Total Synthesis of Nuclear Factor of Activated T-Cells-68 (NFAT-68): Sequential Use of Chiral Allenylsilane and Titanium Alkoxide-Mediated Reductive Coupling Bond Construction

Abstract

Highly enantioenriched chiral allenylsilanes 4 were prepared in high yield through a scalable synthetic sequence, employing a modified copper-catalyzed SN2' reaction. These reagents were used for the production of enantioenriched homoproparglylic ethers 5, which were subjected to titanium alkoxide-mediated reductive coupling with acetylenic esters to produce (E,E)-dienes 6 bearing α,β,γ,δ-unsaturated esters. Both enantiomers of nuclear factor of activated T-cells-68 (NFAT-68) were synthesized in five steps with the sequential use of the two methods.

Strategic Applications of the β‐Silicon Effect

“…[109] The method was used by the same group in their total synthesis of (NFAT-68) 206 (Scheme 44). [110] In a similar body of work, the same authors explored the addition of these species into iminium ions derived from 208 and 209 in the presence of TMSOTf (Scheme 45). Once again, the enantioselectivity is locked in from a kinetic resolution of the initial alcohol, before subsequent rearrangement and addition affords 210.…”

Stereo- and Regioselective Synthesis of (E,E)-Dienes: Evolution from the Transition-Metal-Catalyzed Cross-Coupling to Titanium Alkoxide-Based Alkyne–Alkyne Reductive Coupling

“…To demonstrate the synthetic applicability of the alkyne-alkyne reductive coupling method in complex molecule syntheses, both Micalizio group [67] and our operation [15,16] have independently reported the utilization of this method in the convergent total synthesis of natural products. In 2020, Cai and Panek have reported the first example of amide and carbamate directing effect in the titanium alkoxide-mediated reductive coupling [43] and its application in the small-molecule synthesis as well as the generation of analogues of NFAT-68, [42] further expanding this underexplored reaction which will be discussed in the following sections.…”

“…Their hypothesis was based on the work from Micalizio, [7,36,45] Schafer [77][78][79][80] and their earlier work. [42] The Micalizio group had carried out extensive studies and established a solid foundation in the mechanistic interpretation of operational intermediates and transition states leading to selective reductive coupling in the titanium-mediated reductive coupling (Scheme 36A). [7,8,36,39,45] Central to Micalizio's proposal is the proposed Ti(II) dimer.…”

Axial Chirality Beyond Atropisomerism: Allenes and Related Compounds

“…Besides, the application in the synthesis of both enantiomers of a polyketide natural product, NFAT-76 has been reported. 65 The three-component propargylation reaction between aromatic aldehyde 74, (benzyloxy)trimethylsilane, and chiral silane (S)-73 or (R)-73, produced internal alkynes 75 and ent-75 with good yield, diastereoselectivity and excellent ee's values (Scheme 29). In both cases, syn products are obtained as the major diastereomer.…”