D-Camphorsulfonates

Sulfoxides were first prepared in optically active form in 1926 by the classical technique of diastereomeric salt formation followed by separation of the diastereomers by recrystallization16 17. Sulfoxides 1 and 2 were treated with d-camphorsulfonic acid and brucine, respectively, to form the diastereomeric salts. These salts were separated by crystallization after which the sulfoxides were regenerated from the diastereomers by treatment with acid or base, as appropriate. Since then numerous sulfoxides, especially those bearing carboxyl groups, have been resolved using this general technique. 

Molecules having only a sulfoxide function and no other acidic or basic site have been resolved through the intermediacy of metal complex formation. In 1934 Backer and Keuning resolved the cobalt complex of sulfoxide 5 using d-camphorsulfonic acid. More recently Cope and Caress applied the same technique to the resolution of ethyl p-tolyl sulfoxide (6). Sulfoxide 6 and optically active 1-phenylethylamine were used to form diastereomeric complexes i.e., (-1-)- and ( —)-trans-dichloro(ethyl p-tolyl sulfoxide) (1-phenylethylamine) platinum(II). Both enantiomers of 6 were obtained in optically pure form. Diastereomeric platinum complexes formed from racemic methyl phenyl (and three para-substituted phenyl) sulfoxides and d-N, N-dimethyl phenylglycine have been separated chromatographically on an analytical column L A nonaromatic example, cyclohexyl methyl sulfoxide, did not resolve. 

The chirality of compound 16b was completely inverted, to give 2,3-0-cyclohexylidene-L-ribonolactone (19), by means of a procedure (28) that involves oxidation of the hydroxymethyl group of 16b by ruthenium te-traoxide, followed by reduction of the lactone group. The resulting intermediate 1,5-lactone (18) underwent isomerization (with cyclohexylidene migration) upon refluxing in xylene, in the presence of a catalytic amount of D-camphorsulfonic acid [in Ref. (28) the formulas for the series were erroneously depicted]. 

In 2006, Xu and Xia et al. revealed the catalytic activity of commercially available D-camphorsulfonic acid (CS A) in the enantioselective Michael-type Friedel-Crafts addition of indoles 29 to chalcones 180 attaining moderate enantiomeric excess (75-96%, 0-37% ee) for the corresponding p-indolyl ketones 181 (Scheme 76) [95], This constitutes the first report on the stereoselectivity of o-CSA-mediated transformations. In the course of their studies, the authors discovered a synergistic effect between the ionic liquid BmimBr (l-butyl-3-methyl-l/f-imidazohum bromide) and d-CSA. For a range of indoles 29 and chalcone derivatives 180, the preformed BmimBr-CSA complex (24 mol%) gave improved asymmetric induction compared to d-CSA (5 mol%) alone, along with similar or slightly better yields of P-indolyl ketones 181 (74-96%, 13-58% ee). The authors attribute the beneficial effect of the BmimBr-D-CSA combination to the catalytic Lewis acid activation of Brpnsted acids (LBA). Notably, the direct addition of BmimBr to the reaction mixture of indole, chalcone, d-CSA in acetonitrile did not influence the catalytic efficiency. 

Synthesis (Pohland, 1953 1955 1963 janssen and Karel (Janssen)1956 Sullivan et al., 1963) In the Grignard reaction of 3-dimethylamino-2-methyl-1-phenyl-propan-lone with benzylmagnesium chloride 4-dimethylamino-3-methyl-1,2-diphenyl-butan-2-ol is formed. The preferred product is the a-diastereomer(75 % a-form, 15 % p-form). The a-form crystallizes and the diastereomeric p-form remains in solution, because of its better solubility. Racemic resolution to obtain the analgetically (+) enantiomer can be achieved on the pure a-Grignard product via fractional crystallization of the salts with D-camphorsulfonic acid. Alternatively the resolution can be achieved by treating the racemic mannich product 3-dimethylamino-2-methyl-1-phenyl-propan-1-one with (-)-dibenzoyltartaric acid in acetone as solvent. 

D-Camphorsulfonic acid (d-CSA) was identified as catalyst for the enantioselec-tive Michael-type Friedel-Crafts reactions of indoles with aromatic enones ArCH= CHCOAr to afford the corresponding /i-indolyl ketones in excellent yields and moderate enantioselectivities. A surprising synergistic effect was discovered between [Bmim] Br and d-CSA, which may originate from the catalytic Lewis acid activation of the Brpnsted acid.162... 

Resolution of the optical isomers by the use of d-camphorsulfonic acid in acetone... 

Splitting off the d-camphorsulfonic acid by using ammonium hydroxide and conversion of the desired a-dextro isomer to the hydrochloride only the dextro isomer is active as an analgesic... 

Illustrated in Table III are the solvent effects. The carbonyl compound used is a-phenylpropionaldehyde and the optically active acid is D-camphorsulfonic acid. The figure reveals that when hydrolysis is carried out, less miscible solvents are more effective suggesting that interfacial reactions are effective for stereoselectivity of asymmetric transformations. 

Salts of 2-aminophenoxatellurin with d-tartaric acid and d-camphorsulfonic acid were prepared1 in unsuccessful attempts to resolve 2-aminophenoxatellurin into optically active isomers. 

The first enantioselective total synthesis of tetracyclic sesquiterpenoid (+)-cyclomyltaylan-5a-ol, isolated from a Taiwanese liverwort, was accomplished by H. Hagiwara and co-workers. They started out from Hajos-Parrish ketone analogue, (S)-(+)-4,7a-dimethyl-2,3,7,7a-tetrahydro-6/-/-indene-1,5-dione, that could be synthesized from 2-methylcyclopentane-1,3-dione and ethyl vinyl ketone in an acetic acid-catalyzed Michael addition followed by an intramolecular aldol reaction. The intramolecular aldol reaction was carried out in the presence of one equivalent (S)-(-)-phenylalanine and 0.5 equivalent D-camphorsulfonic acid. The resulting enone was recrystallized from hexane-diethyl ether to yield the product in 43% yield and 98% ee. Since the absolute stereochemistry of the natural product was unknown, the total synthesis also served to establish the absolute stereochemistry. 

The first total synthesis of barbacenic acid, a bisnorditerpene containing five contiguous stereocenters, was achieved by A. Kanazawa et. al. They started out from a Wieland-Miescher ketone analogue that could be synthesized with high yield and excellent enantioselectivity by the procedure of S. Takahashi. According to this procedure, the Michael addition product 2-methyl-2-(3-oxo-pentyl)-cyclohexane-1,3-dione was cyclized in the presence of (S)-(-)-phenylalanine and D-camphorsulfonic acid. 

Diltiazem hydrochloride and its related compounds can be separated in both bulk drug and finished tablets using a Waters pBondapak C18 column (10 pm particle size, 300 mm x 3.9 mm I.D.) and a mobile phase of buffer methanol acetonitrile (50 25 25, v/v) at a flow rate of about 1.6 mL/minute. The buffer is 0.1 M aqueous sodium acetate containing 5mM d-camphorsulfonic acid (99%) adjusted to pH 6.2 with 0.1 M aqueous sodium hydroxide. Detection of the compounds is achieved using UV absorbance at 240 nm. The method provides for the resolution of trans-diltiazem and seven known and unidentified related compounds. Diltiazem hydrochloride elutes at approximately 21 minutes under these conditions. The minimum detectable amounts are less than 0.1% for all related compounds except for one of the synthetic intermediates for which there is a limit of about 2% (27). 

Later investigations showed that the "ar-d" form was the analgesic, while the "or-l" form exhibited no analgesic properties. A description of the resolution of the "a-dl" mixture is found in literature2. Essentially, the resolution is achieved by fractional crystallization of the d-camphorsulfonic acid salt. This technique allows production of the pure "o -d" isomer now known as propoxyphene hydrochloride. 

Burn at Hoffmann-La Roche chose to couple the two monomeric units via an intramolecular Wadsworth-Emmons reaction rather than lactonization (see Scheme 4.16). Thus dithiane 70, obtained by formylation of the anion derived from 69, underwent a regiospecific 1,3 dipolar cycloaddition with acetonitrile oxide to afford isoxazoline 71. Dibal reduction to the related amino alcohol followed by optical resolution with D-camphorsulfonic acid led to the isolation... 

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