Synthesis of Gossypol Analogues

Abstract

Dedicated to the memory of Professor Dr. Pierre CrahhP (24. XI. 88) Two gossypol analogues 2a and 2b were synthesized for biological evaluation as male contraceptive agents. The naphthol 8c was prepared by analogy with a known procedure starting from 3-isopropylcatechol (3). (t-Bu)?02-Mediated phenolic coupling of 8c furnished the binaphthol9c which, after pyrane ring closure, deprotection, and selective bisformylation with SnCI,/CI,CHOCH,, gave the target compound 2a. The corresponding tetrahydroxy analogue 2b was prepared in a similar way.

Reaction chemistry of gossypol and its derivatives

“…12) in 5% overall yield by Edwards and Cashaw (36)(37)(38). From this pioneering work, much research (47,54,56,175,(184)(185)(186)(187)(188)(189)(190)(191)(192)(193) has followed to devise new, higher-yielding methodologies to prepare gossypol's basic naphthalene framework. This work is beyond the scope of this review.…”

Regioselective Oxidative Dehydrogenation under Nonenzymatic Conditions: A Synthetic Route to Gossypol

“…The complete decomposition of hemigossypol was observed when m ‐CPBA was employed as the oxidant (see Table 2, Entries 2 and 3). To our delight, using ( t BuO) 2 12d with the reaction mixture at 130 °C afforded the desired gossypol ( 1 ) in 45.7 % yield. Taking into consideration the instability of hemigossypol and gossypol, a decrease in the reaction temperature may improve the yield.…”

“…A Dakin oxidation of aromatic aldehyde 6 gave the corresponding phenol 7 , and subsequent protection with methyl iodide followed by flash column chromatography provided substituted bromobenzene 8 in 61.3 % yield (four steps from 4 ). The halogen–lithium exchange of 8 followed by a formylation reaction, a Stobbe condensation with dimethyl succinate, and then an electrophilic cyclization with sodium acetate afforded the highly substituted naphthalene 11 12d. The acetyl‐protected naphthol was converted into methyl ether 12 , which was isolated in 53.8 % yield over five steps from bromobenzene 8 .…”

Synthesis of benzyl substituted naphthalenes from benzylidene tetralones

“…Bromination of 1-ethyl-2,3-dimethoxybenzene ( 4 ) at 0 °C using bromine, via an electrophilic aromatic substitution mechanism, afforded compound 5 in a 90% yield. 22,23 In some preparations small amounts of another regioisomer 1-bromo-4-ethyl-2,3-dimethoxybenzene were formed. To avoid the formation of both isomers an alternate efficient and highly regioselective silica gel catalyzed synthesis using N -bromosuccinimide produced the desired regioisomer in a 97% yield 24 and avoided the use of corrosive bromine.…”