Hydroxy acids Titanium chloride

Chlorophenyl)glutarate monoethyl ester 87 was reduced to hydroxy acid and subsequently cyclized to afford lactone 88. This was further submitted to reduction with diisobutylaluminium hydride to provide lactol followed by Homer-Emmons reaction, which resulted in the formation of hydroxy ester product 89 in good yield. The alcohol was protected as silyl ether and the double bond in 89 was reduced with magnesium powder in methanol to provide methyl ester 90. The hydrolysis to the acid and condensation of the acid chloride with Evans s chiral auxiliary provided product 91, which was further converted to titanium enolate on reaction with TiCI. This was submitted to enolate-imine condensation in the presence of amine to afford 92. The silylation of the 92 with N, O-bis(trimethylsilyl) acetamide followed by treatment with tetrabutylammonium fluoride resulted in cyclization to form the azetidin-2-one ring and subsequently hydrolysis provided 93. This product was converted to bromide analog, which on treatment with LDA underwent intramolecular cyclization to afford the cholesterol absorption inhibitor spiro-(3-lactam (+)-SCH 54016 94. 

Polymerization Catalysed by Acids and Bases. Carbonium ions and carbanions respectively are carriers of the chain transfer in cationic and anionic polymerizations respectively. Ionic polymerization mechanism was exploited for the synthesis of polymeric stabilizers in comparison with the free-radical polymerization only exceptionally. The cationic process was used for the synthesis of copolymers of 2,6-di-tert-butyl-4-vinylphenol with cyclopentadiene and/or for terpolymers with cyclopentadiene and isobutylene [109]. System SnCWEtsAlCla was used as an initiator. Poly(lO-vinylphenothiazin) was prepared by means of catalysis with titanium chlorides [110]. Polymers of 4-[a-(2-hydroxy-3,5-dimethylphenyl)ethyl]-vinylbenzene [111] and 3-allyl-2-hydroxyacetophenone [112] were also prepared under conditions of cationic polymerization. 

The Mukaiyama reaction is an aldol-type reaction between a silyl enol ether and an aldehyde in the presence of a stoichiometric amount of titanium chloride. The reaction, which displays a negative volume of activation, could be performed without acidic promoter under high pressure [58]. In this case, the major product is the syn hydroxy ketone, not as for the TiCl4-promoted reactions which lead mostly to the anti addition product. Since the syn or anti selectivity is the result of two transition states with different activation volumes (AV n < AVfnti), it was of great interest to investigate the aldol reaction in water. Indeed, the reaction of the silyl enol ether of cyclohexanone with benzaldehyde in aqueous medium was shown to proceed without any catalyst and under atmospheric pressure, with the same syn... 

The pharmaceutical interest in the tricyclic structure of dibenz[6,/]oxepins with various side chains in position 10(11) stimulated a search for a convenient method for the introduction of functional groups into this position. It has been shown that nucleophilic attack at the carbonyl group in the 10-position of the dibenzoxepin structure renders the system susceptible to water elimination. Formally, the hydroxy group in the enol form is replaced by nucleophiles such as amines or thiols. The Lewis acids boron trifluoride-diethyl ether complex and titanium(IV) chloride have been used as catalysts. 

Acetylsultam 15 is also used for stereoselective syntheses of a-unsubstituted /1-hydroxy-carboxylic acids. Thus, conversion of 15 into the silyl-A/O-ketene acetal 16 and subsequent titanium(IV) chloride mediated addition to aldehydes lead to the predominant formation of the diastereomers 17. After separation of the minor diastereomer by flash chromatography, alkaline hydrolysis delivers /f-hydroxycarboxylic acids 18, with liberation of the chiral auxiliary reagent 1919. 

Chemical reduction [with aqueous titanium(III) chloride in dilute acetic acid] or catalytic reduction (in the presence of 10% palladium-on-charcoal by transfer hydrogenation from cyclohexene or with hydrogen) of 3-nitro-4//-pyrido[l,2-a]pyrimidin-4-ones 176 (R = H, 8-Me, 8-OMe, 7-C1) gave 3-amino-4//-pyrido[l,2-a]pyrimidin-4-ones [90JCR(S)308]. Chemical and catalytic reduction of 3,8-dinitro-9-hydroxy-4//-pyrido[l,2-a]pyrimidin-4-one yielded an unstable product. 

P-HYDROXY CARBOXYLIC ACIDS (R)-2-Ace-toxy-1,1,2-triphenylethanol. Ketene bis(trimethylsilyl) ketals. Titanium(IV) chloride. 

By contrast, there are many examples of intramolecular ene reactions that involve aldehydes and ketones without these special restrictions. A variety of Lewis acids have been employed in the ene reaction with aldehydes and ketones as eneophiles. The nature of the Lewis acid is important but specific requirements seem to be quite system dependent, varying both with the alkene and the carbonyl compound 56-64. Generally either tin(IV) chloride or titanium(IV) chloride are to be recommended although frequently these and other strong Lewis acids must be used in equivalent amounts. It appears that strong acids become irreversibly complexed with the hydroxy group of the product and as a consequence become sufficiently deactivated so as to be ineffective except with unusually reactive alkenes. 

Interesting synthetic approaches for the construction of the tricyclo[5.2.2.0k5]undecane skeleton of the eremanes have been developed, but only two have been successful. The synthesis of ( )-eremolactone relied on an acid-catalysed double Michael addition on the silyloxydiene (Scheme 45) (127). This on treatment with mesityl oxide in the presence of titanium (IV) chloride gave, inter alia, an inseparable 1 2 mixture of diastereisomers (189) in 64% yield. Reduction with NaBH4 gave the separable hydroxy ketones (190 and 191, 1 2), the relative stereochemistry of which was secured from an X-ray study of 190. Following the introduction of the double bond, the side chain was elaborated on each of the two diastereoisomers as shown in Scheme 45. This synthesis has a number of problems. A complex mixture of isomers is generated in the first step, the cyclohexene... 

The reaction of the siloxycyclopropane with titanium(IV) chloride produces the titanium homoenolate (3-titaniopropionate) in good yield this, however, is relatively unreactive (eq 2). Addition of one equivalent of Ti(OR )4 generates a more reactive RTiChOR species, which smoothly reacts with carbonyl compounds below room temperature. The y-hydroxy ester adducts are useful synthetic intermediates and serve as precursors to y-lactones and cyclopropanecarboxylates. A useful variation involves the use of the cyclopropanecarboxylate ester as a functionalized homoenolate precursor to obtain levulinic acid derivatives (eq 3). ... 

TiCU is a powerful activator of carbonyl groups and promotes nucleophilic attack by a silyl enol ether. The product is a titanium salt of an aldol which, on hydrolysis, yields a p-hydroxy ketone. TiCU is generally the best catalyst for this reaction. The temperature range for reactions with ketones is normally 0-20 °C aldehydes react even at —78 °C, which allows for chemoselec-tivity (eq 9). In a- or p-alkoxy aldehydes, the aldol reaction can proceed with high 1,2- or 1,3-asymmetric induction. With the nonchelating Lewis acid Boron Trifluoride Etherate, the diastere-oselectivity may be opposite to that obtained for the chelating TiCU or Tin(IV) Chloride (eq 10). ... 

---