Construction of Carbo- and Heterocycles Using Radical Relay Cyclizations Initiated by Alkoxy Radicals

Abstract

An efficient method for the rapid construction of carbo- and heterocycles has been developed using radical relay cyclizations initiated by alkoxy radicals. Linear substrates were cyclized to form a wide range of cyclopentane, pyrrolidine, tetrahydropyran, and tetrahydrofuran derivatives in excellent yields. This methodology was utilized as a key step in the synthesis of the tetrahydrofuran fragment in (-)-amphidinolide K.

Strategies to Control Alkoxy Radical-Initiated Relay Cyclizations for the Synthesis of Oxygenated Tetrahydrofuran Motifs

“…We focused our studies on the oxa-analogues of previously studied relay cyclization substrates. 8 Synthetic routes to the cyclization precursors are outlined in Scheme 2.…”

“…8 We chose this same fragment to test our new branched relay cyclizations because it provides a good point of comparison to evaluate the efficiency of our new transformation. Furthermore, the branched relay cyclization products provide direct access to the opposite alcohol protection pattern of (−)-amphidinolide K THF fragment 11 (Scheme 1), which avoids two additional protection and deprotection steps.…”

“…Characterization for compounds 30b, 30d, 30f, and 31h have been previously reported. 8 Methyl((4-((2S,3S)-3-methyltetrahydrofuran-2-yl)butan-2-yl)-oxy)diphenylsilane (30a). N-Alkoxyphthalimide 19a (285 mg, 0.93 mmol) was subjected to general cyclization procedure A.…”

“…The synthesis of these polyketides has received considerable attention, and construction of the THF ring is often a key component of the overall strategy. 7 Our strategy 8 to synthesize the THF rings in these important macrolides is to utilize radical relay (or translocation) cyclization cascades 9−11 initiated by alkoxy radicals (Figure 2). 12,13 The first step of these cascade reactions involves the generation of a highly reactive alkoxy radical species (3) that can undergo a 1,5-hydrogen atom transfer (1,5-HAT) of an unactivated or an activated carbon−hydrogen bond to form carbon radical 4.…”

Synthesis and Biological Evaluation of RGD-Conjugated MEK1/2 Kinase Inhibitors for Integrin-Targeted Cancer Therapy

“…General Procedure for the Synthesis of Tert-butyl-(2-hydroxyethyl)carbamate 3a and Its Derivatives (3b-e) [25][26][27][28][29] To a solution of 2a (or 2b-e, 20 mmol) in a mixture of dioxane (15 mL) and H 2 O (7 mL), was added 5N NaOH (4.8 mL) and a solution of Boc 2 O (5.0 g, 23 mmol) in dioxane at 0 °C. After stirred at rt overnight, the reaction mixture was concentrated in vacuo.…”