Isopropylidene acetals

Isopropylidene, Benzylidene, and Related Acetals Isopropylidene or benzylidene acetals are formed either by direct condensation of the diol with the appropriate carbonyl compound (acetone or benzaldehyde, respectively) or by transacetalation with the corresponding dimethoxy acetal. Both processes are carried out in acidic conditions [ 123]. 

Methylene A cetals Ethylidene Acetals BenzyUdene A cetals Substituted BenzyUdene Acetals Isopropylidene Ketals Cyclohexylidene and Other Ketals Cyclic Orthoesters... 

The formation of ethyl isopropylidene cyanoacetate is an example of the Knoevenagel reaction (see Discussion before Section IV,123). With higher ketones a mixture of ammonium acetate and acetic acid is an effective catalyst the water formed is removed by azeotropic distillation with benzene. The essential step in the reaction with aqueous potassium cyanide is the addition of the cyanide ion to the p-end of the ap-double bond ... 

Isopropylidene and benzylidene hydrazones of selenazole unsubstituted in the 5-position react with p-nitrosodimethylanilines or p-nitrosodiethyl-anilines when heated in organic solvents in the presence of acetic acid or pyridine (49). Highly colored crystalline 2-hydrazono-5-(p-dialkylamino-phenylimino)selenazoles are recovered from the reaction medium (Table X-10). 

CYCLIC ACETALS AND KETALS 123 7. Acetonide (Isopropylidene Ketal) (Chart 3)... 

A chiral titanium complex with 3-cinnamoyl-l,3-oxazolidin-2-one was isolated by Jagensen et al. from a mixture of TiCl 2(0-i-Pr)2 with (2R,31 )-2,3-0-isopropyli-dene-l,l,4,4-tetraphenyl-l,2,3,4-butanetetrol, which is an isopropylidene acetal analog of Narasaka s TADDOL [48]. The structure of this complex was determined by X-ray structure analysis. It has the isopropylidene diol and the cinnamoyloxazolidi-none in the equatorial plane, with the two chloride ligands in apical (trans) position as depicted in the structure A, It seems from this structure that a pseudo-axial phenyl group of the chiral ligand seems to block one face of the coordinated cinnamoyloxazolidinone. On the other hand, after an NMR study of the complex in solution, Di Mare et al, and Seebach et al, reported that the above trans di-chloro complex A is a major component in the solution but went on to propose another minor complex B, with the two chlorides cis to each other, as the most reactive intermediate in this chiral titanium-catalyzed reaction [41b, 49], It has not yet been clearly confirmed whether or not the trans and/or the cis complex are real reactive intermediates (Scheme 1.60). 

A solution of 50 mg of 6a-fluoro-triamcinolone acetonide in 1 ml of pyridine and 1 ml of acetic anhydride is allowed to stand at room temperature for 18 hours. Removal of the reagents in vacuo gives a crystalline residue which after crystallization from acetone-hexane gives the pure 16a,17a-isopropylidene 6o -fluoro-triamcinolone 21 acetate (fluocinonide), as described in U.S. Patent 3,197,469. 

Fortunately, the oxidation of l,2 5,6-di-0-isopropylidene-a-D-glucofura-nose to l,2 5,6-di-0-isopropylidene-a-D-nfoo-hexofuranos-3-ulose (1) can be accomplished using either phosphorus pentoxide (10, 44) or acetic anhydride (10, 52) in methyl sulfoxide although this oxidation is effected with ruthenium tetroxide (6,7, 46), it is exceeding difficult with other oxidizing agents (53). Keto-sugar 1 is reduced stereospecifically... 

Acetyl-5-deoxy-5-iodo-l, 2-O-isopropylidene-p - l - arabinofuranose (38). Acetylation of 5-deoxy-5-iodo-l,2-0-isopropylidene-/ -L-arabino-furanose (37) (27) in pyridine as described above for the D-xylo-isomer afforded the 3-acetate (38) as a colorless sirup which did not crystallize. [ ]D24 + 13.7° (c, 3.5). Anal Calcd. for C10H15IO5 C, 35.1 H, 4.4. Found C, 35.0 H, 4.5. 

F rom 5-deoxy-5-iodo-1,2-0-isopropylidene-/ -l-arabinofura-nose (37). Anhydrous silver fluoride (600 mg.) was added to a solution of 300 mg. of 37 in pyridine (4.0 ml.), and the mixture was shaken at room temperature for 24 hours. Ether (4 ml.) was added, and the mixture was passed through a column of silica gel (1.5 X 12 cm.). The column was washed with ether/pyridine, 1 1 v/v. (10 ml.), and the effluent, which contained 5-deoxy-l,2-0-isopropylidene-/ -L-threo-pent-4-enofuranose (33), was concentrated to 4 ml. Acetic anhydride (0.2 ml.) was added, and the reaction mixture was kept at room temperature for 16 hours. Concentration afforded a sirup from which the last traces of solvent were removed by storage in high vacuum at 20°C. The sirup was distilled at 90°C. (bath) at 2.5 X HHmm. The distillate (110 mg., 51%), which crystallized on standing, had physical constants which were identical to material prepared as above. 

Carbohydrate-derived titanium cnolates also provide yvn-x-amino-/l-hydroxy esters of high diastcrcomeric and enantiomeric purity. For this purpose, the lithium enolate derived from ethyl (2,2,5,5-tetramcthyl-2,5-disilapyrrolidin-l-yl)acetate is first transmctalated with chloro(cy-clopentadienyl)bis(1,2 5,6-di-0-isopropylidene-a-D-glucofuranos-3-0-yl)titanium and subsequently reacted with aldehydes.. vj-n-a-Amino-/ -hydroxy esters are almost exclusively obtained via a predominant /te-side attack (synjanti 92 8 to 96 4 87-98% ee for the xvn-adducts)623-b. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

This section is completed with a brief review of the synthesis and properties of this epimer (20) of the precursor of thiazole in bacteria. This pentulose is conveniently accessible by an unconventional route (Scheme 19). Methyl 2,3 4,6-di-O-isopropylidene-a-D-mannopyranoside, readily available from methyl ot-D-mannopyranoside, is converted to the ketonic glycoside by butyllithium in 91% yield, following a method first published by Klemer and Rodemeyer43 and scaled up by Horton and Weckerle.44 This was converted by means of lithium hydroxide in a water-ether mixture into 3,5-0-benzylidene-l-deoxy-D-eryf/iro-2-pen-tulose in 55% yield. Hydrolysis to the free pentulose (20) proceeded in 73% yield in aqueous acetic acid. This product was obtained as a syrup with a characteristic absorption band at 1705 cm 1 as a film. Thus, there is a fair proportion of the open-chain ketone under these conditions, as with the D-threo epimer.45... 

The two -OH groups in l,2 5,6-di-0-cyclohexylidene-wii/o-inositol and its di-O-isopropylidene analog are trans. The X-ray crystal structure of the latter compound suggests that the ring is in a skew conformation with the 0-3 and 0-4 -OH groups both in ax positions, but NMR studies and ab initio calculations indicate that a mixture of the skew and chair conformations, with 0-3 and 0-4 both in eq positions, is present. Formation of a dibutylstannylene acetal presumably locks these two compounds in the latter conformation. 

Protective Groups for Diols. Diols represent a special case in terms of applicable protecting groups. 1,2- and 1,3-diols easily form cyclic acetals with aldehydes and ketones, unless cyclization is precluded by molecular geometry. The isopropylidene derivatives (also called acetonides) formed by reaction with acetone are a common example. 

CisH2407 (1 S)-5,7-Anhy dro-8-deoxy-1,2 3,4-di-O-isopropylidene-aZde-hydo-D-glycero-D-galacto-octos-6-methyl acetal AGLGAO 37 399... 

Further examination of the extracts of A. cannabina revealed axisonitrile-4 (7), axisothiocyanate-4 (8) and axamide-4 (9) [33], A vinylic isonitrile function was supported by H NMR signals at <51.67 and 1.89, which were assigned to the two isopropylidene methyls of 7. Difficulty in isolating the natural product 9 was circumvented, when isonitrile 7 was transformed to 9, mp 81-84 °C, by acetic acid in anhydrous ether. The absolute configurations of both axanes 1 and 7 and their analogs were later established [31] by studies including X-ray diffraction of the p-bromoaniline derivative of 2 and by CD data of ( + )-10-methyldecalone-l obtained from ozonolysis of the reduction (Na/NH3) product of 1 [1]. 

Isopropylidene acetals are convenient protecting groups in carbohydrate chemistry, particularly for the protection of 1,2- and 1,3-diols, and are readily formed by reaction of the diol with acetone or 2,2-dimethoxypropane under acidic conditions. Several protic and Lewis acids have been reported as catalysts for this purpose.98... 

Scheme 24. Selective deprotection of sugar di-O-isopropylidene acetals using acid zeolites.

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