Polystyrene-bound cyclo-BINOLs. New heterogeneous ligands for asymmetric catalysis

Article abstract of DOI:10.1016/S0040-4039(00)01660-9

BINOL and substituted BINOLs, which have been tethered between the 7 and 7' sites (i.e. 'cyclo-BINOLs'), can be attached via this linkage to polystyrene resins using a simple acetalization. Efficacy associated with these new ligands is demonstrated in het

Full text of DOI:10.1016/S0040-4039(00)01660-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9515–9521
Polystyrene-bound cyclo-BINOLs. New heterogeneous
ligands for asymmetric catalysis†
Bruce H. Lipshutz* and Young-Jun Shin
Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA 93106, USA
Received 3 August 2000; revised 18 September 2000; accepted 19 September 2000
Abstract
BINOL and substituted BINOLs, which have been tethered between the 7 and 7% sites (i.e. ‘cyclo-
BINOLs’), can be attached via this linkage to polystyrene resins using a simple acetalization. Efficacy
associated with these new ligands is demonstrated in heterogeneous asymmetric catalysis (e.g. aryl alkyl
sulfide oxidations, and 1,2-additions of Et2Zn to aryl aldehydes). © 2000 Elsevier Science Ltd. All rights
reserved.
Nonracemic BINOL, first recognized by Noyori1 as a ligand for metal-mediated homogeneous
asymmetric synthesis,2 has spawned an impressive array of applications and continues to serve
as the focal point of many new technologies. Issues associated with this nonracemic biaryl, such
as catalyst recovery and re-use, simplification of reaction workup, and product purification, have
fostered many efforts in search of heterogeneous equivalents.3–5 In this report, we describe the
first examples of 3-mono and 3,3%-unsymmetrically disubstituted BINOLs in their cyclo-BINOL
form, which are covalently bound to polystyrene resins.
Our modular route to substituted, nonracemic cyclo-BINOLs6 provided us with an entry to
BINOL arrays possessing oxygen functionality in the form of an acetonide at a distal site relative
to that of eventual metal complexation (1, Scheme 1). Removal of the diol protecting group (aq.
HCl, MeOH, rt) in 1 led to diol species 3 that was smoothly attached to formylated polystyrene
(PS) beads 2 (either 1 or 2% cross-linked polystyrene, prepared from the corresponding
chloromethylated material7 via oxidation with NaHCO3/DMSO; Scheme 2).8 Traditional Kagan
acetalization conditions (benzene or toluene, cat TsOH, reflux, Dean–Stark trap, 1 day)9 sufficed
to arrive at acetals 4. A series of polymer-supported cyclo-BINOLs has been prepared (Table 1),
which includes the parent system (4A), a 3-monosubstituted case (4B), 3,3%-symmetri-cally
disubstituted examples (4C, 4D), and two 3,3%-unsymmetrically disubstituted derivatives (4E, 4F).
* Corresponding author. E-mail: lipshutz@chem.ucsb.edu
†
Warmly dedicated to Professor Harry H. Wasserman on this most special birthday occasion. For almost three
decades he continues to be an incredible inspiration to this PI; indeed, he is a model teacher, an exceptional
researcher, an especially valued advisor, and a great friend.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01660-9

9516
Scheme 1.
Scheme 2.
To test these novel ligands in their capacity as heterogeneous equivalents of known solution-
based BINOLs, two sequences were studied: (1) the oxidation of aryl sulfides to nonracemic
sulfoxides;10 and (2) the 1,2-addition of Et2Zn to aryl aldehydes.11 Pre-treatment of 4 (R, R%=H;
1% cross-linked polystyrene) with Ti(O-i-Pr)4 in THF at reflux for 1.5 h leads to orange beads
presumably composed of in situ generated complex 5 (R=i-Pr). Reaction of methyl p-tolyl
sulfide 6 with t-BuOOH in THF at 0°C for 60 h in the presence of catalyst 5 (25 mol%) afforded
(R)-sulfoxide 8 [67% yield; 78% ee; [h]D25=112 (c=1.1, acetone); Scheme 3].10 Methyl phenyl
sulfide 7, under similar conditions (72 h, 50 mol% 5) gave sulfoxide 9 [65% yield; 88% ee;
[h]2D5=129 (c=2.1, acetone)].10 Both results compare favorably with literature methods involving
homogeneous conditions in THF.12 Isolation of what was anticipated to be ligand 4 (R, R%=H)
was actually material which had retained complexed titanium (i.e. catalyst 5 (R%%=i-Pr), or
possibly a derivative such as R%%=H). Re-exposure of the reclaimed Ti-complexed catalyst (from
each experiment) to sulfide 7 in two additional trials led to essentially the same results in terms
of chemical yields and ee’s (cf. Scheme 3).

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Table 1
Preparation of 1% cross-linked polystyrene-supported (R)-cyclo-BINOLs
Scheme 3.
Employing an identical modular strategy,6 2% cross-linked polystyrene-mounted 3,3%-symmet-
rically substituted (R)-cyclo-BINOL 10 was prepared, as was the corresponding homogeneous
catalyst 11.13 Results from a series of 1,2-additions of Et2Zn to aryl aldehydes 12 in toluene/hex-
ane at room temperature in the presence of 10 mol% 10 are summarized in Table 2.3a
Benzaldehyde afforded R product alcohol 13 in 89% yield with an ee of 96%. Resubmission of
this isolated ligand to fresh starting materials and reagents led to essentially the same results
over three additional cycles (entries 1a–d). Increasing the amount of catalyst 10 to 20 mol%
decreased the reaction time somewhat (8 h versus 12 h), but did not significantly impact the yield

9518
Table 2
1,2-Additions of Et2Zn to aldehydes catalyzed by 10
Entry
1 (a)
Ar in 12
Yield of 13 (%)
% ee
Comments
1st use
89
96a
(b)
(c)
(d)
(e)
92
90
83
94
90
92b
90b
93b
93c
95d
2nd use
3rd use
4th use
2
3
4
84
98e
56
69
84f
82c
a [h]2D5=43.5 (c 5.2, CHCl3).17
b Results from recycled 10.
c Results from 10 mol% 11.
d [h]2D5=31.8 (c 3.5, PhH).17
e [h]2D5=25.1 (c 2.0, PhH).18
f [h]2D5=−22.6 (c 6.9, PhH).19
or product alcohol ee (92% yield; 96% ee). As a control experiment, non-polymer-bound
cyclo-BINOL 11 reacted faster (3.5 h), but with an otherwise similar outcome (94% yield; 93%
ee; entry 1e). Other aryl aldehydes likewise led to aryl carbinols of good ee’s. The one case
examined of an alkyl aldehyde, under either hetero- or homogeneous conditions, was not as high

9519
yielding nor as responsive in terms of observed ee (entry 4), to be expected based on literature
precedent for polystyrene-supported catalysts.3b Thus, other than affecting to a minor degree
the rate of 1,2-addition, the overall effectiveness of this ligand under heterogeneous conditions
at delivering the ethyl group in a highly stereocontrolled fashion is comparable to that seen
under homogeneous conditions. These results are also competitive with the corresponding
polybinaphthyls extensively developed by Pu,3 with the exception of attempts to apply our
heterogeneous conditions to 1,2-additions of Ph2Zn which did not afford synthetically useful
levels of induction (20–40% ee’s).4,5
Lastly, the potential for unsymmetrical polystyrene-bound cyclo-BINOLs to enhance the
level of stereoinduction relative to the parent BINOL was demonstrated in comparison
reactions of related Et2Zn additions to aryl aldehydes in the presence of Ti(O-i-Pr)4 (Table 3).5
Under homogeneous conditions, Ti-precomplexed (S)-BINOL catalyzes the 1,2-addition of
Et2Zn to benzaldehyde to afford the S alcohol (S)-14 with 92% ee. The corresponding
polymer-supported (R)-cyclo-BINOL (4A) gives an identical level of enantiomeric excess in
product (R)-14. With para-anisaldehyde, both (S)-BINOL and PS-(R)-cyclo-BINOL gave
inferior results (<79% ee’s). However, the 3-phenyl-substituted PS-cyclo-BINOL 4B led to the
desired products (R)-14 not only in high isolated yields (>92%), but most notably, with >95%
ee for both aldehydes.
Table 3
Catalysis by an unsymmetrical, heterogeneous, 3-substituted (R)-cyclo-BINOL (4B)

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In summary, a modular approach has been utilized to arrive at variously substituted
polystyrene-bound cyclo-BINOLs via attachment of precursor ligands to formylated commercial
samples of (1 and 2% cross-linked) polystyrene beads. Efficacy has been demonstrated for
conversions of sulfides to nonracemic sulfoxides, as well as in 1,2-additions of Et2Zn to aryl
aldehydes. The ligands are easily handled, are reusable without significant loss of efficiency, and
provide for very simple workup procedures which minimize losses of material.14 With these
results in hand, we can now focus on the corresponding polymer-supported (substituted)
cyclo-NOBIN15 and cyclo-BINAP16 systems, reports on which will be submitted in due course.
Acknowledgements
Financial support provided by the NIH (GM 56764) is warmly acknowledged.
References
1. Noyori, R.; Tomino, I.; Tanimoto, Y. J. Am. Chem. Soc. 1979, 101, 3129.
2. (a) In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993. (b) Noyori, R. Asymmetric
Catalysis in Organic Synthesis; Wiley: New York, 1994.
3. (a) Huang, W.-S.; Pu, L. Tetrahedron Lett. 2000, 41, 145. Huang, W.-S.; Pu, L. J. Org. Chem. 1998, 64, 4222.
Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem. 1998, 64, 2798. Huang, W.-S.; Hu, Q.-S.; Pu, L. J. Org. Chem.
1998, 63, 1364. Hu, Q.-S.; Huang, W.-S.; Vitharana, D.; Zheng, X.-F.; Pu, L. J. Am. Chem. Soc. 1997, 119,
12454. (b) Huang, W.-S.; Hu, Q.; Pu, L. J. Org. Chem. 1999, 64, 7940.
4. For related studies on supported BINOLs, see Kobayashi, S.; Kusakabe, K.; Ishitani, H. Org. Lett. 2000, 2, 1225.
Takata, T.; Furusho, Y.; Murakawa, K.; Endo, T.; Matsuoka, H.; Hirasa, T.; Matsuo, J.; Sisido, M. J. Am.
Chem. Soc. 1998, 120, 4530. Yamago, S.; Furukawa, M.; Azuma, A.; Yoshida, J. Tetrahedron Lett. 1998, 39,
3783.
5. 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. Zhang, F.; Yip, C.; Cao, R.; Chan, A. Tetrahedron: Asymmetry 1997, 8, 585.
6. Lipshutz, B. H.; Shin, Y.-J. Tetrahedron Lett. 1998, 39, 7017.
7. The resin used was a commercially available copolymer of styrene–divinylbenzene in the form of 200–400 mesh
resin beads containing 1 or 2% divinylbenzene.
8. Frechet, J. M.; Schuerch, C. J. Am. Chem. Soc. 1971, 93, 492.
9. Dumont, W.; Poulin, J.; Dang, T.; Kagan, H. J. Am. Chem. Soc. 1973, 95, 8295.
10. (a) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 4529. (b) Mislow, K.; Green,
M. M.; Laur, P.; Melillo, J. T.; Simmons, T.; Ternary, A. L. J. Am. Chem. Soc. 1965, 87, 1958. (c) Jacobus, J.;
Mislow, K. J. Am. Chem. Soc. 1967, 89, 5228.
11. For a review on 1,2-additions of Et2Zn to aldehydes, see Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
12. Bolm, C.; Dabard, O. Synlett. 1999, 360.
13. The (R) stereochemical assignments for the precursors to 4A–F and 11 were confirmed by comparison of the CD
spectrum of 11 with that for (S)-BINOL; cf. Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky, P. J.
Org. Chem. 1992, 57, 1917.
14. Typical procedure for the synthesis of polystyrene-bound cyclo-BINOLs (e.g. 4B). To a well-dried 100 mL round
bottom flask was added formylated resin (1.82 g, 1.83 mmol) and the cyclo-BINOL 3 (R=Ph, R%=H; 1.0 g, 1.82
mmol). Benzene (50 mL) and p-toluenesulfonic acid (7 mg) were added to the reaction flask and the mixture was
refluxed with continuous removal of water with a Dean–Stark trap. After 24 h, the reaction flask was cooled. The
resin was collected on
a glass filter and washed with dioxane, acetone, N,N-dimethylformamide,
dichloromethane, and finally methanol. There was obtained 2.97 g (91%) of polystyrene-bound (R)-cyclo-BINOL
4B after drying at 60°C under high vacuum for 10 h.
Typical procedure for asymmetric oxidation of aryl alkyl sulfides (e.g. 7 to 9). Polystyrene-bound (R)-cyclo-

9521
BINOL 4A (1.15 g, 0.78 mmol) was suspended in anhydrous tetrahydrofuran (15 mL). To the suspension was
added Ti(O-i-Pr)4 (1 M in toluene, 319 mL, 0.39 mmol) at rt. The reaction mixture was refluxed for 1.5 h. After
cooling to rt, H2O (105 mL) was added and the mixture was stirred for 2 h at rt. Methyl phenyl sulfide (229 mL,
1.96 mmol) was added and the reaction mixture cooled to 0°C. TBHP (t-butylhydroperoxide) in water (70%, 541
mL, 3.91 mmol) was then added dropwise. After stirring for 72 h at the same temperature, the solid was filtered
and washed with dichloromethane. The solution was concentrated in vacuo, absorbed onto silica gel and the
product sulfoxide isolated by column chromatography with ether as eluent (Rf=0.32) to afford a white crystalline
solid (178 mg, 65%, 88% ee), [h]2D5=+129.2° (c 2.18, acetone).
Typical procedure for the asymmetric addition of diethylzinc to an aryl aldehyde (Table 2, entry 1a).
Polystyrene-bound cyclo-BINOL 10 (196 mg, 0.10 mmol) was suspended in dichloromethane (15 mL) and stirred
for 1 h at rt. To the suspension was slowly added diethylzinc (405 mL, 3.94 mmol) followed by continued stirring
for 15 min. The reaction mixture was then cooled to 0°C and benzaldehyde (100 mL, 0.98 mmol) was added. After
stirring for 7 h at 0°C, saturated aqueous NH4Cl (5 mL) was introduced and the mixture stirred for an additional
20 min. The solid was then filtered and the resulting solution was extracted with dichloromethane (15 mL). The
combined organic solvents were dried over anhydrous MgSO4, concentrated in vacuo, and purified by column
chromatography (petroleum ether/ethyl acetate=7/1, Rf=0.43) to afford the product as a colorless liquid (119
mg, 89%), [h]2D5=+43.5 (c 5.20, acetone). The solid material was transferred into a 50 mL beaker and treated with
15 mL of 2N NaOH. After stirring for 2 h, the solid was filtered and washed with H2O, dioxane, N,N-dimethyl-
formamide, dichloromethane and methanol. 320 mg of polystyrene-bound cyclo-BINOL 4B was recovered and
showed no decrease in activity after drying at 60°C under vacuum (ca. 10 mmHg) for 10 h.
15. Voskocil, S.; Jaracz, S.; Smrcina, M.; Sticha, M.; Hanus, V.; Polasek, M.; Kocovsky, P. J. Org. Chem. 1998, 63,
7727.
16. For polystyrene-bound BINAP, see: Batston, D. J.; Fraser, J. L.; Ashton, M. R.; Baxter, A. D.; Polywka, M. E.
C.; Moses, E. J. Org. Chem. 1998, 63, 3137.
17. Pickard, R. H.; Kenyon, J. J. Chem. Soc. 1914, 1115.
18. Capillon, J.; Guette, J. Tetrahedron 1979, 35, 1817.
19. Sato, T.; Gotoh, Y.; Wakabayashi, Y.; Fujisawa, T. Tetrahedron Lett. 1983, 24, 4123.
.