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The synthesis and chemistry of benzodipyrroles287 views
Author
Hamilton, Gregory Scott, Department of Chemistry, University of Virginia
Advisors
Sundberg, Richard, As-Chemistry, University of Virginia
Mcgarvey, Glenn, As-Chemistry, University of Virginia
Carey, Francis A., Department of Chemistry, University of Virginia
Volk, Wesley A. , University of Virginia
Abstract
Two cyclization routes for the synthesis of substituted benzo [1,2-b: 4,3-b'] dipyrroles were investigated. These compounds are of interest for the synthesis of the <i>B</i> and <i>C</i> rings of the potent antitumor antibiotic CC-1065. Also, the preparation of deoxy analogues was considered of significance due to the possibility of synthesizing less toxic analogues of CC-1065 that retain the antitumor activity of the parent compound. The key intermediates in both routes were 3- (3-pyrrolyl) thiopyrrolidines. The use of both the allyl and benzyl groups as nitrogen-protecting groups was investigated.
[Note: See Diagram in PDF]
In the first case, where z = COCH<sub>3</sub>, the 5-acetyl substituted benzodipyrrole (Y = COCH,sub>3</sub>) was obtained by an aldol-type cyclization. The key goal in this path was the elaboration of this substrate to the natural products PDE-I and PDE-II, which would in essence constitute a synthesis of the <i>B</i> and <i>C</i> rings of CC-1065. It proved not to be possible to methylate the phenolic moiety when R was an alkyl group. Dealkylation of the indoline nitrogen when R = benzyl or allyl also did not prove feasible by electrophilic reagents. However, treatment of the N-ally1 benzodipyrrole with tetrakis (triphenylphosphine) rhodium hydride provided an efficient method for the obtention of indoline <i>44</i>. Conversion of this compound to either an amide or carbamate allowed for high-yielding methylation of the phenol to obtain methoxy benzodipyrroles <i>50</i> and <i>53</i>. Deprotection of the carbamate with zinc and acetic acid provided compound <i>54</i> in good yield. Since the
[Note: See Diagram in PDF]
oxidation of such substrates to the 5-hydroxy compounds has been described by Boger, this route constitutes a formal total synthesis of PDE-I and PDE-II.
In the case where Z = CH=N=N, decomposition of the diazoketone with boron trifluoride-etherate delivered the stable thiepinone 10 in excellent yield. Treatment of this compound with Raney nickel in refluxing ethanol effected ring contraction-desulfurization to furnish the s-unsubstituted benzodipyyrole in acceptable yield. Methylation of this compound with diazomethane led to the methoxy compound 91, which could be converted to the triphloroethoxycarbonyl
[Note: See Diagram in PDF]
derivative. Deprotection of this compound and conversion to the amide provides a 5-deoxy analogue of rings JVC of cc- 1065.
Note: Abstract extracted from PDF file via OCR.
Hamilton, Gregory Scott. The synthesis and chemistry of benzodipyrroles. University of Virginia, Department of Chemistry, PHD (Doctor of Philosophy), 1987-01-01, https://doi.org/10.18130/V3-WMBY-HZ26.
