title: Tandem Intramolecular Diels-Alder/1,3-Dipolar Cycloaddition Cascade of 1,3,4-Oxadiazoles: Initial Scope and Applications.
abstract: A summary of the development and initial studies on the scope of a powerful tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles is detailed and provides the foundation for its subsequent use in organic synthesis. Implemented with substrates in which both the initiating dienophile and subsequent dipolarophile are tethered to the 1,3,4-oxadiazoles, the studies expanded the scope of oxadiazoles that participate in the reaction cascade, permitted the use of differentiated dienophiles and dipolarophiles, extended their use to unsymmetrical dienophiles and dipolarophiles, provided exclusive control of the cycloaddition regioselectivities, and imposed exquisite control on the cycloaddition stereochemistry. As key reactivity and stereochemical features of the reactions were being defined, the cascade cycloaddition reaction was implemented in the total synthesis of a series of alkaloids including (-)-vindoline, (-)-vindorosine, the closely related natural products (+)-4-desacetoxyvindoline and (+)-4-desacetoxyvindorosine, natural minovine, (+)-N-methylaspidospermidine, (+)-spegazzinine, (-)-aspidospermine, and a number of key analogues. Most recently, it was used in the divergent total syntheses of (+)-fendleridine, (-)-kopsinine, (-)-kopsifoline D, and (-)-deoxoapodine, in which four different strategic bonds in four different classes of the hexacyclic alkaloids were formed from a common cascade cycloaddition intermediate. A large number of vindoline analogues were prepared by variations on the cascade cycloaddition reaction for single step incorporation into analogues of vinblastine. These structural changes to vindoline permitted both systematic alterations to the peripheral substituents as well as deep-seated changes to the core structure and embedded functionality of vinblastine not previously accessible. Although explored initially for accessing vindoline and vinblastine, the use of the cycloaddition cascade in the total synthesis of an impressive range of additional natural products illustrate the power of the methodology. Alternative tethering strategies for the cascade cycloaddition reaction, combined intramolecular and intermolecular variants of either the initiating Diels-Alder reaction or the subsequent carbonyl ylide 1,3-dipolar cycloaddition, an expanded examination of the tethered dipolarophile scope, and applications to additional natural product classes represent attractive areas for future work.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Sears
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute , 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D061565:Cycloaddition Reaction; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry*; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*
chemical_list: D010069:Oxadiazoles; D014747:Vinblastine
references.citation: J Med Chem. 2013 Jan 24;56(2):483-95
references.pmid: 23252481
references.citation: ACS Med Chem Lett. 2011 Dec 8;2(12):948-952
references.pmid: 22247789
references.citation: J Org Chem. 2002 Oct 18;67(21):7361-4
references.pmid: 12375965
references.citation: J Org Chem. 1998 Feb 6;63(3):556-565
references.pmid: 11672045
references.citation: J Am Chem Soc. 2010 Sep 29;132(38):13533-44
references.pmid: 20809620
references.citation: Org Lett. 2013 Oct 18;15(20):5306-9
references.pmid: 24087969
references.citation: J Am Chem Soc. 2012 Aug 15;134(32):13240-3
references.pmid: 22856867
references.citation: Acc Chem Res. 2015 Mar 17;48(3):653-62
references.pmid: 25586069
references.citation: Angew Chem Int Ed Engl. 2006 Jan 16;45(4):620-2
references.pmid: 16355429
references.citation: J Am Chem Soc. 2014 Jan 29;136(4):1300-3
references.pmid: 24428640
references.citation: Tetrahedron. 2015 Jun 3;71(22):3741-3746
references.pmid: 26074629
references.citation: J Am Chem Soc. 2010 Mar 24;132(11):3685-7
references.pmid: 20187641
references.citation: Org Lett. 2015 Nov 6;17(21):5460-3
references.pmid: 26457536
references.citation: ACS Med Chem Lett. 2013 Sep 9;4(10):null
references.pmid: 24223237
references.citation: Angew Chem Int Ed Engl. 2012 Mar 5;51(10):2298-338
references.pmid: 22337341
references.citation: J Am Chem Soc. 2009 Apr 8;131(13):4904-16
references.pmid: 19292450
references.citation: J Am Chem Soc. 2002 Sep 25;124(38):11292-4
references.pmid: 12236743
references.citation: Org Lett. 2012 Mar 16;14(6):1428-31
references.pmid: 22369097
references.citation: J Am Chem Soc. 2008 Jan 16;130(2):420-1
references.pmid: 18081297
references.citation: J Am Chem Soc. 2010 Jun 23;132(24):8489-95
references.pmid: 20518465
references.citation: J Am Chem Soc. 2006 Aug 16;128(32):10589-95
references.pmid: 16895427
references.citation: Org Biomol Chem. 2005 Aug 21;3(16):2899-906
references.pmid: 16186917
references.citation: Chem Rev. 1996 Feb 1;96(1):137-166
references.pmid: 11848747
references.citation: J Am Chem Soc. 2014 Feb 26;136(8):3312-7
references.pmid: 24499015
references.citation: J Am Chem Soc. 2010 Mar 10;132(9):3009-12
references.pmid: 20148585
references.citation: J Am Chem Soc. 2014 Jan 29;136(4):1304-7
references.pmid: 24428607
references.citation: J Am Chem Soc. 2012 Aug 22;134(33):13588-91
references.pmid: 22860624
references.citation: J Med Chem. 2013 Feb 14;56(3):628-39
references.pmid: 23244701
references.citation: Chem Soc Rev. 2009 Nov;38(11):3072-81
references.pmid: 19847342
references.citation: Org Lett. 2012 Apr 20;14(8):2078-81
references.pmid: 22480368
references.citation: J Am Chem Soc. 2012 Dec 5;134(48):19604-6
references.pmid: 23153381
references.citation: Org Lett. 2013 Feb 15;15(4):868-70
references.pmid: 23391149
references.citation: J Am Chem Soc. 2006 Aug 16;128(32):10596-612
references.pmid: 16895428
references.citation: Angew Chem Int Ed Engl. 2012 Jan 9;51(2):314-25
references.pmid: 22121084
references.citation: Org Lett. 2005 Sep 29;7(20):4539-42
references.pmid: 16178578
references.citation: Chemistry. 2001 Aug 3;7(15):3406-14
references.pmid: 11531127