Enantioselective Synthesis of the Spirotropanyl Oxindole Scaffold through Bimetallic Relay Catalysis

Abstract

Spirotropanyl oxindole alkaloids like alstonisine and chitosenine show a wide range of bioactivites. We report the first enantioselective synthesis of the spirotropanyl oxindole scaffold by means of a bimetallic relay catalysis strategy. A new class of E-oximino α-diazo ketones was developed for the intramolecular generation of transient azomethine ylides catalyzed by an achiral Rh complex and a subsequent intermolecular 1,3-dipolar cycloaddition catalyzed by a chiral N,N'-dioxide Nd Lewis acid complex. The enantioselectively catalyzed transformation has broad scope and yields the desired spirotropanyl oxindole cycloadducts in high yields and with very high enantio- and diastereoselectivity.

Harnessing the Chemistry of the Indole Heterocycle to Drive Discoveries in Biology and Medicine

“…As structural motifs of proteins are limited, underlying scaffold classes of natural products are selected for; therefore, compound classes derived from or inspired by natural products can be considered “biologically prevalidated” starting points for compound collection development and subsequent biological investigation . Using this rationale, Waldmann and co‐workers have pioneered a biology‐oriented synthesis (BIOS) approach for the design and synthesis of natural product‐inspired compound collections …”

“…[125] Using this rationale, Waldmann and co-workers have pioneered ab iology-oriented synthesis (BIOS) approachf or the design and synthesis of naturalp roduct-inspired compound collections. [126][127][128][129][130] Spirotryprostatin B( 163)i sanaturally-occurring spirooxindole that hasr eceived great interest from the scientific community as ap otentiala nti-cancer drug. [125] Spirotryprostatin B induces cell cycle arrest at the G2/M phase due to its inhibitory properties against tubulin polymerization.…”

Asymmetric Synthesis of Oxa‐Bridged Oxazocines through a Catalytic RhII/ZnII Relay [4+3] Cycloaddition Reaction

“…Bimetallic relay catalysis [7] combines two metal catalysts in one sequence,w hich enables the synthesis of complex molecules from simple starting materials without the isolation of unstable intermediates,s hows unique potential in asymmetric synthesis. [8] In 2013, Suga and co-workers combined Rh II with Pybox-Ph 2 -Ln III to realize an enantioselective [3+ +2]-cycloaddition of oxazolidinones with isomünchnones, thereby generating chiral bicyclic compounds in high efficiency (Scheme 1c). [9] However,t he highly enantioselective [4+ +3]-cycloaddition [10] of isomünchnone has not been achieved.…”

“…Changing the ester group (R 1 )from methyl to abulkier aliphatic isopropyl, cyclopentyl, or benzyl group,the yields and ee values could still remain (entries 1-4). b,g-Unsaturated a-ketoesters with electron-withdrawing or electron-donating substituents at different positions of the phenyl group can react smoothly to afford the corresponding products in good yields (71-90 %y ield) and excellent ee values (97-99 % ee;e ntries [5][6][7][8][9][10][11][12][13][14][15][16]. It was worth mentioning that a-ketoester 1j,which contains ahydroxy group,was also compatible,p roducing the product 3ja in 88 %y ield with 97 % ee (entry 10).…”

Enantioselective Synthesis of the Spirotropanyl Oxindole Scaffold through Bimetallic Relay Catalysis

“…Thes tructures and the absolute configuration of the diastereomers of 3m were unambiguously determined by crystal structure analysis. [19] Different E-oximino a-diazo ketones 1 were then investigated. Oximes with different protecting groups (R 3 )r anging from benzyl to tert-butyl gave the products 3t and 3u in ah ighly enantioselective and diastereoselective manner.V ariation of the R 4 group adjacent to the oxime moiety showed that ethyl and butyl groups led to slightly decreased yields of the products 3v and 3w with comparable enantio-and diastereoselectivity.I nterestingly, product 3x,which incorporates acyclopropyl group as R 1 ,was isolated, albeit with lower enantioselectivity.U se of diazo compounds that should give rise to afive-or seven-membered azomethine ylide (see Figure S1) did not result in product [b] exo/ endo [c] ee [%] [d] 1R h 2 (OAc) 4 Angewandte Chemie Zuschriften formation.…”