Asymmetric Catalytic Concise Synthesis of Hetero-3,3?-Bisoxindoles for the Construction of Bispyrroloindoline Alkaloids

Open AccessCCS ChemistryCOMMUNICATION1 Jul 2021Asymmetric Catalytic Concise Synthesis of Hetero-3,3?-Bisoxindoles for the Construction Bispyrroloindoline Alkaloids Jian Xu, Ziwei Zhong, Mingyi Jiang, Yuqiao Zhou, Xiaohua Liu and Xiaoming Feng Xu Key Laboratory Green Chemistry & Technology, Ministry Education, College Chemistry, Sichuan University, Chengdu 610065 Google Scholar More articles by this author , Zhong Jiang Zhou *Corresponding authors: E-mail Address: [email protected] https://doi.org/10.31635/ccschem.020.202000443 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Asymmetric nucleophilic addition 3-substituted N-Boc oxindoles 3-bromooxindoles was designed directly construct hetero-3,3?-bisoxindoles, with varying vicinal quaternary carbon stereocenters N-substituents. The reaction progressed efficiently high yields, good diastereo- enantioselectivity (up >99% ee) under mild conditions catalyzed chiral N,N?-dioxide/metal complexes. This methodology enabled facile transformation generated hetero-3,3’-bisoxindoles into diverse hexahydropyrroloindole alkaloids potential antiparasitic anticancer properties. Download figure PowerPoint Introduction Dimeric polymeric hexahydropyrroloindoles (HPIs) are a family alkaloid natural products essential biological activities (Scheme 1).1–3 existence similar subunits contiguous stereogenic atoms within these molecules is great interest organic synthetic chemists. After preparation structure validation through total synthesis,4–7 aspect asymmetric catalysis intricate selectively as HPI-type has received widespread attention over last decade. Generally, focus difficulty catalytic approaches construction sterically hindered all-carbon at C3a C3a? positions, where C3a–C3a? bond weak, according length determined X-ray structural analysis.8–11 existed examples usually involved reactions using oxindole derivatives starting materials.12–16 Although various investigators earlier reported alkylation 3-hydroxyoxindoles related materials,12–15 well an indoles isatylidene-3-acetaldehydes16 enable formation one-quaternary-centered derivatives, several steps were required achieve bisoxindole units. enantioselective synthesis HPIs from tryptamine provided alternative route assembling dimeric polyoligomers HPIs.17–21 Noteworthily, direct stereocentered bisoxindoles cyclotryptamine arose use homo-bisoxindole A–C 1). included double Michael N-Boc-protected A initiated Kanai Matsunaga’s group,22 homo/hetero dialkylation Tu’s group,23 Pd-catalyzed decarboxylative allylic (Pd-DAAA) dienol dicarbonate B Trost’s group,24 allylation ester-bearing meso-precursor C Bisai’s group.25,26 Scheme 1 | Representative strategies products. 3a,3a?-bispyrrolidino[2,3-b]indoline embedded core unit in selected four shown 1, variation N–H or N-methyl substituents pyrrolidine indoline moieties. Despite wonderful pioneering novel systems, limitation exists regarding acquisition diastereoselectivity heterologous N-substitution key 3,3?-bisoxindole synthons. We envisioned that it would be appealing develop versatile readily available compounds both N-protection groups facilitate concise homo- hetero-HPI alkaloids. Herein, we developed entirely new centers two types series hetero 3,3?-disubstituted single protective group obtained yield enantioselectivities 92% yield, >19?1 dr, 99% ee). Upon simple modification, syntheses hetero- home-dimers HPI product accessible. Experimental Methods General procedure coupling 2a conducted Ni(BF4)2·6H2O (3.4 mg, 0.01 mmol, 10 mol%), L3-PiPr2 (6.5 3-bromo-3-methyl (22.5 0.10 mmol) tetrahydrofuran (THF; 1.0 mL). mixture stirred 35 °C 30 min. (0.15 tripropylamine (nPr3 N, 23 µL, 0.12 1.2 equiv) added, resulting 50 air until complete conversion crude 3, detected thin-layer chromatography (TLC) (24–72 h). subjected column on silica gel eluted petroleum ether:ethyl acetate = 3?1 afford corresponding pure 3. 1b 2b–2p MgBr2·Et2O (2.6 L3-PiEt3 (7.2 0.011 11 3-bromo-3-substituted 2 (0.10 THF (0.5 concentrating vacuo, (45.8 0.15 mmol), K3PO4 (25.5 equiv), 1,2-dichloromethane (DCM; mL) added. 20 (24–48 h), (TLC). then 4?1 Results Discussion hetero-coupling units based o-azaxylylene, 3-halooxindoles 2, assistance base.27–35 Racemic moderate poor presence either inorganic base. As described 1a 3-bromo-3-methyloxindole model substrates show efficiency route. Feng’s N,N’-dioxide–metal complex catalysts used control stereoselectivity view their performance reactions.36–42 An initial exploration showed performed well, adapting nickel N,N’-dioxide L3-PiPr2, demonstrated promising catalyst silyl ketene imines indol-2-one species previous report.43 High DCE THF, but reactivity slightly increased higher temperature THF. desired hetero-3-acetate-3?-methyl-substituted 3aa isolated 88% 95?5 95% ee 2). Following optimized condition, first evaluated scope different (Table found ester had slight effect reaction, affording excellent results 3ba?3da (80–92% 19?1 92–97% When 3-benzyl-substituted used, dropped little, major diastereomer 3ea (80% 10?1 dr). 3-methyl-containing gave 3,3?-dimethyl 3fa 76% 9?1 equally each (90% 91% after reduced °C. electron-donating electron-withdrawing backbone no noticeable reaction. 3ga? 3na yields dr values (59–91% 87–95% 3-acetate chloro-substituent positions yielded 3ga– 3ia satisfactory lower temperature. Besides, diastereoisomers hetero-bisoxindoles 3 separated chromatography, absolute configuration confirmed (3 R,3?R) crystal diffraction analysis (see supporting crystallographic data 3aa). These free charge Cambridge Crystallographic Data Center (CCDC 2009509). 3aa. Table 1. Substrate Scope N-Boc-Protected Oxindolesa aUnless otherwise noted, 1a–1n (1.5 (nPr3N, L3-PiPr2/Ni(BF4)2·6H2O (10 mol%, 1?1) (1.0 atmosphere 24 h. high-performance liquid (HPLC) stationary phase, 1H NMR bAt 40 72 cIn 16 dAt Exposure 3-bromo-3-benzoyloxindole 2b system consisting Ni(BF4)2·6H2O, nPr3 N led outcome ( 3bb, 57% 90?10 30% ee; see Supporting information S5). Next, investigated critical electrophilic 3-benzoyloxindole methyl 3-acetate-substituted 3). improved 83% if metal precursor. Finally, established 2,4,6-triethylaniline delivered hetero-bisoxindole 3bb 66% (1.2 base DCM atmosphere. (79?21 dr), observed diastereoisomer (94/95% 3bb. Further, magnesium L3-PiEt3/MgBr2·Et2O, applied wide range 3-substituted-3-bromooxindoles coupled 3bc– 3bp could most cases. diastereoselectivities decreased (2.3?1–9?1 dr) enhancing steric hindrance 3-substituent 3bc, 3be vs. 3bd, 3bh). Notably, 3-allyl 3-acetate-substituted-3-bromooxindoles also amenable 3bf (93–96% ee), which played roles Moreover, other aryl heteroaromatic groups, including thienyl, furyl, 1-naphthyl 3bg, 3bi, 3bj). Also, employed 3-benzyl-3-bromooxindoles, containing benzyl moiety, afforded 3bl– bp) decent (95–99%), reasonable (52–61%), (3?1–19?1). 3-Bromooxindolesa L3-PiEt3/MgBr2·Et2O 1.1?1) HPLC bThe L3-PiPr2/Sc(OTf)3 1.1?1), 18 scalable allowed ready production gram 3-acetate-3?-vinyl 8?1 94/98% diastereomers 4). elegant (?)-chimonanthidine N,N?-Boc-protected analogues23 along methods groups,24,25 enantiomeric alkaloids, (+)-chimonanthidine further methylated (+)-folicanthine feasible. importantly, heterodimeric characterized one N-protective implied more possibilities N–H-based For instance, optically enriched 3bf. determination via its such 6 needed particular notice because easy crystallization racemic compound solvents. derivative 7 (3R,3?R) careful contained 7. CCDC deposition 2012382). Thus, methylation (3R,3?R)- (>19?1 93% ee, chromatography) following deprotection substituted 4 another protected heterobisoxindole 5 90% yield. building block diol-intermediate effciently (79% yield) reducing LiBH4, maintained enantioselectivity, converted (+)-calycanthidine three steps, reports Overman’s group.44–46 chimonanthine follow N-Bn introduced diol, removed final step. In addition, been polypyrrolidinoindoline (+)-idiospermuline steps.45,46 result, selective protection reactions. Gram scale-up formal (+)-chimonanthidine, (+)-calycanthidine, related. stereocontrol considered studies structures47,48 process. attack (Figure 1) generating isomers suggested. base, partner o-azaxylylene 3-bromooxindole might activated cation salt. 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