Mitsunobu Cyclization Research Articles

Stereoselective total synthesis of (−)-(5S,8R,13S,16R)-pyrenophorol

The total synthesis of 16-membered C 2-symmetric dilactone (−)-(5S,8R,13S,16R)-pyrenophorol was accomplished starting from enantiomerically pure propylene oxide prepared by hydrolytic kinetic resolution of (±)-propylene oxide with key steps of cross-metathesis and intermolecular Mitsunobu cyclization for the construction of macrolactone.

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

AbstractA 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.

Laboratory and practical synthesis of Suvorexant, a selective dual orexin receptor antagonist

The development of a laboratory and practical synthesis of Suvorexant 1, using intramolecular Mitsunobu cyclization reaction of intermediate 5 as the key reaction, has been reported. Compound 5 was obtained from known chiral ester 2 in three steps, and the key cyclization proceeded smoothly to provide the core seven-membered ring compound 6, which was transformed into 1 by an additional four-step sequence. The procedure described here needs no chiral-HPLC separation, no classical resolution, and no unique enzyme reactions, and offers an alternative practical synthesis of 1.

Improved synthesis of structural analogues of (−)-epicatechin gallate for modulation of staphylococcal β-lactam resistance

The high-yielding synthesis of enantiomerically pure epicatechin gallate analogues where the A and/or B-ring hydroxylation is reduced or altered has been achieved by optimising routes to the catechin stereochemistry. The B-ring analogues were synthesised by using an electrophilic ring closure onto an enantiomerically enriched epoxide as a key step. The A and B-ring hydroxyl-deleted analogues were synthesised through a Mitsunobu cyclisation. For the B-ring analogues, the anti- (catechin) stereochemistry was converted to the syn- (epicatechin) stereochemistry by a known oxidation/reduction protocol. Absolute stereochemistry was derived from either a Sharpless epoxidation or asymmetric dihydroxylation.

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization

An operationally simple protocol for the synthesis of 2,3-dihydrobenzo[f][1,4]oxazepin-3-ones, based on an Ugi reaction of an ortho-(benzyloxy)benzylamine, glycolic acid, an isocyanide and an aldehyde, followed by an intramolecular Mitsunobu substitution was developed. The required ortho-(benzyloxy)benzylamines have been in situ generated from the corresponding azides, in turn prepared in high yields from salicylic derivatives.

Synthesis of polyhydroxylated indolizidines and piperidines from Garner's aldehyde: total synthesis of (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity

Diastereoselective and diverse synthesis of polyhydroxylated indolizidines and piperidines have been described, where a common chiral intermediate 2-(hydroxymethyl) piperidine-3-ol is converted into (−)-swainsonine, (+)-1,2-di-epi-swainsonine, (+)-8,8a-di-epi-castanospermine, pentahydroxy indolizidines, (−)-1-deoxynojirimycin, (−)-1-deoxy-altro-nojirimycin, and related diversity. The key steps were hydroxy directed intramolecular aminomercuration, Mitsunobu cyclization, and diastereoselective dihydroxylation.

Kilogram Synthesis of (S)-3-Aminopyran from l-Glutamic Acid

We describe the development of a concise route to prepare kilogram quantities of (<i>S</i>)-3-aminopyran, a key intermediate in the synthesis of a Jak1 inhibitor. The chiral amine was introduced via a chiral-pool approach and involves using inexpensive, commercially available <sc>l</sc>-glutamic acid as the key starting material. Global protection, followed by reduction afforded the <i>N</i>-Boc-amino diol. Intramolecular Mitsunobu cyclization and deprotection afforded the desired compound in 30% overall yield over four steps without the use of chromatography.

The homo‐PADAM Protocol: Stereoselective and Operationally Simple Synthesis of α‐Oxo‐ or α‐Hydroxy‐γ‐acylaminoamides and Chromanes

A straightforward and fully stereoselective synthesis of a new class of peptidomimetics, that is α-oxo-γ-acylaminoamides, was achieved starting from various benzaldehydes by a sequence of 1) an asymmetric organocatalytic Mannich reaction, 2) a Passerini multicomponent reaction, 3) an amine deprotection-acyl migration protocol, and 4) a final oxidation. The whole sequence can be performed without purification of the intermediates and represents the first example of a homo-Passerini-amine deprotection-acyl migration (PADAM) strategy. Highly stereoselective reduction of the α-oxo-γ-acylaminoamides afforded α-hydroxy-γ-acylaminoamides as well. In some cases both diastereomers were obtained by simply changing the reducing agent. Finally, starting from protected salicylaldehyde, the same sequence, followed by a Mitsunobu cyclization, afforded highly substituted chromanes.

Protecting group directed diversity during Mitsunobu cyclization of a carbohydrate derived diamino triol. Synthesis of novel bridged bicyclic and six-membered iminocyclitols

A novel protecting group directed diversity leading to the synthesis of bridged bicyclic and six-membered iminocyclitols from a common carbohydrate derived diamino triol under Mitsunobu conditions is reported. When the intramolecular cyclization of benzoyl derivative 16 was carried out under Mitsunobu conditions, an unprecedented one-pot domino intramolecular "cyclization-N→O benzoyl migration-cyclization" reaction sequence occurred resulting in the formation of a chiral 2,6-diazabicyclo[3.2.1]octane-4,8-diol 21 in high yield. The structure of this novel bridged bicyclic compound was established through detailed NMR studies and single crystal X-ray analysis. On the other hand, the tert-butyldimethylsilyl derivative of the same substrate afforded protected 6-amino-1,6-dideoxy-l-gulonojirimycin 32 as the sole product under identical conditions. An attempt has been made to explain this difference in their reactivity through conformational analysis. The glycosidase inhibition studies of new compounds reported in this manuscript revealed that these molecules display moderate but selective inhibition against β-N-acetylhexosaminidase.

A Practical Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate, the Key Intermediate of Rho–Kinase Inhibitor K-115

A practical synthesis of (<i>S</i>)-<i>tert</i>-butyl 3-methyl-1,4-di­azepane-1-carboxylate has been established for supplying this key intermediate of Rho–kinase inhibitor K-115 in a multikilogram production. The chiral 1,4-diazepane was constructed by intramolecular Fukuyama–Mitsunobu cyclization of a <i>N</i>-nosyl diamino alcohol starting from the commercially available (<i>S</i>)- or (<i>R</i>)-2-aminopropan-1-ol. In the same manner, an enantiomeric pair of a structural isomer were prepared for demonstration of the synthetic utility.

TBAHS-Catalyzed Synthesis of 2-Dihydroquinazolin-2-ylquinoline: An Efficient and Practical Synthesis of Naturally Occurring Alkaloids Luotonin A, B, and E

A synthesis of 2-dihydroquinazolin-2-ylquinoline using a phase-transfer catalyst (TBAHS) in semi-aqueous phase, followed by Mitsunobu cyclization as key steps for an efficient and practical synthesis of naturally occurring alkaloids luotonin A, B, and E starting from o-nitrobenzaldehyde is reported. The new approach presents the advantage of a shorter route with high overall yield (57%, 45%, and 37%, respectively) and ease of operation.

ChemInform Abstract: Synthesis of 2,3‐Dihydro‐4(1H)‐quinolones and the Corresponding 4(1H)‐Quinolones via Low‐Temperature Fries Rearrangement of N‐Arylazetidin‐2‐ones.

AbstractCompounds (I) and (IV) are synthesized by Goldberg—Buchwald cross‐coupling and compounds (VII) by intramolecular Mitsunobu cyclization.

Stereoselective Synthesis of the C1-C11 Tetrahydropyran Core Unit of (+)-Zincophorin

Synthesis of the C1-C11 tetrahydropyran core unit of (+)-zincophorin using a desymmetrization strategy is reported. Horner­-Wadsworth-Emmons (HWE) and Mitsunobu cyclization reactions are the key transformations.

Intramolecular monomer-on-monomer (MoM) Mitsunobu cyclization for the synthesis of benzofused thiadiazepine-dioxides.

The utilization of a monomer-on-monomer (MoM) intramolecular Mitsunobu cyclization reaction employing norbornenyl-tagged (Nb-tagged) reagents is reported for the synthesis of benzofused thiadiazepine-dioxides. Facile purification was achieved via ring-opening metathesis (ROM) polymerization initiated by one of three metathesis catalyst methods: (i) free metathesis catalyst, (ii) surface-initiated catalyst-armed silica, or (iii) surface-initiated catalyst-armed Co/C magnetic nanoparticles.

Synthesis of 2,3-Dihydro-4(1H)-quinolones and the Corresponding 4(1H)-Quinolones via Low-Temperature Fries Rearrangement of N-Arylazetidin-2-ones

N-Arylazetidin-2-ones of the general form 1, which are readily prepared by Goldberg–Buchwald-type copper-catalyzed coupling of N-unsubstituted azetidin-2-ones with the relevant aryl halide or using Mitsunobu cyclization processes, undergo smooth Fries-rearrangement in triflic acid at 0–18°C to give the isomeric 2,3-dihydro-4(1H)-quinolones (2). Dehydrogenation of the latter compounds using 10% Pd on C in 1.0 M aqueous sodium hydroxide/propan-2-ol mixtures at ca. 82°C provides the corresponding 4(1H)-quinolones (3).

Regioselective Ring‐Opening of Amino Acid‐Derived Chiral Aziridines: an Easy Access to cis‐2,5‐Disubstituted Chiral Piperazines

An efficient four-step synthetic strategy for cis-2,5-disubstituted chiral piperazines derived from amino-acid-based aziridines is described. The key steps in this strategy are the highly regioselective boron trifluoride diethyl etherate (BF(3)·OEt(2))-mediated ring-opening of less-reactive N-Ts chiral aziridines by α-amino acid methyl ester hydrochloride followed by Mitsunobu cyclization. This protocol has been used in an attempt to construct the piperazine core framework of natural product (+)-piperazinomycin.

Design and synthesis of new C-nucleosides as potential adenosine deaminase inhibitors

A number of new pyrazolo[3,4- c] and [4,3- b]pyridine C-nucleosides, which can be viewed as 4- or 6-deazaformycin analogues were synthesized and examined as potential adenosine deaminase (ADA) inhibitors. The compounds were prepared through the condensation of a suitably substituted, lithiated 2- or 4-methylpyridine with tri- O-benzyl- d-ribonolactone, followed by borohydride reduction of the resulting hemiacetals, intramolecular Mitsunobu cyclisation of the derived diols, formation of the pyrazolopyridine ring system and subsequent removal of the protecting groups. These derivatives were designed on the structural basis provided by docking simulations performed within the enzyme catalytic site, however they demonstrated weak ADA inhibitory activity. Theoretical calculations assisted in the interpretation of the obtained biological data, thus providing guidance for rational structural modifications within this molecular scaffold.

ChemInform Abstract: A New Preparation of 2,5-Dihydro-1-benzoxepins Using Mitsunobu Cyclization, and the Synthesis of Natural Radulanins.

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A new synthesis of amino acid-based enantiomerically pure substituted 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines

A new series of enantiomerically pure 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxalines were synthesized for the first time in twelve steps from 1-fluoro-2-nitrobenzene and S-amino acids with 13-20% overall yields. First use of intramolecular Mitsunobu cyclization for 1,2,3,4-tetrahydroquinoxalines followed by PPh(3)/I(2)/imidazole mediated 6-exo-tet cyclization were the key steps.

Multicomponent synthesis of dihydrobenzoxazepinones, bearing four diversity points, as potential α-helix mimics

A very short convergent synthesis of dihydrobenzoxazepinones, bearing four diverse diversity points, based on coupling the Ugi reaction with a Mitsunobu cyclization, was developed. These compounds are potential α-helix mimics, where three of the four appendages are expected to imitate the residues in i, i + 4 and i + 7 positions. A library of 22 compounds bearing lipophilic substituents, designed to interact with the hydrophobic cleft of anti-apoptotic protein Bcl-xL, was synthesized. Preliminary biochemical tests, based on competitive binding, have already been carried out.