(4R,5R)-2,2-Dimethyl-4,5-bis(hydroxydiphenylmethyl)-1,3-dioxolane-Titanium(IV) Chloride

(R1 = Me, R2 = Me, Ar = Ph)

[93379-49-8]  · C31H30O4  · (4R,5R)-2,2-Dimethyl-4,5-bis(hydroxydiphenylmethyl)-1,3-dioxolane  · (MW 466.61) (R1 = mesityl, R2 = H, Ar = Ph)

[114026-75-4]  · C38H36O4  · (4R,5R)-2-Mesityl-4,5-bis(hydroxydiphenylmethyl)-1,3-dioxolane  · (MW 556.74) (R1 = Me, R2 = Me, Ar = 1-naphthyl)

[137536-94-8]  · C47H38O4  · (4R,5R)-2,2-Dimethyl-4,5-bis(hydroxydi-1-naphthylmethyl)-1,3-dioxolane  · (MW 666.85) (R1 = t-Bu, R2 = H, Ar = Ph)

[114026-72-1]  · C33H34O4  · (4R,5R)-2,t-Butyl-4,5-bis(hydroxydiphenylmethyl)-1,3-dioxolane  · (MW 494.67) (R1 = Ph, R2 = Me, Ar = Ph)

[109306-21-0]  · C36H32O4  · (4R,5R)-2-Methyl-2-phenyl-4,5-bis(hydroxydiphenylmethyl)-1,3-dioxolane  · (MW 528.65) (R1 = Et, R2 = Et, Ar = 3,5-Me2C6H3)

[138710-29-9]  · C41H50O4  · (4R,5R)-2,2-Diethyl-4,5-bis(hydroxydi-3,5-xylylmethyl)-1,3-dioxolane  · (MW 606.91)

(chiral alkyltitanium reagent for asymmetric alkylation reaction;1 chiral Lewis acid for asymmetric Diels-Alder reaction, [2 + 2] cycloaddition reaction, and intramolecular ene reaction;2 reagent for asymmetric hydrocyanation of aldehydes and for kinetic resolution of a-aryl carboxylic acid derivatives2)

Preparative Methods: chiral titanates are usually prepared by mixing dichlorodiisopropoxytitanium and a chiral 1,4-diol in toluene. Other solvents such as ether and dichloromethane can also be employed. The alcohol exchange reaction takes place immediately at rt. Wherever necessary, liberated isopropyl alcohol is removed by azeotropic removal with toluene.3 The chiral 1,4-diols are prepared from dimethyl (or diethyl) tartrate by a two-step procedure comprising acetalization followed by the addition of an aryl Grignard reagent.4,5

Handling, Storage, and Precautions: chiral titanates are usually prepared just before use under argon atmosphere. Care should be taken to avoid moisture, especially when a catalytic amount of the reagent is used.

Chiral Alkylating Reagent.

The chiral methyltitanium reagent prepared from (1) and Methyllithium or methyl Grignard reagent adds to various aldehydes with moderate to good enantioselectivity (eq 1).6 Furthermore, the ate complex prepared from the chiral tetraalkoxytitanium (2) and methyllithium adds to aromatic aldehydes with more than 90% ee (eq 2).7 The chiral allyltitanium reagent (3) having a cyclopentadienyl group on titanium adds to various aldehydes to give the corresponding allylated products with high optical purity (eq 3).8

Chiral titanates can be employed as catalysts for the alkylation of aldehydes using dialkylzinc reagents. For example, by the use of a catalytic amount of the chiral titanium reagent (4), addition of Diethylzinc to various aldehydes occurs with high enantioselectivity in the presence of Titanium Tetraisopropoxide (eq 4).9 Furthermore, by using the chiral tetraalkoxytitanium (2), the alkylation reaction can be carried out in ether, which enables the use of various dialkylzinc reagents prepared in situ from the corresponding Grignard reagents and Zinc Chloride (eq 5).10

Chiral Lewis Acid.

These chiral titanium reagents are widely used as chiral Lewis acid catalysts. The Diels-Alder reaction of methyl acrylate and cyclopentadiene affords the endo adduct in moderate enantioselectivity when a stoichiometric amount of the chiral titanium reagent (5) is employed (eq 6).6 Use of 3-(2-alkenoyl)-1,3-oxazolidin-2-ones as dienophiles greatly improves the optical purity of the cycloadduct when the 2-phenyl-2-methyl-1,3-dioxolane derivative (6) is used as a chiral ligand. Most importantly, the reaction proceeds with the same high enantioselectivity for the combination of various dienophiles and dienes even when 5-10 mol % of the chiral titanium reagent is employed in the presence of molecular sieves 4A (eqs 7 and 8).11

The origin of the high enantioselectivity is found to lie in an attractive p-p interaction between the aryl group of the diol moiety and the dienophiles. Replacement of the phenyl group by a 3,5-dimethylphenyl group (as shown in 7), which has higher p-basicity than a phenyl group, affords improved enantioselectivities in some cases (eq 9).12

The chiral titanium reagent (6) also catalyzes the [2 + 2] cycloaddition reaction of 1,3-oxazolidin-2-one derivatives of a,b-unsaturated carboxylic acids and ketene dithioacetals in the presence of MS 4A to give cyclobutanone dithioacetal derivatives with high optical purity (eq 10).13 Vinyl sulfides, alkynyl sulfides, and 1,2-propadienyl sulfides can also be employed in this reaction to give the corresponding cyclobutanes, cyclobutenes and methylenecyclobutane derivatives with high optical purity (eqs 11 and 12).13-15

By using a stoichiometric amount of the chiral titanium reagent prepared by mixing chiral diol, Titanium(IV) Chloride, and titanium tetraisopropoxide, the asymmetric [2 + 2] cycloaddition reaction of 1,4-benzoquinones and styrenes gives the corresponding cyclobutane derivatives with high optical purity. These rearrange to 2,3-dihydrobenzofuran derivatives on mild acid treatment (eq 13).16

The asymmetric intramolecular ene reaction of 1,3-oxazolidin-2-one derivatives of a diene carboxylic acid is also promoted by a stoichiometric amount of the chiral titanium reagent (6) to give cyclopentane or cyclohexane derivatives with high optical purity (eq 14).17

Other Reactions.

Chiral titanates can be employed in several other asymmetric reactions. For example, the chiral titanate (6) promotes hydrocyanation of aryl aldehydes by Cyanotrimethylsilane at low temperature (-65 °C) to give the corresponding cyanohydrins with high optical purity (eq 15).18 Alkyl aldehydes are also converted into their cyanohydrins in high optical purity by employing the chiral titanium dicyanide species prepared in situ from the chiral titanate (6) and TMSCN at rt (eq 16).18

In the presence of a catalytic amount of the chiral titanium reagent (8) prepared from titanium tetraisopropoxide and the (R)-1,4-diol, kinetic resolution of S-(2-pyridyl) thioesters of a-aryl carboxylic acids is achieved with high relative rate of both the enantiomers to give the (R)-isopropyl esters with high optical purity (eq 17).19

The enantioselective iodolactonization of a-hydroxy carboxylic acid derivatives is achieved by using a stoichiometric amount of the chiral titanium reagent (8) (eq 18).20

Related Reagents.

Chloro(h5-cyclopentadienyl)[(4R,trans)-2,2-dimethyl-a,a,a,a-tetraphenyl-1,3-dioxolane-4,5-dimethanolato(2-)-Oa,Oa]titanium; Dichlorotitanium Diisopropoxide; 2,2-Dimethyl-a,a,a,a-tetraphenyl-1,3-dioxolane-4,5-dimethanolatotitanium Diisopropoxide.

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2. Narasaka, K. S 1991, 1.
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11. (a) Narasaka, K.; Inoue, M.; Okada, N. CL 1986, 1109. (b) Narasaka, K.; Inoue, M.; Yamada, T. CL 1986, 1967. (c) Narasaka, K.; Inoue, M.; Yamada, T.; Sugimori, J.; Iwasawa, N. CL 1987, 2409. (d) Iwasawa, N.; Sugimori, J.; Kawase, Y.; Narasaka, K. CL 1989, 1947. (e) Narasaka, K.; Tanaka, H.; Kanai, F. BCJ 1991, 64, 387. (f) Narasaka, K.; Yamamoto, I. T 1992, 48, 5743.
12. Corey, E. J.; Matsumura, Y. TL 1991, 32, 6289.
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14. Hayashi, Y.; Narasaka, K. CL 1990, 1295.
15. Hayashi, Y.; Niihata, S.; Narasaka, K. CL 1990, 2091.
16. Engler, T. A.; Letavic, M. A.; Reddy, J. P. JACS 1991, 113, 5068.
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18. (a) Narasaka, K.; Yamada, T.; Minamikawa, H. CL 1987, 2073. (b) Minamikawa, H.; Hayakawa, S.; Yamada, T.; Iwasawa, N.; Narasaka, K. BCJ 1988, 61, 4379.
19. Narasaka, K.; Kanai, F.; Okudo, M.; Miyoshi, N. CL 1989, 1187.
20. Kitagawa, O.; Hanano, T.; Tanabe, K.; Shiro, M.; Taguchi, T. CC 1992, 1005.

K. Narasaka & N. Iwasawa

The University of Tokyo, Japan

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