Mitsunobu Cyclization Research Articles

Solid-Phase Synthesis of Nannocystin Ax and Its Analogues.

Solid-phase total synthesis of nannocystin Ax (1) was disclosed. A coupling reaction between a peptide and a polyketide moiety was conducted on a solid support, and macrocyclization was achieved by Mitsunobu cyclization. The established synthetic route was efficient to prepare its analogues, which contain different types of peptide moieties.

Ru(II)-Catalyzed Asymmetric Transfer Hydrogenation of Chalcones in Water: Application to the Enantioselective Synthesis of Flavans BW683C and Tephrowatsin E.

The oxo-tethered-Ru(II) precatalyst promoted the one-pot C═C/C═O reduction of chalcones using sodium formate as the hydrogen source in water through asymmetric transfer hydrogenation. Twenty-seven 1,3-diarylpropan-1-ols were obtained in good to excellent yields (up to 96%) and enantiomeric purities (up to 98:2). Our data suggested that the enones are first reduced to the corresponding dihydrochalcones (1,4-selectivity) and then into 1,3-diarylpropan-1-ols (C═O reduction). The stereoelectronic effects of electron-donating and electron-withdrawing groups at the ortho, meta and para positions of both aromatic rings were evaluated. The 2-OH group at the B ring was well tolerated, allowing a straightforward enantioselective synthesis of two flavans through the Mitsunobu cyclization, the antiviral (S)-BW683C and the natural flavan (S)-tephrowatsin E.

Synthesis and Biological Evaluation of N-Aminoimidazolidin-2-one-Containing Angiotensin-(1-7) Peptidomimetics.

N-Aminoimidazolidin-2-one (Aid)-containing peptides with a constrained backbone present a novel class of peptidomimetics for drug discovery. The introduction of Aid residues into peptide sequences has been achieved by intramolecular Mitsunobu cyclization of a serine side chain onto the α-NH of an aza-glycine residue. The effectiveness of this new strategy was demonstrated by synthesizing six Aid-containing analogues of angiotensin-(1-7) on solid support. The Aid analogues of angiotensin-(1-7) exhibited increased peptidase stability against human ACE and DPP3 and improved anti-inflammation and antiproliferation activity.

Stereoselective total synthesis of (−)-pyrenophorin

Stereoselective total synthesis of (−)-pyrenophorin was accomplished from commercially available starting material 2-bromo epoxide using regioselective ring opening and the intermolecular Mitsunobu cyclization as key steps.

Ru(II)-Catalyzed C-H Hydroxyalkylation and Mitsunobu Cyclization of N-Aryl Phthalazinones.

Ruthenium(II)-catalyzed C(sp2)-H functionalization of N-aryl phthalazinones with a range of aldehydes and activated ketone is described. Initial formation of hydroxyalkylated phthalazinones and subsequent Mitsunobu cyclization provided facile access to biologically relevant indazolophthalazinones. The utility of this method is highlighted by synthetic transformations into a series of potentially bioactive scaffolds.

Successive Nucleophilic and Electrophilic Allylation for the Catalytic Enantioselective Synthesis of 2,4-Disubstituted Pyrrolidines.

Successive nucleophilic and electrophilic allylation mediated by the bis-Boc-carbonate derived from 2-methylene-1,3-propane diol enables formation of enantiomerically enriched 2,4-disubstituted pyrrolidines. An initial enantioselective iridium-catalyzed transfer hydrogenative carbonyl C-allylation is followed by Tsuji-Trost N-allylation using 2-nitrobenzenesulfonamide. Subsequent Mitsunobu cyclization provides the N-protected 2,4-disubstituted pyrrolidines.

Ene reactions of 2-borylated α-methylstyrenes: a practical route to 4-methylenechromanes and derivatives.

4-Methylenechromanes were prepared via a three-step process from 2-borylated α-methylstyrenes. This sequence is based on a key glyoxylate-ene reaction catalyzed by scandium(iii) triflate. The resulting γ-hydroxy boronates, which cyclise to seven-membered homologues of benzoxaborole on silica gel, were cleanly oxidized with sodium perborate, and then cyclised under Mitsunobu conditions. Additionally, several further functional transformations of 4-methylenechromanes or their precursors were carried out to illustrate the synthetic potential of these intermediates.

An alternative stereoselective total synthesis of (-)-pyrenophorol

The total synthesis of 16-membered C2–Symmetric dilactone (-)-Pyrenophorol was accomplished starting from commercially available (S)-epoxide prepared by hydrolytic kinetic resolution of (±) – epoxide with key steps of Grignard reaction, Swern oxidation, Wittig reaction and cyclization was achieved by intermolecular Mitsunobu cyclization. The synthesis of (-)-Pyrenophorol accomplished from cheaply available starting material, easily work-up procedures and reduction of cost in industrial process were major advantages of this route.

A Mitsunobu reaction to functionalized cyclic and bicyclic N-arylamines

The scope of an unexpected Mitsunobu cyclisation to prepare N-arylated Fsp3-enriched azacycles was investigated. In the current study, we have identified whether a pKa-dependent Mitsunobu cyclodehydration or a pKa-independent Mitsunobu intramolecular reaction was in operation. A Mitsunobu reaction, creating a leaving group, followed by intramolecular nucleophilic displacement was determined to be the dominant pathway.

Synthesis and β-sheet propensity of constrained N-amino peptides

The stabilization of β-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable β-hairpin folds based on peptide strand N-amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between α-hydrazino acid residues and a serine or homoserine side chain. Acyclic and cyclic N-amino peptide building blocks were then evaluated for their effect on β-hairpin stability in water using a GB1-derived model system. Our results demonstrate the strong β-sheet stabilizing effect of the peptide N-amino substituent, and provide useful insights into the impact of covalent dipeptide constraint on β-sheet folding.

Synthesis of ( S )-3-amino-benzo[ b ][1,4]oxazepin-4-one via Mitsunobu and S N Ar reaction for a first-in-class RIP1 kinase inhibitor GSK2982772 in clinical trials

Two new synthetic routes were developed to prepare the RIP1 kinase inhibitor clinical candidate GSK2982772 involving a key (S)-3-amino-benzo[b][1,4]oxazepin-4-one intermediate prepared via Mitsunobu and SNAr cyclization reactions. Both routes are practical and cost effective compared to the initial medicinal chemistry route and are also applicable to kilogram scale-up to support on-going clinical studies.

A Modular Synthesis of 2-Alkyl- and 2-Arylchromans via a Three-Step Sequence

A convergent three-step method for the synthesis of 2-substituted chromans is described. These results have been accomplished via the Heck coupling of readily accessible allylic alcohols and 2-iodophenols, followed by reduction and Mitsunobu cyclization. The utility and generality of this method is demonstrated through the synthesis of a series of 2-aryl-, 2-heteroaryl- and 2-alkylchromans, as well as an azachroman derivative. The asymmetric version of this approach via a Noyori-catalyzed ketone reduction and subsequent cyclization is likewise highlighted.

A Concise Synthesis of Fused Tricyclic Pyrrolo[3,2-d]pyrimidines

A concise approach to partially saturated fused tricyclic pyrrolo[3,2-d]pyrimidines has been developed. Herein, we report a three-step route to the core templates, starting with a Sonogashira coupling and utilising either a CuI-catalysed or base-mediated 5-endo-dig cyclisation to form the pyrrolopyrimidine ring, followed by Mitsunobu cyclisation to afford the tricyclic system. This method facilitates synthetic access to a structural class with limited representation in the literature and is amenable to further elaboration by virtue of a halide incorporated at the 4-position.

ChemInform Abstract: Recent Progress on the Asymmetric Synthesis of Chiral Flavanones

AbstractReview: [30 refs.

Studies on the Synthesis of Novel Four-Membered Cyclic Oxaphosphetanes via Intramolecular Mitsunobu Reaction of Bishydroxyalkylphosphinic Acids

Studies on the synthesis of novel four-membered cyclic oxaphosphetanes from bishydroxyphosphinic acids is reported. Investigations showed that the conversion proceeds through an intramolecular Mitsunobu cyclisation of bishydroxyphosphinic acids with a mixture of triphenylphosphine and diisopropylazodicarboxylate (DIAD) in toluene–CH2Cl2 at room temperature. The treatment of two diastereomers of bishydroxymethylphosphinic acids (dl pair and meso) with a mixture of triphenylphosphine and DIAD gives only one stereoisomer of the cyclic oxaphosphetane.

Recent Progress on the Asymmetric Synthesis of Chiral Flavanones

Flavanone and its derivatives are privileged natural products that show a wide range of biological activities. The importance of these compounds has driven research developments toward the preparation of flavanones, especially enantioenriched examples. This account reviews recent approaches for the asymmetric synthesis of chiral flavanones. The synthetic methods involve reduction, intramolecular addition, and intermolecular addition. 1 Introduction 2 Asymmetric Reduction 3 C–C Bond Formation (Intermolecular Conjugate Additions to 4-Chromanones) 4 C–O Bond Formation 4.1 Intramolecular Oxa-Michael Additions 4.2 Tandem Reactions of Chromones 4.3 Intramolecular Mitsunobu Cyclization 5 Conclusion

ChemInform Abstract: Asymmetric Syntheses of 3,4‐Disubstituted Tetrahydroquinoline Derivatives Using (+)‐Sparteine‐Mediated Electrophilic Substitution.

AbstractA novel methodology for the asymmetric synthesis of trans‐3,4‐diaryl‐substituted tetrahydroquinolines via sparteine‐assisted stereoselective lithiation of o‐substituted N‐pivaloylanilines (I), kinetic resolution of epoxides in substitution and a stereospecific Mitsunobu cyclization is developed.

ChemInform Abstract: A Diastereoselective Route to trans‐2‐Aryl‐2,3‐dihydrobenzofurans Through Sequential Cross‐Metathesis/Isomerization/Allylboration Reactions: Synthesis of Bioactive Neolignans.

A new highly diastereoselective synthetic route to trans-2,3-dihydrobenzofuran systems, in particular those bearing an aryl substituent at the C2 position, is described. The cornerstone of our strategy is the implementation of a cross-metathesis/isomerization/allylboration sequence starting from 2-allyl-substituted phenols and aldehydes. After an intramolecular Mitsunobu cyclization step, the anti-homoallylic alcohols allow the synthesis of the desired skeleton in a stereoselective fashion. As an illustration, we used this strategy for the preparation of the dihydrodehydrodiconiferyl alcohol (1a), a natural dihydrobenzofuran neolignan, as well as for a formal synthesis of its O-demethylated derivative 1b. An enantioselective version of this approach employing a chiral phosphoric acid in the allylboration step is also studied.

Asymmetric Syntheses of 3,4‐Disubstituted Tetrahydroquinoline Derivatives Using (+)‐Sparteine‐mediated Electrophilic Substitution

A novel methodology for the asymmetric synthesis of trans-3,4-diaryl-substituted tetrahydroquinolines via sparteine-assisted stereoselective lithiation of o-substituted N-pivaloylanilines (I), kinetic resolution of epoxides in substitution and a stereospecific Mitsunobu cyclization is developed.

Asymmetric synthesis of cytospolides C and D through successful exploration of stereoselective Julia–Kocienski olefination and Suzuki reaction followed by macrolactonization

Asymmetric total synthesis of two naturally occurring nonenolides cytospolides C (3) and D (4) was accomplished through successful exploration of stereoselective Julia–Kocienski (JK) olefination reaction for the construction of the required E-olefinic geometry (C4–C5) present in the target molecule. In an alternative approach Suzuki cross coupling reaction of an E-vinylic bromide and an alkylborane species was also efficiently applied to access the macrolactonization precursor. Late stage lactonization through Mitsunobu cyclization afforded the target molecules in good yield.