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

• Lisa Moni,
• Luca Banfi,
• Andrea Basso,
• Alice Brambilla and
• Renata Riva

Beilstein J. Org. Chem. 2014, 10, 209–212, doi:10.3762/bjoc.10.16

• 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. Keywords: benzoxazepines; diversity-oriented synthesis; multicomponent reactions; Mitsunobu reaction; Ugi reaction; Introduction Although the classical Ugi 4-component reaction (U-4CR) leads to acyclic peptide-like compounds, post-condensation cyclizations can afford a huge variety of drug-like

• reactions [2], especially the intramolecular Mitsunobu reaction of alcohols with phenols or sulfonamides. By exploiting a single post-MCR transformation (the Mitsunobu reaction) it is possible to obtain several diverse heterocyclic scaffolds by installing the two additional groups in any of the four

Synthesis of the B-seco limonoid core scaffold

• Hanna Bruss,
• Hannah Schuster,
• Rémi Martinez,
• Markus Kaiser,
• Andrey P. Antonchick and
• Herbert Waldmann

Beilstein J. Org. Chem. 2014, 10, 194–208, doi:10.3762/bjoc.10.15

• alcohol 18 and Mitsunobu reaction installed the required stereochemistry at C14. The free C14 hydroxy group was masked with protecting groups (MOM and TIPS) of different size and chemical nature to examine the face-selectivity of the [3,3]-sigmatropic rearrangement. After selective desilylation, alcohols

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• -adamantane-2-spiro-3’-8’-[[(1’-methyl-1’H-tetrazol-5’-yl)thio]methyl]-1’,2’,4’-trioxaspiro[4.5]decane 186 through nucleophilic substitution of the mesyl group by the thio group of tetrazole 185 (Scheme 49) [297]. Ozonide 188 was synthesized by Mitsunobu reaction of alcohol 183 with pyridin-4-ol (187) (Scheme

A unified approach to the important protein kinase inhibitor balanol and a proposed analogue

• Tapan Saha,
• Ratnava Maitra and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2013, 9, 2910–2915, doi:10.3762/bjoc.9.327

• yield of 64% over two steps. The undesired anti-isomer 23 could be effectively converted to the desired syn-isomer 22 by a Mitsunobu-type inversion [64]. The major syn-isomer 22 was then acetylated and the resulting diene 24 was subjected to ring-closing metathesis [65] in the presence of Grubbs’ second

Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

• James A. B. Laurenson,
• John A. Parkinson,
• Jonathan M. Percy,
• Giuseppe Rinaudo and
• Ricard Roig

Beilstein J. Org. Chem. 2013, 9, 2660–2668, doi:10.3762/bjoc.9.301

• distinct retention times in the chiral HPLC chromatograms. For the inversion of the diol stereochemistry to be synthetically useful, a less basic synthetic equivalent for hydroxide was required. When Mitsunobu chemistry fails, O’Doherty and co-workers have achieved hydroxy group inversion by triflation and

The total synthesis of D-chalcose and its C-3 epimer

• Jun Sun,
• Song Fan,
• Zhan Wang,
• Guoning Zhang,
• Kai Bao and
• Weige Zhang

Beilstein J. Org. Chem. 2013, 9, 2620–2624, doi:10.3762/bjoc.9.296

• mixture of diastereomers [19]. This mixture was separated using silica gel chromatography to achieve a 78% overall yield over three steps. The unwanted syn-diastereomer 4' was converted into the required anti-diastereomer 4 via Mitsunobu inversion followed by removal of the benzoate group under basic

• achieved using a similar route in 24% overall yield. Key epimeric intermediates 4 and 4′ could be interconverted via Mitsunobu reaction, and their absolute configurations were assigned after their transformation into D-chalcose (I) and its C-3 epimer (I′), respectively. Notably, the stereocenter on C3 was

Bidirectional cross metathesis and ring-closing metathesis/ring opening of a C₂-symmetric building block: a strategy for the synthesis of decanolide natural products

• Bernd Schmidt and
• Oliver Kunz

Beilstein J. Org. Chem. 2013, 9, 2544–2555, doi:10.3762/bjoc.9.289

• 19:1, it was converted to 26 via Mitsunobu inversion [55] with acetic acid as the nucleophile. The synthesis of stagonolide E commenced with the desilylation of 26 and Steglich esterification of the resulting allyl alcohol 27. One-flask reaction of 28 with catalyst B, followed by treatment with NaH

Cyclopamine analogs bearing exocyclic methylenes are highly potent and acid-stable inhibitors of hedgehog signaling

• Johann Moschner,
• Anna Chentsova,
• Nicole Eilert,
• Irene Rovardi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2013, 9, 2328–2335, doi:10.3762/bjoc.9.267

• . Deprotetion of the 4-methoxybenzyl ether (DDQ, DCE/pH 7 phosphate buffer, 25 °C, 59%) and cyclization under Mitsunobu conditions (n-Bu3P, DEAD, toluene, 0 °C→25 °C, 93%) yielded piperidine 18. Deprotection of the benzyl ether by using previously devised conditions (DDQ, DCE/pH 7 phosphate buffer, 44 °C, 70

• steps) gave sulfonylamide 21. Reduction of the ester in 21 to the primary alcohol (DIBAl-H, THF, −78 °C to −40 °C, 97%) and cyclization by employing Mitsunobu conditions (n-Bu3P, DEAD, toluene, 0 °C→25 °C, 81%) yielded pyrrolidine 22. Previously devised conditions for the deprotection (1. DDQ, DCE/pH 7

Synthesis of enantiomerically pure N-(2,3-dihydroxypropyl)arylamides via oxidative esterification

• Akula Raghunadh,
• Satish S More,
• T. Krishna Chaitanya,
• Yadla Sateesh Kumar,
• Suresh Babu Meruva,
• L. Vaikunta Rao and
• U. K. Syam Kumar

Beilstein J. Org. Chem. 2013, 9, 2129–2136, doi:10.3762/bjoc.9.250

• . The phthalimido-protected chiral hydroxypropyl benzoate 5a could be synthesized by the reaction of nitrogen heterocyclic carbene, benzaldehyde and phthalimido-epoxide 4a. Phthalimido-epoxide 4a was synthesized by treating (S)-glycidol (3) with phthalimide (2) under Mitsunobu reaction conditions

• (Scheme 2). The Mitsunobu reaction yielded the product (S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (4a) [23][24][25][26][27] in 80% yield and in 99% ee. Then 4a was converted to hydroxypropyl benzoate 5a [28][29][30][31][32] by NHC-mediated oxidative esterification of aryl aldehydes (7a–f) [33][34][35

An approach towards azafuranomycin analogs by gold-catalyzed cycloisomerization of allenes: synthesis of (αS,2R)-(2,5-dihydro-1H-pyrrol-2-yl)glycine

• Jörg Erdsack and
• Norbert Krause

Beilstein J. Org. Chem. 2013, 9, 1936–1942, doi:10.3762/bjoc.9.229

• -catalyzed cycloisomerization proceeded uneventfully (Scheme 3). Desilylation of allenes 6a and 6b with tetrabutylammonium fluoride trihydrate afforded the α-hydroxyallenes 7a/b in high yield, and these were converted into the aminoallenes 8a/b under standard Mitsunobu conditions (DEAD, PPh3, phthalimide

• . Fortunately, the correct stereoisomer was enriched at the stage of the dihydropyrrole 18 due to several purification steps. Desilylation of 15 with tetrabutylammonium fluoride trihydrate (94% yield) and conversion of 16 into the α-aminoallene 17 under Mitsunobu conditions (45% yield) [38][39][62] set the

The application of a monolithic triphenylphosphine reagent for conducting Ramirez gem-dibromoolefination reactions in flow

• Kimberley A. Roper,
• Malcolm B. Berry and
• Steven V. Ley

Beilstein J. Org. Chem. 2013, 9, 1781–1790, doi:10.3762/bjoc.9.207

• immobilising the triphenylphosphine on a solid-support [48]. A polymer-supported equivalent of triphenylphosphine has also been successfully utilised by our group and by others in batch Wittig reactions [49][50], Mitsunobu and Staudinger aza-Wittig reactions [51][52], as well as many examples concerning the

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• installation of a trifluoroacetamide and O-demethylation gave the intermediate 118 used in a Mitsunobu reaction with 2-hydroxyethyl tosylate (119). Amine deprotection to 120 and installation of the [18F] label gave the target compound 98. Both 97 and 98 showed good affinity for Aβ1-42 aggregates (Ki = 4.5 nM

Intramolecular carbonickelation of alkenes

• Rudy Lhermet,
• Muriel Durandetti and
• Jacques Maddaluno

Beilstein J. Org. Chem. 2013, 9, 710–716, doi:10.3762/bjoc.9.81

• alkylnickel intermediates. Crotyl and cyclohexenyl ethers and amines were thus employed instead of the allyl. Compounds 5 and 6 were easily prepared by a Mitsunobu condensation involving 2-iodophenol or 2-iodo-N-mesylaniline and crotyl alcohol or cyclohex-2-enol (Scheme 2). An N-mesyl derivative was retained

• quaternary ring junction. Substrate 13 was prepared by a simple Mitsunobu condensation between 2-methylcyclohex-2-enol (12), a known compound prepared in three steps from commercially available 2-methylcyclohexanone and 2-iodophenol (Scheme 6). The carbonickelation protocol applied to 13 led in one hour to

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• excess (>98% ee), we utilized the Mitsunobu reaction of 2-mercaptobenzimidazoles with an amide obtained from (L)-lactic acid (17). Using one equivalent each of 2-mercaptobenzimidazole and α-hydroxyamide 13 (prepared from thionyl chloride-mediated coupling of (L)-lactic acid (17) and 2-chloro-4

Iridium-catalyzed intramolecular [4 + 2] cycloadditions of alkynyl halides

• Andrew Tigchelaar and
• William Tam

Beilstein J. Org. Chem. 2012, 8, 1765–1770, doi:10.3762/bjoc.8.201

• ). Deprotonation of 8 with sodium hydride, followed by trapping with propargyl bromide provided 9 in 60% yield, and a Mitsunobu reaction between 8 and sulfonamide 10 (prepared as per reference [47]) provided 11 in 74% yield. Bromination of 9 and 11 provided diene-tethered alkynyl halides 1c (57%) and 1e (83

A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues

• James R. Cochrane,
• Dong Hee Yoon,
• Christopher S. P. McErlean and
• Katrina A. Jolliffe

Beilstein J. Org. Chem. 2012, 8, 1344–1351, doi:10.3762/bjoc.8.154

• esterification to give the methyl ester 14 in excellent yield. Reaction of 14 with di(tert-butoxycarbonyl)guanidine under Mitsunobu conditions [27] proceeded smoothly to give 15 in 86% yield. Hydrolysis of the methyl ester followed by acidic work up to enable extraction of the resulting carboxylic acid gave 12

Exploring chemical diversity via a modular reaction pairing strategy

• Joanna K. Loh,
• Sun Young Yoon,
• Thiwanka B. Samarakoon,
• Alan Rolfe,
• Patrick Porubsky,
• Benjamin Neuenswander,
• Gerald H. Lushington and
• Paul R. Hanson

Beilstein J. Org. Chem. 2012, 8, 1293–1302, doi:10.3762/bjoc.8.147

• nucleophilic aromatic substitution (SNAr) diversification pathway is reported. Eight benzofused sultam cores were generated by means of a sulfonylation/SNAr/Mitsunobu reaction pairing protocol, and subsequently diversified by intermolecular SNAr with ten chiral, non-racemic amine/amino alcohol building blocks

• , namely sulfonylation, Mitsunobu alkylation and SNAr, which when combined in different sequences or with different coupling reagents, give access to skeletally diverse sultams, including the title compounds and the 8-membered bridged, benzofused sultams [32]. Building on this strategy, we herein report

• on multigram scale through the use of three efficient steps, namely sulfonylation, Mitsunobu alkylation and SNAr, to generate both stereoisomers of each core [37] (Scheme 2). The bridged benzofused sultam scaffolds were prepared by a sulfonylation intramolecular SNAr protocol, reported previously [32

Combined bead polymerization and Cinchona organocatalyst immobilization by thiol–ene addition

• Kim A. Fredriksen,
• Tor E. Kristensen and
• Tore Hansen

Beilstein J. Org. Chem. 2012, 8, 1126–1133, doi:10.3762/bjoc.8.125

• organocatalyst 2 was prepared from quinine, via the azide, in a two-step sequence by using the Bose–Mitsunobu reaction followed by Staudinger reduction, as described by others [15]. Thiourea Cinchona organocatalyst 3 was easily obtained from catalyst 2 by reaction with the appropriate aromatic isothiocyanate [15

Synthesis of a library of tricyclic azepinoisoindolinones

• Bettina Miller,
• Shuli Mao,
• Kara M. George Rosenker,
• Joshua G. Pierce and
• Peter Wipf

Beilstein J. Org. Chem. 2012, 8, 1091–1097, doi:10.3762/bjoc.8.120

• ring [19]. We have now developed this concept further toward a library synthesis of functionalized azepino-isoindolinone derivatives. Results and Discussion N-Alkylation of phthalimide with 4-penten-1-ol under Mitsunobu conditions, followed by NaBH4 reduction and pivaloate protection of the

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

• Kieron M. G. O’Connell,
• Monica Díaz-Gavilán,
• Warren R. J. D. Galloway and
• David R. Spring

Beilstein J. Org. Chem. 2012, 8, 850–860, doi:10.3762/bjoc.8.95

• intramolecular conjugate addition. Three of these compounds (1–3) were obtained from the corresponding alcohols [19][20] in three steps: Mitsunobu reaction with NH-Boc-tosylate, followed by tosyl deprotection with magnesium, and finally two-directional cross metathesis with ethyl acrylate to install the desired

Synthesis of (−)-julocrotine and a diversity oriented Ugi-approach to analogues and probes

• Ricardo A. W. Neves Filho,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2011, 7, 1504–1507, doi:10.3762/bjoc.7.175

• heterocyclic precursor as an amino input in Ugi four-component reactions (Ugi-4CR) [1]. Keywords: diversity oriented synthesis; julocrotine; leishmania; Mitsunobu reaction; Ugi reaction; Introduction Julocrotine (1) is a natural glutarimide alkaloid isolated from several plants of the genus Croton [2][3][4

• chiral center of 4 can be observed even in the presence of weak bases such as potassium carbonate [17]. Thus, we decided to use a base-free N-alkylation protocol, namely the Mitsunobu reaction of 3 and the readily available 2-phenylethanol [18]. This protocol gave the desired optically active product in

Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

• Ian Cumpstey,
• Jens Frigell,
• Elias Pershagen,
• Tashfeen Akhtar,
• Elena Moreno-Clavijo,
• Inmaculada Robina,
• Dominic S. Alonzi and
• Terry D. Butters

Beilstein J. Org. Chem. 2011, 7, 1115–1123, doi:10.3762/bjoc.7.128

• electrophilicity at the allylic position, facilitating coupling reactions. Mitsunobu coupling between nosylamides and 2,3-unsaturated-4-alcohols gave the 4-amino-pseudodisaccharides with inversion of configuration as single regio- and diastereoisomers. A palladium-catalysed coupling between an amine and a 2,3

• glycosidase inhibitory activity. Keywords: amination; glycomimetics; glycosidases; Mitsunobu; pseudodisaccharides; Introduction We have been interested in synthesising molecules consisting of two monosaccharides linked by formal condensation without using the anomeric position [1]. Such molecules, termed

• investigations into this area [6] we found that the installation of amine linkages between primary–primary carbons of monosaccharides was relatively straightforward; this was achieved by Mitsunobu coupling between carbohydrate C-6 alcohols and carbohydrate C-6 sulfonamides. Primary–secondary linkages were more

Long-range diastereoselectivity in Ugi reactions of 2-substituted dihydrobenzoxazepines

• Luca Banfi,
• Andrea Basso,
• Valentina Cerulli,
• Valeria Rocca and
• Renata Riva

Beilstein J. Org. Chem. 2011, 7, 976–979, doi:10.3762/bjoc.7.109

• condensation of 1 with racemic alcohols 2a,b through a Mitsunobu reaction. The moderate yields are due to the consumption of alcohols 2, which undergo side-reactions, resulting in incomplete transformation of 1, even when using 1.3–1.5 equiv of 2. The use of a larger excess of 2 would probably increase the

• noting that the Mitsunobu reaction is not effective on unprotected salicylaldehyde. 2,3-Dihydrobenzo[f][1,4]oxazepines similar to 5a,b have been previously prepared, but through less general routes [22][23][24]. Compounds 5a,b were reacted with a series of isocyanides and carboxylic acids to give, in

High chemoselectivity in the phenol synthesis

• Matthias Rudolph,
• Melissa Q. McCreery,
• Wolfgang Frey and
• A. Stephen K. Hashmi

Beilstein J. Org. Chem. 2011, 7, 794–801, doi:10.3762/bjoc.7.90

• procedure of Fukumoto et al. [38] gave 13. Addition of ethynylmagnesium bromide to 13 led to 14, which reacted with furan 15 [40] under Mitsunobu conditions [39] to afford 8. While the yields were good for the first two steps of the reaction sequence, the yield of the last step was only 32%. With AuCl3 the

• reaction with 15 under Mitsunobu conditions yielded 27. Deprotection of the alkyne 27 and the silyl ether 28, followed by the oxidation of the resulting alcohol 29 finally led to 16. It was not possible to remove both silyl groups simultaneously with TBAF, longer reaction times which would be necessary for

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• regioselective invertive epoxide opening. 1.1.3 Mitsunobu reactions The Mitsunobu reaction offers an operationally straightforward method for activating simple alcohols to invertive substitution, and it is widely used for constructing new stereodefined carbon–heteroatom bonds [24][25]. The Mitsunobu reaction

• proceeds by reaction of a phosphine and DIAD or DEAD with an alcohol 23 to form an O-phosphinite leaving group (Scheme 9). SN2 substitution to yield 24 is accompanied by formation of a phosphine oxide. There are many examples of the use of sulfur nucleophiles in the Mitsunobu reaction [25][26][27]: The

• reaction is successful with a wide range of primary and secondary alcohols, but Mitsunobu-type reactions are very sensitive to steric bulk at the electrophilic carbon atom. For example, reaction of alcohol 25 with a phenol under standard Mitsunobu conditions at 50 °C for 16 hours provides only a trace