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Enantioselective Medium Ring Lactone Synthesis Through a NHCCatalyzed Intramolecular Desymmetrization of Prochiral 1,3-Diols Zijun Wu, and Jian Wang ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02302 • Publication Date (Web): 29 Sep 2017 Downloaded from http://pubs.acs.org on September 30, 2017
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ACS Catalysis
Zijun Wu,† and Jian Wang*,† †
School of Pharmaceutical Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Bioorganic Phosphorous Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing, 100084 (China)
ABSTRACT: The highly enantioselective intramolecular annulation reaction of 1,3-diols, catalyzed by a triazolium NHC pre-catalyst, is disclosed, affording the corresponding medium-sized lactones in moderate to good yields with high enantioselectivities. It is worth to noting that this compatible catalytic system has been successfully applied to assemble a broad range of chiral medium-sized lactones, including eight-, nine-, ten-, eleven-, and twelve-membered ring.
KEYWORDS: medium-sized lactones, N-heterocyclic carbine, desymmetrization, asymmetric catalysis, cooperative catalysis, 1,3-diols
Due to the unfavorable entropy effect and the transannular interactions,5-7 the construction of mediumring scaffolds, via a highly enantioselective fashion, remains a formidable challenge. Over the past few decades, a number of powerful tools Scheme 1. (a) "Carbonyl-centered" Macrolactonization (past work); (b) Enantioselective Medium (eight to twelve-membered) Ring Lactone Synthesis Via a NHC-catalyzed Intramolecular Desymmetrization Strategy (this work).
Introduction Medium-sized lactones (typical 8 to 12 member-ring) are core structures in numerous natural products and pharmaceuticals1-3. Owing to their unique molecular architecture, medium-sized rings open an avenue for scientists to explore their biological and medicinal properties2-7. In this context, medium-ring lactones are one of the most promising members4-6. As outlined in Figure 11,2, on the basis of lactone scaffold, medium-ring molecules exhibited a variety of important medicinal properties, such as antifungal, insecticidal, olfactory, etc.
Stoichiometric reaction Chirality is pre-assembled in starting materials Generally suitable for "5-7" and ">12" membered-ring synthesis
Major Challenge: Enantioselective control for medium ring synthesis Protocol compatibility in the assembly of all "8 to 12" medium rings Substrate scope and functional group tolerance
Figure 1. Representative chiral medium-ring lactones.
have been made to assemble macrocyclic ring systems4,8, including ring-closing metathesis9, Diels–Alder macrocyclization10, intramolecular cross-coupling11-14, and Horner–
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Wadsworth–Emmons-type olefination15. Nevertheless, the “carbonyl-centered” activation mode4,16, completed by the addition of a stoichiometric amount of activating reagents to carboxylic acid, has been used prevalently in the process of macrolactonization, thus proving to be a reliable and high-yielding procedure. However, this protocol limits to resolve the process chemistry problem with regard to step17 and atom18 economy (Scheme 1(a)). Additionally, several elegant approaches (e.g. Corey−Nicolaou19, KeckSteglich20, Mitsunobu21, Shiina22a and Yamaguchi lactonizations22b) have also been uncovered, but still restricts to macro-ring synthesis. Furthermore, the harsh conditions used in above lactonization methods often caused a few of unpredictable side reactions, such as isomerization, migration, and epimerization4. Notably, although above macrolactonizations are very straightforward and powerful, the chirality of products is controlled by the used chiral starting materials23. In contrast to asymmetric catalysis, they belong to classic substrate-controlled strategies24,25 (Scheme 1(a)). Consequently, the development of new strategy for the highly enantioselective synthesis of medium-ring lactones has been a long held goal. Table 1. Optimization of the Reaction Conditionsa
entry cat. additive yield (%)b erc 1 A1 NR 2 A2
