Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• cycloaddition, and Ugi reactions followed by Mitsunobu cyclization, among other strategies (Figure 2) [16]. Central nervous system diseases Central nervous system (CNS) diseases are the main cause of disability and the second cause of mortality worldwide, indeed, according to the 2019 World Health Organization

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• showed that DFT features could train probabilistic surrogate models more effectively and that the optimization efficiency was superior to manual adjustments made by professional chemists. They also applied this approach to the Mitsunobu reaction and deoxyfluorination reaction, rapidly identifying medium

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• substrates according to this method. However, attempts to carry out the reaction sequence with unprotected hydrazine were unsuccessful. Alternatively, Mitsunobu reagent 23 can be reacted with in situ generated benzyne (from o-(trimethylsilyl)phenyl triflate) to provide the hydrazides for the concomitant

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• no products at room temperature (see Table 1) presumably due to the low solubility of Cs2CO3 in dioxane. They also provided a single example of a Mitsunobu reaction utilizing n-pentanol, dibutyl azodicarboxylate (DBAD), and PPh3. Therefore, there is still a great need to develop an operationally

• the presence of Cs2CO3. To explore the possibility of N2-selectivity, we hypothesized that the phosphine intermediate of a Mitsunobu reaction could provide chelation control, directing alkylation to the indazole N2-atom while using identical alcohols as described above. Thus, we subjected 6 to simple

• and mild Mitsunobu conditions for the preparation of N2-substituted indazole analogs 16a–q. By directly reacting compound 6 with alcohols 13a–q (2 equiv), diethyl azodicarboxylate (DEAD, 2 equiv), and triphenylphosphine (TPP, 2 equiv) in THF at 50 °C (conditions B), the corresponding N2-substituted

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• the byproduct triphenylphosphine oxide, necessitating chromatography which resulted in some hydrolysis. There are a number of catalytic activation strategies for Appel or Mitsunobu reactions such as those described by the Denton group [30], and Rutjes and co-workers [31], and while these may prove

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• Markowska et al. in 1993 [134]. As detailed in Figure 28, the synthesis starts with a Mitsunobu esterification of 28.1 with thioacetic acid to produce the thioester 28.2. Then, the reduction with lithium aluminium hydride produced the thiol 28.3. Finally, the phosphocholine moiety was introduced by using

Synthesis of medium and large phostams, phostones, and phostines

• Jiaxi Xu

Beilstein J. Org. Chem. 2023, 19, 687–699, doi:10.3762/bjoc.19.50

• chemical synthesis of macrocyclic lactones which are the key structural motifs in some biologically active compounds, 14-methyl-2-phenoxy-1-oxa-2-phosphacyclotetradecane 2-oxide (74) was synthesized as the hapten from phenyl hydrogen (12-hydroxytridecyl)phosphonate (73) via Mitsunobu reaction. The

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• Cham–Lam reactions [23][24][25][26]. However, it has been described that a Mitsunobu reaction of the seco-acid was particularly prone to an SN1 reaction, once the activated allylic alcohol yields an oxyphosphonium ion intermediate due to the conjugation to electron-rich aromatic ring, requiring some

• coupling reaction. Thus, the olefination reaction of aldehyde 15 with phosphonate 23, followed by the reduction of the obtained ester 24 using DIBAL led to the alcohol 25. The latter was submitted to the reaction with carboxylic acid 26 under Mitsunobu conditions [30], giving the corresponding ester 27 in

• compound 2 in an overall yield of 25% after 5 steps, bypassing the macrolactonization problem evidenced in the previously envisaged route. Intrigued by the problem encountered by Boger, Deshpande decided to investigate different reaction conditions for the formation of the macrocycle using the Mitsunobu

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• retention of configuration at C3 [17]. In 2008, a direct dehydroxyazidation of cholesterol by treatment of the steroid with a zinc azide–pyridine complex, diisopropyl azodicarboxylate (DIAD), and PPh3 was described [18]. This Mitsunobu-like reaction occurred with complete inversion at C3 to afford 3α

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• after each step prompted us to apply a Mitsunobu and Staudinger reaction for the preparation of amine 2 (Scheme 1) [33]. This one-pot reaction gave the desired amine 2 in 56% yield. Then, the corresponding isothiocyanate 3a was prepared by reaction of amine 2 with CS2 and DCC according to the reported

Strategies for the synthesis of brevipolides

• Yudhi D. Kurniawan and
• A'liyatur Rosyidah

Beilstein J. Org. Chem. 2021, 17, 2399–2416, doi:10.3762/bjoc.17.157

• using DDQ to form alcohol 40. At this point, the stereogenic center at the C6’ carbon required an inversion to match the target molecule. Thus, a standard Mitsunobu procedure followed by basic methanolysis were conducted. The desired inverted product 16, however, did not form. The authors hypothesized a

• acid (17) (Scheme 4). The β-hydroxy moiety in 44 can be installed via Sharpless dihydroxylation of the silyl enol ether derived from ketone 45. The 5,6-dihydro-α-pyrone group in ketone 45 is envisaged from protected diol 46 by the sequence of Mitsunobu esterification, ring-closing metathesis, and base

• ester 56 was achieved through reaction of 55 with the pre-activated acid 17 with N,N’-diisopropylcarbodiimide (DIC) and DMAP. Removal of the TBS protection with a fluoride source and succeeding Mitsunobu inversion with 3-butenoic acid (37) went smoothly to give ester 57. This intermediate accommodated

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• of regiocontrol (ratio N-1:N-2 > 99:1) (Table 1, entry 22). The N-alkylation of methyl ester 9 was also investigated under Mitsunobu conditions (see Supporting Information File 1), in the presence of n-pentanol (Scheme 2). Notably, the latter conditions demonstrated a strong (ca. three-fold

• . C-3 substituted indazole derivatives (12–24) employed to investigate C-3 substituent effects on indazole N-alkylation regioselectivity. Synthetic approaches to N-1 substituted indazole derivatives [12][13][14]. N-Alkylation of indazole 9 under Mitsunobu conditions shows a strong preference (ratio N

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• key intermediate. The treatment of 9 with benzoyl chloride under suitable conditions to selectively protect the 3-NH group of the uracil moiety afforded N3-benzoyluridine (10). The reaction of TIPDS-protected hydroxynucleoside 9 with N3-benzoylthymine under Mitsunobu reaction conditions, followed by

• synthesized from ᴅ-ribose in six steps following a procedure reported in the literature [48]. The Mitsunobu reaction of ribose derivative 30 and N3-(benzyloxymethyl)thymine afforded nucleoside 31 which was subjected to Vorbrüggen coupling with silylated uracil to give the protected double-headed nucleoside 32

• the second nucleobase thymine through Mitsunobu reaction followed by deprotection steps in the presence of TBAF and methanolic ammonia (Scheme 28) [30][65]. The nucleoside monomer 118 was phosphitylated and then incorporated into oligodeoxynucleotides but stabilization in the secondary structures due

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• trimethylsilyl cyanide (TMSCN) in THF at −10 °C. The reaction product 142 was obtained in quantitative yield and good diastereomeric ratio. Further hydrolysis of the cyclic acetal, and subsequent epoxidation of the resulting diol under typical Mitsunobu conditions led to epoxide derivative 143. The piperidine

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• synthesis of the basic part was initiated by converting quinine to quinineamine via a Mitsunobu reaction, followed by a Staudinger reduction [40]. Then it was coupled with the acidic part, which was obtained by the nitration of 2,4,6-trimethylbenzenesulfonyl chloride [39] to obtain organocatalyst 5 (Scheme

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• coupling reagents including the Mitsunobu reagent. Synthesis of α-phosphonodepsipeptides N,N’-Dicyclohexylcarbodiimide (DCC) was the first attempted coupling reagent in the synthesis of phosphonyl depsipeptides 108 from hydrogen 4-phenylbutylphosphinic acid (105) and 2-hydroxypropanoic acid derivatives 106

• -Bu) 150, deprotected again with piperidine, and cleaved with TFA and trapping agents. The free phosphonodepsipeptide 151 was obtained in 45% yield after HPLC purification (Scheme 25) [38]. A general and high yielding synthesis of phosphonodepsidipeptides 152 was realized via a Mitsunobu reaction of

• -hydroxyglutarate (84) in a Mitsunobu reaction to generate the γ-phosphonodepsipeptide 79 in a high yield of 66% (Scheme 27) [28]. Synthesis of phosphonodepsipeptides via the multicomponent condensation of amides, aldehydes, and phosphites followed by alcoholysis with hydroxy esters Previously, the Mannich-type

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• -halopurines [41]. O-Alkylation of guanosine and inosine with Cu(I)-stabilized carbenes derived form α-diazocarbonyl compounds is also known [42]. Alkylation of 6-oxopurine derivatives under Mitsunobu conditions which usually proceeds with O-regioselectivity are mostly described for guanine derivatives [43][44

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• 14 resulted in the formation of alcohol 22, which was then reacted with nucleoside analogs via a Mitsunobu reaction to generate the racemic difluorinated carbocyclic homonucleoside analogs 23 and 24 in good yields. (Triphenylphosphonio)difluoroacetate (PDFA, Ph3P+CF2CO2−) as a difluorocarbene source

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• (OEt)3 Next, we switched to pathway B (Scheme 2) and prepared 2,6-diazidopurine derivative 5 from 2,6-dichloropurine (11) via a Mitsunobu alkylation and SNAr reaction with NaN3 (Scheme 5) [22]. 2,6-Bistriazolylpurine derivatives 6a–i were obtained in CuAAC reactions with various alkynes in 35–76% yield

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• the good yields in this step, both intermediates were obtained with excellent enantiomeric excesses (97% for R = n-C5H11 and 90% for R = CH3). Compounds 60a and 60b were converted to azido ketones 61a and 61b by Mitsunobu reaction, and then these azido ketones underwent cyclization to furnish

Chiral anion recognition using calix[4]arene-based ureido receptors in a 1,3-alternate conformation

• Tereza Horáčková,
• Jan Budka,
• Vaclav Eigner,
• Wen-Sheng Chung,
• Petra Cuřínová and
• Pavel Lhoták

Beilstein J. Org. Chem. 2020, 16, 2999–3007, doi:10.3762/bjoc.16.249

• latter type of receptor, bearing double chiral units in the immediate proximity to the preorganised ureido cavity. Results and Discussion The introduction of the chiral alkyl moiety based on (S)-2-methylbutan-1-ol into the starting calix[4]arene 1 was carried out using recently described Mitsunobu

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• oxidation stereoselectively generated the spirocyclic epoxide 76. A second-protecting group shuffle afforded the primary alcohol 77. A Mitsunobu substitution of 77 with 2-mercaptobenzothiazole, followed by an oxidation with a large excess of mCPBA afforded the sulfone 78. While not producing the identical

• of the C-6 stereocenter (Scheme 13) [15][16]. The administration of the vinyllithium reagent, generated from the addition of the vinyl bromide 80 to 79, gave a separable 1:1 mixture of the diastereomeric alcohols 81a and 81b. The undesired stereoisomer 81b was converted into 81a by a Mitsunobu

Nonenzymatic synthesis of anomerically pure, mannosyl-based molecular probes for scramblase identification studies

• Giovanni Picca,
• Markus Probst,
• Simon M. Langenegger,
• Oleg Khorev,
• Peter Bütikofer,
• Anant K. Menon and
• Robert Häner

Beilstein J. Org. Chem. 2020, 16, 1732–1739, doi:10.3762/bjoc.16.145

• MPC-1 and MPC-2. Compound β-4Ac-Man-CEP was prepared in 4 steps from ᴅ-mannose (see Supporting Information File 1) [35][36]. Compound Cit-BZP-yne was prepared via a Mitsunobu reaction of tetrahydropyranyl (THP)-protected citronellol and a hydroxylated benzophenone derivative [10][37][38]. Compound Cit

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• -galactopyranoside (93)) from methyl α-D-glucopyranoside (90) through a Mitsunobu thioacetylation, mesylation, thioacetate hydrolysis with the treatment of sodium bicarbonate, and a subsequent intramolecular nucleophilic displacement. In the displacement step, the formation of the four-membered thietane ring is

• 3,5-anhydro-3-thiopentofuranosides 104 from methyl α- and β-arabinosides 101 through a Mitsunobu reaction, mesylation, and hydrolysis sequence followed by an intramolecular displacement. The in situ generated thiolate nucleophilically attacked the mesylate to form the thietane ring [51] (Scheme 22

• converted into 3,5-anhydro-3-thiopentofuranosides 135 through a Mitsunobu reaction with thiolacetic acid and hydrolysis followed by an intramolecular nucleophilic ring-opening of the oxirane ring. The newly generated thiolate underwent a nucleophilic ring-opening of the oxirane to generate the thietane ring