Abstract:
9-dihydro-13-acetylbaccatin III, one of the chemicals obtained from  Taxus canadensis  is used to produce, inter alia, 10-decetylbaccatin III, a useful intermediate for the preparation of paclitaxel and analogues thereof The 9-dihydro-13-acetylbaccatin III is converted into the 10-deacetylbaccatin III by a simple three step process involving (a) replacement of the C-7 hydroxyl group of tho 9-dihydro compound with a protecting group, (b) the oxidizing of the C-7 protected compound to produce a C-9 ketone, and (c) the deprotecting of the C-9 ketone to produce 10-deacetylbaccatin III.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to a method of converting 9-dihydro-13-acetylbaccatin III to 10-deacetylbaccatin III. 
     2. Discussion of the Prior Art 
     Many taxanes, e.g. paclitaxel and docetaxol are being aggressively studied and tested for use as cancer treating agents. As described in many publications such as Canadian Patent Application No. 2,188,190, published Apr. 18, 1998 in the name of Zamir et al, which is incorporated herein by reference, the taxanes are active in various tumor systems. Taxanes are substances occurring naturally in yew trees such as  Taxus canadensis , which is common in Eastern Canada and the United States. One of the chemicals extracted from the needles of  Taxus canadensis  is 9-dihydro-13-acetylbaccatin III, which is used to produce, inter alia, 10-deacetylbaccatin III—a useful intermediate for the preparation of paclitaxel and analogues thereof. 
     Various methods of converting 9-dihydro-13-acetylbaccatin III into 10-deacetylbaccatin III have been proposed (see, for example the above mentioned CA 2,188,190). However, it has been found that such methods result in poor yields of finished product. Thus, a need still exists for an efficient method for converting 9-dihydro-13 acetylbaccatin III to 10-deacetylbaccatin III (DAB III). 
     GENERAL DESCRIPTION OF THE INVENTION 
     The object of the present invention is to meet the above defined need by providing a relatively efficient method of converting 9-dihydro-13-acetylbaccatin III to DAB III. 
     Accordingly, the invention relates to a method of converting 9-dihydro-13-acetylbaccatin III into 10-deacetylbaccatin III comprising the steps of 
     (a) protecting the C-7 group of 9-dihydro-13-acetylbaccatin III by replacing the C-7 hydroxyl group with a protecting group; 
     (b) oxidizing the C-9 hydroxyl group in the resulting product to produce a C-9 ketone; and 
     (c) deprotecting the C-9 ketone to form 10-deacetylbaccatin III. 
     DESCRIPTION OF THE PREFERRED EMBODIMENT 
     General Procedure 
     The first step in the method of the present invention involves the dissolving of 9-dihydro-13-acetylbaccatin III in dry solvent such as CH 2 Cl 2 , CHCl 3 , THF, Et 2 O or Bz. A dry base, e.g. pyridine, TEA or NaHCO 3  and/or a catalytic amount of p-N,N-dimethylaminopyridine (DMAP) is added to the solution, followed by 1-6 equivalents of a protecting reagent (TMSCl, TESCl or Ac 2 O) at a temperature of between room temperature and −78° C. The mixture is stirred continuously for 0.5-6 hours before being quenched by the addition of water. The mixture is poured into ethyl acetate and washed sequentially with dilute acid, water and brine, and dried over magnesium sulfate. The solution is evaporated under vacuum to give a crude solid (7-OH protected-9-baccatin III up to 91% yield) 
     A 3,5-disubstituted pyrazole such as 3,5-dimethyl-pyrazole is added to a suspension of metal oxide, e g. chromium trioxide (2-20 equivalents) in a solvent. Suitable solvents include CH 2 Cl 2 , CHCl 3 , THF, Et 2 O and Bz. The mixture is stirred at room temperature for at least 15 minutes. A 7-OH protected 9-dihydro-13-acetylbaccatin III in the same solvent is added to the solution in one portion, and the mixture is stirred for 0.5 hour to one week to produce a C-9 ketone in up to 90% yield. 
     The C-9 ketone is dissolved in a suitable organic solvent such as an alcohol, an ether, CH 2 Cl 2  or CHCl 3  with or without water, and reacted with an acid, a base, or a strong nucleophile, such as a bicarbonate, a carbonate, ammonia, an amine, a hydrazine, a hydroxide, a hydroperoxide or an alyllithium. The reaction mixture thus produced is stirred at a controlled temperature (0° C. to solvent reflux). The reaction is monitored by thin-layer chromatography until it has progressed satisfactorily. Routine liquid extraction is performed followed by solvent evaporation to produce crude 10-deacetylbaccatin III in up to 85% yield. 
     The reaction scheme for the above described general procedure is as follows                           
     In accordance with a preferred embodiment of the invention, R in the above formula is an acetyl group. The reaction scheme for the preferred embodiment is as follows                           
    
    
     EXAMPLES 
     Selective Protection of 7-hydroxyl Group of 9-dihydro-13-acetylbaccatin III 
     
       
                 
         
             
             
         
      
     
     Several experiments were carried out using a variety of reagents to produce 7-OH protected-9-baccatin III with different protecting groups in the 7-position. The results of the experiments are listed in Tables 1 and 2 (for the sake of simplicity, all tables are found at the end of this description). 
     Additional experiments were conducted in which R in the above formulae was an acetyl group.                           
     In the method of producing 9-dihydro-7,13-diacetylbaccatin III, 9-dihydro-13-acetylbaccatin III (0 1 mmole) was dissolved in 2.5 mL of dry methylene chloride and cooled to −23° C. using a slurry of CCl 4  and liquid nitrogen. 0.6 mmole of dry pyridine and a catalytic amount of DMAP (5% in mole) were added to the mixture followed by 0.3 mmole of acetic anhydride. The mixture was stirred for 1 5 h and then the reaction was quenched by the addition of 5.0 mL of water. The mixture was poured into 25 mL of ethyl acetate and washed sequentially with 15 mL of 1% HCl, 15 mL water and mL brine, and dried over MgSO 4 . The solution was evaporated under vacuum and gave a crude solid (95% yield, 91% 9-dihydro-7,13-diacetylbaccatin III). The details and results of similar experiments are listed in Table 2. 
     Oxidation of the Protected 9-dihydro-13 acetylbaccatin III 
     
       
                 
         
             
             
         
      
     
     Details of experiments using a variety of reagents and conditions are listed in Table 3 
     Subsequent oxidation experiments (which are listed as Examples 45 to 49 in Table 4) were conducted using 9-dihydro-7,13-diacetylbaccatin III as the starting material.                           
     In one experiment, 3 3 mmole of 3,5-dimethylpyrazole (DMP) was added to a suspension of 3.0 mmole of chromium trioxide (CrO 3 ) in CH 2 Cl 2 , and the mixture was stirred for 15 minutes. 0.15 mmole of 9-dihydro-7,13-diacetylbaccatin III in the same solvent was added to the resulting DMP/CrO3 solution, and the mixture thus produced was stirred for two days. The mixture was filtered through silicia gel and evaporated to yield a solid product. 
     Details of the experiments (Examples 45 to 49) are found in Table 4.                           
     Several experiments were conducted using various reagents and conditions. Details of the experiments are listed in Examples 50 to 75 in Tables 5 and 6. 
     Additional experiments were carried out using 7,13-diacetylbaccatin III as the starting material to produce the desired product, DAB-III. In a specific reaction of this type, a solution of 4.5 mg (0.00675 mmole) of 7,13-diacetylbaccatin III in 0.08 mL of 95% ethanol was cooled to 7° C. 0 08 ml of hydrazine hydrate was added to the solution, which was then kept at 7° C. for 141 5 hours. The resulting mixture was diluted with ethyl acetate, and then washed sequentially with saturated aqueous ammonium chloride, water and brine. The organic layer was dried over MgSO 4 , filtered and evaporated in vacuo to yield 4.2 mg of crude product. NMR spectroscopy revealed that the product consisted mainly of 10-deacetylbaccatin III plus trace amounts of by-products. The conditions and results of the hydrazine-based hydrolysis experiments are listed in Examples 76 to 112 in Table 6. 
     From the foregoing, and in particular from the specific examples, it is readily apparent that the preferred method of converting 9-dihydro-13-acetylbaccatin III into 10-deacetylbaccatin III involves the steps of: 
     (a) protecting the C-7 position of the 9-dihydro-13-acetylbaccatin III with an acetyl group using acetic anydride in the presence of a base and DMAP to produce 9-dihydro-7,13-diacetylbaccatin III, 
     (b) oxidizing the 9-dihydro-7,13-diacetylbaccatin III using CrO 3 /DMP to produce 7,13-diacetylbaccatin III, (the choice of oxidant here is important to success),and 
     (c) replacing the C-7, C-10 and C-13 OAc groups in the 7,13-diacetylbaccatin III with OH groups using hydrazine hydrate. 
     
       
         
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Example 
                 Reagents and Conditions 
                 Yield 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 R = TES 
                 TES-Cl (7.5 eq), pyr, CH 2 Cl 2 , RT, 24h 
                   43% 
               
               
                 2 
                 R = TES 
                 TES-Cl (5 eq), TEA, CH 2 Cl 2 , RT, 2.5H 
               
               
                 3 
                 R = TES 
                 TES-Cl (3 eq), pyr, CH 2 Cl 2 , RT, 24h 
               
               
                 4 
                 R = TES 
                 TES-Cl (5 eq), TEA, CH 2 Cl 2 , −89° C., 4h 
                 &gt;90% 
               
               
                 5 
                 R = TES 
                 TES-Cl (5 eq), TEA, CH 2 Cl 2 , −89° C., 2.5h 
                 &gt;95% 
               
               
                 6 
                 R = TES 
                 TES-Cl (5 eq), TEA, CH 2 Cl 2 , −89° C. 
                 &gt;97% 
               
               
                 7 
                 R = Ac 
                 Ac 2 O (10 eq), TEA, DMAP, CH 2 Cl 2 , −89° C. 
                 &gt;51% 
               
               
                 8 
                 R = CBz 
                 Cl 2 CBz (4 eq), TEA, CH 2 Cl 2 , RT, 20h 
                 a 
               
               
                 9 
                 R = CO 2 Me 
                 MeOCOCl (2 eq), DMAP, TEA, CH 2 Cl 2 , RT, 24h 
                 b 
               
               
                 10 
                 R = CO 2 Me 
                 MeOCOCl (5 eq), TMP, CH 2 Cl 2 , RT, 24h 
                 c 
               
               
                 11 
                 R = CO 2 CF 3   
                 (CF 3 CO) 2 O (5 eq), Pyr, RT, 24h 
                 d 
               
               
                 12 
                 R = Ac 
                 Ac 2 O (5 eq), Pyr, DMP, CH 2 Cl 2 , 0° C., 6h 
                 &gt;50% 
               
               
                 13 
                 R = CO 2 CCl 3   
                 CCl 3 COCl (2 eq), TEA, CH 2 Cl 2 , 0° C., 24 h 
                 e 
               
               
                   
               
               
                 a: no reaction  
               
               
                 b: formed carbonate with 9-OH  
               
               
                 c: major product 7,9-carbonate  
               
               
                 d: decomposed  
               
               
                 e: low yield  
               
             
          
         
       
     
     
       
         
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                   
                 9-DHB 
                 Ac 2 O 
                 Solvents 
                   
                 Temperature 
                 Reaction 
                 Yield 
                 7-Acetyl 
               
               
                 Example 
                 (mmole) 
                 (mmole) 
                 (mL) 
                 DMAP 
                 (° C.) 
                 Time 
                 (%) 
                 (%) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 14 
                 0.25 
                 0.375 
                 Pyr (5) 
                 Yes 
                 0-RT 
                 20   
                 55 
                 76 
               
               
                 15 
                 0.1 
                 0.3 
                 Pyr (2.5) 
                 Yes 
                 0 
                 1:20′ 
                 &gt;95 
                 78-82 
               
               
                 16 
                 0.1 
                 0.3 
                 Pyr (2.5) 
                 Yes 
                 RT 
                 1:20′ 
                 &gt;95 
                 55-69 
               
               
                 17 
                 0.1 
                 0.3 
                 TEA (2), THF (1) 
                 Yes 
                 0 
                 2   
                 &gt;95 
                 42-62 
               
               
                 18 
                 0.1 
                 0.3 
                 Pyr (2.5) 
                 Yes 
                 0 
                 53′  
                 &gt;90 
                 71-83 
               
               
                 19 
                 0.1 
                 0.3 
                 Pyr (2.5), THF (1) 
                 Yes 
                 −23 
                 3   
                 &gt;92 
                 84-92 
               
               
                 20 
                 0.1 
                 0.3 
                 Pyr (1), DCM (2) 
                 Yes 
                 −23 
                 1.5 
                 &gt;97 
                 85-89 
               
               
                 21 
                 0.1 
                 0.3 
                 Pyr (1), DCM (2) 
                 Yes 
                 −43 
                 1.5 
                 &gt;93 
                 85-95 
               
               
                 22 
                 0.1 
                 0.3 
                 Pyr (6 eq), DCM (2.5) 
                 Yes 
                 −23 
                 1.5 
                 &gt;95 
                 87-94 
               
               
                 23 
                 0.1 
                 0.3 
                 TEA (6 eq), DCM (2.5) 
                 Yes 
                 −23 
                 1.5 
                 &gt;96 
                 79 
               
               
                   
               
             
          
         
       
     
     
       
         
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Example 
                 Reagents and Conditions 
                 Yield 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 24 
                 R = TES 
                 CrO 3 Pyr 2 (12 eq), CH 2 Cl 2 , RT 
                 a 
               
               
                 25 
                 R = TES 
                 DMSO (4.8 eq), (COCl) 2  (2.2 eq), TEA (5 eq), CH 2 Cl 2   
                 a 
               
               
                 26 
                 R = TES 
                 DMSO (4.8 eq), (COCl) 2  (2.2 eq), TEA (5 eq), CH 2 CL 2   
                 a 
               
               
                 27 
                 R = TES 
                 DMSO (9.6 eq), (COCl) 2  (4.4 eq), TEA (10 eq), CH 2 CL 2   
                 a 
               
               
                 28 
                 R = TES 
                 DMSO (2.2 eq), (COCl) 2  (2.2 eq), TEA (5 eq), CH 2 CL 2   
                 a 
               
               
                 29 
                 R = TES 
                 DMSO (2.4 eq), (COCl) 2  (2.2 eq), TEA (5 eq), CH 2 CL 2   
                 a 
               
               
                 30 
                 R = TES 
                 DMSO (9.6 eq), (COCl) 2  (4.4 eq), TEA (10 eq), CH 2 CL 2   
                 a 
               
               
                 31 
                 R = TES 
                 DMSO (9.6 eq), (COCl) 2  (4.4 eq), TEA (10 eq), CH 2 CL 2   
                 a 
               
               
                 32 
                 R = TES 
                 DMSO (5 eq), (COCl) 2  (5.5 eq), TEA (6 eq), CH 2 CL 2   
                 a 
               
               
                 33 
                 R = TES 
                 DMSO (5.5 eq), (COCl) 2  (5 eq), TEA (6 eq), CH 2 CL 2   
                 a 
               
               
                 34 
                 R = TES 
                 NaClO 2 , NaH 2 PO 4 , 1-BuOH, 2-Methyl-2-butene 
                 b 
               
               
                 35 
                 R = TES 
                 Al(OPr-) 3 , Acetone, C 8 F 5 OH 
                 b 
               
               
                 36 
                 R = TES 
                 CrO 3  (8 eq), 3.5-DMP (6.3 eq), CH 2 Cl 2   
                 b 
               
               
                 37 
                 R = TES 
                 Br 2 , HMPA, CH 2 Cl 2   
               
               
                 38 
                 R = TES 
                 Ca(OCl) 2  HOAc 
                 b 
               
               
                 39 
                 R = Ac 
                 CrO 3  (10 eq), 3,5-DMP (12 eq), CH 2 Cl 2   
                 85% 
               
               
                 40 
                 R = Ac 
                 DMSO (12 eq), (COCl) 2  (10 eq), TEA (20 eq), CH 2 Cl 2   
                 b 
               
               
                 41 
                 R = Ac 
                 CrO 3 -Pyr 3  (6 eq), CH 2 Cl 2 , RT, 2 days 
                 b 
               
               
                 42 
                 R = TES 
                 CrO 3  (10 eq), 1H-Tetrazole (10.2 eq), CH 2 Cl 2   
                 a 
               
               
                 43 
                 R = TES 
                 CrO 3  (10 eq), 2-(1H)-Pyridone (10.2 eq), CH 2 Cl 2   
                 b 
               
               
                 44 
                 A = Ac 
                 MnO 2  (20 eq), CH 2 Cl 2 , RT, 2 days 
                 b 
               
               
                   
               
               
                 a: decomposed  
               
               
                 b: no reaction  
               
             
          
         
       
     
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                   
                   
                 Weight of 
                 Yield 
               
               
                 Example 
                 Reagents and Conditions 
                 SM (mg) 
                 % 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 45 
                 CrO 3  (20 eq), DMP (22 eq), CH 2 Cl 2 , RT, 2 days 
                 43.2 
                 80-90 (a) 
               
               
                 46 
                 CrO 3  (2.7 eq), DMP (2.7 eq), CH 2 Cl 2 , RT, 3 days 
                 20.4 
                 80-90 (a) 
               
               
                 47 
                 CrO 3  (10 eq), DMP (11 eq), CH 2 Cl 2 , RT, 7 days 
                 250.0 
                 68 (b,c) 
               
               
                 48 
                 CrO 3  (20 eq), DMP (22 eq), CH 2 Cl 2 , RT, 5 eq CrO 3 - 
                 100.9 
                 80-90 (a) 
               
               
                   
                 DMP complex added after 1 hr of rxn, 2 days 
               
               
                 49 
                 CrO 3  (3 eq), DMP (3 eq), CH 2 Cl 2 , RT, 3 eq CrO 3 -DMP 
                 103.2 
                 80-90 (a) 
               
               
                   
                 complex added after 23 hrs of rxn, 26 hrs 
               
               
                   
               
               
                 sm: starting material  
               
               
                 a: yield based on nmi of crude product  
               
               
                 b: yield based on isolated pure product  
               
               
                 c: side products were formed  
               
             
          
         
       
     
     
       
         
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Example 
                 Reagents and Conditions 
                 Notes 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 50 
                 R = Ac 
                 CH 3 Li (15 eq), THF, −89° C., ca 2h 
                 a 
               
               
                 51 
                 R = Ac 
                 H 2 NNH 2 , H 2 O, 95% EtOH, 13h 
                 (4) and (5)(b) 
               
               
                 52 
                 R = Ac 
                 H 2 NNH 2 , H 2 O, 95% EtOH, 20h 
                 (4) and (5)(b) 
               
               
                 53 
                 R = Ac 
                 n-BuLi (6 eq), THF, −89° C., ca 2h 
                 (6)(c) 
               
               
                 54 
                 R = Ac 
                 H 2 NNH 2 , MeOH, H 2 O, 3 days 
                 (4) and (5)(b) 
               
               
                 55 
                 R = Ac 
                 NH 3 , H 2 O, MeOH, H 2 O, 4 days 
                 Decomposed 
               
               
                 56 
                 R = Ac 
                 NHMe 2 , MeOH, H 2 O, 20h 
                 Decomposed 
               
               
                 57 
                 R = Ac 
                 NMe 3 , MeOH, H 2 O, 20h 
                 Decomposed 
               
               
                 58 
                 R = Ac 
                 NaHCO 3 , MeOH, 3 days at RT, 3.5h at 50° C. 
                 Decomposed 
               
               
                 59 
                 R = Ac 
                 NHEt 2 , MeOH, H 2 O, ca 20h 
                 Decomposed 
               
               
                 60 
                 R = Ac 
                 H 2 NNHCOPh, MeOH, 2 days at RT, ca 5h at 50° C. 
                 No reaction 
               
               
                 61 
                 R = Ac 
                 DMAP, MeOH, ca 2 days at 50° C. 
                 No reaction 
               
               
                 62 
                 R = Ac 
                 NaHCO 3 , H 2 O 2 , THF, 3 days at RT 
                 No reaction 
               
               
                 63 
                 R = Ac 
                 H 2 NNH 2 , MeOH, ca 26h 
                 Complicated 
               
               
                 64 
                 R = Ac 
                 n-BuLi (6 eq), THF, −89° C., ca 0.5h 
                 (6)(c) 
               
               
                 65 
                 R = Ac 
                 n-BuLi (6 eq), THF, −40 to −45° C., ca 1h 
                 (6)(c) 
               
               
                 66 
                 R = Ac 
                 n-BuLi (6 eq), CH 2 Cl 2 , −40 to −45° C., ca 5h 
                 Complicated 
               
               
                 67 
                 R = Ac 
                 LiOh, H 2 O 2 , THF, 20h at RT 
                 (5)(d) 
               
               
                 68 
                 R = Ac 
                 sec-BuLi (20 eq), THF, −40 to −45° C., at 0.5, 1 day at rt 
                 No reaction 
               
               
                 69 
                 R = Ac 
                 n-BuLi (3 eq), THF, −40 to −45° C., ca 5h 
                 Complicated 
               
               
                 70 
                 R = Ac 
                 n-BuOLi (10 eq), THF, −40 to −45° C., ca 6h 
                 Complicated 
               
               
                 71 
                 R = Ac 
                 H 2 NNH 2 , MeOH, ca 26h at 50-55° C. 
                 Decomposed 
               
               
                 72 
                 R = Ac 
                 LiOH, H 2 O 2 , THF, 20h at RT 
                 (5)(d) 
               
               
                 73 
                 R = Ac 
                 H 2 NNH 2 , THF, ca 26h at RT 
                 Decomposed 
               
               
                 74 
                 R = Ac 
                 H 2 NNH 2 , 95% EtOH, 50-55° C., 24h 
                 Decomposed 
               
               
                 75 
                 R = Ac 
                 n-BuLi (6 eq), THF, −40 to −50° C., ca 0.5h 
                 (5)(d) 
               
               
                   
               
               
                 a: complicated product, reagent (CH 3 Li) was not titrated  
               
               
                 b: complicated products containing (5) as a major one and minor (6) plus other unknown products  
               
               
                 c: compound (4) as a major product plus other unknown products  
               
               
                 d: compound (5) as a major one, n-Butylithium was not titrated  
               
             
          
         
       
     
     
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                   
                 Amount of 
                 Reagents 
                   
                   
               
               
                   
                 7.13-DABIII 
                 and 
                   
                   
               
               
                 Example 
                 (mg) 
                 Solvent 
                 Conditions 
                 Products (Yield) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 76 
                 9.1 
                 HMH, 
                 room temperature, 
                 a(55.4%) 
               
               
                   
                   
                 95% EtOH 
                 25.5 hours 
                 b(27.0%) 
               
               
                   
                   
                   
                   
                 plus 1 by-product 
               
               
                 77 
                 1.9 of a 
                 HMH, 
                 room temperature, 
                 starting material 
               
               
                   
                   
                 95% EtOH 
                 71 hours 
               
               
                 78 
                 15.1 
                 HMH, 
                 room temperature, 
                 a(53.0%) 
               
               
                   
                   
                 95% EtOH 
                 72.5 hours 
                 b(18.0%) 
               
               
                   
                   
                   
                   
                 plus 1 by-product 
               
               
                 79 
                 2.4 
                 HMH, 
                 45-50° C., 
                 a(50.0%) 
               
               
                   
                   
                 95% EtOH 
                 23.5 hours 
                 b(49.4%) 
               
               
                   
                   
                   
                   
                 plus 1 by-product 
               
               
                 80 
                 10.8 
                 DIBAL, −78° C. room 
                 b(42.5%) 
               
               
                   
                   
                 dry THF 
                 temperature, 
                 c(20.2%) 
               
               
                   
                   
                   
                 22 hours 
                 plus 1 by-product 
               
               
                 81 
                 5.6 
                 HMH 
                 room temperature 
                 6.5 mg of crude 
               
               
                   
                   
                 dry THF 
                 30 hours 
                 a 
               
               
                   
                   
                   
                   
                 starting material 
               
               
                 82 
                 6.1 
                 Anhydrous 
                 room temperature 
                 7.1 mg of crude 
               
               
                   
                   
                 hydraxine, 
                 30 hours 
                 a 
               
               
                   
                   
                   
                   
                 starting material 
               
               
                 83 
                 7.0 
                 HMH 
                 room temperature 
                 b(42.0%) 
               
               
                   
                   
                 0.75 eq. DMAP, 
                 50 hours 
                 plus 2 by-products 
               
               
                   
                   
                 95% EtOH 
                   
               
               
                 84 
                 25.0 
                 HMH 
                 room temperature 
                 a(37.0%) 
               
               
                   
                   
                 0.5 eq. DMAP 
                 48.5 hours 
                 b(34.9%) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 1 by-product 
               
               
                 85 
                 20.6 
                 HMH 
                 40° C., 22 hours 
                 decomposition 
               
               
                   
                   
                 0.5 eq. DMAP 
               
               
                   
                   
                 95% EtOH 
               
               
                 86 
                 19.9 
                 HMH 
                 room temperature 
                 a(17.8%) 
               
               
                   
                   
                 0.75 eq. DMAP 
                 69 hours 
                 b(26.6%) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 2 by-products 1,2   
               
               
                 87 
                 20.6 
                 HMH 
                 room temperature 
                 a(11.7%) 
               
               
                   
                   
                 2.5 eq. DMAP 
                 22 hours 
                 b(22.1%) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 3 by-products 2   
               
               
                 88 
                 5.8 
                 HMH 
                 0-−4° C. 
                 7.4 mg crude 
               
               
                   
                   
                 2.5 eq. DMAP 
                 334 hours 
                 a(major) 
               
               
                   
                   
                 95% EtOH 
                   
                 b(minor) 
               
               
                 89 
                 5.8 
                 HMH 
                 room temperature 
                 a(33.5%) 
               
               
                   
                   
                 2.5 eq. DMAP 
                 73 hours 
                 b(65.8%) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 1 by-product 2   
               
               
                 90 
                 6.4 
                 HMH 
                 room temperature 
                 a(82.5%) 
               
               
                   
                   
                 2.5 eq. DMAP 
                 75 hours 
                 b(38.5%) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 1 by-product 2   
               
               
                 91 
                 4.7 of b 
                 HMH 
                 room temperature 
                 3.9 mg of crude 
               
               
                   
                   
                 2.5 eq. DMAP 
                 187 hours 
                 starting material 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 3 other 
               
               
                   
                   
                   
                   
                 products 1,2   
               
               
                 92 
                 6.9 
                 HMH 
                 room temperature 
                 a(36.4%) 
               
               
                   
                   
                 5 eq. Pyridine 
                 70 hours 
                 b(57.0%) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 1 by-product 2   
               
               
                 93 
                 5.7 
                 HMH 
                 7° C., 335 hours 
                 7.6 mg of crude 
               
               
                   
                   
                 2.5 eq. DMAP 
                   
                 a(minor) 
               
               
                   
                   
                 95% EtOH 
                   
                 b(major) 
               
               
                   
                   
                   
                   
                 plus 2 by-products 1,2   
               
               
                 94 
                 3.7 
                 HMH 
                 room temperature 
                 3.5 mg of crude 
               
               
                   
                   
                 2.5 eq. Imidazole 
                 70 hours 
                 a(minor) 
               
               
                   
                   
                 95% EtOH 
                   
                 b(major) 
               
               
                   
                   
                   
                   
                 plus 2 by-products 1,2   
               
               
                 95 
                 3.6 
                 HMH 
                 room temperature 
                 3.6 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 70 hours 
                 a(very minor) 
               
               
                   
                   
                 Diisopropylamine 
                   
                 b(major) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 2 by-products 1,2   
               
               
                 96 
                 3.3 
                 HMH 
                 room temperature 
                 4.2 mg of crude 
               
               
                   
                   
                 2.5 eq. collidine 
                 71 hours 
                 starting material 
               
               
                   
                   
                 95% EtOH 
                   
                 (very minor) 
               
               
                   
                   
                   
                   
                 a(major) 
               
               
                   
                   
                   
                   
                 b(minor) 
               
               
                   
                   
                   
                   
                 plus 2 by-products 1,2   
               
               
                 97 
                 3.5 
                 HMH 
                 room temperature 
                 3.7 mg of crude 
               
               
                   
                   
                 2.5 eq. TEA 
                 71 hours 
                 starting material 
               
               
                   
                   
                 95% EtOH 
                   
                 (very minor) 
               
               
                   
                   
                   
                   
                 a(major) 
               
               
                   
                   
                   
                   
                 b(minor) 
               
               
                   
                   
                   
                   
                 plus 2 by-products 
               
               
                   
                   
                   
                   
                 (major) 1,2   
               
               
                 98 
                 3.3 
                 HMH 
                 room temperature 
                 3.9 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 71.5 hours 
                 starting 
               
               
                   
                   
                 N-methylmorpholine 
                   
                 material (minor) 
               
               
                   
                   
                 95% EtOH 
                   
                 a(major) 
               
               
                   
                   
                   
                   
                 b(minor) 
               
               
                   
                   
                   
                   
                 plus 2 by-products 1,2   
               
               
                 99 
                 3.8 
                 HMH 
                 room temperature 
                 4.3 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 72 hours 
                 starting 
               
               
                   
                   
                 3-Quinuclidinol 
                   
                 material (major) 
               
               
                   
                   
                 95% EtOH 
                   
                 a(major) 
               
               
                   
                   
                   
                   
                 b(minor) 
               
               
                   
                   
                   
                   
                 plus 1 by-products 1   
               
               
                 100 
                 2.7 
                 HMH 
                 room temperature 
                 2.7 mg of crude 
               
               
                   
                   
                 2.5 eq. Imidazole 
                 23.5 hours 
                 a(minor) 
               
               
                   
                   
                 95% EtOH 
                   
                 b(major) 
               
               
                   
                   
                   
                   
                 plus 1 by-product 
               
               
                   
                   
                   
                   
                 (major) 2   
               
               
                 101 
                 2.7 
                 HMH 
                 room temperature 
                 3.7 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 23 hours 
                 a(minor) 
               
               
                   
                   
                 Diisopropylamine 
                   
                 b(major) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 2 by-products 
               
               
                   
                   
                   
                   
                 (major) 2   
               
               
                 102 
                 3.7 
                 HMH 
                 room temperature 
                 4.1 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 25 hours 
                 a(minor) 
               
               
                   
                   
                 Diisopropylamine 
                   
                 b(major) 
               
               
                   
                   
                 acetontrile 
                   
                 plus 3 by-products 1,2   
               
               
                 103 
                 3.4 
                 HMH 
                 room temperature 
                 3.6 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 25 hours 
                 a(minor) 
               
               
                   
                   
                 Diisopropylamine 
                   
                 b(major) 
               
               
                   
                   
                 DMG 
                   
                 plus 3 by-products 1,2   
               
               
                 104 
                 3.7 
                 HMH 
                 room temperature 
                 4.8 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 25.5 hours 
                 a(minor) 
               
               
                   
                   
                 Diisopropylamine 
                   
                 b(major) 
               
               
                   
                   
                 DMSO 
                   
                 plus 3 by-products 1,2   
               
               
                 105 
                 3.6 
                 HMH 
                 room temperature 
                 5.0 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 25.5 hours 
                 a(minor) 
               
               
                   
                   
                 Diisopropylamine 
                   
                 b(major) 
               
               
                   
                   
                 HMPA 
                   
                 plus 3 by-products 1,2   
               
               
                 106 
                 4.5 
                 HMH 
                 room temperature 
                 4.6 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 197 hours 
                 b 
               
               
                   
                   
                 Diisopropylamine 
                   
                 plus 3 by-products 
               
               
                   
                   
                 MEOH 
               
               
                 107 
                 3.6 
                 HMH 
                 room temperature 
                 4.2 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                 197 hours 
                 b 
               
               
                   
                   
                 Diisopropylamine 
                   
                 plus 3 by-products 
               
               
                   
                   
                 iso-Butanol 
               
               
                 108 
                 4.5 
                 HMH 
                 7° C., 141.5 hours 
                 4.2 mg of crude 
               
               
                   
                   
                 2.5 eq. DMAP 
                   
                 virtually no a 
               
               
                   
                   
                 95% EtOH 
                   
                 b(major) 
               
               
                   
                   
                   
                   
                 plus 2 by-products 
               
               
                   
                   
                   
                   
                 (minor) 
               
               
                 109 
                 5.0 
                 HMH 
                 7° C., 141.5 hours 
                 5.4 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                   
                 virtually no a 
               
               
                   
                   
                 Imidazole 
                   
                 b(major) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 2 by-products 
               
               
                   
                   
                   
                   
                 (minor) 
               
               
                 110 
                 4.7 
                 HMH 
                 7° C., 142 hours 
                 4.2 mg of crude 
               
               
                   
                   
                 2.5 eq. 
                   
                 virtually no a 
               
               
                   
                   
                 Diisopropylamine 
                   
                 b(major) 
               
               
                   
                   
                 95% EtOH 
                   
                 plus 2 by-products 
               
               
                   
                   
                   
                   
                 (minor) 
               
               
                 111 
                 4.5 
                 HMH 
                 4° C., 42 hours 
                 a 
               
               
                   
                   
                 2.5 eq. DMAP 
                   
                 b 
               
               
                   
                   
                 95% EtOH 
               
               
                 112 
                 4.7 
                 HMH 
                 4° C., 42 hours 
                 a 
               
               
                   
                   
                 2.5 eq. 
                   
                 b 
               
               
                   
                   
                 Imidazole 
               
               
                   
                   
                 95% EtOH 
               
               
                   
               
               
                 HMH: hydrazine monohydrate  
               
               
                 a: C-10 group is OH, C-13 group is OAc in product (5)  
               
               
                 b: C-10 group is OH, C-13 group is OH in product (4), which is DAB-III  
               
               
                 c: C-10 group is OAc, C-13 group is OH in product (6)