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. 2011 Jul 13;475(7355):183-8.
doi: 10.1038/nature10232.

Collective synthesis of natural products by means of organocascade catalysis

Spencer B Jones  1 , Bryon Simmons, Anthony Mastracchio, David W C MacMillan
Affiliations

Collective synthesis of natural products by means of organocascade catalysis

Spencer B Jones et al. Nature. .

Abstract

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

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Figures

Figure 1
Figure 1. Cascade catalysis in biosynthesis
In nature, transform-specific enzymes in continuous catalytic cascades rapidly produce common biosynthetic intermediates and natural products. Preakuammicine serves as a biosynthetic precursor to a range of structurally diverse members of the Strychnos, Aspidosperma and Kopsia alkaloid families, including strychnine and vincadifformine. Et, ethyl; Gluc, glucose; Me, methyl.
Figure 2
Figure 2. Collective natural product synthesis: nature-inspired application of cascade catalysis
Synthesis of six structurally diverse Strychnos, Aspidosperma and Kopsia alkaloids is expected to proceed from a common intermediate tetracycle prepared by means of organocascade catalysis. Boc, tert-butoxycarbonyl; Im, iminium catalysis.
Figure 3
Figure 3. Proposed mechanism of organocascade cycles for the generation of a common tetracyclic intermediate (1)
An organocascade reaction between 2-vinyl indole 2 and propynal is expected to proceed through an organocatalytic Diels–Alder/β-elimination/amine conjugate addition sequence along path A, involving iminium ion catalysis, or path B, involving Brønsted acid catalysis. 1-Nap, 1-naphthyl; SeMe, selenomethyl.
Figure 4
Figure 4. Twelve-step enantioselective total synthesis of (−)-strychnine
Reagents and conditions are as follows. a, NaH, PMBCl, dimethylformamide (DMF), 0 °C. PMB, para-methoxybenzyl. b, SeO2, dioxane, H2O, 100 °C. c, (EtO)2P(O)CH2SeMe, 18-crown-6, potassium bis(trimethylsilyl)amide (KHMDS), tetrahydrofuran (THF), −78 °C to room temperature (RT, 23 °C). e.e., enantiomeric excess. d, (Ph3P)3RhCl, toluene, PhCN, 120 °C. e, COCl2, Et3N, toluene, −45 °C to RT, then MeOH,−30 °C to RT. f, DIBAL-H,CH2Cl2, −78 °C to RT, then trifluoroacetic acid (TFA), −78 °C to RT. g, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3, DMF, (Z)-4-bromo-3-iodobut-2-enyl acetate (13), RT. h, DIBAL-H, CH2Cl2, −78 °C. i, 25 mol% Pd(OAc)2, Bu4NCl, NaHCO3, EtOAc, RT. j, PhSH, TFA, 45 °C. k, NaOAc, Ac2O, AcOH, malonic acid, 120 °C. Ac, acetyl.
Figure 5
Figure 5. Ten-step enantioselective synthesis of (−)-akuammicine
Reagents and conditions are as follows. a, TFA, PhSH, 60 °C. b, (Z)-1-bromo-2-iodobut-2-ene (18), K2CO3, DMF, RT. c, 20 mol% Pd(OAc)2, NaHCO3, Bu4NCl, MeCN, 65 °C.
Figure 6
Figure 6. Enantioselective total syntheses of (+)-aspidospermidine and (+)-vincadifformine
Reagents and conditions are as follows. a, NaH, DMF, BnBr, RT. b, SeO2, dioxane, H2O, 100 °C. c, (EtO)2P(O)CH2SeMe, 18-crown-6, KHMDS, THF, −78 °C to RT. ent-, enantio-. d, Ph3PCH3I, n-butyllithium, THF, 0 °C, then AcOH, NaCNBH3, 0 °C. Bn, benzyl. e, TFA, CH2Cl2, RT. f, (Z)-3-bromo-1-iodoprop-1-ene (22), K2CO3, DMF, RT. g, (Ph3P)4Pd, Et3N, toluene, 80 °C. h, Pd(OH)2, H2 (200 p.s.i.), MeOH, EtOAc, RT. i, CH2Cl2, DMSO, (COCl)2. j, n-butyllithium, NCCO2Me, THF, −78 °C to RT.
Figure 7
Figure 7. Enantioselective total syntheses of (−)-kopsinine and (−)-kopsanone
Reagents and conditions are as follows. a, Et3N, CH2Cl2, Me3SiI, 0 °C, then MeOH, H2C=CHPPh3Br, 40 °C, then CH2Cl2, THF, KOt-Bu, 0 °C. b, COCl2, Et3N, toluene, −45 °C to RT, then MeOH, −30 °C to RT. c, Pd/C,H2, EtOAc, EtOH, 0 °C. d, H2C=CHSO2Ph, benzene, 100 °C. e, Raney Ni, EtOH, 78 °C. f, 1N HCl, 130°C.
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References

    1. Walji A, MacMillan DWC. Strategies to bypass the Taxol problem. Enantioselective cascade catalysis, a new approach for the efficient construction of molecular complexity. Synlett. 2007:1477–1489.
    1. Va P, Campbell EL, Robertson WM, Boger DL. Total synthesis and evaluation of a key series of C5-substituted vinblastine derivatives. J. Am. Chem. Soc. 2010;132:8489–8495. - PMC - PubMed
    1. Huang Y, Walji AM, Larsen CH, MacMillan DWC. Enantioselective organocascade catalysis. J. Am. Chem. Soc. 2005;127:15051–15053. - PubMed
    1. Simmons B, Walji A, MacMillan DWC. Cycle-specific organocascade catalysis: application to olefin hydroamination, hydro-oxidation, and amino-oxidation, and to natural product synthesis. Angew. Chem. Int. Ed. 2009;48:4349–4353. - PMC - PubMed
    1. Dewick PM. Medicinal Natural Products: A Biosynthetic Approach. 3rd edn. Wiley; 2008.

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