Stereoselective Palladium‐Catalyzed Approach to Vitamin D₃ Derivatives in Protic Medium

Abstract

We describe an efficient convergent synthesis of vitamin D metabolites and analogues. The synthetic strategy relies on a tandem Pd-catalyzed A-ring closure and Suzuki-Miyaura coupling to the CD-side chain component to set directly the vitamin D triene system under protic conditions. This strategy enables rapid access to vitamin D and 3-epi-vitamin D metabolites and analogues modified at the side chain for biological evaluation and structural and metabolic studies.

Recent Advances in Pd‐Catalyzed Suzuki‐Miyaura Cross‐Coupling Reactions with Triflates or Nonaflates

“…They relied on different strategies, especially on a domino carbocyclization‐SM cross‐coupling with vinyl triflates. Here, a Pd(II) catalyst, like PdCl 2 (PPh 3 ) 2 or Pd(dppf)Cl 2 , was tested in different reaction systems, revealing that PdCl 2 (PPh 3 ) 2 suited the best in a K 2 CO 3 and THF/H 2 O base/solvent system stirred at RT (Scheme 42), while the bidentate ligand Pd(dppf)Cl 2 led to a complex mixture [60] …”

“…Here, a Pd(II) catalyst, like PdCl 2 (PPh 3 ) 2 or Pd(dppf)Cl 2 , was tested in different reaction systems, revealing that PdCl 2 (PPh 3 ) 2 suited the best in a K 2 CO 3 and THF/H 2 O base/solvent system stirred at RT (Scheme 42), while the bidentate ligand Pd(dppf)Cl 2 led to a complex mixture. [60] Jana et al developed in 2014 a mild SM crosscoupling reaction involving o-azidoarylboronic acid pinacolate esters and vinyl triflates towards a stepeconomic synthesis of 2-alkenylaryl azides, which were further converted to different N-heterocycles. They proved that a smaller number of phosphine ligands coordinating to the Pd center could improve the yield.…”

Pd(0)‐Catalyzed‐Mediated Synthesis of Vitamin D Compounds

“…A synthetic approach to A-ring-synthon 85, required for the synthesis of 25-hydroxyvitamin D 3 metabolites and analogs was carried out in Mouriño's laboratory. [109] This approach is summarized in Scheme 18. Ozonolysis of (S)-(+)-limonene oxide followed by acetylation of the resulting hydroperoxide with Ac 2 O and Criegee rearrangement of the resulting peroxyester provided, after protection, epoxide 100.…”

Design, Synthesis, Evaluation and Structure of Allenic 1α,25‐Dihydroxyvitamin D3 Analogs with Locked Mobility at C‐17

“…The formation of the vitamin D triene system involves a stereoselective Pd 0 -catalyzed ring closure of enoltriflate 4 and subsequent Suzuki-Miyaura coupling with unprotected alkenyl-boronic ester 3 in protic medium following procedures developed in this laboratory. [17] At this point, the stability of the allenic unit under the Pdcatalyzed reaction conditions was uncertain. The boronates 3 are envisaged to arise from the allene 5 by conventional chemistry.…”

“…Treatment of 5 with methyl magnesium bromide in THF provided the tertiary alcohol 8 a (98 %), which was deprotected to alcohol 9 a (98 %) with tetrabutylammonium fluoride in THF. Pyridinium dichromate oxidation of 9 a in CH 2 Cl 2 followed by Wittig-olefination of the resulting ketone 10 a with ylide Ph 3 P=CHBr, [21] prepared from (Ph 3 PCH 2 Br)Br and KOtBu in toluene, led to (E)-alkenyl bromide 11 a in 69 % yield (two steps), which was converted to the desired upper boronate 3 a (58 % yield) without protection of the side-chain-hydroxyl group by Miyaura's modified method [17,22] using bis(pinacolato)diboron and KOAc in the presence of catalytic [1,1'bis(diphenylphosphino) ferrocene] dichloropalladium(II) in DMSO.…”