Mitsunobu Reaction Conditions Research Articles

Triflic Acid-Assisted Regioselective Bromination of Quinoxaline Derivatives Enables a Facile Synthesis of Polymer PTQ10.

Poly[(thiophene)-alt-(6,7-difluoro-2(2-hexyldecyloxy)quinoxaline)] (PTQ10) emerges as a promising candidate for donor materials in organic solar cells (OSCs) due to its high efficiency, simplified synthesis, and cost-effectiveness. The acceptor unit of PTQ10 is derived from the alkylation of 5,8-dibromo-6,7-difluoroquinoxaline-2-ol, emphasizing the importance of its economical synthesis for commercial viability. This study investigates triflic acid-assisted regioselective bromination of quinoxaline derivatives and proposes an alternative synthetic pathway for PTQ10. The developed route benefits from concise synthetic steps, a dependable procedure, and high overall yield. Starting with the condensation of 4,5-difluorobenzene-1,2-diamine with ethyl oxoacetate to yield 6,7-difluoroquinoxaline-2-ol, subsequent triflic acid-assisted regioselective bromination produces 5,8-dibromo-6,7-difluoroquinoxaline-2-ol in high yield. Alkylation under Mitsunobu reaction conditions yields 5,8-dibromo-6,7-difluoro-2-(2-hexyldecyloxy)quinoxaline, followed by polymerization with 2,5-distannylated thiophene under Stille reaction conditions to afford PTQ10. This research provides insights into efficient synthetic strategies for PTQ10, advancing its potential for commercial application in OSCs.

Total Synthesis of 4α-Hydroxyallosecurinine and Securingine F, Securinega Alkaloids with a C4-Hydroxy Handle for Biofunctional Derivatizations

AbstractWe describe the first total synthesis of the C4-hydroxylated securinega alkaloids 4α-hydroxyallosecurinine and securingine F. The synthetic route features an Ellman’s light-mediated hydrogen-atom-transfer-based epimerization reaction that effectively sets the desired configuration at the C2 position. Simultaneous skeletal rearrangement from neosecurinane to securinane frameworks and stereochemical reversal at the C4 site was achieved under Mitsunobu reaction conditions. The C4-hydroxy group is envisioned to serve as a handle for potential biofunctional derivatizations.

Studies towards the synthesis of polyhydroxylated pyrrolidine alkaloids isolated from Broussonetia kazinoki (moraceae)

The syntheses of L-AB1, L-DMDP, and the novel compounds, (−)-phenethyl-L-AB1, (−)-10′-deoxobroussonetine C, (−)-10′-deoxobroussonetine E, (−)-1′-epi-10′-deoxobroussonetine E, and (−)-(6S)-12′-hydroxydodecylmoranoline are reported. These syntheses start from d-xylose employing the Petasis borono-Mannich reaction to stereoselectively introduce the amino group, followed by a chemo- and regioselective O-mesylation to deliver the fully functionalized pyrrolidine moiety after intramolecular SN2-cyclisation. The synthesis of the latter targeted compound involved a ring expansion process of a prolinol moiety to a piperidine derivative under Mitsunobu reaction conditions. An attempted synthesis of desired ent-broussonetine C was unsuccesful due to formation of an unexpected tetrahydrofuran derivative in the final stage of the synthesis. The glycosidase inhibitory activities of four of the new target compounds against a panel of ten glycosidaes is also presented.

Total Synthesis of (-)-Kopsifoline A and (+)-Kopsifoline E.

We report the first total synthesis of (-)-kopsifoline A and (+)-kopsifoline E. Our synthetic strategy features a biogenetically inspired regioselective C17-functionalization of a versatile intermediate containing the pentacyclic core of aspidosperma alkaloids. The vinylogous urethane substructure of this intermediate affords (-)-kopsifoline D via C3-C21 bond formation under the Mitsunobu reaction conditions, while it enables selective C17-functionalization en route to (-)-kopsifoline A and (+)-kopsifoline E.

Improved preparation of vitexin from hot water extract of Basella alba, the commercially available vegetable Malabar spinach ("Tsurumurasaki" in Japanese) and the application to semisynthesis of chafuroside B.

Hot water extraction of D-arabinofuranosylvitexin from the raw leaves of commercially available Basella alba "Tsurumurasaki" and subsequent acidic hydrolysis was improved to be a procedure using a high-pressure steam sterilizer to afford vitexin. The amount was estimated to be 14.1 mg from 1g of dry weight of the raw leaves, whose recovery was calculated to be 95% based on the estimated content of D-arabinofuranosylvitexin in B. alba raw leaves. The product was dehydratively cyclized between hydroxy groups on the carbohydrate and flavone skeletons under modified Mitsunobu reaction conditions in N,N-dimethylformamide to give chafuroside B, which is known to be a bioactive Oolong tea polyphenol. Through these transformations, 10.2 mg of chafuroside B could be semisynthesized from 1g of dry weight of the raw leaves, and the efficiency was improved compared to that from the extraction from Oolong tea (3.4μg from 1g of dry weight).

Stereoselective total synthesis of (−)-pyrenophorol

A simple and efficient stereoselective synthesis of macrodilactone of (−)-pyrenophorol (1) has been accomplished in 12 steps in 8.3% overall yield, from inexpensive and commercially available (S)-ethyl lactate. This convergent synthesis utilizes an oxidation–reduction protocol and cyclodimerisation under the Mitsunobu reaction conditions as key steps.

Chemical synthesis of the innate immune modulator – bacterial d - glycero -β- d - manno- heptose-1,7-bisphosphate (HBP)

Abstract The bacterial metabolite and potent innate immune modulator d - glycero -β- d - manno -heptose-1,7-bisphosphate (HBP) and its α-configured counterpart d - glycero -α- d - manno -heptose-1,7-bisphosphate were synthesized via stereoselective anomeric phosphorylation of the peracetylated d , d -heptose 7-dibenzylphosphate by exploiting different nucleophilicity of equatorial and axial lactols in the d - manno -series. We also report a novel approach for anomeric phosphorylation using modified Mitsunobu reaction conditions and provide the first full structural characterization of HBP. The first chemical synthesis of HBP offers access to an anomerically pure structurally defined probe for biological studies and to a lead compound operating as a powerful stimulator of intracellular signaling for possible therapeutic immunomodulation.

Synthesis of Nucleosides through Direct Glycosylation of Nucleobases with 5-O-Monoprotected or 5-Modified Ribose: Improved Protocol, Scope, and Mechanism.

Simplifying access to synthetic nucleosides is of interest due to their widespread use as biochemical or anticancer and antiviral agents. Herein, a direct stereoselective method to access an expansive range of both natural and synthetic nucleosides up to a gram scale, through direct glycosylation of nucleobases with 5-O-tritylribose and other C5-modified ribose derivatives, is discussed in detail. The reaction proceeds through nucleophilic epoxide ring opening of an in situ formed 1,2-anhydrosugar (termed "anhydrose") under modified Mitsunobu reaction conditions. The scope of the reaction in the synthesis of diverse nucleosides and other 1-substituted riboside derivatives is described. In addition, a mechanistic insight into the formation of this key glycosyl donor intermediate is provided.

Photocatalytic esterification under Mitsunobu reaction conditions mediated by flavin and visible light.

The usefulness of flavin-based aerial photooxidation in esterification under Mitsunobu reaction conditions was demonstrated, providing aerial dialkyl azodicarboxylate recycling/generation from the corresponding dialkyl hydrazine dicarboxylate. Simultaneously, activation of triphenylphosphine (Ph3P) by photoinduced electron transfer from flavin allows azo-reagent-free esterification. An optimized system with 3-methylriboflavin tetraacetate (10%), oxygen (terminal oxidant), visible light (450 nm), Ph3P, and dialkyl hydrazine dicarboxylate (10%) has been shown to provide efficient and stereoselective coupling of various alcohols and acids to esters with retention of configuration.

Synthesis and CYP17α hydroxylase inhibition activity of new 3α- and 3β-ester derivatives of pregnenolone and related ether analogues

A new class of 3α-ester derivatives of pregnenolone, using Mitsunobu reaction conditions, is described. The scheme involved the conversion of pregnenolone (4) into 20-(2-hydroxyethyl)imino-pregn-5-en-3β-ol (8), followed by tritylation to give the analogue 9. Treatment of 9 with various aryl carboxylic acids afforded the tritylated 3α-ester pregnenolone analogues 18–23. Detritylation with AcOH furnished the 3α‐substituted aryl ester derivatives 24–29. Analogously, the 3β-ester analogues 31 and 32 were synthesized from pregnenolone (4) and its analogue 30, using Steglich coupling method, by treatment with rhodamine B in the presence of DCC/DMAP. These derivatives were screened for their CYP17α hydroxylase inhibition activity expressed in Escherichia coli. Compound 27 was the most active inhibitor among both series, with IC50 value of 1.12 μM and selectivity profile of 88.56 % inhibition of CYP17α hydroxylase enzyme.

Facile Access to 5'-S-(4,4'-Dimethoxytrityl)-2',5'-Dideoxyribonucleosides via Stable Disulfide Intermediates.

Thionucleosides represent an important class of modified nucleos(t)ides that have found distinct applications in the chemical biology of synthetic oligonucleotides, but the use of these compounds is substantially lessened by the instability or high reactivity of the sulfhydryl group. This unit describes a protocol for the synthesis of 2',5'-dideoxy-5'-thioribonucleoside disulfides by utilizing Mitsunobu reaction conditions on 3'-O-levulinyl-2'-deoxyribonucleosides in the presence of thiobenzoic acid followed by facile hydrolysis and in situ oxidation of the resulting 5'-thiolated nucleosides using methanolic ammonia. The utility of these disulfides has been demonstrated as stable precursors for the synthesis of 5'-thio-modified 2'-deoxynucleosides. To validate the potential of the methodology, 5'-S-(4,4'-dimethoxytrityl)-2',5'-dideoxythymidine phosphoramidite has been synthesized by in situ cleavage of the disulfide linkage of 2',5'-dideoxy-5'-thiothymidine disulfide followed by protection with a dimethoxytriphenyl (DMT) group and 3'-phosphitylation using 2-cyanoethyl N,N-diisopropylchlorophosphoramidite.

ChemInform Abstract: Azodicarboxylates: Synthesis and Functionalization of Organic Compounds.

The data on transformations of dialkyl azodicarboxylates and their analogues involving various substrates are generalized. Nucleophilic addition and oxidation, pericyclic reactions and reactions occurring under the Mitsunobu reaction conditions are considered. Ample opportunities for application of these compounds in fine organic synthesis are shown. The bibliography includes 245 references.

Regio- and stereochemistry of Na-mediated reductive cleavage of alkyl aryl ethers

We have investigated the regio- and stereochemistry of the reductive dealkoxylation of alkyl aryl ethers. Chiral non-racemic secondary alcohols were converted into the corresponding m-terphenyl or 2-biphenyl ethers either via inversion of configuration under Mitsunobu reaction conditions or with retention of configuration under SNAr conditions. The successive cleavage of the aromatic CO bond occurred in the presence of a stoichiometric amount of Na metal in dry tetrahydrofuran at rt with retention of configuration, thus highlighting that the overall inversion or retention of configuration for the whole two-step procedure is dictated by the stereochemistry of the first synthetic step.

Synthesis of N-(2-(Methylamino)ethyl) Derivatives of 2H-Phthalazin-1-ones

A series of new alkyl, tosyl, acetyl, and tert-butoxycarbonyl derivatives of 2-(2-aminoethyl)-phthalazinones were efficiently synthesized by reaction of lactams with N-Boc-, N-acetyl-, or N,O-ditosyl derivatives of N-methylethanolamine in the presence of MeONa or under Mitsunobu reaction conditions. Selected compounds were converted into corresponding 2-[2-(methylamino)ethyl]phthalazinones in good yields.

Efficient transformation of 7,14-dihydroxy-ent-kaurenes to novel ent-abietanes having cis-fused α-methylene γ-lactones under Mitsunobu reaction conditions and their cytotoxicities

Transformation of plant-origin 7,14-dihydroxy-ent-kaurenes to ent-abietanes having a cis-fused α-methylene γ-lactones was accomplished efficiently under the Mitsunobu reaction conditions. The yields of the desired products were apparently influenced by the steric hindrance at C-1. The cytotoxic activity on P388 murine leukemia cells of the ent-abietanes having cis-fused α-methylene γ-lactones produced were assayed.

Synthesis and Biological Evaluation of Methylenecyclopropane Analogues of Nucleosides

Starting from a chiral methylenecyclopropane building block, readily obtained by enzymatic desymmetrization of a meso-diol, two types of methylenecyclopropane analogues of nucleosides were synthesized. The first type of nucleosides was obtained from the direct coupling of the chiral building block with 6-chloropurine under Mitsunobu reaction conditions followed by the functionalization of the purine base. The second type of nucleosides featured a Curtius rearrangement as the key step and the uracil heterocycle was then constructed by a linear methodology. These derivatives were evaluated as potential agents against important viral pathogens. None of the new compounds had significant antiviral activity at a concentration of 100 μg/mL, which was the highest concentration tested.

Synthesis of Functionalized Lipids, and Their Use for a Tunable Hydrophobization of Nucleosides and Nucleic Acids

AbstractTwo series of functionalized single and double side‐chained lipid molecules (Schemes 1 and 2) were prepared. The compounds carry either terminal COOH, OH, or halogen substituents. Moreover, the double side‐chained lipid 18 carries an internal alkyne functionality. The latter compound was used to hydrophobize thymidine at N(3) by base‐catalyzed alkylation. Additionally, fully protected thymidine, 32, was N(3)‐alkylated with the double side‐chained alcohol 9 applying Mitsunobu reaction conditions.

ChemInform Abstract: A Convenient Synthesis of Novel Glycosyl Azetidines under Mitsunobu Reaction Conditions.

A facile, simple, and high-yielding protocol for synthesis of novel glycosyl azetidines was developed from glycosyl β-amino alcohols via intramolecular cyclization under Mitsunobu reaction conditions.

A highly expeditious synthesis of a bicyclic iminosugar using the novel key step of [NMM]+[HSO4]− promoted conjugate addition and Mitsunobu reaction

A simple and highly facile protocol has been developed for the stereoselective synthesis of 1-deoxy-norcastanospermine from readily available D-glucose. N-Methylmorpholinium hydrogen sulphate was seen for the first time as a suitable catalyst for the facile conjugate addition of an amine to a glycosyl olefinic ester. Furthermore, the key step of this strategy is the internal reductive amination of glycosyl azetidine, obtained from glycosyl β-amino alcohol under Mitsunobu reaction conditions.

A Convenient Synthesis of Novel Glycosyl Azetidines Under Mitsunobu Reaction Conditions

A facile, simple, and high-yielding protocol for synthesis of novel glycosyl azetidines was developed from glycosyl β-amino alcohols via intramolecular cyclization under Mitsunobu reaction conditions.