Enantioselective Synthesis of the Tetrahydrobenzylisoquinoline Alkaloid (-)-Norarmepavine Using Polymer Supported Reagents (2003)

We describe, in full, the enantioselective synthesis of the tetrahydrobenzylisoquinoline alkaloid (-)-norarmepavine (1) in 77% e.e.This compound was prepared using solid-supported reagents and scavengers in multi-step sequences of reactions to give materials that required no conventional purification at the individual steps.The utilization of solid-supported reagents in chemical synthesis has been shown to markedly improve productivity in many critical aspects of the generation of new chemical entities and complex target molecules. 1The potential to configure the reactions in both a serial and convergent fashion offers many distinct advantages compared to solid-phase on-bead synthesis.In addition, the simple removal of spent reagents through filtration enables reactions to be driven to completion through the addition of excess reagents and for lower yielding reactions to be worked up using scavenger resins.We have previously reported on the use of these concepts in the sequential multi-step synthesis of various natural products using solid-supported reagents and scavengers to effect all the individual steps. 2 As a consequence, no chromatographic purification procedures were necessary and all steps proceeded with minimum optimization.In order to extend these methods to the asymmetric synthesis of natural compounds we have investigated in this work the preparation of the tetrahydrobenzylsoquinoline alkaloid (-)-norarmepavine (1). 3 Norarmepavine was isolated in 1963 from the American lotus, Nelumbo lutea (Nymphaeaceae). 4This alkaloid has been tested for biological activity in three pharmacological screening procedures. 4,5In mice it produces mydriasis, bradypnea and a decrease in spontaneous motor activity after oral doses of 200 mg/Kg.NH O O CH 3 H HO N O O BnO O O NH 2 CH 3 OBn O O CH 3 N H O BnO O O CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 (-)-Norarmepavine (1) 2 4 5 3 Scheme 1 The synthesis begins with commercially available 2-(3,4-dimethoxyphenyl)ethylamine (4) and ethyl 4-benzyloxyphenylacetate (5).Microwave irradiation (MW) under solvent-free conditions of a mixture of these components led to the amide (3) in better than 90 % yield (see Scheme 2). 7The amide formed was pure enough to take through the next reaction without further purification.The route to the isoquinoline nucleus involved the Bischler-Napierlaski reaction of the amide (3).Initial experiments to catalyse this reaction using trifluoromethanesulfonic anhydride (Tf 2 O) 8 and polymer-supported 4-dimethylaminopyridine ( -DMAP) in CH 2 Cl 2 followed by treatment with polymer-supported N-(2-aminoethyl)aminomethyl polystyrene ( -NH 2 ), in order to destroy the excess of Tf 2 O, led to the iminium triflate (7) (see Scheme 3).Treatment in situ of the salt with polymer-supported2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine ( -BEMP) generated the free base (2). 9In order to guarantee the success of this reaction, it is very important that the order and timing of the addition of the reagents is strictly followed (see Table 1).The best yields were obtained with the slow addition of a solution of Tf 2 O in CH 2 Cl 2 over 6 h to a mixture of the amide and -DMAP at 0 o C (Entry 5 in Table 1).If the addition of reagents is done faster the proportion of unreacted starting material increases dramatically.O O NH 2 CH 3 OBn O O O O CH 3 NH O OBn N BnO O O CH 3 NH BnO O O CH 3 (i) (ii) (iii) (iv) NH HO O O CH 3 H H 2 4 5 3 (-)-Norarmepavine (1) 6 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 (i) MW, 100˚C 30 sec, 200˚C 30 min, remove solvent 200˚C 30 min 90%.(ii) (a) -DMAP, Tf 2 O, DCM, 0˚C; (b) -NH 2 ; (c) -BEMP 67% (5:1) (imine (2) : amide (3)).(iii) (a) starting material added to the reducing agent dropwise over 15 min, (10b) in DCM at -35˚C and slowly warmed until -10˚C for 1 h and then at 0 o C for 4 h, evaporation of solvent (b) Amberlyst 15 ( -SO 3 H), CH 3 OH (catch) 45 min then filtrated and release with NH 3 /CH 3 OH overnight.82% e.e.=78% (Mosher ester), [α] D 20 -12.4 o (c=0.805,CHCl 3 ).(iv) H 2 , Pd(OH) 2 /C, CH 3 OH, rt, overnight, 90%.e.e.=77% (Pirkle reagent) 13 , [α] D 20 -9.5 o (c=0.825,CHCl 3 ) 4,6, and 14 Scheme 2 CH 3 NH O O OBn