The synthesis and chemistry of benzodipyrroles

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 B and C 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 = COCH3, the 5-acetyl substituted benzodipyrrole (Y = COCH,sub>3) 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 B and C 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 44. Conversion of this compound to either an amide or carbamate allowed for high-yielding methylation of the phenol to obtain methoxy benzodipyrroles 50 and 53. Deprotection of the carbamate with zinc and acetic acid provided compound 54 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.

Degree:
PHD (Doctor of Philosophy)
Keywords:
Antineoplastic antibiotics, Synthesis, Heterocyclic compounds, Organic compounds
Language:
English
Rights:
All rights reserved (no additional license for public reuse)
Issued Date:
1987