Rapid assembly of complex cyclopentanes employing chiral, α,β-unsaturated acylammonium intermediates

Journal name:
Nature Chemistry
Year published:
Published online


With the intention of improving synthetic efficiency, organic chemists have turned to bioinspired organocascade or domino processes that generate multiple bonds and stereocentres in a single operation. However, despite the great importance of substituted cyclopentanes, given their prevalence in complex natural products and pharmaceutical agents, the rapid, enantioselective assembly of these carbocycles lags behind cyclohexanes. Here, we describe a Michael–aldol-β-lactonization organocascade process for the synthesis of complex cyclopentanes utilizing chiral α,β-unsaturated acylammonium intermediates, readily generated by activation of commodity unsaturated acid chlorides with chiral isothiourea catalysts. This efficient methodology enables the construction of two C–C bonds, one C–O bond, two rings and up to three contiguous stereogenic centres delivering complex cyclopentanes with high levels of relative and absolute stereocontrol. Our results suggest that α,β-unsaturated acylammonium intermediates have broad utility for the design of organocascade and multicomponent processes, with the latter demonstrated by a Michael–Michael–aldol-β-lactonization.

At a glance


  1. Natural products and pharmaceutical agents bearing complex cyclopentanes and accessible cyclopentyl systems employing the described NCMAL process.
    Figure 1: Natural products and pharmaceutical agents bearing complex cyclopentanes and accessible cyclopentyl systems employing the described NCMAL process.

    a, Bioactive natural products and drugs including polycyclics possessing highly substituted cyclopentane cores (red). b, Natural products possessing β-lactone-fused cyclopentanes and a cyclohexane (red). c, Several diverse cyclopentane scaffolds accessible by the described NCMAL process.

  2. Generation and reactivity of the chiral unsaturated acylammonium 3, with contrast to related chiral intermediates 4–6, and a proposed catalytic cycle leading to bicyclic-β-lactones 14.
    Figure 2: Generation and reactivity of the chiral unsaturated acylammonium 3, with contrast to related chiral intermediates 4–6, and a proposed catalytic cycle leading to bicyclic-β-lactones 14.

    a, Proposed synthesis of α,β-unsaturated acylammonium intermediate 3 from acid chlorides 1 and nucleophilic amines 2. b, Related chiral intermediates include the acylammonium intermediate 4, ammonium enolate 5 and ammonium dienolate 6. c, Latent, triple reactivity of the α,β-unsaturated acylammonium 3 first leads to an ammonium enolate 7 following Michael addition. The latter nucleophilic intermediate leads to α-addition of an electrophile, delivering acylammonium 8, and final acyl substitution leads to overall functionalization of three carbons of an α,β-unsaturated acid halide 1. d, Proposed catalytic cycle employing a latent, triply-reactive species 11, such as the keto anion 10, possessing two nucleophilic sites and one electrophilic site, capable of reaction with unsaturated acylammonium 3 to form three bonds resulting in cyclopentanes 14 bearing a fused β-lactone through a Michael–aldol-lactonization organocascade process.

  3. Rapid molecular complexity generation, structural modifications of cyclopentane products, and extensions of both accessible Michael donors and unsaturated acylammonium intermediates.
    Figure 3: Rapid molecular complexity generation, structural modifications of cyclopentane products, and extensions of both accessible Michael donors and unsaturated acylammonium intermediates.

    All NCMAL reactions were performed under the standard reaction conditions shown in Table 2 unless noted otherwise. ac, Monocyclic Michael donors with acryloyl chloride deliver tricyclic 5,5- and 5,6-fused cyclopentyl systems 14t and 14u (a), bridged tricyclic cyclopentanes (b), truncated steroid intermediates through bis-decarboxylation (c). d, Mild Pd(0)-mediated reductive decarboxylation leads to cyano-substituted cyclopentane 14x. e, Application of aldehyde-containing Michael donors. f, In situ generation of a tosyl anhydride from unsaturated acids provides a useful bicyclic ring annulation procedure. Relative stereochemistry of 14t, 14v, 14x was determined by X-ray analysis (Supplementary Figs 8–10). Insets are single-crystal X-ray structures of 14v and 14x.

  4. Proposed transition-state arrangements to rationalize the stereochemical outcome of the NCMAL and extension to a multicomponent cascade process.
    Figure 4: Proposed transition-state arrangements to rationalize the stereochemical outcome of the NCMAL and extension to a multicomponent cascade process.

    a, Transition-state arrangement rationalizing facial selectivity with respect to both the Michael donor (enolate) and Michael acceptor (α,β-unsaturated acylammonium) during the Michael addition, premised on the X-ray structure of the HBTM-unsaturated acylammonium by Smith38. The rationale for the diastereoselectivity of the aldol step is premised on minimization of A1,3-strain leading to cyclopentane 14 as the only observed product following β-lactonization. b, Development of a Michael–Michael–aldol-β-lactonization multicomponent organocascade employing (S)-benzotetramisole (BTM, 2c), leading to 6,5,4-tricyclic cyclohexane (+)-23. Subsequent ring opening with p-bromobenzylamine delivered crystalline amide 24 (inset, single-crystal X-ray structure, phenyl rings omitted for clarity) enabling stereochemical confirmation.


70 compounds View all compounds
  1. Acryloyl chloride
    Compound 1a Acryloyl chloride
  2. (E)-But-2-enoyl chloride
    Compound 1b (E)-But-2-enoyl chloride
  3. (E)-Ethyl 4-chloro-4-oxobut-2-enoate
    Compound 1c (E)-Ethyl 4-chloro-4-oxobut-2-enoate
  4. Cinnamoyl chloride
    Compound 1d Cinnamoyl chloride
  5. (E)-3-(4-Nitrophenyl)acryloyl chloride
    Compound 1e (E)-3-(4-Nitrophenyl)acryloyl chloride
  6. (E)-3-(4-Methoxyphenyl)acryloyl chloride
    Compound 1f (E)-3-(4-Methoxyphenyl)acryloyl chloride
  7. (2E,4E)-Hexa-2,4-dienoyl chloride
    Compound 1g (2E,4E)-Hexa-2,4-dienoyl chloride
  8. Methacryloyl chloride
    Compound 1h Methacryloyl chloride
  9. (E)-2-Methylbut-2-enoyl chloride
    Compound 1i (E)-2-Methylbut-2-enoyl chloride
  10. (S)-2-Phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine
    Compound 2b (S)-2-Phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine
  11. (S)-2-Phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole
    Compound 2c (S)-2-Phenyl-2,3-dihydrobenzo[d]imidazo[2,1-b]thiazole
  12. Dimethyl 2-(2-oxopropyl)malonate
    Compound 10a Dimethyl 2-(2-oxopropyl)malonate
  13. Di-tert-butyl 2-(2-oxopropyl)malonate
    Compound 10b Di-tert-butyl 2-(2-oxopropyl)malonate
  14. Diallyl 2-(2-oxopropyl)malonate
    Compound 10c Diallyl 2-(2-oxopropyl)malonate
  15. Dibenzyl 2-(2-oxopropyl)malonate
    Compound 10d Dibenzyl 2-(2-oxopropyl)malonate
  16. 3-Acetylhexane-2,5-dione
    Compound 10e 3-Acetylhexane-2,5-dione
  17. 2-(2-Oxopropyl)malononitrile
    Compound 10f 2-(2-Oxopropyl)malononitrile
  18. Methyl 2-acetyl-4-oxopentanoate
    Compound (±)-10g Methyl 2-acetyl-4-oxopentanoate
  19. Methyl 2-cyano-4-oxopentanoate
    Compound (±)-10h Methyl 2-cyano-4-oxopentanoate
  20. Allyl 2-cyano-4-oxopentanoate
    Compound (±)-10i Allyl 2-cyano-4-oxopentanoate
  21. Dimethyl 2-(3-oxobutan-2-yl)malonate
    Compound (±)-10j Dimethyl 2-(3-oxobutan-2-yl)malonate
  22. Dimethyl 2-(2-oxocyclopentyl)malonate
    Compound (±)-10k Dimethyl 2-(2-oxocyclopentyl)malonate
  23. Dimethyl 2-(2-oxocyclohexyl)malonate
    Compound (±)-10l Dimethyl 2-(2-oxocyclohexyl)malonate
  24. Methyl 2,5-dioxocyclohexane-1-carboxylate
    Compound (±)-10m Methyl 2,5-dioxocyclohexane-1-carboxylate
  25. Dimethyl 2-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)malonate
    Compound (±)-10n Dimethyl 2-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)malonate
  26. Diethyl 2-(2-oxoethyl)malonate
    Compound 10o Diethyl 2-(2-oxoethyl)malonate
  27. Dimethyl 2-oxohexahydropentaleno[6a,1-b]oxete-4,4(2H)-dicarboxylate
    Compound (±)-14 Dimethyl 2-oxohexahydropentaleno[6a,1-b]oxete-4,4(2H)-dicarboxylate
  28. Dimethy 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14a Dimethy 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  29. Dimethyl (1S,5R)-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (+)-14a Dimethyl (1S,5R)-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  30. Di-tert-butyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14b Di-tert-butyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  31. Diallyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14c Diallyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  32. (1S,5R)-Diallyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (+)-14c (1S,5R)-Diallyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  33. Dibenzyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14d Dibenzyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  34. (1S,5R)-Dibenzyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (+)-14d (1S,5R)-Dibenzyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  35. 1,1'-(5-Methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-diyl)bis(ethan-1-one)
    Compound (±)-14e 1,1'-(5-Methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-diyl)bis(ethan-1-one)
  36. 1,1'-((1S,5R)-5-Methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-diyl)diethanone
    Compound (+)-14e 1,1'-((1S,5R)-5-Methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-diyl)diethanone
  37. 5-Methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarbonitrile
    Compound (±)-14f 5-Methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarbonitrile
  38. Methyl 3-acetyl-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3-carboxylate
    Compound (±)-14g Methyl 3-acetyl-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3-carboxylate
  39. Allyl 3-cyano-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3-carboxylate
    Compound (±)-14i Allyl 3-cyano-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3-carboxylate
  40. Dimethyl 4,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14j Dimethyl 4,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  41. Dimethyl 2,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14k Dimethyl 2,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  42. Dimethyl (1S,2S,5R)-2,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (+)-14k Dimethyl (1S,2S,5R)-2,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  43. 2-Ethyl 3,3-dimethyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-2,3,3-tricarboxylate
    Compound (±)-14l 2-Ethyl 3,3-dimethyl 5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-2,3,3-tricarboxylate
  44. 2-Ethyl 3,3-dimethyl (1S,2S,5R)-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-2,3,3-tricarboxylate
    Compound (+)-14l 2-Ethyl 3,3-dimethyl (1S,2S,5R)-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-2,3,3-tricarboxylate
  45. 2-Ethyl 3,3-dimethyl (1R,2R,5S)-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-2,3,3-tricarboxylate
    Compound (-)-14l 2-Ethyl 3,3-dimethyl (1R,2R,5S)-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-2,3,3-tricarboxylate
  46. Dimethy 5-methyl-7-oxo-2-phenyl-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14m Dimethy 5-methyl-7-oxo-2-phenyl-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  47. Dimethyl (1S,2R,5R)-5-methyl-7-oxo-2-phenyl-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (+)-14m Dimethyl (1S,2R,5R)-5-methyl-7-oxo-2-phenyl-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  48. Dimethyl 5-methyl-2-(4-nitrophenyl)-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14n Dimethyl 5-methyl-2-(4-nitrophenyl)-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  49. Dimethyl 2-(4-methoxyphenyl)-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14o Dimethyl 2-(4-methoxyphenyl)-5-methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  50. Dimethyl 5-methyl-7-oxo-2-((E)-prop-1-en-1-yl)-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14p Dimethyl 5-methyl-7-oxo-2-((E)-prop-1-en-1-yl)-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  51. Dimethyl (1S,2S,5R)-5-methyl-7-oxo-2-((E)-prop-1-en-1-yl)-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (+)-14p Dimethyl (1S,2S,5R)-5-methyl-7-oxo-2-((E)-prop-1-en-1-yl)-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  52. Dimethyl (1R,2R,5S)-5-methyl-7-oxo-2-((E)-prop-1-en-1-yl)-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (-)-14p Dimethyl (1R,2R,5S)-5-methyl-7-oxo-2-((E)-prop-1-en-1-yl)-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  53. Dimethyl 1,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14q Dimethyl 1,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  54. Dimethyl (1S,5R)-1,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (+)-14q Dimethyl (1S,5R)-1,5-dimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  55. Dimethyl 1,2,5-trimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14r Dimethyl 1,2,5-trimethyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  56. Diallyl (1S,2S,5R)-5-methyl-7-oxo-2-((E)-prop-1-en-1-yl)-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (+)-14s Diallyl (1S,2S,5R)-5-methyl-7-oxo-2-((E)-prop-1-en-1-yl)-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  57. Dimethyl 2-oxohexahydro-2H-indeno[7a,1-b]oxete-4,4(4aH)-dicarboxylate
    Compound (±)-14u Dimethyl 2-oxohexahydro-2H-indeno[7a,1-b]oxete-4,4(4aH)-dicarboxylate
  58. Methyl 3,7-dioxo-2-oxatricyclo[,4]decane-6-carboxylate
    Compound (±)-14v Methyl 3,7-dioxo-2-oxatricyclo[,4]decane-6-carboxylate
  59. 5-Methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3-carbonitrile
    Compound (±)-14x 5-Methyl-7-oxo-6-oxabicyclo[3.2.0]heptane-3-carbonitrile
  60. Diethyl 7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
    Compound (±)-14y Diethyl 7-oxo-6-oxabicyclo[3.2.0]heptane-3,3-dicarboxylate
  61. Dimethyl 2a-methyl-1-oxohexahydro-1H,4H-pentaleno[1,6a-b]oxete-4,4-dicarboxylate
    Compound (±)-14z Dimethyl 2a-methyl-1-oxohexahydro-1H,4H-pentaleno[1,6a-b]oxete-4,4-dicarboxylate
  62. Dimethyl 2-oxo-2a,3,5,6-tetrahydro-2H-benzo[6,7]indeno[7a,1-b]oxete-4,4(4aH)-dicarboxylate
    Compound (±)-15 Dimethyl 2-oxo-2a,3,5,6-tetrahydro-2H-benzo[6,7]indeno[7a,1-b]oxete-4,4(4aH)-dicarboxylate
  63. Dimethyl 2,3a,4,5-tetrahydro-3H-cyclopenta[a]naphthalene-3,3-dicarboxylate
    Compound (±)-16 Dimethyl 2,3a,4,5-tetrahydro-3H-cyclopenta[a]naphthalene-3,3-dicarboxylate
  64. Methyl 2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate
    Compound (±)-17 Methyl 2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-3-carboxylate
  65. Cyclopent-1-ene-1-carboxylic acid
    Compound 20a Cyclopent-1-ene-1-carboxylic acid
  66. Cyclopent-1-enecarboxylic 4-methylbenzenesulfonic anhydride
    Compound 20b Cyclopent-1-enecarboxylic 4-methylbenzenesulfonic anhydride
  67. Ethyl 2-oxocyclopentane-1-carboxylate
    Compound (±)-21 Ethyl 2-oxocyclopentane-1-carboxylate
  68. Dibenzyl 2-methylenemalonate
    Compound 22 Dibenzyl 2-methylenemalonate
  69. (2aR,3R,5aS,8aR)-4,4-Dibenzyl 3,5a-diethyl 2-oxohexahydro-2H-indeno[3a,4-b]oxete-3,4,4,5a(5H)-tetracarboxylate
    Compound (+)-23 (2aR,3R,5aS,8aR)-4,4-Dibenzyl 3,5a-diethyl 2-oxohexahydro-2H-indeno[3a,4-b]oxete-3,4,4,5a(5H)-tetracarboxylate
  70. 5,5-Dibenzyl 3a,6-diethyl (3aS,6R,7R,7aR)-7-((4-bromobenzyl)carbamoyl)-7a-hydroxyhexahydro-5H-indene-3a,5,5,6(4H)-tetracarboxylate
    Compound (-)-24 5,5-Dibenzyl 3a,6-diethyl (3aS,6R,7R,7aR)-7-((4-bromobenzyl)carbamoyl)-7a-hydroxyhexahydro-5H-indene-3a,5,5,6(4H)-tetracarboxylate


  1. Pellissier, H. Stereocontrolled domino reactions. Chem. Rev. 113, 442524 (2013).
  2. Grondal, C., Jeanty, M. & Enders, D. Organocatalytic cascade reactions as a new tool in total synthesis. Nature Chem. 2, 167178 (2010).
  3. Jones, S. B., Simmons, B., Mastracchio, A. & MacMillan, D. W. C. Collective synthesis of natural products by means of organocascade catalysis. Nature 475, 183188 (2011).
  4. Enders, D., Huttl, M. R., Grondal, C. & Raabe, G. Control of four stereocentres in a triple cascade organocatalytic reaction. Nature 441, 861863 (2006).
  5. Gawley, R. E. The Robinson annelation and related reactions. Synthesis 777794 (1976).
  6. Bui, T. & Barbas, C. F. III A proline-catalyzed asymmetric Robinson annulation reaction. Tetrahedron Lett. 41, 69516954 (2000).
  7. Sakakura, A., Ukai, A. & Ishihara, K. Enantioselective halocyclization of polyprenoids induced by nucleophilic phosphoramidites. Nature 445, 900903 (2007).
  8. Nicolaou, K. C., Synder, S. A., Montagnon, T. & Vassilikogiannakis, G. The Diels–Alder reaction in total synthesis. Angew. Chem. Int. Ed. 41, 16681698 (2002).
  9. Jorg, H. The Pauson–Khand reaction in the synthesis of pharmacologically active compounds. Curr. Org. Chem. 14, 11391152 (2010).
  10. Trost, B. M. & Chan, D. M. T. New conjunctive reagents. 2-Acetoxymethyl-3-allyltrimethylsilane for methylenecyclopentane annulations catalyzed by palladium(0). J. Am. Chem. Soc. 101, 64296432 (1979).
  11. Streit, U. & Bochet, C. G. The arene–alkene photocycloaddition. Beilstein J. Org. Chem. 7, 525542 (2011).
  12. Vaidya, T., Eisenberg, R. & Frontier, A. J. Catalytic Nazarov cyclization: the state of the art. Chem. Catal. Chem. 3, 15311548 (2011).
  13. Heasley, B. Stereocontrolled preparation of fully substituted cyclopentanes: relevance to total synthesis. Eur. J. Org. Chem. 14471489 (2009).
  14. Moyano, A. & Ramon Rios, R. Asymmetric organocatalytic cyclization and cycloaddition reactions. Chem. Rev. 111, 47034832 (2011).
  15. Tan, B., Candeias, N. R. & Barbas, C. F. III Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst. Nature Chem. 3, 473477 (2011).
  16. Remes, M. & Vesely, J. Highly enantioselective organocatalytic formation of functionalized cyclopentane derivatives via tandem conjugate addition/α-alkylation of enals. Eur. J. Org. Chem. 37473752 (2012).
  17. Albertshofer, K., Tan, B. & Barbas, C. F. III Assembly of spirooxindole derivatives containing four consecutive stereocenters via organocatalytic Michael–Henry cascade reactions. Org. Lett. 14, 18341837 (2012).
  18. Barrero, A. F., Quilez del Moral, J. F., Herrador, M. M., Rodriguez, H. & Morales, M. C. P. Cyclopentane sesquiterpenes from fungi: occurrence–bioactivity, biosynthesis and chemical synthesis. Curr. Org. Chem. 18, 11641181 (2009).
  19. Cortez, G. S., Tennyson, R. & Romo, D. Intramolecular nucleophile catalyzed aldol-lactonization (NCAL) reactions: catalytic, asymmetric synthesis of bicyclic β-lactones. J. Am. Chem. Soc. 123, 79457946 (2001).
  20. Leverett, C. A., Purohit, V. C. & Romo, D. Enantioselective, organocatalyzed intramolecular aldol-lactonizations with ketoacids leading to bicyclic and tricyclic β-lactones and topology morphing transformations. Angew. Chem. Int. Ed. 122, 96699673 (2010).
  21. Liu, G., Shirley, M. E. & Romo, D. A diastereoselective, nucleophile-promoted aldol-lactonization of ketoacids leading to bicyclic-β-lactones. J. Org. Chem. 77, 24962500 (2012).
  22. France, S., Guerin, D. J., Miller, S. J. & Lectka, T. Nucleophile chiral amines as catalysts in asymmetric synthesis. Chem. Rev. 103, 29853012 (2003).
  23. Fu, G. C. Asymmetric catalysis with ‘planar-chiral’ derivatives of 4-(dimethylamino)pyridine. Acc. Chem. Res. 37, 542547 (2004).
  24. Birman, V. B., Uffman, E. W., Jiang, H., Li, X. & Kilbane, C. J. 2,3-Dihydroimidazo[1,2-a]pyridines:  a new class of enantioselective acyl transfer catalysts and their use in kinetic resolution of alcohols. J. Am. Chem. Soc. 126, 1222612227 (2004).
  25. Kobayashi, M. & Okamoto, S. Unexpected reactivity of annulated 3H-benzothiazol-2-ylideneamines as acyl transfer catalyst. Tetrahedron Lett. 47, 43474350 (2006).
  26. Gaunt, M. J. & Johansson, C. C. C. Recent developments in the use of catalytic asymmetric ammonium enolates in chemical synthesis. Chem. Rev. 107, 55965605 (2007).
  27. Wynberg, H. & Staring, E. G. Asymmetric synthesis of (S)- and (R)-malic acid from ketene chloral. J. Am. Chem. Soc. 104, 166168 (1982).
  28. Nelson, S. C., Zhu, C. & Shen, X. Catalytic asymmetric acyl halide–aldehyde cyclocondensation reactions of substituted ketenes J. Am. Chem. Soc. 126, 1415 (2004).
  29. Lectka, T. et al. Catalytic, asymmetric α-chlorination of acid halides. J. Am. Chem. Soc. 126, 42454255 (2004).
  30. Morrill, L. C., Lebl, T., Slawin, A. M. A. & Smith, A. D. Catalytic asymmetric α-amination of carboxylic acids using isothioureas. Chem. Sci. 3, 20882093 (2012).
  31. Abraham, C. J., Paull, D. H., Scerba, M. T., Grebinski, J. W. & Leckta, T. Catalytic, enantioselective bifunctional inverse electron demand hetero-Diels–Alder reactions of ketene enolates and o-benzoquinone diimides. J. Am. Chem. Soc. 128, 1337013371 (2006).
  32. Bekele, T. et al. Catalytic, enantioselective [4+2] cycloadditions of ketene enolates and o-quinones: efficient entry to chiral, α-oxygenated carboxylic acid derivatives. J. Am. Chem. Soc. 128, 18101811 (2006).
  33. Wolfer, J., Bekele, T., Abraham, C. J., Dogo-Isonagie, C. & Lectka, T. Catalytic, asymmetric synthesis of 1,4-benzoxazinones: a remarkably enantioselective route to α-amino acid derivatives from o-benzoquinone imides. Angew. Chem. Int. Ed. 45, 73987400 (2006).
  34. Belmessieri, D., Morrill, L. C., Simal, C., Slawin, A. M. Z. & Smith, A. D. Organocatalytic functionalization of carboxylic acids: isothiourea-catalyzed asymmetric intra- and intermolecular Michael addition-lactonizations. J. Am. Chem. Soc. 133, 27142720 (2011).
  35. Simal, C., Lebl, T., Slawin, A. M. Z. & Smith, A. D. Dihydropyridones: catalytic asymmetric synthesis, N- to C-sulfonyl transfer, and derivatizations. Angew. Chem. Int. Ed. 51, 36533657 (2012).
  36. Tiseni, P. S. & Peters, R. Catalytic asymmetric formation of δ-lactones by [4+2] cycloaddition of zwitterionic dienolates generated from α,β-unsaturated acid chlorides. Angew. Chem. Int. Ed. 46, 53255328 (2007).
  37. Bappert, E., Muller, P. & Fu, G. C. Asymmetric [3+2] annulations catalyzed by a planar-chiral derivative of DMAP. Chem. Commun. 42, 26042606 (2006).
  38. Robinson, E., Fallan, C., Simal, C., Slawin, A. & Smith, A. D. Anhydrides as α,β-unsaturated acyl ammonium precursors: isothiourea-promoted catalytic asymmetric annulation processes. Chem. Sci. 4, 21932200 (2013).
  39. Böttcher, T. & Sieber, S. A. β-Lactams and β-lactones as activity-based probes in chemical biology. Med. Chem. Commun. 3, 408417 (2012).
  40. Yang, X. & Birman, V. B. Homobenzotetramisole-catalyzed kinetic resolution of α-aryl-, α-aryloxy-, and α-arylthioalkanoic acids. Adv. Synth. Catal. 351, 23012304 (2009).
  41. Taylor, J. E., Bull, S. D. & Williams, J. M. J. Amidines, isothioureas, and guanidines as nucleophilic catalysts. Chem. Soc. Rev. 41, 21092121 (2012).
  42. Blanchette, M. A. <i>et. al.</i> Horner–Wadsworth–Emmons reaction: use of lithium chloride and an amine for base-sensitive compounds. Tetrahedron Lett. 25, 21832186 (1984).
  43. Birman, V. B. & Li, X. Homobenzotetramisole: an effective catalyst for kinetic resolution of aryl-cycloalkanols. Org. Lett. 6, 11151118 (2008).
  44. Tsuji, H. et al. Palladium-catalyzed decarboxylation–allylation of allylic esters of α-substituted β-keto carboxylic, malonic, cyanoacetic, and nitroacetic acid. J. Org. Chem. 52, 29882995 (1997).
  45. Lang, A. Gibberellins: structure and mechanism. Annu. Rev. Plant Physiol. 21, 537570 (1970).
  46. Wilds, A. L., Harnik, M., Shimizu, R. Z. & Tyner, D. A. Methods for total synthesis of steroids. XVII. Δ14–16-Keto steroid approach to ring d. H. Introduction of 17-caboxy group. Synthesis of 14α,17β and 14β,17α isomers of rac-estra-5(10),6,8-triene-17-carboxylic acid. J. Am. Chem. Soc. 88, 799804 (1965).
  47. Minami, I., Nisar, M., Yuhara, M., Shimizu, I. & Tsuji, M. New methods for the syntheses of α,β-unsaturated ketones, aldehydes, and nitriles by the palladium-catalyzed reactions of allyl β-oxo esters, allyl 1-alkenyl carbonates, and allyl α-cyano esters. Synthesis 992999 (1987).
  48. Candish, L. & Lupton, D. W. N-Heterocyclic carbene-catalyzed Ireland–Coates Claisen rearrangement: synthesis of functionalized β-lactones. J. Am. Chem. Soc. 135, 5861 (2013).
  49. Birman, V. B., Li, X. & Han, Z. Nonaromatic amidine derivatives as acylation catalysts. Org. Lett. 9, 3740 (2007).
  50. Seayad, J. & List, B. in Multicomponent Reactions (eds Zhu, J. & Bienaymé, H.) 277299 (Wiley-VCH, 2005).
  51. Wang, Y., Tennyson, R. & Romo, D. β-Lactones: intermediates for natural product total synthesis and new transformations. Heterocycles 64, 605658 (2004).
  52. Ranieri, B., Robles, O. & Romo, D. Concise synthesis of the isothiourea organocatalysts homobenzotetramisole and derivatives. J. Org. Chem. 78, 62916296 (2013).
  53. Vellalath, S., Van, K. N. & Romo, D. Direct catalytic asymmetric synthesis of N-heterocycles from commodity acid chlorides by employing α,β-unsaturated acylammonium salts. Angew. Chem. Int. Ed. http://dx.doi.org/10.1002/anie.201306050 (2013).

Download references

Author information

  1. These authors contributed equally to this work

    • Gang Liu &
    • Morgan E. Shirley



G.L. initiated the studies of the α,β-unsaturated acylammonium intermediate from acid chlorides. D.R., G.L. and M.E.S. were involved in the design of experiments for exploration of the NCMAL. D.R. and K.N.V. conceived and developed the three-component NCMAL process. G.L., M.E.S., K.N.V. and R.L.M. performed the experiments. D.R., G.L. and M.E.S. composed the manuscript with input from all authors.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Author details

Supplementary information

PDF files

  1. Supplementary information (6,217 KB)

    Supplementary information

Crystallographic information files

  1. Supplementary information (17 KB)

    Crystallographic data for compound (+)-S16

  2. Supplementary information (15 KB)

    Crystallographic data for compound (±)-14k

  3. Supplementary information (16 KB)

    Crystallographic data for compound (±)-14m

  4. Supplementary information (16 KB)

    Crystallographic data for compound (+)-14p

  5. Supplementary information (16 KB)

    Crystallographic data for compound (±)-14q

  6. Supplementary information (15 KB)

    Crystallographic data for compound (±)-14t

  7. Supplementary information (14 KB)

    Crystallographic data for compound (±)-14v

  8. Supplementary information (13 KB)

    Crystallographic data for compound (±)-14x

  9. Supplementary information (28 KB)

    Crystallographic data for compound (-)-24

Additional data