Unified Synthesis of Right Halves of Halichondrins A–C

Abstract

The right halves of halichondrins A-C were synthesized by coupling the common C20-C37 building block 9 with the C1-C19 building blocks 10a-c, respectively. Catalytic, asymmetric Ni/Cr-mediated coupling was used for three C-C bond formations. For all cases, the stereochemistry was controlled with the Cr catalyst prepared from the chiral sulfonamide identified via the toolbox approach. For (3 + 4)-, (6 + 7)-, and (9 + 10)-couplings, the stereoselectivity of 28:1, >40:1, and ∼20:1 was achieved by the Cr catalysts prepared from (S)-H, (S)-I, and (R)-L, respectively. Unlike the first and second couplings, the third coupling used the structurally complex nucleophile. It was demonstrated that the coupling efficiency was excellent even with the electrophile/nucleophile molar ratio = 1.0/1.1. In addition, the third coupling was achieved with the substrate bearing a free hydroxyl group. The products obtained in the Ni/Cr-mediated couplings were converted to the right halves of halichondrins A-C in excellent overall yields. The right halves of halichondrins A-C (1a-c) were synthesized in 28, 24, and 24 steps from commercial d-galactal in 13.4%, 21.1%, and 16.7% overall yield, respectively.

Stereocontrolled Synthesis of Left Halves of Halichondrins

“…As presented in the preceding paper, we synthesized C37-iodides 1a – c as the right halves (upper half in Scheme ). On the other hand, we chose thiopyridine esters 2a – c as the left halves from the following considerations (lower half in Scheme ). First, the TES-protecting group at C41 was chosen from its behavior in the following deprotection step.…”

“…The crude lactone was recrystallized from CH 2 Cl 2 /hexanes to give lactone 5 (9.68 g from first recrystallization and 300 mg from second recrystallization: total 9.98 g, 29.1 mmol, 100% for two steps) as a colorless crystal. For the spectroscopic data, see ref .…”

“…FTIR (film): 2952, 2929, 2855, 1463, 1252, 1138, 1003, 833, 768 cm −1 . HRMS (ESI) m/z: [M + Na] + calcd for C 25 H 50 O 4 Si 2 Na 493.3140, found 493.3142.Hydroxyl Epoxide S17.To a stirred suspension of molecular sieve 4 Å (1.5 g, activated powder) in CH 2 Cl 2 (50 mL) were added Ti(OiPr) 4 (0.72 mL, 2.43 mmol, 15 mol %) and a solution of (+)-DET (0.55 mL, 3.21 mmol, 20 mol %) in CH 2 Cl 2 (5.0 mL) at −20 °C 7. After being stirred for 15 min at the same temperature, the reaction mixture was added to TBHP solution (4.5 mL of ∼5.5 M in decane over molecular sieve 4, Å (ca.…”

Total Synthesis and Antimicrobial Activities of All Stereoisomers of (16Z,20E)-Eushearilide and (16E,20E)-Eushearilide

“…In view of minimizing the number of synthetic processes and improving the overall yield, we next reduced the number of protection and deprotection steps compared to our previous synthetic strategy. We prepared a seco acid with a free hydroxy group at C3 as a ring-closure precursor and attempted to cyclize the seco acid by 2-methyl-6-nitrobenzoic anhydride (MNBA)-promoted lactonization promoted by nucleophilic catalysts under basic conditions, , as outlined in Scheme .…”

The Tetrahydrofuran Motif in Polyketide Marine Drugs

“…Structure of halichondrins, norhalichondrins and homohalichondrins.Great efforts by Kishi's group have been devoted to the synthesis of this family of compounds. To finally reach the total synthesis, Kishi et al first established the synthesis of different fragments of halichondrins such as: C1-C19, through key Ni/Cr-mediated coupling of polyhalogenated nucleophiles[54,55], C14-C38 fragment, by oxy-Michael cyclization[56,57], and those combined led to the C1-C37 right halves of halichondrins A-C[58]. In 2017, Kishi and co-workers accomplished a general and scalable total synthesis of halichondrins[59].…”