Synthesis of the C8’-epimeric thymine pyranosyl amino acid core of amipurimycin

• Pramod R. Markad,
• Navanath Kumbhar and
• Dilip D. Dhavale

Beilstein J. Org. Chem. 2016, 12, 1765–1771, doi:10.3762/bjoc.12.165

• ] (Scheme 2). Selective protection of the C5 primary hydroxy group as PMP ether using p-methoxyphenol under Mitsunobu reaction conditions afforded 4 that on benzylation of the C3 hydroxy group (NaH and benzyl bromide in DMF) gave compound 5. Upjohn dihydroxylation of 5 using K2OsO4·2H2O followed by

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• . Some of these post-MCR transformations are: intramolecular cycloaddition reactions, Knoevenagel condensations, metathesis reactions, aza-Wittig reactions, Mitsunobu reactions, etc. [21]. Up to now, two review articles have been reported on azaheterocyclic phosphonates [22][23], but no overview article

Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization

• Barry M. Trost,
• Michael C. Ryan and
• Meera Rao

Beilstein J. Org. Chem. 2016, 12, 1136–1152, doi:10.3762/bjoc.12.110

• bicycloisomerization reaction can be readily accessed in two steps. Alkylation of a secondary propargylamide can be achieved by sodium hydride deprotonation of its acidic proton and SN2 substitution of a substituted propargyl bromide (Scheme 5a). Alternatively, the same propargylamide can be alkylated under Mitsunobu

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• muraymycins (Scheme 5) [98]. A fully protected ureidomuraymycidine tripeptide was prepared through lactone opening followed by urea formation and a final Mitsunobu ring closure as key steps. A Strecker reaction of the benzylimine 34 followed by several steps afforded the alcohol 35. A thermal lactonisation as

• obtained precursor 42 was treated with DIAD and PPh3 in a final step for an intramolecular Mitsunobu ring closure to finish the synthesis of the fully protected ureidomuraymycidine 43 (Scheme 5) [98]. In 2010, Ducho et al. reported an alternative synthesis of the naturally occurring uridine-derived

Asymmetric α-amination of 3-substituted oxindoles using chiral bifunctional phosphine catalysts

• Qiao-Wen Jin,
• Zhuo Chai,
• You-Ming Huang,
• Gang Zou and
• Gang Zhao

Beilstein J. Org. Chem. 2016, 12, 725–731, doi:10.3762/bjoc.12.72

• Mannich-type reaction. As an extension of this work, we then wondered if other electrophilic partners instead of methyl acrylate could be used to generate similar catalytically active species in situ. Also inspired by the Mitsunobu reaction [43], we reported herein the reaction of azodicarboxylates with 3

• spectra research in CD2Cl2. The mimetic activation mode of Mitsunobu reaction. Scale-up of the reaction and deprotection of the product. Proposed transition-state model. Catalyst screening. Optimization of conditions. Substrate scope. Supporting Information Supporting Information File 32: Experimental

Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins

• Guozheng Huang,
• Simon Schramm,
• Jörg Heilmann,
• David Biedermann,
• Vladimír Křen and
• Michael Decker

Beilstein J. Org. Chem. 2016, 12, 662–669, doi:10.3762/bjoc.12.66

• , Prague 4, CZ-14220, Czech Republic 10.3762/bjoc.12.66 Abstract Various Mitsunobu conditions were investigated for a series of flavonolignans (silybin A, silybin B, isosilybin A, and silychristin A) to achieve either selective esterification in position C-23 or dehydration in a one-pot reaction yielding

• the biologically important enantiomers of hydnocarpin D, hydnocarpin and isohydnocarpin, respectively. This represents the only one-pot semi-synthetic method to access these flavonolignans in high yields. Keywords: dehydration; flavonoid; hydnocarpin; Mitsunobu; silybin; Introduction Flavonolignans

• ; 5% catalyzed by horseradish peroxidase) [14]. To study the biological activities of hydnocarpin-type compounds, a new and robust method for their preparation is required. It is known that elimination can occur in some cases as a side reaction in Mitsunobu esterifications with structurally hindered

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• literature-known procedure [47]. Regioselective reduction with sodium borohydride, followed by dehydration under Mitsunobu conditions and silylation of the tertiary alcohol furnished trimethylsiloxy ketone 78. The ketone functionality was then diastereoselectively reduced under Corey–Bakshi–Shibata

Stereoselective synthesis of hernandulcin, peroxylippidulcine A, lippidulcines A, B and C and taste evaluation

• Marco G. Rigamonti and
• Francesco G. Gatti

Beilstein J. Org. Chem. 2015, 11, 2117–2124, doi:10.3762/bjoc.11.228

• ) stereogenic center by means of a Mitsunobu reaction, followed by transesterification of the ester to give 4 (Scheme 1). (S)-Isopulegone was prepared by Jones oxidation of (−)-isopulegol following a reported procedure [14]; but on a large scale we have observed that a partial loss of the optical purity of the

• . The best performances were obtained with the Thermoanaerobium brokii ADH; but even if the de was excellent (>99%) the conversion was still too low (about 36% by GC) to be really exploited on a preparative scale. Finally, we tried the Mitsunobu reaction, which gave the best results (method D) [19

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• , however, insufficient deprotonation of the alcohol 50 under flow conditions (NaHMDS or BEMP instead of using a suspension of NaH as used in batch) required a modification to the planned approach. To this end a Mitsunobu protocol based on the orchestrated mixing of four reagent streams (50, 54 and reagents

First chemoenzymatic stereodivergent synthesis of both enantiomers of promethazine and ethopropazine

• Paweł Borowiecki,
• Daniel Paprocki and
• Maciej Dranka

Beilstein J. Org. Chem. 2014, 10, 3038–3055, doi:10.3762/bjoc.10.322

• identified as a key step in optimizing the process to avoid racemization. To save one step less, we initiated our efforts by direct transformation of the sec-alcohol functionality in afore-obtained compound (±)-3 under modified Mitsunobu [78][79] reaction conditions using Ph3P (1.1 equiv), DEAD (1.1 equiv

• ), and the respective amine (1 equiv of Et2NH or Me2NH) conducted in dry THF. Since the Mitsunobu condensation protocol is considered as particularly attractive due to the superior reactivity of the in situ-generated corresponding oxyphosphonium intermediate on nucleophilic substitution, we envisioned

• disappointment, none of these attempts led to success. When Mitsunobu chemistry fails, a hydroxy group inversion by tosylation and displacement using amine was performed. Unfortunately, attempts to carry out the reaction at higher temperature led to complete decomposition of the tosylate substrate. In the

Synthesis of phosphoramidites of isoGNA, an isomer of glycerol nucleic acid

• Keunsoo Kim,
• Venkateshwarlu Punna,
• Phaneendrasai Karri and
• Ramanarayanan Krishnamurthy

Beilstein J. Org. Chem. 2014, 10, 2131–2138, doi:10.3762/bjoc.10.220

• for the introduction of the canonical nucleobases by a SN2 displacement reaction. At this point, we chose the Mitsunobu reaction (Scheme 1), which has been widely employed [16]. The reaction with the N3-benzoyl protected thymine delivered 5 in good yield. However, the reaction with N6-benzoyladenine

• protecting group approach. We silylated 1 to afford 8 whose ketal was deprotected followed by tritylation to give the derivative 10, which is expected to be suited for the introduction of nucleobases by an SN2 reaction (Scheme 2). Once again, the Mitsunobu reaction with thymine proceeded smoothly. However

• yield 16. The use of 16 in the subsequent Mitsunobu reaction afforded 68% of the desired product 17. With derivatives 11 and 17 in hand we proceeded to prepare the corresponding phosphoramidite derivatives 13 and 19, respectively, under standard conditions as outlined in Scheme 2. We proceeded to

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry

• J. Alexander Willms,
• Rita Beel,
• Martin L. Schmidt,
• Christian Mundt and
• Marianne Engeser

Beilstein J. Org. Chem. 2014, 10, 2027–2037, doi:10.3762/bjoc.10.211

• ). An SN2 reaction with 5 [55] led to 8. We abandoned our initial shorter synthetic route based on a Mitsunobu reaction leading from 6 directly to 8 due to severe purification difficulties. Compound 8 could be charge-tagged to 9 using ethyl bromide. Finally, the free catalyst 1 was obtained by acidic

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

• Mahesh K. Lakshman,
• Manish K. Singh,
• Mukesh Kumar,
• Raghu Ram Chamala,
• Vijayender R. Yedulla,
• Domenick Wagner,
• Evan Leung,
• Lijia Yang,
• Asha Matin and
• Sadia Ahmad

Beilstein J. Org. Chem. 2014, 10, 1919–1932, doi:10.3762/bjoc.10.200

• compounds, those with a C–O–N bond are less common. Typically the latter are synthesized by the alkylation of BtOH with alkyl halides [17][18], quaternary alkyl ammonium salts [19], or via a Mitsunobu reaction (Scheme 1) [20]. Herein, we report a facile approach to 1-alkoxy-1H-benzo- (Bt-OR) and 7

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• work-up provided alcohol 141. Coupling under Mitsunobu conditions with an appropriate alcohol, e.g., 3-hydroxypyridine, reduction of the tert-butyl ester with DIBAL-H, and treatment with TBS triflate gave silyl ether 142. Hydrogenolysis of 142 using Pd/BaSO4 produced the free aziridine, which was then

Efficient routes toward the synthesis of the D-rhamno-trisaccharide related to the A-band polysaccharide of Pseudomonas aeruginosa

• Aritra Chaudhury,
• Sajal K. Maity and
• Rina Ghosh

Beilstein J. Org. Chem. 2014, 10, 1488–1494, doi:10.3762/bjoc.10.153

• synthesis of monomeric D-rhamnose has been highly streamlined by Roy et al. in 2007 [26], and further improvement on this method was reported by Kiefel et al. in 2011 [27]. However, the deoxygenation protocol involving halogenation under Mitsunobu conditions was found to be inefficient when applied to

Rasta resin–triphenylphosphine oxides and their use as recyclable heterogeneous reagent precursors in halogenation reactions

• Xuanshu Xia and
• Patrick H. Toy

Beilstein J. Org. Chem. 2014, 10, 1397–1405, doi:10.3762/bjoc.10.143

• ; polymer-supported reagent; rasta resin; triphenylphosphine oxide; Introduction One of the major drawbacks of the Wittig [1] and Mitsunobu [2][3] reactions is that they result in the formation of a stoichiometric quantity of triphenylphosphine oxide (1) as a byproduct. From an atom economy perspective

Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ₀)

• Sabin Llona-Minguez and
• Simon P. Mackay

Beilstein J. Org. Chem. 2014, 10, 1333–1338, doi:10.3762/bjoc.10.135

• both alcohols showed a diastereomeric purity of >99% by 1H NMR. Mitsunobu reaction on the secondary alcohols using DEAD or DIAD did not provide the desired azides [42][43] nor did a one-pot Appel reaction/nucleophilic substitution/Staudinger reaction protocol involving a double inversion of

4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions

• Michael J. Burns,
• Thomas O. Ronson,
• Richard J. K. Taylor and
• Ian J. S. Fairlamb

Beilstein J. Org. Chem. 2014, 10, 1159–1165, doi:10.3762/bjoc.10.116

• using them as nucleophilic partners in oxa-Michael additions and the Mitsunobu reaction. The reactions proceed in moderate to excellent yields on a range of substrates containing useful functionality. The reactions serve as practical and valuable synthetic methods to construct complex 2-pyronyl ethers

• , which are found embedded in a number of natural products. Keywords: heterocycles; Mitsunobu reaction; oxa-Michael addition; 2-pyrone; vinyl ethers; Introduction The 2-pyrone motif is a prevalent structural feature of many complex natural products and biologically active compounds [1][2]. Various

• degradation under harsh conditions, representing an interesting synthetic chemistry challenge to address. The ability to install more complex functionality on the hydroxy group of 6-alkyl-4-hydroxy-2-pyrones would be of considerable synthetic value. The Mitsunobu reaction is a well-established, widely used

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