Cyclopropanation Strategies in Recent Total Syntheses

Abstract

Complex molecular architectures containing cyclopropanes present significant challenges for any synthetic chemist. This review aims to highlight the strategic considerations for introduction of the cyclopropane motif in a collection of recent total syntheses. At first, an overview of the most important and widely used cyclopropanation techniques is presented, followed by a discussion of elegant approaches and clever solutions that have been developed to enable the synthesis of various unique cyclopropane natural products or use of cyclopropanes as versatile strategic intermediates.

Copper‐Catalyzed [3+2] Cycloaddition and Interrupted Fischer Indolization to Prepare Polycyclic Furo[2,3‐b]indolines from N‐Aryl Isatin Nitrones and Methylenecyclopropanes

“…[9] Cyclopropanes are prevalent in drug molecules and bioactive compounds, usually showing distinct bioactivity. [10] Furthermore, the Brandi-Guarna rearrangement, namely, the NÀO bond cleavage of 5-spirocyclopropane-isoxazoline cycloadducts produced by the cycloaddition of nitrones and methylenecyclopropanes, which can then undergo rearrangement to afford piperidin-4-ones owing to the highly strained spirocyclopropane ring, has been successfully applied to natural product synthesis. [11] During our studies on the preparation and cycloaddition of isatin nitrones, [12,13] we surmised that the carbonyl group in isatin nitrones could act as a directing group and coordinate with a catalyst to control diastereoselectivity in the cycloaddition of isatin nitrones and methylenecyclopropanes.…”

“…[15] To our delight, adding Cu(OAc) 2 (10 mol%) as catalyst afforded product 3 aa in 66% yield and 5:1 dr after only 24 h ( Table 1, entry 3). The yield of 3 aa decreased when using other copper salts, while the dr of 3 aa was increased to 20:1 using Cu(II), and decreased to 3:1 using Cu(I) ( Table 1, entries [10][11][12]. Solvent screening showed that product 3 aa was afforded in moderate yields in toluene, MeCN, THF, and DMSO; with diastereomeric ratios ranging from 1.6:1 to 4:1 ( Table 1, entries 4-7).…”

“…Other copper salts and metal catalysts were also examined to test the efficiency. The yield of 3 aa decreased when using other copper salts, while the dr of 3 aa was increased to 20:1 using Cu(II), and decreased to 3:1 using Cu(I) ( Table 1, entries [10][11][12]. Other Lewis acids, such as Pd(OAc) 2 , Fe(OTf) 3 , Sc(OTf) 3 , and Yb(OTf) 3 , did not greatly improve the yield and dr of 3 aa (Table 1, entries [13][14][15][16].…”

gem‐Dichlorocyclopropanation of Dicarbonyl Derivatives

“…[3][4][5] Moreover,t hese rings are intrinsically related to important pharmaceutical properties, such as enhanced drug potency, metabolic stability,a nd ar eduction of side effects. [6] Dihalosubstituted cyclopropanes have recently attracted great interest from the scientificc ommunity,m ainly due to their versatile reactivity, [7] allowing their use as intermediates in aw ide range of applications,s uch as ring expansions, Friedel-Crafts reactions, and Doering-Moore-Skattebøl reactions. [8] The gem-dihalocyclopropanes are also substrates in the preparation of monohalocyclopropanes, cyclopropenes, cyclopentane, and av ariety of other usefulf unctional groups.…”

Rhodium(I)/Zn(OTf)2‐Catalyzed Asymmetric Ring Opening/Cyclopropanation of Oxabenzonorbornadienes with Phosphorus Ylides

“…which, in contrast to sulfur ylides,have still not yet been fully explored in cyclopropanation reactions. [10,11] TM-catalyzed asymmetric ring-opening (ARO) reactions of oxabenzonorbornadienes have received considerable attention since the seminal of Lautens. [12] Although various nucleophiles have been employed successfully in ARO, leading to substituted hydroxyl dihydronaphthalenes, [12,13] the use of P-ylides as the nucleophile in TM-catalyzed ARO with oxabenzonorbornadienes has not been previously realized.…”