Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• consisting of training set design, classification, MLR and extrapolation to predict a new class of CPA catalysts with enhanced enantioselectivity. Subsequently, the new catalyst class was tested for cyclodehydration and oxetane desymmetrisation reactions, where a comprehensive model was developed for the

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• mesylate 1, whose basic treatment promoted the substitution of the mesylate group at C-21 by the 17α-hydroxy group and the oxetane ring formation in a 16% yield (Scheme 1) [10]. Winkler et al. developed the synthesis of alkylated derivatives of 17-spirooxetanosteroids from non-alkylated frameworks (Scheme

• . The oxetane compound 6 was further derivatized to incorporate a pyrrolidine moiety in presence of ammonia. Upon debenzylation at C-3, the target compound 7 was obtained in an 18% overall yield from 3. The pyrrolidino-oxetane derivative exhibited potent inhibition of Hedgehog signaling, comparable to

• cyclopamine. Comparing the biological results of the compound with the activity of desmethylveramiline (a des-E analogue of cyclopamine) has suggested that the rigidity of the oxetane ring is crucial for the potency of compound 7 [12]. Spiro-β-lactone steroids Beller et al. reported a selective method for

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• success. Being conscious about the challenges associated with intermolecular ring openings at four-membered heterocycles, we considered an in situ tethering approach, which has proved an attractive alternative in our recent study on oxetane-ring openings [31]. Therefore, electron-deficient ketone 7 was

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• photoredox nickel-catalyzed arylation of α-oxy C–H bonds of tetrahydrofuran (THF) and oxetane were also shown. Further, the catalytic system also proved compatible for the C‒H arylation of the benzylic system. As shown in Figure 2 [54], the mechanism for the transformation is proposed to involve the

Lipophilicity trends upon fluorination of isopropyl, cyclopropyl and 3-oxetanyl groups

• Benjamin Jeffries,
• Zhong Wang,
• Robert I. Troup,
• Anaïs Goupille,
• Jean-Yves Le Questel,
• Charlene Fallan,
• James S. Scott,
• Elisabetta Chiarparin,
• Jérôme Graton and
• Bruno Linclau

Beilstein J. Org. Chem. 2020, 16, 2141–2150, doi:10.3762/bjoc.16.182

• isopropyl substituent led to larger lipophilicity modulation compared to fluorination of the cyclopropyl substituent. Keywords: aliphatic fluorination; cyclopropane; isopropyl; isostere; lipophilicity; oxetane; Introduction The introduction of small alkyl groups onto bioactive compounds as space filling

• clearly indicates that further research towards theoretical lipophilicity prediction based in relative Gibbs energies in water and (wet) octanol is required. Examples of lipophilicity modulation for geminal dimethyl to cyclopropyl and oxetane modifications (measured experimentally via shake-flask method

• ). Lipophilicity modulation examples involving fluorinated cyclopropane derivatives (measured experimentally via shake-flask method). Lipophilicity changes upon fluorination of isopropyl, cyclopropane and oxetane rings (Series A, C: measured experimentally via shake-flask method; series B: measured experimentally

Selective preparation of tetrasubstituted fluoroalkenes by fluorine-directed oxetane ring-opening reactions

• Clément Q. Fontenelle,
• Thibault Thierry,
• Romain Laporte,
• Emmanuel Pfund and
• Thierry Lequeux

Beilstein J. Org. Chem. 2020, 16, 1936–1946, doi:10.3762/bjoc.16.160

• -opening reaction with bromide ions, even in the presence of bulky substituents. Keywords: acyclonucleotide; fluorine; monofluoroalkene; oxetane; selective ring-opening reaction; tetrasubstituted alkene; Introduction The introduction of fluorine atoms into organic compounds is known to modify their

• envisioned an alternative approach starting from fluoroalkylidene-oxetane derivatives and to the end we have studied the selectivity of the oxetane ring-opening reaction (Figure 3). Results and Discussion The preparation of a series of fluoroalkylidene-oxetanes 1–3 was previously reported from 3-oxetanone

• would allow ready access to novel fluorinated ACN precursors. At the outset the opening of the oxetane ring of 1 by a range of nucleophiles was trialed under acidic conditions. Inspired by Yadav et al. [23], methanol (20 equiv) was used as nucleophile in the presence of camphorsulfonic acid (CSA, 1

Recent synthesis of thietanes

• Jiaxi Xu

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

• displacements of 1,3-dihaloalkanes with different sulfide salts, thiourea was also used as a nucleophile in the double displacements, actually following the preparation procedure of thiols, affording thietane derivatives. Thiourea reacted with 3,3-bis(chloromethyl)oxetane (76) in the presence of HClO4 to yield

• photoreaction of N-methylthiosuccinimide (236) with 2,3-dimethylbut-2-ene (215a) gave rise to a mixture of thietane and oxetane derivatives 238 and 239, with thietane 238 as the major component. However, the reaction of the aromatic counterpart, N-methylmonothiophthalimide (237a) with olefins 215a and 186b

• from that of enones. The latter underwent the [2 + 2] annulation with olefins at their olefinic center to yield cyclobutane derivatives, and rarely undergo oxetane formation completely. The reaction parameters such as solvent affected the balance between the cyclobutane and oxetane formation. Whereas

Aldehydes as powerful initiators for photochemical transformations

• Maria A. Theodoropoulou,
• Nikolaos F. Nikitas and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2020, 16, 833–857, doi:10.3762/bjoc.16.76

• proved to transfer the triplet state energy more efficiently than benzaldehyde (8). Furthermore, the triplet state of the carbonyl compound was thought to be the intermediate for both the Paterno–Büchi oxetane formation and the olefin isomerization. Two possible mechanistic pathways for the Paterno–Büchi

• reaction were described. The first one included an attack on the π-system of the olefin by the oxygen atom of the excited carbonyl compound, forming a biradical intermediate 72. Then, the biradical intermediate 72 could either cyclize to produce an oxetane 73 or dissociate to form again the carbonyl

• compound 44 and a triplet state olefin molecule 17 in a nonplanar configuration. Both processes, oxetane formation and isomerization, were thought to proceed via the triplet state of benzaldehyde. The alternative pathway includes a polarization of the π-system of the olefin, forming a transition state

SO₂F₂-mediated transformation of 2'-hydroxyacetophenones to benzo-oxetes

• Revathi Lekkala,
• Ravindar Lekkala,
• Balakrishna Moku,
• K. P. Rakesh and
• Hua-Li Qin

Beilstein J. Org. Chem. 2019, 15, 976–980, doi:10.3762/bjoc.15.95

• satisfactory yields from the functionalized acyclic precursors generally requires good leaving groups and anions. A large number of synthetic methods has been described for the formation of oxetane derivatives and among them, two common strategies are widely applied. The first strategy engages an

• intramolecular etherification reaction, which is called Williamson ether synthesis (Scheme 1a). This method was first utilized to synthesize oxetanes in 1878 and has remained as general tool in the synthesis of complex oxetane-containing compounds since then [17][18][19][20]. The second strategy involves a [2

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• protonation using a fully substituted alkene. Nitroalkenes that were activated by the incorporation of an oxetane or N-Boc-azetidine ring at the β-position reacted well with both thioacetic acid and thiobenzoic acid (Scheme 38a). Various R2 substituents were compatible with the reaction, including an

• isopropyl group and a pendent methyl ester. Generally, the azetidine nitroalkenes provided the 1,2-nitrothioacetates in higher yields and enantioselectivity (81–99% yield, 95:5 to 98:2 er). The oxetane and N-Boc azetidine nitroalkenes were activated toward conjugate addition by the release of ring-strain

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

• Ivan Bassanini,
• Karl Hult and
• Sergio Riva

Beilstein J. Org. Chem. 2015, 11, 1583–1595, doi:10.3762/bjoc.11.174

• to synthesize a number of functionalized polymers. For instance, Müller and Frey used 3,3-bis(hydroxymethyl)oxetane in different blends with 1,8-octanediol and sebacic acid to get polymers with a varied content of oxetane groups (Figure 16). Oxetane is a very acid sensitive moiety, but the mild

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• signature oxetane moiety. Ether cleavage [144] and Swern oxidation resulted in the formation of ketone 169. HWE-olefination followed by reduction to the allyl alcohol led to allylic ester 170 after a Johnson–Claisen rearrangement [145] upon treatment with triethyl orthoacetate. Ester 170 was saponificated

• (see Scheme 21), followed by the formation of an acid-azide. Shiori version [146][147] of the Curtius rearrangement with concomitant addition of MeOH to the intermediate isocyanate afforded carbamate 171. Oxetane 171 was then opened under Lewis-acidic conditions. The deprotected alcohol was protected

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

• , desilylation, and recyclization accompanied by a ring opening of oxirane or oxetane (Scheme 62 and Scheme 63). Cobalt(II) acetylacetonate (acac) or bis-2,2,6,6-tetramethylheptane-3,5-dienoate (thd) were used as the catalyst for the peroxidation of 219. The cyclization of the intermediate peroxide 220 was

• synthesized in a similar way starting with the peroxidation of 2-methyl-2-(3-methylbut-3-enyl)oxetane (222), followed by oxetane-ring opening in triethyl(2-methyl-4-(2-methyloxetan-2-yl)butan-2-ylperoxy)silane (223) (Scheme 63) [250]. Dioxanes can also be synthesized by inramolecular cyclizations with the

• materials for the synthesis of cyclic peroxides [250][251][252][332]. For example, the ozonolysis of the double bond in the oxetane-containing compound, 2-methyl-2-(3-methylbut-3-enyl)oxetane (244) afforded 2-(3-hydroperoxy-3-methoxybutyl)-2-methyloxetane (245), which underwent recyclization in the presence

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• 191a promotes the formation of the tertiary carbenium ion 194, which isomerizes via the oxetane intermediate 195 to the benzylic cation 196. Expulsion of acetone then yields indene 197 in excellent yield. Avoiding this side reaction could only be achieved by exchanging the methyl ether protecting group

Exploration of an epoxidation–ring-opening strategy for the synthesis of lyconadin A and discovery of an unexpected Payne rearrangement

• Brad M. Loertscher,
• Yu Zhang and
• Steven L. Castle

Beilstein J. Org. Chem. 2013, 9, 1179–1184, doi:10.3762/bjoc.9.132

• generated. Alcohol 27, or the aforementioned regioisomer that would have resulted from ring-opening of epoxide 25 at the more hindered carbon, would have afforded terminal epoxide 30 or oxetane 31, respectively, when subjected to this two-step sequence. While these observations do not shed light on the

Formation of macrocyclic lactones in the Paternò–Büchi dimerization reaction

• Junya Arimura,
• Tsutomu Mizuta,
• Yoshikazu Hiraga and
• Manabu Abe

Beilstein J. Org. Chem. 2011, 7, 265–269, doi:10.3762/bjoc.7.35

• lactones 2a,b with Ci symmetry including two oxetane-rings, which are the Paternò–Büchi dimerization products, were isolated in ca. 20% yield. The intramolecular cyclization products, such as 3-alkoxyoxetane and 2,7-dioxabicyclo[2.2.1]hept-5-ene derivatives, were not detected in the photolysate. Keywords

• : furans; macrocyclic lactone; oxetane; Paternò–Büchi reaction; photochemical reaction; Findings Photochemical [2 + 2] cycloaddition reaction of alkenes with carbonyls, so-called Paternò–Büchi reaction [1][2][3][4][5][6][7][8][9][10][11][12][13], is one of the most efficient methods for preparing

• oxetane 2OX after the intersystem crossing (ISC). Alternatively, 2,7-dioxabicyclo[2.2.1]hept-5-ene OBH would be formed from the 1,6-biradical form. The regioisomeric oxetane 3OX should be formed via the regioisomeric biradical BR’. Biradical BR is energetically more stable than BR’, because BR can undergo

Heavy atom effects in the Paternò–Büchi reaction of pyrimidine derivatives with 4,4’-disubstituted benzophenones

• Feng-Feng Kong,
• Jian-Bo Wang and
• Qin-Hua Song

Beilstein J. Org. Chem. 2011, 7, 113–118, doi:10.3762/bjoc.7.16

• 1,4-diradical. Ring-close of the latter gives an oxetane. The higher selectivity observed for the triplet reaction is rationalized by the optional conformation of the intermediate 2-oxabutane-1,4-diyl for ISC to the singlet diradical, which is preferentially controlled by spin-orbit coupling, thus

• . Photoproducts 2 and 3 have no significant absorption for light at above 290 nm. Hence, a secondary photolysis of the oxetane products (2 or 3) should not occur unless there is prolonged irradiation. Compositions in photoreaction mixture were quantified by 1H NMR spectroscopy (300 MHz) directly on the crude

Acid catalyzed cyclodimerization of 2,2-bis(trifluoromethyl)-4-alkoxy-oxetanes and -thietanes. Synthesis of 2,2,6,6-tetrakis(trifluoromethyl)-4,8-dialkoxy-1,5-dioxocanes and 3,3,7,7-tetrakis(trifluoromethyl)-9-oxa-2,6-dithia-bicyclo[3.3.1]nonane

• Viacheslav A. Petrov and
• Will Marshall

Beilstein J. Org. Chem. 2010, 6, No. 46, doi:10.3762/bjoc.6.46

• -dioxocanes, isolated in 31–42% yield. The structures of two products (R = C2H5O and n-C3H7O) were established by single crystal X-ray diffraction. The corresponding oxetane carrying the bulky t-C4H9O group has different reactivity towards BF3·OEt2, slowly producing a mixture of two acyclic, unsaturated

• -2-(trifluoromethyl)but-3-en-2-ol [2]. Some compounds containing two 2,2-bis(trifluoromethyl)oxetane units, such as bis-4,4-(trifluoromethyl)oxetan-2-yl ether, were reported to undergo Lewis acid catalyzed polymerization [3]. Known reactions of 2,2-bis(trifluoromethyl)-4-alkoxythietanes (R = CH3O and

• different reaction course. The addition of boron trifluoride etherate catalyst to a solution of the oxetane in dichloromethane resulted in a spontaneous and mildly exothermic reaction. A very interesting feature of this process is the appearance of highly intensive blue or blue-green colour upon the

(Pseudo)amide-linked oligosaccharide mimetics: molecular recognition and supramolecular properties

• José L. Jiménez Blanco,
• Fernando Ortega-Caballero,
• Carmen Ortiz Mellet and
• José M. García Fernández

Beilstein J. Org. Chem. 2010, 6, No. 20, doi:10.3762/bjoc.6.20

• investigations have demonstrated that incorporation of SAAs in peptide structures can circumvent the adverse properties of bioactive natural systems. Thus, SAAs containing amino and carboxylic functional groups, and a rigid ring system (pyran, furan, oxetane) have emerged as versatile and conformationally

• and co-workers undertook the synthesis of carbopeptoids based on the oxetane template (Figure 7) [46][47][48]. Conformational analysis was carried out for two oxetane β-SAA hexamers with the 6-deoxy-L-altro and D-arabino configurations by means of detailed NMR and IR studies in combination with

• molecular mechanics [49]. These studies identified a left-handed helical secondary structure for the 6-deoxy-L-altro-oxetane hexamer and a right-handed helical structure for the D-arabino-configured oxetane hexamer 21 (having the opposite absolute configuration at C-2 and C-3) stabilised in both instances