title: Methodological Advances Permit the Stereocontrolled Construction of Diverse Fully Synthetic Tetracyclines Containing an All-Carbon Quaternary Center at Position C5a.
abstract: Here we describe chemical innovations that enable the preparation of fully synthetic tetracyclines containing an all-carbon quaternary, stereogenic center at position C5a, a structurally novel class of compounds in this important family of therapeutic agents. In the key transformation and an important extension of the powerful Michael-Claisen cyclization (AB plus D) approach to the construction of fully synthetic tetracyclines, we show that the six-membered C ring comprising a C5a quaternary carbon center can be assembled by highly stereocontrolled coupling reactions of β-substituted AB enones and o-toluate ester anion D-ring precursors. Novel and versatile β-functionalization reaction sequences employing tris(methylthio)methyllithium and 2-lithio-1,3-dithiane have been developed to transform the AB enone 1 (the key precursor to fully synthetic tetracyclines) into a diverse range of β-substituted AB enone products, including a highly efficient, single-operation method for the synthesis of a β-methyl ester-substituted AB enone. A C5a-C11a-bridged cyclopropane tetracycline precursor was found to undergo efficient and regioselective ring-opening reactions with a range of nucleophiles in the presence of magnesium bromide, thus providing another avenue for the preparation of fully synthetic tetracyclines containing an all-carbon quaternary center at position C5a. Two compounds prepared from the bridged cyclopropane intermediate served as (further) diversifiable branch-points, allowing maximally expedient synthesis of C5a-substituted tetracyclines by final-step diversification.
authors.affiliation: Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Wright
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Myers
references.citation: Org Lett. 2008 Jul 3;10(13):2809-12
references.pmid: 18522391
references.citation: J Med Chem. 2011 Jun 9;54(11):3704-31
references.pmid: 21500832
references.citation: Org Lett. 2005 Nov 10;7(23):5223-5
references.pmid: 16268543
references.citation: J Org Chem. 2007 Sep 14;72(19):7390-3
references.pmid: 17715971
references.citation: Chem Sci. 2011 Sep;2(9):1710-1718
references.pmid: 21949588
references.citation: J Am Chem Soc. 2006 May 17;128(19):6312-3
references.pmid: 16683784
references.citation: EMBO J. 2001 Apr 17;20(8):1829-39
references.pmid: 11296217
references.citation: Science. 2005 Apr 15;308(5720):395-8
references.pmid: 15831754
references.citation: Helv Chim Acta. 1976 Mar 10;59(2):439-52
references.pmid: 1254499
references.citation: J Am Chem Soc. 2008 Dec 31;130(52):17913-27
references.pmid: 19053822
references.citation: J Org Chem. 2004 Jan 9;69(1):122-9
references.pmid: 14703387
references.citation: Angew Chem Int Ed Engl. 2002 Mar 15;41(6):996-1000
references.pmid: 12491292
references.citation: J Med Chem. 2008 May 22;51(10):2871-8
references.pmid: 18260614
references.citation: Angew Chem Int Ed Engl. 2008;47(35):6579-82
references.pmid: 18651685
references.citation: J Med Chem. 2011 Mar 10;54(5):1511-28
references.pmid: 21302930
references.citation: Cell. 2000 Dec 22;103(7):1143-54
references.pmid: 11163189