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Radkowski, Karin Seidel, Günter Lacombe, Fabrice Gabor, Barbara Mynott, Richard A convergent total synthesis of the antibiotic macrolide myxovirescin A₁ (1) is described that is largely based on reagent- and catalyst-controlled transformations. This includes a highly regioselective Negishi reaction of dibromo-alkene 48 with an alkynylzinc reagent, and a palladium catalyzed alkyl-Suzuki coupling of the resulting enyne derivative 12 with the 9-BBN-adduct derived from alkene 61. The latter was obtained via an asymmetric hydrogenation of the chlorinated β-ketoester 49 and an anti-selective oxyallylation of the functionalized aldehyde 53 as the key steps. The preparation of the bis-borylated allyl-donor 57 used in the oxyallylation step, however, required careful optimization and led to important insights into the nature of the classical hydroborating agent “di(isopinocampheyl)borane (Ipc₂BH)”. It was unambiguously shown by X-ray crystallography that in the solid state this compound is dimeric, but it is prone to undergo an essentially quantitative mono-deborylation when dissolved in CH₂Cl₂ or benzene; its composition in ethereal solvents is even more complex as evident from ¹¹B NMR data. Product 71 derived from 12 and 61 was elaborated into the enyne–yne derivative 75, which served as the substrate for an exquisitely selective ring closing alkyne metathesis reaction (RCAM) catalyzed by the molybdenum tris-amido complex 20 activated in situ with CH₂Cl₂. The resulting cyclic enyne 76 was subjected to a ruthenium catalyzed trans-hydrosilylation/proto-desilylation tandem. Although [Cp*Ru(MeCN)₆]PF₁ had previously been recommended as catalyst of choice for trans-hydrosilylation reactions of internal alkynes, this complex failed to afford the desired product, whereas its sterically less hindered congener [CpRu(MeCN)₃]PF₆ permitted the reaction to be performed in appreciable yield, but at the expense of a lower stereoselectivity. AgF-mediated proto-desilylation of the isomeric silanes 79 and 80 followed by cleavage of the remaining acetal protecting groups afforded myxovirescin A₁ and its hitherto unknown 14Z-isomer 81, respectively. Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society Service Department Mynott (NMR), Max-Planck-Institut für Kohlenforschung, Max Planck Society Service Department Mynott (NMR), Max-Planck-Institut für Kohlenforschung, Max Planck Society 2007-10-26 http://purl.org/escidoc/metadata/ves/publication-types/article Text 8762-8783 escidoc:2111614 eterms:DOI: 10.1002/chem.200700926 Chemistry – A European Journal 13 31 eng Fürstner Alois Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society escidoc:1445584 http://pubman.mpdl.mpg.de/cone/persons/resource/persons58380 Bonnekessel Melanie Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society escidoc:1445584 http://pubman.mpdl.mpg.de/cone/persons/resource/persons58444 Blank Jarred T. Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society escidoc:1445584 http://pubman.mpdl.mpg.de/cone/persons/resource/persons58432 Radkowski Karin Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society escidoc:1445584 http://pubman.mpdl.mpg.de/cone/persons/resource/persons58907 Seidel Günter Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society escidoc:1445584 http://pubman.mpdl.mpg.de/cone/persons/resource/persons58992 Lacombe Fabrice Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society escidoc:1445584 http://pubman.mpdl.mpg.de/cone/persons/resource/persons58731 Gabor Barbara Service Department Mynott (NMR), Max-Planck-Institut für Kohlenforschung, Max Planck Society escidoc:1445627 http://pubman.mpdl.mpg.de/cone/persons/resource/persons58558 Mynott Richard Service Department Mynott (NMR), Max-Planck-Institut für Kohlenforschung, Max Planck Society escidoc:1445627 http://pubman.mpdl.mpg.de/cone/persons/resource/persons58838 Total Synthesis of Myxovirescin A₁ eng 10.1002/chem.200700926 2007-06-18 2007-09-04 2007-10-26 http://purl.org/eprint/status/PeerReviewed Chemistry – A European Journal Chem. – Eur. J. Chem. Eur. J. 13 31 8762 8783 VCH Verlagsgesellschaft Weinheim, Germany 0947-6539 http://pubman.mpdl.mpg.de/cone/journals/resource/954926979058 22 A convergent total synthesis of the antibiotic macrolide myxovirescin A₁ (1) is described that is largely based on reagent- and catalyst-controlled transformations. This includes a highly regioselective Negishi reaction of dibromo-alkene 48 with an alkynylzinc reagent, and a palladium catalyzed alkyl-Suzuki coupling of the resulting enyne derivative 12 with the 9-BBN-adduct derived from alkene 61. The latter was obtained via an asymmetric hydrogenation of the chlorinated β-ketoester 49 and an anti-selective oxyallylation of the functionalized aldehyde 53 as the key steps. The preparation of the bis-borylated allyl-donor 57 used in the oxyallylation step, however, required careful optimization and led to important insights into the nature of the classical hydroborating agent “di(isopinocampheyl)borane (Ipc₂BH)”. It was unambiguously shown by X-ray crystallography that in the solid state this compound is dimeric, but it is prone to undergo an essentially quantitative mono-deborylation when dissolved in CH₂Cl₂ or benzene; its composition in ethereal solvents is even more complex as evident from ¹¹B NMR data. Product 71 derived from 12 and 61 was elaborated into the enyne–yne derivative 75, which served as the substrate for an exquisitely selective ring closing alkyne metathesis reaction (RCAM) catalyzed by the molybdenum tris-amido complex 20 activated in situ with CH₂Cl₂. The resulting cyclic enyne 76 was subjected to a ruthenium catalyzed trans-hydrosilylation/proto-desilylation tandem. Although [Cp*Ru(MeCN)₆]PF₁ had previously been recommended as catalyst of choice for trans-hydrosilylation reactions of internal alkynes, this complex failed to afford the desired product, whereas its sterically less hindered congener [CpRu(MeCN)₃]PF₆ permitted the reaction to be performed in appreciable yield, but at the expense of a lower stereoselectivity. AgF-mediated proto-desilylation of the isomeric silanes 79 and 80 followed by cleavage of the remaining acetal protecting groups afforded myxovirescin A₁ and its hitherto unknown 14Z-isomer 81, respectively. alkynes; antibiotics; macrocyclization; metathesis; natural products 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung pending Object created. ct Monika Lickfeld Monika Lickfeld Object created. pending ---1 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung pending Object created. ct Monika Lickfeld Monika Lickfeld Object created. pending 2015-03-13T08:19:47.687Z 1 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung submitted ct Monika Lickfeld Monika Lickfeld submitted 2015-03-13T08:19:47.687Z 1 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung submitted ct Monika Lickfeld Monika Lickfeld submitted 2015-03-13T08:20:57.087Z 1 hdl:11858/00-001M-0000-0025-7411-5 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung submitted ct Monika Lickfeld Monika Lickfeld submitted 2015-03-13T08:20:57.087Z 1 hdl:11858/00-001M-0000-0025-7411-5 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung submitted ct Monika Lickfeld Monika Lickfeld submitted 2015-03-13T11:09:14.724Z 1 hdl:11858/00-001M-0000-0025-7412-3 hdl:11858/00-001M-0000-0025-7411-5 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung submitted ct Monika Lickfeld Monika Lickfeld submitted 2015-03-13T11:09:14.724Z 1 hdl:11858/00-001M-0000-0025-7412-3 hdl:11858/00-001M-0000-0025-7411-5 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung submitted ct Monika Lickfeld Monika Lickfeld submitted 2015-03-13T11:09:15.314Z 1 hdl:11858/00-001M-0000-0025-7412-3 hdl:11858/00-001M-0000-0025-7412-3 hdl:11858/00-001M-0000-0025-7411-5 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung released ct Renate Lohmer Monika Lickfeld released 2015-03-13T11:09:15.314Z 1 1 --- hdl:11858/00-001M-0000-0025-7412-3 hdl:11858/00-001M-0000-0025-7412-3 hdl:11858/00-001M-0000-0025-7411-5 1.3.10-SNAPSHOT Publications of the MPI für Kohlenforschung released ct Renate Lohmer Monika Lickfeld released 2015-03-13T11:09:15.833Z 1 1 2015-03-13T11:09:15.833Z hdl:11858/00-001M-0000-0025-7412-3 1 2015-03-13T11:09:15.833Z released URL /ir/item/escidoc:2111614/resources/version-history#v1e1426244955817 released 2015-03-13T11:09:15.833Z escidoc-internal escidoc:1457805 escidoc-internal escidoc:2111614 URL /ir/item/escidoc:2111614/resources/version-history#v1e1426244955300 assignVersionPid 2015-03-13T11:09:14.793Z versionPid assigned escidoc-internal escidoc:1457805 escidoc-internal escidoc:2111614 URL /ir/item/escidoc:2111614/resources/version-history#v1e1426244954719 assignObjectPid 2015-03-13T08:20:57.162Z objectPid assigned escidoc-internal escidoc:1457805 escidoc-internal escidoc:2111614 URL /ir/item/escidoc:2111614/resources/version-history#v1e1426234857073 submitted 2015-03-13T08:20:57.087Z escidoc-internal escidoc:1474884 escidoc-internal escidoc:2111614 URL /ir/item/escidoc:2111614/resources/version-history#v1e1426234787726 create 2015-03-13T08:19:47.687Z Object created. escidoc-internal escidoc:1474884 escidoc-internal escidoc:2111614