Cartas al editor

In part I of this thesis are described our studies in the area of aza steroids. These investigations involve chemical and spectroscopic studies of these compounds. Lithium aluminum hydride reduction of 3β-hydroxy-11-aza-5a, 22β-spirost-8(9)-en-12-one (72) provides the enamine, (73), which upon subsequent conversion to its iminium salt, (75), and borohydride reduction yields 11-aza-5a, 8ξ, 9a, 22β-spirostan-3β-o1 (76). This reaction furnishes a convenient sequence for reduction of the 8, 9-double bond in 11-aza steroid derivatives. Degradation of the sapogenin side chain then allows entry into 11-aza pregnane derivatives. The synthetic sequence provides the first examples of 11-aza steroid analogues in which ring C is six-membered and completely saturated. A detailed discussion of the mass spectra of 6- and 11-aza steroid derivatives is presented. In part II of this thesis is described our work which relates to a synthetic approach to the Iboga and Aspidosperma alkaloids. The first section involves the synthesis of 2-carbomethoxy-3-[a-hydroxy-β-(3-carbomethoxy-N-piperidyl)-ethyl]-indole (78) and 3-[β-(3-carbomethoxy-N-piper-dyl)-ethyl]-indole-2-acetic acid methyl ester (93). The Hoesch reaction was used for the synthesis of 2-carbomethoxy-3-chloroacetylindole (75) from 2-carbomethoxy-indole (74) and chloroaceto-nitrile. Treatment of 75 with 3-carbomethoxy piperidine (76) yielded 2-carbomethoxy ‒3 ‒ (3-carbomethoxy-N-piperidyl)-acetylindole (77). The latter compound was reduced with sodium borohydride or by catalytic hydrogenation with Raney nickel to 78. Prolonged hydrogenation of 77 or 78 with Raney nickel catalyst provided 2-carbomethoxy-3-[a-hydroxy-β-(3-carbomethoxy-N-piperidyl)-ethyl]-4, 5, 6, 7-tetrahydro-indole (79). Similarly 2-carbomethoxy-indole (74) was reduced to 2-carbomethoxy-4, 5, 6, 7-tetrahydro- indole (80) by hydrogenation with platinum oxide catalyst. The Hoesch reaction was also used for the synthesis of 3-chloro-acetylindole-2-acetic acid methyl ester (89) from indole-2-acetic acid methyl ester (88) and chloroacetonitrile. Treatment of 89 with 2-carbomethoxy piperidine (76) provided 3-(3-carbomethoxy-N-piperidyl)-acetyl-indole-2-acetic acid methyl ester (92). The latter substance was reduced with diborane to 93. The second section provides the synthesis of 1, 2 , 3, 5, 6, 11, 11b (ξ)-heptahydro-2ξ-(ɜ-chloropropyl)-2ξ-ethyl-3-oxo-indolo(2, 3-g)indolizine (118). The fundamental reaction involved condensation of tryptamine with either ethyl a-keto-ʏ-(ʏ-benzyloxypropyl)-ʏ-ethyl-glutarate (70b) or ethyl-a-(ʏ-benzyloxypropyl)-a-ethyl-syccinate (70a). When glutarate 70b was condensed with tryptamine the amides 110 and 111 were obtained. On the other hand, the succinate 70a reacted with tryptamine to afford the desired N-[β- (3-indolyl)-ethyl-a- (ʏ-benzyloxypropyl)-a-ethyl-succinimide (112). Treatment of the latter substance with boron tribromide yielded N-[β-(3-indolyl)-ethyl]-a-(3-hydroxypropyl)-a-ethyl-succinimide (115), which was subsequently converted to N-[β-(3-indolyl)-ethyl]-a-(3-chloropropyl)-a-ethyl-succinimide (116) with thionyl chloride. Cyclization of the latter substance with phosphorus pentoxide afforded 2, 3, 5, 6, 11-pentahydro-2ξ-(3-chloropropyl)-2ξ-ethyl-3-oxo-indolo(2, 3-g) indolizine (117), which on hydrogenation with platinum oxide yielded 118. The glutarate 70b and the succinate 70a involved in the above syntheses were obtained via a series of established reactions, starting from benzyl ʏ-chloropropyl ether (101). / Science, Faculty of / Chemistry, Department of / Graduate

Ozonization of Ʒβ, 20β -diacetoxy-5-pregnene-7-one (XII) gave methyl Ʒβ ,20β -diacetoxy-5-oxo-5,7-seco-6-norpregnan-7-oate (XIII). Treatment of the latter with sodium hydroxide yielded methyl 20β -acetoxy-5-oxo-5,7-seco-6-nor-Ʒ-pregnen-7-oate (XIV), which upon reduction gave methyl 20β -acetoxy-5-oxo-5,7-seco-6-norpregnan-7-oate (XV) in high yield (see Figure 20). Upon treatment of the latter with benzylamine, ring closure occurred and the enol lactam, 20β -acetoxy-N-benzyl-6-aza-4-pregnen-7-one (XVI) was formed. Catalytic reduction of the double bond followed by reduction of the carbonyl with lithium aluminum hydride yielded 20β -hydroxy-N-benzyl-6-aza-5§ -pregnane (XVIII) . / Science, Faculty of / Chemistry, Department of / Graduate

In Part A of this thesis evidence is presented concerning the location and configuration of the bromine atom in each of the two isomeric monobromo derivatives (8a and 9a) of 5α,25R-spirostan (7, desoxytigogenin) and in each of the two isomeric monobromo derivatives (8b and 9b) of 3β-acetoxy-5α,25R-spirostan (tigogenin acetate) prepared by the action of bromine in acetic acid on the parent compounds. From a study of the mass spectra and nuclear magnetic resonance spectra obtained for the monobromotigogenins, it was established that the bromine atom was located at the C-23 site. In addition, the configuration of the bromine atom in each of the compounds studies was determined. In Part B of this thesis the syntheses of several derivatives of 4β-dihydrocleavamine (116) having a substituent at the C-18 site are described. The method employed an apparent SN₂’ displacement of chloride ion from the α-methyleneindoline form (118, R=H) of the chloroindolenine (113) of 4β-dihydrocleavamine. The chloroindolenine was prepared by the action of tertbutyl hypochlorite on 4β-dihydrocieavamine and was allowed to react with several nucleophiles under a variety of conditions. Using suitable conditions 18α-methoxy-4β-dihydrocleavamine (140), 18β-methoxy-43-dihydrocleavamine (141), 18β-hydroxy-4β-dihydrocleavamine (142), and 18β-cyano-4β-dihydrocleavamine (143) were prepared. The last compound was transformed into 18β-carbomethoxy-4β-dihydrocleavamine (139) by unexceptional means. This transformation provided a crucial link in the total syntheses of the Vinca alkaloid, coronaridine (45) and it C-4 epimer dihydrocatharanthine (46) In Part B of this thesis are also described the syntheses of dimeric compounds. The chloroindolenine of 4β-dihydrocleavamine was allowed to react with deacetylvindoline hydrazide (114) to give a dimer (115) . The coupling of the two units was shown to have taken place between the C-18 site of 4β-dihydrocleavamine and the C-15 site of deacetylvindoline hydrazide. The dimeric Vinca alkaloids isoleurosine A (110) and vincaleukoblastine (as the methiodide salt, 109) are coupled in the same manner. Isoleurosine A and vincaleukoblastine have in common a carbomethoxy group at the C-18 site of the dihydrocleavamine portion. The syntheses of two dimers (147 and 148) are described which also have this feature. The syntheses were accomplished in the manner of the previous coupling using the chloroindolenine (117, R=COOMe) of 18β-carbomethoxy-4β-dihydrocleavamine in place of the chloroindolenine of 4β-dihydrocleava;nine. In Part C of this thesis an effective method for preparing tritium and deuterium labelled indole alkaloids is described. Tritium labelled trifluoroacetic acid or trifluoroacetic acid-d was used. A combination of the methods of mass spectrometry and nuclear magnetic resonance spectroscopy was used to establish that the deuterium atoms were located primarily in the benzene portion of deuterium labelled 18α-carbomethoxy-4α-dihydrocleavamine (67) and 18β-carbomethoxycieavamine (73). Also in Part C of this thesis are described tracer experiments of a preliminary nature in Vinca rosea L. plants using [22-¹⁴ C]-18β-carbomethoxy-4β-dihydrocleavamine and [T-aromatic]-18β-carbomethoxycleavamine and tracer experiments in Vinca minor L. plants using [T-aromatic]-vincadine (74) and [T-aromatic]-vincaminoreine (75). / Science, Faculty of / Chemistry, Department of / Graduate

The total synthesis of trans-syn-cis-C-nor-2-methoxy-8, 11-dihydroxy-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11-undecahydro chrysene (87) is described. This compound has been synthesized from the C-nor-D-homo hydroxy aldehyde (67) via the olefin (71) by oxidative hydroboration. This sequence has the advantage of giving a much higher overall yield of (87). The conversion of the said compound (87), to the a-methyl ketone (74), a relay compound which has been used to synthesize verarine (76) is now nearing completion. Contrary to previous speculations⁸⁸, pyrolidene enamine methylation of model compounds (77,78) did not prove as fruitful as methylation of trapped enolates (figure 13). [diagram omitted] / Science, Faculty of / Chemistry, Department of / Graduate

A sequence leading to the total synthesis of trans-anti-trans- and trans-syn-cis-C-nor-2-methoxy-8,11-diketo-10a-methyl-4b,5,6,6a,7,8,9,10,10a,10b,11-undecahydrochrysene (LXXXI and LXXXII,respectively) from the known compound, 2-methoxy-8-keto-10a-methyl-5,6,8,9, 10,10a,11,12-octahydrochrysene (XLIII), is described. Oxidation of trans-anti-trans-2-methoxy-8β-acetoxy-10a-methyl-4b,5,6,6as7,8,9,10,10a,10b,11,12-dodecahydrochrysene (LXV) by means of t-butyl chromate led mainly to the 12-keto derivative (LXVIII). An olefinic bond at the 11,12 position (LXXI) was introduced by mild reduction of LXVIII with sodium borohydride followed by dehydration with phosphorus pentoxide. Subsequent reaction at the olefinic linkage by osmium tetroxide provided mainly the β-diol LXXII which upon treatment with periodic acid gave trans-anti-trans-11 ,12-seco-11,12-dioxo-2-methoxy-8β-acetoxy-10a-methyl-4b,5,6,6a,7,8,9, 10,10a,10b11,12-dodecahydrochry-sene (LXXIV). Intramolecular aldol condensation of IXXIV with sodium hydroxide gave the C-nor-D-homo diol aldehyde LXXIX. Oxidation of the latter with Jones reagent followed by deformylacion of the resulting diketo aldehyde IXXX provided the isomeric diketones LXXXI and LXXXII. It is felt that these latter substances show promise as useful intermediates for the total synthesis of Veratrum alkaloids. In another sequence designed as a model for the subsequent elaboration of LXXXI and LXXXII to the Veratrum alkaloid system, trans-anti-trans-anti-2-keto-8β-hydroxy-10a-methyl -2,3,4,4a, 4b, 5,6, 6a,7, 8,9,10,10a,10b,11,12-hexadecahydrochrysene (XCII) was methylated at C-1via the pyrrolidyl dienamine XCIII. A detailed discussion of the nuclear magnetic resonance spectra of the hydrochrysene compounds is also presented. / Science, Faculty of / Chemistry, Department of / Graduate

The metabolic and endocrine effects of anabolic compounds, viz., Zeranol, diethylstilbestrol (DES) and Synovex-S were investigated in growing steers in order to understand their biochemical mechanisms of action. The growth promoting properties of certain anabolic compounds were established. A marked reduction in the plasma concentration of urea nitrogen, alpha amino nitrogen and amino acids was found in steers implanted with anabolic compounds. The results suggested that anabolic compounds significantly alter the nitrogen metabolism of steers by increasing the efficiency of utilization of absorbed nitrogenous compounds. Implantations of DES and Synovex-S were more effective than Zeranol in enhancing the growth rate and altering the nitrogen metabolism of the animals. The usefulness of measuring NT-methylhistidine in urine as a non-destructive, in vivo index of myofibrillar protein degradation and the developmental aspects of muscle protein metabolism in cattle were demonstrated. The implantation of anabolic compounds, in general, increased the efficiency of muscle protein synthesized and protein deposited by the steers. Implantations of DES and Synovex-S were more effective than Zeranol due to a reduction in the muscle protein degradation per unit synthesized. Hydroxyproline excretion in the urine was used as an in vivo indicator of collagen turnover in steers. As the animals gained weight and advanced in maturity, its excretion in the urine decreased indicating a reduction in collagen turnover. Implantation of DES increased the hydroxyproline excreted by steers, while, Zeranol and Synovex-S had very little effect. These results indicate that DES implantation increases the amount of collagen and its turnover in steers. DES and Synovex-S exerted a significant influence on the activity of the thyroid gland and caused an elevation in the circulating concentrations of free and total thyroxine. On the other hand, the implantation of Zeranol resulted in plasma thyroxine concentrations similar to or lower than in the controls. Plasma triiodothyronine concentrations were not influenced by any of the compounds studied. Increased plasma thyroxine concentration observed in the DES or Synovex-S implanted steers was shown to be due to an increase in the secretion and a decrease in the metabolic clearance rates of thyroxine. The implantation of Zeranol appeared to increase the secretion rate of thyroxine, and resulted in slightly depressed plasma thyroxine concentration due to a higher metabolic clearance rate. Implantations of anabolic compounds resulted in an increase in the circulating concentration of growth hormone. Implantations of DES and Synovex-S were more effective than Zeranol in increasing the plasma growth hormone concentration. The kinetic parameters of growth hormone metabolism in growing steers were determined. The anabolic compounds increased the secretion rate of growth hormone from the pituitary gland suggesting that these compounds evoke growth promotion in steers through changes in the endogenous growth hormone status. These changes involved an increased secretion rate of growth hormone with very little alteration in the metabolic clearance rate. The metabolism of insulin was influenced to a significant extent in steers implanted with anabolic compounds. Zeranol increased the insulin secretion rate to a greater extent than Synovex-S or DES. The data indicated that the implantation of anabolic compounds altered the metabolism of steers significantly and enhanced the secretion rate of thyroxine, growth hormone and insulin. They altered the metabolism of the steers in such a way that there was an efficient utilization of absorbed nutrients. The mechanisms of action of anabolic compounds have been discussed in detail and the directions for future research suggested. / Land and Food Systems, Faculty of / Graduate

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