Enantioselective synthesis of (-)-cis-clavicipitic acid

An enantioselective synthetic method for (-)-cis-clavicipitic acid (1) was reported. 1 was obtained in 10 steps (99% ee and 20% overall yield) from 1H-indole-3-carboxylic acid methyl ester (9) via asymmetric phase-transfer catalytic alkylation and diastereoselective Pd(II)-catalyzed intramolecular aminocyclization as key steps.     

Free-radical-mediated conjugate additions. Enantioselective synthesis of butyrolactone natural products: (-)-enterolactone, (-)-arctigenin, (-)-isoarctigenin, (-)-nephrosteranic acid, and (-)-roccellaric acid

Lewis acid-mediated conjugate addition of alkyl radicals to a differentially protected fumarate 10 produced the monoalkylated succinates with high chemical efficiency and excellent stereoselectivity. A subsequent alkylation or an aldol reaction furnished the disubstituted succinates with syn configuration. The chiral auxiliary, 4-diphenylmethyl-2-oxazolidinone, controlled the stereoselectivity in both steps. Manipulation of the disubstituted succinates obtained by alkylation furnished the natural products (-)-enterolactone, (-)-arctigenin, and (-)-isoarctigenin. The overall yields for the target natural products were 20-26% over six steps. Selective functionalization of the disubstituted succinates obtained by aldol condensation gave the paraconic acid natural products (-)-nephrosteranic acid (8) and (-)-roccellaric acid (9). The overall yield of the natural products 8 and 9 over four steps was 53% and 42%, respectively.     

Enantioselective synthesis of (-)-pentalenene

A short, enantioselective synthesis of (-)-pentalenene is described. Catalytic enantioselective cyclopropenation with (R,R)-Rh2(OAc)(DPTI)3 was used to set the absolute stereochemistry, and an intramolecular Pauson-Khand reaction of the resulting cyclopropenyne was used to establish the quaternary center.     

Enantioselective synthesis of (-)-paeonilide

The first enantioselective synthesis of (-)-paeonilide is reported. Starting from inexpensive furan-3-carboxylic acid the targeted monoterpene was obtained in 12 steps via an asymmetric cyclopropanation-lactonization cascade and a stereoselective side chain insertion at an acetal-like position.     

Enantioselective synthesis of the antiinflammatory agent (-)-acanthoic acid.

An enantioselective synthesis of the potent antiinflammatory agent (-)-acanthoic acid (1) is described. The successful strategy departs from (-)-Wieland-Miescher ketone (10), which is readily available in both enantiomeric forms and constitutes the starting point toward a fully functionalized AB ring system of 1. Conditions were developed for a regioselective double alkylation at the C4 center of the A ring, which produced compound 32 as a single stereoisomer. Construction of the C ring of 1 was accomplished via a Diels-Alder reaction between sulfur-containing diene 43 and methacrolein (36), which after desulfurization and further functionalization yielded synthetic acanthoic acid. The described synthesis confirms the proposed stereochemistry of the natural product and represents a fully stereocontrolled entry into an underexplored class of biologically active diterpenes.     

Enantioselective synthesis of (-)-basiliskamide A

Basiliskamide A is an antifungal polyketide natural product isolated by Andersen and co-workers from a Bacillus laterosporus isolate, PNG-276. A nine-step enantioselective synthesis of (-)-basiliskamide A is reported, starting from commercially available β-hydroxy ester 7. The synthesis features a highly diastereoselective mismatched double asymmetric δ-stannylallylboration reaction of aldehyde 5 with the bifunctional allylborane reagent 4.     

Enantioselective total synthesis of (-)-dactylolide

[reaction: see text] The enantioselective total synthesis of (-)-dactylolide is reported. The absolute stereochemistry of the tetrahydropyran was established by catalytic asymmetric Jacobsen hetero-Diels-Alder reaction. The remote C19 stereocenter was introduced by a sequence of chelation-controlled Grignard addition and Ireland-Claisen rearrangement.     

Enantioselective total synthesis of (-)-laurenditerpenol

A highly convergent total synthesis of (-)-laurenditerpenol has been accomplished through an organolithium to aldehyde nucleophilic addition. Preparation of the prerequisite key intermediates in optically pure form was based on an improved, short, and efficient synthesis of "wine lactone" from (S)-limonene and Corey's catalytic enantioselective Diels-Alder reaction of 2,5-dimethyl furan with diethyl fumarate.     

Enantioselective synthesis of (-)-codeine and (-)-morphine

A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth-Horner phosphate reagent. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.     

Enantioselective synthesis of (−)-pinellic acid

An enantioselective convergent approach toward the total synthesis of pinellic acid 1 from 1,9-nonanediol is described. The synthetic strategy features iterative Sharpless asymmetric dihydroxylation, Sonogashira coupling and Birch reduction.     

Enantioselective synthesis of (−)-galantinic acid

An efficient enantioselective synthesis of (−)-galantinic acid 1, a non-proteogenic amino acid is described using Sharpless asymmetric epoxidation, dihydroxylation and the regioselective nucleophilic opening of a cyclic sulfite as the key steps.     

Enantioselective synthesis of (-)-wikstromol using a new approach via malic acid

The total synthesis of (-)-wikstromol, a bioactive alpha-hydroxylated lactone lignan, from natural malic acid using a consecutive alkylation strategy is presented. First, alkylation of a malic acid ester provided the monobenzyl derivative, which was then converted to an alpha-substituted dioxolanone. This derivative was reacted in a second alkylation step to a double benzylated dioxolanone, which was transformed to bis-O-benzyl-protected (-)-wikstromol and subsequently to the natural product. Only six steps were required to produce wikstromol in 30% overall yield. A second approach from malic acid, the double alkylation of dienolates from 5-oxo-1,3-dioxolan-4-yl acetic acid derivatives, was not successful. No reaction conditions were found to afford the dienolates. Instead, rapid fragmentation of the dioxolanones to fumaric acid derivatives and pivalaldehyde occurred even at -105 degrees C, and aldol reaction products with good stereoselectivity were formed. The relative configuration of the major isomer was determined by X-ray structure analysis. By comparison of NMR data it is shown that a previous assignment of the configuration of one of the described aldol products was incorrect.     

Enantioselective total synthesis of (-)-erinacine B

The first enantioselective total synthesis of (-)-erinacine B has been achieved. Our approach features convergent construction of the 5-6-7 tricyclic cyathane core system via chiral building blocks prepared using asymmetric catalysis developed by us and highly stereoselective construction of all stereogenic centers in the aglycon. [reaction: see text].     

Enantioselective total synthesis of (-)-heliannuol A

An efficient and enantiocontrolled total synthesis of (-)-heliannuol A has been accomplished by employing ring closing metathesis and sequential diastereoselective epoxidation and regioselective reductive cleavage of the epoxide ring.     

Enantioselective total synthesis of (-)-kibdelone C

The kibdelones are aromatic polyketide natural products featuring isoquinolinone and tetrahydroxanthone ring systems. They display potent cytotoxicity toward a range of human cancer cell lines. Here, we present an enantioselective total synthesis of kibdelone C that utilizes a Shi epoxidation to establish the absolute and relative stereochemistry, an acid-catalyzed cyclization to form the tetrahydroxanthone, and a C-H arylation to complete the hexacyclic skeleton.     

Enantioselective synthesis of (S)-(+)-pantolactone

[reaction: see text] The Prins reaction of a chiral alkylidene morpholinone derived from (1R,2S)-ephedrine and 3-methyl-2-oxobutanoic acid proceeds with good diastereoselectivity to generate a spiro bis-acetal. Lewis acid mediated diastereoselective reductive cleavage of the spiro acetal and subsequent removal of the ephedrine portion generates a alpha-hydroxy-gamma-methoxy carboxamide which is readily converted to (S)-(+)-pantolactone with high enantiomeric excess.     

Enantioselective total synthesis of (-)-clavosolide B

Enantioselective synthesis of 2, a revised structure for (-)-clavosolide B, was accomplished by a convergent approach, where syn-selective aldol, hydroxy-directed cyclopropanation, Mitsunobu inversion, Schmidt-type glycosylation, and macrolactonization reactions were utilized as key reactions. Comparison of 1H and 13C NMR spectra and optical rotation measurement confirmed the relative and absolute stereochemistry of clavosolide B (2).