Regioselective S_N2' Mitsunobu reaction of Morita–Baylis–Hillman alcohols: A facile and stereoselective synthesis of α-alkylidene-β-hydrazino acid derivatives

• Silong Xu,
• Jian Shang,
• Junjie Zhang and
• Yuhai Tang

Beilstein J. Org. Chem. 2014, 10, 990–995, doi:10.3762/bjoc.10.98

• Silong Xu Jian Shang Junjie Zhang Yuhai Tang Department of Chemistry, School of Science, Xi’an Jiaotong University, Xi’an 710049, P. R. China 10.3762/bjoc.10.98 Abstract A highly regioselective SN2' Mitsunobu reaction between Morita–Baylis–Hillman (MBH) alcohols, azodicarboxylates, and

• triphenylphosphine is developed, which provides an easy access to α-alkylidene-β-hydrazino acid derivatives in high yields and good stereoselectivity. This reaction represents the first direct transformation of MBH alcohols into hydrazines. Keywords: azodicarboxylate; hydrazine; Mitsunobu reaction; Morita–Baylis

• acetates with azodicarboxylates in the presence of PPh3 (Mitsunobu reaction conditions), which gives an efficient access to α-alkylidene-β-hydrazino acid derivatives, an important precursor for many bioactive compounds [25][26][27][28][29][30] including β-amino acids [25] (Scheme 1, top). However, the

Structure elucidation of female-specific volatiles released by the parasitoid wasp Trichogramma turkestanica (Hymenoptera: Trichogrammatidae)

• Armin Tröger,
• Teris A. van Beek,
• Martinus E. Huigens,
• Isabel M. M. S. Silva,
• Maarten A. Posthumus and
• Wittko Francke

Beilstein J. Org. Chem. 2014, 10, 767–773, doi:10.3762/bjoc.10.72

• -cis-2,4,6-trimethylcyclohexanone. Subsequent Baeyer–Villiger oxidation, followed by reduction of the obtained lactone, yielded syn,syn-2,4-dimethylheptan-1,6-diol 16 (Figure 4). Protection of the primary hydroxy group gave 17 followed by a Mitsunobu sequence involving the secondary hydroxy group

Phosphinate-containing heterocycles: A mini-review

• Olivier Berger and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2014, 10, 732–740, doi:10.3762/bjoc.10.67

• which are 1,3-azaphospholidine and 1,4-azaphosphorine derivatives 26, 29 [26]. For the 5-membered ring 26, hydroxymethyl-H-phosphinic acid (24) underwent a sila-Arbuzov reaction with the bromide 25, the crude mixture was esterified with diphenyldiazomethane, cyclized using Mitsunobu conditions and then

• sodium borohydride to afford an alcohol intermediate 28. This product was cyclized using Mitsunobu conditions and finally hydrogenolyzed to deliver the 6-membered heterocycle 29 in 12% overall yield (Scheme 12) [26]. In this particular study phosphinates 26 and 29 were tested as inhibitors of aspartate

• malonate anion. Tandem hydrophosphinylation/Michael/Michael reaction of allenyl-H-phosphinates. 5-Membered “cyclo-PALA” via intramolecular Mitsunobu reaction. 6-Membered “cyclo-PALA” via intramolecular Mitsunobu reaction. Intramolecular Kabachnik–Fields reaction. Tandem Kabachnik–Fields/alkylation reaction

Synthesis of (2S,3R)-3-amino-2-hydroxydecanoic acid and its enantiomer: a non-proteinogenic amino acid segment of the linear pentapeptide microginin

• Rajendra S. Rohokale and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2014, 10, 667–671, doi:10.3762/bjoc.10.59

• hemiacetal with NaIO4 and reduction with NaBH4 gave triol 6b,which was monosilylated with TBDPSCl to give 7b. Conversion of the secondary hydroxy group in 7b to azide 8b according to the Mitsunobu protocol, and deprotection followed by oxidation of the primary hydroxy group gave azido acid 10b. Finally

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• to provide sufficient substance amounts for clinical tests [41][42]. Additionally, alternatives in reactions driven by the formation of phosphine oxides from phosphines (e.g. the Appel and Mitsunobu reaction) are highly desired to improve atom economy (reduced waste amounts) and to circumvent

• inexpensive phosphites (P(OR)3) have only been applied as phosphine substitutes in one single example: Beal [46] utilized tri-isopropylphosphite in a Mitsunobu condensation of a guanine-derived nucleoside analog with benzylic alcohols providing simplified byproduct separation through improved water solubility

• conditions (I2, PPh3) [81][82] surpassed by far Mitsunobu conditions and sulfonation (with MsCl, TsCl) induced cyclisations (see Supporting Information File 1 for more details): Under optimized conditions (1.1 equiv I2, Et3N in MeCN at −40 °C) the cyclic products 11a–c were isolated in 68–77% yield and 90–99

Synthesis of new enantiopure poly(hydroxy)aminooxepanes as building blocks for multivalent carbohydrate mimetics

• Léa Bouché,
• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 213–223, doi:10.3762/bjoc.10.17

• Mitsunobu conditions with diphenylphosphoryl azide according to a protocol by Bose [46]. The desired bicyclic azide 23 was now isolated in 79% yield and its subsequent reduction and deprotection with TBAF gave compound 24 in essentially quantitative yield (over two steps). After protection of the two

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