Ruthenium-Catalyzed Mild C-H Oxyfunctionalization of Cyclic Steroidal Ethers1 Jong Seok Lee,§ Hui Cao, and Philip L. Fuchs* Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
[email protected] ReceiVed March 2, 2007
Ruthenium-catalyzed site-specific C-H oxyfunctionalization of steroidal ethers with periodate or bromate as terminal oxidants in phosphate buffer provided the acid-sensitive C-16 hydroxy compounds in high yields. Phosphate buffer (pH 7.5) significantly inhibits formation of unwanted side products generated under more acidic reaction conditions. A key example is demonstrated at the 100 g scale. Mild synthetic methods for C-H R-oxyfunctionalization of cyclic ethers with transition metal complexes2,3 and organic oxidants4,5 are excellent in specific instances, but their scope is often limited when applied to acid-sensitive molecules. In the * Address correspondence to this author. § Current address: The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037.
(1) Part of the following series: Cephalostatin Studies 34. Oxidation 9. (2) (a) Fuchs, P. L., Ed. Handbook of Reagents for Organic Synthesis, Vol. 8, Reagents for Direct Functionalization of C-H Bonds; J. Wiley: New York, 2007. (b) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (3) (a) Stahl, S. S.; Labinger, J. A.; Bercaw, J. E. Angew. Chem., Int. Ed. 1998, 37, 2180. (b) Zerella, M.; Mukhopadhyay, S.; Bell, A. T. Chem. Commun. 2004, 1948. (c) Muehlhofer, M.; Strassner, T.; Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1745. (d) Jones, C. J.; Taube, D.; Ziatdinow, V. R.; Periana, R. A.; Nielsen, R. J.; Oxgaard, J.; Goddard, W. A., III Angew. Chem., Int. Ed. 2004, 43, 4626. (e) MacDonnell, F. M.; Fackler, N. L. P.; Stern, C.; O’Halloran, T. V. J. Am. Chem. Soc. 1994, 116, 7431. (f) Miyafuji, A.; Katsuki, T. Tetrahedron 1998, 54, 10339. (g) Miyafuji, A. Synlett 1997, 7, 836. (h) Zhang, C.; Liang, H.; Kim, E.; Shearer, J.; Helton, M.; Kim, E.; Kaderli, S.; Incarvito, C.; Karlin, K. D. J. Am. Chem. Soc. 2003, 125, 634. (i) Kelm, H.; Kruger, H. Angew. Chem., Int. Ed. 2001, 40, 2344. (j) LeCloux, D.; Barrios, A. M.; Lippard, S. J. Bioorg. Med. Chem. 1999, 7, 763. (k) Reetz, M. T.; Toellner, K. Tetrahedron Lett. 1995, 36, 9461. (l) Che, C.; Ho, C.; Lau, T. J. Chem. Soc., Dalton Trans. 1991, 5, 1259. (m) Che, C.; Leung, W. J. Chem. Soc., Chem. Commun. 1987, 18, 1376. (4) Dimethyldioxirane: (a) Arnone, A.; Cavicchioli, M.; Montanari, V.; Resnati, G. J. Org. Chem. 1994, 59, 5511. (b) Bovicelli, P.; Lupattelli, P.; Fracassi, D. Tetrahedron Lett. 1994, 35, 935. (c) Bovicelli, P.; Lupattelli, P.; Fracassi, D. Tetrahedron Lett. 1993, 34, 6103. (d) Voigt, B.; Porzel, A.; Adam, W.; Adam, G. Tetrahedron 1996, 52, 10653. (e) Wender, P. A.; Hilinski, M. K.; Mayweg, A. V. W. Org. Lett. 2005, 7, 79. (5) Methyl(trifluoromethyl)dioxirane: Curci, R.; Accolti, L.; Fiorentino, M.; Fusco, C.; Adam, W. Tetrahedron Lett. 1992, 33, 4225.
course of our goal to develop a practical synthesis of cephalostatin 1 5, there was a pressing need to develop an improved synthesis of key hemiketal 3. Our previous synthesis employed C-16 oxidation of steroidal ether 2 using DMDO (dimethyldioxirane),6 but this method is limited by the preparation of massive amounts of DMDO needed for large-scale conversion of 2 to the C14,16-diol 3 (Scheme 1).7 An additional long-term liability is the stoichiometric chromium oxidation of the C-12 mixture of alcohols 1 from the Prins reaction. Furthermore, a subsequent Cr-mediated C-H oxidation of 2 yielded 3 efficiently, but suffered consecutive production of unwanted acid-catalyzed transketalization product 6.8 Herein, we report a ruthenium(VIII)-catalyzed C-H oxidation of steroidal ethers performed under neutral reaction conditions using periodate or the much less expensiVe bromate9 as the terminal oxidant. While additional mechanistic work is required, the (3 + 2) transition state A f B recently modeled and discussed by Drees and Strassner represents an excellent working hypothesis (Scheme 2).10 Our initial survey revealed that reactions with either 3 equiv of CrO3/3 equiv of Bu4NMnO411 or 2 equiv of vanadium oxo complex 712 were unsatisfactory in terms of reaction conversion and mildness (entries 1 and 2, Table 1). Ru-catalyzed reaction of 2 with 10 mol % (Ph3P)3RuCl2 with t-BuOOH13 gave ∼20% of C14,16-diol 3, but could not be further improved (entry 3, Table 1). RuO2-catalyzed reaction with 5 equiv of Oxone and 2.5 equiv of NaHCO3 (pH 4.0) afforded only transketalized compound 6 (entry 4, Table 1). While the RuO2-catalyzed reaction with 5 equiv of Oxone and 15.5 equiv of NaHCO3 (pH 7.0) smoothly converted ketoalcohol 2 to the desired diol 3 in moderate yield (entry 5, Table 1), the short lifetime of persulfate in contact with heavy metals14 required further addition of Oxone to the reaction in 20 to 40 min intervals, resulting in exothermic bursts of reactivity, transient yellow reaction color, carbon dioxide release, inconsistent yields, and variable reaction times. In particular, the dramatic difference in entries 4 and 5 is likely due to the presence of insufficient bicarbonate to avoid the unfavorable decrease to pH 4, which triggered the observed transketalization of 3 to 6. While entry 5 gave no evidence of transketalized product 6, the reduced yield and formation of polar materials as evidenced by TLC is indicative of a less-than-ideal reaction, (6) Lee, J. S.; Fuchs, P. L. Org. Lett. 2003, 5, 2247. (7) For conversion of 18.5 g of C14-OH hecogenin acetate 2 to 3, ∼750 mL of DMDO was used. See the Supporting Information of ref 5. (8) (a) Lee, S.; Fuchs, P. L. J. Am. Chem. Soc. 2002, 124, 13978. (b) Lee, S.; Fuchs, P. L. Org. Lett. 2004, 6, 1437. (9) Kanemoto, S.; Tomika, H.; Oshima, K.; Nozaki, H. Chem. Soc. Jpn. 1986, 59, 105. (10) Drees, M.; Strassner, T. J. Org. Chem. 2006, 71, 1755. (11) Lee, S. Unpublished results. (12) (a) Minoun, H.; Saussine, L.; daire, E.; Postel, M.; Fischer, J.; Weiss, R. J. Am. Chem. Soc. 1983, 105, 3101. (b) Bonchio, M.; Conte, V.; Di Furia, F.; Modena, G. J. Org. Chem. 1989, 54, 4368. (13) (a) Murahashi, S.-I.; Naota, T.; Miyaguchi, N.; Noda, S. J. Am. Chem. Soc. 1996, 118, 2509. (b) Murahashi, S.-I.; Naota, T.; Yonemura, K. J. Am. Chem. Soc. 1988, 110, 8256. (c) Murahashi, S.-I.; Naota, T.; Kuwabara, T.; Saito, T.; Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1990, 112, 7820. (d) Murahashi, S.-I.; Oda, Y.; Naota, T. J. Am. Chem. Soc. 1992, 114, 7913. (14) DuPont Oxone monopersulfate, Technical information. 10.1021/jo070382s CCC: $37.00 © 2007 American Chemical Society
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Published on Web 06/23/2007
SCHEME 1.
Synthesis of the North 1 Segment of Cephalostatin 1
SCHEME 2.
Proposed Reaction Mechanism
TABLE 1. Screening Oxyfunctionalization Catalysts
entry
catalyst
co-oxidant
solvent
temp (°C)
time (h)f
conversion
1a 2b 3 4
CrO3 vanadium catalyst 7 10 mol % (Ph3P)3RuCl2 5 mol % RuO2‚xH2O
0.5 19 3 8
3 41%; 6 40%g 80% 6
25
9
>85% 3
25
9
>85% 3
25 25
8 10
NR 88% 3
a 3 equiv of CrO /3 equiv of Bu NMnO was used. b 2 equiv of catalyst was used. c Oxone and NaHCO were premixed. d 4 × 10-4 M EDTA‚Na 3 4 4 3 2 solution was used. e pH 7.5, 0.8 M phosphate buffer was used. f Reactions were monitored by silica gel TLC. g Isolated yield. h pH 4.0. i pH 7.0. j Bu4NIO4 is essentially insoluble in this media and the reaction has three phases; the reaction does not evidence the yellow color associated with RuO4. k Use of NMO, t-BuOOH, or NaOCl in the phosphate system gave very low yields of product.
possibly resulting from overoxidation of 3 or 6 during the miniexotherms that accompanied each addition of Oxone. Reactions with co-oxidants such as NMO, Bu4NHSO5, Bu4NIO4, and Na2S2O8 were unsuccessful (entries 6, 7, 8, and 13, Table 1). Since NaIO4 has been used as a co-oxidant in many Ru-
catalyzed oxidations,15 reaction of 5 mol % RuO2‚xH2O with 5 equiv of NaIO4 was also examined, but exclusively afforded transketalized compound 6 (entry 9, Table 1). (15) For a recent review see: Plietker, B. Synthesis 2005, 2453.
J. Org. Chem, Vol. 72, No. 15, 2007 5821
TABLE 2. Ru-Catalyzed, Site-Specific Oxyfunctionalization of Steroids
a All reactions were carried out with 5 mol % RuCl ‚xH O, EtOAc/CH CN/phosphate buffer (pH 7.5, 0.8 M) at room temperature. b 4.5 equiv of NaIO 3 2 3 4 was used. c 4 equiv of NaIO4 was used. d 4 equiv of NaBrO3 was used.
At this point, it was envisioned that addition of a base or buffer would significantly reduce the generation of 6, but adding NaHCO3 provided no success (entry 10, Table 1). Fortunately, addition of phosphate buffer completely inhibited the generation of 6 (entries 11 and 12, Table 1). Optimization of Ru-catalyzed oxyfunctionalization revealed that compound 2 could be completely converted to the desired diol 3 with only 2.5 equiv of NaIO4, using EtOAc/CH3CN/ phosphate buffer (pH 7.5, 0.8 M) ) 1:1:2. Using CH2Cl2 instead of EtOAc or different solvent ratios gave either multiple products or incomplete conversion. RuO2‚xH2O (5 mol %) and RuCl3‚ xH2O (5 mol %) were equally efficient precatalysts. Catalytic oxidation of other steroidal ethers also proved effective. Low solubility of tigogenin acetate 8 required a modified solvent, which afforded 9 in 88% yield (entry 3, Table 2). Site-specific oxyfunctionalization of hecogenin acetate and compound 11 gave C16-OH acetate 10 and compound 12 in 86% and 88% yields, respectively (entries 4 and 5, Table 2). Significantly, reaction of keto-alcohol 2 under standard conditions provided the desired keto-diol 3 in 85% yield (entry 2, Table 2). This protocol was also applicable to [5,5]-spiroketal ring systems. For example, compound 13 is converted to hemiketal 14 in 86% yield (entry 6, Table 2). Compound 15, an inseparable mixture of C25-S and C25-R diastereomers, gave hemiketals 16 and 17 in 65% and 17% yields, respectively (entry 7, Table 2). Further investigation revealed that the reaction scope could be expanded to F-ring opened compounds such as terminal olefin 18 and diacetate 21. With olefin 18, hemiketal 19 was obtained in 62% yield via concurrent oxidative cleavage of the terminal olefin along with 11% of ketone 20 (entry 8, Table 2). The 5822 J. Org. Chem., Vol. 72, No. 15, 2007
reaction of diacetate 21 rapidly provided hemiketal 22 in 30 min in 85% yield (entry 9, Table 2). Of considerable practical significance with regard to a largescale synthesis of cephalostatin analogues, the phosphate buffered ruthenium-catalyzed oxidation of diol 1 with periodate or the much more economical NaBrO3 effected both oxidation of the secondary alcohol at C-12 as well as C-H oxidation at C-16 to deliver 3 in >80% yield without formation of any transketalized product 6 (entry 14, Table 1 and entry 1, Table 2). In addition to the high yield, this process is noteworthy because it has completely avoided using chromium oxidants. In summary, we have demonstrated a very mild protocol for site-specific carbon-hydrogen oxyfunctionalization of cyclic steroidal ethers using cat. RuCl3‚xH2O/2.5 equiv of NaIO4 (or NaBrO3) and biphasic EtOAc/MeCN/phosphate buffer (pH 7.5). Acid-sensitive hemiketals, difficult to obtain via other methods, are now available in high yields. Application of this new protocol at the hundred-gram scale with 1 afforded an 88% yield of intermediate 3, which is employed for the synthesis of the cephalostatin 1 5 North hemisphere. Experimental Section Representative Procedure for Reactions Providing a Single Product (Entries 1, 2, 3, 4, 5, 8, and 9, Table 1, Procedure A). To a solution of C14-OH hecogenin acetate 2 (1.10 g, 2.25 mmol) in 5 mL of EtOAc, 5 mL of MeCN, and 10 mL of phosphate buffer (pH 7.5, 0.8 M) was added 2.5 equiv of NaIO4 (1.20 g) and the resulting slurry was stirred for 5 min at room temperature. RuCl3‚ xH2O (5 mol %; 23.3 mg)16 was added at once and the reaction was stirred for 10 h at rt. When TLC showed no starting material remained in the reaction, 5 mL of diethyl ether was added to quench
the remaining ruthenium peroxo species (yellow RuO4 turned to black RuO2).17 After 10 min of stirring (potassium iodide strip showed no peroxo species left in the reaction), the reaction was poured into a silica gel pad and filtered with EtOAc/nHex ) 1:3 to 1:1. The resulting organic solution was evaporated under reduced pressure to give diol 3 (962.3 mg, 1.91 mmol, 85%) as a white solid (mp 179-180 °C, toluene); 1H NMR (300 MHz, CDCl3) δ 4.60-4.65 (m, 1H), 3.44-3.60 (m, 3H), 3.21 (d, J ) 8.5 Hz, 1H), 2.24-2.44 (m, 3H), 2.02-2.21 (m, 2H), 1.94 (s, 3H), 1.17 (s, 3H), 1.00 (d, J ) 6.9 Hz), 0.87 (s, 3H), 0.80 (d, J ) 6.1 Hz); 13C NMR (75 MHz, CDCl3) δ 211.9, 170.2, 113.1, 107.2, 86.1, 72.8, 67.6, 61.7, 58.2, 46.4, 46.3, 44.1, 43.4, 39.1, 36.6, 36.2, 35.8, 33.6, 31.6, 29.8, 28.2, 27.8, 27.2, 26.9, 21.1, 16.8, 14.5, 14.2, 11.6; HRMS (EI) for C29H44O7 [M]+ calcd 504.3087, found 504.3068. Representative Procedure for Reactions Providing Two Products (Entries 6 and 7, Table 1, Procedure B). To a C25S/-R ) 4.1:1 mixture of benzoate 15 (102.6 mg, 0.15 mmol) in 0.5 mL of EtOAc, 0.5 mL of MeCN, and 1 mL of phosphate buffer (pH 7.5, 0.8 M) was added 2.5 equiv of NaIO4 (78.5 mg) and the resulting slurry was stirred for 5 min at rt. RuCl3‚xH2O (5 mol %; 1.5 mg) was added at once and the reaction was stirred at rt. After 12 h, it was checked that no oxidant was left in the reaction by potassium iodide strip. NaIO4 (1 equiv) was added twice in a 6 h interval to complete the reaction. Diethyl ether (1 mL) was added to quench the reaction and the resulting slurry was stirred for an additional 10 min at rt. The reaction was poured into a silica gel pad and filtered with EtOAc only. After removal of solvent in vacuo, the residue was purified by flash column chromatography (EtOAc/nHex ) 1:4) to give the corresponding C25-S hemiketal 16 (68.2 mg, 0.09 mmol, 65%) and C25-R hemiketal 17 (17.8 mg, 0.02 mmol, 17%). C25-R hemiketal 17: colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.94-7.98 (m, 4H), 7.51-7.55 (m, 2H), 7.37-7.43 (m, 4H), 4.94 (dd, J ) 10.8, 4.1 Hz, 1H), 4.63-4.70 (m, 1H), 4.08 (dd, J ) 29.9, 11.1 Hz, 2H), 2.15 (q, J ) 7.0 Hz, 1H), 1.99 (s, 3H), 1.48 (s, 3H), 0.95 (s, 3H), 0.83 (s, 3H), 0.71 (d, J ) 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.6, 166.3, 165.6, 133.1, 132.9, 130.6, 129.9, 129.5, 129.4, 128.4, 128.3, 121.6, 115.1, 83.5, 81.6, 73.4, 69.6, 69.4, 53.7, 52.4, 46.4, 44.4, 39.4, 37.9, 36.5, 35.6, 33.9, 33.8, 33.2, 31.4, 28.3, 27.2, 26.9, 25.6, 21.4, 13.9, 12.1, 10.7; HRMS (ESI) C43H54O9Na [M + Na]+ calcd 737.3666, found 737.3669.
Large-Scale Preparation of 14,16-Dihydroxyhecogenin Acetate 3. To a 5-L flask equipped with mechanical stirrer and a thermometer was added the C-12,14 dihydroxy hecogenin acetate 1 (100 g, 204 mmol), NaBrO3 (131 g, 868 mmol, 4.25 equiv), phosphate buffer (1000 mL, pH 7.5, 0.8 M), ethyl acetate (500 mL),and acetonitrile (500 mL). The flask was placed in a water bath. The mixture was stirred for 30 min before RuCl3‚3H2O (1.86 g, 7.14 mmol, 3.5 mol %)18 was added. The inside temperature was maintained between 22 and 24 °C. The mixture was stirred for ∼30 h and monitored by TLC. According to the TLC, the C-12 OH was oxidized to the ketone in less than 8 h and then more slowly converted to the desired product. By the end of the reaction, the intermediate C-12 ketone had been almost completely consumed as judged by TLC. Ice was added to the reaction mixture and bath to lower the temperature to
