otal synthesis and configuration of 9, 10-dihydroxystearic acid

• Main Author: Schlein, Herbert Nathan
• Language: en_US
• Published: Boston University 2014
• Online Access: https://hdl.handle.net/2144/8092

Thesis (Ph.D.)--Boston University === Although the 9,10-dihydroxystearic acids have been known for sixty years, the assignment of configuration of these acids has not been definite. All of the pertinent arguments have been based either on the known stereospecificity of the reagents used to produce these acids from oleic acid, or on physical measurements on the product. The purpose of this research was to demonstrate the configuration of these acids by unequivocal means. The methods starting from the stereospecificity of reagents, have as their basis the analogy that the stereospecificity would be carried over to this new reactant. The interpretation of the physical measurements requires an assumption of a certain conformation that is reasonable on the basis of X-ray diffraction measurements on similar compounds but has never been demonstrated in the compounds studied in this investigation. Both of these methods give concordant results in assigning the threo configuration to the lower melting 9,10-dihydroxystearic. The method of attack on this problem was the synthesis of an eighteen carbon compound having the elements of symmetry lacking in 9, 10-dihydro:xystearic acid and capable of conversion to 9,10-dihydroxystearic acid. The compound chosen was 9,10-dihydroxyoctadecanedioic acid. This acid exists in two forms, meso and racemic. The configuration at the nine and ten positions could be demonstrated unequivocally in this case by the actual resolution of the racemic mixture. Conversion of the racemic 9,10-dihydroxyoctadecanedioic acid to 9,10-dihydroxystearic acid would produce the threo configuration if no inversion took place at the nine and ten positions. In this manner, a total synthesis of 9,10-dibydroxystearic acid would also be accomplished. The synthesis of the desired 9,10-dibydroxyoctadecanedioic acid was accomplished as outlined below. 8-Chlorooctyne-1 and 1-iodo-6-chlorohexane were prepared from hexamethylene glycol. Condensation of these compounds afforded 1,14-dichlorotetradecyne-7. This, after conversion to the diiodo compound and reaction with ethyl malonate in sodium ethoxide solution, afforded 1,1,16,16-tetracarbethoxyhexadecyne-8. A partially saponified and decarboxylated byproduct was also isolated but its constitution was not definitely established. Hydrolysis and decarboxylation of the pure tetraester afforded 9-octadecynedioic acid. From the yield data from reactions with tetraester of different history, it was found that the highest yield of pure 9-octadecynedioic acid was obtained when the tetraester had been exposed least to alkali. Migration of the acetylenic bond under alkaline conditions is a possible explanation for this observation. The position of the acetylenic bond in the 9-octadecynedioic acid was determined by ozonolysis. Hydrogenation of 9-octadecynedioic acid afforded cis 9-octadecenedioic acid, agreeing in physical constants with those reported in the literature. A remarkable example of a poisoned palladium catalyst was discovered in developing this reaction. Analytically pure 9-octadecynedioic acid absorbed two molar equivalents of hydrogen with the rate of hydrogen absorption slower during the absorption of the second mole. However, material that had a wider melting point range absorbed only molar equivalent of hydrogen even on prolonged exposure to hydrogen. The cis 9-octadecynedioic acid was hydroxylated (a) with potassium permanganate and (b) with performic acid. These two methods had been used to produce the two forms of 9,10-dihydroxystearic acid from oleic acid. In this case, two different dihydroxy acids, m.p.'s 157° and 122°, were produced. The acid, m.p. 122° (phloionic acid) was also isolated from cork. Two methods were emplqyed to determine the configuration, meso or racemic, of these 9,10-dihydroxyoctadecanedioic acids. One method involved the formation of a cyclic benzylidene compound by reaction with benzaldehyde. Consideration of the geometry of these molecules indicated that the meso compound would afford a mixture of two compounds that should be separable whereas the racemic modification would afford only one compound. Experiment showed that only one compound was isolated when the 122° acid was used whereas the 157° acid afforded material that melted over a wide range. The analytical figures for this mixture were in agreement with those expected for the benzylidene compound. Crystallization from several solvents, and chromatography on several adsorbents were tried but with no success in separating the mixture. Since separation of the mixture was not accomplished, this proof of configuration is not conclusive. However, the method indicated that the 122° acid is racemic and the 157° acid is the meso modification. The configuration of the 9,10-dihydroxyoctadecanedioic acids was established definitely by resolution of the 122° acid as its brucine salt. The resolution was accomplished by equilibrating the salt of the racemic acid with small amounts of cold ethanol. The residue after eight equilibrations differed in specific rotation from the starting material. The salt was decomposed with concentrated hydrochloric acid and the free acid was isolated. This acid was optically active with a specific rotation of + 4.4 ± 1.1°. No claim is made that this material is optically pure since no further resolution attempts were made. For the purpose of the establishment of configuration, the demonstration of optical activity is sufficient. This activity was enhanced by benzoylation. The activity was not due to impurities since this acid was analytically pure. Examination of the alcoholic solution from the equilibration afforded an acid that had a specific rotation of -0.5 ± 1.0°. This activity is within experimental error and is not too significant. Naturally occurring phloionic acid was found to be optically inactive. This material would appear to originate from non-enzymatic processes since otherwise it would be optically active. The optically active acid appears resistant to racemization. No further work was done on the state or origin of phloionic acid in cork and cork wax. The last part of the problem was the conversion of the racemic 9,10-dihydroxyoctadecanedioic acid (phloionic acid) to 9,10-dihydroxystearic acid which would be the threo modification. This conversion was accomplished in the following way: Phloionic acid was converted to the monoester by transesterification with ethyl acetate and sulfuric acid. Normal Fischer esterification afforded the diester mainly even when the reaction was interrupted at shorter time intervals. Hydrolysis of the diester with sodium hydroxide afforded phloionic acid with very small amounts of monoester being formed at the point of half hydrolysis. These facts would indicate that the rate of hydrolysis of the monoester is faster than the diester, and that the monoester is hydrolyzed as rapidly as it is formed. In the transesterification reaction, unchanged starting material was always recovered, a fact indicating that this reaction involved no change in the configuration at the nine and ten positions. The ethyl hydrogen phloionate was reduced to 9,10,18-trihydroxystearic acid by a modification of the Bouvealt-Blanc procedure with sodium in absolute ethanol. The reaction proceeded smoothly and in good yield. A sample of phloionic acid was subjected to these conditions and was recovered unchanged. This observation demonstrated that the nine and ten positions were not involved in this reaction. The 9,10,18-trihydroxystearic acid isolated from this reaction differed in physical constants from the values reported by Zetsche in 1938 for a trihydroxystearic isolated from cork wax and called phloionolic acid. The structure proof was not very conclusive since the degradation products were not compared directly with the known compounds. Phloionolic acid may possibly have the other configuration (erythro). However, this research makes it doubtful that the erythro form would have a lower melting point than the threo form. If this conclusion is correct, Zetsche has incorrectly assigned the 9,10,18-tribydroxystearic acid structure to phloionolic acid. The conversion of threo 9,10,18-trihydroxystearic acid to threo 9,10-dihydroxystearic acid was accomplished in a manner analogous to the conversion of glucose to 6-desoxyglucose. The 18-tosyl ester was formed without protection of the vicinal hydroxyl groups by isopropylidene formation. The ester grouping was converted to the 18-iodo compound by reaction with sodium iodide in acetone. Iodine was replaced by hydrogen by reaction with zinc and hydrochloric acid in glacial acetic acid solvent. The material isolated was identical in analysis, melting point, and mixed melting point with authentic 9,10-dihydroxystearic acid, m.p. 95°. Both forms of 9,10-dihydroxystearic acid were carried through this process unchanged. The conversion of the racemic 9,10-dihydroxyoctadecanedioic acid to 9,10-dihydroxystearic acid without alteration of configuration at the nine and ten positions definitely establishes the low-melting 9,10-dibydroxystearic acid as the threo form. In summary, the accomplishments of this research are: 1. The definite assignment of the three configuration to the low-melting 9,10-dibydroxystearic acid. 2. The first recorded total synthesis of tb.e 9,10-dihydroxystearic acids from materials that are not derived from fats and oils. 3. A synthesis of oleic and elaidic acids, since Ames and Bowman have shown that the dihydroxystearic acids can be converted to the unsaturated acids in a stereospecific manner so that the erythro acid affords oleic acid exclusively and threo, elaidic. 4. The demonstration of configuration of the 9,1.0-dibydroxyoctadecanedioic acids. 5· The questioning of the assignment assigned by Zetsche to phloionolic acid as a 9,10,18-tribydroxyetearic acid. 6. The assignment of configuration to aleurtic acid, 9,10,16-trihydroxypalmitic acid, as threo as a corollary of this work. The assignment is made on the basis of the formation of a trans unsaturated acid when treated in the manner of Bowman, the ease of isoproproylidene formation analogous to the reactivity of the now known threo 9, 10-dihydroxystearic acid, and its lower melting point than its isomer.