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. 2014 Oct 22;136(42):14951-8.
doi: 10.1021/ja5076426. Epub 2014 Oct 13.

Stereospecific cross-coupling reactions of aryl-substituted tetrahydrofurans, tetrahydropyrans, and lactones

Emily J Tollefson  1 , David D Dawson, Charlotte A Osborne, Elizabeth R Jarvo
Affiliations

Stereospecific cross-coupling reactions of aryl-substituted tetrahydrofurans, tetrahydropyrans, and lactones

Emily J Tollefson et al. J Am Chem Soc. .

Abstract

The stereospecific ring-opening of O-heterocycles to provide acyclic alcohols and carboxylic acids with controlled formation of a new C-C bond is reported. These reactions provide new methods for synthesis of acyclic polyketide analogs with complex stereochemical arrays. Stereoselective synthesis of the cyclic template is utilized to control relative configuration; subsequent stereospecific nickel-catalyzed ring-opening affords the acyclic product. Aryl-substituted tetrahydrofurans and tetrahydropyrans undergo nickel-catalyzed Kumada-type coupling with a range of Grignard reagents to furnish acyclic alcohols with high diastereoselectivity. Enantioenriched lactones undergo Negishi-type cross-coupling with dimethylzinc to afford enantioenriched carboxylic acids. Application in a two-step enantioselective synthesis of an anti-dyslipidemia agent is demonstrated.

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Figures

Scheme 1
Scheme 1. Stereoselective Ring-Opening and C–C Bond Formation Strategy
Scheme 2
Scheme 2. Enantiospecific Nickel-Catalyzed THP Opening
Scheme 3
Scheme 3. Diastereoselective Cross-Coupling Reactions
Scheme 4
Scheme 4. Synthesis of Substituted THFs
Scheme 5
Scheme 5. Diastereoselective Synthesis of Tetrahydropyrans
(a) Montmorillonite K10 (1.1 equiv), MeOH, C6H6, reflux, 18 h; (b) p-TSA (1.0 equiv), MgBr2 (1.1 equiv), CH2Cl2, rt, 18 h; (c) Ni(cod)2 (10 mol %), bathophenanthroline (BPhen) (20 mol %), ArB(OH)2 (1.2 equiv), KOtBu (1.6 equiv), s-BuOH, 60 °C, 24 h.
Scheme 6
Scheme 6. Diels–Alder Reaction of Furan 57
Yield determined by 1H NMR based on comparison to PhTMS as internal standard. Isolated yield after column chromatography.
Scheme 7
Scheme 7. Enantiospecific Synthesis of Anti-Dyslipidemia Agent 61
(a) Ni(acac)2 (10 mol %), Xantphos (20 mol %), ZnMe2 (3.0 equiv), PhMe, rt, 24 h; (b) (i) (COCl)2 (1.3 equiv), C6H6, rt, 2 h; (ii) anthranilic acid (1.1 equiv), C6H6, rt, 3 h.
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