Part I. Diels -Alder reactions of heterocyclic azadienes: Total syntheses of prodigiosin, prodigiosene and desmethoxyprodigiosin. Part II. Preparation of functionalized cis-delta(6)-1-octalones: A probe of Diels -Alder stereocontrol utilizing a rigid cyclic dienophile

Mona Patel, Purdue University

Abstract

The total synthesis of prodigiosin (1), a red pigment first isolated from Serratia marcescens, possessing the characteristic pyrrolylpyrromethene skeleton of a class of naturally occurring polypyrroles exhibiting antimicrobial and cytotoxic properties, is detailed. The approach is based on the application of an inverse electron demand Diels-Alder reaction of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate in a 1,2,4,5-tetrazine $\to$ 1,2-diazine $\to$ pyrrole strategy for preparation of prodigiosin pyrrole ring B and the subsequent implementation of an effective intramolecular palladium(II)-promoted 2,2$\sp\prime$-diaryl coupling for construction of the prodigiosin 2,2$\sp\prime$-bipyrrole AB ring system. In situ generated activated ester derivatives of pyrrole-1-carboxylic acid or the use of pyrrole-1-carboxylic acid anhydride proved suitable for the generation of mixed 1,1$\sp\prime$-carbonyldipyrrole compounds for use in the palladium(II)-promoted mixed 2,2$\sp\prime$-bipyrrole coupling. Extensions of this approach to the preparation of indole-1-carboxylic acid anhydride (36) and its use in selective, controlled coupling reactions resulted in the preparation of indole-N-carbonyl compounds. Further application of the palladium(II)-promoted mixed 2,2$\sp\prime$-bipyrrole coupling allowed for the preparation of the naturally occurring parent pyrrolylpyrromethene, prodigiosene (2a), and 2-methyl-3-pentylprodigiose (2e, desmethoxyprodigiosin) are detailed. A comparison of the in vitro cytotoxic properties of prodigiosin (1), prodigiosene (2a), and 2-methyl-3-pentylprodigiosene (2e) are reported and reveal exceptional cytotoxic potency (3.7 $\times$ 10$\sp{-4}$ $\mu$g/mL = 3.7 $\times$ 10$\sp{-10}$ g/mL) for prodigiosin against 9PS (P388) mouse leukemia which may be attributed to the presence of the prodigiosin C-6 methoxy substituent. A study of the regioselectivity of the intermolecular Diels-Alder reaction of (nitrosocarbonyl)benzene and methyl nitrosoformate with representative electron-rich and electron deficient 2-substituted 1,3-cyclohexadienes is described. The observed results arc consistent with the prediction that nitrosocarbonyl compounds behave as dependable electron-deficient 2$\pi$ components in a normal (HOMO$\sb{\rm diene}$ controlled) Diels-Alder reaction with electron-rich 2-substituted dienes and additionally illustrate that they may serve as useful 2$\pi$ components in regioselective Diels-Alder reactions with electron-deficient 2-substituted 1,3-cyclohexadienes. The latter results are consistent with either a normal (HOMO$\sb{\rm diene}$ controlled) or inverse electron-demand (LUMO$\sb{\rm diene}$ controlled) Diels-Alder reaction. Utilization of the nitrosocarbonyl Diels-Alder adducts in a stereospecific preparation of functionalized, cis-$\Delta\sp6$-1-octalones is detailed. A study of the pi-facial selectivity of the Diels-Alder reaction of N-benzoyl 5-methoxycarbonyl-2-aza-oxabicyclo (2.2.2) oct-4-ene, a rigid electron deficient dienophile bearing two allylic axial heteroatom substituents, with 1-methoxy-3-(trimethylsilyl)oxybutadiene, a representative electron rich diene, is detailed.

Degree

Ph.D.

Advisors

Boger, Purdue University.

Subject Area

Organic chemistry

COinS