Taking the strain: The asymmetric total synthesis and stereochemical assignment of (-)-cavicularin, which features a highly strained polycyclophane ring system, has been achieved. The key features of this synthesis are 1) macrocyclization by an SN Ar reaction, 2) group-selective reaction to induce planar chirality in a highly stereoselective manner, and 3) radical transannulation to construct the highly strained ring system.
Riccardin C (1) has been synthesized by exploiting an intramolecular S N Ar reaction of ¡-sulfinylfluorobenzene by an internal phenolate, providing the key 18-membered ring closure in excellent yield.Riccardin C (1) represents a class of macrocyclic bisbibenzyl natural products, which are phenolic metabolites characteristic to liverworts.1 The intriguing structure of 1 featuring an 18-membered macrocycle as well as the interesting biological activities 2 stimulated considerable synthetic interests toward this and related compounds. The major synthetic challenge is the construction of the strained macrocyclic ring including ortho-, meta-, and two parasubstituted benzenes. Upon comparison of five previous syntheses of 1 by how the 18-membered ring was constructed (Figure 1), four syntheses employed intramolecular CC bond formation at the benzylic positions (bond a or b), 3a3d whereas one relied on biaryl bond formation (bond c).3e The critical issue, however, is that these macrocyclizations generally suffer from poor yields, due mostly to the molecular strain within the macrocycle.In our recent interest in cyclophanes, 4 we became interested in the synthesis of 1 by exploiting the biaryl ether formation (bond d in Figure 1) through an intramolecular S N Ar reaction, converting the acyclic starting material I to the strained cyclized product II (Figure 2). Our hope was that the Meisenheimer intermediate A would be less strained by the nonplanar structure around the ether linkage. The conversion of A to II would increase the strain, which would, however, be compensated by the aromatization energy.Herein, we describe a positive answer to this assumption, achieving the concise synthesis of 1 via the high-yield S N Ar reaction for the key macrocyclization.
An intramolecular benzyne–phenolate [4+2] cycloaddition is reported. Benzyne precursors, having vicinal halogen‐sulfonate functionalities, linked with a phenol(ate) by various tether groups undergo efficient intramolecular [4+2] cycloaddition by treatment with either Ph3MgLi or nBuLi for halogen–metal exchange to form various benzobarrelenes.
The total syntheses of pusilatins A (2), B (3), and C (5), macrocyclic bisbibenzyl dimers isolated from Japanese liverwort are reported. The common monomeric unit (6) was prepared via macrocyclization of an o-sulfinylfluorobenzene derivative by SAr attack of an internal phenol, which was exploited for site-selective dimerizations en route to 2, 3, and 5.
Herein
is reported the nine-step commercial synthesis of delgocitinib,
a Janus kinase inhibitor approved for the treatment of atopic dermatitis
in 2020. Its chiral spirodiamine core was selectively constructed
by an intramolecular SN2 reaction of the suitably designed
γ-lactone substrate and a few subsequent steps including a selective
γ-lactone ring-opening reaction with potassium phthalimide,
hydrazine-free mild dephthaloylation, and one-pot reduction of β-
and γ-lactams. The route affords chemically and stereochemically
pure delgocitinib in 39% yield.
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