Cobalt-Catalyzed Diastereoselective Cross-Couplings between Alkynylzinc Pivalates and Functionalized Cyclic Iodides or Bromides

Abstract

Various 1,2-, 1,3-, and 1,4-substituted cyclic iodides or bromides undergo highly diastereoselective cross-couplings (diastereoselectivity (dr) up to 99:1) with a range of alkynylzinc pivalates, using CoCl (20 mol %) and trans- N, N, N', N'-tetramethylcyclohexane-1,2-diamine as a catalytic system.

Enantioselective synthesis of (R)‐Cinacalcet via cobalt‐catalysed asymmetric Negishi cross‐coupling

“…Transition‐metal‐catalysed asymmetric cross‐coupling reactions of alkyl electrophiles with organozinc reagents are powerful methods for the formation of chiral tertiary and quaternary carbon atoms . Moreover, the inexpensive and lower toxicity of cobalt has led to a significant progress on cobalt‐catalysed Negishi cross‐coupling reactions . Recently, we have developed the first cobalt‐catalysed enantioselective Negishi cross‐coupling to construct the stereogenic benzylmethyl center directly .…”

Late‐Stage Functionalization of Peptides and Cyclopeptides Using Organozinc Reagents

“…[26] In general, this kind of assessment is of impor-tance in the course of fine-tuning properties and structureactivity relationships during the drug discovery process.T he membrane permeability and solubility parameters of the modified cyclopeptides 14-16 were compared to the results of in silico calculations.T hus,t his set of nine cross-coupling products (14-16)was submitted to molecular dynamics (MD) simulations followed by calculation of the solvent-accessible polar surface area (abbreviated SAPSA) to result in an in silico assessment of permeability properties in the first instance (Table 2). Thel ow solubility measured for the starting materials (11)(12)(13)was in most of the cases improved by the pyridyl core (see Table 2, entries 4-9 and 12), and on the basis of the PA MPA( Parallel Artificial Membrane Permeability Assay) results,a ll cyclic peptides display high permeability.However,inthe cellular assessment (MDCK;M adin Darby canine kidney cells assay), the position of the pyridyl linkage seems to be sensitive regarding transport across the cellular membrane.A si nt he in silico analyses,t he para-phenylalanine-substituted analogues showed reduced transport rates. Cross-couplingreactions of tyrosine derivatives 3a,b with organozinc halides 5a-e leading to alkylated tyrosine derivatives 6a-f. Boc = tert-butoxycarbonyl, Cbz = benzyloxycarbonyl.…”

“…[6] Therefore,t he Negishi coupling should be well suited for the late-stage functionalization of complex molecules.F urthermore,o rganozinc halides are readily prepared and tolerate the presence of various functional groups. [11] Herein, we wish to report aq uite general late-stage functionalization of small peptides and cyclopeptides bearing an ortho-iodotyrosine or an iodophenylalanine amino acid via Negishi cross-couplings with organozinc pivalates (1). [11] Herein, we wish to report aq uite general late-stage functionalization of small peptides and cyclopeptides bearing an ortho-iodotyrosine or an iodophenylalanine amino acid via Negishi cross-couplings with organozinc pivalates (1).…”

“…Additionally,w eh ave extended this late-stage functionalization to four iodocyclopeptides,o ne derived from tyrosine (3e)a nd three derived from phenylalanine (11)(12)(13). As indicated in Scheme 4, ar ange of arylzinc pivalates bearing either electron-donating or -accepting groups as well as heteroarylzinc pivalates were used in Negishi cross-couplings to give the expected products (7a-f, 8a-d,a nd 9a-c)i n3 8-92 %y ield.…”

Spätphasenfunktionalisierung von Peptiden und Cyclopeptiden mithilfe von Organozinkreagenzien

“…[6] Die Negishi-Kupplung sollte daher fürd ie Spätphasenfunktionalisierung von komplexen Molekülen gut geeignet sein. [11] Hier wird eine relativ allgemeingültige Spätphasenfunktionalisierung von kleinen Peptiden und Cyclopeptiden, die entweder eine ortho-Iodtyrosin-oder eine Iodphenylalanin-Aminosäure enthalten, mittels Negishi-Kreuzkupplungen mit Organozinkpivalaten 1 gezeigt. [7] Wirk onnten zeigen, dass Organozinkpivalate [8] des Ty ps 1,m it der allgemeinen Formel RZnX·Mg(OPiv) 2 ·LiCl [9] (abgekürzt RZnOPiv), eine verbesserte Feuchtigkeits-und Luftstabilitäta ufweisen.…”