Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Total synthesis of (-)-pseudolaric acid B.

ABSTRACT: We report the enantioselective synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon, which displays interesting antifungal, antifertility, and cytotoxic activity against multidrug resistant cell lines. Our synthesis utilizes a highly efficient metal-catalyzed [5 + 2] vinylcyclopropane-alkyne intramolecular cycloaddition to construct the polyhydroazulene core of the natural product. Elaboration to the tricyclic scaffold of the pseudolaric acids was completed with an intramolecular alkoxycarbonyl radical cyclization to form the quaternary center and a highly diastereoselective cerium acetylide addition to a methyl ketone for introduction of the acid side chain.

SUBMITTER: Trost BM

PROVIDER: S-EPMC2535803 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Total synthesis of (-)-pseudolaric acid B.

Trost Barry M BM Waser Jerome J Meyer Arndt A

Journal of the American Chemical Society 20071107 47

We report the enantioselective synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon, which displays interesting antifungal, antifertility, and cytotoxic activity against multidrug resistant cell lines. Our synthesis utilizes a highly efficient metal-catalyzed [5 + 2] vinylcyclopropane-alkyne intramolecular cycloaddition to construct the polyhydroazulene core of the natural product. Elaboration to the tricyclic scaffold of the pseudolaric a ...[more]

PMID: 17985906

Similar Datasets

Total synthesis of (-)-pseudolaric acid B.

Project description:We report a full account of our work toward the total synthesis of pseudolaric acid B (1a), a diterpene acid isolated from the bark of Pseudolarix kaempferi Gordon (pinaceae). Compound 1a is an antifungal and antifertility agent. Furthermore, its capacity for inhibiting tubulin polymerization makes it a potential lead for cancer therapy. Herein, we describe the use of a Ru- or Rh-catalyzed [5 + 2] intramolecular cycloaddition reaction of an alkyne and a vinylcyclopropane for the construction of the polyhydroazulene core of the molecule. Our first unsuccessful strategy for the introduction of the quaternary center based on an epoxide opening with cyanide led to the discovery of a new TBAF-mediated isomerization of a 1,4-diene to a 1,3-diene and a vinylogous eliminative opening of an epoxide to form a dienol. Our second strategy, based on the cyclization of an alkoxycarbonyl radical upon a diene system, succeeded in forming the quaternary center. Detailed studies showed the dependence of this underutilized approach for the synthesis of lactones on substrate structure and reaction conditions. In the late stage of the synthesis, the unique capacity of cerium organometallic reagents to add to a sensitive, sterically hindered ketone was demonstrated. The easy formation of an oxo-bridged derivative was the major hurdle to the completion of the synthesis and showcased the intriguing reactivity of the complex core of the pseudolaric acids.

| S-EPMC2698933 | biostudies-literature

Total synthesis of (+/-)-actinophyllic acid.

Project description:The first total synthesis of (+/-)-actinophyllic acid (1) is reported. Key steps of this synthesis include an intramolecular oxidative coupling of ketone and malonic ester enolates and an aza-Cope-Mannich rearrangement that assembled the core structure of the natural product's unique ring system. The synthesis was accomplished from di-tert-butyl malonate in 8% overall yield by a concise sequence that proceeds by way of only seven isolated intermediates.

| S-EPMC2654095 | biostudies-literature

Total synthesis of (+/-)- and (-)-actinophyllic acid.

Project description:Development of efficient sequences for the total syntheses of (+/-)-actinophyllic acid (rac-1) and (-)-actinophyllic acid (1) are described. The central step in these syntheses is the aza-Cope/Mannich reaction, which constructs the previously unknown hexacyclic ring system of actinophyllic acid in one step from much simpler tetracyclic precursors. The tetracyclic hexahydro-1,5-methano-1H-azocino[4,3-b]indole ketone rac-37 is assembled from o-nitrophenylacetic acid in four steps, with oxidative cyclization of a dienolate derivative of tricyclic precursor rac-35 being the central step. In the first-generation synthesis, this intermediate is transformed in two steps to homoallyl amine rac-43, whose formaldiminium derivative undergoes efficient aza-Cope/Mannich reaction to give pentacyclic ketone rac-44. In four additional steps, this intermediate is advanced to (+/-)-actinophyllic acid. The synthesis is streamlined by elaborating ketone rac-37 to beta-hydroxyester intermediate rac-53, which is directly transformed to (+/-)-actinophyllic acid upon exposure to HCl and paraformaldehyde. This concise second-generation total synthesis of (+/-)-actinophyllic acid is realized in 22% overall yield from commercially available di-tert-butyl malonate and o-nitrophenylacetic acid by a sequence that proceeds by way of only six isolated intermediates. The first enantioselective total synthesis of (-)-actinophyllic acid (1) is accomplished by this direct sequence from tricyclic keto malonate (S)-35. Catalytic enantioselective reduction of alpha,beta-unsaturated ketone 66 is the key step in the preparation of intermediate (S)-35 from the commercially available Boc-amino acid 65. Discussed also is the possibility that the aza-Cope/Mannich reaction might be involved in the biosynthesis of (-)-actinophyllic acid.

| S-EPMC2851836 | biostudies-literature

Total Synthesis of (-)-Nodulisporic Acid D.

Project description:A convergent total synthesis of the architecturally complex indole diterpenoid (-)-nodulisporic acid D has been achieved. Key synthetic transformations include vicinal difunctionalization of an advanced ?,?-unsaturated aldehyde to form the E,F-trans-fused 5,6-ring system of the eastern hemisphere and a cascade cross-coupling/indolization protocol leading to the CDE multisubstituted indole core.

| S-EPMC4479160 | biostudies-literature

Concise total synthesis of (±)-actinophyllic acid.

Project description:A concise total synthesis of the complex indole alkaloid (±)-actinophyllic acid was accomplished by a sequence of reactions requiring only 10 steps from readily-available, known starting materials. The approach featured a Lewis acid-catalyzed cascade of reactions involving stabilized carbocations that delivered the tetracyclic core of the natural product in a single chemical operation. Optimal conversion of this key intermediate into (±)-actinophyllic acid required judicious selection of a protecting group strategy.

| S-EPMC4034156 | biostudies-literature

Enantioselective total synthesis of (+)-lithospermic acid.

Project description:An enantioselective synthesis of (+)-lithospermic acid, a potent anti-HIV agent, has been accomplished in a convergent manner in nine steps. The synthesis features an enantioselective intramolecular oxa-Michael addition catalyzed by a quinidine derivative, a hypervalent iodine-mediated rearrangement of chromanone to dihydrobenzofuran, an enantioselective ?-oxyamination, and an intermolecular C-H olefination.

| S-EPMC3482163 | biostudies-literature

Interaction of pseudolaric acid B with the colchicine site of tubulin.

Project description:We purified pseudolaric acid B (PAB) from the root and stem bark of Pseudolarix kaempferi (Lindl.) Gorden. Confirming previous findings, we found that the compound had high nanomolar IC₅₀ antiproliferative effects in several cultured cell lines, causing mitotic arrest and the disappearance of intracellular microtubules. PAB strongly inhibited tubulin assembly (IC₅₀, 1.1 μM) but weakly inhibited the binding of colchicine to tubulin, as demonstrated by fluorescence and with [³H]colchicine. Kinetic analysis demonstrated that the mechanism of inhibition was competitive, with an apparent K(i) of 12-15 μM. Indirect studies demonstrated that PAB bound rapidly to tubulin and dissociated more rapidly from tubulin than the colchicine analog 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone, whose complex with tubulin is known to have a half-life of 17s at 37 °C. We modeled PAB into the colchicine site of tubulin, using the crystal structure 1SA0 that contains two αβ-tubulin heterodimers, both bound to a colchicinoid and to a stathmin fragment. The binding model of PAB revealed common pharmacophoric features between PAB and colchicinoids, not readily apparent from their chemical structures.

| S-EPMC3402633 | biostudies-literature

Total synthesis of (+/-)-halichlorine, (+/-)-pinnaic acid, and (+/-)-tauropinnaic acid.

Project description:The related marine natural products halichlorine, pinnaic acid, and tauropinnaic acid have been synthesized. The described route provided access to all three compounds from a common, late-stage intermediate. The synthesis began with 1-pyrrolidino-1-cyclopentene from which an intermediate possessing the three contiguous stereocenters of the natural products was synthesized in just four steps. Olefin cross metathesis followed by a hydrogenation/hydrogenolysis reaction stereoselectively formed the piperidine ring. Use of a beta-lactam group provided internal protection for the highly congested nitrogen atom during side-chain elaboration. The beta-lactam was subsequently reduced directly to an amino aldehyde, which after the Horner-Wadsworth-Emmons reaction was elaborated to pinnaic acid. The same amino aldehyde was also transformed into halichlorine after a thiol-mediated cyclization sequence to form the dehydroquinolizidine ring system.

| S-EPMC514438 | biostudies-literature

Enantioselective total synthesis of plectosphaeroic acid B.

Project description:The first total synthesis of a member of the plectosphaeroic acid family of fungal natural products is reported. Key steps include the late-stage formation of the hindered N6-C9" bond and stereoselective introduction of the two methylthio substituents.

| S-EPMC3611964 | biostudies-literature

Total Synthesis of (-)-Nahuoic Acid Ci (Bii).

Project description:A convergent total synthesis of (-)-nahuoic acid Ci(Bii) (3), a novel cis-decalin polyketide, has been achieved. Key synthetic transformations include Type II Anion Relay Chemistry (ARC) to construct the polyol chain, a Ti-catalyzed asymmetric Diels-Alder reaction to generate the cis-decalin skeleton, and a late-stage large fragment union exploiting a Micalizio alkoxide-directed alkyne-alkene coupling tactic.

| S-EPMC5655813 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data