title: Stereoselective Halogenation in Natural Product Synthesis.
abstract: At last count, nearly 5000 halogenated natural products have been discovered. In approximately half of these compounds, the carbon atom to which the halogen is bound is sp(3) -hybridized; therefore, there are an enormous number of natural products for which stereocontrolled halogenation must be a critical component of any synthesis strategy. In this Review, we critically discuss the methods and strategies used for stereoselective introduction of halogen atoms in the context of natural product synthesis. Using the successes of the past, we also attempt to identify gaps in our synthesis technology that would aid the synthesis of halogenated natural products, as well as existing methods that have not yet seen application in complex molecule synthesis. The chemistry described herein demonstrates yet again how natural products continue to provide the inspiration for critical advances in chemical synthesis.
authors.affiliation: Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, South Korea. wjchung@gist.ac.kr.
authors.forename: Won-jin
authors.initials: WJ
authors.lastname: Chung
authors.affiliation: Department of Chemistry, University of California, Irvine, CA, USA. cdv@uci.edu.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Vanderwal
mesh_terms: D001688:Biological Products / Q000138:chemical synthesis*; D054879:Halogenation; D013237:Stereoisomerism
chemical_list: D001688:Biological Products
keywords: asymmetric synthesis; halogenation; natural products; stereochemistry; total synthesis
references.citation: Org Lett. 2015 Apr 17;17(8):1878-81
references.pmid: 25811099
references.citation: Curr Drug Targets. 2010 Mar;11(3):303-14
references.pmid: 20210755
references.citation: Expert Opin Drug Discov. 2012 May;7(5):375-83
references.pmid: 22462734
references.citation: J Org Chem. 2009 Jan 16;74(2):696-702
references.pmid: 19053592
references.citation: Chemistry. 2004 Aug 6;10(15):3822-35
references.pmid: 15281167
references.citation: J Org Chem. 2014 Feb 7;79(3):880-7
references.pmid: 24437567
references.citation: Org Lett. 2002 May 30;4(11):1855-7
references.pmid: 12027631
references.citation: J Am Chem Soc. 2006 Mar 29;128(12):3900-1
references.pmid: 16551084
references.citation: Angew Chem Int Ed Engl. 2009;48(42):7899-903
references.pmid: 19757473
references.citation: Tetrahedron. 2008 May 19;64(21):4674-4699
references.pmid: 22859865
references.citation: J Org Chem. 2012 Sep 21;77(18):7883-90
references.pmid: 22913294
references.citation: Chemosphere. 2003 Jul;52(2):299-312
references.pmid: 12738254
references.citation: J Am Chem Soc. 2013 Sep 4;135(35):12960-3
references.pmid: 23952929
references.citation: J Chem Inf Model. 2014 Jan 27;54(1):69-78
references.pmid: 24372485
references.citation: J Am Chem Soc. 2010 Oct 13;132(40):14303-14
references.pmid: 20858010
references.citation: Angew Chem Int Ed Engl. 2014 Nov 3;53(45):12205-9
references.pmid: 25220828
references.citation: Angew Chem Int Ed Engl. 1998 Aug 17;37(15):2085-2087
references.pmid: 29711050
references.citation: Chem Biol. 2008 Feb;15(2):99-109
references.pmid: 18291314
references.citation: Angew Chem Int Ed Engl. 2014 May 19;53(21):5401-4
references.pmid: 24711268
references.citation: Biochemistry. 1973 Oct 23;12(22):4469-72
references.pmid: 4750256
references.citation: Angew Chem Int Ed Engl. 2006 Aug 18;45(33):5510-5
references.pmid: 16906500
references.citation: Angew Chem Int Ed Engl. 2007;46(25):4726-8
references.pmid: 17492815
references.citation: J Am Chem Soc. 2008 Sep 17;130(37):12514-8
references.pmid: 18717563
references.citation: Org Biomol Chem. 2009 May 21;7(10):2005-12
references.pmid: 19421434
references.citation: Org Lett. 2010 Oct 15;12(20):4678-81
references.pmid: 20845932
references.citation: Chem Commun (Camb). 2008 Mar 28;(12):1419-21
references.pmid: 18338042
references.citation: Chemistry. 2011 May 16;17(21):5766-76
references.pmid: 21509840
references.citation: Org Lett. 2004 Nov 25;6(24):4487-9
references.pmid: 15548057
references.citation: Org Biomol Chem. 2012 Aug 14;10(30):5861-72
references.pmid: 22504866
references.citation: J Am Chem Soc. 2014 Apr 16;136(15):5627-30
references.pmid: 24697791
references.citation: J Org Chem. 1996 Nov 1;61(22):7955-7958
references.pmid: 11667761
references.citation: Org Lett. 2011 Mar 4;13(5):908-11
references.pmid: 21288044
references.citation: Chem Rev. 2011 Nov 9;111(11):7523-56
references.pmid: 21851053
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 30;107(48):20655-60
references.pmid: 20705900
references.citation: Chemistry. 2013 Mar 11;19(11):3596-608
references.pmid: 23420709
references.citation: Prog Chem Org Nat Prod. 2023;121:1-546
references.pmid: 37488466
references.citation: Org Lett. 2001 May 17;3(10):1535-8
references.pmid: 11388860
references.citation: Org Lett. 2013 Apr 19;15(8):1914-7
references.pmid: 23550817
references.citation: Org Lett. 2007 Aug 30;9(18):3703-6
references.pmid: 17691801
references.citation: Angew Chem Int Ed Engl. 2008;47(33):6138-71
references.pmid: 18666089
references.citation: J Am Chem Soc. 2006 Feb 8;128(5):1448-9
references.pmid: 16448105
references.citation: Org Lett. 2003 Feb 20;5(4):439-41
references.pmid: 12583738
references.citation: Org Lett. 2005 Jan 6;7(1):75-7
references.pmid: 15624981
references.citation: Chem Commun (Camb). 2011 Aug 28;47(32):9051-3
references.pmid: 21766132
references.citation: Org Biomol Chem. 2013 Feb 13;11(10):1702-5
references.pmid: 23370443
references.citation: Angew Chem Int Ed Engl. 1999 Jul 12;38(13-14):1928-1931
references.pmid: 34182675
references.citation: Nature. 2009 Aug 13;460(7257):848-54
references.pmid: 19675645
references.citation: Angew Chem Int Ed Engl. 2012 Dec 21;51(52):13066-9
references.pmid: 23161813
references.citation: J Am Chem Soc. 2011 Oct 5;133(39):15308-11
references.pmid: 21859086
references.citation: Annu Rev Microbiol. 1996;50:375-99
references.pmid: 8905085
references.citation: J Am Chem Soc. 2010 Feb 3;132(4):1232-3
references.pmid: 20058922
references.citation: Org Lett. 1999 Jul 29;1(2):319-22
references.pmid: 10822569
references.citation: Org Lett. 2010 Sep 17;12(18):4034-7
references.pmid: 20726562
references.citation: Org Lett. 2007 Nov 22;9(24):5083-6
references.pmid: 17975920
references.citation: J Org Chem. 2010 Aug 20;75(16):5425-37
references.pmid: 20441229
references.citation: J Am Chem Soc. 2001 Feb 21;123(7):1533-4
references.pmid: 11456742
references.citation: Nat Chem Biol. 2014 Nov;10(11):921-3
references.pmid: 25218740
references.citation: Org Lett. 2006 Dec 21;8(26):6055-8
references.pmid: 17165928
references.citation: Nature. 2007 Feb 22;445(7130):900-3
references.pmid: 17314976
references.citation: J Am Chem Soc. 2007 Feb 28;129(8):2269-74
references.pmid: 17279755
references.citation: J Am Chem Soc. 2014 Oct 22;136(42):14710-3
references.pmid: 25275668
references.citation: Chem Commun (Camb). 2011 Sep 14;47(34):9705-7
references.pmid: 21792443
references.citation: Angew Chem Int Ed Engl. 2012 Oct 29;51(44):10938-53
references.pmid: 23011853
references.citation: J Am Chem Soc. 2008 Jan 23;130(3):810-1
references.pmid: 18163634
references.citation: Nat Prod Rep. 2011 Jan;28(1):15-25
references.pmid: 21125121
references.citation: Chem Commun (Camb). 2013 Sep 21;49(73):7985-96
references.pmid: 23903206
references.citation: J Org Chem. 2009 Mar 6;74(5):1835-41
references.pmid: 19199664
references.citation: Org Lett. 2003 Nov 13;5(23):4477-80
references.pmid: 14602029
references.citation: J Am Chem Soc. 2008 Dec 10;130(49):16807-11
references.pmid: 19049472
references.citation: Org Lett. 1999 Sep 9;1(5):823-4
references.pmid: 10823211
references.citation: Org Lett. 2011 Jul 15;13(14):3664-6
references.pmid: 21688862
references.citation: Angew Chem Int Ed Engl. 2013 Sep 16;52(38):10052-5
references.pmid: 23929596
references.citation: J Am Chem Soc. 2009 Jun 10;131(22):7570-2
references.pmid: 19445461
references.citation: Chem Rev. 2007 Dec;107(12):5471-569
references.pmid: 18072803
references.citation: Org Lett. 2014 Mar 7;16(5):1458-61
references.pmid: 24571064
references.citation: J Am Chem Soc. 2011 Jun 1;133(21):8134-7
references.pmid: 21542622
references.citation: Org Lett. 2008 Oct 16;10(20):4629-32
references.pmid: 18800844
references.citation: J Am Chem Soc. 2011 Sep 7;133(35):13922-5
references.pmid: 21846138
references.citation: Org Lett. 2011 Mar 4;13(5):904-7
references.pmid: 21291262
references.citation: J Am Chem Soc. 2009 Mar 25;131(11):3832-3
references.pmid: 19245198
references.citation: Chem Commun (Camb). 2006 May 21;(19):2001-11
references.pmid: 16767258
references.citation: J Am Chem Soc. 2011 Oct 12;133(40):15898-901
references.pmid: 21919540
references.citation: J Am Chem Soc. 2014 May 14;136(19):6908-11
references.pmid: 24758725
references.citation: J Am Chem Soc. 2002 Sep 4;124(35):10396-415
references.pmid: 12197742
references.citation: J Org Chem. 1996 Oct 18;61(21):7309-7315
references.pmid: 11667655
references.citation: Org Lett. 2005 Apr 28;7(9):1679-82
references.pmid: 15844879
references.citation: J Org Chem. 2013 Oct 18;78(20):10031-57
references.pmid: 24032758
references.citation: Angew Chem Int Ed Engl. 2011 Aug 16;50(34):7940-3
references.pmid: 21744447
references.citation: Org Lett. 2010 Aug 6;12(15):3548-51
references.pmid: 20670018
references.citation: Nat Commun. 2015 Apr 23;6:6903
references.pmid: 25903019
references.citation: J Am Chem Soc. 2010 Mar 3;132(8):2542-3
references.pmid: 20141139
references.citation: J Am Chem Soc. 2009 Sep 2;131(34):12084-5
references.pmid: 19663441
references.citation: Chemosphere. 2003 Jul;52(2):289-97
references.pmid: 12738253
references.citation: J Med Chem. 2013 Feb 28;56(4):1363-88
references.pmid: 23145854
references.citation: J Org Chem. 2007 Jun 22;72(13):4872-6
references.pmid: 17542637
references.citation: Angew Chem Int Ed Engl. 2001 Feb 2;40(3):603-607
references.pmid: 29712021
references.citation: Nature. 2009 Jan 29;457(7229):573-6
references.pmid: 19177127
references.citation: Angew Chem Int Ed Engl. 1999 Nov 2;38(21):3175-3177
references.pmid: 10556893
references.citation: J Org Chem. 2001 Jan 12;66(1):180-5
references.pmid: 11429897
references.citation: Biochemistry. 1972 Dec 5;11(25):4839-44
references.pmid: 4347704
references.citation: Angew Chem Int Ed Engl. 2007;46(34):6481-4
references.pmid: 17668434
references.citation: J Am Chem Soc. 2005 May 4;127(17):6178-9
references.pmid: 15853316
references.citation: Nature. 2006 Mar 16;440(7082):368-71
references.pmid: 16541079
references.citation: J Am Chem Soc. 2005 Apr 27;127(16):5806-7
references.pmid: 15839676
references.citation: ACS Catal. 2013 Jun 7;3(6):1076-1091
references.pmid: 23828735
references.citation: Org Lett. 2004 Nov 11;6(23):4383-5
references.pmid: 15524489
references.citation: J Biol Chem. 2009 Jul 10;284(28):18577-81
references.pmid: 19363038
references.citation: J Am Chem Soc. 2012 Oct 24;134(42):17714-21
references.pmid: 23057834
references.citation: J Am Chem Soc. 2004 Apr 7;126(13):4108-9
references.pmid: 15053591
references.citation: J Am Chem Soc. 2013 Jan 16;135(2):628-31
references.pmid: 23282101
references.citation: Org Lett. 2014 Sep 5;16(17):4460-3
references.pmid: 25124334
references.citation: Org Lett. 2009 Sep 17;11(18):4236-8
references.pmid: 19739690
references.citation: J Am Chem Soc. 2004 Nov 24;126(46):15038-9
references.pmid: 15547995
references.citation: Angew Chem Int Ed Engl. 2013 Mar 25;52(13):3642-5
references.pmid: 23427090
references.citation: J Am Chem Soc. 2003 Aug 27;125(34):10238-40
references.pmid: 12926946
references.citation: J Org Chem. 1997 Oct 17;62(21):7094-7095
references.pmid: 11671809
references.citation: Chem Asian J. 2012 Mar 5;7(3):456-65
references.pmid: 22315237
references.citation: J Am Chem Soc. 2006 Aug 16;128(32):10491-5
references.pmid: 16895415
references.citation: Angew Chem Int Ed Engl. 2002 Mar 1;41(5):841-3
references.pmid: 12491354
references.citation: Angew Chem Int Ed Engl. 2000 Oct 2;39(19):3430-3432
references.pmid: 11091378
references.citation: Alkaloids Chem Biol. 2012;71:1-165
references.pmid: 23189746
references.citation: Org Lett. 2006 Dec 7;8(25):5757-60
references.pmid: 17134265
references.citation: Chemistry. 2013 Sep 16;19(38):12649-52
references.pmid: 23956022
references.citation: Nat Prod Rep. 2013 Feb;30(2):227-36
references.pmid: 23258610
references.citation: J Am Chem Soc. 2014 Oct 29;136(43):15403-13
references.pmid: 25328977
references.citation: J Am Chem Soc. 2015 Mar 25;137(11):3795-8
references.pmid: 25738419
references.citation: Angew Chem Int Ed Engl. 2010;49(4):752-6
references.pmid: 20029867
references.citation: Chirality. 2014 Jul;26(7):328-43
references.pmid: 24339201
references.citation: J Am Chem Soc. 2009 Apr 29;131(16):5744-5
references.pmid: 19338329
references.citation: J Am Chem Soc. 2004 Apr 21;126(15):4790-1
references.pmid: 15080678
references.citation: Mar Drugs. 2015 Jun 30;13(7):4044-136
references.pmid: 26133553
references.citation: J Med Chem. 2009 May 14;52(9):2854-62
references.pmid: 19358610
references.citation: J Am Chem Soc. 2001 Feb 21;123(7):1531-2
references.pmid: 11456741
references.citation: Org Lett. 2001 Feb 22;3(4):503-5
references.pmid: 11178810
references.citation: J Am Chem Soc. 2008 Feb 13;130(6):2087-100
references.pmid: 18198870
references.citation: Nat Chem. 2014 Feb;7(2):146-52
references.pmid: 25615668
references.citation: Curr Opin Chem Biol. 1998 Apr;2(2):279-85
references.pmid: 9667930
references.citation: Nat Prod Rep. 2004 Feb;21(1):180-8
references.pmid: 15039842
references.citation: J Org Chem. 2014 Mar 7;79(5):2226-41
references.pmid: 24494597
references.citation: Angew Chem Int Ed Engl. 2005 Apr 15;44(16):2324-7
references.pmid: 15827954
references.citation: J Am Chem Soc. 2010 Mar 24;132(11):3664-5
references.pmid: 20192183
references.citation: Nature. 2005 Aug 25;436(7054):1191-4
references.pmid: 16121186
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10111-6
references.pmid: 16002467
references.citation: J Am Chem Soc. 2003 Jul 2;125(26):7822-4
references.pmid: 12822999
references.citation: Chem Rev. 2005 Dec;105(12):4730-56
references.pmid: 16351060
references.citation: J Am Chem Soc. 2014 May 14;136(19):6884-7
references.pmid: 24824195
references.citation: Chem Rev. 2006 Aug;106(8):3364-78
references.pmid: 16895332
references.citation: Chem Commun (Camb). 2006 Feb 28;(8):819-24
references.pmid: 16479280
references.citation: Org Lett. 2006 Aug 3;8(16):3597-9
references.pmid: 16869669
references.citation: Org Biomol Chem. 2014 Apr 21;12(15):2333-43
references.pmid: 24595745
references.citation: Curr Opin Chem Biol. 2007 Oct;11(5):553-60
references.pmid: 17881282
references.citation: Angew Chem Int Ed Engl. 2011 Aug 8;50(33):7641-4
references.pmid: 21739540
references.citation: Tetrahedron Lett. 1988;29(26):3205-3206
references.pmid: 31595095
references.citation: Org Lett. 2011 Mar 4;13(5):1222-5
references.pmid: 21309525
references.citation: Org Lett. 2012 Jan 6;14(1):256-9
references.pmid: 22145621
references.citation: Angew Chem Int Ed Engl. 2007;46(7):1132-5
references.pmid: 17191285