Stereoselective Total Synthesis Research Articles

Stereoselective Total Synthesis of (+)-Casuarine via a Functionalized Pyrrolidine

AbstractThe stereoselective total synthesis of (+)-casuarine has been achieved via a functionalized pyrrolidine obtained from a chiral 1,3-oxazine. The synthetic strategy includes a stereoselective dihydroxylation reaction using osmium tetroxide and stereoselective Grignard-type vinyl addition reaction as the key steps to generate the two new stereocenters. The dihydroxylation catalyzed by osmium tetroxide formed anti-amino alcohol, and the vinyl addition formed syn-alcohol. (+)-Casuarine was prepared from the functionalized pyrrolidine over 11 steps in an overall yield of 16%.

Chiral pool approach to the total synthesis of phomonol

We report a stereoselective total synthesis of a natural product, phomonol, from readily available D-aspartic acid. The key steps include Wittig olefination, Sharpless asymmetric dihydroxylation, Grignard addition, diastereoselective reductive etherification and Wacker oxidation.

Stereoselective Total Synthesis of (+)-Brevipolide H from d-Galactal

AbstractAn efficient and concise synthesis of cytotoxic 5,6-dihydro-α-pyrone (+)-brevipolide H has been accomplished in 12 long linear steps in 8.65% overall yield from readily available chiral synthons, d-galactal and ethyl l-lactate. The features of this synthesis are highly diastereoselective Simmons–Smith cyclopropanation and carbohydrate-based chiron approach to rapid access to key 5,6-dihydro-α-pyrone skeleton.

Transition-Metal-Mediated Chemo- and Stereoselective Total Synthesis of (−)-Galanthamine

An asymmetric synthetic route to (-)-galanthamine (1), a pharmacologically active Amaryllidaceae alkaloid used for the symptomatic treatment of early onset Alzheimer's disease, was successfully established with very high levels of stereocontrol. The key to achieving high chemo- and stereo-selectivity in this approach was the use of transition-metal-mediated reactions, namely, enyne ring-closing metathesis, Heck coupling, and titanium-based asymmetric allylation.

Total syntheses of ent-hypocoprin A and ent-hypocoprin B.

This study reports the stereoselective total syntheses of the antipodes of the unique 3/10 bicyclic skeletal sesquiterpenoids, namely, hypocoprin A and hypocoprin B. The synthesis involved conjugate addition accelerated by trimethylsilyl chloride, construction of the ten-membered ring via the intramolecular SN2 reaction promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene, and osmium-mediated π-facial selective dihydroxylation to functionalize the 1,1-disubstituted alkene.

Total synthesis of the antibacterial polyketide natural product thailandamide lactone.

Stereoselective total synthesis of the structurally intriguing polyketide natural product thailandamide lactone was accomplished, and done so using a convergent approach for the first time to the best of our knowledge. The key features of this synthesis included use of a Crimmins acetate aldol reaction, Evans methylation, Urpi acetal aldol reaction, Sharpless asymmetric epoxidation and subsequent γ-lactonization for the installation of six asymmetric centers and the use of the Negishi reaction, Julia-Kocienski olefination, cross metathesis, HWE olefination and intermolecular Heck coupling for construction of a variety of unsaturated linkages. Pd(i)-based Heck coupling was introduced, for the first time to the best of our knowledge, quite efficiently to couple the major eastern and sensitive western segments of the molecule. The antibacterial activity of thailandamide lactone was also evaluated.

Stereoselective total synthesis of (−)-hygrophorone A12 and 4-epi-2,3-dihydrohygrophorone H12

Stereoselective total synthesis of anti-fungal cyclopentenone (−)-hygrophorone A12 and cyclopentanone 4-epi-2,3-dihydrohygrophorone H12 were achieved in high overall yields from d-ribose. An aqueous KOH mediated diastereoselective formation of β-hydroxy ketone with three contiguous chiral centres served as a key step in this synthesis.

Catalysis‐Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester

AbstractA concise and stereoselective total synthesis of the clinically relevant tricyclic prostaglandin D2 metabolite (tricyclic‐PGDM) methyl ester in racemic form was accomplished in eight steps from a readily available known cyclopentene‐diol derivative. The synthesis features a nickel‐catalyzed Ueno–Stork‐type dicarbofunctionalization to generate two consecutive stereocenters, a palladium‐catalyzed carbonylative spirolactonization to build the core oxaspirolactone, and a Z‐selective cross‐metathesis to introduce the (Z)‐3‐butenoate side chain, a group challenging to introduce through traditional Wittig protocols and troublesome for the two previous total syntheses. A general Z‐selective cross‐metathesis protocol to construct (Z)‐β,γ‐unsaturated esters was also developed that has broad functional group tolerance and high stereoselectivity. Additionally, our synthesis already accumulated 75 mg of valuable material for an 18O‐tricyclic‐PGDM‐based assay used in clinical settings for inflammation.

Catalysis-Enabled Concise and Stereoselective Total Synthesis of the Tricyclic Prostaglandin D2 Metabolite Methyl Ester.

A concise and stereoselective total synthesis of the clinically relevant tricyclic prostaglandin D2 metabolite (tricyclic-PGDM) methyl ester in racemic form was accomplished in eight steps from a readily available known cyclopentene-diol derivative. The synthesis features a nickel-catalyzed Ueno-Stork-type dicarbofunctionalization to generate two consecutive stereocenters, a palladium-catalyzed carbonylative spirolactonization to build the core oxaspirolactone, and a Z-selective cross-metathesis to introduce the (Z)-3-butenoate side chain, a group challenging to introduce through traditional Wittig protocols and troublesome for the two previous total syntheses. A general Z-selective cross-metathesis protocol to construct (Z)-β,γ-unsaturated esters was also developed that has broad functional group tolerance and high stereoselectivity. Additionally, our synthesis already accumulated 75 mg of valuable material for an 18 O-tricyclic-PGDM-based assay used in clinical settings for inflammation.

A Chiral Pool Approach for Total Synthesis of (+)‐Diaportinol, (−)‐Peniisocoumarin H and (+) & (−)‐Desmethyldiaportinol; Their Structural Revision

AbstractFirst stereoselective total synthesis of (+)‐diaportinol, (−)‐peniisocoumarin H and (+)‐ & (−)‐desmethyldiaportinol is demonstrated and their absolute stereochemistry was revised accordingly. A convergent approach has been developed that uses L‐malic acid as chiral synthons for the synthesis of 2, and D‐malic acid for 1 and 3. O,O‐Dimethylorsellinic acid ester was prepared and coupled with Weinreb amide 6 or 6D via lateral lithiation carbonylation and a subsequent base catalyzed cyclization provided the isochromenone moiety and a selective deprotection was achieved using BBr3.

Stereoselective Synthesis of (±)-Cephanolide B.

A concise and stereoselective total synthesis of (±)-cephanolide B was achieved in 15 steps. The key steps in the synthesis were as follows: (i) an intermolecular Diels-Alder reaction followed by lactonization to form the oxabicyclo[2.2.2]octane DE ring; (ii) a tandem reaction, featuring an intramolecular Pauson-Khand reaction, a 6π-electrocyclization, and an oxidative aromatization by O2, to construct the ABC-tricyclic rings (6-5-6); and (iii) a phthaloyl peroxide-mediated arene oxygenation to install the C-13 phenol group.

Total synthesis of (3R, 4S)-4-hydroxylasiodiplodin

An efficient stereoselective total synthesis of (3R, 4S)-4-hydroxylasiodiplodin has been accomplished starting from known starting materials. The key steps involved in this synthesis are Stille cross coupling, alkylation of 1,3-dithiane and Yamaguchi macrolactonization.

Stereoselective total synthesis of (-)-curvularin

A concise total synthesis of (-)-Curvularin have been synthesized from commercially available (S)-(−)-propylene epoxide and (3,5-Dimethoxyphenyl)acetic acid. The key steps involved in the synthesis are Vilsmeier-Haack formylation, Grignard reaction, alkylation of 1,3-dithiane and Yamaguchi macrolactonization.

Correction to “Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E”

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to “Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E”Pei QuPei QuMore by Pei Qu and Scott A. Snyder*Scott A. SnyderMore by Scott A. Snyderhttps://orcid.org/0000-0003-3594-8769Cite this: J. Am. Chem. Soc. 2021, 143, 41, 17300–17301Publication Date (Web):October 5, 2021Publication History Published online5 October 2021Published inissue 20 October 2021https://doi.org/10.1021/jacs.1c08386Copyright © 2021 American Chemical SocietyRIGHTS & PERMISSIONSACS AuthorChoiceCC: Creative CommonsBY: Credit must be given to the creatorArticle Views2161Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (653 KB) Get e-Alerts Get e-Alerts

Stereoselective Total Synthesis of (±)-Pleurospiroketals A and B.

A full account of our efforts toward the stereoselective total synthesis of sesquiterpenoid-derived natural products (±)-pleurospiroketals A and B is described. Commercially available 3-methyl-2-cyclohexenone and 2,2-dimethyloxirane were used as key building blocks, and the substrate-controlled stereoselection was exploited to access the entire stereochemistry of these natural products. Initially, a planned synthetic route involving a [6,5]-bicyclic lactone intermediate was found to be insurmountable, and the later strategy comprising OsO4-NMO-mediated dihydroxylation of 3-methyl-2-cyclohexenone, followed by Luche reduction, Eschenmoser methylenation, and Brønsted acid-induced spiroketalization steps, was ultimately identified as the reliable strategy.

Catalytic δ-hydroxyalkynone rearrangement in the stereoselective total synthesis of centrolobine, engelheptanoxides A and C and analogues

A catalytic stereoselective total synthesis of centrolobine and engelheptanoxides A and C has been completed via a metal-free catalytic δ-hydroxyalkynone rearrangement to 2,3-dihydro-4H-pyran-4-one and diastereoselective hydrogenation to the all syn-2,4,6-trisubstituted pyran strategy. The onliest required chirality was introduced by Jacobsen kinetic resolution, which further directed the diastereoselective hydrogenation. A first stereoselective synthesis of engelheptanoxide A is also accomplished. The analogues and derivatives of centrolobine and engelheptanoxides prepared were evaluated for antitubercular activity against M. tuberculosis H37Rv ATCC 27294.

Cp2TiCl-Mediated Reductive Cyclization: Total Synthesis of Pestalotiolactone A, Myrotheciumone A, and Scabrol A.

The first stereoselective total syntheses of fungal secondary metabolites monoterpenoid (+)-pestalotiolactone A, meroterpenoid (-)-myrotheciumone A, and iridoid lactone (+)-scabrol A have been accomplished in an expedient unified approach starting from d-(+)-malic acid employing an epoxide opening-radical cyclization protocol initiated by Cp2Ti(III)Cl as a key step to assemble the core bicyclic lactone moieties of these molecules with complete diastereoselective control. Finally, the deoxygenation and methylation delivered the target natural products.

Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E.

The annotinolides are one of the most recent additions to the Lycopodium family of alkaloids, with its members possessing challenging, caged structures that include a [3.2.1]-bicyclic core bearing six contiguous stereocenters, including four that are fully substituted. Herein, we document a concise and stereoselective route that achieves the first total syntheses of three of its members: annotinolides C, D, and E. Key operations include a gold(I)-catalyzed Conia-ene reaction that fashions much of the main core in a single operation, as well as a number of other challenging and chemoselective transformations to generate the remaining elements. Moreover, efforts utilizing the natural products themselves, seeking adjustments in their oxidation states and the rearrangement of individual ring systems, shed light on their potential biogenesis with some outcomes counter to those originally proposed. Finally, formal enantioenriched syntheses of the target molecules are also presented.

Verification of the versatility of the in vitro enzymatic reaction giving (+)-cis-12-Oxo-phytodienoic acid

Jasmonic acid (JA) is a plant hormone involved in the defense response against insects and fungi. JA is synthesized from α-linolenic acid (LA) by the octadecanoid pathway in plants. 12-oxo-Phytodienoic acid (OPDA) is one of the biosynthetic intermediates in this pathway. The reported stereo selective total synthesis of cis-(+)-OPDA is not very efficient due to the many steps involved in the reaction as well as the use of water sensitive reactions. Therefore, we developed an enzymatic method for the synthesis of OPDA using acetone powder of flax seed and allene oxide cyclase (PpAOC2) from Physcomitrella patens. From this method, natural cis-(+)-OPDA can be synthesized in the high yield of approximately 40%. In this study, we investigated the substrate specificity of the enzymatic synthesis of other OPDA analogs with successions to afford OPDA amino acid conjugates, dinor-OPDA (dn-OPDA), and OPDA monoglyceride, and it was suggested that the biosynthetic pathway of arabidopsides could occur via MGDG.

Modular Total Synthesis of iso-Archazolids and Archazologs

Full details on the design, development, and successful implementation of suitable synthetic strategies directed toward the total synthesis of iso-archazolids and archazologs are reported. Both a biomimetic and a multistep total synthesis of iso-archazolid B, the most potent and least abundant archazolid, are described. The bioinspired conversion from archazolid B was realized by a high-yielding 1,8-Diazabicyclo[5.4.0]undec-7-ene catalyzed one-step double-bond shift. A highly stereoselective total synthesis was accomplished in 25 steps, involving a sequence of highly stereoselective aldol reactions, an efficient aldol condensation to forge two elaborate fragments, and a challenging ring-closing metathesis macrocyclization with an unusual Stewart-Grubbs catalyst. These strategies proved to be generally useful and could be successfully implemented for the preparation of three novel iso-archazolids as well as five novel archazologs, lacking the thiazole side chain. A wide variety of further archazolids and archazologs may now be targeted for exploration of the promising anticancer potential of these polyketide macrolides.