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. 2019 Aug 7;141(31):12246-12250.
doi: 10.1021/jacs.9b07346. Epub 2019 Jul 23.

A Radical-Polar Crossover Annulation To Access Terpenoid Motifs

William P Thomas  1 , Devon J Schatz  1 , David T George  1 , Sergey V Pronin  1
Affiliations

A Radical-Polar Crossover Annulation To Access Terpenoid Motifs

William P Thomas et al. J Am Chem Soc. .

Abstract

A new catalytic radical-polar crossover annulation between two unsaturated carbonyl compounds is described. The annulation proceeds under exceptionally mild conditions and provides direct and expedient access to complex terpenoid motifs. Application of this chemistry allows for synthesis of forskolin, a densely functionalized terpenoid, in 14 steps from commercially available material.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1.
Figure 1.
Radical-polar crossover annulation allows for rapid assembly of complex terpenoid motifs.
Scheme 1.
Scheme 1.
Annulation en Route to Forskolin (1)
Scheme 2.
Scheme 2.
Synthesis of (±)-Forskolin (1)
See this image and copyright information in PMC

References

    1. For selected reviews, see:
    2. Jung ME A review of annulation. Tetrahedron 1976, 32, 3.
    3. Trost BM Fuünfgliedrige ringe durch [3 + 2]-cycloaddition mit trimethylenmethan und syntheseäquivalenten. Angew. Chem 1986, 98, 1.
    4. Posner GH Multicomponent one-pot annulations forming three to six bonds. Chem. Rev 1986, 86, 831.
    5. Larock RC Palladium-catalyzed annulation. J. Organomet. Chem 1999, 576, 111.
    6. Molander GA Diverse methods for medium ring synthesis. Acc. Chem. Res 1998, 31, 603.
    7. Dötz KH; Tomuschat P Annulation reactions of chromium carbene complexes: scope, selectivity and recent developments. Chem. Soc. Rev 1999, 28, 187.
    8. Rheault TR; Sibi MP Radical-mediated annulation reactions. Synthesis 2003, 2003, 0803. - PubMed
    9. Mal D; Pahari P Recent advances in the Hauser annulation. Chem. Rev 2007, 107, 1892. - PubMed
    1. For selected reviews, see:
    2. Boger DL Diels-Alder reactions of heterocyclic azadienes: scope and limitations. Chem. Rev 1986, 86, 781.
    3. Winkler JD Tandem Diels-Alder cycloadditions in organic synthesis. Chem. Rev 1996, 96, 167. - PubMed
    4. Corey EJ Catalytic enantioselective Diels–Alder reactions: methods, mechanistic fundamentals, pathways, and applications. Angew. Chem., Int. Ed 2002, 41, 1650. - PubMed
    5. Nicolaou KC; Snyder SA; Montagnon T; Vassilikogiannakis G The Diels-Alder reaction in total synthesis. Angew. Chem., Int. Ed 2002, 41, 1668. - PubMed
    6. Takao K; Munakata R; Tadano K Recent advances in natural product synthesis by using intramolecular Diels–Alder reactions. Chem. Rev 2005, 105, 4779. - PubMed
    1. For selected examples of bimolecular Diels–Alder reactions with highly substituted 1,3-dienes and relevant discussions, see:
    2. Roush WR; Limberakis C; Kunz RK; Barda DA Diastereoselective synthesis of the endo- and exo-spirotetronate subunits of the quartromicins. The first enantioselective Diels-Alder reaction of an acyclic (Z)-1,3-diene. Org. Lett 2002, 4, 1543. - PubMed
    3. Du X; Chu HV; Kwon O A concise synthesis of the functionalized [5–7–6] tricyclic skeleton of guanacastepene A. Tetrahedron Lett 2004, 45, 8843.
    4. Usuda H; Kuramochi A; Kanai M; Shibasaki M Challenge toward structural complexity using asymmetric catalysis: target-oriented development of catalytic enantioselective Diels-Alder reaction. Org. Lett 2004, 6, 4387. - PubMed
    5. Jung ME; Ho D; Chu HV Synthesis of highly substituted cyclohexenes via mixed Lewis acid-catalyzed Diels-Alder reactions of highly substituted dienes and dienophiles. Org. Lett 2005, 7, 1649. - PubMed
    6. Jung ME; Guzaev M Trimethylaluminum-triflimide complexes for the catalysis of highly hindered Diels-Alder reactions. Org. Lett 2012, 14, 5169. - PubMed
    7. Huwyler N; Carreira EM Total synthesis and stereochemical revision of the chlorinated sesquiterpene (±)-gomerone C. Angew. Chem., Int. Ed 2012, 51, 13066. - PubMed
    8. Ishihara Y; Mendoza A; Baran PS Total synthesis of taxane terpenes: cyclase phase. Tetrahedron 2013, 69, 5685. - PMC - PubMed
    1. For elegant solutions to this problem, see:
    2. Zutterman F; Krief A Synthesis and Diels-Alder reactions of allylidenecyclopropane. J. Org. Chem 1983, 48, 1135.
    3. Kienzle F; Stadlwieser J; Mergelsherg I 42. Diels-Alder-reactionen mit 3-cyclopropylidenprop-1-enyl-ethyl-ether als 1,3-dien. Helv. Chim. Acta 1989, 72, 348.
    4. Stork G; Chan TY Temporary magnesium and aluminum connections in 4 + 2 cycloadditions. J. Am. Chem. Soc 1995, 117, 6595.
    1. George DT; Kuenstner EJ; Pronin SV A concise approach to paxilline indole diterpenes. J. Am. Chem. Soc 2015, 137, 15410–15413. - PMC - PubMed
    2. Godfrey NA; Schatz DJ; Pronin SV Twelve-step asymmetric synthesis of (−)-nodulisporic acid. J. Am. Chem. Soc 2018, 140, 12770. - PMC - PubMed

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