Fuji, Kaoru

Fujita, Eiichi

Kajimoto, Tetsuya

Node, Manabu

Kyoto University Research Information Repository

TitleRegioselective Hydroxylation in the C Ring of ent-Kaurene ;Syntheses of ent-11α-Hydroxykaurene and ent-11α-Hydroxykauren-15-oneAuthor(s)Node, Manabu; Kajimoto, Tetsuya; Fujita, Eiichi; Fuji, KaoruCitationBulletin of the Institute for Chemical Research, KyotoUniversity (1987), 65(3): 129-133Issue Date1987-09-24URL http://hdl.handle.net/2433/77193RightType Departmental Bulletin PaperTextversionpublisherKyoto University         Bull. Inst. Chem. Res., Kyoto Univ., Vol. 65, No. 3, 1987  -Regioselective Hydroxylation in the C Ring of ent-Kaurene;                Syntheses of ent-lla-Hydroxykaurene andent-11a-Hydroxykauren-15-one                        ManabuNODE*, Tetsuya 'KAJtMOTo**, Eiichi FuJrrn***                                        and Kaoru FuJt*                                        ReceivedMay30, 1987            Regioselective hydroxylation at the C-11 position of ent-kaurene (5) was achieved via radical cycliza-         tion of the hydroxy group at the C-17 position. Naturally occurring ent-lla-hydroxykauren-15-one (3)          was synthesized from the hydroxylated kaurene 4 in two steps.              KEY WORDS: Hydroxylation/ ent-Kaurene/ ent-lla-Hydroxykaurene/ nt-11a,15j9-                             Dihydroxykaurene/ ent-1 la-Hydroxykauren-15-one/Radical Cycli-                           zation/ Lead Tetraacetate/ Tosylhydrazone/            In the course of our investigation on thephysiologically active diterpenoids, we found that ent-15j9-hydroxykaur-16-ene (1) had a potent stimulating effect on corticosterone production in        isolated rat adrenal cells') and that poly hydroxylated kaurenoids uch asoridonin (2) showed         strong antitumor activity against. Ehrlich asites carcinoma in mice.2lThese findings timu-       lated our interset into investigating the steroidogenic effect of varioushydroxykaurenes and the         antitumor effect of various hydroxykaurenones, because it is anticipatedthat the hydroxy group        in the kaurene skeleton plays an important role in the action of physiologically active          kaurenoids.            In oder to prepare various hydroxykaurenoids, we recently succeeded in regioselective         hydroxylations ofthe unactivated carbon atoms (C-7, —9, —12 and—14) on the B and C rings         in the kaurene skeletone through radical cyclization of a hydroxymethyl group on the D ring.3l         Though a report concerning the hydroxylation of the C-11 positionon the kaurene has already         been published by Kato and coworkers,4l the synthetic method forthe preparation of ent-1 la-        hydroxykauren-15-one (3)by Kato requires comparatively ong synthetic steps (total 11 steps HO      lotHO •OH        /H~ »,,R ®H~ • H ,~ R OH 1; R= OH - 2 3; R= 0 5; R =H4; R=H2            * I" , f : Institute for Chemical Research, Kyoto University, Uji, Kyoto 611. ** fx* jj : Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto             862. *** p W— : Osaka University of Pharmaceutical Science, 10-65 Kawai 2-Chome, Matsubara 580. ( 129 )                          M. NODE, T.  KAJiMOTO, E. FUJITA and K. Fuji from kaurene). No report on the synthesis of ent-11a-hydroxykaurene (4) has appeared to date. Here we report the convenient short syntheses of ent-1 la-hydroxykauren-15-one (3) and ent-lla-hydroxykaurene (4) from ent-kaurene (5).    A method for the transformation of kaurene (5) into the lactone 6 was published by McCrindle5) and Kato,4) respectively (Scheme I). However, radical cyclization of the alcohol 7 into the cyclic ether 8 proceeded in a yield of less than 41% according to thier method. The yield was improved to 80% by the use of the modified reaction conditions (See experimental section). 0O O         SI OH411,5—0. ,s--N. on 7g                                            SchemeI   The transformation of the lactone 6 into the hydroxykaurenone 3 via 4 is shown in Scheme II. Thus, reduction of the lactone 6 with diisobutyl aluminum hydride gave a mixture of epimeric hemiacetals 9, which was converted to the tosylhydrazone 10 in 70% overall yield by the treatment with tosylhydrazone in the presence of acetic acid. The configuration of hydrazone moiety in the structure of 10 was considered to be a /3-configuration because the torsional strain between the 13-hydrogen and the 17-carbon atom6) prevents the inversion of the configuration from (3 to a under the reaction conditions. The attempted Shapiro reaction') on the hydrazone 10 with n-butyl lithium (execss) did not afford the desired kaurenol 4, but the butylated product 11.8) On the other hand, use of lithium diisopropylamide which is a non-nucleophilic base gave the intended product 4 in low yield (16%). Several non-nucleophilic bases were tried to improve the yield without success. •H O n HOH       ~®ipRse,  6owl•H              910 ; R = CH=N-NH-Ts4 it ; R = (CH2)4CH3 HO 3 / H~ ••.OH 12                           Scheme II ( 130 )                   Regioselective Hydroxylation in the C Ring of  eni-Kaurene    Allylic oxidation of kaurenol 4 by Sharpless method9l proceeded smoothly to give dihyd-roxykaurene 12 resulting from the less hindered a-side attack of the reagent. Subsequent oxidation of the allylic alcohol 12 with manganese dioxide afforded the a,/9-unsaturated ketone 3, which was identified with naturally occuring ent-11a-hydroxykauren-15-one101 by the com-parison of the spectroscopic data.    Investigation of the physiological activity of synthesized 11-hydroxykaurene and its deriva-tives is now in progress.                        EXPERIMENTAL SECTION    Infrared (IR) spectra were recorded with a Hitachi 215 spectrophotometer or a JASCO A-202 spectrophotometer, and 1H—NMR spectra were obtained with JEOL FX-400 spectrometer. Chemical shift are reported relative to internal tetramethylsilane. Mass spectra (MS) were determined on a JEOL JMS—O 1 SG double-focusing mass spectrometer or a JEOL JMS—DX 300 mass spectrometer. Melting points were determined with a Yanagimoto apparatus and are uncorrected.     ent-kaurene (5) isolated from the leaves of Cryptomeria japonica1) was converted to the kauranol 7 by the hydroboration-oxidation reaction.1~1 Radical Cyclization of Kauranol 7 with Lead Tetraacetate    A solution of 7 (301 mg) and lead tetraacetate (12.5 g) in dry cyclohexane was stirred with refluxing under irradiation with 100 W tungsten lamp until kauranol on TLC disappeared (ca. 2.5 h). After filtration, the residue was washed with ether. The combined organic layer was washed with aqueous sodium thiosulfate and brine successively. After being dried over Na2SO4, the solvent was evaporated in vacuo and the residue was chromatographed on silica gel column to give the cyclic ether 8 (249 mg, 80% yield).51 ent-(16R)-Kauran-17,11a-olide (6)    To a solution of 8 (4.51 g) in a mixture of carbon tetrachloride (35 ml) and acetonitrile (35 ml) were added aqueous sodium periodate (13.5 g in 50 ml water) and ruthenium trichloride (32 mg). The mixture was vigorously stirred for 2.5 h at room temperature. After being quenched with iso-propanol to destroy remaining RuO4i the reaction mixture was diluted with water. The extract with dicholromethane was treated as usual to give a crude product, which was chromatographed on silica gel column to afford lactone 65) (4.25 g, 90% yield), mp 177-178°C, Tosylhydrazone 10    To a solution of 6 (45.8 mg) in dry tetrahydrofuran (2.5 ml) was added hexane solution (2.5 ml) of 20% diisobutylaluminium hydride, and the mixture was stirred for 1 h at 0°C. After being quenched with water, the reaction mixture was filtered with celite. ° The filtrate was evaporated to give a crude crystalline product (72 mg) which contained epimeric mixture of 9. To a solution of the crude 9 dissolved in dichloromethane (1 ml) and acetic acid (1 ml) was added tosylhydrazone (83 mg) and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was then poured into cold aqueous solution of sodium bicarbonate. Usual ( 131 )                          M. NODE, T.  KAJIM0ro, E. FuJITA and K. Fuji work up including extraction with ethyl acetate gave a crude material (126.5 mg) which was chromatographed on the silica gel column to yield tosylhydrazone 10 (50.7 mg, 70%), colorless powder from hexane—ethyl acetate, mp 161.5-162.5°C. IRumaxcm-1 (CHC13): 3320, 1714 and 1610. 1H-NMR 8 (CDC13): 7.81, 7.30 (each 2H, q of AB type, J=8 Hz, Aromatic-H), 6.40 (1H, s, N-H), 4.26 (1H, d, changed to singlet by D2O, J=11 Hz, 11-H), 4.06 (1H, s, 17-H), 3.85 (1H, d, J=11 Hz, -OH), 2.43 (3H, s, Ar-CH3), 0.92, 0.85 and 0.81 (each 3H, s, 3 X CH3), Anal. Calcd for C27H40O3N2S: C, 68.61; H, 8.51; N, 5.93. Found: C, 68.93; H, 8.65; N, 5.91. Shapiro Reaction with Tosylhydrazone 10    To a solution of 10 (20.3 mg) in dry ether (1.5 ml) was added n-butyl lithium (1.5 M THE solution, 0.25 ml) and the mixture was stirred at room temperature for 1 h. Usual work up of the extract gave a crude substance which was chromatographed on the silica gel column to give butyulated compound 11 (10.1 mg, 67%) as oil. IRvmax cm-1 (CHC13): 3600, 3450, 1455, 1395 and 965. 1H-NMR S (CDCI3): 3.86 (1H, d, J=6.6 Hz, 11-H), 2.03 (1H, m), 0.88, 0.85 and 0.78 (each 3H, s, 3XCH3). High-resolution MS m/z; M+ Calcd for C24H42O: 346.3234. Found: 346.3233. ent-11a-Hydroxykaurene (4)    To a solution of tosylhydrazone 10 (23.1 mg) in dry ether (1 ml) was added an ether solution of lithium diisopropylamid (0.75 M, 0.5 ml) and the mixture was stirred at room temperature for 1.5 h. Usual work up of the extract gave a crude substance, which was chromatographed on the silica gel column to separate kaurenol 4 (2.3 mg, 16%), colorless powder from methanol — ethy acetate, mp 131-132°C. 1H-NMR 6 (CDC13): 5.03, 4.85 (each 1H, s, 17-H2), 3.87 (1H, br s, 11-H), 2.70 (1H, br s, 13-H), 0.90, 0.88 and 0.81 (each 3H, s, 3XCH3). MSm/z; 288 (Mt), and 270 (M+-H2O). ent-1la,15/3-Dihydroxykaurene (12)    To a solution of SeO2 (11.0 mg) in CH2C12 (1 ml) was added 75 pl of 70% aqueous tert-butyl hydroperoxide. After the mixture had been stirred for 1 h at room tepmperature, a solution of kaurenol 4 (50 mg) in dicholromethane (3 ml) was added and the mixture was stirred for 1.5 h at room temperature. After being quenched with aqueous sodium thiosul-phate, usual work up of the extract gave an oily substance (70.8 mg), which was chromatog-raphed on a silica gel column to give diol 12 (38 mg, 76%), colorless needles (from hexane). mp 192.5-193.2°C. IRvmax cm-1: 3650. 1H-NMR 8 (CDC13): 5.27, 5.25 (each 1H, s, 17-H2), 4.26 (1H, s, 15-H), 3.88 (1H, d, J=5.1 Hz, 11-H), 2.78 (1H, br s, 13-H), 0.92, 0.89 and 0.82 (each 3H, s, 3XCH3). High-resolution MSm/z; M+ Calcd for C20H32O2: 304.240. Found: 304.238. ent-lla-Hydroxykauren-15-one (3)    To a solution of 12 (9.2 mg) in CH2C12 (1 ml) was added maganese dioxide (49.8 mg) and the mixture was stirred for 3 days at room temperature. After filtration, the residue was washed with dichloromethane. The combined solution was evaporated off to give a residue which was chromatographed on a silica gel column to separate crystalline ketone 3 (3.4 mg, ( 132 )                   Regioselective Hydroxylation in the C Ring of ent-Kaurene 37%).    The obtained ketone 3 was identified as  ent-11a-hydroxykauren-15-one" by the compari-son of the IR and 1H—NMR data.                        REFERENCES AND NOTES (1) K. Moriwaki, M. Gomi, Y. Itoh, S. Iida, M. Tsugawa, S. Tarui, K. Fuji, M. Node and T. Kajimoto,     Life Science, 1986, 38, 453. (2) E. Fujita, Y. Nagao, M. Node, K. Kaneko, S. Nakazawa and H. Kuroda, Experientia, 1976, 32, 203;      E. Fujita, Y. Nagao, K. Kaneko, S. Nakazawa and H. Kuroda, Chem. Pharm. Bull., 1976, 24, 2118;      E. Fujita, Y. Nagao, T. Kohno, M. Matsuda and M. Ozaki, Chem. Pharm. Bull., 1981, 29, 3208; M.      Node, M. Sai, K. Fuji, E. Fujita, S. Takeda and N. Unemi, Chem. Pharm. Bull., 1983, 31, 1433; K.      Fuji, M. Node, N. Ito, E. Fujita, S. Takeda and N. Unemi, Chem. Pharm. Bull., 1985, 33, 1038. (3) M. Node, T. Kajimoto, K. Nishide, E. Fujita and K. Fuji, Tetrahedron Lett., 1984, 25, 219; M. Node,      T. Kajimoto, N. Ito, J. Tamada, E. Fujita and K. Fuji, J. Chem. Soc., Chem. Commun. 1986, 1165. (4) N. Fukazawa, M. Funamizu, Y. Kitahara and T. Kato, Chem. Lett., 1976, 1253. (5) A. J. McAlees and R. McCrindle, Can. J. Chem., 1973, 51, 4103. (6) J. MacMillan and E. R. H. Walker, J. C. S. Perkin I, 1972, 986. (7) For an extensive review, R. H. Shapiro, Org. React., 1976, 23, 405. (8) In the reaction of tosylhydrazone with alkyllithium, substitution occasionally competes with elimina-    tion (see ref. 7). (9) M. A. Umbreit, K. B. Sharpless, J. Am. Chem. Soc., 1977, 99, 5526. (10) J. D. Connolly and M. S. Thornton, J. C. S. Perkin I, 1973, 736. (11) R. A. Appleton, R. McCrindle and K. H. Overton, Phytochemistry, 1968, 7, 135. (12) J. R. Hanson, Tetrahedron, 1967, 73, 801. (133)

Regioselective Hydroxylation in the C Ring of ent-Kaurene ; Syntheses of ent-11α-Hydroxykaurene and ent-11α-Hydroxykauren-15-one

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Regioselective Hydroxylation in the C Ring of ent-Kaurene ; Syntheses of ent-11α-Hydroxykaurene and ent-11α-Hydroxykauren-15-one

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