CoChat
Sign Up
Cited by 34Asymmetric Synthesis and CatalysisN-Heterocyclic Carbenes in Organic and Inorganic ChemistrySynthesis of β-Lactam Compounds

Enantioselective Synthesis of Tricyclic β-Lactones by NHC-Catalyzed Desymmetrization of Cyclic 1,3-Diketones

Open access
Shee, Sayan, Mukherjee, Subrata, Gonnade, Rajesh G., Biju, Akkattu T.·2020·Organic Letters
DOI 10.1021/acs.orglett.0c01756
Open this paper in CoChat — free accountOpen PDF

Abstract

The NHC-catalyzed desymmetrization of cyclic-1,3-diketones allowing the enantioselective construction of tricyclic β-lactones with five contiguous stereocenters, including two quaternary stereocenters, has been developed. The mild and operationally simple addition of α-bromoenals to cyclopentane-1,3-diketone derivatives proceeds via the initial formation of chiral α,β-unsaturated acylazolium intermediates and culminates in a cascade reaction, following the Michael-aldol-lactonization pathway to deliver the β-lactone derivatives in moderate to good yields and excellent selectivity.

AI snapshot

Written from the paper’s full text.

TL;DR

An NHC-catalyzed desymmetrization of cyclic 1,3-diketones with 2-bromoenals delivers tricyclic β-lactones in high diastereo- and enantioselectivity. Optimized conditions (triazolium salt 4, Na2CO3, LiOAc, 4 Å MS, CHCl3, 25 °C, 48 h) give up to 65% yield with >20:1 dr and >99% ee.

Key findings

  • Optimization of the model reaction (1a + 2a) identified the best conditions as triazolium salt 4 (10 mol%), Na2CO3 (3.2 equiv), 20 mol% LiOAc, 4 Å MS, CHCl3 (3 mL), 25 °C, 48 h, giving 65% yield, >20:1 dr, >99% ee (entry 35); the same conditions without LiOAc/MS gave 54% yield and 5:1 dr (entry 23).
  • The substrate scope generally afforded >99% ee with yields ranging from 38% (3t) to 71% (3i); a few substrates were lower (3h 86% ee, 3d 90% ee, 3q 96% ee, 3r 98% ee, 3w 98% ee).
  • X-ray crystallography of 3a established the absolute configuration as S, R, R, R and R at C1, C2, C4, C5 and C6, with a Flack parameter of 0.05(3).
  • A 1.0 mmol scale reaction of 3a gave 61% yield, >99% ee and >20:1 dr; ring-opening/functionalization gave 7 (94% yield), amide 8 (84% yield) and enone 9 (87% yield).

Methods

  • Optimization screening of the model reaction between 2-bromocinnamaldehyde 1a and 2-methyl-2-(2-nitroethyl)cyclopentane-1,3-dione 2a, varying NHC precatalyst, base, solvent, temperature, stoichiometry and additives; yields determined by ¹H NMR with CH2Br2 internal standard, dr by ¹H NMR, ee by chiral HPLC.
  • General enantioselective procedure: diketone 2 (0.25 mmol), 2-bromoenal 1 (0.5 mmol), triazolium salt 4 (10 mol%), LiOAc (0.05 mmol), 4 Å MS (100 mg), Na2CO3 (0.8 mmol), CHCl3 (3 mL), 25 °C (or 50 °C for some substrates), 48 h; products purified by flash chromatography and characterized by NMR, HRMS, FTIR, optical rotation and chiral HPLC.
  • Single-crystal X-ray diffraction of 3a (Cu Kα, 100 K, chiral space group P2₁) used to assign absolute configuration; racemic standards prepared with N-mesityl triazolium-derived carbene.

Limitations

  • Not stated in the paper (the provided text is the Supporting Information and contains no explicit limitations section).
  • Evident from the data: several substrates required elevated temperature (50 °C) and gave modest yields (38–51%, e.g. 3t, 3u, 3v, 3w, 3x), and a few products showed reduced enantioselectivity (86–98% ee for 3h, 3d, 3q, 3r, 3w), indicating the scope is not uniformly high-yielding or highly selective.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1021/acs.orglett.0c01756

Cites

73 of 73 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

  • Findingown data

    Compound 3x was obtained in 45% yield.

    “afforded (2aR,3S,4R,5aR,8aR)-5a-cinnamyl--3-phenylhexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione (3x) as a white solid (47 mg, 45% yield).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Compound 3w was obtained with 98% enantiomeric excess.

    “ee = 98%”
    Quote in the paperSubstantial claim
  • Findingown data

    Compound 3y was obtained in 60% yield.

    “afforded (2aR,3S,4R,5aR,8aR)-5a-methyl-4-nitro-3phenyl-3,4,5,5a-tetrahydro-2H-indeno [3a,4-b]oxete-2,6(2aH)-dione 3y as a white solid (47 mg, 60% yield).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Compound 3s was obtained in 42% yield.

    “afforded(2aR,3S,4R,5aR,8aR)-5a-methyl-4-nitro-3-(thiophen-3-yl)hexahydro-2H-indeno [3a,4-b]oxete-2,6(2aH)-dione 3s as a colorless solid (33 mg, 42% yield).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Compound 7 was obtained in 94% yield.

    “afforded methyl(3aR,4R,5S,6R,7aR)-3a-hydroxy-7a-methyl-6-nitro-1-oxo-5phenyloctahydro-1H-indene-4-carboxylate 7as a yellow solid (65 mg, 94% yield).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 14
  • May combine two claims. 11
  • The quote only partly states this claim. 10

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingnone given

    Compound 3v was obtained with >99% enantiomeric excess.

    “ee = >99%”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Compound 3u was obtained in 40% yield.

    “afforded (2aR,3S,4R,5aR,8aR)-5a-(4-methoxybenzyl)-4-nitro-3-phenylhexahydro-2H-indeno[3a,4b]oxete-2,6(2aH)-dione 3u as a white solid (42 mg, 40% yield).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingnone given

    Compound 3z was obtained with >99% enantiomeric excess.

    “ee = >99%”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    3j was obtained in 65% yield with >99% ee.

    “afforded (2aR,3S,4R,5aR,8aR)-5a-methyl-4-nitro-3-(o-tolyl)hexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione 3j as a colorless solid (54 mg, 65% yield).”
    • Also stated in: § 2-Methyl-2-(2-nitroethyl)-1H-indene-1,3(2H)-dione (2z) · plain
      “ee = >99%”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    3i was obtained in 71% yield with >99% ee.

    “afforded (2aR,3S,4R,5aR,8aR)-3-(2-methoxyphenyl)-5a-methyl-4-nitrohexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione 3i as a yellow solid (62 mg, 71% yield).”
    • Also stated in: § 2-Methyl-2-(2-nitroethyl)-1H-indene-1,3(2H)-dione (2z) · plain
      “ee = >99%”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    3o was obtained in 53% yield with >99% ee.

    “afforded(2aR,3S,4R,5aR,8aR)-3-(3-bromo-4methoxyphenyl)-5a-methyl-4-nitrohexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione 3o as a yellow solid ( 56.3 mg, 53% yield).”
    • Also stated in: § 2-Methyl-2-(2-nitroethyl)-1H-indene-1,3(2H)-dione (2z) · plain
      “ee = >99%”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Using 20 mol% LiOAc as additive under the modified conditions (entry 30) gives 59% yield, >20:1 dr, and >99% ee.

    “30 g 20 mol% LiOAc as additive 59 >20:1 >99”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    3k was obtained in 45% yield with >99% ee.

    “afforded(2aR,3S,4R,5aR,8aR)-3-(2-fluorophenyl)-5a-methyl-4nitrohexahydro-2H-indeno [3a,4-b]oxete-2,6(2aH)-dione 3k as a white solid (35 mg, 45% yield).”
    • Also stated in: § 2-Methyl-2-(2-nitroethyl)-1H-indene-1,3(2H)-dione (2z) · plain
      “ee = >99%”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Compound 8 was obtained in 84% yield.

    “afford the (3aR,4R,5S,6R,7aR)-N-benzyl-3a-hydroxy-7a-methyl-6-nitro-1-oxo-5-phenyloctahydro-1Hindene-4-carboxamide (8) as a yellow solid (44.3 mg, 84% yield).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Compound 3w was obtained in 40% yield.

    “afforded(2aR,3S,4R,5aS,8aR)-5a-(furan-2-ylmethyl)-4-nitro-3-phenylhexahydro-2H indeno [3a,4-b]oxete-2,6(2aH)-dione 3w as a white solid (38 mg, 40% yield).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Compound 3h was obtained in 46% yield.

    “afforded (2aR,3S,4R,5aR,8aR)-5a-methyl-4nitro-3-(4-(trifluoromethyl)phenyl)hexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione 3h as a colorless solid (44 mg, 46% yield).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingnone given

    Compound 3u was obtained with >99% enantiomeric excess.

    “ee = >99%”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Using 20 mol% LiOAc and 4 Å MS as additive (entry 35) gives 65% yield, >20:1 dr, and >99% ee.

    “35 g 20 mol % LiOAc, & 4 Å MS as additive 65 >20:1 >99”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Compound 7 was obtained with >99% enantiomeric excess.

    “ee = >99%”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Using 20 mol% LiOAc and 4 Å MS as additive (entry 32) gives 61% yield, >20:1 dr, and >99% ee.

    “32 g 20 mol% LiOAc & 4 Å MS as additive 61 >20:1 >99”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Compound 3t was obtained in 38% yield.

    “afforded (2aR,3S,4R,5aR,8aR)-5a-benzyl-4-nitro-3-phenylhexahydro-2H-indeno[3a,4b]oxete-2,6(2aH)-dione 3t as a white solid (37 mg, 38% yield).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    3q was obtained in 52% yield with 96% ee.

    “afforded (2aR,3R,4R,5aR,8aR)-3-(furan-2-yl)-5a-methyl-4-nitrohexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione 3q as a white solid (40 mg, 52% yield).”
    • Also stated in: § (2aR,3S,4R,5aR,8aR)-3-(3-Bromo-4-methoxyphenyl)-5a-methyl-4-nitrohexahydro-2Hindeno[3a,4-b]oxete-2,6(2aH)-dione (3o) · plain
      “ee = 96%”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    2-(4-Nitrobenzyl)-2-(2-nitroethyl)cyclopentane-1,3-dione (2v) was obtained in 70% yield.

    “afforded 2-(4-nitrobenzyl)-2-(2-nitroethyl)cyclopentane-1,3-dione 2v as a yellow solid (302 mg, 70% yield).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Compound 3z was obtained in 55% yield.

    “afforded methyl (2R,3S,4R,4aS,9aR)-4a-hydroxy-9a-methyl-2-nitro-9-oxo-3-phenyl-2,3,4,4a,9, 9a-hexahydro-1H-fluorene-4-carboxylate 3z as a white solid (54 mg, 55% yield).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingnone given

    Compound 3f was obtained with >99% enantiomeric excess.

    “ee = >99%”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Compound 3r was obtained in 45% yield.

    “afforded (2aR,3R,4R,5aR,8aR)-5a-methyl-4-nitro-3-(thiophen-2-yl)hexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione 3r as a white solid (37 mg, 45% yield).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Under standard conditions (1a 0.25 mmol, 2a 0.25 mmol, 4 10 mol%, Na2CO3 2.2 equiv, CHCl3 2.0 mL, 25 °C, 12 h), the reaction gives 35% yield, 4:1 dr, and 96% ee.

    “1 none 35 4:1 96”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingnone given

    Compound 3y was obtained with >99% enantiomeric excess.

    “ee = >99%”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    3n was obtained in 46% yield with >99% ee.

    “afforded (2aR,3S,4R,5aR,8aR)-3-(3,4-dichloro phenyl)-5a-methyl-4-nitrohexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione 3n as a yellow solid (44 mg, 46% yield).”
    • Also stated in: § 2-Methyl-2-(2-nitroethyl)-1H-indene-1,3(2H)-dione (2z) · plain
      “ee = >99%”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Compound 3m was obtained in 44% yield.

    “afforded (2aR,3S,4R,5aR,8aR)-3-(3-chlorophenyl)-5a-methyl-4-nitrohexahydro-2H-indeno[3a,4-b]oxete-2,6(2aH)-dione 3m as a white solid (38 mg, 44% yield).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Compound 9 was obtained with >99% enantiomeric excess.

    “ee = >99%”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    3l was obtained in 51% yield with >99% ee.

    “ee = >99%”
    Quote in the paperNot a substantial claim
27 of 27

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The proton count reported for 2y falls short of its formula

    Minor

    The listed 1H NMR integrations total eight hydrogens, including a two-hydrogen methyl singlet, whereas the stated formula contains nine hydrogens.

  • The bromoenal for compound 3l is labeled as a diketone-series compound

    Minor

    The 3l procedure calls its bromoenal "2l," although the general procedure assigns the 1 series to bromoenals and the 2 series to cyclopentane-1,3-dione derivatives.

  • Compound 3j's stated mass-spectrometry adduct conflicts with its formula

    Minor

    The peak is labeled as a sodium adduct, but the stated calculated formula contains potassium (K) rather than sodium (Na).

3 of 3

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. 10.3762/bjoc.12.47 · DOI
  2. 10.1055/s-0034-1378692 · DOI

Cited by

Sorted by citations

Related

Authors
Shee, S., Mukherjee, S., Gonnade, R. G., & Biju, A. T.
Affiliations
  • Indian Institute of Science Bangalore (IN)
  • National Chemical Laboratory (IN)
Corresponding author
Biju, Akkattu T.
ORCID
Venue
Organic Letters
Publisher
American Chemical Society (ACS)
Published
2020-07-01
Volume
22
Issue
14
Pages
5407-5411
ISSN
  • 1523-7052 (ISSN-L)
  • 1523-7060
DOI
10.1021/acs.orglett.0c01756
OpenAlex
W3039364618
Semantic Scholar
d878ec335328bcd21ca59186e5e463fdea6138dc
Cited by
34
References
72
Citations by year
2025: 3 · 2024: 7 · 2023: 4 · 2022: 6 · 2021: 12 · 2020: 2
FWCI
2.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Organic Letters (publishedVersion)
  • PubMed (publishedVersion)
  • NOT FOUND REPOSITORY (Indian Institute of Science Bangalore) (submittedVersion)
Funders
  • Science and Engineering Research Board (EMR/2016/007021)
  • Indian Institute of Science
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Asymmetric Synthesis and Catalysis
  • Physical Sciences › Chemistry › Organic Chemistry › N-Heterocyclic Carbenes in Organic and Inorganic Chemistry
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis of β-Lactam Compounds
Keywords
asymmetric synthesis, N-heterocyclic carbene catalysis, desymmetrization, cyclic 1,3-diketones, cascade reactions, quaternary stereocenters, contiguous stereocenters

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review