Abstract
Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular SNAr or SN2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.
Highlights
Introduction and Recently Approved Macrocyclic DrugsMacrocycles continue to serve as an important class of compounds and have had a profound impact on chemistry, biology, and medicine [1,2,3]
We previously reviewed macrocyclic drugs and general synthetic strategies toward macrocycles [1]
Since 2014, a number of new macrocyclic drugs have been approved by the US Food and Drug Administration (FDA), and their chemical structures, brand, and generic drug names, and the year of the approval are shown in Figures 1 and 2
Summary
On-resin Suzuki–Miyaura macrocyclizations of 99 and 101 were performed using Pd2(dba) (0.2 eq), SPhos (0.4 eq), and KF (4 eq) in DME/EtOH/H2O (9/9/2) under MW irradiation at 120 ◦C for 30 min, followed by simultaneous resin cleavage and side-chain deprotection in TFA/TIPS/H2O to provide 100 and 102 in 16% and 22% overall yields, respectively (Scheme 29) This methodology demonstrates the synthesis of biaryl cyclopeptides with a p-Phe-m-Tyr or m-Tyr-m-Tyr linkage via solid-phase intramolecular Suzuki–Miyaura cross-coupling [105]. Suzuki– Miyaura macrocyclization of 113 was performed on solid-support using Pd2(dba) (0.2 eq), SPhos (0.4 eq), and KF (4 eq) in DME/EtOH/H2O (9/9/2) at 120 or 140 ◦C under MW irradiation for 30 min, followed by simultaneous resin cleavage and side-chain deprotections in TFA/TIS/H2O to provide 114 (Scheme 33) By using this developed methodology, several other analogs, including cyclolipopeptides 115 and 116, were synthesized [112].
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