Joseph P. Michael

Enaminones: versatile intermediates for natural product synthesis

Efforts in our laboratories to devise a general approach to the synthesis of alkaloids focus on the versatile reactivity of enaminones and related compounds containing the structural unit N-CaC-Z (Za COR, CO2R, CN, NO2 ,S O 2Ar, etc.). This lecture presents an overview of our research with these useful building blocks. Themes to be elaborated include chemo- selectivity and diastereoselectivity in reactions of enaminones, and the challenge of controlling absolute stereochemistry.

Reformatsky reactions with N-arylpyrrolidine-2-thiones: synthesis of tricyclic analogues of quinolone antibacterial agents

Abstract A convenient synthesis of 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2- a ]quinoline-4-carboxylic acids, tricyclic analogues of the quinolone antibiotics, is described. Key steps in the route are a novel zinc-mediated Reformatsky reaction between diethyl bromomalonate and N -arylpyrrolidine-2-thiones 18 , and cyclisation of the resulting diethyl pyrrolidinylidenemalonate intermediates 19 in polyphosphoric acid. The products proved to be devoid of biological activity.

The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity.

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki-Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki-Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)(2) and NaBH(4) afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 microg/mL) against the Gram-positive micro-organism Bacillus cereus.

Nitroalkenes as precursors to the aromatic spiroketal skeleton of γ-rubromycin. A Nef-type reaction mediated by Pearlman's catalyst

Abstract The first synthesis of the benzannelated spiroketal core of γ-rubromycin using Henry condensations and a novel Nef-type reaction induced by Pearlmans catalyst is described.

Synthesis of pyrrolo[1,2-a]indoles by intramolecular Heck reaction of N-(2-bromoaryl) enaminones

Abstract Treatment of N-(2-bromoaryl) enaminones 4 , prepared by several different methods, with palladium (II) acetate, triarylphosphine and triethylamine in boiling acetonitrile gave pyrrolo[1,2- a ]indoles 8 yields of 50% – 100%. The hydroxy-substituted products 8k could be oxidised to the mitosene-like quinone 9 with Fremys salt.

The synthesis of ventiloquinone L, the monomer of cardinalin 3

Readily available ethyl-4-acetoxy-6,8-dimethoxynaphthalene-2-carboxylate was converted into 1-[3-allyl-4-(benzyloxy)-6,8-dimethoxy-2-naphthyl)-1-ethanol in seven steps. Subjection of this compound to Wacker oxidation conditions provided 5-benzyloxy-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochromene in good yield. Hydrogenation of the isochromene afforded (+/-)-cis-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochroman-5-ol as the major product, which was readily converted into ventiloquinone L.

A NOVEL SYNTHESIS OF SUBSTITUTED NAPHTHALENES

Irradiation of 2-allylated acylbenzenes in DMF in the presence of potassium tert-butoxide constitutes a novel synthesis of substituted naphthalenes, including arylnaphthalenes. Typical examples include the conversions (1) → (2), (8) → (11) and (15 → (16).

Enaminones as intermediates in the synthesis of indolizidine alkaloids

The use of Vinylogous urethanes as pivotal intermediates m the synthesis of mdolizidine alkaloids is illustrated with reference to mdolizidines 209B (1) and 167B (2), two simple alkaloids isolated fiom dendrobatid fiogs. Methodology is optimized for the diastereoselective synthesis of the racemic alkaloids, after which modifications leading towards the enantioselective synthesis of (-tmdolizidine 209B are presented.

Synthesis of an isochroman analogue of the michellamines

The synthesis of racemic 5-iodo-6,8-dimethoxy-1,3-trans-dimethylisochroman (16) in eleven steps from 2,4-dimethoxybenzaldehyde is outlined. Compound (16) was coupled by means of Suzuki methodology with 4-isopropoxy-5-methoxy-7-methylnaphthaleneboronic acid (19) to yield (20). This was converted into (6), a racemic isochroman analogue of the michellamines.

The synthesis of isochroman-4-ols and isochroman-3-ols: models for naturally occurring benzo[g]isochromanols

Abstract The synthesis of isochromanes containing hydroxy substituents at the 4- and 3-positions has been achieved. The key step for the synthesis of the isochroman-4-ols entailed an oxidative mercury mediated ring closure of 2-(prop-1-enyl)phenylmethanol derivatives, while in the synthesis of the isochroman-3-ols the key step involved ozonolysis of 2-(prop-2-enyl)phenylmethanol derivatives.