Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• dioxazolone bearing a linear alkyl group was efficiently converted to the N-vinylamide 26a in good yield. The observed regioselectivity followed the anti-Markovnikov fashion stemming from the regioselective hydrozirconation of the alkyne using Schwartz’s reagent [100]. Aryl substituents on the dioxazolone

• phenylacetylene was confirmed. Based on previous mechanistic insight from electrophilic amidation studies [101][102], the catalytic amidation of alkynes is proposed as shown in Figure 8. First, the alkenylzirconium complex INT-29, formed through hydrozirconation of alkyne 25, undergoes transmetalation with the

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

• -alkynylketones 129 in good yields. Conjugate additions with organozirconium reagents The hydrozirconation of alkenes and alkynes generates mild organozirconium compounds that can be used in various transformations. Fletcher and co-workers developed the utilization of organozirconium reagents in Cu-catalyzed

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

• Benedikt Kolb,
• Daniela Silva dos Santos,
• Sanja Krause,
• Anna Zens and
• Sabine Laschat

Beilstein J. Org. Chem. 2023, 19, 176–185, doi:10.3762/bjoc.19.17

• reactivity and complex synthesis. Based on previous work and own initial results, a new stereospecific sequential hydrozirconation/Pd-catalyzed acylation of enynes with acyl chlorides towards conjugated (2E,4E)-dienones is reported. We investigated a number of substrates with different alkyl and aryl

• ; hydrozirconation; palladium catalysis; Schwartz's reagent; terpenes; Introduction Conjugated dienones are recurring structural motifs in natural products. Several biologically relevant compounds carry (2Ε,4E)-unsaturated ketones or the corresponding esters or amides. Selected examples are clifednamide H (1) which

• ]. Since the early work by Wailes, Schwartz and Buchwald on the Schwartz reagent Cp2Zr(H)Cl and its reactivity towards alkynes, alkenes, and C–X double bonds particularly hydrozirconation has gained much attention [25][26][27][28][29][30]. It has been successfully employed in methodology studies [31][32

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• coupling revealed the incompatibility of the lactone function; therefore, it was reduced with DIBAL-H then transformed into 19 by a one pot acetalization–desilylation procedure (91:9 mixture of diastereomers) [17]. Hydrozirconation followed by treatment with iodine furnished the target vinyl iodide 20

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• Schwartz’s reagent. It is employed principally for hydrozirconation of double and triple carbon–carbon bonds [10], and its application in chemistry of amides is quite recent. It can be also utilized in reduction of other unsaturated moieties, e.g., Pace et al. have shown reduction of isocyanates to

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

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

• produced 46. The hydrozirconation of 46 with Schwartz’s reagent under equilibrating conditions, followed by the reaction with I2 gave the vinyl iodide 47. Finally, the activation of the C-14 hydroxy group and the SN2 displacement with azide gave the C-8–C-16 fragment 48. Ghosh relied on a reductive

• compared to the IC50 values of 1.3, 1.0, and 0.36 nM, respectively, for spliceostatin A (4) against the same cell lines. Fragment union via Pd-catalyzed sp2–sp2 coupling A Negishi coupling reaction [42] was used in the Jacobsen synthesis of FR901464 (1, Scheme 23) [17][18]. The hydrozirconation of 91

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• . Organozirconium compounds are another class of organometallic reagents that have been used widely in the synthesis of complex molecules. Recently, Fletcher and co-workers demonstrated the applicability of a hydrozirconation in the ACA reaction to non-heterocyclic conjugated substrates [22][23][24][25][26], while

• the Šebesta group was the first to report the copper-catalysed addition of organozirconium reagents to N-substituted 2,3-dehydro-4-piperidones (Scheme 4A) [27]. In the latter work, the organozirconium reagents were generated first in situ by the hydrozirconation of alkenes. Subsequently, the L1/Cu

Synthesis of the polyketide section of seragamide A and related cyclodepsipeptides via Negishi cross coupling

• Jan Hendrik Lang and
• Thomas Lindel

Beilstein J. Org. Chem. 2019, 15, 577–583, doi:10.3762/bjoc.15.53

• alkyne terminus. Hydrozirconation/iodination of alkyne 17 required freshly prepared Schwartz reagent (3 equiv) and iodine (3 equiv) to obtain yields of (E)-olefin 18 above 80% with perfect stereo- and regioselectivity. For comparison, as part of a study towards kendomycin, Arimoto and co-workers had

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

• –Gilbert homologation [128][129] under Bestmann–Ohira conditions [130][131], a Schwartz hydrozirconation/iodination sequence [132], and appropriate protecting group manipulations. Vinyl iodide 21, which comprises the C8–C13 segment was prepared from TBDPS-protected (R)-hydroxy-2-methylbut-3-ene 20 that was

• obtained according to literature procedures [133], thus setting the stereochemistry at C12. The five-step sequence from 20 to vinyl iodide 21 included a (poorly diastereoselective) epoxidation, epoxide opening with a propynyl anion and a hydrozirconation/iodination reaction to generate the vinyl iodide

Transition-metal-free one-pot synthesis of alkynyl selenides from terminal alkynes under aerobic and sustainable conditions

• Adrián A. Heredia and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2017, 13, 910–918, doi:10.3762/bjoc.13.92

• presence of Pd and Cu catalysts to afford (E)-α-selenylstannanes for the synthesis of trisubstituted alkenes [13] and hydrozirconation with further replacement of Zr atom by hydrogen or halogen [14] or their use in the preparation of α-seleno-α,β-unsaturated ketones [15]. Besides, hydrogen halide-addition

Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins

• Alejandro Castán,
• Ramón Badorrey,
• José A. Gálvez and
• María D. Díaz-de-Villegas

Beilstein J. Org. Chem. 2017, 13, 612–619, doi:10.3762/bjoc.13.59

• organocatalysts with a bulky substituent at C2 were synthesized from chiral imines derived from (R)-glyceraldehyde acetonide by diastereoselective allylation followed by a sequential hydrozirconation/iodination reaction. The new compounds were found to be effective organocatalysts for the Michael addition of

• lead to high levels of enantioselectivity in asymmetric transformations in which enamine intermediates are formed. The substituent R1 in the 1,3-dioxolane moiety in pyrrolidines C could be varied to modulate the reactivity and selectivity of the new organocatalysts. The sequential hydrozirconation

• enantioselectivites from 72–84% ee. Conclusion In conclusion, we have prepared 2-substituted pyrrolidines using a hydrozirconation/iodination reaction of chiral homoallylic amines. The latter were obtained on a multigram scale from imines derived from glyceraldehyde. These easily available compounds are new tuneable

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

• synthesis of diastereomers of dioxanes 252a,b containing triple bonds. Hydroperoxides 251a,b that were synthesized by the ozonolysis of 250 were treated with potassium tert-butoxide. One of the diastereomers, 252a, was then modified first via the stereoselective hydrozirconation and iodination to 253a and

Total synthesis of the endogenous inflammation resolving lipid resolvin D2 using a common lynchpin

• John Li,
• May May Leong,
• Alastair Stewart and
• Mark A. Rizzacasa

Beilstein J. Org. Chem. 2013, 9, 2762–2766, doi:10.3762/bjoc.9.310

• . Desilylation of 11 followed by hydrozirconation and iodination gave the vinyl iodide 4 and Sonogashira coupling between this compound and enyne 3 provided alkyne 18. Acetonide deprotection, partial reduction and ester hydrolysis then gave resolvin D2 (1). Keywords: catalysis; eicosanoid; natural product

• stereoisomer analogues of RvD2 (1). Removal of the TIPS group with TBAF gave terminal alkyne 12. Alkyne 12 then underwent smooth hydrozirconation utilizing the procedure reported by Negishi [24] were ZrCp2HCl is generated in situ by reduction of ZrCp2Cl2 with DIBALH in THF. Iodinolysis of the zirconium species

Garner’s aldehyde as a versatile intermediate in the synthesis of enantiopure natural products

• Mikko Passiniemi and
• Ari M.P. Koskinen

Beilstein J. Org. Chem. 2013, 9, 2641–2659, doi:10.3762/bjoc.9.300

• the reaction with other serinal derivatives, but the best results were achieved with (S)-1. Alkynes can be converted to (E)-vinyl nucleophiles through hydrozirconation. In view of the relatively low electronegativity (1.2–1.4) of Zr, which is roughly comparable with that of Mg and somewhat lower than

• diastereoselectivity was observed. Peter Wipf has done pioneering work on the hydrozirconation–transmetallation sequence [78][79]. Murakami used this information when investigating the reaction of transmetallated 1-(E)-pentadecenylzirconocene chloride with (S)-1 [46][47]. When the reaction was performed in THF at 0 °C

• inverted, and the anti-adduct 49 was favoured (12:1 anti/syn). We have also been interested in the use of hydrozirconation–transmetallation process while working on the synthesis of galactonojirimycin (Scheme 21) [48]. We used the TBS-protected propargyl alcohol 31 as the nucleophile, which had been

Synthesis of the spiroketal core of integramycin

• Evgeny. V. Prusov

Beilstein J. Org. Chem. 2013, 9, 2446–2450, doi:10.3762/bjoc.9.282

• required ketone precursor was efficiently constructed from two simple and easily accessible subunits by means of a hydrozirconation/copper catalyzed acylation reaction. The effects of different protecting groups on the spiroketalization step were also investigated. Keywords: anti-infectives

• ; hydrozirconation; natural products; spiroketals; total synthesis; Findings Integramycin is a polyketide natural product isolated from Actinoplanes sp. by the Singh group at Merck [1] (Figure 1). The compound was found to inhibit HIV-1 integrase coupled strand transfer reactions with IC50 values of 3 and 4 μM

• spiroketal core of integramycin based on a hydrozirconation/acylation reaction sequence is reported. The synthesis of the aryl-substituted part of the spiroketal fragment was started from 3,5-dihydroxybenzoate 8 which was converted into aldehyde 9 via protection and partial reduction [6] (Scheme 1

A reductive coupling strategy towards ripostatin A

• Kristin D. Schleicher and
• Timothy F. Jamison

Beilstein J. Org. Chem. 2013, 9, 1533–1550, doi:10.3762/bjoc.9.175

• ethylenediamine complex of lithium acetylide in a 1:1 THF/DMSO solvent mixture at 0 °C allowed the terminal alkyne to be accessed in 84% yield without rearrangement to the internal alkyne. Silyl protection afforded alkyne 50, which was prone to decomposition upon extended storage, even at −20 °C. Hydrozirconation

Alternaric acid: formal synthesis and related studies

• Michael C. Slade and
• Jeffrey S. Johnson

Beilstein J. Org. Chem. 2013, 9, 166–172, doi:10.3762/bjoc.9.19

• iodide 26 was generated by hydrozirconation/iodination of the free alkyne with Schwartz’s reagent [47]. The vinyl nucleophile 27 could be generated by Knochel’s Mg/I exchange [48] and employed successfully in the three-component-coupling reaction with silyl glyoxylate 1a and aldehyde 16ba to assemble 28

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

• Bettina Miller Shuli Mao Kara M. George Rosenker Joshua G. Pierce Peter Wipf Center for Chemical Methodologies & Library Development (CMLD), Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA 10.3762/bjoc.8.120 Abstract Hydrozirconation of 1-hexyne

• ; epoxide aminolysis; hydrozirconation; isoindolinones; metathesis; N-acyliminium ion; Introduction Isoindolinones represent a common scaffold seen in naturally occurring compounds such as magallanesine [1], lennoxamine [2] and clitocybin A [3], or drug candidates such as pagoclone [4] (Figure 1). These

• intermediate hemiaminal, provided alkene 1 in 59% overall yield (Scheme 1). After hydrozirconation of 1-hexyne with zirconocene hydrochloride [20][21][22][23], addition of trimethylaluminium activated the in situ generated alkenylzirconocene and allowed the displacement of the pivaloate on 1 in 55% yield to

Homoallylic amines by reductive inter- and intramolecular coupling of allenes and nitriles

• Peter Wipf and
• Marija D. Manojlovic

Beilstein J. Org. Chem. 2011, 7, 824–830, doi:10.3762/bjoc.7.94

• Peter Wipf Marija D. Manojlovic Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA 10.3762/bjoc.7.94 Abstract The one-pot hydrozirconation of allenes and nitriles followed by an in situ transmetalation of the allylzirconocene with dimethylzinc or zinc

• chloride provides functionalized homoallylic amines. An intramolecular version of this process leads to 3-aminotetrahydrofurans and 3-aminotetrahydropyrans. Keywords: allene; 3-aminotetrahydrofurans; 3- and 4-aminotetrahydropyrans; hydrozirconation; nitrile; transmetalation; Introduction The reversible

• , the utility of the hydrozirconation of nitriles can be enhanced by using Lewis acids to engage nitrile-derived acylimines in Friedel–Crafts reactions, generating indanyl or tetrahydronaphthyl derivatives [34][35]. Previous work in our group had concentrated on the transmetalation of alkenyl- and