A biosynthetically inspired synthesis of (−)-berkelic acid and analogs

We describe a complete account of our total synthesis and biological evaluation of (?)-berkelic acid and analogs. We delineate a synthetic strategy inspired by a potentially biomimetic union between the natural products spicifernin and pulvilloric acid. After defining optimal parameters, we executed a one-pot silver-mediated in situ dehydration of an isochroman lactol to methyl pulvillorate, the cycloisomerization of a spicifernin-like alkynol to the corresponding exocyclic enol ether, and a subsequent cycloaddition to deliver the tetracyclic core of berkelic acid. Our studies confirm that the original assigned berkelic acid structure is not stable and equilibrates into a mixture of 4 diastereomers, fully characterized by X-ray crystallography. In addition to berkelic acid, C22-epi-berkelic acid, and nor-berkelic acids, we synthesized C26-oxoberkelic acid analogs that were evaluated against human cancer cell lines. In contrast to data reported for natural berkelic acid, our synthetic material and analogs were found to be devoid of activity.     

Total synthesis of (−) verbenalol and (−) epiverbenalol

The first asymmetric synthesis of (−) verbenalol and (−) epiverbenalol, starting from the organometallic complex (−) 1, is described.     

The total synthesis of (−)-indolactam I

The first total synthesis of (−)-indolactam I (1) is reported. An efficient synthetic route was established to furnish the natural product in 8 steps. This strategy employed a copper-catalyzed amino acid arylation, peptide coupling, and Lewis acid-mediated macrocyclization to yield 1 from readily available building blocks. In addition, the cell growth inhibition activity of the natural product was examined through assays with the K562 leukemia cell line.     

A stereocontrolled synthesis of (−)-detoxinine from l-ascorbic acid

A stereoselective synthesis of (−)-detoxinine, the core unit of the detoxifying agent detoxin D₁, is presented. The approach, characterized by the use of an inexpensive starting material and by the easy and stereoselective preparation of the key 4,5-disubstituted oxazolidin-2-one 11, proves to be a suitable alternative to the known procedures.     

Enantioselective synthesis of γ-lactones from thioglycolic acid: Syntheses of (−)-muricatacin and 5-epi-(−)-muricatacin

An approach for the enantioselective synthesis of functionalized γ-lactones and its application to the syntheses of (−)-muricatacin 1a and 5-epi-(−)-muricatacin 1b is reported. A sequential oxidation of the intermediate 4 with m-chloroperoxybenzoic acid was conducted to realize the reaction mechanism.     

The first total synthesis of (−)-sinulariol-B and three other cembranoids

The first total synthesis of (−)-sinulariol-B, a marine cembrandiol, was achieved from geraniol. Three other cembranoids were also synthesized from (−)-sinulariol-B.     

Asymmetric synthesis of (S)-(−)-acromelobinic acid

A total synthesis of (S)-(−)-acromelobinic acid 2, which was isolated from clitocybe acromelalga, was achieved via an asymmetric hydrogenation protocol. Dehydroamino acid derivative 12 was prepared from 2,5-lutidine 5 and subjected to asymmetric hydrogenation using (S,S)-[Rh(Et-DuPHOS)(COD)]BF₄ to give the (S)-(+)-pyridylalanine derivative 13 in 93% yield and >96% e.e. Removal of the protecting groups in (S)-(+)-13 afforded (S)-(−)-acromelobinic acid 2.     

Asymmetric total synthesis of (+)-isocryptotanshinone and formal synthesis of (−)-cryptotanshinone

The first asymmetric total synthesis of (+)-isocryptotanshinone was achieved in 12 linear steps with 12% overall yield from commercially available dihydrobenzopyrone. The key step was a base-mediated cyclization reaction. In addition, the synthetic strategy included the formal synthesis of (−)-cryptotanshinone.     

Enantiodivergent synthesis of (+)- and (−)-isolaurepan

The enantiodivergent synthesis of (+)-and (?)-isolaurepan was achieved from a common chiral template easily available from tri-O-acetyl-d-glucal, using as key step a diastereoselective thermal Claisen rearrangement, combined with a ring expansion reaction using trimethylsilyldiazomethane.     

Stereoselective synthesis of peracetylated (−)-gloeosporiol via acid catalysed intramolecular etherification

A simple and an efficient strategy have been developed for the stereoselective synthesis of peracetylated (?)-gloeosporiol by acid catalysed cyclisation from the commercially available starting materials.     

Stereoselective synthesis of (−)-cytoxazone

A novel stereoselective synthesis of (−)-cytoxazone 1 was achieved via addition of p-methoxyphenylmagnesium bromide to the benzylimine derived from (S)-2,3-O-isopropylidene glyceraldehyde followed by one-step regioselective cyclization of N-Boc amino diol 7.     

Total synthesis of (−)-lentiginosine

A simple and practical synthesis of (−)-lentiginosine 2 with good overall yield has been achieved from the commercially available diethyl d-tartarate. The key steps are a highly stereoselective Grignard reaction on an aldehyde and a Staudinger reduction.     

Total synthesis of (−)-vindoline

In this full paper, a stereocontrolled strategy for the total synthesis of (?)-vindoline is described. This synthetic route features: 1) rapid construction of the stereochemical center at C19 through a highly diastereoselective vinylogous Mannich addition; 2) tandem Heathcock/aza-Prins cyclization to install rings C and E in vindoline; 3) oxidative transformation of β-ketoester to enone; 4) stereoselective inversion of C4 stereochemistry with triphenylphosphine and carbon tetrabromide followed by Brønsted acid.     

Stereoselective synthesis of (−)-centrolobine

The stereoselective synthesis of (−)-centrolobine has been accomplished starting from d-glyceraldehyde acetonide by a combination of chelation-controlled diastereoselective alkylation and ring-closing metathesis. A high degree of 1,3-asymmetric induction has been realized in an ether system.     

Total synthesis of (−)-isoaltholactone

A short and efficient stereoselective synthesis of a styryllactone (-)-isoaltholactone has been achieved in seven steps and 33% overall yield, starting from the readily available carbohydrate D-mannose. The key steps of our synthesis involve intramolecular tetrahydrofuran cyclization and one-pot acetonide deprotection-lactonization.     

Total synthesis of (−)-haploscleridamine

Asymmetric total synthesis of the imidazole containing β-carboline natural product, haploscleridamine, from histidine is described. Key to the successful assembly of this alkaloid is a ring-closing metathesis reaction of an imidazole derived allylic alcohol to construct a 3-piperidinone. Application of the Buchwald-modification of the classical Fischer indolization and deprotection of the N-tosyl moiety delivered haploscleridamine.     

Total synthesis and cytotoxicity of (−)-jorumycin and its analogues

(?)-Jorumycin and its 15 C-22 analogues were prepared employing l-tyrosine as the chiral starting material via 21 steps. These analogues, along with (?)-jorumycin itself, were evaluated in vitro for cytotoxicity against HCT-8, BEL-7402, Ketr3, A2780, MCF-7, A549, BGC-823, Hela, HELF, and KB cells. The IC₅₀ values of the cytotoxicity of most of these analogs were at the level of nM, which was similar to that of (?)-jorumycin. Among these analogs including (?)-jorumycin, hippuric acid ester derivative 23 exhibited the most potent and broad-spectrum cytotoxic activity against the ten cell lines with an average IC₅₀ of 2.12 nM.     

Total synthesis of (−)-vitrenal and its biological activity

(−)-Vitrenal, the enantiomer of a natural sesquiterpene aldehyde isolated from a liverwort, has been synthesized starting from (+)-Δ³-carene, and its activity as a plant-growth regulator has been tested.     

An efficient and simple synthesis of (−)-wine lactone

A, short and efficient diastereoselective synthesis of (−)-wine lactone (−)-4a involving FeCl₃/NaI-mediated iodolactonization of γ,δ-unsaturated acid 7 as the key step is described.