Diastereoselective Synthesis of -Methylspiroindolines by Intramolecular Mizoroki-Heck Annulations

Overview

Journal ACS Omega

Publisher American Chemical Society

Specialty Chemistry

Date 2022 Sep 19

PMID 36120037

Authors

Jens Lindman

Greeshma Gopalan

Carlos Palo-Nieto

Peter Brandt

Johan Gising

Mats Larhed

Affiliations

Soon will be listed here.

Abstract

Spiroindolines represent a privileged structure in medicinal chemistry, although stereocontrol around the spirocarbon can be a synthetic challenge. Here we present a palladium(0)-catalyzed intramolecular Mizoroki-Heck annulation reaction from ()-Vince lactam-derived cyclopentenyl-tethered 2-bromo--methylanilines for the formation of -methylspiroindolines. A series of 14 -methylspiroindolines were synthesized in 59-81% yield with diastereoselectivity >98%, which was rationalized by density functional theory calculations and confirmed through X-ray crystallography. One spiroindoline was converted to an N- and C-terminal protected rigidified unnatural amino acid, which could be orthogonally deprotected.

Citing Articles

Two-Chamber Aminocarbonylation of Aryl Bromides and Triflates Using Amino Acids as Nucleophiles.

Lindman J, Yadav A, Gising J, Larhed M J Org Chem. 2023; 88(18):12978-12985.

PMID: 37639573 PMC: 10507664. DOI: 10.1021/acs.joc.3c00972.

References

Kumar A, Vachhani D, Modha S, Sharma S, Parmar V, Van der Eycken E . Post-Ugi gold-catalyzed diastereoselective domino cyclization for the synthesis of diversely substituted spiroindolines. Beilstein J Org Chem. 2013; 9:2097-102. PMC: 3817510. DOI: 10.3762/bjoc.9.246. View

Xia Z, Zheng C, Wang S, You S . Catalytic Asymmetric Dearomatization of Indolyl Dihydropyridines through an Enamine Isomerization/Spirocyclization/Transfer Hydrogenation Sequence. Angew Chem Int Ed Engl. 2018; 57(10):2653-2656. DOI: 10.1002/anie.201712435. View

Adeyemi A, Odell L, Larhed M . Regio- and Stereoselective Synthesis of Allylic Spiroethers (Spirobenzofuranes) via an Intramolecular Mizoroki-Heck Reaction. J Org Chem. 2020; 85(12):7648-7657. DOI: 10.1021/acs.joc.9b03329. View

Qiao J, Wang T, Ruel R, Thibeault C, LHeureux A, Schumacher W . Conformationally constrained ortho-anilino diaryl ureas: discovery of 1-(2-(1'-neopentylspiro[indoline-3,4'-piperidine]-1-yl)phenyl)-3-(4-(trifluoromethoxy)phenyl)urea, a potent, selective, and bioavailable P2Y1 antagonist. J Med Chem. 2013; 56(22):9275-95. DOI: 10.1021/jm4013906. View

Narancic T, Almahboub S, OConnor K . Unnatural amino acids: production and biotechnological potential. World J Microbiol Biotechnol. 2019; 35(4):67. DOI: 10.1007/s11274-019-2642-9. View

Wetzel A, Bergman J, Brandt P, Larhed M, Branalt J . Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki-Heck Reactions. Org Lett. 2017; 19(7):1602-1605. DOI: 10.1021/acs.orglett.7b00325. View

Desrosiers J, Hie L, Biswas S, Zatolochnaya O, Rodriguez S, Lee H . Construction of Quaternary Stereocenters by Nickel-Catalyzed Heck Cyclization Reactions. Angew Chem Int Ed Engl. 2016; 55(39):11921-4. DOI: 10.1002/anie.201606955. View

Xu Z, Li S, Meng J, Tang D, He L, Lei J . Functionalized Spiroindolines with Anticancer Activity through a Metal-Free Post-Ugi Diastereoselective One-Pot Cascade Reaction. Chemistry. 2018; 24(26):6732-6736. PMC: 6042644. DOI: 10.1002/chem.201801081. View

Pan Z, Liu Y, Hu F, Liu Q, Shang W, Ji X . Enantioselective Synthesis of Spiroindolines via Cascade Isomerization/Spirocyclization/Dearomatization Reaction. Org Lett. 2020; 22(4):1589-1593. DOI: 10.1021/acs.orglett.0c00181. View

10.

Brindisi M, Senger J, Cavella C, Grillo A, Chemi G, Gemma S . Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies. Eur J Med Chem. 2018; 157:127-138. DOI: 10.1016/j.ejmech.2018.07.069. View

11.

Georgsson J, Hallberg A, Larhed M . Rapid palladium-catalyzed synthesis of esters from aryl halides utilizing Mo(CO)(6) as a solid carbon monoxide source. J Comb Chem. 2003; 5(4):350-2. DOI: 10.1021/cc0201086. View

12.

Saraswati A, Relitti N, Brindisi M, Osko J, Chemi G, Federico S . Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation. ACS Med Chem Lett. 2020; 11(11):2268-2276. PMC: 7667836. DOI: 10.1021/acsmedchemlett.0c00395. View

13.

Lindemann M, Deuther-Conrad W, Moldovan R, Sekhar K, Brust P, Wenzel B . Do spiroindolines have the potential to replace vesamicol as lead compound for the development of radioligands targeting the vesicular acetylcholine transporter?. Bioorg Med Chem. 2017; 25(19):5107-5113. DOI: 10.1016/j.bmc.2017.03.028. View

14.

Walia A, Kang S, Silverman R . Microwave-assisted protection of primary amines as 2,5-dimethylpyrroles and their orthogonal deprotection. J Org Chem. 2013; 78(21):10931-7. PMC: 3850750. DOI: 10.1021/jo401778e. View

15.

Yang S, Ho G, Tulshian D, Greenlee W, Fernandez X, McLeod R . Structure-activity relationships of 3-substituted N-benzhydryl-nortropane analogs as nociceptin receptor ligands for the treatment of cough. Bioorg Med Chem Lett. 2008; 18(24):6340-3. DOI: 10.1016/j.bmcl.2008.10.088. View

16.

Singh R, Vince R . 2-Azabicyclo[2.2.1]hept-5-en-3-one: chemical profile of a versatile synthetic building block and its impact on the development of therapeutics. Chem Rev. 2012; 112(8):4642-86. DOI: 10.1021/cr2004822. View

17.

Nordeman P, Odell L, Larhed M . Aminocarbonylations employing Mo(CO)6 and a bridged two-vial system: allowing the use of nitro group substituted aryl iodides and aryl bromides. J Org Chem. 2012; 77(24):11393-8. DOI: 10.1021/jo302322w. View

18.

Ravn A, Johansen M, Skrydstrup T . Controlled Release of Reactive Gases: A Tale of Taming Carbon Monoxide. Chempluschem. 2020; 85(7):1529-1533. DOI: 10.1002/cplu.202000319. View

19.

Bhonsle J, Clark T, Bartolotti L, Hicks R . A brief overview of antimicrobial peptides containing unnatural amino acids and ligand-based approaches for peptide ligands. Curr Top Med Chem. 2013; 13(24):3205-24. DOI: 10.2174/15680266113136660226. View

20.

Wu K, Dai L, You S . Palladium(0)-catalyzed dearomative arylation of indoles: convenient access to spiroindolenine derivatives. Org Lett. 2012; 14(14):3772-5. DOI: 10.1021/ol301663h. View