Organocatalytic Enantioselective Thermal [4 + 4] Cycloadditions

Abstract

Chiral eight-membered carbocycles are important motifs in organic chemistry, natural product chemistry, chemical biology, and medicinal chemistry. The lack of synthetic methods toward their construction is a challenge preventing their rational design and stereoselective synthesis. The catalytic enantioselective [4 + 4] cycloaddition is one of the most straightforward and atom-economical methods to obtain chiral cyclooctadiene derivatives. We report the first organocatalytic asymmetric [4 + 4] cycloaddition of 9H-fluorene-1-carbaldehydes with electron-deficient dienes affording cyclooctadiene derivatives in good yields and with excellent control of peri-, diastereo-, and enantioselectivities. The reaction concept is based on the aminocatalytic formation of a polarized butadiene component incorporated into a cyclic extended π-system, with restricted conformational freedom, allowing for a stereocontrolled [4 + 4] cycloaddition. FMO analysis unveiled that the HOMO and LUMO of the two reacting partners resemble those of butadiene. The methodology allows for the construction of cyclooctadiene derivatives decorated with various functionalities. The cyclooctadienes were synthetically elaborated, allowing for structural diversity demonstrating their synthetic utility for the formation of, for example, chiral cyclobutene- or cyclooctane scaffolds. DFT computational studies shed light on the reaction mechanism identifying the preference for an initial but reversible [4 + 2] cycloaddition delivering an off-cycle catalyst resting state, from which catalyst elimination is not possible. The off-cycle catalyst-bound intermediate undergoes a retro-[4 + 2] cycloaddition, followed by a [4 + 4] cycloaddition generating a cycloadduct from which catalyst elimination is possible. The reaction pathway accounts for the observed peri-, diastereo-, and enantioselectivity of the organocatalytic [4 + 4] cycloaddition.

Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3‐Dipolar Cycloaddition of 3‐Oxidopyridinium Betaines and Dienamines

“…Furthermore, a reversal of the second‐bond formation in Int‐IIa‐(5+4) is energetically feasible (ΔΔ G =8.6 kcal mol −1 ), which allows the reaction to pursue the productive catalytic pathway by reforming Int‐Ia . This mechanistic scenario is similar to our recent investigations of [4+4] cycloadditions with chiral dienamines [35] . As reported by Harmata, Krenske, and Burns, direct interconversion between (5+4) and (5+2) cycloadducts may also be possible via a Cope rearrangement [20b,25b] .…”

“…This mechanistic scenario is similar to our recent investigations of [4 + 4] cycloadditions with chiral dienamines. [35] As reported by Harmata, Krenske, and Burns, direct interconversion between (5 + 4) and (5 + 2) cycloadducts may also be possible via a Cope rearrangement. [20b,25b] However, a concerted rearrangement TS from Int-IIa-(5 + 4) to Int-IIa-(5 + 2) could not be located (see Supporting Information), but formation of Int-IIa-(5 + 2) from Int-IIa-(5 + 4) via Int-Ia can be mechanistically classified as a stepwise Cope rearrangement.…”

Pd-catalyzed enantioselective [4 + 4] dipolar cycloaddition of aliphatic 1,4-dipoles with azadienes to access eight-membered N-heterocycles

“…5 The synthesis of chiral medium-sized rings, especially chiral eight-membered rings, still remains rare in the literature. There are only a few reports on the preparation of eight-membered rings through higher-order cycloadditions, 6 for example, the Xiao group disclosed an enantioselective synthesis of eight-membered lactones through a Pd-catalyzed [6 + 2] dipolar cycloaddition reaction with the assistance of visible light (Scheme 1a). 6 b New higher-order dipolar cycloaddition reactions concerning novel 1, n -dipoles will be highly desirable to obtain eight-membered N-heterocycles fused with privileged structures such as benzofuran 7 and indene.…”

High atomic utilization conversion of ethers into furancarbaldehydes via an ether oxidation iminium-ion activation cascade strategy

“…Notably, in our previous work, the alkyl component released by oxidation of cinnamyl alkyl ether did not participate in the subsequent reaction, resulting in low atomic utilization. 1–25 However, we recently envisaged designing a novel ether oxidation cascade with high atomic utilization: the enol fragment released by ether oxidation continues to participate in the subsequent cascade as a reactant, instead of leaving like a protective group.…”

“…9 Organocatalytic enal-derived iminium-enamine activated asymmetric transformations have been demonstrated as powerful approaches for constructing enantiomerically enriched and functionalized aldehydes. [10][11][12][13][14][15][16][17][18][19][20][21] To our knowledge, the oxidative cleavage of cinnamyl alkyl ethers to access enal-derived iminium ions should be an attractive synthetic strategy in which ethers can be used as "masked" aldehydes for further iminium catalysis. Therefore, we previously reported an oxidative iminium-ion activation strategy using cinnamyl alkyl ethers as substrates to synthesis α-spirocyclopropane derivatives 22 (Scheme 1a).…”