Hodges and Raphael 11. Elaboration Products of Podocarpic Acid. By R. HODGES and R. A. RAPHAEL. Podocarpic acid has been converted into trans-1,2.3,4,9,10,1lIl2-octa-hydro-7-methoxy-1 1 12-trimethylphenanthrene thus establishing the ab-solute stereochemistry of the latter. THE total synthesis of racemic trauts-l,2,3,4,9,10,11,12-octahydro-7-rnethoxy-I, 1,IZ-tri-methylphenanthrene (VIII; R = Me) has been rep0rted.l In view of the value of this compound for terpene syntheses it was obviously desirable to establish the absolute con- figuration of its enantiomorphs. This has now been achieved by the production of the dextrorotatory enantiomorph from podocarpic acid. Wolff-Kishner reduction of 1p-formyl-trans-1,2,3,4,9,10,11,12-octahydro -1,lZ -di -methyl-6-methoxyphenanthrene (obtained from podocarpic acid by published procedures) yielded the phenanthrene (I; R = Me R’ = H) which on nitration could be converted into either the mononitro-compound (I; R = Me R’ = NO,) or the corresponding dinitro- phenol (IV).It was hoped that the methoxyl group in the mononitro-derivative could be replaced by hydrogen via the corresponding thiophenol or disulphide. However we were unable to obtain any useful products from the reaction of the phenanthrene (I; R = Me R‘ = NO,) with sodium sulphide or disulphide either intractable gums resulting or starting material being recovered. As it was thought that displacement of the toluenesulphonyl group in the derivative (I; R = Ts R‘ = NO,) might take place more readily the methoxy-compound (I; R = Me R’ = H) was demethylated with sodamide in piperidineJ2 and the resulting phenol nitrated with cuprk nitrate in acetic anhydride giving (I; R = H R’ = NO,).All efforts to replace the toluenesulphonyl group in the nitro-toluenesulphonate (I; R = Ts R‘ = NO,) by sodium sulphide again failed. An attempt to remove the phenolic grouping in Barltrop and Rogers J. 1958 2566. a Brotherton and Bunnett Chem. and Ind.,1957 80. [19601 Elaboration Products of Podocarpic Acid. the nitro-compound (I; R = H R’ = NO,) by conversion into the diethyl phosphate followed by reduction with lithium in ammonia gave the amino-phenol (I; R = H K’ = NH,). A new approach to the introduction of a substituent in the 7-position was then adopted. srans-1,2,3,4,9,10,11,12-Octahydro-l p-hydroxymethyl-l,l2-dimethylphenanthrene* was oxidised to the corresponding aldehyde (11).Wolff-Kishner reduction of the aldehyde (11) gave the hydrocarbon (111) together with a product corresponding to the azine. Controlled oxidation of the hydrocarbon (111) produced the expected 9-0x0-derivative (V; R = H) and a substance containing three oxygen atoms. It had infrared and ultra- violet absorptions consistent with its formulation as an a-diketone and formed a quinoxaline which contained a hydroxyl group (infrared spectrum). In view of the known 5a-hydroxyl- ation of steroids by chromic acid5 and the suggested formulation of a similarly derived substance (VI),6structure (VII) seems the most probable for the by-product.Nitration of cc-tetralone yields a mixture of 7-nitro- and 5-nitro-cc-tetralone in the ratio of 93 7. Hence it was expected that nitration of the ketone (V; R = H) would yield almost exclusively (V; R = NO,). Only one product was indeed isolated which was shown in the sequel to possess the expected structure. Removal of the keto-group was achieved by reduction with sodium borohydride to the corresponding alcohol followed by acetylation and reduction with lithium in ammonia to give 7-amino-trans-1,2,3,4,9,10,11,12-octahydro-l,1,12-trimethylphenanthrene.The hydrochloride was diazotised converted into the phenol (VIII; R = H) and thence into (+)-trans-1,2,3,4,9,10,11,12-octahydro-7-methoxy-l, 1,12-trimethylphenanthrene (VIII ; R = Me). In view of the established stereochemistry of podocarpic acid the absolute configuration of (VIII; R = Me) must therefore be represented as shown.Although precedents were strongly against it there remained a possibility that the nitration of the ketone (V; R = H) had proceeded to give the corresponding 5-nitro- derivative rather than (V; R = NO,). To procure further evidence on this point the derived phenol was dinitrated. That the product was a 2,6-dinitrophenol (IX)as expected was confirmed by the comparison of its ultraviolet absorption spectrum in the range 320460 mp with 2,6-and 2,kdinitrophenols of known structure as shown in the Table. While this work was in progress a new diterpene phenolic ketone nimbiol was reported. The light-absorption data suggested structure (X) for this compound.Accordingly (X) Kenner and Williams J. 1955 522. Wenkert and Jackson J. Amev. Chem. SOC.,1958 80 217. Martin-Smith J. 1958 523. Ohta and Ohmori Pharm. Bull. Japan 1957 5 91. Schroeter Ber. 1930 63,1308. 8 Sengupta Choudhury and Khastgir Chem. and Ind. 1958 861. Hodges and Raphael Ultraviolet absorfition of dinitro@henolsin 0.005N-sodium hydroxide in 90% methanol. A*a,x. (mp) E ~max.(mp) E 6-Methyl-2,4-dinitrophenol........................ 371 16,600 403 13,900 5,6,7,8-Tetrahydro-2,4-dinitro-l-naphthol ... 370 15,600 410 14,100 4-Methyl-2,6-dinitrophenol........................ 447 7600 3,4-Dimethyl-2,6-dinitrophenol.................. 425 6300 (IV) ......................................................437 5300 (IX) ...................................................... 428 7100 was prepared by the chromium trioxide oxidation of the acetate (I; R = Ac R' = H). However the physical constants of compound (X) conclusively showed that it was not identical with nimbiol although the two compounds obviously contain similar chromo-phores. EXPERIMENTAL Rotations were determined in chloroform at room temperature unless otherwise stated. M. p.s were determined on a Kofler block and are corrected. Alumina of activity I11 was employed for chromatography and the light petroleum used for elution had b. p. 60-80". trans-1,2,3,4,9,10,11,12- Octahydro-6-rnethoxy -1,1,12-trimethylphenanthrene (I; R = Me K' = H).-lp -Formyl-trans-1,2,3,4,9,10,11 ,12-octahydro -6-methoxy-1,12-dimethylphenan -threne (23-7g.) and hydrazine (60nil.; 60%) were heated under reflux in diethylene glycol (400ml.) for 90 min.The solution temperature was raised to 200" by distillation potassium hydroxide (30g.) was added and the mixture was kept under reflux for a further 4 hr. The product in benzene was filtered through alumina (200 g.) and crystallised from methanol forming needles (16.2g.) of the methoxy-compound (I; R = Me R = H) m. p. 30.5-31.5" [a] +72" (c 2-3)(Found C 83.3; H 9.8; OMe 11.6. C,,H,,O requires C,83.65; H 10.15; OMe 12-Oyo). trans-1,2,3,4,9,10,11,12-Octahydro-6-methoxy-l,1,12-trimethyl-7-nitro~henanthreneR = (I; Me R' = NO,).-The methoxy-compound (I; R = Me R = H) (710 mg.) cupric nitrate (355mg.of trihydrate) and acetic anhydride (20 ml.) were stirred at room temperature for 12 hr. The mixture was poured into water and the product adsorbed on alumina (30g.) from light petroleum Elution with benzene-light petroleum (1 1) gave the nitro-compound (I; R = Me R = NO,) as needles (260 mg.) (from aqueous methanol) m. p. 133-134.5' [a] +274" (c 0.7) (Found C 70-9; H 8.2; N 4.7. C,,H,,O,N requires C 71-25;H 8.3; N 4.6%). trans-1,2,3,4,9,1O,11,12-Octahydro-6-hydroxy-l,lJl2-t~imethy~-~,7-d~nitro~~~enant~rene (IV).-The methoxy-compound (I; R = Me R' = H) (1.90 g.) benzene (10 ml.) and nitric acid (8 ml.; 35%) were stirred for 1 hr. at 5'. Extraction from benzene with Claisen's alkali gave a product which was adsorbed from benzene on alumina (100g.)deactivated with 10% of 10% acetic acid and eluted with ether.Crystallisation from aqueous methanol gave the dinitro-phenanthrens (IV) as yellow needles (550 mg.) m. p. 138.5-139-5" [a]=+273" (c 0.9) (Found C 60-85;H 6.6; N,8-15. C,,H,,O,N requires C 61.05; H 6.65; N,8.4%). The alkali- insoluble fraction afforded the mononitro-compound (I; R = Me R' = NO,) (80 mg.). Demethylation of trans-1,2,3,4,9,10,11 ,12-Octahydro-6-methoxy-l,lJl2-trimethylphenant~rene (I; R = Me R' = H).-The methyl ether (8-98.) was heated under reflux with a suspension of sodamide (from 10g. of sodium) in dry piperidine (60ml.) for 16hr. The product crystallised from hexane as needles (7.95 g.) of trans-1,2,3,4,9,10,11,12-octahydro-6-hydroxy-l,l,l2-tri-methylphenanthrene (I; R = R' = H) m.p. 140-141'. Treatment with toluene-p-sulphonyl chloride in pyridine gave the corresponding toluene-sulphonate which crystallised as needles (from methanol) m. p. 72-74' [a] +56" (c 0.8) (Found C 72.75; H 7-6. C21H,o0,S requires C 72.3; H 7.6%). trans-1,2,3,4,9,10,11,12-Octahydro-6-hydroxy-l, 1,12-trimeth~l-7-nitro~henanthrene(I; R = H R' = NO,).-The hydroxy-compound (I; R = R' = H) (2.75g.) cupric nitrate (1.46g. of trihydrate) and acetic anhydride (30ml.) were stirred at room temperature for 20 hr. and then diluted with water. Cyrstallisation of the precipitate from aqueous methanol or light petroleum gave (I; R = H R' = NO,) as yellow needles (2.43g.) m. p. 113.5-114.5" (Found C,70.6; H 7-45;N,5-2. C1,H,,O,N requires C 70.55; H 8.0; N,4.85%). Attempts to nitrate the toluenesulphonate of (I; R = R' = H) by this method afforded only starting material.[I1960] Elaboration Products of Podocarpic Acid. 7 -Amino-trans-1,2,3,4,9,10,11,12-octahydro-1,1,12 -trimethyl -6-toluene -p-suZphonyZoxy- Phenanthrene (I; K = Ts R' = NH,).-The nitro-compound (I; R = H R' = NO,) (1.79 g.) toluene-9-sulphonyl chloride (1.25 g.) and pyridine (0.53ml.) were heated under reflux in dry benzene (50 ml.) for 12 hr. After being washed with water 2~-sulphuric acid and sodium hydrogen carbonate solution the benzene solution was filtered through alumina (70 g.) deactiv-ated with 5% of 10% acetic acid. Evaporation to dryness yielded crude ester (I; R = Ts R = NO,) as a yellow oil (2.1 g.) which could not be crystallised.This oil (534 mg.) was hydrogenated in benzene (50 ml.) Adams's catalyst (25 mg.) being used. After adsorption from benzene on alumina (50 g.) and elution with ether-methanol (19 l) the ester (I; R = Ts R = NH,) crystallised as neeales (276 mg.) (from light petroleum) m. p. 137-138" [a] +72O (c 0.8) (Found C 69.7; H 7.45. C,4H3103NS requires C 69-7; H 7.55%). 11,12-octahydro-6-hydroxy-l, 7-Amino-trans-1,2,3,4,9,10 l112-trimethylphenanthrene (I; R = H R' = NH,).-The nitro-compound (I; R = H R' = NO,) (65 mg.) was subjected to Kenner's deoxygenation procedure. The product would not crystallise from chloroform-light petroleum or aqueous methanol a gelatinous suspension being formed. However after sub- limation (3 times at 140°/0-003 mm.) it formed fine needles (26 mg.) of the amine (I; R = H R' = NH,) m.p. 174-176" [aID+86" (c 0-15) (Found C 78-45; H 9.65; N 5.8. C,,H,,ON C 78.7; H 9.7; N 5.4%). l~-Formyl-trans-1,2,3,4,9,lOJ1lJl2-octahyd~o-lJl2-d~methyl~henanth~ene (II).-Oxidation of 1~-hydroxymethyl-trans-l,2,3,4,9,10,11,12-octahydro-l, 12-dimethylphenanthrene (22.7 g.) in acetone (300 ml.) with chromic acid (SN) gave the aldehyde (11)which crystallised as flat prisms (17.6 g.) (from methanol) m. p. 106-108° [a] +89" (c 1.4) (Found C 84.5; H 8.95. C1,H,,O requires C 84.25; H 9.15%). trans-1,2,3,4,9,10J11 12-Octahydro-1,1,12-trimethyEphenanthrene (111).-The aldehyde (11) (14.1 g.) hydrazine (50 ml. BOY0) and diethylene glycol (250 ml.) were heated under reflux for 1 hr. Potassium hydroxide (15 g.) was added and the temperature raised to 210" by distillation.After 5 hr. the product was extracted with light petroleum filtered through alumina (300 g.) and crystallised forming prisms (12.9 g.) of the hydrocarbon (111)(from chloro- form-methanol) ,m. p. 16-17" b. p. 96-97"/18 mm.,[a]=+63" (c 3-3) (lit.9 [a]=+65") (Found C 89.65; H 10.55. C,,H, requires C 89.4; H 10.6%). Further elution with benzene-ether (4 1)gave the azine (110 mg.) as prisms (from aqueous methanol) m. p. 214-216*5" [a] +223" (c 0.6) [Found C 84-35; H 9.0; N 5.7%; M (mass spectrometer) 480 f3. C34H44N2 requires C 84-95; H 9.25; N 5.85% ; M 480); Amx. (hexane) 213 mp (c = 37,600); v (Nujol) 1630 cm.-l (N=N). trans-1,2,3,4,9,10,11,12-Octahydro-l,1,12-triunet~zyl-9-oxo~henanthrene (V; R = H) .-The hydrocarbon (111)(8-13g.) chromium trioxide (4.78 g.) and acetic acid (120 ml.) were heated at 70-75" for 10 min.The product was freed from acidic material and adsorbed on alumina (300 g.) from light petroleum. Elution with light petroleum gave unchanged hydrocarbon (111) (930 mg.). Elution with benzene gave the Ketone (V; R = H) as prisms (5.5 g.) (from aqueous methanol) m. p. 82-83-5" [alD +1S0 (c 1.6) (Found C 84.55; H 8-85. C17H,,0 requires C 84.25; H 9.15y0) A,,,. (in methanol) 251 mp (E = 10,200). Further elution with methanol gave a yellow oil which was adsorbed from benzene-light petroleum (1 1)on alumina (20 g.)deactivated with 5% of 10% acetic acid and eluted with benzene. Crystallisation from light petroleum-chloroform gave trans-1,2,3,4,9,10,11,12-octahydro-l la-hydroxy-1 ,1,12-tri- methyl-9,lO-dioxophenanthrene(VII) (52 mg.) as yellow needles m.p. 167-169" [a] +221° (G 0.6) (Found C 74.85; H 7-5. C,,H,,O requires C 74.95; H 7.4%); A, (in methanol) 281 my (E = 6200); v (in carbon disulphide) 1690 and 1731 crn.-l. The quinoxaline derivative crystallised as white needles (from light petroleum) m. p. 208-209" (Found C 79-75; H 7.0; N 8.55. C2,H,40N requires C 80-2; H 7.0; N 8.15%). trans -1,2,3,4,9,10,11,12-Octahydro-1,1,12-trimethyl -7 -nitro -9 -oxophenanthrene (V; R = NO2).-A mixture of nitric acid (2.51 ml.; 70% w/w) and sulphuric acid (4-2 ml.) was added dropwise to a stirred solution of the ketone (V; R = H) (9.6 8.) in sulphuric acid (10 ml.) maintained at 0". After being stirred for 10 min.the mixture was poured on ice and the product crystallised from methanol forming plates (10-67 g.) of the nitro-ketone (V; R = NO,) m. p. 169-5-170" [o]~+36" (c 1.0) (Found C 70-7; H 7-25; N 4-95. C17H2103N requires C 71-05; H 7.35; N 4.85%); Amx. (in methanol) 237 (E = 25,400) 268 mp (E = 10,250). trans-1,2,3,4,9,10,11,12-Octahydro-9-hydroxy- 1,l112-trimethyl- 7-nitrophenantlzrene.-The S Ohta and Ohmori Pharm. Bull. Japan 1957 5 96. Elaboration Products of Podocarpic Acid. nitro-ketone (V; R = NO,) (380 mg.) was reduced with sodium borohydride (100 mg.) in dioxan (10ml.) for 1 hr. at room temperature. Acetic acid and water were added and the product was crystallised from aqueous methanol giving needles (340 mg.) of trans-1,2,3,4,9,10,11,12-octahydro-9-hydroxy-1,1,12-t~i~ethyZ-7-nit~o~henanthrene,145-147.5", m.p. [a& +115" (c 0.8) (Found C 70.85; H 7.7; N 4.8. C,,H2,0,N requires C 70-55;H 8.0; N 4.85%). 11,12 -0ctahydro -1,1J12-trimethyl-9-Acetoxy-trans-1,2,3,4,9,10 7-niti*ophenanthrene.-The 9-hydroxy-derivative (168 mg.) acetic anhydride (5 ml.) and sodium acetate (200 mg.) were heated under reflux for 3 hr. The product isolated by precipitation with water crystallised from methanol as flat prisms (152 mg.) of 9-acetoxy-trans-1,2,3,4,9,lOJll,l2-octah~dro-lJl,l2-triunethyl-7-nitrophenanthrene,m. p. 104-105.5" [a] f79" (c 0-7)(Found C,68-65;H 7-8. C,,H2,0,N requires C 68-85; H 7.6%). 7-Amino-trans-1,2,3,4,9,10,11,12-octahydro-l,1,12-trimethyl~henanthrene.-9-Acetoxy-trans-1,2,3,4,9,10,11 (8.14 g.) in ether (50 ml.) 12-octahydro-lJl,12-trimethyl-7-nitrophenanthrene was added to liquid ammonia (250 ml.).Lithium (5 g.) was added the mixture stirred for 10 min. and the excess of lithium destroyed by the addition of ammonium chloride. The product was isolated as the amine hydrochloride (5-3g.) precipitated from ether by hydrogen chloride. Acetylation gave 7-acetamido-trans-lJ2,3,4,9, 10,11,12-octahydro-l,l,12-trimethyl- phenanthrene crystallising as long prisms m. p. 151-154" [a],,+75" (c l-l),from chloroform- light petroleum (Found C 80.35; H 9.6; N,5.55. C1,H170N requires C,79.95; H 9.55; N 5.6%). trans-1,2,3,4,9 10,ll,12-Octahydro-7-hydroxy-1,1,12-trimethylphenanthrene (VIII; R = H).-Sodium nitrite (33mg.) in sulphuric acid (0.25 ml.) was added dropwise to a stirred solution of 7-amino-trans-lJ2,3,4,9 12-octahydro-l,1,12-trimethylphenanthrenehydrochloride (128 10JllJ mg.) in acetic acid (2ml.) at 0".After the mixture had been stirred for 30 min. ice (10 g.) was added and the mixture was poured into a solution of sulphuric acid (20%) and sodium sulphate in water maintained at 120" under reflux. The product was extracted from benzene with Claisen's alkali adsorbed from petrol on alumina (20g.) deactivated with 10% of 10% acetic acid eluted with benzene-light petroleum (2:3) and crystallised from light petroleum giving needles of the phenol (VIII; R = H) (44mg.) m. p. 132-134". [a] +61" (G 1.3) (Found C,83-05; H 10.3. C17H2,0 requires C 83-55;H 9.9%). trans-1,2,3,4,9,10,11,12-Octahydro-7-methoxy-lJ1,12-trirnethylphenanthrene (VIII; R = Me).-The potassium salt of the above phenol (800 mg.) prepared with molecular potassium in benzene was methylated with methyl iodide.The product in light petroleum was filtered through alumina (50g.) and crystallised from methanol forming plates (644mg.) of the methyl ether (VIII; R = Me) m. p. 86-88" [aID+54O (c 1.7) (Found C,83-45;H 10-4;OMe 11-6. C1,H,,O requires C 83.65; H 10.15; OMe 12-Oyo). trans-l,2,3,4,9,1OJ1l,12-Octahydro-7-hydroxy-(IX).-1,1,12-trimethyl-6,8-dinitro~henanth~ene Nitric acid (0-0087ml.; 70% w/w) was added to a solution of trans-1,2,3,4,9,10,11,12-octahydro-7-hydroxy-l,1, 12-trimethylphenanthrene (23 mg.) in acetic anhydride (2 ml.) at room tem- perature.The mixture was heated to 70" for 10 min. and then poured into water and the product filtered off. Adsorption on alumina (5 g.) deactivated with 10% of 10% acetic acid followed by elution with benzene gave the dinitro-compound (IX) (6 mg.) as yellow needles m. p. 110-112" from aqueous methanol (Found C 61.05; H 6.7; N 8.3. C,,H,,O,N requires C,61.05; H 6-65;N 8.4%). trans-I,2,3,4,9,10,11,12-0ctahydro-6-hydroxy-1,1,12-trimethyZ-9-oxophenanthrene(X).-trans-1,2,3,4,9,1OJ11,12-Octahydro-6-hydroxy-1, 1,12-trimethylphenanthrene(1 15 mg.) was heated under reflux with sodium acetate (200 mg.) and acetic anhydride (5 ml.) for 1 hr. The crude product in acetic acid (10 ml.) was treated with chromium trioxide (60 mg.) at 70-75" for 10 min. Extraction with light petroleum washing with sodium hydrogen carbonate solution and adsorption on alumina (20 g.) followed by elution with ether gave the crude ketone (X).This was purified by chromatography on alumina deactivated with 5% of 10% acetic acid the product being obtained as needles (24mg.) m. p. 217-219" [a]=+28O (c 1.0),from aqueous methanol (Found C 78.65; H 8.65. Cl,H,,O requires C 79-05; H 8.6%); A, (in methanol) 230 (E = 11,550) and 286 mp (E = 12,950). Nimbiol has A,,,. 231 and 286 mp (E = 11,800 and 11,500). The dinitrophenylhydrazone of our product formed needles m. p. 266-268" from methanol (Found C 63-25;H 5.75. C,,H,,O,N requires C,63.0; H 6.0%) ; Amx. (in methanol) 400 mp (E = 23,000). [19601 EriC Goode and Ibbitson. The authors thank Mr. J. M. L. Cameron and his associates for microanalyses Dr. G. Eglinton and Mrs. F. Lawrie for assistance with infrared spectra Dr. R. I. Reed for mass-spectrographic determinations of molecular weight and Mr. I. R. McDonald Dominion Laboratory New Zealand for a generous gift of podocarpic acid. DEPARTMENT OF GLASGOW. [Received June 121h 1959.1 CHEMISTRY THE UNIVERSITY