Asymmetric synthesis of naturally occurring spiroketals

Spiroketals are widely found as substructures of many naturally occurring compounds from diverse sources including plants, animals as well as microbes. Naturally occurring spiroketals are biologically active and most of them are chiral molecules. This article aims at reviewing the asymmetric synthesis of biologically active spiroketals for last 10 years (1998-2007).     

First total synthesis of cassiarin A, a naturally occurring potent antiplasmodial alkaloid

The first total synthesis of cassiarin A, an antiplasmodial alkaloid isolated from Cassia siamea, was achieved via sequential alkynylation of arenes with Sonogashira coupling and 6- endo-dig-cyclization of phenolic oxygens to the resulting alkynes.     

First total synthesis of hormaomycin, a naturally occurring depsipeptide with interesting biological activities

Some unique features were disclosed during the structure elucidation of the cyclic depsipeptide hormaomycin (1), first isolated in 1989 from a Streptomyces griseoflavus strain and found to have quite an interesting spectrum of biological activities. Besides one residue of the proteinogenic amino acid isoleucine [(S)-Ile], it contains two units of 3-methylphenylalanine [(betaMe)Phe], one of (2R)-allo-threonine [a-Thr] as well as two moieties of 3-(trans-2-nitrocyclopropyl)alanine [(3-Ncp)Ala] and one of 4-(Z)-propenylproline [(4-PE)Pro]. The latter two have never been found in any natural product before. The side chain of 1 is terminated with the residue of 5-chloro-1-hydroxypyrrole-2-carboxylic acid [Chpca]. This first synthetic access to hormaomycin 1 will make it possible to prepare structural analogues of this interesting natural depsipeptide in order to elucidate structure-activity relationships and the biologically active minimal unit.     

Efficient total synthesis of naturally occurring anti-TMV compound gramniphenol G

An efficient synthesis of Gramniphenol G identified as 2-(4′-Methoxyphenyl)-7,7-dimethyl-7H-furo[3,2-g]chromene and originally isolated from the plant Arundina gramnifolia belonging to orchidaceae family was accomplished starting from resorcinol. The key step involves the oxidative cyclization of o-vinyl phenol to provide benzofuran moiety.     

Asymmetric synthesis, stereochemistry and rearrangement reactions of naturally occurring 7'-hydroxylignano-9,9'-lactones

The asymmetric synthesis of a series of (7'S,8R,8'R)-7'-hydroxylignano-9,9'-lactones is presented, among them the mammalian lignan (7'S)-hydroxyenterolactone and (7'S)-parabenzlactone, allowing the stereochemistry of natural occurring (-)-parabenzlactone to be re-assigned. A hydroxylactone rearrangement and its possible mechanisms are discussed. Finally a brief survey of the current naming and numbering variants of 7'-hydroxylignano-9,9'-lactones is presented, along with a suggestion for harmonization of the nomenclature.     

An efficient and enantioselective total synthesis of naturally occurring L-783277

Naturally occurring L-783277 which belongs to 14-membered resorcylic acid lactones (RALs) turned out to be a potent kinase inhibitor against MEK (MAP kinase kinase). We successfully accomplished efficient and enantioselective total synthesis of L-783277 based on convergent assembly of one aromatic unit and two chiral building blocks with efficient orthogonal protection-deprotection strategy. Three key steps composed of olefin cross metathesis, addition of acetylene derivative to aldehyde, and Yamaguchi macrolactonization were subsequently employed to construct the framework of L-783277. The optical rotation value of L-783277 is for the first time presented in this Letter.     

Concise formal total synthesis of hybocarpone and related naturally occurring naphthazarins

A concise formal total synthesis of the cytotoxic bisnaphthazarin derivative hybocarpone has been completed through the development of routes to the synthetic precursor, 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone. The oxidation of 3-ethyl-1,2,4,5,7,8-hexamethoxy-6-methylnaphthalene under Rapoport conditions gave 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone in modest yields after basic hydrolysis. In addition, treatment of 3-ethyl-1,2,4,5,7,8-hexamethoxy-6-methylnaphthalene with boron tribromide provided access to the naturally occurring naphthazarin, boryquinone. The analogous oxidative demethylation of 3,6-dimethyl-1,2,4,5,7,8-hexamethoxynaphthalene and 3-ethyl-1,2,4,5,7,8-hexamethoxynaphthalene resulted in the synthesis of 2,5,7,8-tetrahydroxy-3,6-dimethyl-1,4-naphthoquinone (aureoquinone) and 3-ethyl-2,5,7,8-tetrahydroxy-1,4-naphthoquinone, respectively. An alternative selective synthetic route to 3-ethyl-2-hydroxy-5,7,8-trimethoxy-6-methyl-1,4-naphthoquinone was also developed utilizing an intramolecular Claisen condensation of methyl 2-butyryl-3,5,6-trimethoxy-4-methylphenylacetate with concomitant in situ aerial oxidation.     

Regiospecific synthesis of isopestacin, a naturally occurring isobenzofuranone antioxidant

A DBU promoted aldol cyclocondensation of hydroxyisobenzofuranone 15 with cyclohexane-1,3-dione, followed by aromatization has resulted in the first short synthesis of isopestacin (1).     

Asymmetric synthesis of naturally occurring nonenolide xyolide through cross metathesis and macrolactonization reaction

Asymmetric total synthesis of xyolide, a small ring macrolide is presented in this article. The synthesis is achieved through an ‘E’ selective cross metathesis (CM) reaction between two appropriate fragments followed by lactonization by Shiina method. One of the fragments containing 7S,8S,9R stereocenters of xyolide is accessed from n-nonanal by adopting an organocatalytic asymmetric α-aminooxylation, Z-selective Ando olefination, and substrate directed dihydroxylation reaction. The other fragments containing 4S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method.     

Asymmetric synthesis of naturally occurring (−)-seimatopolides A and B

Asymmetric total synthesis of polyhydroxylated naturally occurring nonenolide seimatopolide A (3S,6S,7S,9R) and seimatopolide B (3S,6R,9R) is described in this article. An E-selective cross metathesis (CM) reaction between two suitable fragments followed by macrolactonization reaction is the main highlight of our synthesis for the two natural products. The fragment containing 6S,7S,9R stereocenters for seimatopolide A has been synthesized from l-tartaric acid as a chiral pool starting material, by employing (R)-CBS-mediated stereoselective keto reduction reaction. Another fragment, which is common for both the molecules, containing the 3S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method. The fragment having 6R,9R stereocenters for seimatopolide B has been prepared from n-decanal by adopting (R)-CBS-mediated keto reduction and Brown asymmetric allylation reaction.     

The chemistry of naturally occurring polyamines. A total synthesis of thermospermine

methodology for distinguishing the similar basic sites in spermidine has led to the first synthesis of thermospermine $\text{1}$.     

A short enantioselective synthesis of guggultetrol,a naturally occurring lipid

An enantioselective synthesis of the naturally occurring lipid, guggultetrol, is described with an overall yield of 24% starting from commercially available l-pentadecanol in ten linear steps. The key chiral-inducing steps include a Sharpless asymmetric epoxidation of allylic alcohol and a dihydroxylation of an α,β-unsaturated ester.     

A novel palladium-catalyzed synthesis of β-carbolines: application in total synthesis of naturally occurring alkaloids

Two naturally occurring β-carbolines, 6-methoxy-2-methyl-1,2,3,4-tetrahydro-β-carboline and bauerine A, have been prepared using a Stille-type coupling, followed by a palladium-phosphine catalyzed N-heteroannulation as the key steps.     

A convenient synthesis of naturally occurring quinizarins

A general and regiospecific method for the preparation of quinizarins involves the cycloaddition of electron-rich dienes. Advantageous syntheses of several natural products, 2-methylquinizarin, islandicin, digitopurpone, erythroglaucin, 5-0-methylislandicin and 8-0-methyl-digitopurpone illustrate this procedure. A structure attributed to ventinone B is incorrect and 1,4,8-trihydroxy-6-methylanthraquinone is different from a natural substance so described.     

Photochemical synthesis of naturally occurring β-diketones

Photochemical syntheses of pongamol, ovalitenone, and milletone from the corresponding 2′-methoxychalcone epoxides are reported.     

Catalytic antibody route to the naturally occurring epothilones: total synthesis of epothilones A-F

Naturally occurring epothilones have been synthesized starting from enantiomerically pure aldol compounds 9-11, which were obtained by antibody catalysis. Aldolase antibody 38C2 catalyzed the resolution of (+/-)-9 by enantioselective retro-aldol reaction to afford 9 in 90% ee at 50 % conversion. Compounds 10 and 11 were obtained in more than 99% ee at 50% conversion by resolution of their racemic mixtures using newly developed aldolase antibodies 84G3, 85H6 or 93F3. Compounds 9, 10 and 11 were resolved in multigram quantities and then converted to the epothilones by metathesis processes, which were catalyzed by Grubbs' catalysts.