title: Total synthesis of complestatin: development of a Pd(0)-mediated indole annulation for macrocyclization.
abstract: Full details of the initial development and continued examination of a powerful intramolecular palladium(0)-mediated indole annulation for macrocyclization closure of the strained 16-membered biaryl ring system found in complestatin (1, chloropeptin II) and the definition of factors impacting its intrinsic atropodiastereoselectivity are described. Its examination and use in an alternative, second-generation total synthesis of complestatin are detailed in which the order of the macrocyclization reactions was reversed from our first-generation total synthesis. In this approach and with the ABCD biaryl ether ring system in place, the key Larock cyclization was conducted with substrate 36 (containing four phenols, five secondary amides, one carbamate, and four labile aryl chlorides) and provided the product 37 (56%) exclusively as a single atropisomer (>20:1, detection limits) possessing the natural (R)-configuration. In this instance, the complexity of the substrate and the reverse macrocyclization order did not diminish the atropodiastereoselectivity; rather, it provided an improvement over the 4:1 selectivity that was observed with the analogous substrate used to provide the isolated DEF ring system in our first-generation approach. Just as significant, the atroposelectivity represents a complete reversal of the diasteroselectivity observed with analogous macrocyclizations conducted using a Suzuki biaryl coupling.
authors.affiliation: Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimamura
authors.forename: Steven P
authors.initials: SP
authors.lastname: Breazzano
authors.forename: Joie
authors.initials: J
authors.lastname: Garfunkle
authors.forename: F Scott
authors.initials: FS
authors.lastname: Kimball
authors.forename: John D
authors.initials: JD
authors.lastname: Trzupek
authors.forename: Dale L
authors.initials: DL
authors.lastname: Boger
mesh_terms: D002733:Chlorophenols / Q000138:chemical synthesis*; D003500:Cyclization; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry; D010165:Palladium / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000138:chemical synthesis*
chemical_list: D002733:Chlorophenols; D007211:Indoles; D047028:Macrocyclic Compounds; D010456:Peptides, Cyclic; D010165:Palladium; C023490:complestatin; C030374:indole
references.citation: J Org Chem. 1997 Apr 4;62(7):2054-2069
references.pmid: 11671510
references.citation: J Org Chem. 1999 Jan 8;64(1):70-80
references.pmid: 11674087
references.citation: J Am Chem Soc. 2001 Mar 7;123(9):1862-71
references.pmid: 11456806
references.citation: J Antibiot (Tokyo). 1997 Jan;50(1):58-65
references.pmid: 9066767
references.citation: Angew Chem Int Ed Engl. 2010 Mar 8;49(11):2018-22
references.pmid: 20148426
references.citation: J Am Chem Soc. 2006 Mar 8;128(9):2885-92
references.pmid: 16506767
references.citation: Bioorg Med Chem Lett. 2003 Feb 10;13(3):573-5
references.pmid: 12565974
references.citation: J Am Chem Soc. 2003 Feb 19;125(7):1877-87
references.pmid: 12580615
references.citation: J Nat Prod. 2001 Jul;64(7):874-82
references.pmid: 11473415
references.citation: J Am Chem Soc. 2005 May 25;127(20):7334-6
references.pmid: 15898781
references.citation: Biochem Biophys Res Commun. 1991 Aug 30;179(1):243-50
references.pmid: 1715691
references.citation: J Antibiot (Tokyo). 1994 Oct;47(10):1173-4
references.pmid: 7961171
references.citation: Org Lett. 1999 Nov 4;1(9):1443-6
references.pmid: 10825992
references.citation: Thromb Haemost. 1997 Jan;77(1):137-42
references.pmid: 9031464
references.citation: Org Lett. 2007 Jun 7;9(12):2401-4
references.pmid: 17497871
references.citation: J Am Chem Soc. 2002 May 15;124(19):5288-90
references.pmid: 11996568
references.citation: Chem Biol. 2006 Jun;13(6):607-14
references.pmid: 16793518
references.citation: Thromb Res. 1997 Sep 15;87(6):571-6
references.pmid: 9330439
references.citation: Org Lett. 2004 Oct 28;6(22):4129-32
references.pmid: 15496116
references.citation: Med Res Rev. 2001 Sep;21(5):356-81
references.pmid: 11579438
references.citation: J Antibiot (Tokyo). 1997 Jan;50(1):66-9
references.pmid: 9066768
references.citation: J Immunol. 1980 Mar;124(3):1194-8
references.pmid: 6898640
references.citation: J Antibiot (Tokyo). 1989 Feb;42(2):236-41
references.pmid: 2925515
references.citation: J Am Chem Soc. 2004 Apr 7;126(13):4310-7
references.pmid: 15053621
references.citation: J Org Chem. 2001 Jun 29;66(13):4525-42
references.pmid: 11421771
references.citation: J Am Chem Soc. 2009 Nov 11;131(44):16036-8
references.pmid: 19839632
references.citation: J Am Chem Soc. 2003 Jul 30;125(30):9032-4
references.pmid: 15369357
references.citation: Chem Pharm Bull (Tokyo). 2005 Oct;53(10):1277-90
references.pmid: 16204984
references.citation: Angew Chem Int Ed Engl. 2008;47(22):4167-72
references.pmid: 18404759
references.citation: Bioorg Med Chem Lett. 2004 Apr 5;14(7):1697-702
references.pmid: 15026053