New Syntheses of E7389 C14−C35 and Halichondrin C14−C38 Building Blocks: Double-Inversion Approach

Abstract

With sequential use of catalytic asymmetric Cr-mediated coupling reactions, E7389 C14-C35 and halichondrin C14-C38 building blocks have been stereoselectively synthesized. The C19-C20 bond is first formed via the catalytic asymmetric Ni/Cr-mediated coupling, i.e., 8 + 9 --> 10 (90%; dr = 22:1), in which vinyl iodide 8 is used as the limiting substrate. The C23-C24 bond is then formed via the catalytic asymmetric Co/Cr-mediated coupling, i.e., 13 + 14 --> 4 (82%; dr = 22:1), in which the alkyl-iodide bond in 14 is selectively activated over the vinyl-iodide bond. The catalytic asymmetric Ni/Cr-mediated reaction is employed to couple C14-C26 segment 19 with E7389 C27-C35 segment 20 (91%; dr = >55:1). In this synthesis, the C23-O bond is stereoselectively constructed via a double-inversion process, i.e., 21 --> 22, to furnish E7389 C14-C35 building block 22 in 84% yield. The same synthetic sequence has been employed to synthesize halichondrin C14-C38 building block 18b, i.e., 16a + 19 --> 18b.

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

“…[9b] Despite the success with total synthesis,the limited supply of halichondrin Bwas acritical issue in the early 1990s,which was eased, in particular, by the discovery of the potencyo f simplified analogue eribulin, or E7389 ( Figure 2). [18a] In addition to the synthetic efforts by the Kishi group, [19] the synthesis of the C14-C35 fragment (13)o fe ribulin (Scheme 2) has been optimized for process development on akilogram scale.This most recent route put forth by Eisai Inc. in 2013 begins with conversion of dihydrofuran (1)into C14-C19 fragment 3,through atin-mediated bromoallylation with 2,3-bromopropene (2;S cheme 1). [20] Fragment C20-C26 (5) was synthesized from 1,2-epoxyhex-5-ene (4)i ns even steps by ah ydrolytic kinetic resolution (HKR) with aJ acobsen catalyst.…”

Catalytic Asymmetric Synthesis of Allylic Alcohols and Derivatives and their Applications in Organic Synthesis

“…[170] Here, [Zr(Cp) 2 Cl 2 ] was used instead of TMSCl to dissociate the chromium alkoxide (Scheme 73, B). [172] The great efficiency of these new ligands has been demonstrated in the total synthesis of various challenging natural products and intermediates, [173] including building blocks of E7389 and halichondrin B/C [174] (Figure 6 and Schemes 74 and 75) as well as aplyrorine A-mycalolide B hybrid compound [175] (Figure 6, Recently, Kishi and co-workers studied the influence of the Ni II source on the addition of (Z)-disubstituted alkenyl iodide 176 to 171 (Scheme 77). [171] Over the last decade, effective, structurally diverse chiral sulfonamide ligands have been developed (139-143, Figure 4) for the selective synthesis of chiral allylic alcohols by Cr/Nimediated addition of alkenyl iodides to aldehydes.…”

“…[171] Over the last decade, effective, structurally diverse chiral sulfonamide ligands have been developed (139-143, Figure 4) for the selective synthesis of chiral allylic alcohols by Cr/Nimediated addition of alkenyl iodides to aldehydes. [172] The great efficiency of these new ligands has been demonstrated in the total synthesis of various challenging natural products and intermediates, [173] including building blocks of E7389 and halichondrin B/C [174] (Figure 6 and Schemes 74 and 75) as well as aplyrorine A-mycalolide B hybrid compound [175] (Figure 6…”

Organometallic‐Mediated Radical Polymerization: Developing Well‐Defined Complexes for Reversible Transition Metal‐Alkyl Bond Homolysis

“…In 2008, Poli, Smith and coworkers reported the use of 15 and V-70 for OMRP of VOAc. [56] Gratifyingly, ancillary ligand electronic effects were manifested in the OMRP reaction profile upon changing the para-substituent in mixed-aryl Nacnac ligands (15, Ar¼ 2,6-i Pr 2 C 6 H 3 , Ar' ¼ 4-XC 6 H 4 : X ¼ CF 3 , H, OMe). The ethylene polymerization activity of 16-Cl (Ar ¼ Ar' ¼ Ph) upon activation with AlEt 3 was recently reported, [57] raising the possibility of creating PVOAcblock-PE polymers.…”