Cobalt-Catalyzed Hartung–Mukaiyama Cyclization of γ-Hydroxy Olefins: Stereocontrolled Synthesis of the Tetrahydrofuran Moiety of Amphidinolide N

Abstract

Cobalt-catalyzed Mukaiyama-type cyclization of γ-hydroxy olefins is known as an atom-and step-economical means for stereoselective synthesis of 2,5-trans-substituted tetrahydrofuran derivatives. In this study, we investigated the synthesis of a series of 2,5-substituted tetrahydrofuran derivatives by means of a cobalt-catalyzed Hartung−Mukaiyama cyclization. The stereochemical consequence of the reaction was found to be largely dependent on the substitution pattern and relative configuration of γ-hydroxy olefins. 2,5-cis-Substituted tetrahydrofuran derivatives could be obtained diastereoselectively from appropriately substituted γ-hydroxy olefins. Additionally, relatively bulky olefin substituents and unprotected hydroxy groups at non-interfering positions (e.g., α and δ) were well tolerated in the reaction. Finally, the synthetic versatility of the Hartung−Mukaiyama cyclization was demonstrated through a stereocontrolled synthesis of the tetrahydrofuran moiety of amphidinolide N, a potent cytotoxic macrolide of marine origin. This study expands the capacity of Mukaiyama-type cyclization in that it can be used in convergent assembly of complex tetrahydrofuran motifs from internal olefins.

Total Synthesis of (+)-Muricatetrocin B via a Late-Stage Co-Catalyzed Hartung–Mukaiyama Cyclization

“…Optimization of this reaction required some experimentation, which involved examination of the H atom source, substrate concentration, and reaction temperature (Table ). Although the configuration of the tetrahydrofuran ring of 28 could not be determined by NMR spectroscopic analysis due to heavy signal overlap, we tentatively assigned the 2,5- trans configuration of the tetrahydrofuran ring on the basis of a model experiment, as well as relevant cases reported in our previous work . Notably, the E / Z ratio of 5 changed between the time before and after the reaction.…”

“…Koert and co-workers disclosed the first total synthesis of 1 from methyl acetoacetate over 18 longest linear steps, although they did not claim that they confirmed the absolute configuration of (+)- 1 because of the inconsistency in the specific rotation value of their synthetic material with that of the natural product . Here we report our total synthesis of (+)-muricatetrocin B ( 1 ), which capitalized on an olefin cross-metathesis and a Co-catalyzed Hartung–Mukaiyama cyclization , for late-stage convergent assembly of the 2,5- trans -configured tetrahydrofuran ring …”

“…1:2 selectivity (Scheme ). The configuration of the generated olefin within 5 was of no matter to the stereochemical outcome of subsequent cyclization. , Thus, upon treatment of 5 with 10 mol % of Co II complex I in 1,4-cyclohexadiene/toluene (1:1, v/v) at 60 °C under air for 2 h, Hartung–Mukaiyama cyclization proceeded to afford 2,5- trans -configured tetrahydrofuran 28 in 50% yield with >95:5 diastereoselectivity, along with 10% of unreacted 5 (56% based on recovered 5 )…”

The Tetrahydrofuran Motif in Polyketide Marine Drugs

“…However, despite the efforts of different researchers, no total synthesis of this compound has been reported so far. There are different approaches focused on the synthesis of the fragment which contains the tetrahydrofuran ring [27][28][29][30], a total synthesis of 7,10-epimer [31,32], and a recently described enantioselective synthesis of des-epoxy-amphidinolide N, which failed in the last epoxidation step towards amphidinolide N [33]. Both Sasaki's [27] and Kuwahara's [29] strategies to build the tetrahydrofuran moiety consisted of an intramolecular cyclization of a diol mesylate obtained by Sharpless asymmetric dihydroxylation (SAD) of mesyl protected alkenol 22 using AD-mix-β.…”

“…Subsequent cyclization, mediated by base, afforded the desired 2,5-trans-disubstituted tetrahydrofuran 23 (Scheme 4). Recently, Fuwa proposed the application of cobalt-catalyzed Hartung-Mukaiyama cyclization of γ-hydroxy olefins to obtain the tetrahydrofuran fragment [30]. Mukaiyama cyclization is known to afford 2,5-trans substituted tetrahydrofurans with a 2-hydroxy substituent.…”