2,2-Dimethyl-a,a,a“,a“-tetraphenyl-1,3-dioxolane-4,5-dimethanolatotitanium Diisopropoxide1

(1a; R1 = R2 = Me; Ar = Ph; X = Y = i-PrO)

[144121-63-1]  · C37H42O6Ti  · 2,2-Dimethyl-a,a,a“,a“-tetraphenyl-1,3-dioxolane-4,5-dimethanolatotitanium Diisopropoxide  · (MW 630.66) (1b; R1 = R2 = Me; Ar = Ph; X = Y = Cl)

[109457-91-2]  · C31H28Cl2O4Ti  · 2,2-Dimethyl-a,a,a“,a“-tetraphenyl-1,3-dioxolane-4,5-dimethanolatotitanium Dichloride  · (MW 583.37) (ent-1b; R1 = R2 = Me; Ar = Ph; X = Y = Cl)

[139341-84-7]  · C31H28Cl2O4Ti  · 2,2-Dimethyl-a,a,a“,a“-tetraphenyl-1,3-dioxolane-4,5-dimethanolatotitanium Diisopropoxide  · (MW 583.37) (1c; R1 = R2 = Me; Ar = Ph; X = i-PrO; Y = Cl)

[114031-33-3]  · C34H35ClO5Ti  · 2,2-Dimethyl-a,a,a“,a“-tetraphenyl-1,3-dioxolane-4,5-dimethanolatotitanium Chloride Isopropoxide  · (MW 607.02) (1d; R1 = R2 = Me; Ar = 2-naphthyl; X = Y = i-PrO)

[144121-64-2]  · C53H50O6Ti  · 2,2-Dimethyl-a,a,a“,a“-tetrakis(2-naphthyl)-1,3-dioxolane-4,5-dimethanolatotitanium Diisopropoxide  · (MW 830.90) (1e; R1 = Me; R2 = Ar = Ph; X = Y = Cl)

[109414-72-4]  · C36H30Cl2O4Ti  · 2-Methyl-2,a,a,a“,a“-pentaphenyl-1,3-dioxolane-4,5-dimethanolatotitanium Dichloride  · (MW 645.44) (1f; R1 = R2 = Me; Ar = Ph; X = Cp; Y = Cl)

[132068-98-5]  · C36H33ClO4Ti  · Chloro(h5-cyclopentadienyl)[(4R,trans)-2,2-dimethyl-a,a,a“,a“-tetraphenyl-1,3-dioxolane-4,5-dimethanolato(2-)-Oa,Oa]titanium  · (MW 613.02)

(chiral auxiliaries and Lewis acids for stoichiometric and catalytic enantioselective transformations)

Alternate Name: Ti-TADDOLates.


Ti-TADDOLates are a,a,a“,a“-tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanolatotitanium derivatives. The most common substituents are R1, R2 = Me/Me and Ph/Me, Ar = Ph and 2-naphthyl, X, Y = Cl/Cl, i-PrO/Cl, Cp/Cl, and i-PrO/i-PrO. The corresponding TADDOLs (2) are available in both enantiomeric forms from tartrate esters which are acetalized (R1R2CO) and allowed to react with aryl Grignard reagents.1a,g,2 The reactions performed in the presence of Ti-TADDOLates or with Ti-TADDOLate derivatives include: nucleophilic additions to aldehydes1a,b,f,g,j,2a,3-5 and nitroalkenes6 of alkyl,1a,b,g,2a,3-5 aryl,5 and allylic1d,f groups; aldol additions;1d,f hydrophosphonylations7 and cyanohydrin reactions1j of aldehydes; inter- and intramolecular Diels-Alder additions;1e,h,i,2a,8,9 [2 + 2] cycloadditions;1e,h,i,10 intra-1e,h,i and intermolecular11 ene reactions; iodolactonizations;12 and transesterifications.1h,i Analogous compounds of other metals, and TADDOL derivatives containing one or two amino,13 phosphinic, phosphonic, and/or phosphite groups,13,14 have also been made and used for various reactions such as: LiAlH4 reductions;15 Grignard additions to ketones;16 Li enolate additions to nitroalkenes;17 hydrosilylations of ketones;14a Pd-catalyzed allylations;14b and metathesis reactions.18 Finally, the TADDOLs themselves have been proved to be useful as NMR shift reagents;2c,19 as components for enantioselective formation of host-guest complexes;20,21 and for enantioselective solid-state reactions.22 (R,R)-Ti-TADDOLates and (P)-Ti-BINOLates often give the same products in enantioselective reactions.9

Preparation of Ti-TADDOLate Solutions.

Five different procedures have been mostly used for the preparation of TADDOLates (1).

  • 1)TADDOLate (1f) can be obtained from Trichloro(cyclopentadienyl)titanium and TADDOL (2), with removal of HCl (eq 1).1d,f
  • 2)TADDOLates (1b) and (1e) are prepared from (2) and Dichlorotitanium Diisopropoxide, without removal of the i-PrOH formed (eq 2). They are typically used in the presence of 4 Å molecular sieves.1e,h,i,8b,c,9,10
  • 3)Diisopropoxy Ti-TADDOLates (1a) and (1d) are conveniently made from (2) and Titanium Tetraisopropoxide with removal of i-PrOH by evaporation under reduced pressure or by azeotropic distillation (eq 3).1a,b,g,2a,3e
  • 4)TADDOLate (1a) can be synthesized alcohol-free from spirotitanate (3) and (i-PrO)4Ti (eq 4).
  • 5)Likewise, TADDOLate (1b) can be prepared from (3) and Titanium(IV) Chloride (eq 5).

    An additional procedure leading from a titanate (1) (X = Y = i-PrO) to the corresponding dichloride (X = Y = Cl) is to treat the former with Tetrachlorosilane and pump off (i-PrO)2SiCl2.8a A method in which the Ti-TADDOLate is present together with another Lewis acid (Lithium Chloride) is to treat a TADDOL (2) with 2 equiv n-Butyllithium, followed by TiCl4.9

    Spirotitanate (3) was obtained by reacting TADDOL and 0.5 equiv (EtO)4Ti or (i-PrO)4Ti, with azeotropic removal of the alcohol in refluxing toluene (eq 6). In the solid state it is rather stable to air (storage form);3a,d,e its crystal structure has been determined.1g Numerous TADDOLates of type (1) have been prepared and identified by NMR spectroscopy.1g,3e,8a,23 Normally, they are used in situ in solvents such as toluene, petroleum ethers, CH2Cl2, Et2O, or THF between -75 and +20 °C.

    Nucleophilic Additions of Polar Organometallic Compounds to Aldehydes.

    Ti-TADDOLates (1) have been used for both stoichiometric and catalytic nucleophilic additions to aldehydes. Thus the alcohols (4), (9), and (10) (eq 7) were obtained with the corresponding R2Zn reagents3d in the presence of 0.2 equiv of (1d)3c,e or ent-(1d) and 1.2 equiv (i-PrO)4Ti. Alcohol (5) results from acetaldehyde and (i-PrO)3TiPh mediated by 0.2 equiv of (1a).5 (R)-Cyanohydrins such as (6) are formed from equimolar amounts of aldehydes, Cyanotrimethylsilane, and (1e).1e,h-j,24 Alcohol (7) and threonine derivative (8) are the result of additions to aldehydes of the CpTi-TADDOLates prepared in situ from (1f) and crotyl Grignard reagent1f,25 or a glycine Li enolate derivative.1f As can be seen, highly diastereoselective (dr = diastereomer ratio) and enantioselective (er = enantiomer ratio) conversions can be achieved. A number of examples have been reported in the literature.1-7 (R,R)-TADDOL derivatives (1) always give rise to Si addition (rel. topicity unlike);26 the mechanism of these reactions has been discussed.1g,9

    Cycloadditions and Ene Reactions.

    These reactions were mostly studied with the Cl2Ti-TADDOLate (1e) as prepared by the procedure shown in eq 2. In all cases, conditions are critical. There are numerous examples in the literature,1c,e,h,i including the Diels-Alder addition of 3-crotonyl-1,2-oxazolidin-2-one to cyclopentadiene8a,27 (leading to (11) (X = 1,3-oxazolidin-2-on-3-yl) in (11), (12), (14), and (16)) and to open-chain dienes,27 as well as the intramolecular version of this reaction (see, for instance, (12)1i). It was shown that the Diels-Alder reaction leading to (11) can be done with (1), (Ar = 2-naphthyl, R1 = R2 = Me, X = Y = Cl) with almost the same results as with (1e); with the analogous 1-naphthyl derivative the stereochemical course of the reaction reverses.9 All these reactions are highly enantioselective and require ca. 10 mol % of the chiral catalyst. Some of these reactions have been carried out on a 45 mmolar scale.9b,27 Other dienophiles such as methoxyquinones can also be employed. For the reactions leading to (13) and (15), somewhat different procedures were used.8b,10b Thus (13) was obtained with excellent enantioselectivity using stoichiometric amounts of a Ti-TADDOLate (1e).8b Likewise, [2 + 2] cycloadditions, again with the acyloxazolidinone (see the cyclobutene 14)10a or with methoxyquinone (see 15, a precursor to benzodihydrofurans),10b have been studied and occur with high regio-, diastereo-, and enantioselectivities; the nucleophilic components of these cycloadditions are electron-rich alkenes, allenes, or alkynes (cation-stabilizing substituents on the double or triple bond) such as o-methylstyrenes,10b thioenol ethers,1i allenyl thioethers,28 ketene dithioacetals,28 or sulfenylated alkynes.10a,28 The acyloxazolidinones derived from a,b-unsaturated carboxylic acids also lend themselves for intramolecular ene reactions. For instance, cyclopentane derivative (16) was formed from the corresponding open-chain 2,7-nonadienoic acid derivative.29

    As in other applications of N-acyl-1,3-oxazolidin-2-ones,30 -2-thiones, and -thiazolidine-2-thiones,31 chelation of the Lewis acid center for restricted rotation is considered decisive for the reactions occurring under the influence of the Ti-TADDOLates. Generally, the attack of the nucleophilic component (diene or ene) on the chelated electrophile occurs from the bottom face if the chelate ring is drawn as shown in structures (17) and (18),8a,9,27 (19),8b,f and (20).8d,e For the oxazolidinones, this means that the trigonal a-carbonyl center is approached from the (Re)-face when an (R,R)-Ti-TADDOLate is used (rel. topicity like);26 the mechanism of this reaction has been discussed.1g,9

    Other Enantioselective Transformations Mediated by Ti-TADDOLates.

    The iodolactonization of 2-allyl-2-hydroxy-4-pentenoic acid shown in eq 8 gives (21) in a 67% yield (after cyclization of some iodo isopropyl ester formed as a side product),12 the iodolactone is a single (-)-diastereoisomer with a 5:1 (S,S)/(R,R) ratio. The TADDOLate generated in situ was employed in stoichiometric amount. The two enantiomers of 2-pyridyl 2-phenylthiobutyrate react with a rate difference of 39:1 with excess isopropanol in the presence of 0.1 equiv of a Ti-TADDOLate under the conditions specified in eq 9. This leads to the isopropyl ester (22) containing 96% of the (R)-enantiomer in a 69% yield.32 Thus the complex (23) reacts much faster than the (R,R)/(S) isomer in the S/O transesterification.

    Use of TADDOLate Ligands on Other Metal Centers.

    Of the many possible and actually studied applications of the readily available TADDOLs, only two may be mentioned here: enantioselective reduction and Grignard addition to aryl ketones. A chiral Lithium Aluminum Hydride derivative prepared from (2) reduces aryl ketones in THF to the corresponding alcohols of (S)-configuration with an enantioselectivity of ca. 20:1 (eq 10).15

    This procedure works with a smaller reagent excess and at higher temperatures than the analogous procedure using (R)-1,1“-Bi-2,2“-naphthol for similar results.33 There is an added benefit in that the enantiomer excess of the alcohols formed in the reduction may sometimes be increased by a clathrating effect during the workup and isolation step (cf. the reviews).20 Another useful application of the TADDOL (2) (Ar = Ph, R1 = R2 = Me) is the highly enantioselective Grignard addition to aryl ketones. The procedure involves in situ reaction of 3 equiv RMgX with the TADDOL, followed by addition of the ketone at -100 °C in THF (eq 11).16

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    Robert Dahinden, Albert K. Beck & Dieter Seebach

    Eidgenössische Technische Hochschule Zürich, Switzerland

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