINOL as a Versatile Route to New
Ligands with Axial Chirality
Yu Chen, Shahla Yekta, L. James P. Martyn, Juan Zheng, and Andrei K. Yudin*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, M5S 3H6 Canada
ayudin@chem.utoronto.ca
Received August 7, 2000
ABSTRACT
Nucleophilic substitution of aromatic fluorine in F8BINOL offers the possibility of selectively introducing a variety of substituents at the 6, 6′,
7, and 7′ positions. The configurational integrity of the homochiral precursors is maintained under the conditions described, allowing one to
carry out these modification protocols on a microscale without the need for subsequent resolution steps. The resulting chiral ligands have
been investigated as precursors to new asymmetric catalysts.
Parallel synthesis and combinatorial chemistry have had a
major impact on homogeneous catalysis.1 In particular, the
structural variation of chiral ligands using high-throughput
methods provides a means to efficiently fine-tune the rate
and selectivity of the corresponding asymmetric catalysts.2
This is commonly achieved by generating libraries of
structurally related ligands using either solution- or solid-
phase synthesis methods followed by screening of the derived
catalysts.2 The ligands that are prepared from several
components offer the possibility of straightforward introduc-
tion of diverse substituents by choosing different building
blocks at the synthesis stage. Alternatively, direct modifica-
tion of the ligand can introduce elements of chemical
diversity into its scaffold. The latter approach has not been
widely utilized in parallel synthesis. In this regard, mild and
high-yielding reactions that install substituents into selected
positions of valuable chiral ligands are in high demand.
Derivatives of 2,2′-binaphthol (BINOL, 1) are among the
most widely used chiral ligands in asymmetric catalysis.3 A
(2) For examples, see: (a) Liu, G.; Ellman, J. A. J. Org. Chem. 1995,
60, 7712. (b) Gilbertson, S. R.; Wang, X. Tetrahedron Lett. 1996, 37, 6475.
(c) Burgess, K.; Lim, H.-J.; Porte, A. M.; Sulikowski, G. A. Angew. Chem.
Int. Ed. Engl. 1996, 35, 220. (d) Cole, B. M.; Shimizu, K. D.; Krueger, C.
A.; Harrity, J. P. A.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1668. (e) VidalFerran, A.; Moyano, A.; Pericas, M.
A.; Riera, A. J. Org. Chem. 1997, 62, 4970. (f) Shimizu, K. D.; Snapper,
M. L.; Hoveyda, A. H. Chem. Eur. J. 1998, 4, 1885. (g) Sigman, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 1988, 110, 4901. (h) Gao, X.; Kagan,
H. B. Chirality 1998, 10, 120. (i) Gennari, C.; Ceccarelli, S.; Piarulli, U.;
Montalbetti, C. A. G. N.; Jackson, R. F. W. J. Org. Chem. 1998, 63, 5312.
(j) Taylor, S. J.; Morken, J. P. Science 1998, 280, 267. (k) Boussie, T. R.;
Coutard, C.; Turner, H. W.; Murphy, V.; Powers, T. S. Angew. Chem., Int.
Ed. 1998, 37, 3272. (l) Burgess, K.; Porte, A. M. Tetrahedron: Asymmetry
1998, 9, 2465. (m) Reetz, M. T.; Becker, M. H.; Kuhling, K. M.; Holzwarth,
A. Angew. Chem., Int. Ed. 1998, 37, 2647. (n) Porte, A. M.; Reibenspiess,
J.; Burgess, K. J. Am. Chem. Soc. 1998, 120, 9180. (o) Matsuo, J.;
Odashima, K.; Kobayashi, S. Org. Lett. 1999, 1, 345. (p) Reetz, M. T.;
Becker, M. H.; Klein, H. W.; Stockigt, D. Angew. Chem., Int. Ed. 1999,
38, 1758. (q) Francis, M. B.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1999,
38, 937. (r) LaPointe, A. M. J. Comb. Chem. 1999, 1, 101. (s) Kobayashi,
S.; Kusakabe, K.; Ishitani, H. Org. Lett. 2000, 2, 1225. (t) Kobayashi, S.
Curr. Opin. Chem. Biol. 2000, 4, 338. (u) Sigman, M. S.; Vachal, P.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2000, 39, 1279.
(1) Jandeleit, B.; Schaefer, D. J.; Powers, T. S.; Turner, H. W.; Weinberg,
W. H. Angew. Chem., Int. Ed. 1999, 38, 2494.
10.1021/ol006428k CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/05/2000

Scheme 1
number of modifications of the BINOL scaffold aimed at
resulting chiral ligands have been investigated as precursors
to new titanium-based catalysts. Worthy of note, the 7 and
7′ positions cannot be accessed through direct electrophilic
modification routes that are commonly used in order to
modify BINOL. Most importantly, the configurational in-
tegrity of the homochiral precursors is not perturbed under
the conditions described herein. More forceful conditions
allow one to introduce substituents into the 6 and 6′ positions.
Nucleophilic displacement of aromatic fluorine is a well-
known reaction with a wide scope and utility.6 A variety of
nucleophiles are known to participate in this chemistry. When
5,5′,6,6′,7,7′,8,8′-octafluoro-1,1′-binaphthyl (2b) was sub-
jected to the substitution protocol with sodium methoxide,
the nucleophilic displacement of fluorine did take place but
a complicated mixture of poly(methoxylated) products
signaled lack of regioselectivity. Gratifyingly, the presence
of the methoxy substituents at the 2 and 2′ positions in bis-
(methyl) ether 2c was sufficient to secure high regioselec-
tivity of the methoxylation reaction (Scheme 1). Double
substitution resulted in the 7,7′-bis(methoxy) product 3a in
improving catalytic performance have been documented.3 We
recently reported the synthesis and first catalytic applications
of F8BINOL (2a), an isostere of BINOL with modulated
coordination preferences and remarkable configurational
stability under a wide range of reaction conditions.4 The
application of 2a in titanium-catalyzed asymmetric sulfide
oxidation with organic hydroperoxides revealed increased
activity of the derived catalyst compared to that of BINOL.5
The opposite sense of chiral induction in asymmetric
sulfoxidation was observed for BINOL and F8BINOL of the
same absolute configuration, indicating significant difference
in the nature of the catalytically active species obtained from
these two ligands. A related goal of our research is to develop
mild routes to diversely functionalized ligands with axial
chirality based on the electronically perturbed polyfluoro-
binaphthol scaffold. The challenge of improving catalytic
efficiency can be approached by a ligand modification
reaction that proceeds in high yield on a sub-millimole scale
without concomitant racemization. A useful process should
accomplish one (or both) of the following goals: (a)
introduce substituents into positions that have electronic
influence over the hydroxyl groups (e.g., 6 and 6′) or (b)
introduce substituents into the positions that modulate steric
effects (e.g., 7,7′ or 3,3′). If these requirements are met, rapid
generation of diverse catalyst libraries should become
straightforward. The present Letter highlights the possibility
of selective introduction of a variety of substituents at the 7
and 7′ positions via nucleophilic substitution of fluorine. The
(3) For representative applications of BINOL derivatives in asymmetric
catalysis, see: (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994. (b) Pu, L. Chem. ReV. 1998, 98, 2405. (c) Rosini,
C.; Franzini, L.; Rafaelli, A.; Salvadori, P. Synthesis 1992, 503. (d) Maruoka,
K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. J. Am. Chem. Soc. 1988, 110,
310. (e) Kitajima, H.; Katsuki, T. Synlett 1996, 568. (f) Reetz, M. T.; Merk,
C.; Naberfeld, G.; Rudolph, J.; Griebenow, N.; Goddard, R. Tetrahedron
Lett. 1997, 38, 5273. (g) Chan, A. S. C.; Zhang, F. Y.; Yip, C. W. J. Am.
Chem. Soc. 1997, 119, 4080. (h) Morita, T.; Arai, T.; Sasai, H.; Shibasaki,
M. Tetrahedron: Asymmetry 1998, 9, 1445. (i) Iida, T.; Yamamoto, N.;
Matsunaga, S.; Woo, H.-G.; Shibasaki, M. Angew. Chem., Int. Ed. 1998,
37, 2223. (j) Kobayashi, S.; Kusakabe, K.; Komiyama, S.; Ishitani, H. J.
Org. Chem. 1999, 64, 4220. (k) Nakamura, Y.; Takeuchi, S.; Ohgo, Y.;
Curran, D. P. Tetrahedron 2000, 56, 351. (l) Ishitani, H.; Yamashita, Y.;
Shimizu, H.; Kobayashi, S. J. Am. Chem. Soc. 2000, 122, 5403.
(4) Yudin, A. K.; Martyn, L. J. P.; Pandiaraju, S.; Zheng, J.; Lough, A.
Org. Lett. 2000, 2, 41.
(5) Martyn, L. J. P.; Pandiaraju, S.; Yudin, A. K. J. Organomet. Chem.
2000, 603, 98.
(6) Welch, J. T.; Peters, D.; Miethchen, R.; Il’chenko, A. Y.; Ru¨diger,
S.; Podlech, J. In Organo-fluorine Compounds, 4th ed.; Baasner, B.,
Hagemann, H., Tatlow, J. C., Eds.; Georg Thieme Verlag: Stuttgart, 2000;
Vol. E10b/Part 2, pp 293-459.
3434
Org. Lett., Vol. 2, No. 22, 2000

good chemical yield and with high regioselectivity which
was elucidated by single-crystal X-ray analysis (Figure 1).7
The utility of the poly(alkoxylated) ligands in asymmetric
catalysis was examined using diethylzinc addition to alde-
hydes (Scheme 2).8 We have observed high levels of
Scheme 2
Figure 1. Molecular structure of 3a.
This process should enable one to select appropriate nucleo-
philes in order to modulate steric requirements of the
FnBINOL system by remote substitution. The major byprod-
uct of this process is the 6,6′,7,7′-tetramethoxylated deriva-
tive. In fact, subjecting 3a to further methoxylation afforded
compound 5 in 32% yield. This reaction was slower than
the first one and required 5 days to completion. Preliminary
results indicate that sulfur- and nitrogen-based nucleophiles
also participate in this substitution chemistry, albeit in lower
yields.
Other alkoxy nucleophiles behaved in a manner similar
to that of sodium methoxide (Scheme 1). However, subse-
quent demethylation with boron tribromide suffered from
poor chemoselectivity despite the anticipated reactivity
difference between the two halves of the aromatic system
in 3a due to the electron-poor character of the fluorinated
ring. Thus, it is essential to use the bis(benzyl) ether 2d which
benefits from selective deprotection via hydrogenation and
leads to ligand 4a via 3e. The 7,7′-bis(ethoxy) and 7,7′-bis-
(isopropoxy) ligands 4b and 4c were obtained from 2d in
79% and 77% yields, respectively (see Supporting Informa-
tion). Most importantly, no racemization was observed in
the course of any of these substitution processes (monitored
by chiral HPLC) when enantiomerically pure precursors were
used in the alkoxylation reaction. Similar to the case of 2a,
we attribute this configurational stability to the electronic
effect of aromatic fluorine.4
enantioselectivity in titanium-catalyzed addition of diethyl-
zinc to aldehydes using the hexafluoro derivative 4a under
the conditions where formation of the monomeric catalyst
precursors of 1:1 composition is favored (7:1 Ti/L ratio).8c
The enantioselectivity of this process was found to be the
same as in the case of F8BINOL, indicating that steric effects
at remote positions are relatively insignificant in this case.
On the other hand, catalytic asymmetric oxidation of methyl
p-tolyl sulfide revealed a significant difference between 2a
and 4a. The enantioselectivity with the 4a/Ti catalyst was
only 51% (F8BINOL: 77%ee) with the same sense of chiral
induction.9 Despite this unsatisfactory result, it is clear that
bis-substitution may lead to different catalytic activity, which
is in fact encouraging and warrants the need for high-
throughput reaction screening protocols with the catalysts
produced using the outlined chemistry. Our current efforts
are directed toward other catalyst systems which are sensitive
to steric effects at remote positions.
In summary, the outlined chemistry should provide a
convenient method for introducing diverse substituents into
the 7 and 7′ positions which should in turn facilitate
positional scanning protocols for F8BINOL as well as help
place a binding site in that region. It should now become
possible to “fine-tune” sterics through 7 and 7′ substitution.
Another potentially useful extension of this methodology is
(7) Crystal Data for 1 C24H16O4F6, M ) 482.37, orthorhombic, space
group Pbca, (No. 61) T ) 100(1) K, a ) 8.3124(2), b ) 16.8836(3), c )
28.9812(6) Å, V ) 4067.32(15)(2) Å3, Z ) 8, Dc ) 1.575 g cm-3, µ(Mo
KR) ) 0.143 mm-1, 31743 reflections collected, R1 ) 0.0696, wR2 )
0.1187 for all 3584 independent reflections, [R1 ) 0.0461, wR2 ) 0.1074
for 2694 data with F >4σ(Fo)]. The data that were collected on a Nonius
Kappa-CCD were integrated and scaled using the DENZO-SMN package
(Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307-326). The
structures were solved and refined using SHELXTL V5.0 (Sheldrick, G.
M. SHELXTL\PC V5.1, Bruker Analytical X-ray Systems, Madison, WI,
1997).
(8) For examples, see: (a) Chow, H. F.; Ng, M. K. Tetrahedron:
Asymmetry 1996, 7, 2251. (b) Ng, M.-K.; Chow, H.-F. Tetrahedron Lett.
1996, 37, 2979. (c) Zhang, F. Y.; Yip, C. W.; Cao, R.; Chan, A. S. C.
Tetrahedron: Asymmetry 1997, 8, 585. (d) Mori, M.; Nakai, T. Tetrahedron
Lett. 1997, 38, 6233. (e) Yang, X. W.; Sheng, J. H.; Da, C. S.; Wang, H.
S.; Su, W.; Wang, R.; Chan, A. S. C. J. Org. Chem. 2000, 65, 295. (f)
Yang, X. W.; Su, W.; Liu, D. X.; Wang, H. S.; Shen, J. H.; Da, C. S.;
Wang, R.; Chan, A. S. C. Tetrahedron 2000, 56, 3511. (g) Nakamura, Y.;
Takeuchi, S.; Ohgo, Y.; Curran, D. P. Tetrahedron Lett. 2000, 41, 57.
(9) Studies aimed at understanding the effect of remote substitution on
kinetic resolution of sulfoxides in this system are in progress.
Org. Lett., Vol. 2, No. 22, 2000
3435

straightforward attachment of F8BINOL-derived catalysts to
solid support using the bis(nucleophile) linker strategy.
Screening of a variety of metals should enable one to
rigorously and quickly establish the structure/reactivity
relationships for the resulting catalyst libraries. Configura-
tional integrity of the ligand core in the course of the
substitution process is the key advantage that enables one
to run these reactions on a sub-millimole scale with no
requirement for a subsequent resolution step, impossible to
carry out in a high-throughput fashion. The outlined chem-
istry should also find use in “noncatalytic” applications of
the binaphthol scaffold, such as molecular recognition and
design of novel materials.7b
Acknowledgment. We thank the National Science and
Engineering Research Council (NSERC), Canada Foundation
for Innovation, the Research Corporation, and the University
of Toronto for financial support. Dr. Alan Lough is acknowl-
edged for the X-ray analysis.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 2-5. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL006428K
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Org. Lett., Vol. 2, No. 22, 2000