(R)-1,1-Bi-2,2-naphthotitanium Dichloride1

(X = Cl)

[116051-73-1]  · C20H12Cl2O2Ti  · (R)-1,1-Bi-2,2-naphthotitanium Dichloride  · (MW 403.10) (X = Br)

[128030-80-8]  · C20H12Br2O2Ti  · (R)-1,1-Bi-2,2-naphthotitanium Dibromide  · (MW 492.00) (X = ClO4)

[138645-47-3]  · C20H12Cl2O10Ti  · (R)-1,1-Bi-2,2-naphthotitanium Diperchlorate  · (MW 531.09) (X = OSO2CF3)

[139327-61-0]  · C22H12F6O8S2Ti  · (R)-1,1-Bi-2,2-naphthotitanium Ditriflate  · (MW 630.32)

(chiral Lewis acid for ene reactions,2 Mukaiyama aldol reactions,16 Diels-Alder reactions,24 and cyanosilylations27)

Alternate Name: BINOL-TiX2.

Solubility: insol propionitrile; sol toluene, dichloromethane, and nitroethane.

Handling, Storage, and Precautions: titanium is reputed to be of low toxicity.


The (R)-1,1-bi-2,2-naphthotitanium dihalides (BINOL-TiX2; X = Br or Cl) are most conveniently prepared in situ from the reaction of diisopropoxytitanium dihalides (i-PrO)2TiX2; X = Br2 or Cl3) with (R)-1,1-Bi-2,2-naphthol (BINOL) in the presence of molecular sieves (MS 4A) (eq 1).2 When BINOL is mixed with Dichlorotitanium Diisopropoxide in the absence of MS 4A, almost no change is observed on the hydroxy-carbon signal of BINOL in the 13C NMR spectrum. However, the addition of MS 4A to the solution of BINOL and (i-PrO)2TiCl2 leads to a downfield shift of the hydroxy-carbon signal, indicating the formation of the BINOL-derived chiral catalyst. MS (zeolite) serves as an acid/base catalyst4 and significantly facilitates the alkoxy ligand exchange in the in situ preparation of the chiral catalyst, BINOL-TiX2. A 1:1 mixture of (i-PrO)2TiX2 and (R)-BINOL in the presence of MS 4A in dichloromethane provides a red-brown solution. The molecularity of BINOL-TiX2 in dichloromethane is ca. 2.0, depending on the concentration, particularly of homochiral (R)(R)- or (S)(S)-dimer which tends to dissociate to the monomer in lower concentration.5

The chiral titanium complexes modified by the perchlorate or trifluoromethanesulfonate ligand such as (R)-1,1-bi-2,2-naphthotitanium diperchlorate (BINOL-Ti(ClO4)2) or (R)-1,1-bi-2,2-naphthotitanium ditriflate ((R)-BINOL-Ti(OTf)2) can easily be prepared by the addition of Silver(I) Perchlorate or Silver(I) Trifluoromethanesulfonate (2 equiv) to BINOL-TiCl2 (eq 2).6

Asymmetric Catalysis of Carbonyl-Ene Reaction.

(R)-1,1-Bi-2,2-naphthotitanium dihalides exhibit a remarkable level of asymmetric induction in the carbonyl-ene reaction of prochiral glyoxylate to provide practical access to a-hydroxy esters, a class of compounds of biological and synthetic importance7 (eq 3).2 The catalyst derived from (R)-BINOL leads consistently to the (R)-alcohol product, whereas the catalyst derived from (S)-BINOL affords the (S)-enantiomer. Generally speaking, the dibromide is superior to the dichloride in both reactivity and enantioselectivity for the reactions involving a methylene hydrogen shift in particular. On the other hand, the dichloride is lower in reactivity but superior in enantioselectivity for certain reactions involving methyl hydrogen shift. The present asymmetric catalysis is applicable to a variety of 1,1-disubstituted alkenes to provide the ene products in extremely high enantiomeric excess by judicious choice of the dibromo or dichloro catalyst. The reactions of mono- and 1,2-disubstituted alkenes afford no ene product. However, vinylic sulfides and selenides serve as alternatives to mono- and 1,2-disubstituted alkenes, giving the ene products with virtually complete enantioselectivity along with high diastereoselectivity (eq 4).8 The synthetic advantage of vinylic sulfides and selenides is exemplified by the synthesis of enantiomerically pure (R)-(-)-ipsdienol, an insect aggregation pheromone.

Positive Nonlinear Effect5 (Asymmetric Amplification9).

A nonclassical phenomenon of asymmetric catalysis by the chiral BINOL-derived titanium complex is the remarkable positive nonlinear effect observed, which is of practical and mechanistic importance.5 Convex deviation is observed from the usually assumed linear relationship between the enantiomeric purity of the BINOL ligand and the optical yield of the product. The glyoxylate-ene reaction catalyzed by the chiral titanium complex derived from a partially-resolved BINOL of 33.0% ee, for instance, provides the ene product with 91.4% ee in 92% chemical yield (eq 5). The optical yield thus obtained with a partially resolved BINOL ligand is not only much higher than the % ee of BINOL employed but is also very close to the value of 94.6% ee obtained using the enantiomerically pure BINOL. Thus the use of 35-40% ee of BINOL is sufficient to provide the equally high (>90% ee) level obtained with enantiomerically pure BINOL.

Asymmetric Desymmetrization.10

Desymmetrization of an achiral, symmetrical molecule is a potentially powerful but relatively unexplored concept for the asymmetric catalysis of carbon-carbon bond formation. While the ability of enzymes to differentiate between enantiotopic functional groups is well known,11 little is known about the similar ability of nonenzymatic catalysts to effect carbon-carbon bond formation. The desymmetrization by the enantiofacial selective carbonyl-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote internal12 asymmetric induction which is otherwise difficult to attain (eq 6).10 The (2R,5S)-syn product is obtained in >99% ee along with more than 99% diastereoselectivity. The desymmetrized product thus obtained can be transformed stereoselectively by a more classical diastereoselective reaction (e.g. hydroboration).

Kinetic Resolution.13

On the basis of the desymmetrization concept, the kinetic resolution of a racemic substrate might be recognized as an intermolecular desymmetrization.10 The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides an efficient access to remote relative12 asymmetric induction. Both the dibromide and dichloride catalysts provide the (2R,5S)-syn product with >99% diastereoselectivity along with more than 95% ee (eq 7). The high diastereoselectivity, coupled with the high % ee, strongly suggests that the catalyst/glyoxylate complex efficiently discriminates between the two enantiomeric substrates to accomplish effective kinetic resolution. In fact, the relative rates with racemic ethers are quite large, ca. 60 and 700, respectively. As expected, the reaction of (S)-ene using the catalyst (R)-BINOL-TiCl2 (matched catalytic system) provides complete (>99%) 1,4-syn diastereoselectivity in high chemical yield, whereas the reaction of (R)-ene using (R)-BINOL-TiCl2 (mismatched catalytic system) affords a diastereomeric mixture in quite low yield (eq 8).

Ene Cyclization.14

The asymmetric catalysis of the intramolecular carbonyl-ene reaction not only of type (3,4) but also (2,4) employs the BINOL-derived titanium complexes ((R)-BINOL-TiX2; X = ClO4 or OTf), modified by the perchlorate and trifluoromethanesulfonate ligands.6 The trans-tetrahydropyran is thus preferentially obtained in 84% ee (eq 9). The seven-membered cyclization of type 7-(2,4) gives the oxepane in high ee, where the gem-dimethyl groups are unnecessary (eq 10).

Mukaiyama Aldol Condensation.

As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis.15 Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-type aldol reaction of not only ketone silyl enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11).16

Carbonyl Addition of Allylic Silanes and Stannanes.17

The chiral titanium complex BINOL-TiCl2 also catalyzes the asymmetric carbonyl addition reaction of allylic silanes and stannanes.18 Thus the addition reaction of glyoxylate with (E)-2-butenylsilane and -stannane proceeds smoothly to give the syn product in high enantiomeric excess (eq 12). The syn product thus obtained can be readily converted to the lactone portion of verrucaline A. The reaction of aliphatic and aromatic aldehydes with allylstannane is also catalyzed by BINOL-TiCl2 to give remarkably high enantioselectivity (eq 13).19

Hetero Diels-Alder Reaction.20

The hetero-Diels-Alder reaction involving glyoxylate as the dienophile provides an efficient access to the asymmetric synthesis of monosaccharides.21 The hetero Diels-Alder reaction with methoxydienes proceeds smoothly with catalysis by BINOL-TiCl2 to give the cis product in high enantiomeric excess (eq 14).22 The dibromide affords a higher cis selectivity, however, with a lower enantioselectivity, particularly in the trans adduct. The product thus obtained can be readily converted to the lactone portion of HMG-CoA inhibitors such as mevinolin or compactin.23

Diels-Alder Reaction.24

The Diels-Alder reaction of methacrolein with 1,3-dienol derivatives can also be catalyzed by the chiral BINOL-derived titanium complex BINOL-TiCl2. The endo adduct was obtained in high enantioselectivity (eq 15).22a,25 The sense of asymmetric induction is exactly the same as observed for the asymmetric catalytic reactions shown above. Asymmetric catalytic Diels-Alder reactions with naphthoquinone derivatives as the dienophile provide an efficient entry to the asymmetric synthesis of anthracyclinone aglycones (eq 16).26


Another preparative procedure of BINOL-TiCl2 and the use thereof was reported in the asymmetric catalysis of the addition reaction of cyanotrimethylsilane to aldehydes.28 The dilithium salt of BINOL in ether was treated with Titanium(IV) Chloride, the red-brown mixture was warmed to room temperature, and the ether removed in vacuo. Dry benzene was added and the nondissolved solid was separated via filtration under nitrogen. Removal of the solvent delivered 50% of a sensitive red-brown solid which showed a single set of 13C NMR signals (eq 17). The BINOL-TiCl2 thus obtained was utilized to prepare the cyanohydrin of 3-methylbutanal in <82% ee (eq 18).

Related Reagents.

(R)-1,1-Bi-2,2-naphthol; (R)-1,1-Bi-2,2-naphthotitanium Diisopropoxide; Titanium(IV) Chloride.

1. (a) Mikami, K.; Shimizu, M. CRV 1992, 92, 1021. (b) Mikami, K.; Terada, M.; Narisawa, S.; Nakai, T. SL 1992, 255.
2. (a) Mikami, K.; Terada, M.; Narisawa, S.; Nakai, T. OS 1992, 71, 14. (b) Mikami, K.; Terada, M.; Nakai, T. JACS 1990, 112, 3949. (c) Terada, M.; Nakai, T. JACS 1989, 111, 1940.
3. Dijkgaaf, C.; Rousseau, J. P. G. Spectrochim. Acta 1968, 24A, 1213.
4. (a) Thomas, J. M.; Theocaris, C. R. Modern Synthetic Methods; Springer: Berlin, 1989. (b) Onaka, M.; Izumi, Y. Yuki Gosai Kagaku Kyokaishi 1989, 47, 233. (c) Dyer, A. An Introduction to Zeolite Molecular Sieves; Wiley: Chichester, 1988.
5. (a) Mikami, K.; Terada, M. T 1992, 48, 5671. (b) Terada, M.; Mikami, K.; Nakai, T. CC 1990, 1623.
6. (a) Mikami, K.; Sawa, E.; Terada, M. TA 1991, 2, 1403. (b) Mikami, K.; Terada, M.; Sawa, E.; Nakai, T. TL 1991, 32, 6571.
7. (a) Omura, S. J. Synth. Org. Chem., Jpn. 1986, 44, 127; (b) Hanessian, S. Total Synthesis of Natural Products: The Chiron Approach; Pergamon: Oxford, 1983. (c) Seebach, D.; Hungerbuhler, E. Modern Synthetic Methods; Otto Salle: Frankfurt am Main, 1980.
8. Terada, M.; Matsukawa, S.; Mikami, K. CC 1993, 327.
9. (a) Noyori, R.; Kitamura, M. AG(E) 1991, 30, 49. (b) Wynberg, H. C 1989, 43, 150. (c) Puchot, C.; Samuel, O.; Duñach, E.; Zhao, S.; Agami, C.; Kagan, H. B. JACS 1986, 108, 2353.
10. Mikami, K.; Narisawa, S.; Shimizu, M.; Terada, M. JACS 1992, 114, 6566.
11. Ward, R. S. CSR 1990, 19, 1.
12. Bartlett, P. A. T 1980, 36, 3.
13. (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. (b) Brown, J. M. CI(L) 1988, 612.
14. (a) Oppolzer, W.; Snieckus, V. AG(E) 1978, 17, 476. (b) Taber, D. F. Intramolecular Diels-Alder and Alder Ene Reactions; Springer: Berlin, 1984.
15. (a) Masamune, S.; Choy, W.; Peterson, J. S.; Sita, L. R. AG(E) 1985, 24, 1. (b) Heathcock, C. H. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic: New York, 1984. (c) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1. (d) Mukaiyama, T. OR 1982, 28, 203.
16. Mikami, K.; Matsukawa, S. JACS 1993, 115, 7039; 1994, 116, 4077.
17. (a) Sakurai, H. SL 1989, 1. (b) Hosomi, A. ACR 1988, 21, 200. (c) Yamamoto, Y. ACR 1987, 20, 243. (d) Hoffmann, R. W. AG(E) 1982, 21, 555.
18. Aoki, S.; Mikami, K.; Terada, M.; Nakai, T. T 1993, 49, 1783. Also see: Mikami, K.; Matsukawa, S. TL 1994, 35, 3133.
19. Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. JACS 1993, 115, 7001.
20. (a) Bednarski, M. D.; Lyssikatos, J. P. COS, 1991, 2, Chapter 2.5. (b) Boger, D. L.; Weinreb, S. M. Hetero-Diels-Alder Methodology in Organic Synthesis; Academic: New York, 1987. (c) Konowal, A.; Jurczak, J.; Zamojski, A. T 1976, 32, 2957.
21. (a) Konowal, A.; Jurczak, J.; Zamojski, A. T 1976, 32, 2957. (b) Danishefsky, S. J.; DeNinno, M. P. AG(E) 1987, 26, 15.
22. (a) Mikami, K.; Motoyama, Y.; Terada, M. JACS 1994, 116, 2812. (b) Terada, M.; Mikami, K.; Nakai, T, TL 1991, 32, 935.
23. Rosen, T.; Heathcock, C. H. T 1986, 42, 4909.
24. (a) Kagan, H. B.; Riant, O. CRV 1992, 92, 1007. (b) Oppolzer, W. COS, 1991, 5, Chapter 1.2. (c) Fringuelli, F.; Taticchi, A. Dienes in the Diels-Alder Reaction; Wiley: New York, 1990. (d) Taschner, M. J. Org. Synth. Theory Appl. 1989, 1, 1. (e) Paquette, L. A. In Asymmetric Synthesis, Morrison, J. D., Ed.; Academic: New York, 1984; Vol. 3B, Chapter 7.
25. Mikami, K.; Terada, M.; Motoyama, Y.; Nakai, T. TA 1991, 2, 643.
26. (a) Krohn, K. T 1990, 46, 291. (b) Krohn, K. AG(E) 1986, 25, 790. (c) Broadhurst, M. J.; Hassall, C. H.; Thomas, G. J. CI(L) 1985, 106. (d) Arcamone, F. Med. Res. Rev. 1984, 4, 153.
27. Rasmussen, J. K.; Heilmann, S. M.; Krepski, L. R. Adv. Silicon Chem. 1991, 1, 65.
28. Reetz, M. T.; Kyung, S.-H.; Bolm, C.; Zierke, T. CI(L) 1986, 824.

Koichi Mikami

Tokyo Institute of Technology, Japan

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