Solid-phase synthesis of dihydrovirginiamycin S1, a streptogramin B antibiotic

We describe the first solid-phase synthesis of dihydrovirginiamycin S(1), a member of the streptogramin B family of antibiotics, which are nonribosomal-peptide natural products produced by Streptomyces. These compounds, along with the synergistic group A components, are "last line of defense" antimicrobial agents for the treatment of life-threatening infections such as vancomycin-resistant enterococci. The synthesis features an on-resin cyclization and is designed to allow production of streptogramin B analogues with diversification at positions 1', 1, 2, 3, 4, and 6. Several synthetic challenges known to hinder the synthesis of this class of compounds were solved, including sensitivity to acids and bases, and epimerization and rearrangements, through the judicious choice of deprotection conditions, coupling conditions, and synthetic strategy. This work should enable a better understanding of structure-activity relationships in the streptogramin B compounds, possible identification of analogues that bypass known resistance mechanisms, and perhaps the identification of analogues with novel biological activities.     

Chemoenzymatic approach to enantiopure streptogramin B variants: characterization of stereoselective pristinamycin I cyclase from Streptomyces pristinaespiralis

Streptogramin B antibiotics are cyclic peptide natural products produced by Streptomyces species.In combination with the synergistic group A component, they are "last line of defense" antimicrobial agents against multiresistant cocci. The racemization sensitivity of the phenylglycine (Phg(7)) ester is a complex challenge in total chemical synthesis of streptogramin B molecules. To provide fast and easy access to novel streptogramin antibiotics, we introduce a novel chemoenzymatic strategy in which diversity is generated by standard solid phase protocols and stereoselectivity by subsequent enzymatic cyclization. For this approach, we cloned, overproduced, and biochemically characterized the recombinant thioesterase domain SnbDE TE of the pristinamycin I nonribosomal peptide synthetase from Streptomyces pristinaespiralis. SnbDE TE catalyzes regioselective ring closure of linear peptide thioester analogues of pristinamycin I as well as stereoselective cyclization out of complex in situ racemizing substrate mixtures, enabling synthesis of Streptogramin B variants via a dynamic kinetic resolution assay. A remarkable substrate tolerance was detected for the enzymatic cyclization including all the seven positions of the peptide backbone. Interestingly, SnbDE TE was observed to be the first cyclase from a macrolactone forming NRPS which is additionally able to catalyze macrolactamization of peptide thioester substrates. An N-methylated peptide bond between positions 4 and 5 is mandatory for a high substrate turnover. The presented strategy is potent to screen for analogues with improved activity and guides our understanding of structure--activity relationships in the important class of streptogramin antibiotics.     

The total synthesis of tubulysin D

The first total synthesis of tubulysin D is reported. The development and application of new tert-butanesulfinamide methods allowed for rapid syntheses of the tubuvaline and tubuphenylalanine fragments. Most significantly, a route was devised and implemented to introduce and carry forward the highly labile N,O-acetal functionality. Tubulysin D is the most active member of the tubulysin family, and the efficient synthetic route described herein will allow for the rapid syntheses of analogues to probe the biological activity of this important class of natural products.     

Chemoenzymatic route to macrocyclic hybrid peptide/polyketide-like molecules

Hybrid peptide-polyketides are a class of medically and biologically important natural products characterized by stereochemical and functional diversity. In their biosynthesis, hybrids are often macrocyclized to achieve rigid structures that populate bioactive conformations. We herein present a chemoenzymatic strategy to access the stereochemical and functional diversity found in macrocyclic hybrid natural products in a manner amenable to efficient library synthesis. Our method makes use of small building blocks in the form of Fmoc-protected epsilon-amino acids containing embedded polyketide functionality. The building block approach allows for combinatorial synthesis of linear molecules that can be activated as soluble thioesters or tethered to a solid-phase resin. We demonstrate that these linear molecules are substrates for macrocyclization by a tolerant catalyst, TycC TE, derived from a nonribosomal peptide synthetase. The method should allow for access to diverse structures with hybrid peptide-polyketide character that can be screened for improved or novel activities.     

A protecting-group-free synthesis of arbusculone,andirolactone, pinnatolide,ipomolactone, cyclocapitelline and isocyclocapitelline

A general approach for a collective synthesis of natural products containing substituted THF ring is described. In this paper, Arbusculone, a small molecule natural product accomplished using a short route, is used as the key intermediate to achieve the total synthesis of Andirolactone, Pinnatolide, Ipomolactone, Cyclocapitelline, Isocyclocapitelline and their two isomers in less than ten steps. The present effort highlights protecting-group-free total syntheses and the shortest route to access these natural products from commercially available cheap starting materials.     

Unsaturated Sugars : An Alternative Route to 3, 5, 6-Trideoxy-1, 2-O-Isopropylidene-α-D-Glycero-Hex-3, 5-Dienofuranose

Unsaturated sugars are among the most important and useful compounds in carbohydrate chemistry. They assume key roles in the synthesis of modified sugars and complex natural products. The title compound 5, an unsaturated sugar containing a conjugated diene system, has been reported¹ recently and its potential synthetic value for Diels-Alder reaction giving access to functionalized annulated furanoses has been pointed out.² For a different synthetic purpose we prepared this compound by an alternative route albeit from the same starting material used by the previous authors. Our synthetic sequence is outlined in the following scheme.     

Total synthesis of ovalifoliolatin B, acerogenins A and C

A short and concise route for the synthesis of ovalifoliolatin B, a highly strained macrocyclic diaryl ether heptanoid natural product that also provides quick access to acerogenins A and C natural products has been reported.     

The total synthesis of (-)-callystatin A

Callystatin A is a prominent member of a class of natural products which display promising growth inhibition of cancer cells in their biological profile. The challenging structure and the interesting biological activity of (-)-callystatin A fueled our interest in the synthesis of this marine natural product. We achieved the total synthesis using a highly convergent approach joining four subunits together with a Wittig olefination, a selective Heck reaction and an aldol reaction as the pivotal steps. The aldol reaction as one of the final transformations during the synthesis opens fast access to a variety of structural analogues and circumvents tedious protecting group manipulations. Here we report an improved synthesis utilizing a modified vinyl iodide which shortens the synthesis by two steps. Additionally, first biological results will be reported.     

Total synthesis of the naphthyridine alkaloid jasminine

The synthesis of (±)-jasminine (1), a member of a small group of naphthyridine alkaloids, has been achieved. The synthetic route takes advantage of the reactivity of dihydropyridine intermediates for the preparation of trisubstituted pyridine 4, which gives access to the alkaloid by a reductive amination-lactamization tandem reaction.     

Total synthesis of potent antifungal marine bisoxazole natural products bengazoles A and B

The bengazoles are a family of marine natural products that display potent antifungal activity and a unique structure, containing two oxazole rings flanking a single carbon atom. Total syntheses of bengazole A and B are described, which contain a sensitive stereogenic centre at this position between the two oxazoles. Additionally, the synthesis of 10-epi-bengazole A is reported. Two parallel synthetic routes were investigated, relying on construction of the 2,4-disubstituted oxazole under mild conditions and a diastereoselective 1,3-dipolar cycloaddition. Our successful route is high yielding, provides rapid access to single stereoisomers of the complex natural products and allows the synthesis of analogues for biological evaluation.     

An approach to the synthesis of dimeric resveratrol natural products via a palladium-catalyzed domino reaction

A route for the rapid assembly of the carbon framework of several resveratrol natural products is presented. A palladium-catalyzed domino reaction of bromostilbene derivative 6 and tolane 7, involving two sequential Heck coupling reactions, provides access to the benzofulvene-based core of various resveratrol-derived natural products. The carbon skeleton of pallidol and its congeners is achieved by a Lewis acid-induced Nazarov-type oxidative cyclization of 9.     

A practical method for the stereoselective generation of beta-2-deoxy glycosyl phosphates

Beta-2-Deoxy sugar nucleotides are substrates used by a variety of glycosyltransferases (Gtfs). We have developed a chemical route to synthesize beta-2-deoxy sugar phosphates that starts from alpha-glycosyl chlorides. Our approach reliably provides access to a range of NDP beta-2-deoxy sugars essential for studying glycosyltransferases involved in the synthesis of biologically active natural products.     

Total synthesis of (-)-tirandamycin C

Tirandamycin C is a newly isolated member of the tetramic acid family natural products. We described herein the first enantioselective synthesis of natural (-)-tirandamycin C, the postulated biosynthetic precursor of other members of this family. The highly stereoselective (>15:1) mismatched double asymmetric γ-stannylcrotylboration reaction of aldehyde 8 with crotylborane reagent (R)-E-9 was utilized to access the key anti,anti-stereotriad 18.     

New Approach to the Synthesis of the Natural Product Aripuanin

Abstract

Aripuanin is a megastigmane that exists in the leaves of Ficus aripuanensis C.C. Berg (Moraceae). The present study describes a new approach to the total synthesis of this natural product starting from the readily available β-ionone. The proposed synthetic route provided racemic aripuanin in moderate yields (~31%). This route can be applied to the synthesis of other natural products bearing the megastigmane moiety, as well as to the enantioselective synthesis of aripuanin derivatives.     

A Short Scalable Route to (−)‐α‐Kainic Acid Using Pt‐Catalyzed Direct Allylic Amination

An increased supply of scarce or inaccessible natural products is essential for the development of more sophisticated pharmaceutical agents and biological tools, and thus the development of atom‐economical, step‐economical and scalable processes to access these natural products is in high demand. Herein we report the development of a short, scalable total synthesis of (?)‐α‐kainic acid, a useful compound in neuropharmacology that is, however, limited in supply from natural resources. The synthesis features sequential platinum‐catalyzed direct allylic aminations and thermal ene‐cyclization, enabling the gram‐scale synthesis of (?)‐α‐kainic acid in six steps and 34 % overall yield.     

Total Synthesis of Keramamides A and L from a Common Precursor by Late‐Stage Indole Synthesis and Configurational Revision

The marine natural products keramamide A and L, members of the class of anabaenopeptin‐type peptides, were synthesized for the first time by a convergent and flexible route. The installation of the substituted tryptophan moieties was accomplished at the very end of the synthesis on the cyclic peptides, and thus enabled the synthesis of both natural products from one common precursor. The preparation of several epimers clearly indicates that the originally proposed relative configurations of both Keramamides A and L were not correct.     

A stereoselective synthesis of (+)-gonyautoxin 3

An asymmetric synthesis of the paralytic shellfish poison (PSP), (+)-gonyautoxin 3, is described. A unique, Rh-catalyzed amination reaction provides rapid access to the heteratom-rich, tricyclic core of the toxin, which is common to more than 30 related natural products. The completed route should facilitate the preparation of other naturally occurring PSPs and designed analogues thereof.     

Palladium(II)‐Catalyzed meta‐CH Olefination: Constructing Multisubstituted Arenes through Homo‐Diolefination and Sequential Hetero‐Diolefination

Divinylbenzene derivatives represent an important class of molecular building blocks in organic chemistry and materials science. Reported herein is the palladium‐catalyzed synthesis of divinylbenzenes by meta‐C? H olefination of sulfone‐based arenes. Successful sequential olefinations in a position‐selective manner provided a novel route for the synthesis of hetero‐dialkenylated products, which are difficult to access using conventional methods. Additionally, 1,3,5‐trialkenylated compounds can be generated upon successful removal of the directing group.     

Palladium(II)‐Catalyzed meta‐C?H Olefination: Constructing Multisubstituted Arenes through Homo‐Diolefination and Sequential Hetero‐Diolefination

Divinylbenzene derivatives represent an important class of molecular building blocks in organic chemistry and materials science. Reported herein is the palladium‐catalyzed synthesis of divinylbenzenes by meta‐C H olefination of sulfone‐based arenes. Successful sequential olefinations in a position‐selective manner provided a novel route for the synthesis of hetero‐dialkenylated products, which are difficult to access using conventional methods. Additionally, 1,3,5‐trialkenylated compounds can be generated upon successful removal of the directing group.     

Convergent, stereoselective syntheses of the glycosidase inhibitors broussonetines C, O and P

The first syntheses of the polyhydroxylated alkaloids (iminosugars) broussonetines O and P, glycosidase inhibitors of the pyrrolidine class, have been performed in a convergent, stereocontrolled way from d-serine as the chiral starting material. The synthesis of broussonetin C, a further member of this compound family, is also reported. A cross-metathesis step was one key feature of the synthesis. The versatility of the synthetic concept chosen permits the access to many members of this compound family, both natural ones and analogues thereof.