New benzoquinone synthesis. Applications to the total synthesis of isoarnebifuranone and rational drug design

During 1985 a new synthesis of trimethylsilyl substituted 1,4-benzoquinones from the thermolysis of 4-alkynylcyclobuteneones was reported for the first time. Since that time the scope, limitation and mechanism for this new and general 1,4-benzoquinone synthesis has been studied. The scope of this reaction has been expanded to include the synthesis of 2,6-dialkyl substituted 1,4-benzoquinones, 2,3-dialkyl substituted 1,4-benzoquinones, t-butyldimethylsilyl substituted 1,4-benzoquinones, and methylene cyclopenten-1,4-diones. The scope and limitation of this method towards the synthesis of 1,4-benzoquinones has been shown to be somewhat limited in that the formation of methylene cyclopenten-1,4-diones may be the sole or major product from the thermolysis of some 4-alkynylcyclobutenones. The mechanism of this reaction is believed to involve the stereoselective electrocyclic ring opening of the 4-alkynylcyclobutenones to yield (2-alkynylethenyl)ketenes, a previously unknown class of compounds. Ring closure of (2-alkynylethenyl)ketenes yield five and/or six membered ring intermediates whose formation depends on the alkyne substitutent. The five and/or six membered ring intermediates were described as a set of four contributing resonance structures and these intermediates eventually lead to the formation of 1,4-benzoquinones or methylene cyclopenten-1,4-diones. The nature of the five and/or six membered ring intermediates remains unclear.;Two applications of this new 1,4-benzoquinone synthesis are also reported. The first application involves the first total synthesis of the proposed structure of arnebifuranone, a monoterpenyl 2,3-dimethoxy-1,4-benzoquinone. The total synthesis involved an eight step procedure from 3-bromofuran in 4.6% overall yield. The physical properties of the synthetic material did not correspond to the physical properties of the naturally occuring material. This discrepency led to a revised structure of arnebifuranone. The revised structure was based on two independent observations. A synthesis of the revised structure was attempted but was not accomplished. The second application involved the synthesis of potential bioreductive alkylating agents. Several electron rich 1,4-benzoquinones were prepared having the structural features necessary to function as potential bioreductive alkylating agents. Testing of these compounds revealed a promising anti-tumor chemotherapeutic agent. (Abstract shortened with permission of author.).