Study on the synthesis of brassinolide and related compounds. Part 15. Formal synthesis of brassinolideviastereoselective sulphenatendash;sulphoxide transformation

摘要

J. CHEM SOC. PERKIN TRANS. 1 1991 Study on the Synthesis of Brassinolide and Related Compounds. Part 15.t Formal Synthesis of Brassinolide via Stereoselective Sulphenate-Sulphoxide Transformation Wei-Shan Zhou * and Zheng-Wu Shen Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling L u, Shanghai 2000032, China A formal synthesis of the natural growth-promoting steroid brassinolide is described, which involves construction of (22R,23euro;) -24-methyl-5P-cholest-23-ene-3~~6~,22-triolby methylation of (24R) -and (24s) -(22E) -24- phenylsulphinyl- 5P-cholest -22-ene- 3a,6a-d iol followed by 1,3 -sulp hoxide- h yd roxy transposition. Brassinolide 1 and related compounds are plant-growth-promoting steroids. Owing to their novel structural features and their remarkable physiological activity, much effort has been expanded on the development of methods for their syntheses.' Recently, we reported a novel method for the construction of the side-chain of brassinolide,' utilizing the P-alkylative 1,3- carbonyl transp~sition,~ i.e.2 -4. Stereoselective reduction of compound 4 with diisobutylaluminium hydride (DIBAL) gave the (22R,23E)-24-methyl compound 5 which is the key intermediate for the construction of the side-chain of brassinolide (Scheme 1). We now report another novel, efficient method for the construction of the side-chain of this compound by 1,3-sulphoxide-hydroxy transp~sition,~ i.e.11-5and 12 5. This transposition could be achieved from the sulphenate ester of the alcohols (R,Z)-9 and (S,Z)-10 which underwent 2,3- sigmatropic rearrangement to give the sulphoxide (24R,E)-11 and (24S,E)-12 followed by methylation to give (22R,23E)-24- methyl compound 5.Compounds 9 and 10 were readily prepared either by stereoselective alkylation of C-20 carbaldehyde 6 If with but-1-ynyl-3-methylstannane or with l,l-dibromo-3-methyl- but- 1-ene 'followed by catalytic hydrogenation of the resulting compounds 7 and 8 (Scheme 1). Treatment of (22R,Z)-9 in tetrahydrofuran (THF) containing Et,N with benzenesulphenyl chloride at -78 "C underwent 2,3-sigmatropic rearrangement to afford the (24R,22E)-24- sulphoxide 11, which was treated with lithium diisopropyl- amide (LDA) and iodomethane at -78 "C to give, uia rearrangement, the sulphenate ester of alcohol 5 uia the transition state A, and then cleavage at room temperature with trimethyl phosphite to give a mixture of (22R)-5' (47) and (22S)-5' (604) in the ratio 8.4:l in 53 overall yield.Thus, conversion of 2-enol (22R)-9 into E-enol (22R)-5 was readily accomplished, although the yield of this reaction has not been optimized. The structure assignment of product 5' was made based on that of its isomer 5. Since the 22-@-nitrobenzoyl) derivative of 5' exhibited a positive Cotton effect at 262 nm (Aamp; 12.36), the configuration at C-22 could be assigned as being S.* t Part 14 is Z. W. Shen and W. S. Zhou, J. Chern. Soc., Perkin Truns. I, 1990, 1765. $The mixture of enols 9 and 10 was prepared by catalytic hydrogenation of the mixture of compounds 7 and 8 obtained from the reaction of the C-20 carbaldehyde 6 with l,l-dibromo-3-methylbut-l-ene.' The overall yield of this two-step reaction is up to 90.The advantages of using the Z-isomers 9 and 10 over the corresponding E-isomers were the high yield of the catalytic hydrogenation and the ease of manipulation. Similarly, when this reaction sequence was carried out on the (22S,Z)-enol 10, a mixture of enols 5 and 5' was also readily obtained in the ratio 6: 1 in 56 overall yield. Since either enol 9 or 10 gave the same compound 5 in this 1,3-sulphoxide-hydroxy transposition process, this same reaction sequence was carried out on a mixture of substrates 9 and 10 j: to yield a mixture of enols 5 and 5' in the ratio -7: 1 in 46 overall yield.The present method for the preparation of enol (22R)-5 is both highly stereoselective and highly efficient. Hydroxy-directed epoxidation ofenol5 with rn-chloroperoxy- benzoic acid (MCPBA) afforded epoxide 132 in 93 yield. Completion of the side-chain synthesis by reduction of the oxirane 13 with LiBH,-Ti(OPr'), with inversion at C-24 showed 7 :1 regioselectivity for formation of the vicinal glycol, protected as its acetonide 14, in 84 yield. The overall yield from C-20 carbaldehyde 6 to the acetonide 14 in six steps was 33. This is one of the best methods to date for the construction of the side-chain of brassinolide. Compound 14 could be readily converted into brassinolide 1 by a known procedure.Experimental The silica gel used for flash chromatography was silica gel H (10-40 p) (Qingdao Chemical Plant, China). Iodine vapour and vanillin were used for colour development. M.p.s were determined on a Buchi 535 instrument and are uncorrected. Optical rotations were measured on an Autopol I11 polarimeter. IR spectra were recorded for KBr disks on a Zeiss-75 model spectrometer. 'H NMR spectra were recorded on Varian XL-200 (200 MHz), EM 360L (60 MHz) and JEOL SX-90 (90 MHz) spectrometers with SiMe, as internal standard. J-Values are given in Hz. Mass spectra were run on JMS-01 and MAT- 71 1 spectrometers. CD measurements were made on a JASCO 500-C instrument. HPLC was performed on a Waters HPLC 2462 instrument on p-Bondapak CN 3.9-150 mm, 20000 psi column.Elemental analyses were performed by the Analytical Department of this Institute. Light petroleum refers to the fraction boiling in the range 60-90 "C. (22R)-5P-Cholest-23-yne-3~,6x,22-triol7 und (22S)-5P-Chol-est-23-yne-3~,6~,22-triol8.--Method A. To a stirred solution of 1,l -dibromo-3-methylbut-i -ene (1.6 cm3) in dry THF (500 cm3) at -78 "C was added 1.5 mol dm-3 BuLi in diethyl ether (10 cm3) under N, and the mixture was stirred for 1 h, then was warmed to room temperature for ca. I h, then was recooled to -78 "C and a solution of aldehyde 6 (R = Ac) (500mg) in dry THF (10 cm3) was added. The reaction mixture 2828 J. CHEM. SOC. PERKIN TRANS. 1 1991 2 3 4 5 7 9 10PhS-0 8 PhS-0 PhS-0 11 f -{fly A B 12 -... h P 5 13 14 1 Brassinolide R=H,Ac Scheme 1 Reagents: a, TiCl,, Bu,SnCzCPr' or BuLi, Pr'CHXBr,; b, H,, Pd/BaSO,; c, PhSCI, Et,N, THF; d, LDA, THF; e, MeI; f, P(OMe),, MeOH; g, MCPBA, CH,Cl,; h, (i) Ti(OPr'),, LiBH,, C,H,-THF; then (ii) (MeO),CMe,, PTSA was stirred at this temperature for 2 h and then quenched with as usual gave a crude product, which was chromatographed on saturated aq.NH,CI. After extraction with CH2C12, the silica gel light petroleum-acetone (4:l) as eluent to give combined extracts were washed with brine and then dried over compound 7 (272 mg, 5704, m.p. 159-160 "C; .ID 18.6" (c Na2S0,. After removal of the solvent under reduced pressure, 1.05, CHCl,) (lit.,7 m.p.159-160 "C; .ID 19.03" (c 0.89)) the oily residue was dissolved in 2 KOH-MeOH and the and compound 8 (138 mg, 29), m.p. 153-155 "C; .ID 13.8" mixture was stirred at room temperature overnight. Work-up (c 0.83, CHCI,) (lk7 m.p. 154 "C; ID 12.8" (c 0.59, J. CHEM. SOC. PERKIN TRANS. 1 1991 CHCl,)). The spectroscopic data were identical with those previously rep~rted.~ Method B. To a stirred solution of compound 6 (200 mg) in dry THF (20 cm3) at -78 "C was added tributyl-(3-methylbut- 1-yny1)stannane (1 cm3) under N,. After the reaction mixture had been stirred at -78 "C for 10 min, TiCl, (1 cm3) was added and the reaction mixture was stirred at -78 "C for 1 h. The reaction mixture was then allowed to warm to -20 "C, and was then worked up as usual.The oily residue was dissolved in stirred 5 KOH-MeOH at room temperature overnight. After removal of the solvent under reduced pressure the residue was extracted with CH,Cl,. The extract was worked up as usual to give a mixture of compounds 7 and 8 in the ratio 9: 1 (HPLC). Flash chromatography on silica gel light petroleum-acetone (3:l) as eluent gave compound 7 (128 mg, 71.1), m.p. 157- 159 'C. The m.p. of this compound was not depressed on admixture with the compound obtained in the above experiment, and spectroscopic data were also identical with those obtained in the above experiment. (22R723Z)-5P-Cholest-23-ene-3cr,6a,22-triol9 and (22S723Z)- 5P-Cholest-23-ene-3x76u,22-triol10.-To a suspension of Lindlar catalyst (50 mg) in ethanol (10 cm3) was added compound 7 (100 mg).The mixture was hydrogenated for 6 h, the catalyst was filtered off, and the solvent was removed under reduced pressure to give compound 9 (96 mg, 9.573, m.p. 162- 164 "c; =ID 11.30" (c 0.3, CHCl,); v,,,(KBr)/cm-' 3300 (OH) and 1680 (CS); 6,(60 MHz; CCl,) 0.63 (3 H, s, 18-H3), 0.80 (3 H, s, 19-H,), 0.91 (9 H, s, 21-, 26- and 27-H,), 3.60 (1 H, m, 3-H), 4.00 (1 H, m, 6-H), 4.10 (1 H, m, 22-H) and 5.20 (2 H, m, 23- and 24-H); m/z 418 (M+), 400 (M+ -H,O) and 382 (M+ -2H,O) (Found: C, 74.3; H, 10.8. C27H4603-H20 requires C, 74.31; H, ll.Oly4). Catalytic hydrogenation of compound 8 (100 mg) was performed with Lindlar catalyst (50 mg). After work-up as described for compound 7, the enol 10 was obtained (95 mg, 9473, m.p.126-127 "C; aID 21.8" (c 0.196, CHCl,) (lit.,7 m.p. 125-127 "C; ID -21.14" (MeOH)). The spectroscopic data were identical with those previously rep~rted.~ Catalytic hydrogenation of a mixture of ynols 7 and 8 (200 mg) obtained from method A was performed as described above to give a mixture (181 mg) of enols 9 and 10 in the ratio 2:1, which was used for the following experiment, part C. (22R,23E)-24-Methyl-5~-cholest-23-ene-3cr76~,22-triol and5 (22S,23E)-24-Meth~~l-5C)-cholest-23-ene-3cx,6r,22-triol5'.--A. To a stirred solution of compound 9 (200 mg, 0.48 mmol) in dry THF (10 cm3) at -78 "C were added Et,N (1 cm3) and benzenesulphenyl chloride (0.5 cm3, 4.32 mmol) under N,.The reaction mixture was kept at -78 "C for 2 h and was then quenched with saturated aq. NH,Cl and extracted with CH,Cl,. The combined extracts were washed with brine, dried over Na,SO,. and concentrated under reduced pressure to give compound 11 as an oily residue, which was triturated with light petroleum to afford a solid (205 mg), which was used directly in the next step. To a solution of compound 11 (190 mg, 0.37 mmol) in dry THF (12 cm3) at -78 "C was added LDA (1.5 cm3, 1.0 mol dm-3 in THF) under N,. The reaction mixture was kept at -78 C for 2 h, and then Me1 (54 mg, 0.37 mmol) was added. The reaction mixture was stirred at -78 "C for 2 h and was then warmed to room temperature. A solution of (MeO),P (1.2 cm3) in MeOH (5 cm3) was added and the mixture was stirred at room temperature overnight before being quenched with saturated aq.NH4Cl and extracted with CH2C12. The extracts were washed with brine and then dried over Na,SO,. The solvent was removed under reduced pressure to give a mixture of enols 5 and 5' as a solid in the ratio 8.4: 1 (HPLC). This mixture was separated by flash chromatography on 2829 silica gel acetone-light petroleum (1:4) as eluent to give compound 5 (76 mg, 4773, m.p. 173-174 "C; ID -14.6" (c 1.1, CHCl,) {lit.,2b m.p. 173-174 'C; .ID -14.59 (c 1.1, CHCI,)); v,,,(KBr)/cm-' 3300 (OH) and 1630 (C=C); 6,(60 MHz; CDC1,) 0.64 (3 H, s, 18-H3), 0.97 (3 H, s, 19-H3), 0.90 (6 H, d, J4, 26- and 27-H,), 1.04 (3 H, s, 2l-H,), 1.60 (3 H, s, 24-Me), 3.60 (1 H, m, 6-H), 4.01 (1 H, m, 3-H), 4.46 (1 H, dd, J 7.2, 1.4, 22-H) and 5.36 (1 H, d, J 7.2, 23-H); m/z 433 (M+ + l), 414 (Mf -H,O) and 396 (M' -2H,O) (Found: c, 77.4; H, 11.4.CalC. for C28H4803: c, 77.70 H, 11.1 1). B. The procedure as described for compound 9 was carried out in this case using compound 10 (120 mg, 0.287 mmol) in THF (5 cm3), triethylamine (1 cm3) and benzenesulphenyl chloride (0.5cm3, 4.32 mmol). After work-up as described for compound 9, the sulphoxide 12 was obtained (128 mg, 86",). This product was used directly for the next step. The procedure as described for compound 11 was performed with the isomer 12 (120 mg, 0.23 mmol) in THF (10 cm3), LDA (1 cm3; 1.0 mol dm-, in THF), Me1 (33 mg, 0.238 mmol) and a solution of (MeO),P (1 cm3) in MeOH (1 cm3).After work-up as described for compound 11, enols 5 (72 mg, 61.8) and 5' (10 mg, 8.6) were obtained. The overall yield was 70.4. Compound 5 had m.p. 173-174 "c, ID -15.5 (c 0.37, CHCI,). The product showed no depression of m.p. when admixed with the product obtained from reaction A. The spectroscopic data were also identical with those of the product from reaction A. Compound 5' had m.p. 104-107"C, rD -12.71' (c 0.60, CHC1,); v,,,(KBr)/cm-' 3350 (OH) and 1640 (C=C); 6,(60 MHz; CDCl,) 0.65 (3 H, s, 18-H3), 0.90 (6 H, s, 19- and 2l-H,), 3.4-3.9 (2 H, m, 3- and 6-H), 4.10 (1 H, d, J 7, 22-H) and 5.30 (1 H, d, J 7, 23-H); n7/2 414 (M+ -H20) and 396 (M + -2H,O). C. The procedure as described for compound 9 was carried out with, in this case, a mixture of substrates 9 and 10 (-2: 1) (74 mg, 0.173 mmol) in THF (10 cm3), triethylamine (1 cm3) and benzenesulphenyl chloride (0.3 cm', 0.52 mmol).The product obtained was used directly for the next step. The procedure as described for compound 11 was performed with LDA (1 cm3; 1.0 mol dm-, in THF), Me1 (30 mg, 0.2 mmol) and a solution of (MeO),P (1 cm3) in MeOH (1 cm3). After work-up as described for compound 11, enols 5 (29 mg, 37.99/,) and 5' (4 mg, 5.2:/") were obtained. Compound 5 had m.p. 170-173 'C. ID-13.9" (c 0.6, CHCI,). It showed no m.p. depression when admixed with the product obtained from reaction A. The spectroscopic data were also identical with those of the product obtained from reaction A.(22R723R,24S)-23,24-Epo.~~-24-meth?~l-SP-c.holc..bsol;tune-3x,6x,-22-trio1 13.-To a solution of enol 5 (50 mg) in dry CH,Cl, (10 cm3) was added MCPBA (45 mg) and the mixture was stirred at room temp. for 20 h before being washed successively with saturated aq. NaHCO,, brine, and water and dried over Na,S04. After removal of the solvent under reduced pressure the solid residue was recrystallized from CH,Cl,-light petroleum to give compound 13(48 mg, 939;)). m.p. 139--140 -C; .ID -9.2" (c 0.74, CHCl,). The spectroscopic data were identical with those previously reported., (22R,23R724S)-22,23-Isopr~p~lideneu'io.~?~-24-t~~t~t~z?~l-5P-c~ho-lestune-3x76x,diol 14.-To a solution of compound 13 (1 5 mg) in dry THF (0.5 cm3) were added benzene (2 cm3) and Ti(OPr'), (0.2 cm3) under N, at room temp.After the reaction mixture had been stirred for 10 min LiBH, (10 mg) was added and the reaction mixture was stirred at room temperature for 10 h. After addition of diethyl ether (10 cm3) and 57; H,SO, (1 cm3) the mixture was extracted with CH,CI,. The extract was washed with water and dried over Na,SO,. The solvent was removed under reduced pressure. The oily residue was dissolved in acetone (5 cm3) and treated with toluene-p-sulphonic acid (PTSA) (3 mg) 2,2-dimethoxypropane (0.2 cm3). The reaction mixture was then stirred at room temp. for 3 h. Work-up as usual gave compound 14 (15 mg, 84), m.p. 167-168 "C: (lit.,2 166167 'C); v,,,(KBr)/cm-' 3450 (OH) and 1380 (CHMe,); 6,(200 MHz; CDCI,) 0.65 (3 H, s, 18-H3), 0.80 and 0.84 (6 H, 2 d, J 8, 26- and 27-H,), 0.99 (3 H, s, 19-H,), 1.34 (3 H, s, CMe), 1.36 (3 H, s, CMe), 3.68 (1 H, m, 6-H), 3.80 (1 H, m, 3-H), 3.82 (1 H, dd, J 9, 4, 23-H) and 3.98 (1 H, d, J 9, 22-H); m/z 490 (Mf) and 472 (Mf -H,O) (Found: C, 73.6; H, 10.9.Calc. for C,,H,,O,-H,O: C, 73.20 H, 11.00). Acknowledgements This investigation was supported by the National Natural Sciences Foundation of China. References 1 (a)S. Fung and J. B. Siddall, J. Am. Chem. Soc., 1980,102,6580;(h)M. Ishiguro, S. Takatsuto, M. Morisaki and N. Ikekawa, J. Chem. Soc., Chem. Commun., 1980, 962; (c) S. Takatsuto, N. Yazawa, M. J. CHEM SOC. PERKIN TRANS. I 1991 Ishiguro, M.Morisaki and N. Ikekawa, J. Chem. Soc., Prrkin 7run.y. I, 1984, 139; (d) M. Sakakibara and K. Mori, Agric. Biol. Chem., 1983, 47, 663; (e) M. J. Thompson, N. B. 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Paper 1/02023D Received 30th April 1991 Accepted 17th June 1991