Divergent Synthesis and Evaluation of Inhibitory Activities against Cyclooxygenases-1 and -2 of Natural Withasomnines and Analogues

Abstract

The divergent synthesis of natural withasomnines and analogues was achieved from 4-hydroxypyrazoles, which was prepared via alkaline hydrolysis of the Baeyer-Villiger oxidation products from 4-formylpyrazoles. Key steps of this synthesis are regioselective Claisen rearrangement of 4-allyloxypyrazoles and the Suzuki-Miyaura coupling of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl trifluoromethanesulfonate and commercially available arylboronic acids. The Suzuki-Miyaura coupling at the final step of this strategy enabled facile access to natural withasomnines and their analogues. The biological activities of the twelve synthesized compounds against cyclooxygenases-1 and -2 (COX-1 and COX-2) were evaluated.

Synthesis of Dihydrooxepino[3,2-c]Pyrazoles via Claisen Rearrangement and Ring-Closing Metathesis from 4-Allyloxy-1H-pyrazoles

“…The MW reaction conditions were 200 °C and 30 min. In the reaction of substrate 1b (R = benzyl), 5-allylated product 2b was obtained exclusively in a similar yield (98%, entry 2) as DEA ( 2b : 92%) reported previously [ 13 , 14 ]. Improved regioselectivity was observed for substrate 1d bearing an n -butyl group, affording 5-allylate 2d as the sole product in 97% yield (entry 4), whereas a mixture of 2d (65%) and 3d (20%) was obtained in the MW reaction with DEA.…”

“…Improved regioselectivity was observed for substrate 1d bearing an n -butyl group, affording 5-allylate 2d as the sole product in 97% yield (entry 4), whereas a mixture of 2d (65%) and 3d (20%) was obtained in the MW reaction with DEA. Surprisingly, reversed regioselectivity was observed in the reaction of substrate 1c bearing a p -toluenesulfonyl substituent at the N 1 position in DME, giving 3-allylated 3c (55%, entry 3), whereas 2c was formed as the major product (65%) and as the minor product (20%) in the MW-assisted Claisen rearrangement in DEA in our previous study [ 14 ]. However, we do not have a plausible explanation for this reversed selectivity.…”

“…As mentioned in our previous paper, Claisen rearrangement of 1a in 1,2-dimethoxyethane (DME) showed improved regioselectivity for 2a (65%): 3a (1%) compared to the same reaction in N , N -diethylaniline (DEA) ( 2a (61%): 3a (3%)) [ 14 ]. Another merit of using DME as a solvent is easier purification of the reaction products.…”

“…Direct functionalization of pyrazoles has been rarely reported; it is a synthetic challenge. We have been studying the direct functionalization of pyrazoles and reported the synthesis of 4-arylpyrazoles via Kumada–Tamao coupling [ 9 ], Suzuki–Miyaura coupling [ 10 ], and the Heck–Mizoroki reaction [ 11 ]; 2 H -indazoles via a double Sonogashira coupling followed by Bergmann–Masamune cyclization [ 12 ]; and 4-hydroxy-1 H -pyrazoles by the total synthesis of withasomnine alkaloids as its applications [ 13 , 14 ].…”

“…In our previous synthesis of withasomnines, the key intermediates were 4-allyloxy-1 H -1-tritylpyrazole ( 1a ) and its Claisen rearrangement product, 5-allyl-4-hydroxy-1 H -1-tritylpyrazole ( 2a ) [ 14 ]. Compound 2a or its structural isomer, 3-allyl-4-hydroxy-1 H -1-trityl pyrazole ( 3a ), contains a hydroxyl group, which can be further O -functionalized.…”