Total Synthesis of (+)-CC-1065 Utilizing Ring Expansion Reaction of Benzocyclobutenone Oxime Sulfonate

Abstract

An indole synthesis via ring expansion of benzocyclobutenone oxime sulfonate was developed. Utility of the indole synthesis was demonstrated by the total synthesis of (+)-CC-1065. The middle and right segments were constructed by a sequential ring expansion of the symmetrical benzo-bis-cyclobutenone. The left segment was also constructed via ring expansion of the methyl-substituted benzocyclobutenone oxime sulfonates. After condensation of these three segments, the dienone cyclopropane structure was formed to complete the total synthesis.

Construction of <i>N</i>-Heterocycles Fused with a Highly Substituted Benzene Ring by a Benzyne-Mediated Cyclization/Functionalization Cascade Reaction and Its Application to the Total Synthesis of Marine Natural Products

“…24,25) Total synthesis of congeners bearing methylthio group was more difficult. 39,40) The sensitivity of the alkylthio group toward oxidants hindered the synthesis of the key pyrroloquinoline intermediate and the final oxidation of the benzene ring to the corresponding p-iminoquinone or o-quinone skeletons while leaving the methylthio group intact. Therefore, we planned to construct highly substituted pyrroloquinoline intermediate 89 or 90 having methylthio group by utilizing the benzyne-mediated cyclization/functionalization protocol using 4-bromo-2-methylthiotryptamine derivative 91 26) (Chart 17).…”

“…The remaining tasks for the completion of the total syntheses of isobatzelline A (73) and B (74) were the selective oxidation of the benzene ring to p-iminoquinone skeleton and the introduction of amino group. Oxidation of 103 using ceric ammonium nitrate (CAN) 40) provided a complex mixture including 21% of the desired p-iminoquinone 104 and 36% of 103. The unexpected conversion of 6-chloro-pyrroloquinoline derivative 105 to the desired p-iminoquinone 104 with trifluoroacetic acid circumvented this unsuccessful oxidation.…”

Palladium-Catalyzed β-Arylation of Cyclic α,β-Unsaturated <i>O</i>-Methyl Oximes with Aryl Iodides

“…[16][17][18][19][20][21][22][23] Oxime species are easily prepared from carbonyl compounds, and play an important and versatile role in organic synthesis. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] In metal-promoted direct β-functionalization of acyclic oxime species, the oxime group usually behaves as a directing Ncoordinating functionality [16][17][18][19][20][21][22][23] (Chart 1B). On the other hand, metal-promoted direct β-functionalization of cyclic oxime spe-cies such as 2-cyclohexen-1-one oxime, whose oxime group is not effective as a directing N-coordinating functionality, has not been reported yet (Chart 1C).…”

Divergent Total Syntheses of Isobatzellines A/B and Batzelline A

“…Furthermore, makaluvamine A exhibits potent in vitro cytotoxicity against the human colon tumor cell line HCT116 and inhibitory activity against topoisomerase II . Accordingly, tremendous effort has been devoted to develop reliable synthetic routes for construction of the highly functionalized pyrrolo­[4,3,2- de ]­quinoline skeleton, and several total syntheses have been reported. − However, synthetic routes to isobatzellines A ( 1 ) and B ( 2 ) and batzellines A ( 4 ) and B ( 5 ) bearing the C2-methylthio group have not been fully explored, and their total syntheses have only been reported by Joule’s group. , As part of our ongoing interest in the total synthesis of pyrroloquinoline alkaloids, , we herein report efficient and divergent total syntheses of 1 , 2 , and 4 featuring three key processes, including the ring expansion of benzocyclo­butenone oxime sulfonate with NaSMe to construct 2-methylthioindole, a benzyne-mediated cyclization/functionalization cascade to form the tetrahydroquinoline ring, and a Mn-reagent-dependent oxidative formation of iminoquinone and o- benzoquinone.…”

“…For construction of the highly substituted 2-methylthioindole, we planned to expand the scope of our indole synthesis using the ring expansion of benzocyclobutenone oxime sulfonate developed in the course of our synthetic studies on (+)-CC-1065. Thus, based on our ring-expansion reaction of oxime sulfonates with hydride and cyanide ion sources (Scheme b), we envisaged that 1,2-addition of methanethiolate to oxime sulfonate 25 followed by ring expansion with concomitant N - O bond cleavage would provide 2-methylthioindole 24 . Oxime sulfonate 25 should be easily accessible via regioselective [2 + 2] cycloaddition of benzyne 27 and ketene silyl acetal 26 …”