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Search for "Negishi coupling" in Full Text gives 20 result(s) in Beilstein Journal of Organic Chemistry.
Germanyl triazoles as a platform for CuAAC diversification and chemoselective orthogonal cross-coupling
- John M. Halford-McGuff,
- Thomas M. Richardson,
- Aidan P. McKay,
- Frederik Peschke,
- Glenn A. Burley and
- Allan J. B. Watson
Beilstein J. Org. Chem. 2024, 20, 3198–3204, doi:10.3762/bjoc.20.265
- -coupling to give 32 or chemoselective Negishi coupling to give 33 [74]. Finally, BPin 21 could be oxidised to the phenol derivative 34 or cross-coupled with piperidine under Chan–Lam conditions to give the aniline derivative 35 in good yield [75]. Conclusion In summary, we have developed a general method
Graphical Abstract
Scheme 1: The CuAAC reaction and installation of functional groups for product diversification.
Scheme 2: Scope of germanyl acetylene CuAAC. Alkyne (1.0 equiv), azide (1.1 equiv), CuSO4·5H2O (5.0 mol %), N...
Scheme 3: (a) Application of Ge-alkyne CuAAC to functional molecules. (b) Functionalisation of germylated tri...
Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications
- Matteo Gasparetto,
- Balázs Fődi and
- Gellért Sipos
Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168
- that α-heteroaryl acetates accessed through Negishi coupling can be used as key intermediates towards NCAs (Scheme 1c). Indeed, oximation of these motifs followed by reduction gave access to the desired NCAs. Results and Discussion Negishi cross-coupling step The Negishi reaction provides convenient
- -chlorothiazole only afforded 21% yield (2d). Gratifyingly, the reaction selectively proceeded in position 2 of the ring. Position 4 seems to be inert to the Negishi coupling conditions as illustrated by substrates 2c and 2g. Somewhat surprisingly, LCMS analysis indicated that 1g did not go through oxidative
- scheme, scope and gram scale experiment. The numbers in brackets represent the overall yield for the synthesis of the amino esters from the Negishi coupling till the reduction/protection step. Reactions scheme and results for the on-DNA experiments. The reported values represent the normalized yield for
Graphical Abstract
Scheme 1: Known and improved synthetic strategies to access α-(hetero)aryl-amino acids.
Scheme 2: Reformatsky reagent production.
Scheme 3: Scope of ethyl heteroarylacetates. Isolated yields are given. *Dark reactions were carried out for ...
Scheme 4: Telescoped flow synthesis of heteroarylacetates.
Scheme 5: Potential routes for the preparation of oximes.
Scheme 6: Oxime group insertion step.
Scheme 7: Amino ester production: general scheme, scope and gram scale experiment. The numbers in brackets re...
Scheme 8: Reactions scheme and results for the on-DNA experiments. The reported values represent the normaliz...
Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters
- Carlos R. Azpilcueta-Nicolas and
- Jean-Philip Lumb
Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35
- ), alkynylation [88] (Scheme 24C) and C(sp3)–C(sp3) cross-coupling [89] (Scheme 24D). Finally, similar chemistry has been extended to the decarboxylative borylation of RAEs under Ni [90] and Cu [91] catalysis (Scheme 24E). Importantly, the Wang group has independently studied the decarboxylative Negishi coupling
Graphical Abstract
Scheme 1: Comparison between Barton and NHPI ester radical precursors.
Scheme 2: Overview of the mechanisms and activation modes involved in radical generation from RAEs.
Scheme 3: Common mechanisms in photocatalysis.
Scheme 4: A) Giese-type radical addition of NHPI esters mediated by a reductive quenching photocatalytic cycl...
Scheme 5: A) Minisci-type radical addition of NHPI esters. B) Reaction mechanism involving an “off-cycle” red...
Scheme 6: Activation of NHPI esters through hydrogen-bonding in an oxidative quenching photocatalytic cycle.
Scheme 7: SET activation of RAE facilitated by a Lewis acid catalyst.
Scheme 8: PCET activation of NHPI esters in the context of a radical-redox annulation.
Scheme 9: Activation enabled by a strong excited-state reductant catalyst and its application in the dearomat...
Scheme 10: Proposed formation of an intramolecular charge-transfer complex in the synthesis of (spiro)anellate...
Scheme 11: Formation of a charge-transfer complex between enamides and NHPI esters enabled by a chiral phospha...
Scheme 12: Activation of NHPI ester through the formation of photoactive EDA-complexes.
Scheme 13: A) EDA complex-mediated radical hydroalkylation reactions of NHPI esters. B) Proposed mechanism for...
Scheme 14: Proposed radical chain mechanism initiated by EDA-complex formation.
Scheme 15: A) Photoinduced decarboxylative borylation. B) Proposed radical chain mechanism.
Scheme 16: A) Activation of NHPI esters mediated by PPh3/NaI. B) Proposed catalytic cycle involving EDA-comple...
Scheme 17: A) Radical generation facilitated by EDA complex formation between PTH1 catalyst and NHPI esters. B...
Scheme 18: Proposed catalytic cycle for the difunctionalization of styrenes.
Scheme 19: Formation of a charge-transfer complex between NHPI esters and Cs2CO3 enables decarboxylative amina...
Scheme 20: 3-Acetoxyquinuclidine as catalytic donor in the activation of TCNHPI esters.
Scheme 21: A) Photoinduced Cu-catalyzed decarboxylative amination. B) Proposed catalytic cycle. C) Radical clo...
Scheme 22: A) Photoinduced Pd-catalyzed aminoalkylation of 1,4-dienes. B) Proposed catalytic cycle.
Scheme 23: A) TM-catalyzed decarboxylative coupling of NHPI esters and organometallic reagents. B) Representat...
Scheme 24: Synthetic applications of the TM-catalyzed decarboxylative coupling of NHPI esters and organometall...
Scheme 25: A) Ni-catalyzed cross-electrophile coupling of NHPI esters. B) Representative catalytic cycle.
Scheme 26: A) Synthetic applications of decarboxylative cross-electrophile couplings. B) Decarboxylative aryla...
Scheme 27: A) Activation of tetrachlorophthalimide redox-active esters enabled by a low-valency Bi complex. B)...
Scheme 28: Activation of NHPI esters mediated by Zn0 applied in a Z-selective alkenylation reaction.
Scheme 29: A) Activation of NHPI esters enabled by a pyridine-boryl radical species applied to the decarboxyla...
Scheme 30: A) Decarboxylative coupling of RAE and aldehydes enabled by NHC-catalyzed radical relay. B) Propose...
Scheme 31: A) Decarboxylative C(sp3)–heteroatom coupling reaction of NHPI esters under NHC catalysis B) The NH...
Scheme 32: A) Electrochemical Giese-type radical addition of NHPI esters. B) Reaction mechanism.
Scheme 33: Electrochemical Minisci-type radical addition of NHPI-esters.
Scheme 34: Ni-electrocatalytic cross-electrophile coupling of NHPI esters with aryl iodides.
Scheme 35: A) Decarboxylative arylation of NHPI esters under Ag-Ni electrocatalysis B) Formation of AgNP on th...
Scheme 36: Synthetic applications of decarboxylative couplings of NHPI esters under Ni-electrocatalysis.
Scheme 37: Examples of natural product syntheses in which RAEs were used in key C–C bond forming reactions.
Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners
- Shakeel Alvi and
- Rashid Ali
Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186
- 118 as well as 1,1’-disumanenylferrocene 119 through Pd-catalyzed Negishi coupling of iodosumanene (79) with ferrocenylzinc chloride and 1,1’-bis(chlorozincio)ferrocene (Scheme 28) [9]. These synthesized molecules were confirmed utilizing spectroscopic techniques as well as by virtue of X-ray
Graphical Abstract
Figure 1: Representation of corannulene (1) and sumanene (2), the subunits of fullerene (C60).
Scheme 1: Mehta’s unsuccessful effort for the synthesis of sumanene scaffold 2.
Scheme 2: First synthesis of sumanene 2 by Sakurai et al. from norbornadiene 10.
Scheme 3: Synthesis of trimethylsumanene 28 from easily accessible norbornadiene (10).
Scheme 4: Generation of anions 29–31 and the preparation of tris(trimethylsilyl)sumanene 32.
Scheme 5: Synthesis of tri- and hexa-substituted sumanene derivatives.
Scheme 6: Synthesis of bowl-shaped π-extended sumanene derivatives 37a–f.
Scheme 7: Synthesis of monooxasumanene 38, trioxosumanene 40 along with imination of them.
Scheme 8: Synthesis of trimethylsumanenetrione 46 and exo-functionalized products 45a,b.
Scheme 9: Synthesis of bisumanenylidene 47 and sumanene dimer 48 from 2.
Scheme 10: The mono-substitution of 2 to generate diverse mono-sumanene derivatives 49a–d.
Scheme 11: Synthesis of sumanene building block 53 useful for further extension.
Scheme 12: Synthesis of hexafluorosumanene derivative 55 by Sakurai and co-workers.
Scheme 13: Preparation of sumanene-based carbene 60 and its reaction with cyclohexane.
Scheme 14: Barton–Kellogg reaction for the synthesis of sterically hindered alkenes.
Scheme 15: Synthesis of hydroxysumanene 68 by employing Baeyer–Villiger oxidation.
Scheme 16: Synthesis of sumanene derivatives having functionality at an internal carbon.
Scheme 17: Mechanism for nucleophilic substitution reaction at the internal carbon.
Scheme 18: Synthesis of diverse monosubstituted sumanene derivatives.
Scheme 19: Synthesis of di- and trisubstituted sumanene derivatives from sumanene (2).
Scheme 20: Preparation of monochlorosumanene 88 and hydrogenation of sumanene (2).
Scheme 21: The dimer 90 and bissumanenyl 92 achieved from halosumannes.
Scheme 22: Pyrenylsumanene 93 involving the Suzuki-coupling as a key transformation.
Scheme 23: Synthesis of various hexaarylsumanene derivatives using the Suzuki-coupling reaction.
Scheme 24: Synthesis of hexasubstituted sumanene derivatives 96 and 97.
Scheme 25: Synthesis of thioalkylsumanenes via an aromatic nucleophilic substitution reaction.
Scheme 26: Synthesis of tris(ethoxycarbonylethenyl)sumanene derivative 108.
Scheme 27: Synthesis of ferrocenyl-based sumanene derivatives.
Scheme 28: Synthesis of sumanenylferrocene architectures 118 and 119 via Negishi coupling.
Scheme 29: Diosmylation and the synthesis of phenylboronate ester 121 of sumanene.
Scheme 30: Synthesis of the iron-complex of sumanene.
Scheme 31: Synthesis of tri- and mononuclear sumanenyl zirconocene complexes.
Scheme 32: Synthesis of [CpRu(η6-sumanene)]PF6.
Scheme 33: Preparation of sumanene-based porous coordination networks 127 (spherical tetramer units) and 128 (...
Scheme 34: Synthesis of sumanenylhafnocene complexes 129 and 130.
Scheme 35: Synthesis of 134 and 135 along with PdII coordination complex 136.
Scheme 36: Synthesis of alkali metals sumanene complex K7(C21H102−)2(C21H93−)·8THF (137) containing di- and tr...
Scheme 37: The encapsulation of a Cs+ ion between two sumanenyl anions.
Scheme 38: Synthesis of monothiasumanene 140 and dithiasumanene 141 from 139.
Scheme 39: Synthesis of trithiasumanene 151 by Otsubo and his co-workers.
Scheme 40: Synthesis of trithiasumanene derivatives 155 and 156.
Scheme 41: Synthetic route towards hexathiolated trithiasumanenes 158.
Scheme 42: Synthesis of triselenasumanene 160 by Shao and teammates.
Scheme 43: Synthesis of tritellurasumanene derivatives from triphenylene skeletons.
Scheme 44: Synthesis of pyrazine-fused sumanene architectures through condensation reaction.
Scheme 45: Treatment of the trichalcogenasumanenes with diverse oxidative reagents.
Scheme 46: Ring-opening reaction with H2O2 and oxone of heterasumanenes 178 and 179.
Scheme 47: Synthesis of polycyclic compounds from sumanene derivatives.
Scheme 48: Synthesis of diimide-based heterocycles reported by Shao’s and co-workers.
Scheme 49: Synthesis of pristine trichalcogenasumanenes, 151, 205, and 206.
Scheme 50: Synthesis of trichalcogenasumanenes via hexaiodotriphenylene precursor 208.
Scheme 51: Synthesis of trisilasumanenes 214 and 215.
Scheme 52: Synthesis of trisilasumanene derivatives 218 and 219.
Scheme 53: Synthesis of novel trigermasumanene derivative 223.
Scheme 54: An attempt towards the synthesis of tristannasumanene derivative 228.
Scheme 55: Synthesis of triphosphasumanene trisulfide 232 from commercially available 229.
Scheme 56: The doping of sumanene derivatives with chalcogens (S, Se, Te) and phosphorus.
Scheme 57: Synthesis of heterasumanene containing three different heteroatoms.
Scheme 58: Synthesis of trichalcogenasumanene derivatives 240 and 179.
Scheme 59: Preparation of trichalcogenasumanenes 245 and 248.
Scheme 60: Design and synthesis of trichalcogenasumanene derivatives 252 and 178.
Scheme 61: Synthesis of spirosumanenes 264–269 and non-spiroheterasumanenes 258–263.
Scheme 62: Synthesis of sumanene-type hetero polycyclic compounds.
Scheme 63: Synthesis of triazasumanenes 288 and its sulfone congener 287.
Scheme 64: Synthesis of C3-symmetric chiral triaryltriazasumanenes via cross-coupling reaction.
Scheme 65: Synthesis of mononaphthosumanene 293 using Suzuki coupling as a key step.
Scheme 66: Synthesis of di- and trinaphthosumanene derivatives 302–304.
Scheme 67: Synthesis of hemifullerene skeletons by Hirao’s group.
Scheme 68: Design and construction of C70 fragment from a C60 sumanene fragment.
Syntheses of spliceostatins and thailanstatins: a review
- William A. Donaldson
Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166
- 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
- (123). Arisawa synthesis of a C-1-phenyl analog of FR901464 (1). Jacobsen fragment coupling by a Pd-catalyzed Negishi coupling. Nicolaou syntheses of thailanstatin A and B (7 and 5) and spliceostatin D (9) via a Pd-catalyzed Suzuki–Miyaura coupling. The Ghosh synthesis of spliceostatin G (11) via
Graphical Abstract
Figure 1: Structures of spliceostatins/thailanstatins.
Scheme 1: Synthetic routes to protected (2Z,4S)-4-hydroxy-2-butenoic acid fragments.
Scheme 2: Kitahara synthesis of the (all-cis)-2,3,5,6-tetrasubstituted tetrahydropyran.
Scheme 3: Koide synthesis of (all-cis)-2,3,5,6-tetrasubstituted tetrahydropyran.
Scheme 4: Nicolaou synthesis of the (all-cis)-2,3,5,6-tetrasubstituted tetrahydropyran.
Scheme 5: Jacobsen synthesis of the (all-cis)-2,3,5,6-tetrasubstituted tetrahydropyran.
Scheme 6: Unproductive attempt to generate the (all-cis)-tetrahydropyranone 50.
Scheme 7: Ghosh synthesis of the C-7–C-14 (all-cis)-tetrahydropyran segment.
Scheme 8: Ghosh’s alternative route to the (all-cis)-tetrahydropyranone 50.
Scheme 9: Alternative synthesis of the dihydro-3-pyrone 58.
Scheme 10: Kitahara’s 1st-generation synthesis of the C-1–C-6 fragment of FR901464 (1).
Scheme 11: Kitahara 1st-generation synthesis of the C-1–C-6 fragment of FR901464 (1).
Scheme 12: Nimura/Arisawa synthesis of the C-1-phenyl segment.
Scheme 13: Ghosh synthesis of the C-1–C-6 fragment of FR901464 (1) from (R)-glyceraldehyde acetonide.
Scheme 14: Jacobsen synthesis of the C-1–C-7 segment of FR901464 (1).
Scheme 15: Koide synthesis of the C-1–C-7 segment of FR901464 (1).
Scheme 16: Ghosh synthesis of the C-1–C-5 segment 102 of thailanstatin A (7).
Scheme 17: Nicolaou synthesis of the C-1–C-9 segments of spliceostatin D (9) and thailanstatins A (7) and B (5...
Scheme 18: Ghosh synthesis of the C-1–C-6 segment 115 of spliceostatin E (10).
Scheme 19: Fragment coupling via Wittig and modified Julia olefinations by Kitahara.
Scheme 20: Fragment coupling via cross-metathesis by Koide.
Scheme 21: The Ghosh synthesis of spliceostatin A (4), FR901464 (1), spliceostatin E (10), and thailanstatin m...
Scheme 22: Arisawa synthesis of a C-1-phenyl analog of FR901464 (1).
Scheme 23: Jacobsen fragment coupling by a Pd-catalyzed Negishi coupling.
Scheme 24: Nicolaou syntheses of thailanstatin A and B (7 and 5) and spliceostatin D (9) via a Pd-catalyzed Su...
Scheme 25: The Ghosh synthesis of spliceostatin G (11) via Suzuki–Miyaura coupling.
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
- assembled by solution-phase synthesis and an open-chain analogue of the natural product was obtained. Keywords: jasplakinolide; marine natural products; Negishi coupling; polyketides; stereoselective synthesis; Introduction Our program on the synthesis of biologically active natural products with peptide
Graphical Abstract
Scheme 1: Actin-binding cyclodepsipeptides, photo amino acids, retrosynthetic cuts of polyketide 7 leading to...
Scheme 2: Synthesis of γ-hydroxy esters 11 and 12, followed by Mitsunobu inversion.
Scheme 3: Synthesis of the polyketide section 7.
Scheme 4: Access to methylated D-iodotyrosine derivatives 22, 23, and 25.
Scheme 5: Synthesis of the doubly protected open chain peptide-polyketide 31.
Synthesis of C3-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step
- Sambasivarao Kotha and
- Saidulu Todeti
Beilstein J. Org. Chem. 2019, 15, 371–377, doi:10.3762/bjoc.15.33
- peptide dendrimers. Keywords: amino acids; cyclotrimerization; Negishi coupling; peptide; Introduction Optically active C3-symmetric molecules are valuable synthons to design dendrimers, chiral ligands, polymers, and supramolecules [1][2][3][4]. In this regard, 1,3,5-triarylbenzene derivatives are
- iodo compound 6 was treated with freshly activated Zn in DMF at room temperature to afford the zinc insertion product 7 (Scheme 1) [43]. With the organozinc compound 7 at hand we turned to the synthesis of the halide component for the attempted Negishi coupling. For this 4-iodoacetophenone (8) was
- )4) as catalyst to provide the Negishi coupling product 10 (68%). Having the trimeric AAA derivative 10 in hand, it was treated with trifluoroacetic acid (TFA) in CH2Cl2 (1:1) at room temperature for 1 h to deliver the Boc-deprotected compound. Then, without further purification the deprotected
Graphical Abstract
Figure 1: Exemplar C3-symmetric peptide scaffolds reported in the literature.
Scheme 1: Preparation of compound 7 from L-serine (3).
Scheme 2: Preparation of the trimerized product 9.
Scheme 3: Synthesis of compound 11 via Negishi cross-coupling reaction.
Scheme 4: Synthesis of C3-symmetric trimers 12, 13 and 14.
Cobalt- and rhodium-catalyzed carboxylation using carbon dioxide as the C1 source
- Tetsuaki Fujihara and
- Yasushi Tsuji
Beilstein J. Org. Chem. 2018, 14, 2435–2460, doi:10.3762/bjoc.14.221
- Negishi coupling with aryl bromide, affording the corresponding sterically congested alkene 17b-Ar in 56% yield after two steps. The Negishi coupling with benzyl chloride and the Cu-catalyzed allylation of allyl bromide also afforded the corresponding products 17b-Bn and 17b-Allyl, respectively, in good
Graphical Abstract
Scheme 1: Optimization of the Co-catalyzed carboxylation of 1a.
Scheme 2: Co-catalyzed carboxylation of propargyl acetates 1.
Scheme 3: Plausible reaction mechanism for the Co-catalyzed carboxylation of propargyl acetates 1.
Scheme 4: Optimization of the Co-catalyzed carboxylation of 3a.
Scheme 5: Co-catalyzed carboxylation of vinyl triflates 3.
Scheme 6: Co-catalyzed carboxylation of a sterically hindered aryl triflate 5.
Scheme 7: Optimization of the Co-catalyzed carboxylation of 7a.
Scheme 8: Scope of the reductive carboxylation of α,β-unsaturated nitriles 7.
Scheme 9: Scope of the carboxylation of α,β-unsaturated carboxamides 9.
Scheme 10: Optimization of the Co-catalyzed carboxylation of 11a.
Scheme 11: Scope of the carboxylation of allylarenes 11.
Scheme 12: Scope of the carboxylation of 1,4-diene derivatives 14.
Scheme 13: Plausible reaction mechanism for the Co-catalyzed C(sp3)–H carboxylation of allylarenes.
Scheme 14: Optimization of the Co-catalyzed carboxyzincation of 16a.
Scheme 15: Derivatization of the carboxyzincated product.
Scheme 16: Co-catalyzed carboxyzincation of alkynes 16.
Scheme 17: Plausible reaction mechanism for the Co-catalyzed carboxyzincation of alkynes 16.
Scheme 18: Co-catalyzed four-component coupling of alkynes 16, acrylates 18, CO2, and zinc.
Scheme 19: Proposed reaction mechanism for the Co-catalyzed four-component coupling.
Scheme 20: Visible-light-driven hydrocarboxylation of alkynes.
Scheme 21: Visible-light-driven synthesis of γ-hydroxybutenolides from ortho-ester-substituted aryl alkynes.
Scheme 22: One-pot synthesis of coumarines and 2-quinolones via hydrocarboxylation/alkyne isomerization/cycliz...
Scheme 23: Proposed reaction mechanism for the Co-catalyzed carboxylative cyclization of ortho-substituted aro...
Scheme 24: Rh-catalyzed carboxylation of arylboronic esters 25.
Scheme 25: Rh-catalyzed carboxylation of alkenylboronic esters 27.
Scheme 26: Plausible reaction mechanism for the Rh-catalyzed carboxylation of arylboronic esters 25.
Scheme 27: Ligand effect on the Rh-catalyzed carboxylation of 2-phenylpyridine 29a.
Scheme 28: Rh-catalyzed chelation-assisted C(sp2)–H bond carboxylation with CO2.
Scheme 29: Reaction mechanism for the Rh-catalyzed C(sp2)–H carboxylation of 2-pyridylarenes 29.
Scheme 30: Carboxylation of C(sp2)–H bond with CO2.
Scheme 31: Carboxylation of C(sp2)–H bond with CO2.
Scheme 32: Reaction mechanism for the Rh-catalyzed C(sp2)–H carboxylation of 2-arylphenols 34.
Scheme 33: Hydrocarboxylation of styrene derivatives with CO2.
Scheme 34: Hydrocarboxylation of α,β-unsaturated esters with CO2.
Scheme 35: Asymmetric hydrocarboxylation of α,β-unsaturated esters with CO2.
Scheme 36: Proposed reaction mechanism for the Rh-catalyzed hydrocarboxylation of C–C double bonds with CO2.
Scheme 37: Visible-light-driven hydrocarboxylation with CO2.
Scheme 38: Visible-light-driven Rh-catalyzed hydrocarboxylation of C–C double bonds with CO2.
Scheme 39: Optimization of reaction conditions on the Rh-catalyzed [2 + 2 + 2] cycloaddition of diyne 42a and ...
Scheme 40: [2 + 2 + 2] Cycloaddition of diyne and CO2.
Scheme 41: Proposed reaction pathways for the Rh-catalyzed [2 + 2 + 2] cycloaddition of diyne and CO2.
Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres
- Myriam Drouin and
- Jean-François Paquin
Beilstein J. Org. Chem. 2017, 13, 2637–2658, doi:10.3762/bjoc.13.262
- , oxidation of the secondary alcohol with pyridinium dichromate into the corresponding cyclopentanone derivative and subsequent olefination using CBr3F gave the monofluoroalkene 96 with a modest selectivity towards the (Z)-alkene. A Negishi coupling then gave alkene 98. Stereoselective reductive amination
Graphical Abstract
Figure 1: Selected amide bond isosteres.
Figure 2: Monofluoroalkene as an amide bond isostere.
Scheme 1: Synthesis of Cbz-Gly-ψ[(Z)-CF=CH]-Gly using a HWE olefination by Sano and co-workers.
Scheme 2: Synthesis of Phth-Gly-ψ[CF=CH]-Gly using the Julia–Kocienski olefination by Lequeux and co-workers.
Scheme 3: Synthesis of Boc-Nva-ψ[(Z)-CF=CH]-Gly by Taguchi and co-workers.
Figure 3: Mutant tripeptide containing two different peptide bond isosteres.
Scheme 4: Chromium-mediated synthesis of Boc-Ser(PMB)-ψ[(Z)-CF=CH]-Gly-OMe by Konno and co-workers.
Scheme 5: Synthesis of Cbz-Gly-ψ[(E)-CF=C]-Pro by Sano and co-workers.
Scheme 6: Synthesis of Cbz-Gly-ψ[(Z)-CF=C]-Pro by Sano and co-workers.
Scheme 7: Stereoselective synthesis of Fmoc-Gly-ψ[(Z)-CF=CH]-Phe by Pannecoucke and co-workers.
Scheme 8: Ring-closure metathesis to prepare Gly-ψ[(E)-CF=CH]-Phg by Couve-Bonnaire and co-workers.
Scheme 9: Stereoselective synthesis of Fmoc-Gly-ψ[(Z)-CF=CH]-Phe by Dory and co-workers.
Scheme 10: Diastereoselective addition of Grignard reagents to sulfinylamines derived from α-fluoroenals by Pa...
Scheme 11: NHC-mediated synthesis of monofluoroalkenes by Otaka and co-workers.
Scheme 12: Stereoselective synthesis of Boc-Tyr-ψ[(Z)-CF=CH]-Gly by Altman and co-workers.
Scheme 13: Synthesis of the tripeptide Boc-Asp(OBn)-Pro-ψ[(Z)-CF=CH)-Val-CH2OH by Miller and co-workers.
Scheme 14: Copper-catalyzed synthesis of monofluoralkenes by Taguchi and co-workers.
Scheme 15: One-pot intramolecular redox reaction to access amide-type isosteres by Otaka and co-workers.
Scheme 16: Copper-mediated reduction, transmetalation and asymmetric alkylation by Fujii and co-workers.
Scheme 17: Synthesis of (E)-monofluoroalkene-based dipeptide isostere by Fujii and co-workers.
Scheme 18: Diastereoselective synthesis of MeOCO-Val-ψ[(Z)-CF=C]-Pro isostere by Chang and co-workers.
Scheme 19: Asymmetric synthesis of Fmoc-Ala-ψ[(Z)-CF=C]-Pro by Pannecoucke and co-workers.
Scheme 20: Synthesis of Fmoc-Val-ψ[(E)-CF=C]-Pro by Pannecoucke and co-workers.
Figure 4: BMS-790052 and its fluorinated analogue.
Figure 5: Bioactivities of pentapeptide analogues based on the relative maximum agonistic activity at 10 nM o...
Figure 6: Structures and affinities of the Leu-enkephalin and its fluorinated analogue. The affinity towards ...
Figure 7: Activation of the opioid receptor DOPr by Leu-enkephaline and a fluorinated analogue.
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
- conceptual difference between Kishi’s 1st and 2nd generation approaches towards the extended mycolactone core structure consists in the fact that macrocyclization in the 2nd generation approach precedes Negishi coupling between a C14–C20 vinyl iodide and a C1–C13 alkyl iodide, thus making the synthesis more
Graphical Abstract
Figure 1: Initial proposal for the core macrolactone structure (left) and the established complete structure ...
Figure 2: Mycolactone congeners and their origins.
Figure 3: Misassigned mycolactone E structure according to Small et al. [50] (11) and the correct structure (6) f...
Figure 4: Schematic illustration of Kishi’s improved mycolactone TLC detection method exploiting derivatizati...
Figure 5: Fluorescent probes derived from natural mycolactone A/B (1a,b) or its synthetic 8-desmethyl analogs...
Figure 6: Tool compounds used by Pluschke and co-workers for elucidating the molecular targets of mycolactone...
Figure 7: Synthetic strategies towards the extended mycolactone core. A) General strategies. B) Kishi’s appro...
Scheme 1: Kishi’s 1st generation approach towards the extended core structure of mycolactones. Reagents and c...
Scheme 2: Kishi’s 2nd generation approach towards the extended core structure of mycolactones. Reagents and c...
Scheme 3: Kishi’s 3rd generation approach towards the extended core structure of mycolactones. Reagents and c...
Scheme 4: Negishi’s synthesis of the extended core structure of mycolactones. Reagents and conditions: a) (i) ...
Scheme 5: Burkart’s (incomplete) 1st generation approach towards the extended core structure of mycolactones....
Scheme 6: Burkart’s (incomplete) 1st, 2nd and 3rd generation approach towards the extended mycolactone core s...
Scheme 7: Altmann’s synthesis of alkyl iodide 91. Reagents and conditions: a) (i) PMB-trichloroacetimidate, T...
Scheme 8: Final steps of Altmann’s synthesis of the extended core structure of mycolactones. Reagents and con...
Scheme 9: Basic principles of the Aggarwal lithiation–borylation homologation process [185,186].
Scheme 10: Aggarwal’s synthesis of the C1–C11 fragment of the mycolactone core. Reagents and conditions: a) Cl...
Scheme 11: Aggarwal’s synthesis of the linear C1–C20 fragment of the mycolactone core. Reagents and conditions...
Figure 8: Synthetic strategies towards the mycolactone A/B lower side chain.
Scheme 12: Gurjar and Cherian’s synthesis of the C1’–C8’ fragment of the mycolactone A/B pentaenoate side chai...
Scheme 13: Gurjar and Cherian’s synthesis of the benzyl-protected mycolactone A/B pentaenoate side chain. Reag...
Scheme 14: Kishi’s synthesis of model compounds for elucidating the stereochemistry of the C7’–C16’ fragment o...
Scheme 15: Kishi’s synthesis of the mycolactone A/B pentaenoate side chain. (a) (i) NaH, (EtO)2P(O)CH2CO2Et, T...
Scheme 16: Feringa and Minnaard's incomplete synthesis of mycolactone A/B pentaenoate side chain. Reagents and...
Scheme 17: Altmann’s approach towards the mycolactone A/B pentaenoate side chain. Reagents and conditions: a) ...
Scheme 18: Negishi’s access to the C1’–C7’ fragment of mycolactone A. Reagents and conditions: a) (i) n-BuLi, ...
Scheme 19: Negishi’s approach to the C1’–C7’ fragment of mycolactone B. Reagents and conditions: a) (i) DIBAL-...
Scheme 20: Negishi’s synthesis of the C8’–C16’ fragment of mycolactone A/B. Reagents and conditions: a) 142, BF...
Scheme 21: Negishi’s assembly of the mycolactone A and B pentaenoate side chains. Reagents and conditions: a) ...
Scheme 22: Blanchard’s approach to the mycolactone A/B pentaenoate side chain. a) (i) Ph3P=C(Me)COOEt, CH2Cl2,...
Scheme 23: Kishi’s approach to the mycolactone C pentaenoate side chain exemplified for the 13’R,15’S-isomer 1...
Scheme 24: Altmann’s (unpublished) synthesis of the mycolactone C pentaenoate side chain. Reagents and conditi...
Scheme 25: Blanchard’s synthesis of the mycolactone C pentaenoate side chain. Reagents and conditions: a) (i) ...
Scheme 26: Kishi’s synthesis of the tetraenoate side chain of mycolactone F exemplified by enantiomer 165. Rea...
Scheme 27: Kishi’s synthesis of the mycolactone E tetraenoate side chain. Reagents and conditions: a) (i) CH2=...
Scheme 28: Wang and Dai’s synthesis of the mycolactone E tetraenoate side chain. Reagents and conditions: a) (...
Scheme 29: Kishi’s synthesis of the dithiane-protected tetraenoate side chain of the minor oxo-metabolite of m...
Scheme 30: Kishi’s synthesis of the mycolactone S1 and S2 pentaenoate side chains. Reagents and conditions: a)...
Scheme 31: Kishi’s 1st generation and Altmann’s total synthesis of mycolactone A/B (1a,b) and Negishi’s select...
Scheme 32: Kishi’s 2nd generation total synthesis of mycolactone A/B (1a,b). Reagents and conditions: a) 2,4,6...
Scheme 33: Blanchard’s synthesis of the 8-desmethylmycolactone core. Reagents and conditions: a) (i) TsCl, TEA...
Scheme 34: Altmann’s (partially unpublished) synthesis of the C20-hydroxylated mycolactone core. Reagents and ...
Scheme 35: Altmann’s and Blanchard’s approaches towards the 11-isopropyl-8-desmethylmycolactone core. Reagents...
Scheme 36: Blanchard’s synthesis of the saturated variant of the C11-isopropyl-8-desmethylmycolactone core. Re...
Scheme 37: Structure elucidation of photo-mycolactones generated from tetraenoate 224.
Scheme 38: Kishi’s synthesis of the linear precursor of the photo-mycolactone B1 lower side chain. Reagents an...
Scheme 39: Kishi’s synthesis of the photo-mycolactone B1 lower side chain. Reagents and conditions: a) LiTMP, ...
Scheme 40: Kishi’s synthesis of a stabilized lower mycolactone side chain. Reagents and conditions: a) (i) TBD...
Scheme 41: Blanchard’s variation of the C12’,C13’,C15’ stereocluster. Reagents and conditions: a) (i) DIBAL-H,...
Scheme 42: Blanchard’s synthesis of aromatic mycolactone polyenoate side chain analogs. Reagents and condition...
Scheme 43: Small’s partial synthesis of a BODIPY-labeled mycolactone derivative and Demangel’s partial synthes...
Scheme 44: Blanchard’s synthesis of the BODIPY-labeled 8-desmethylmycolactones. Reagents and conditions: a) (i...
Scheme 45: Altmann’s synthesis of biotinylated mycolactones. Reagents and conditions: a) (i) CDI, THF, rt, 2 d...
Figure 9: Kishi’s elongated n-butyl carbamoyl mycolactone A/B analog.
Synthesis of tetrasubstituted pyrazoles containing pyridinyl substituents
- Josef Jansa,
- Ramona Schmidt,
- Ashenafi Damtew Mamuye,
- Laura Castoldi,
- Alexander Roller,
- Vittorio Pace and
- Wolfgang Holzer
Beilstein J. Org. Chem. 2017, 13, 895–902, doi:10.3762/bjoc.13.90
- condensation product was confirmed by crystal structure analysis. Keywords: Negishi coupling; NMR (1H; 13C; 15N); pyrazole; pyridine; X-ray structure analysis; Introduction The pyrazole nucleus is a frequently occurring motif in many pharmaceuticals [1][2] and biologically active compounds [3][4
- iodopyrazoles 3a,b under standard conditions are characterized by the occurrence of different (unwanted) products resulting mainly from dehalogenation and homocoupling processes. Nevertheless, the Negishi coupling here seems to be the method of choice for C–C bond formations at pyrazole C-4. In contrast, 3
Graphical Abstract
Scheme 1: Envisaged general approach for the synthesis of the title compounds.
Scheme 2: Synthesis of 4-iodopyrazoles of type 3.
Scheme 3: Lithium–halogen exchange and subsequent carboxylation with iodopyrazoles 3a–d.
Scheme 4: Attempted cross-coupling reactions with 4-halopyrazoles 5 and 3a.
Scheme 5: Negishi couplings with 4-iodopyrazoles 3a,b.
Scheme 6: Formation of pyrazoloquinolizin-6-ium iodide 12 upon reaction of 3a with (phenylethynyl)zinc bromid...
Scheme 7: Prototropic tautomerism of compound 1a.
Figure 1: 1H NMR (in italics), 13C NMR and 15N NMR (in bold) chemical shifts of compound 9a (in CDCl3).
The direct oxidative diene cyclization and related reactions in natural product synthesis
- Juliane Adrian,
- Leona J. Gross and
- Christian B. W. Stark
Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200
- carboxylic acid [50][51]. In 2011, the Donohoe group developed a total synthesis of neodysiherbaine A (14) using an Os(VI)-catalyzed type B oxidative cyclization of a 5,6-dihydroxyalkene (Scheme 5, right) [52]. Commercially available β-D-ribopyranose tetraacetate (11) was converted to 12 via a Negishi
- coupling [53][54]. The oxidative cyclization diastereoselectively led to the THF diol 13 in 88% yield from which neodysiherbaine A (14) was obtained in a further three steps. Ionomycin Ionomycin (19), an ionophore antibiotic isolated from Streptomyces conglobatus in 1978 [55][56][57], has a high affinity
Graphical Abstract
Scheme 1: Putative structures of geraniol 1a (R = H) or 1b (R = H) (in 1924), their expected dihydroxylation ...
Scheme 2: Correlation between the substrate double bond geometry and relative stereochemistry of the correspo...
Scheme 3: Mechanisms and classification for the metal-mediated oxidative cyclizations to form 2,5-disubstitut...
Scheme 4: Synthesis of (+)-anhydro-D-glucitol and (+)-D-chitaric acid using an OsO4-mediated oxidative cycliz...
Scheme 5: Total synthesis of neodysiherbaine A via a Ru(VIII)- and an Os(VI)-catalyzed oxidative cyclization,...
Scheme 6: Formal synthesis of ionomycin by Kocienski and co-workers.
Scheme 7: Total synthesis of amphidinolide F by Fürstner and co-workers.
Scheme 8: Brown`s and Donohoe`s oxidative cyclization approach to cis-solamin A.
Scheme 9: Total synthesis of cis-solamin A using a Ru(VIII)-catalyzed oxidative cyclization and enzymatic des...
Scheme 10: Donohoe´s double oxidative cyclization approach to cis-sylvaticin.
Scheme 11: Permanganate-mediated approach to cis-sylvaticin by Brown and co-workers.
Scheme 12: Total synthesis of membranacin using a KMnO4-mediated oxidative cyclization.
Scheme 13: Total synthesis of membrarollin and its analogue 21,22-diepi-membrarollin.
Scheme 14: Total synthesis of rollidecin C and D using a late stage Re(VII)-catalyzed oxidative polycyclizatio...
Scheme 15: Co(II)-catalyzed oxidative cyclization in the total synthesis of asimilobin and gigantetrocin A.
Scheme 16: Mn(VII)-catalyzed oxidative cyclization of a 1,5-diene in the synthesis of trans-(+)-linalool oxide....
Scheme 17: Re(VII)-catalyzed oxidative cyclization in the total synthesis of teurilene.
Scheme 18: Total synthesis of (+)-eurylene via Re(VII)- and Cr(VI)-mediated oxidative cyclizations.
Scheme 19: Synthesis of cis- and trans-THF Rings of eurylene via Mn(VII)-mediated oxidative cyclizations.
Scheme 20: Cr(VI)-catalyzed oxidative cyclization in the total synthesis of venustatriol by Corey et al.
Scheme 21: Ru(VIII)-catalyzed oxidative cyclization of a 1,5-diene in the synthesis and evaluation of its ster...
Scheme 22: Ru(VII)-catalyzed oxidative cyclization of a 5,6-dihydroxy alkene in the synthesis of the core stru...
Opportunities and challenges for direct C–H functionalization of piperazines
- Zhishi Ye,
- Kristen E. Gettys and
- Mingji Dai
Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70
- ]. This simple and effective diamine-free procedure allowed the reaction to take place at −30 °C, which is more desirable than −78 °C in process chemistry. Under the new reaction conditions, electrophiles such as TMSCl, MeO2CCl, DMF, Ph2CO, and PhBr (via a Negishi coupling process) can be used to install
Graphical Abstract
Figure 1: Selected piperazine-containing small-molecule pharmaceuticals.
Figure 2: Strategies for the synthesis of carbon-substituted piperazines.
Figure 3: The first α-lithiation of N-Boc-protected piperazines by van Maarseveen et al. in 2005 [37].
Figure 4: α-Lithiation of N-Boc-N’-tert-butyl piperazines by Coldham et al. in 2010 [38].
Figure 5: Diamine-free α-lithiation of N-Boc-piperazines by O’Brien, Campos, et al. in 2010 [40].
Figure 6: The first enantioselective α-lithiation of N-Boc-piperazines by McDermott et al. in 2008 [41].
Figure 7: Dynamic thermodynamic resolution of lithiated of N-Boc-piperazines by Coldham et al. in 2010 [38].
Figure 8: Enantioselective α-lithiation of N-Boc-N’-alkylpiperazines by O’Brien et al. in 2013 and 2016 [42,43].
Figure 9: Asymmetric α-functionalization of N-Boc-piperazines with Ph2CO by O’Brien et al. in 2016 [43].
Figure 10: A “chiral auxiliary” strategy toward enantiopure α-functionalized piperazines by O’Brien et al. 201...
Figure 11: Installation of methyl group at the α-position of piperazines by O’Brien et al. 2016 [43].
Figure 12: α-Lithiation trapping of C-substituted N-Boc-piperazines by O’Brien et al. 2016 [43].
Figure 13: Rh-catalyzed reactions of N-(2-pyridinyl)piperazines by Murai et al. in 1997 [52].
Figure 14: Ta-catalyzed hydroaminoalkylation of piperazines by Schafer et al. in 2013 [55].
Figure 15: Photoredox catalysis for α-C–H functionalization of piperazines by MacMillan et al. in 2011 and 201...
Figure 16: Copper-catalyzed aerobic C–H oxidation of piperazines by Touré, Sames, et al. in 2013 [67].
Figure 17: Free radical approach by Undheim et al. in 1994 [68].
Figure 18: Anodic oxidation approach by Nyberg et al. in 1976 [70].
Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity
- Louis P. Sandjo,
- Victor Kuete and
- Maique W. Biavatti
Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183
- h. Therefore, the second Negishi coupling needed to be performed with N,N-dimethylnicotinamidezinc chloride. Synthesis of pyridoacridine analogues The strong antiproliferative activities shown by these alkaloids inspired the design and the synthesis of many pyridoacridines analogues. Scheme 9 shows
Graphical Abstract
Figure 1: Fragments produced by the FAB–MS of dehydrokuanoniamine B (20) [42].
Figure 2: Fragments produced by the EIMS of sagitol (26) [55].
Figure 3: Fragments produced by the EIMS of styelsamine B (4) [45].
Figure 4: Fragments produced by the EIMS of styelsamine D (6) [45].
Figure 5: Fragments produced by the EIMS of subarine (37) [40].
Scheme 1: Synthesis of styelsamine B (4) and cystodytin J (1) [58].
Scheme 2: Synthesis of sebastianine A (38) and its regioisomer 39 [59].
Scheme 3: Synthesis route A of neoamphimedine (12) [61].
Scheme 4: Synthesis route B of neoamphimedine (12) [62].
Scheme 5: Synthesis of arnoamines A (40) and B (41) [63].
Scheme 6: Synthesis of ascididemin (42) [65].
Scheme 7: Synthesis of subarine (37) [66,67].
Scheme 8: Synthesis of demethyldeoxyamphimedine (9) [68].
Scheme 9: Synthesis of pyridoacridine analogues related to ascididemin (42) [70].
Scheme 10: Synthesis of analogues of meridine (56) [71].
Scheme 11: Synthesis of bulky pyridoacridine as eilatin (58) [72].
Scheme 12: Synthesis of AK37 (59), analogue of kuanoniamine A (60) [73].
Figure 6: Biosynthesis pathway I [74].
Figure 7: Reaction illustrating catechol and kynuramine as possible biosynthetic precursors [75].
Figure 8: Biosynthesis pathway B deduced from the feeding experiment A using labelled precursors [76].
Figure 9: Proposed biosynthesis pathway [47].
Figure 10: 4H-Pyrido[2,3,4-kl]acridin-4-one as a cytotoxic pharmacophore.
Figure 11: 7H-Pyrido[2,3,4-kl]acridine as a cytotoxic pharmacophore.
Figure 12: 9H-Quinolino[4,3,2-de][1,10]phenanthrolin-9-one as a cytotoxic pharmacophore.
Figure 13: 8H-Benzo[b]pyrido[4,3,2-de][1,7]phenanthrolin-8-one as a cytotoxic pharmacophore.
Figure 14: Pyrido[4,3,2-mn]pyrrolo[3,2,1-de]acridine as a cytotoxic pharmacophore.
Figure 15: 9H-Pyrido[4,3,2-mn]thiazolo[4,5-b]acridin-9-one and 8H-pyrido[4,3,2-mn]thiazolo[4,5-b]acridine: cyt...
Figure 16: 9H-quinolino[4,3,2-de][1,10]phenanthrolin-9-one as an anti-mycobacterial pharmacophore.
Figure 17: 9H-Quinolino[4,3,2-de][1,10]phenanthrolin-9-one as an antibacterial pharmacophore.
Figure 18: Saturated and less saturated pyridine moieties as aspartyl inhibitor cores.
Figure 19: Iminobenzoquinone and acridone cores as intercalating and TOPO inhibitor motifs found in pyridoacri...
Sonogashira–Hagihara reactions of halogenated glycals
- Dennis C. Koester and
- Daniel B. Werz
Beilstein J. Org. Chem. 2012, 8, 675–682, doi:10.3762/bjoc.8.75
- and Heck reactions, respectively [21]. The dienes obtained during these transformations were successfully converted in Diels–Alder reactions to afford carbocyclic chiral compounds with a sugar backbone. In 2008, Gagné introduced a Ni-mediated Negishi coupling to synthesize alkyl- and aryl-C-glycosides
Graphical Abstract
Scheme 1: Different strategies to access C-glycosides starting from 1-substituted glycals.
Scheme 2: Sonogashira–Hagihara reaction of 1-iodo-2-chloroglucal 12 with phenylacetylene (8a) to afford 13.
Sexithiophenes as efficient luminescence quenchers of quantum dots
- Christopher R. Mason,
- Yang Li,
- Paul O’Brien,
- Neil J. Findlay and
- Peter J. Skabara
Beilstein J. Org. Chem. 2011, 7, 1722–1731, doi:10.3762/bjoc.7.202
- %, respectively). In parallel, dibrominated terthiophene 6 was prepared in an analogous fashion to 4a and 4b with 2.2 equiv of NBS. Subsequent Negishi coupling of compound 6 with organozinc intermediates of 4a and 4b, which were prepared by lithiation followed by reaction with zinc chloride, led to the isolation
Graphical Abstract
Figure 1: Dimethylaminophenylene end-capped sexithiophenes 1a and 1b, and dialkyl end-capped sexithiophenes 2a...
Scheme 1: The synthesis of functionalised oligothiophenes 1a,b and 2a,b. Reagents and conditions: a) NBS, CH3...
Figure 2: Solid-state voltammograms of 1b and 2b, as spin-coated films on ITO glass, versus Ag/AgCl reference...
Figure 3: Absorption spectra in solution (dichloromethane) and solid state.
Figure 4: UV–visible spectroelectrochemical measurements of 1b (left) and 2b (right) drop-cast onto ITO glass....
Figure 5: Absorption spectra for 1b and 2b, together with the absorption and emission profiles for the CdSe(Z...
Figure 6: The absorption spectra of increasing sexithiophene concentration with HDA capped CdSe(ZnS) quantum ...
Figure 7: Photoluminescence quenching experiments; the effect of increasing sexithiophene concentration with ...
An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals
- Marcus Baumann,
- Ian R. Baxendale,
- Steven V. Ley and
- Nikzad Nikbin
Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57
- formaldehyde as by-products [15]. Another possible approach is based on the direct displacement of a benzylic chloride by sodium sulfite and subsequent sulfonamide formation as shown in Scheme 13 [16]. A more recent method utilises a palladium-catalysed Negishi coupling to access a diverse library of benzylic
Graphical Abstract
Figure 1: Structures of atorvastatin and other commercial statins.
Figure 2: Structure of compactin.
Scheme 1: Synthesis of pentasubstituted pyrroles.
Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.
Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.
Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.
Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.
Scheme 6: Convergent synthesis towards atorvastatin.
Figure 3: Binding pocket of sunitinib in the TRK KIT.
Scheme 7: Synthesis of sunitinib.
Scheme 8: Alternative synthesis of sunitinib.
Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.
Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.
Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.
Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
Scheme 13: Alternative introduction of the sulfonamide.
Scheme 14: Negishi-type coupling to benzylic sulfonamides.
Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.
Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.
Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.
Scheme 18: Improved synthesis of rizatriptan.
Scheme 19: Larock-type synthesis of rizatriptan.
Scheme 20: Synthesis of eletriptan.
Scheme 21: Heck coupling for the indole system in eletriptan.
Scheme 22: Attempted Fischer indole synthesis of elatriptan.
Scheme 23: Successful Fischer indole synthesis for eletriptan.
Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction.
Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis.
Scheme 26: Palladium-mediated synthesis of ondansetron.
Scheme 27: Fischer indole synthesis of ondansetron.
Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.
Figure 4: Structures of carvedilol 136 and propranolol 137.
Scheme 29: Synthesis of the carbazole core of carvedilol.
Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.
Scheme 31: Convergent synthesis of etodolac.
Scheme 32: Alternative synthesis of etodolac.
Figure 5: Structures of imidazole-containing drugs.
Scheme 33: Synthesis of functionalised imidazoles towards losartan.
Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.
Scheme 35: Synthesis of trisubstituted imidazoles.
Scheme 36: Preparation of the imidazole ring in olmesartan.
Scheme 37: Synthesis of ondansetron.
Scheme 38: Alternative route to ondansetron and its analogues.
Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.
Scheme 40: Synthesis of benzimidazole core pantoprazole.
Figure 6: Structure of rabeprazole 194.
Scheme 41: Synthesis of candesartan.
Scheme 42: Alternative access to the candesartan key intermediate 216.
Scheme 43: .Medicinal chemistry route to telmisartan.
Scheme 44: Improved synthesis of telmisartan.
Scheme 45: Synthesis of zolpidem.
Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.
Figure 7: Structure of celecoxib.
Scheme 47: Preparation of celecoxib.
Scheme 48: Alternative synthesis of celecoxib.
Scheme 49: Regioselective access to celecoxib.
Scheme 50: Synthesis of pazopanib.
Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.
Scheme 52: Regioselective synthesis of anastrozole.
Scheme 53: Triazine-mediated triazole formation towards anastrozole.
Scheme 54: Alternative routes to 1,2,4-triazoles.
Scheme 55: Initial synthetic route to sitagliptin.
Figure 8: Binding of sitagliptin within DPP-IV.
Scheme 56: The process route to sitagliptin key intermediate 280.
Scheme 57: Synthesis of maraviroc.
Scheme 58: Synthesis of alprazolam.
Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.
Figure 9: Structures of itraconazole, ravuconazole and voriconazole.
Scheme 60: Synthesis of itraconazole.
Scheme 61: Synthesis of rufinamide.
Scheme 62: Representative tetrazole formation in valsartan.
Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.
Scheme 63: Early stage introduction of the tetrazole in losartan.
Scheme 64: Synthesis of cilostazol.
Figure 11: Structure of cefdinir.
Scheme 65: Semi-synthesis of cefdinir.
Scheme 66: Thiazole syntheses towards ritonavir.
Scheme 67: Synthesis towards pramipexole.
Scheme 68: Alternative route to pramipexole.
Scheme 69: Synthesis of famotidine.
Scheme 70: Efficient synthesis of the hyperuricemic febuxostat.
Scheme 71: Synthesis of ziprasidone.
Figure 12: Structure of mometasone.
Scheme 72: Industrial access to 2-furoic acid present in mometasone.
Scheme 73: Synthesis of ranitidine from furfuryl alcohol.
Scheme 74: Synthesis of nitrofurantoin.
Scheme 75: Synthesis of benzofuran.
Scheme 76: Synthesis of amiodarone.
Scheme 77: Synthesis of raloxifene.
Scheme 78: Alternative access to the benzo[b]thiophene core of raloxifene.
Scheme 79: Gewald reaction in the synthesis of olanzapine.
Scheme 80: Alternative synthesis of olanzapine.
Figure 13: Access to simple thiophene-containing drugs.
Scheme 81: Synthesis of clopidogrel.
Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).
Scheme 83: Alternative synthesis of key intermediate 422.
Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.
Scheme 84: Synthesis of timolol.
Scheme 85: Synthesis of tizanidine 440.
Scheme 86: Synthesis of leflunomide.
Scheme 87: Synthesis of sulfamethoxazole.
Scheme 88: Synthesis of risperidone.
Figure 15: Relative abundance of selected transformations.
Figure 16: The abundance of heterocycles within top 200 drugs (5-membered rings).
The preparation of 3-substituted-1,5-dibromopentanes as precursors to heteracyclohexanes
- Bryan Ringstrand,
- Martin Oltmanns,
- Jeffrey A. Batt,
- Aleksandra Jankowiak,
- Richard P. Denicola and
- Piotr Kaszynski
Beilstein J. Org. Chem. 2011, 7, 386–393, doi:10.3762/bjoc.7.49
- and 3b are volatile so care should be exercised during evaporation of solvent to ensure maximum yields. Negishi coupling of tetrahydropyran 3e with propylzinc chloride following a general literature method [45] using PEPPSI-IR as the Pd(0) source gave tetrahydropyran 3d in 69% yield. Tetrahydropyran
Graphical Abstract
Figure 1: Methods for synthesis of dibromides I and their use for preparation of 6-membered heterocycles.
Scheme 1: General methods for preparation of diols VII.
Scheme 2: General methods for preparation of tetrahydropyrans VIII.
Figure 2: Structures of 1,5-dibromomopentanes 1a–1d.
Scheme 3: Preparation of dibromides 1.
Scheme 4: Preparation of diol 2a.
Scheme 5: Preparation of diol 2b.
Scheme 6: Preparation of tetrahydropyrans 3a–3c.
Scheme 7: Preparation of tetrahydropyran 3d.
Scheme 8: Preparation of methylenetetrahydropyrans 6.
Scheme 9: Preparation of bromides 8 and 10.
Scheme 10: Preparation of sulfonium derivatives 11.
A short and efficient synthesis of valsartan via a Negishi reaction
- Samir Ghosh,
- A. Sanjeev Kumar and
- G. N. Mehta
Beilstein J. Org. Chem. 2010, 6, No. 27, doi:10.3762/bjoc.6.27
- -tetrazole (6) and its Negishi coupling with aryl bromide 5 are the key steps of the synthesis. This method overcomes many of the drawbacks associated with previously reported syntheses. Keywords: antihypertensive therapy; aryl bromide; Negishi coupling; tetrazole; valsartan; Introduction Valsartan (Figure
- important goal. In this paper, we report a new, concise and efficient synthesis of valsartan via Negishi coupling. Results and Discussion From a retro-synthetic analysis (Scheme 1), compound 8 could be constructed via Negishi coupling from aryl bromide 5 and 5-phenyl-1-trityl-1H-tetrazole (6), which in turn
- biphenyltetrazole structure of the AT-II antagonists has been developed which involves Negishi coupling of metalated 5-phenyl-1-trityl-1H-tetrazole. The method is commercially viable and applicable to plant scale production. This approach provides an industrial viable procedure for the synthesis of valsartan
Graphical Abstract
Figure 1: Valsartan.
Scheme 1: Retrosynthetic analysis of 8.
Scheme 2: (a) Et3N, CH2Cl2, 0 °C, 95%; (b) NaH, THF, 70%; (c) n-BuLi, 25 °C, THF, anhyd ZnCl2, −20 °C, Q-phos...
Mitomycins syntheses: a recent update
- Jean-Christophe Andrez
Beilstein J. Org. Chem. 2009, 5, No. 33, doi:10.3762/bjoc.5.33
Graphical Abstract
Scheme 1: Aziridine containing natural products.
Scheme 2: Mitomycin structures and nomenclature.
Scheme 3: Base catalysed epimerization of mitomycin B.
Scheme 4: Biosynthesis of mitomycin C (MMC) 7.
Scheme 5: Mode of action of mitomycin C.
Scheme 6: The N–C3–C9a disconnection.
Scheme 7: Danishefsky’s Retrosynthesis of mitomycin K.
Scheme 8: Hetero Diels–Alder reaction en route to mitomycins.
Scheme 9: Nitroso Diels–Alder cycloaddition.
Scheme 10: Frank azide cycloadddition.
Scheme 11: Final steps of mitomycin K synthesis. aPDC, DCM; bPhSCH2N3, PhH, 80 °C; cL-selectride, THF, −78 °C; ...
Scheme 12: Naruta–Maruyama retrosynthesis.
Scheme 13: Synthesis of a leucoaziridinomitosane by nitrene cycloaddition. aAlCl3-Et2O; bNaH, ClCH2OMe; cn-BuL...
Scheme 14: Thermal decomposition of azidoquinone 51.
Scheme 15: Diastereoselectivity during the cycloaddition.
Scheme 16: Oxidation with iodo-azide.
Scheme 17: Williams’ approach towards mitomycins.aDEIPSCl, Imidazole, DCM; bPd/C, HCO2NH4, MeOH; cAllocCl, NaH...
Scheme 18: Synthesis of pyrrolidones by homoconjugate addition.
Scheme 19: Homoconjugate addition on the fully functionalized substrate.
Scheme 20: Introduction of the olefin.
Scheme 21: Retrosynthesis of N–C9a, N–C3 bond formation.
Scheme 22: Synthesis of the pyrrolo[1,2]indole 82 using N-PSP activation.aAc2O, Py; bAc2O, Hg(OAc)2, AcOH, 90%...
Scheme 23: Synthesis of an aziridinomitosane. am-CPBA, DCM then iPr2NH, CCl4 reflux; bK2CO3, MeOH; cBnBr, KH; d...
Scheme 24: Oxidation products of a leucoaziridinomitosane obtained from a Polonovski oxidation.
Scheme 25: Polonovski oxidation of an aziridinomitosane. am-CPBA; bPd/C, H2; cDimethoxypropane, PPTS.
Scheme 26: The C1–C9a disconnection.
Scheme 27: Ziegler synthesis of desmethoxymitomycin A.aIm2C=O, THF; bNH3; cTMSOTf, 2,6-di-tert-butylpyridine, ...
Scheme 28: Transformation of sodium erythorbate.aTBDMSCl; bNaN3; cPPh3; d(Boc)2O, DMAP; eTBAF; fTf2O, Pyr.
Scheme 29: Formation of C9,C10-unsaturation in the mitomycins. am-CPBA, DCM; bO3, MeOH; cMe2S; dKHMDS, (EtO)3P...
Scheme 30: Fragmentation mechanism.
Scheme 31: Michael addition-cyclisation.
Scheme 32: SmI2 8-endo-dig cyclisation.
Scheme 33: Synthesis of pyrrolo[1,2-a]indole by 5-exo-dig radical cyclization.
Scheme 34: The C9–C9a disconnection.
Scheme 35: Intramolecular nitrile oxide cycloaddition.
Scheme 36: Regioselectivity of the INOC.
Scheme 37: Fukuyama’s INOC strategy.
Scheme 38: Synthesis of a mitosane core by rearrangement of a 1-(1-pyrrolidinyl)-1,3-butadiene.
Scheme 39: Sulikowski synthesis of an aziridinomitosene. aPd(Tol3P)2Cl2, Bu3SnF, 140; bH2, Pd/C; cTFAA, Et3N; d...
Scheme 40: Enantioselective carbene insertion.
Scheme 41: Parson’s radical cyclization.
Scheme 42: Cha’s mitomycin B core synthesis.
Scheme 43: The N-aromatic disconnection.
Scheme 44: Kishi retrosynthesis.
Scheme 45: Kishi synthesis of a starting material. aallyl bromide, K2CO3, acetone, reflux; bN,N-Dimethylanilin...
Scheme 46: Kishi synthesis of MMC 7. aLDA, THF, −78 °C then PhSeBr, THF, −78 °C; bH2O2, THF-EtOAc; cDIBAL, DCM...
Scheme 47: Acid catalyzed degradation of MMC 7.
Scheme 48: In vivo formation of apomitomycin B.
Scheme 49: Advanced intermediate for apomitomycin B synthesis.
Scheme 50: Remers synthesis of a functionalized mitosene. aTMSCl, Et3N, ZnCl2 then NBS; bAcOK; cNH2OH; dPd/C, H...
Scheme 51: Coleman synthesis of desmethoxymitomycin A. aSnCl2, PhSH, Et3N, CH3CN; bClCO2Bn, Et3N; cPPh3, DIAD,...
Scheme 52: Transition state and pyrrolidine synthesis.
Scheme 53: Air oxidation of mitosanes and aziridinomitosanes.
Scheme 54: The C9-aromatic disconnection.
Scheme 55: Synthesis of the aziridine precursor. aLHMDS, THF; bNaOH; c(s)-α-Me-BnNH2, DCC, HOBT; dDIBAL; eK2CO3...
Scheme 56: Synthesis of 206 via enamine conjugate addition.
Scheme 57: Rapoport synthesis of an aziridinomitosene.
Scheme 58: One pot synthesis of a mitomycin analog.
Scheme 59: Synthesis of compound 218 via intramolecular Heck coupling. aEtMgCl, THF, then 220; bMsCl, Et3N; cN...
Scheme 60: Elaboration of indole 223. aEt3N, Ac2O; bAcOH; cSOCl2, Et3N; dNaN3, DMF; eH2SO4, THF; fK2CO3, MeOH; ...
Scheme 61: C9-C9a functionalization from indole.
Scheme 62: Synthesis of mitomycin K. a2 equiv. MoO5.HMPA, MeOH; bPPh3, Et3N, THF-H2O; cMeOTf, Py, DCM; dMe3SiCH...
Scheme 63: Configurational stability of mitomycin K derivatives.
Scheme 64: Epimerization of carbon C9a in compound 227b.
Scheme 65: Corey–Chaykovsky synthesis of indol 235.
Scheme 66: Cory intramolecular aza-Darzens reaction for the formation of aziridinomitosene 239.
Scheme 67: Jimenez synthesis of aziridinomitosene 242.
Scheme 68: Von Braun opening of indoline 244.
Scheme 69: C9a oxidation of an aziridinomitosane with DDQ/OsO4.
Scheme 70: Synthesis of epi-mitomycin K. aNaH, Me2SO4; bH2, Pd/C; cMitscher reagent [165]; d[(trimethylsilyl)methyl...
Scheme 71: Mitomycins rearrangement.
Scheme 72: Fukuyama’s retrosynthesis.
Scheme 73: [2+3] Cycloaddition en route to isomitomycin A. aToluene, 110 °C; bDIBAL, THF, −78 °C; cAc2O, Py.; d...
Scheme 74: Final steps of Fukuyama’s synthesis.
Scheme 75: “Crisscross annulation”.
Scheme 76: Synthesis of 274; the 8-membered ring 274 was made using a crisscross annulation. a20% Pd(OH)2/C, H2...
Scheme 77: Conformational analysis of compound 273 and 275.
Scheme 78: Synthesis of a mitomycin analog. aNa2S2O4, H2O, DCM; bBnBr (10 equiv), K2CO3, 18-crown-6 (cat.), TH...
Scheme 79: Vedejs retrosynthesis.
Scheme 80: Formation of the azomethine ylide.
Scheme 81: Vedejs second synthesis of an aziridinomitosene. aDIBAL; bTPAP, NMO; c287; dTBSCl, imidazole.
Scheme 82: Trityl deprotection and new aziridine protecting group 300.
Scheme 83: Ene reaction towards benzazocinones.
Scheme 84: Benzazocenols via homo-Brook rearrangement.
Scheme 85: Pt-catalyzed [3+2] cycloaddition.
Scheme 86: Carbonylative lactamization entry to benzazocenols. aZn(OTf)2, (+)-N-methylephedrine, Et3N, TMS-ace...
Scheme 87: 8 membered ring formation by RCM. aBOC2O, NaHCO3; bTBSCl, Imidazole, DMF; callyl bromide, NaH, DMF; ...
Scheme 88: Aziridinomitosene synthesis. aTMSN3; bTFA; cPOCl3, DMF; dNaClO2, NaH2PO4, 2-methyl-2-butene; eMeI, ...
Scheme 89: Metathesis from an indole.
Scheme 90: Synthesis of early biosynthetic intermediates of mitomycins.
