Stereoselective Introduction Research Articles

Synthesis of Acovenosides: Cardiac Glycosides with Potent Antitumor Activities.

Acovenoside A (1), a cardiac glycoside featuring a unique l-acovenose at C-3 and a 1β,3β,14β-trihydroxy aglycone (namely, acovenosigenin A), shows promising antiproliferative activities. Herein, we report the synthesis of acovenoside A (1) together with a panel of its congeners. The synthesis features the stereoselective introduction of the 1β,14β-OH and C17-butenolide moieties starting from androstenedione (7) and gold(I)-catalyzed glycosylation with superarmed glycosyl ortho-alkynylbenzoates as donors.

Asymmetric Total Synthesis of (+)-Lemnardosinane A.

The asymmetric total synthesis of (+)-lemnardosinane A, a rare rearranged sesquiterpenoid, has been accomplished from (S)-carvone. Key features of the synthesis are the formation of a bicyclo[3.3.1]nonane skeleton using the intramolecular aldol reaction, the stereoselective introduction of an alkyne group, and the stereoselective formation of a tricyclic skeleton via intramolecular pinacol coupling.

Asymmetric Total Synthesis of (-)-Lemnalemnane A.

The asymmetric total synthesis of lemnalemnane A, a rare rearranged sesquiterpenoid, has been accomplished in 13 steps from (S)-carvone. The key features of the synthesis are the removal of the isopropenyl group derived from (S)-carvone via a radical intermediate, the formation of the bicyclo[3.3.1]nonane skeleton using the Dieckmann condensation, the stereocontrolled construction of five continuous chiral centers by chemo- and stereoselective reduction and stereoselective introduction of the alkyne group, and the formation of the spirolactone moiety via a hemiacetal intermediate.

Total Synthesis and Structure Confirmation of (-)-Asimitrin, a C37 Annonaceous Acetogenin with a Hydroxylated Adjacent Bis-Tetrahydrofuran Core.

The total synthesis and structure confirmation of the potent cytotoxic agent (-)-asimitrin (1), a C37 annonaceous acetogenin having a hydroxylated adjacent bis-tetrahydrofuran (THF) core, are described. The present synthesis features a highly stereoselective, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 17-hydroxy-16,17-erythro-16,19-trans-THF 6, our direct ketone synthesis/l-Selectride reduction protocol for stereoselective introduction of the C(21)-C(34) unit, Sharpless asymmetric dihydroxylation (SAD), and internal Williamson etherification for construction of the 20,23-trans-THF ring.

Chemoenzymatic Total Synthesis of Haemophilus ducreyi Lipooligosaccharide Core Octasaccharides Containing Natural and Unnatural Sialic Acids

The first total synthesis of Haemophilus ducreyi lipooligosaccharide core octasaccharides containing natural and unnatural sialic acids has been achieved by an efficient chemoenzymatic approach. A highly convergent [3 + 3] coupling strategy was developed to chemically assemble a unique hexasaccharide bearing multiple rare higher-carbon sugars d-glycero-d-manno-heptose (d,d-Hep), l-glycero-d-manno-heptose (l,d-Hep), and 3-deoxy-α-d-manno-oct-2-ulosonic acid (Kdo). Key features include sequential one-pot glycosylations for oligosaccharide assembly and the construction of the challenging α-(1 → 5)-linked Hep-Kdo glycosidic bond by gold-catalyzed glycosylation with a glycosyl ortho-alkynylbenzoate donor. Furthermore, the sequential enzyme-catalyzed regio- and stereoselective introduction of a galactose residue using β-1,4-galactosyltransferase and different sialic acids using a one-pot multienzyme sialylation system was efficiently accomplished to provide the target octasaccharides.

Computational 19 F NMR of trifluoromethyl derivatives of alkenes, pyrimidines, and indenes.

The 19 F NMR chemical shifts of 13 trifluoromethyl derivatives of alkenes, pyrimidines, and indenes were calculated at the DFT level using the BhandHLYP, BHandH, PBE, PBE0, O3LYP, B3LYP, KT2, and KT3 functionals in combination with the pcS-2 basis set. Best result was documented for the BHandHLYP functional: The mean absolute error (MAE) of 0.66 ppm for the scaled values was achieved for the range of about 20 ppm. Solvent, vibrational, and relativistic corrections were found to be rather small, especially when taken in combination, generally demonstrating a slight decrease in the difference between calculated and experimental fluorine chemical shifts. As a measure of the practical importance of these compounds, one should recall that the growing number of life science products that contain trifluoromethyl groups provides a continuing driving force for the development of an effective methodology that enables both regio- and stereoselective introduction of trifluoromethyl groups into both aliphatic and aromatic systems.

Synthesis of purine derivatives of Me-TaNA and properties of Me-TaNA-modified oligonucleotides.

We previously reported that pyrimidine derivatives of methylated 2'-O,4'-C-methyleneoxy-bridged nucleic acid (Me-TaNA), a unique consecutive three-acetal-containing nucleic acid, are promising building blocks for chemically modified oligonucleotides. Herein, purine derivatives of Me-TaNA (Me-TaNA-A and -G) were synthesized and introduced into oligonucleotides. During the synthesis, we found stereoselective introduction of a substituent on the 4' carbons by using 2',3'-carbonate compounds as substrates. When forming duplexes with single-stranded RNA, the modified oligonucleotides, including purine derivatives of Me-TaNA, showed higher duplex stability than the natural oligonucleotide. This study enabled the use of Me-TaNA for the chemical modification of various oligonucleotide sequences because synthesis of Me-TaNAs with all four nucleobases was achieved.

Synthesis of chiral azides from C-2 substituted glycals and their transformation to C3-glycoconjugates and α-triazolo-naphthalene polyol.

A Lewis-acid-mediated highly regio- and stereoselective chiral azidation of C2-substituted glycals is reported. This strategy provides excellent, scalable, and mild reaction conditions for the stereoselective introduction of the azido group at the C3-position of various C2-substituted glycals. The reactivity of the various glycals reveals that the electron-withdrawing behavior of the C2-group is crucial for C3-selectivity. The newly installed azido group was used as a handle for the synthesis of various C3-glycoconjugates and α-chiral azido naphthalene polyols.

Total Synthesis of (-)-Cylindricine H.

Starting from (R)-phenylglycinol-derived tricyclic lactam 1, the enantioselective synthesis of (-)-cylindricine H is reported. From the stereochemical standpoint, the key steps are the stereoselective generation of the quaternary C10 stereocenter, the stereoselective introduction of the C4 acetoxy and C2 butyl substituents taking advantage of the lactam carbonyl functionality, and the assembly of the pyrrolidine ring with the required functionalized one-carbon chain at C13 by intramolecular opening of an epoxide.

Synthesis of 3α,6β‐Dihydroxyandrostan‐17‐one 3‐Glucuronides for the Detection of Testosterone Misuse

AbstractThe convenient synthesis of two 3‐glucuronide conjugates of 6β‐hydroxyandrosterone (6OH‐And‐3G 2) and 6β‐hydroxyetiocholanolone (6OH‐Etio‐3G 3) is reported. The conjugates are identified as long‐term markers of endogenous androgenic anabolic steroid abuse in doping control studies. Their resistance to enzymatic hydrolysis by E. coli β‐glucuronidase means they may be missed by conventional GC‐MS analysis protocols. One promising strategy to quantify these markers is by direct methods, which requires sufficient quantities of high purity reference materials. Our convergent synthesis features concurrent stereoselective introduction of 5α/5β hydrogen and 6β‐hydroxy groups on the steroid skeleton, and a mild Schmidt trichloroacetimidate glycosylation strategy.

Stabilization of Glucosyl Dioxolenium Ions by “Dual Participation” of the 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Protection Group for 1,2-cis-Glucosylation

The stereoselective introduction of glycosidic bonds is of paramount importance to oligosaccharide synthesis. Among the various chemical strategies to steer stereoselectivity, participation by either neighboring or distal acyl groups is used particularly often. Recently, the use of the 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) protection group was shown to offer enhanced stereoselective steering compared to other acyl groups. Here, we investigate the origin of the stereoselectivity induced by the DMNPA group through systematic glycosylation reactions and infrared ion spectroscopy (IRIS) combined with techniques such as isotopic labeling of the anomeric center and isomer population analysis. Our study indicates that the origin of the DMNPA stereoselectivity does not lie in the direct participation of the nitro moiety but in the formation of a dioxolenium ion that is strongly stabilized by the nitro group.

Catalytic Asymmetric Construction of CF3-Substituted Chiral sp3 Carbon Centers

AbstractDue to the unique steric and electronic nature of the fluorine atom, organofluorine compounds have received significant attention in the fields of pharmaceuticals and agrochemicals. In particular, the CF3 group is frequently found in biologically active compounds. However, compared to aryl- and alkenyl-CF3-containing molecules, the construction of sp3 carbon-based alkyl-CF3-containing molecules, particularly via catalytic enantioselective synthesis, remains a considerable challenge in spite of their high potential in medicinal applications. This short review focuses on recent advances in this research area, and the reported strategies are categorized according to reaction types and starting substrates. In addition, chiral catalysts, substrate scope, and reaction mechanisms are briefly summarized. 1 Introduction2 Stereoselective Introduction of a CF3 Group2.1 Nucleophilic Addition to Carbonyls and Imines2.2 Electrophilic Substitution at the α Position of Carbonyls2.3 Allylic Nucleophilic Substitution3 Stereoselective Functionalization of CF3-Substituted Molecules3.1 Electrophilic Substitution of α-CF3 Carbonyls3.2 Substitution of α-Halo CF3 Compounds3.3 Addition-Type Reactions with CF3-Substituted Alkenes4 Conclusion and Outlook

Characterization of Mannosyl Dioxanium Ions in Solution Using Chemical Exchange Saturation Transfer NMR Spectroscopy.

The stereoselective introduction of the glycosidic bond remains one of the main challenges in carbohydrate synthesis. Characterizing the reactive intermediates of this reaction is key to develop stereoselective glycosylation reactions. Herein we report the characterization of low‐populated, rapidly equilibrating mannosyl dioxanium ions that arise from participation of a C‐3 acyl group using chemical exchange saturation transfer (CEST) NMR spectroscopy. Dioxanium ion structure and equilibration kinetics were measured under relevant glycosylation conditions and highly α‐selective couplings were observed suggesting glycosylation took place via this elusive intermediate.

Characterization of Mannosyl Dioxanium Ions in Solution Using Chemical Exchange Saturation Transfer NMR Spectroscopy

AbstractThe stereoselective introduction of the glycosidic bond remains one of the main challenges in carbohydrate synthesis. Characterizing the reactive intermediates of this reaction is key to develop stereoselective glycosylation reactions. Herein we report the characterization of low‐populated, rapidly equilibrating mannosyl dioxanium ions that arise from participation of a C‐3 acyl group using chemical exchange saturation transfer (CEST) NMR spectroscopy. Dioxanium ion structure and equilibration kinetics were measured under relevant glycosylation conditions and highly α‐selective couplings were observed suggesting glycosylation took place via this elusive intermediate.

Brown Allylation: Application to the Synthesis of Natural Products

AbstractAsymmetric allylation represents an important reaction applied in the natural product synthesis. The stereoselective introduction of an allyl group allows to obtain versatile chiral building blocks, which may further undergo various transformations due to the presence of the carbon–carbon double bond. In this review, we address the Brown allylation, which involves the conversion of aldehydes into homoallylic alcohols using B‐allyldiisopinocampheylborane as a chiral reagent. We provide a comprehensive overview of the reaction and highlight its application in the synthesis of natural products, while assessing its performance in comparison to other approaches. The total of 17 syntheses have been described, including the synthesis of biologically active macrolides disciformycin B, biselyngbyolide B, peloruside A, and gliomasolide A, bis‐piperidine alkaloid (−)‐anaferine and dysoxylactam A.

Total Synthesis of Stemarene and Betaerene Diterpenoids: Divergent Ring-Formation Strategy and Late-Stage C–H Functionalization

A unified protecting group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first t...

Studies on the Enantioselective Synthesis of E-Ethylidene-bearing Spiro[indolizidine-1,3'-oxindole] Alkaloids.

A synthetic route for the enantioselective construction of the tetracyclic spiro[indolizidine-1,3′-oxindole] framework present in a large number of oxindole alkaloids, with a cis H-3/H-15 stereochemistry, a functionalized two-carbon substituent at C-15, and an E-ethylidene substituent at C-20, is reported. The key steps of the synthesis are the generation of the tetracyclic spirooxindole ring system by stereoselective spirocyclization from a tryptophanol-derived oxazolopiperidone lactam, the removal of the hydroxymethyl group, and the stereoselective introduction of the E-ethylidene substituent by acetylation at the α-position of the lactam carbonyl, followed by hydride reduction and elimination. Following this route, the 21-oxo derivative of the enantiomer of the alkaloid 7(S)-geissoschizol oxindole has been prepared.

Synthesis of both enantiomers of lycoperdic acid, an unusual mushroom-derived amino acid

An efficient synthesis of both enantiomers of lycoperdic acid, a 4-hydroxyglutamic acid derivative from edible mushroom Lycoperdon perlatum, was achieved from a chiral aminoalcohol. The key steps were a stereoselective introduction of a C3 unit into a bicyclic ketone and oxidative cleavage of a cyclic vicinal diol into a dicarboxylic acid. This report provides the first synthesis of (-)-lycoperdic acid.

Highly Selective Hydroiodination of Carbon-Carbon Double or Triple Bonds

Iodine is an element that exhibits characteristic features of heavy halogen, and several compounds containing iodine constitute important synthetic intermediates due to synthetically easy manipulation. To utilize iodine units for organic synthesis, a highly regio- and stereoselective introduction of iodine to versatile building blocks is significant, and a lot of research works for the selective introduction of iodine to alkynes or alkenes have been conducted. In this review article, we describe regio- and stereoselective hydroiodination to multiple bonds of building blocks, and its synthetic applications as key intermediates to construct several important compounds in organic chemistry.

Formation of Bifunctional Octasilsesquioxanes via Silylative Coupling and Cross-Metathesis Reaction.

Bifunctional silsesquioxanes create an attractive group of compounds with a wide range of potential applications, and recently they have gained much interest. They are known to be obtained mainly via hydrosilylation, but we disclose novel synthetic protocols based on different but complementary reactions, i.e., cross-metathesis (CM) and silylative coupling (SC). A series of cubic T8 type silsesquioxane derivatives with a broad scope of styryl substituents were synthesized in a one-pot procedure and characterized by spectroscopic and spectrometric methods. All of the new compounds can be obtained in a one-pot manner, which has an attractive impact on the synthetic procedure, as it is economic in terms of the isolation of intermediate products. Additionally, the methodology disclosed here enables the (E)-stereoselective introduction of styrenes derivative to the cubic T8 type core. The presented compounds can be interesting precursors for a further functionalization that may significantly increase the possibility of their application in the design and synthesis of new functional materials.