Stereoselective gamma-lactam synthesis via palladium-catalysed intramolecular allylation

A novel route to the synthesis of 3-(tolylsulfonyl)-4,5-cis-disubstituted gamma-lactams using a diastereoselective palladium-catalysed intramolecular allylation of amino acid-derived allylic carbonates has been developed.     

Total synthesis of the thiopeptide amythiamicin D

The first total synthesis of the thiopeptide antibiotic amythiamicin D is described.     

Total synthesis of the thiopeptide antibiotic amythiamicin D

The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.     

Solid-phase synthesis of a 4-substituted gamma-lactam library

Pyrrolidin-2-one (gamma-lactam) derivatives have shown a wide range of activities as ligands to diverse receptors, e.g., integrin, CCR5, and CCK. Therefore, we have prepared a large library of these derivatives for high-throughput screening against various protein targets, after developing a synthesis of pyrrolidin-2-ones on solid phase. Exploration of the ring formation was key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-protected amino acids and subsequent deprotection of the Fmoc group were accomplished readily. The resulting resin-bound primary amines were treated with beta-monomethyl itaconate under gentle heat in a mixture of methanol and toluene to yield the desired intermediates. Finally, saponification, amide formation, and cleavage from the resin led to the production of a library of 12,000 pyrrolidin-2-one derivatives. These products were isolated as diastereomeric mixtures of high purity and were obtained in good yields.     

Stereoselective synthesis of highly functionalized thiopeptide thiazole fragments from uronic acid/cysteine condensation products: access to the core dipeptide of the thiazomycins and nocathiacins

We present the stereoselective synthesis of various highly functionalized thiazole dipeptides that are found in thiopeptide antibiotics like thiazomycins and nocathiacins. The condensation of an uronic acid with l-cysteine methyl ester delivers along two different protocols the stereopure thiazolidine lactones or lactams on the multigram scale, respectively. Oxidation of the thiazolidine moiety to the thiazole and tailoring of the sugar chains yield the thiazole dipeptide as present in the core motif of the thiopeptide antibiotics, as well as its epimer and a homolog. The modular assembly of the potent natural products and their analogs relies on the synthetic accessibility of adequately protected building blocks of tailored absolute stereochemistry.     

Synthesis of the pyridine core of cyclothiazomycin

A highly convergent synthesis of the pyridine core of the thiopeptide antibiotic cyclothiazomycin has been developed based on a [2+2+2] cyclotrimerization key step. The regioselective assembly of the heterocyclic center of this important class of antibiotics takes advantage of a temporary silicon tether and the ruthenium-catalyzed cyclotrimerization reaction of a diyne and an electron-poor thiazole nitrile.     

Stereoselective synthesis of selenosteroids

A stereoselective synthesis of selenosteroids 4 and 5 has been achieved. Starting from commercial available cholesterol 1, followed by asymmetric epoxidation, and subsequently, by stereoselective epoxide ring opening, employing a selenium nucleophilic species, the correspondent products were afforded in high yields. The compounds were being evaluated for their biological activity and as a chiral pool for asymmetric transformations.     

Stereoselective synthesis of microcarpalide

The first total synthesis of the naturally occurring nonenolide, microcarpalide, is described. The key step in the synthesis was the ring-closing metathesis of a dienic ester prepared in turn by coupling an acid and an alcohol stereoselectively synthesized from (S,S)-tartaric acid and (R)-glycidol, respectively. [structure: see text]     

Stereoselective synthesis of microcarpalide

Microcarpalide is a strong microfilament disrupting agent. The convergent and stereoselective synthesis of microcarpalide was succeeded via Julia olefination and macrolactonization.     

Stereoselective synthesis of polytetrahydropyrans

We describe a stereoselective synthesis of a bistetrahydropyran ring system with the same trans-syn-trans stereochemistry as is found in the marine polyether ladder yessotoxin.     

Stereoselective synthesis of anamarine

A stereoselective synthesis of the naturally occurring, α,β-unsaturated lactone anamarine is described. The key step was a highly stereoselective aldol reaction of a protected erythrulose derivative with a chiral aldehyde. Another relevant step was an asymmetric aldehyde allylation with a chiral allylborane. The lactone ring was made by means of a ring-closing metathesis.     

Stereoselective synthesis of spicigerolide

The first total synthesis of the naturally occurring, cytotoxic lactone spicigerolide is described. The commercially available sugar l-rhamnose was the chiral starting materal. Key steps in the synthesis were an aldehyde two-carbon homologation via the Corey-Fuchs protocol, an asymmetric Brown-type aldehyde allylation and a ring-closing metathesis.     

Stereoselective synthesis of vinylphosphonate

Dialkyl vinylphosphonate is stereoselectively prepared by palladium-catalyzed reaction of vinyl bromide with dialkyl phosphite.     

Stereoselective synthesis of umuravumbolide

An efficient stereoselective total synthesis of umuravumbolide has been developed. The key features of the synthesis include Jacobsen resolution, Wadsworth Emmons olefination and silyl-tethered ring closing metathesis.     

Stereoselective synthesis of beta-L-rhamnopyranosides

Stereoselective construction of 1,2-cis-beta-L-rhamnopyranoside was achieved by our effective methodology using naphthylmethyl (NAP) ether-mediated intramolecular aglycon delivery (IAD). The complete stereoselective synthesis of the bacterial extracellular polysaccharide, alpha-L-Rhap-(1-->3)-beta-L-Rhap-(1-->4)Glcp from Sphaerotilus natans, was successfully accomplished, clearly demonstrating that the NAP-IAD methodology is highly versatile.     

Stereoselective synthesis of zooxanthellactone

The marine polyunsaturated natural product zooxanthellactone was synthesized in six steps and in 11% overall yield from eicosapentaenoic acid. The key synthetic steps were a Sonogashira cross-coupling reaction and a stereoselective semi-reduction. These efforts, together with NMR and optical rotation data, confirmed the reported structure of zooxanthellactone.     

Stereoselective synthesis of the lituarine tricyclic spiroacetal

[reaction: see text] Oxidative cyclizations of 2-(4-hydroxybutyl)furan derivatives provide spirobutenolide acetals directly; on the basis of this methodology, we describe an asymmetric synthesis of a tricyclic spirobutenolide precursor to the C(7-18) fragment common to lituarines A-C.