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. 2018 Mar 29;2018(12):1460-1464.
doi: 10.1002/ejoc.201800118. Epub 2018 Jan 31.

(Poly)cationic λ3-Iodane Mediated Oxidative Ring Expansion of Secondary Alcohols

Jennifer C Walters  1 , Anthony F Tierno  1 , Aimee H Dubin  1 , Sarah E Wengryniuk  1
Affiliations

(Poly)cationic λ3-Iodane Mediated Oxidative Ring Expansion of Secondary Alcohols

Jennifer C Walters et al. European J Org Chem. .

Abstract

Herein, we report a simplified approach to the synthesis of medium-ring ethers through the electrophilic activation of secondary alcohols with (poly)cationic λ3-iodanes (N-HVI). Excellent levels of selectivity are achieved for C-O bond migration over established α-elimination pathways, enabled by the unique reactivity of a novel 2-OMe-pyridine-ligated N-HVI. The resulting HFIP-acetals are readily derivatized with a range of nucleophiles, providing a versatile functional handle for subsequent manipulations. The utility of this methodology for late-stage natural product derivatization was also demonstrated, providing a new tool for diversity-oriented synthesis and complexity-to-diversity (CTD) efforts. Preliminary mechanistic investigations reveal a strong effect of alcohol conformation on reactive pathway, thus providing a predictive power in the application of this approach to complex molecule synthesis.

Keywords: cyclic ethers; hypervalent iodine; medium-ring; ring expansion.

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Figures

Figure 1
Figure 1
A. Medium ring ether scaffolds in bioactive natural products. B. Hydroxyl groups provide a ubiquitous functional handle in bioactive natural products.
Scheme 1
Scheme 1
Synthesis of medium-ring ethers from secondary alcohols via electrophilic activation with (poly)cationic λ3-iodanes (N-HVIs).
Scheme 2
Scheme 2
Scope of electrophilic ring expansion of secondary alcohols. [a] Low yield due to volatility of acetal products. [b] Ratio of HFIP-acetal to ketone by 1H-NMR. [c] Formation of open chain aldehyde products. [d] Reaction run using N-HVI 10 (1.5 equiv), DCM, −25 °C.
Scheme 3
Scheme 3
Application to complex scaffold derivatization. X= HFIP [a] Ratio of HFIP-acetal to ketone by 1H-NMR. [b] 1H-NMR of 39 shows only two diastereomers, resulting from HFIP-acetal. Lack of epimerization further established after reduction of 39. See SI for details.
Scheme 4
Scheme 4
Role of alcohol conformation on reaction pathway.
Scheme 5
Scheme 5
Functionalization of HFIP-acetals. Lewis Acid: [a] TMSOTf [b] BF3•OEt2. [c] Et2O used in place of DCM [d] Conditions: HCl, 14:1 MeOH:HFIP.
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