Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul 29;24(29):5444-5449.
doi: 10.1021/acs.orglett.2c02170. Epub 2022 Jul 18.

Isothiourea-Catalyzed [2 + 2] Cycloaddition of C(1)-Ammonium Enolates and N-Alkyl Isatins

Yusra Abdelhamid  1 , Kevin Kasten  1 , Joanne Dunne  1 , Will C Hartley  1 , Claire M Young  1 , David B Cordes  1 , Alexandra M Z Slawin  1 , Sean Ng  2 , Andrew D Smith
Affiliations

Isothiourea-Catalyzed [2 + 2] Cycloaddition of C(1)-Ammonium Enolates and N-Alkyl Isatins

Yusra Abdelhamid et al. Org Lett. .

Abstract

Enantioselective [2 + 2] cycloaddition of C(1)-ammonium enolates generated catalytically using the isothiourea HyperBTM with N-alkyl isatins gives spirocyclic β-lactones. In situ ring opening with an amine nucleophile generates isolable highly enantioenriched products in up to 92:8 dr and in >99:1 er.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Tertiary Amine-Catalyzed β-Lactone Syntheses: (a) Romo’s NCAL Intramolecular β-Lactone Synthesis; (b) Previous Work: β-Lactone Synthesis with Perfluoroalkyl Ketones; (c) This Work: β-Lactone Synthesis with Isatins Followed by Ring Opening
Scheme 2
Scheme 2. Optimization and β-Lactone Epimerization
Yield of isolated products. Reported er of major diastereoisomer (er always >99:1 for minor diastereoisomer). 1H NMR of the crude reaction product was used to determine dr. (b) 30 min reaction time before addition of amine; (c) 3 h reaction time before addition of amine.
Figure 1
Figure 1
Scope of the reaction. Combined yield of isolated diastereoisomers. Reported er of major diastereoisomer. Reaction performed on 0.40 mmol scale under air atmosphere. 1H NMR of the crude reaction product used to determine dr. a(2S,3R)-HyperBTM used, product has opposite absolute configuration to that shown.
Figure 2
Figure 2
Proposed catalytic cycle for the intermolecular [2 + 2] cycloaddition to form β-lactones.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. For selected reviews, see:

    2. Mukherjee S.; Biju A. Recent advances in the organocatalytic enantioselective synthesis of functionalized β-lactones. Chem.—Asian J. 2018, 13, 2333.10.1002/asia.201800902. - DOI - PubMed
    3. Romo D.; Tennyson R. L.; Wang Y. β-Lactones as intermediates for natural product total synthesis and new transformations. Heterocycles 2004, 64, 605–658. 10.3987/REV-04-SR(P)3. - DOI

    1. For selected examples see;

    2. Pommier A.; Pons J.-M. The synthesis of natural 2-oxetanones. Synthesis 1995, 1995, 729–744. 10.1055/s-1995-4011. - DOI
    3. Lowe C.; Vederas J. C. Naturally occurring β-lactones: Occurrence, syntheses and properties. A review. Org. Prep. Proced. Int. 1995, 27, 305–346. 10.1080/00304949509458466. - DOI
    4. Yang H. W.; Romo D. Methods for the synthesis of optically active β-lactones. Tetrahedron 1999, 55, 6403–6434. 10.1016/S0040-4020(99)00185-4. - DOI
    5. Böttcher T.; Sieber S. A. β-Lactams and β-lactones as activity-based probes in chemical biology. Med. Chem. Comm. 2012, 3, 408–417. 10.1039/c2md00275b. - DOI

    1. For reviews see:

    2. Schneider C. Catalytic, enantioselective syntheses of β-lactones-versatile synthetic building blocks in organic chemistry. Angew. Chem., Int. Ed. 2002, 41, 744–746. 10.1002/1521-3773(20020301)41:5<744::AID-ANIE744>3.0.CO;2-V. - DOI - PubMed
    3. Douglas J.; Morrill L. C.; Richmond E.; Smith A. D. In Methods and Applications of Cycloaddition Reactions in Organic Syntheses; Nishiwaki N., Ed.; Wiley: Hoboken NJ, 2014; ch. 3, pp 89–114.
    4. Van K. N.; Morrill L. C.; Smith A. D.; Romo D. In Lewis Base Catalysis in Organic Synthesis; Vedejs E., Denmark S. E., Eds.; Wiley-VCH: Weinheim, 2016; Vol. 2, ch. 13, pp 527–653.
    1. Wynberg H.; Staring E. G. J. Asymmetric synthesis of (S)- and (R)-malic acid from ketene and chloral. J. Am. Chem. Soc. 1982, 104, 166–168. 10.1021/ja00365a030. - DOI
    2. Wynberg H.; Staring E. G. J. Catalytic asymmetric synthesis of chiral 4-substituted oxetanones. J. Org. Chem. 1985, 50, 1977–1979. 10.1021/jo00211a039. - DOI
    3. Wynberg H.; Staring E. G. J. The absolute configuration of 4-(trichloromethyl)oxetan-2-one; a case of double anchimeric assistance with inversion. J. Chem. Soc., Chem. Commun. 1984, 1181–1182. 10.1039/c39840001181. - DOI
    4. Calter M. A. J. Org. Chem. 1996, 61, 8006–8007. 10.1021/jo961721c. - DOI - PubMed
    5. Tennyson R.; Romo D. Use of In Situ Generated Ketene in the Wynberg β-Lactone Synthesis: New Transformations of the Dichlorinated β-Lactone Products. J. Org. Chem. 2000, 65, 7248–7252. 10.1021/jo001010l. - DOI - PubMed
    6. Calter M. A.; Orr R. K.; Song W. Org. Lett. 2003, 5, 4745–4748. 10.1021/ol0359517. - DOI - PubMed
    7. Zhu C.; Shen X.; Nelson S. G. J. Am. Chem. Soc. 2004, 126, 5352–5353. 10.1021/ja0492900. - DOI - PubMed
    8. Calter M. A.; Tretyak O. A.; Flaschenriem C. Org. Lett. 2005, 7, 1809–1812. 10.1021/ol050411q. - DOI - PubMed
    9. Green M. E.; Rech J. C.; Floreancig P. E. Angew. Chem., Int. Ed. 2008, 47, 7317–7320. 10.1002/anie.200802548. - DOI - PMC - PubMed
    10. Jiang X.; Fu C.; Ma S. Chem.—Eur. J. 2008, 14, 9656–9664. 10.1002/chem.200801363. - DOI - PubMed
    11. Chandra B.; Fu D.; Nelson S. G. Angew. Chem., Int. Ed. 2010, 49, 2591–2594. 10.1002/anie.200906245. - DOI - PubMed
    12. Vargo T. R.; Hale J. S.; Nelson S. G. Angew. Chem., Int. Ed. 2010, 49, 8678–8681. 10.1002/anie.201004925. - DOI - PubMed
    13. Wan S.; Wu F.; Rech J. C.; Green M. E.; Balachandran R.; Horne W. S.; Day B. W.; Floreancig P. E. J. Am. Chem. Soc. 2011, 133, 16668–16679. 10.1021/ja207331m. - DOI - PubMed
    1. Wilson J. E.; Fu G. C. Asymmetric synthesis of highly substituted β-lactones by nucleophile-catalyzed [2 + 2] cycloadditions of disubstituted ketenes with aldehydes. Angew. Chem., Int. Ed. 2004, 43, 6358–6360. 10.1002/anie.200460698. - DOI - PubMed
    2. Zhu C.; Shen X.; Nelson S. G. Cinchona alkaloid-lewis acid catalyst systems for enantioselective ketene–aldehyde cycloadditions. J. Am. Chem. Soc. 2004, 126, 5352–5353. 10.1021/ja0492900. - DOI - PubMed

    3. For a selected NHC-catalyzed process, see:

    4. He L.; Lv H.; Zhang Y.; Ye S. Formal cycloaddition of disubstituted ketenes with 2-oxoaldehydes catalyzed by chiral N-heterocyclic carbenes. J. Org. Chem. 2008, 73, 8101–8103. 10.1021/jo801494f. - DOI - PubMed
    5. Douglas J.; Taylor J. E.; Churchill G.; Slawin A. M. Z.; Smith A. D. NHC-Promoted asymmetric β-lactone formation from arylalkylketenes and electron-deficient benzaldehydes or pyridinecarboxaldehydes. J. Org. Chem. 2013, 78, 3925–3938. 10.1021/jo4003079. - DOI - PubMed
    6. Davies A. T.; Slawin A. M. Z.; Smith A. D. Enantioselective NHC-Catalyzed Redox [2 + 2] Cycloadditions with Perfluoroketones; A Route to Fluorinated Oxetanes. Chem.—Eur. J. 2015, 21, 18944–18948. 10.1002/chem.201504256. - DOI - PubMed

Publication types