Deconstructive fluorination of cyclic amines Jose Roque , Yusuke Kuroda, Lucas T. Göttemann, Richmond Sarpong Sarpong Research Group, College of Chemistry, University of California, Berkeley, CA, USA 94720 N R F N Bz N Bz NH Bz 2b: 45% 2c: 39% 2d: 70% * 2h: 49% 2f: 33% N R N Bz N Bz N Bz N Bz NH Bz 2e: 40% F NH Bz F N Bz R R N Bz F 2i: 59% N Bz Me Me NH Bz F N Bz H H H H N Bz 2o: 46% N Me 2p: 81% 2q: 56% N Me O O 2g: 67% N Bz N Bz Me Me Me N Bz NH Piv 2r: 43% N Piv O O F F F n n Me 2t: 22% 2s: 28% N Bz CO 2 H N Bz HO 2 C NH Bz F F NH Bz F F 1b: R = Ac 1c: R = Boc 1d: R = Piv 1e 1f 1g 1h 1l 1j: R = Me 1k: R = Et 1m 1i 2m: 43% 2l: 50% (1:1 dr) 2j: 81% 2k: 85% 1o 1p: n = 1 1q: n = 2 1r 1s 1t MeO 2 C MeO 2 C O O O F O F NH Bz F N Bz MeO 2 C MeO 2 C 2n: 68% 1n O O O Substrate Scope N Bz N Bz F OH N Bz F F 11 10 12 N Bz O F F mechanistically driven reaction design O 12a: 76% F + H 2 O [Ag], F + N Bz O F F Me 12b: 54% N Bz 12c: 61% O F F AgBF 4 (0.25 equiv) acetone:H 2 O (1:1) rt, 15 h 10 Catalytic gem-Difluorination of Enamides N Bz F O N Bz OH N Bz O NH Bz F BzHN [Ox] then decarboxylative fluorination O Path B Path A radical ring-opening B C D Selectfluor N O H N F N F H PhthN O H PhthN F N O OH N F D 2a 7 8 9 6 6 H CHO Bz Bz Bz H Bz Bz H N Bz 1a AgBF 4 (4 equiv) acetone:H 2 O (1:9) 40 °C, 1 h 55% AgBF 4 (4 equiv) acetone:H 2 O (1:9) 40 °C, 1 h 70% AgBF 4 (4 equiv) acetone:H 2 O (1:9) 40 °C, 1 h 23% AgBF 4 (4 equiv) acetone:H 2 O (1:9) rt, 16 h 54% Possible Mechanisms for Ring Opening N Bz N Bz OH H 2 O A B 1a Ag(ll) + 5 Ag(l) N 1a Ag(l) Ph O Selectfluor N N Cl 2BF 4 Ag(ll) + Ag(l) 5 (1) F (2) N N F Cl 2BF 4 Selectfluor (1 equiv) AgBF 4 (1 equiv) acetone:H 2 O (1:9) 40 °C, 1 h N N F Cl BF 4 – 1) No consumption of Selectfluor when treated with equimolar amount of AgBF 4 2) Line broadening in the 1H NMR suggests the formation of a paramagnetic Ag(II) complex. 3) Downfield shifts of 1a observed upon addition of AgBF 4 suggests binding of Amide to Ag(I) Proposed Mechanism for Oxidation Step O N R N R E N R N R OH N R O E + A B C 1st stage: α-oxidation 2nd stage: radical ring-opening H 2 O [Ag] E + source deconstructive functionalization [Ag] cyclic amines as latent radical synthons [Ag] N R OH B N R O B N R N R A (1) Silver mediated oxidation - Uknown (3) Over-oxidation of hemiaminal N R N R OH A B H 2 O (2) Transition metal compatible with aqueous media Reaction Design Challenges: Strategy and Design N N F Cl 2BF 4 Selectfluor (4 equiv) N Bz N Bz F O AgBF 4 (4 equiv) acetone:H 2 O (1:9) 40 °C, 1 h entry yield (%) * 1 2 3 4 5 6 81 † 42 0 0 51 52 variation from the standard conditions none AgNO 3 instead of AgBF 4 no [Ag] NFSI instead of Selectfluor MeCN instead of acetone AgBF 4 (50 mol%) 1a 2a * Yield by 1 H NMR integration using Ph 3 CH as an internal standard. † Isolated yield. + Reaction Development N value-added bond construction R N R F O Csp 3 –F bond formation 1) Tune lipophilicity 2) Influence on pKa 3) Conformational tuning 4) Increased metabolic stability H 2 N F n R novel fluorinated building blocks N H H N O O F R complex/late-stage chemical diversification N R Challenges: - Unstrained ring system - Saturated heterocycle N H F paroxetine HO HO O H H N Me morphine N H peptide O O - Cyclic amines are found in drugs, agrochemicals, natural products, and peptides. - Piperidine is the most encountered heterocycle in U.S. FDA approved drugs. N H NH OMe O OMe OMe troxipide N H Me coniine N H N N H Me O H 2 N N O H H NC saxagliptin N H HN O HO 2 C Me HO Me alvimopan anabasine ritalin H N O N H O R OR O R N Me H O epimythrine Application of Deconstructive Functionalization HN Bz H N O Me Me O OMe F N Bz H N O Me Me O OMe HN Bz H N O Me Me N H O Me O OMe F N Bz H N O OMe O Me Me O 3a 4a 4d 4c 76% 50% (25% RSM) 39% (25% RSM) N OMe O O Me NHBz HN OMe O O Me NHBz F 3b 4b AgBF 4 (4 equiv) acetone:H 2 O (1:9) rt, 15 h 38% (40% RSM) AgBF 4 (4 equiv) acetone:H 2 O (1:9) rt, 15 h Peptide Diversification Carbon–Carbon Bond Cleavage (well established) functional group diversity (elusive) skeletal diversity FG C(sp 2 )–C(sp 2 ) bond cleavage (well established) O O olefin metathesis ozonolysis C(sp 3 )–C(sp 3 ) bond cleavage Not readily available (elusive) M [M] O [M] O [M] β-carbon fragmentation C–C activation M σ* M C–C M M C C C–C Bond 80–110 kcal/mol C–M Bond 20–70 kcal/mol Ring Strain 27 kcal/mol Kinetic barrier Thermodynamic considerations Acknowledgements and References 1) Hoveyda, A.H.; Zhugralin, A.R. Nature 2007, 450, 243–251. 2) Vougioukalakis, G.C.; Grubbs, R.H. Chem. Rev. 2010, 110, 1746-1787. 3) Vitaku, E.; Smith, D.T.; Njardason, J.T. J. Med. Chem. 2014, 57, 10257-10274. 4) Sun, H.;Tawa,G.; Wallqvist, A. Drug Discov.Today 2012,17, 310–324. 5) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330. 6) Roque, J. B.; Kuroda , Y.; Göttemann, L. T.; Sarpong, R. Science 2018, 361, 171–174. 7) Roque, J. B.; Kuroda, Y.; Göttemann, L. T.; Sarpong, R. Nature 2018, 564, 244–248. Prof. Richmond Sarpong Dr. Yusuke Kuroda Lucas Göttemann HN Piv O Ph O C-O bond formation HN Piv NC C-C bond formation HN Piv MeS C-S bond formation HN Piv N 3 C-N bond formation N O t Bu Cyclization Peptide Diversification: N Piv CO 2 H NH Piv O O N Bz N Bz 1) [Ag] 2) Base 89% over two steps (94%)* 1) [Ag] NBS 44% one chromatography event 1a 13 15 14 Ring Contraction Skeletal Remodeling H N HN Piv O R N H O CO 2 Me Me Me Me 1) [Ag], NCS 2) Nuc N Piv Other Directions: Deconstructive Diversification . .