David R. Parrish

Antioxidant activity and stability of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid

Abstract6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid in thin layer tests in vegetable oils and animal fats has two-four times the antioxidant activity of butylated hydroxytoluene and butylated hydroxyanisole and is more active than propyl gallate, nordihydroquaiaretic acid, ascorbyl palmitate, and α- and γ-tocopherols. It is also more active than tertiary butylhydroquinone in chicken and pork fats and corn, peanut, sunflower, and safflower oils in thin layer tests. Tertiary butylhydroquinone is slightly more active in corn, soybean, cottonseed, and peanut oils in the active oxygen method, probably due to decomposition of the chroman at 98 C. This decomposition is inhibited by ascorbic acid. The chroman is synergized by ascorbyl palmitate-thiodipropionate and ascorbic acids. Active oxygen method values of 190 hr are obtained in combination with the latter. A spectrofluorometric assay for 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid has been developed. The compound is 95–100% stable for 2 months at room temperature and 45 C, and a low level of toxicity is found. The copper and iron breakdown products of the chroman have been determined. A possible relationship between these products, protection of the chroman by ascorbic acid and ethylene diaminetetraacetic acid, and a mechanism of action is presented.

6-Hydroxychroman-2-carboxylic acids: Novel antioxidants

Abstract6-Hydroxychroman-2-carboxylic acids (I) have been found to be effective antioxidants in animal fats, vegetable oils, and emulsion systems. Two new syntheses of these compounds have been developed. Structure-activity correlations for I with various substitutents at C2, C5, C7, and C8 in various test systems have been obtained. In addition, the homologous chroman acetic acids, which are also antioxidants, and a number of other derived compounds have been synthesized. The most effective antioxidant in this series is the tetramethyl compound I (R2=R5=R7=R8=CH3). This compound has activity which compares well with the better commercial antioxidants.

Total synthesis of optically active (−)17β-hydroxy-Δ9(10)-desA-androsten-5-one

Abstract (±)7,7a-Dihydro-1β-hydroxy-7aβ-methyl-5(6H)-indanone was resolved via the hydrogen phthalate-brucine salt. The dextrorotatory enantiomer (+)4 was then converted in a 5-step stereospecific total synthesis to the important BCD tricyclic intermediate (−)13. The synthesis also adds additional proof for the absolute configuration of the bicyclic keto alcohol (+)4 by correlation with (±_13, a known degradation product of natural steroids.

Improved Syntheses of Nε-Tert-butyloxycarbonyl-L-lysine and Nα-Benzyloxycarbonyl-Nε-tert-butyloxycarbonyl-I-lysine

Abstract Ne-tert-butyloxycarbonyl-L-lysine [4, H-Lys(BOC)-OH] and Nα-benzyloxycarbonyl-Ne-tert-butyloxycarbonyl-L-lysine [7, Z-Lys-(BOC)-OH] are valuable intermediates for peptide syntheses. They have been employed in, among others, solid-phase and/or solution syntheses of nonadecapeptide1 and tetracosapeptide2 segments of ACTH, of somatostatin3–5 and of human β-endorphin.6 We recently had the need to prepare substantial quantities of compounds 4 and 7. The reported syntheses of these materials, due mainly to the groups of Zervas,7,8 Schwyzer9 and Wunsch,10 are plagued by low11,12 and, in our hands, often irreproducable yields. In addition, dangerous and/or obnoxious reagents (e.g., tert-butyl-

An Improved Synthesis of S-3,4-Dehydroproline

Abstract S-3,4-dehydroproline (5, S-Δ3,4-Pro) has been shown1 to be a potent inhibitor of collagen synthesis in mammalian cells due, at least in part, to its action as a prolyl hydroxylase inhibitor. The replacement in peptides of proline with S-Δ3,4-Pro has given analogues with modified biological activities.2,3 In addition, reductive deuteration or tritiation of these S-Δ3,4-Pro containing peptides gives 3,4-2H2-Pro or 3,4-3H2-Pro analogues of high specific enrichment.4 S-Δ3,4-Pro was initially obtained5 by chemical resolution or selective enzymatic hydrolysis of R,S-3,4-dehydroprolinamide. A better process4 involves resolution of R,S-N-t-butyloxycarbonyl-3,4-dehydroproline with R-α-methyl-p-nitrobenzylamine. In this paper, we report improvements in the synthesis of R,S-Δ3,4-Pro (3) and the direct resolution of this material with natural (+)-tartaric acid. An important feature

Syutheses of the Major Metabolites of (2E,4E,6E,8E)- and (22,4E,6E,8E)-3,7-Dimethyl-9-(2,6,6-Trimethyl-1-Cyclohexen-1-YL)-2,4,6,8-Nonatetraenoic Acids (Retinoic Acid and 13-cis-Retinoic Acid)

Abstract Wittig condensation of (2E,4E)-[5-(3-oxo-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2,4-pentadienyl]triphenylphosphonium bromide with ethyl formylcrotonate or 4-hydroxy-3-nethylbutenolide gives, respectively, the (all-E) and (22,4Z)-3,7-dimethyl-9-(2,6,6-trimethyl-3-oxo-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acids. These are converted to oxo and hydroxy metabolites of retinoic acid and 13-cis-retinoic acid.

Apparent proton-catalyzed Meerwein-Ponndorf-Verley type reduction of 8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine

Abstract When treated with 2-propanol in the presence of HCl, reduction of the C4-N double bond in 8-chloro-6-(2-fluorophenyl)-1-methyl-6H-imidazo[1,5-a][1,4]benzodiazepine occurs. Data are presented which indicate 2-propanol is the reductant in a two-step mechanism.

New results in the total synthesis of 19-norsteroids

Abstract Recent endeavors in the field of steroid total synthesis have led to several new approaches which utilize the principle of asymmetric induction. Important developments will briefly be reviewed, followed by a presentation of two novel routes to estrone. The first is based on the use of (—)-(5S)-5-hydroxy-9-oxodecanoic acid lactone which is transformed in several steps to d-(−)-estra-4.9-diene-3, 17-dione and thence to estrone. The second, altogether different route starts with (+)-(7aS)-7,7a-dihydro7a-methyl-1,5(6H)-indandione and involves the preparation of a 9,10- seco ACD-tricyclic intermediate and its conversion into d-(+)-estrone methyl ether.

Selective crystallization of an allylic 7α-bromide : A facile synthesis of (1α,3β)-3-hydroxycholeste-5,7-diene-1,25-diol diacetate

An efficient synthesis of (3β)-7-dehydro-1α,25-diacetoxycholesterol (1) is described. When acetonitrile was used as the crystallizing solvent, only the 7α-bromide 6a was isolated and bromide 6a was prepared in a 69% yield starting from 3β-TBDMS-1α,25-diacetoxycholesterol (5). Dehydrobromination with sym-collidine led to the regioselective formation of only the 5,7-diene 7. After deprotection with concentrated hydrochloric acid, the diene diacetate 1 was obtained in an overall yield of 44% without chromatographic separations. When tetrabutylammonium fluoride trihydrate was used as the base, the 7β-fluoride 10 was isolated.

NEW RESULTS IN THE TOTAL SYNTHESIS OF 19-NORSTEROIDS

Recent endeavors in the field of steroid total synthesis have led to several new approaches which utilize the principle of asymmetric induction. Important developments will briefly be reviewed, followed by a presentation of two novel routes to estrone. The first is based on the use of (—)-(5S)-5-hydroxy-9-oxodecanoic acid lactone which is transformed in several steps to d-(—)-estra-4,9-diene-3,17-dione and thence to estrone. The second, altogether different route starts with (+)-(7aS)-7,7a-dihydro-7a-methyl-1,5(6H)-indandione and involves the preparation of a 9,10-seco ACD-tricyclic intermediate and its conversion into d-(+)-estrone methyl ether.