Current Organic Chemistry - Volume 5, Issue 6, 2001

The well-known antimalarial properties of naturally occurring cyclic peroxides artemisinin (qinghaosu), yingzhaosu A and yingzhaosu C have stimulated the development of new strategies for the synthesis of cyclic peroxides with diverse structures, and the investigation of the chemical transformations and properties of such compounds. In this review, recent progress in the chemistry of mono- and polycyclic organic peroxides with ring sizes of five or greater is highlighted and discussed.

Zaragozic acids (or squalestatins) are very potent inhibitors of squalene synthase. They or simpler analogs have potential as drugs for lowering the endogenous level of cholesterol in human serum. These compounds are Ras farnesyltransferase inhibitors and might become antitumor drugs. They are also antifungal agents. This account presents synthetic studies subsequent to those reviewed by Nadin and Nicolaou (1). A wealth of new chemistry has been developed for the generation of highly oxygenated 2,8-dioxabicyclo(3.2.1)octane-3,4,5-tricarboxylic triacids and analogs, so demonstrating the fascination of synthetic chemists for zaragozic acids.

Recent developments in metallosalen-catalyzed asymmetric oxidation, namely, the epoxidation of simple olefins and the desymmetrization of meso-tetrahydrofurans by using second-generation metallosalen complexes are discussed. As an alternative approach, the enantiospecific ring-enlargement of oxetanes for preparing optically active tetrahydrofurans is also described.Oxygen heterocycles such as epoxides and tetrahydrofurans occur in a wide variety of natural products where their configurations often play an important role in defining biological activity. Furthermore, these oxygen heterocycles can serve as versatile chiral building blocks for the enantiospecific synthesis of various compounds. Obviously, methods for the stereocontrolled synthesis of epoxides and tetrahydrofurans will be of great value for organic synthesis. Accordingly, during the last two decades the development of new methodologies for the stereoselective synthesis of this class of compounds from readily available starting materials has been a major objective in organic synthesis as attested by numerous publications. As a result, many efficient catalysts and reagents have been devised and high enantioselectivities achieved for synthesizing oxygen heterocycles. Examples are chiral titanium-tartrate (1,2), metalloporphyrins (3), (salen)manganese complexes (4,5,6), ketones (via dioxiranes) (7), and iminium salts (via oxaziridinium salts), for achieving epoxidation with high enantioface-selectivity. Moreover, the desymmetrization of meso-heterocycles has been effected with (salen)manganese complexes (4). In the present review, we describe some recent developments in metallosalen-catalyzed asymmetric epoxidation and the desymmetrization of meso-tetrahydrofurans and related compounds. In addition, the enantiospecific ring-enlargement of oxetanes to tetrahydrofurans is briefly described.

alpha,beta-Unsaturated gama-lactones with an alkylidene substituent in the gama-position (“gama-alkylidenebutenolides”) are well-known natural products. They vary in complexity from gama-methylenebutenolide, which is an antibiotic, to peridinin, which is an important pigment for light-harvesting in the ocean. A distinct sub-class within the gama-alkylidenebutenolides consists of the pulvinones and pulvinic acids, which are dyes found in mushrooms. A structural feature shared by all gama-alkylidenebutenolides, except the simplest, is that the Cgama=C off-ring bond is stereogenic. Therefore, in synthesis, this bond must be established stereoselectively. This is usually done in kinetically controlled reactions because the thermodynamic advantage of the Z- vs. E-configuration is often quite small.Section I is devoted to the introduction. Section II starts with the landmark syntheses of the carotenoid gama-alkylidenebutenolides peridinine and pyrrhoxanthine by Ito et al. beta-Elimination pathways from gama-(alpha-heteroalkyl)- substituted butenolides giving Z-configured gama-alkylidenebutenolides or, depending on the choice of the precursor, their E-isomers, follow as Section III. Section IV covers the metallocyclization protonolysis approach to such compounds. Section V concerns a condensation strategy leading to gama-alkylidenebutenolides from methylene-active compounds and derivatives of oxalic acid. Section VI deals with a Horner-Wadsworth-Emmons synthesis of two gama-alkylidenebutenolides starting from selectively enolized 1,2-diketones. Section VII is devoted to methods leading to gama-arylidene-alpha-aryl-beta-hydroxybutenolides (“pulvinones”). The synthetic chemistry of pulvinone-based carboxylic acids (“pulvinic acids”) follows in Sections VIII and IX focusing on condensation and rearrangement routes, respectively.In order to facilitate comparison, comprehension, and analysis, most syntheses are traced back to commercially available starting materials, and pertinent reaction details are included in the footnotes of the Schemes.