A Synthesis of Exiguaquinol Dessulfate.
A concise and stereoselective synthesis of exiguaquinol dessulfate is described. Sequential application of a Diels-Alder cycloaddition, a desymmetrizing aldol addition, and a reductive Heck cyclization established most of the architecture of exiguaquinol, and a carefully choreographed introduction of the polar substituents afforded the title compound; unfortunately, naphthoquinol sulfation could not be achieved to deliver exiguaquinol. Our hypothesis regarding the configurational preference of the N-acyl hemiaminal, which was based upon an analysis of internal hydrogen-bonding interactions with polar functional groups, was proven correct. A late-stage intermediate did not demonstrate bactericidal activity against H. pylori cultures.
Department of Chemistry, University of California, 1102 Natural Sciences II, Irvine, CA, 92697-2025, USA.
Gregg M
GM
Schwarzwalder
Department of Physiology, UC Los Angeles/VA Greater Los Angeles Healthcare System, 11310 Wilshire Blvd, Bldg. 113, Rm. 324, Los Angeles, CA, 90073, USA.
David R
DR
Scott
Department of Chemistry, University of California, 1102 Natural Sciences II, Irvine, CA, 92697-2025, USA.
Christopher D
http://orcid.org/0000-0001-7218-4521
CD
Vanderwal
D000447:Aldehydes / Q000737:chemistry*; D003500:Cyclization; D061565:Cycloaddition Reaction; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure
D000447:Aldehydes; D006873:Hydroquinones; C530467:exiguaquinol; C116609:3-hydroxybutanal
Heck cyclization; antibiotics; epimers; natural product synthesis; sulfation
Angew Chem Int Ed Engl. 2012 Mar 5;51(10):2505-8
22287029
Org Lett. 2008 Jun 19;10(12):2585-8
18489104
Org Lett. 2004 Jan 22;6(2):209-12
14723530
Org Lett. 2013 Dec 6;15(23):6014-7
24219829
Antimicrob Agents Chemother. 2015 Apr;59(4):2337-42
25645840
Bioorg Med Chem Lett. 2009 Feb 1;19(3):930-6
19097892
Bioorg Med Chem Lett. 2008 Aug 15;18(16):4716-22
18640833
Angew Chem Int Ed Engl. 2012 Nov 26;51(48):12068-71
23097322
Gut. 2012 May;61(5):646-64
22491499
Nat Rev Cancer. 2010 Jun;10(6):403-14
20495574
Antimicrob Agents Chemother. 2009 Aug;53(8):3331-6
19433553
JAMA. 2004 Jan 14;291(2):187-94
14722144
Org Lett. 2006 Jan 19;8(2):273-6
16408893
J Am Chem Soc. 2014 Sep 24;136(38):13202-8
25207434
J Org Chem. 2003 Apr 4;68(7):2861-73
12662063
J Org Chem. 1996 Apr 19;61(8):2885-2887
11667129
Microb Biotechnol. 2008 Sep;1(5):345-60
21261855
J Am Chem Soc. 2014 Jul 16;136(28):9878-81
24967720
Bioorg Med Chem Lett. 2012 Sep 1;22(17):5600-7
22877632
Org Lett. 2003 Feb 20;5(4):535-7
12583762
Nature. 2007 Jun 14;447(7146):817-22
17568739
Chem Pharm Bull (Tokyo). 1985 Dec;33(12):5214-24
3833380
Clin Microbiol Infect. 2009 Nov;15(11):971-6
19874380