title: Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst.
abstract: Single-step constructions of molecules with multiple quaternary carbon stereocentres are rare. The spirooxindole structural motif is common to a range of bioactive compounds; however, asymmetric synthesis of this motif is complicated due to the presence of multiple chiral centres. The development of organocatalytic cascade reactions has proven to be valuable for the construction of several chiral centres in one step. Here, we describe a newly designed organocatalytic asymmetric domino Michael-aldol reaction between 3-substituted oxindoles and methyleneindolinones that affords complex bispirooxindoles. This reaction was catalysed by a novel multifunctional organocatalyst that contains tertiary and primary amines and thiourea moieties to activate substrates simultaneously, providing extraordinary levels of stereocontrol over four stereocentres, three of which are quaternary carbon stereocentres. This new methodology provides facile access to a range of multisubstituted bispirocyclooxindole derivatives, and should be useful in medicinal chemistry and diversity-oriented syntheses of this intriguing class of compounds.
authors: The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Bin
authors: B
authors: Tan
authors: Nuno R
authors: NR
authors: Candeias
authors: Carlos F
authors: CF
authors: Barbas
references: Chem Commun (Camb). 2005 Sep 21;(35):4481-3
references: 16136258
references: Org Lett. 2005 May 12;7(10):1967-9
references: 15876031
references: Angew Chem Int Ed Engl. 2009;48(25):4559-61
references: 19455525
references: Org Lett. 2008 Jun 19;10(12):2437-40
references: 18489178
references: J Am Chem Soc. 2008 Feb 27;130(8):2422-3
references: 18251543
references: J Am Chem Soc. 2007 Oct 17;129(41):12396-7
references: 17880222
references: Angew Chem Int Ed Engl. 2004 Dec 17;44(1):105-8
references: 15565669
references: Nat Chem. 2010 Sep;2(9):735-40
references: 20729892
references: Nature. 2006 Jun 15;441(7095):861-3
references: 16778886
references: Angew Chem Int Ed Engl. 2005 Oct 7;44(39):6367-70
references: 16136619
references: J Org Chem. 2005 Nov 11;70(23):9430-5
references: 16268618
references: Angew Chem Int Ed Engl. 2007;46(10):1570-81
references: 17225236
references: Angew Chem Int Ed Engl. 2009;48(39):7200-3
references: 19670284
references: J Am Chem Soc. 2010 Jul 21;132(28):9558-60
references: 20583835
references: Angew Chem Int Ed Engl. 2008;47(33):6138-71
references: 18666089
references: Angew Chem Int Ed Engl. 2006 Nov 6;45(43):7134-86
references: 17075967
references: J Am Chem Soc. 2009 Jul 1;131(25):8758-9
references: 19499923
references: Angew Chem Int Ed Engl. 2002 May 17;41(10):1650-67
references: 19750685
references: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):11929-36
references: 15302925
references: Nat Chem. 2010 May;2(5):380-4
references: 20414238
references: Chem Rev. 2003 Aug;103(8):2945-64
references: 12914487
references: Nat Chem. 2010 Mar;2(3):167-78
references: 21124474
references: Nature. 2008 Sep 18;455(7211):304-8
references: 18800128
references: Angew Chem Int Ed Engl. 2008;47(1):42-7
references: 17943929
references: Angew Chem Int Ed Engl. 2000 Jan;39(1):44-122
references: 10649349
references: J Org Chem. 2010 Jul 16;75(14):4657-73
references: 20540516
references: J Am Chem Soc. 2009 Sep 30;131(38):13819-25
references: 19736987
references: Org Lett. 2010 Jun 18;12(12):2682-5
references: 20469881
references: Acc Chem Res. 2004 Aug;37(8):621-31
references: 15311961
references: J Am Chem Soc. 2004 Aug 18;126(32):9906-7
references: 15303849
references: J Am Chem Soc. 2004 Dec 15;126(49):16077-86
references: 15584743
references: J Am Chem Soc. 2010 Apr 28;132(16):5574-5
references: 20356308
references: Science. 2009 Jul 10;325(5937):161-5
references: 19589993
references: Chem Commun (Camb). 2010 Nov 14;46(42):8064-6
references: 20865203
references: Science. 2010 Sep 3;329(5996):1175-80
references: 20813948
references: J Am Chem Soc. 2005 Jul 27;127(29):10130-1
references: 16028899
references: J Am Chem Soc. 2006 Oct 11;128(40):13151-60
references: 17017795
references: Angew Chem Int Ed Engl. 2010 Oct 11;49(42):7753-6
references: 20821787
references: Org Lett. 2010 Jun 18;12(12):2766-9
references: 20481511
references: Angew Chem Int Ed Engl. 2007;46(46):8748-58
references: 17943924
references: J Am Chem Soc. 2009 Nov 25;131(46):16620-1
references: 19886657
references: Angew Chem Int Ed Engl. 2003 Sep 15;42(35):4233-7
references: 14502744
references: J Am Chem Soc. 2005 Jan 12;127(1):119-25
references: 15631461
references: Chemistry. 2009 Aug 10;15(32):7846-9
references: 19180604
references: Chem Rev. 2007 Dec;107(12):5713-43
references: 18072808
references: Org Biomol Chem. 2011 Apr 21;9(8):2715-21
references: 21369625