title: Asymmetric functional organozinc additions to aldehydes catalyzed by 1,1'-bi-2-naphthols (BINOLs).
abstract: Chiral alcohols are ubiquitous in organic structures. One efficient method to generate chiral alcohols is the catalytic asymmetric addition of a carbon nucleophile to a carbonyl compound since this process produces a C-C bond and a chiral center simultaneously. In comparison with the carbon nucleophiles such as an organolithium or a Grignard reagent, an organozinc reagent possesses the advantages of functional group tolerance and more mild reaction conditions. Catalytic asymmetric reactions of aldehydes with arylzincs, vinylzincs, and alkynylzincs to generate functional chiral alcohols are discussed in this Account. Our laboratory has developed a series of 1,1'-bi-2-naphthol (BINOL)-based chiral catalysts for the asymmetric organozinc addition to aldehydes. It is found that the 3,3'-dianisyl-substituted BINOLs are not only highly enantioselective for the alkylzinc addition to aldehydes, but also highly enantioselective for the diphenylzinc addition to aldehydes. A one-step synthesis has been achieved to incorporate Lewis basic amine groups into the 3,3'-positions of the partially hydrogenated H8BINOL. These H8BINOL-amine compounds have become more generally enantioselective and efficient catalysts for the diphenylzinc addition to aldehydes to produce various types of chiral benzylic alcohols. The application of the H8BINOL-amine catalysts is expanded by using in situ generated diarylzinc reagents from the reaction of aryl iodides with ZnEt2, which still gives high enantioselectivity and good catalytic activity. Such a H8BINOL-amine compound is further found to catalyze the highly enantioselective addition of vinylzincs, in situ generated from the treatment of vinyl iodides with ZnEt2, to aldehydes to give the synthetically very useful chiral allylic alcohols. We have discovered that the unfunctionalized BINOL in combination with ZnEt2 and Ti(O(i)Pr)4 can catalyze the terminal alkyne addition to aldehydes to produce chiral propargylic alcohols of high synthetic utility. The reaction was conducted by first heating an alkyne with ZnEt2 in refluxing toluene to generate an alkynylzinc reagent, which can then add to a broad range of aldehydes at room temperature in the presence of BINOL and Ti(O(i)Pr)4 with high enantioselectivity. It was then found that the addition of a catalytic amount of dicyclohexylamine (Cy2NH) allows the entire process to be conducted at room temperature without the need to generate the alkynylzincs at elevated temperature. This BINOL-ZnEt2-Ti(O(i)Pr)4-Cy2NH catalyst system can be used to catalyze the reaction of structurally diverse alkynes with a broad range of aldehydes at room temperature with high enantioselectivity and good catalytic activity. The work described in this Account demonstrates that BINOL and its derivatives can be used to develop highly enantioselective catalysts for the asymmetric organozinc addition to aldehydes. These processes have allowed the efficient synthesis of many functional chiral alcohols that are useful in organic synthesis.
authors.affiliation: Department of Chemistry, University of Virginia , Charlottesville, Virginia 22904-4319, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Pu
mesh_terms: D000447:Aldehydes / Q000737:chemistry*; D002384:Catalysis; D009284:Naphthols / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry*; D014753:Vinyl Compounds / Q000737:chemistry; D017967:Zinc Compounds / Q000737:chemistry*
chemical_list: D000447:Aldehydes; C406944:BINOL, naphthol; D009284:Naphthols; D009942:Organometallic Compounds; D014753:Vinyl Compounds; D017967:Zinc Compounds
references.citation: J Org Chem. 2010 May 7;75(9):2836-50
references.pmid: 20377255
references.citation: Acc Chem Res. 2000 Jun;33(6):373-81
references.pmid: 10891055
references.citation: Org Lett. 2005 Jun 9;7(12):2381-3
references.pmid: 15932203
references.citation: Angew Chem Int Ed Engl. 2003 Dec 1;42(46):5747-9
references.pmid: 14661213
references.citation: J Org Chem. 2013 Mar 15;78(6):2256-65
references.pmid: 23327411
references.citation: Org Lett. 2008 Jul 3;10(13):2709-12
references.pmid: 18522393
references.citation: Chem Rev. 2003 Aug;103(8):3213-46
references.pmid: 12914496
references.citation: Chem Soc Rev. 2006 May;35(5):454-70
references.pmid: 16636728
references.citation: Angew Chem Int Ed Engl. 2005 Dec 23;45(2):273-7
references.pmid: 16315332
references.citation: Angew Chem Int Ed Engl. 2005 Dec 16;45(1):122-5
references.pmid: 16299819
references.citation: Angew Chem Int Ed Engl. 2004 Feb 13;43(8):1017-21
references.pmid: 14966896
references.citation: J Am Chem Soc. 2001 Oct 3;123(39):9687-8
references.pmid: 11572696
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5417-20
references.pmid: 15026570
references.citation: J Am Chem Soc. 2010 Apr 14;132(14):5186-92
references.pmid: 20307084
references.citation: Angew Chem Int Ed Engl. 2006 Jun 19;45(25):4175-8
references.pmid: 16721894
references.citation: Adv Synth Catal. 2009 May;351(7-8):
references.pmid: 24353484
references.citation: J Org Chem. 2004 Oct 1;69(20):6666-73
references.pmid: 15387588
references.citation: J Am Chem Soc. 2008 Oct 29;130(43):14052-3
references.pmid: 18834121
references.citation: Org Lett. 2002 May 30;4(11):1855-7
references.pmid: 12027631
references.citation: Angew Chem Int Ed Engl. 2011 Mar 1;50(10):2368-70
references.pmid: 21351356
references.citation: Science. 1974 Mar 1;183(4127):803-9
references.pmid: 17780761
references.citation: Chem Commun (Camb). 2002 Jan 21;(2):172-3
references.pmid: 12120356
references.citation: Chem Rev. 1998 Nov 5;98(7):2405-2494
references.pmid: 11848968
references.citation: J Am Chem Soc. 2006 Jan 11;128(1):8-9
references.pmid: 16390095
references.citation: Chem Rev. 2003 Aug;103(8):3155-212
references.pmid: 12914495
references.citation: J Am Chem Soc. 1986 Sep 1;108(19):6071-2
references.pmid: 22175391
references.citation: Org Lett. 2002 Nov 14;4(23):4143-6
references.pmid: 12423107
references.citation: J Org Chem. 1997 Feb 7;62(3):444-445
references.pmid: 11671428
references.citation: J Am Chem Soc. 2005 Jun 15;127(23):8355-61
references.pmid: 15941269
references.citation: J Am Chem Soc. 2006 Aug 30;128(34):10996-7
references.pmid: 16925396
references.citation: Acc Chem Res. 2012 Feb 21;45(2):150-63
references.pmid: 21834528
references.citation: J Am Chem Soc. 2011 Aug 3;133(30):11780-94
references.pmid: 21688803
references.citation: Org Lett. 2006 May 11;8(10):2019-21
references.pmid: 16671771
references.citation: Chem Rev. 2001 Mar;101(3):757-824
references.pmid: 11712502