Acetals diastereoisomerism

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

Addition of a catalyst containing sulfuric acid and acetic anhydride to 3, 5 -di-0-acetylthymidine in acetonitrile results in an equilibrium mixture of a- and ]3-anomers that, after time, gave a substantial quantity of a diastereoisomeric mixture of fully acetylated open-chain nucleosides. These were of type 1.5 with 2 -deoxy and 4 -acetoxy substituents (93TL6779). Open-chain nucleoside was also obtained as well as the expected nucleoside when 5-nitrouracil was condensed with methyl-2,3-dideoxy-3-fluoro-5-0-(4-phenylbenzoyl)-]3-D-cryr/zro-pentofuranoside (94S516). 

Reduction of a mixture of 69a-c or 69a with zinc dust in acetic acid yields two diastereoisomeric 4-hydroxy-phosphinic acid ethyl esters 70 Z and E, or only 70 E. 

Bromination of 3 -chloropropriophenone in dichloromethane generated the a-bromoketone 5, which, on treatment with 2-methyl-2-aminopropan-l-ol in acetonitrile, effected displacement of the bromide with concomitant cyclization to generate the racemic morpholinols 2. Addi lion of DTTA in industrial methylated spirit (IMS) gave the diastereoisomeric salts 2a and 2b, which were separated via crystallization. Subsequent treatment of the enantiomerically pure (S,S)-DTTA salt, 2a, radafaxine DTTA, with base gave a soluhon of radafaxine free base in ethyl acetate which was converted to the desired hydrochloride salt of the API on reaction with anhydrous hydrogen chloride (see Scheme 10.2). 

Thiocarbonyl ylides are both nucleophilic and basic compounds (40,41,86). For example, adamantanethione (5)-methylide (52) is able to deprotonate its precursor, the corresponding 2,5-dihydro-1,3,4-thiadiazole, and a 1 1 adduct is formed in a multistep reaction (40,86). Thioxonium ion (56) (Scheme 5.22) was proposed as a reactive intermediate. On the other hand, thiofenchone (S)-methylide (48) is not able to deprotonate its precursor but instead undergoes electrocyclization to give a mixture of diastereoisomeric thiiranes (41,87,88). The addition of a trace of acetic acid changes the reaction course remarkably, and instead of an electrocyclization product, the new isomer 51 was isolated (41,87) (Scheme 5.18). The formation of 51 is the result of a Wagner-Meerwein rearrangement of thioxonium ion 49. 

This reaction was applied to a mixture of diastereoisomeric diols [113], For instance, a,cx -dimethyl-l,4-benzenedimethanol was treated with Ru complex 30 (S/C=25), Novozyme 435, and 4-chlorophenyl acetate (3 equiv) in toluene at 70 °C to give the R,R diacetate in >99% ee and the meso isomer (R,R meso=98 2) in 77% yield (Scheme 40). Reaction of 1,3-pentanediol and 1,4-hexanediol gave the corresponding R,R diacetate in >99% ee, while the R,R to meso ratio was lower than that of the aromatic diacetate. Nitrogen-containing substrates also gave the desired products in optically pure form. 

Practical advantage of the method is that it does not require dry solvents. The resolving agent can be prepared by simple solution of DBTA monohydrate and half an equivalent amount of calcium oxide in hot 95 % ethyl alcohol. Crystallization of the diastereoisomeric coordination complex can be achieved by cooling and addition of cosolvents (e.g. acetone, toluene, ethyl acetate, etc.) or change ethyl alcohol to an ester type solvent. The enantiomers can be liberated from the crystalline complex by simple acidic workup procedure. [23]... 

In 1986, Minami and his coworkers described the optical resolution of the oxide of tram-his-1,2-(diphcnylphosphino)cyclobutanc (20, Scheme 10.) with stoichiometric amount of DBTA in methanol solution. [30] In the same year, Noyori and his coworkers published the synthesis of optically active BINAP via resolution of BINAP oxide (21) with DBTA. [31] In this process, hot chloroformic solution of racemic 21 was mixed with a molar equivalent amount of DBTA previously solved in ethyl acetate. Optically pure -21 was isolated in 79 % yield from the recrystallized diastereoisomeric complex by... 

A suspension of 30 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in 300 ml acetone is mixed with 18.6 g l,8-diazabicyclo[5.4.0]undec-7-ene. The solution obtained mixed at ca. 0°C with 261 g of a 14% toluene solution of 1-iodoethylisopropyl carbonate. After 4 hours the solution is poured onto a mixture of 600 ml of water and 21 ml cone. HCI. The pH of mixture is adjusted to ca. 1.0. The aqueous phase is extracted with 200 ml of hexane, mixed with 700 ml ethyl acetate and pH is adjusted to ca. 8.2. A solution of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid 1-(isopropoxycarbonyloxy)ethyl ester is obtained. Diastereoisomeric ratio B/(A+B)=0.49 (B is more apolar of the two diastereoisomers). 

To a solution of 37.4 g of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid l-(isopropoxycarbonyloxy)ethyl ester in 689 ml ethyl acetate at 2-3°C is added for 25 min 0.105 moles Z-(2-formamidothiazol-4-yl)-methoxy-acetyl chloride hydrochloride. After 25 min pH is adjusted to ca. 6.5-7.3. After 1 hour the organic layer is washed with water and concentrated. It was obtained a crude 5-thia-l-azabicyclo(4.2.0)oct-2-ene-2-carboxylic acid, 7-(((2Z)-(2-amino-4-thiazolyl)(methoxyimino)acetyl)amino)-3-(methoxymethyl)-8-oxo-, l-(((l-methylethoxy)carbonyl)oxy)ethyl ester, (6R,7R)- (Cefpodoxime proxetil). Diastereoisomeric ratio 0.49. 

The mixture 258 was converted to the unstable benzenesulfonyl aziridine 259 by treatment with an excess of benzenesulfonyl azide in benzene. Ace-tolysis of 259 with acetic acid and sodium acetate at room temperature for several days afforded the crystalline mixture of diastereoisomers represented by the formula 260. The aziridine rearrangement was regiospecific and 260 was the only product detected during this rearrangement. Lithium aluminium hydride reduction of 260 followed by acetylation yielded the mixture 261 in 85% yield. Selective hydrolysis of 261 afforded 262 in quantitative yield. The diastereoisomeric mixture 262 was converted into the diols 263 by hydrogenolysis. The diol mixture was oxidized with chromium trioxide... 

The geometry of the double bonds in the Claisen substrate determines the stereochemistry around the newly-formed carbon-carbon single bond in the product. For example (E)- and (Z)-silyl ketene acetals produce diastereoisomeric products as illustrated in Figure Si3.11. 

Analogous asymmetric, samarium Reformatsky reactions of chiral 3-bro-moacetyl-2-oxazolidinones have been described by Fukuzawa.140 For example, reduction of 124 with Sml2 generates a samarium enolate that then reacts with pivalaldehyde to give the a-unbranched (I-hydroxycarboximide 125 in 87% yield and in high diastereoisomeric excess (Scheme 5.89). The reaction is synthetically noteworthy as highly diastereoselective acetate aldol processes are difficult to achieve. Sm(III) ions are likely to play an important role in the... 

Enantiomerically pure Diels-Alder adducts of Ceo were prepared by Tsuji and co-workers by use of a chiral auxiliary in the diene component and separation of the diastereoisomeric intermediates.385 The starting material for the diene component was a cyclic cyclopentenone acetal (224, Scheme 1.21) derived from L-threitol, reacting via its cyclopentadiene-containing enol ether isomer.385,386 The diastereoisomeric products 225 and 226, formed without significant diastereoselectivity, were isolated as the acetals, separated and subsequently hydrolyzed to afford the enantiomeric ketones (+)-227 and (—)-227. NOE measurements allowed the determination of the absolute configuration of the diastereoisomeric intermediates 225 and 226 and, therefore, also of the enantiomeric ketones (+)-(R,R)-227 and (—)-(S,S)-227 (Scheme 1.21).385... 

Scheme 1.21. Diels-Alder addition of an enatiomerically pure cyclopentadiene derived from (.S, .S )-thrcitol to Cgo- Separation of the diastereoisomeric adducts 225 and 226, followed by cleavage of the acetal protecting group, afforded enantiomerically pure ketones which were configurationally assigned as (+)-(R,R)-227 and (—)-(S,S)-227.

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