AYMMETIC PALLADIUM-CATALYZED ALKEE CABAMIATI EACTI F TE YTEI F CYCLIC ULFAMIDE Chem. Eur. J. 2016, 22, 5919 5922 Zachary J. Garlets, Kaia. Parenti, and John P. Wolfe James Johnson Wipf Group Current Literature 2-11-17 James Johnson @ Wipf Group Page 1 of 19 3/4/2017
2 Alkene Difunctionalization: Carboamination 2 Ethylene is produced from from petroleum and natural gas by thermal cracking. Largest chemical produced organic compound. Alkenes used extensively in the polymer industry. Carboamination 1 2 3 or 1 2 3 Inexpensive starting materials are rapidly functionalized in a single step Easily accessed heterocycles and amine building blocks (amino acids). James Johnson @ Wipf Group Page 2 of 19 3/4/2017
3 Intramolecular Palladium-Catalyzed Carboamination eactions X Y n -B() 2 -Br -Br [Pd] Base X Y n P 1 2 n 3 2 1 3 4 5 6 1 2 3 5 4 1 Boc 1 2 1 Boc 1 2 1 3 2 4 1 3 2 1 2 X 1 1 James Johnson @ Wipf Group Page 3 of 19 3/4/2017
4 Intermolecular Carboamination 2 icl 2 (PMe 3 ) 2 (10 mol%) Zn dust (5 eq.) 2 Cu(Tf) 2 (20 mol%) 1,10-phen (25 mol%) 1 1 Mn 2 (255 mol%) 3 1 toluene, 100 C, 12 h 20 examples 21-90% 1 3 Cbz BF 3 K DCE, 105 C, 24 h 35 examples 35-78% Cbz Ph 2 2Ph 2 F 1 1.6 mol% Cu(C 3 C) 4 BF 4 (2.5 mol%) PhC, 60 C 1 2 2 Ph 1 [Cp*Co(C)I 2 ] (10 mol%) AgbF 6 (20 mol%) CsAc (25 mol%) K 3 P 4 (25 mol%) TFE, 3Å M 40 C, 22 h 17 examples 30-88% 1 s Cat. (20 mol%) 1 2 Fe(phen) 2 3 (bf 6 ) 3 1 3 DME, a 3 2 P 4-10 C, 12 h s 17 examples 50-88% Cat. 2:1 dr to >20:1 dr; 87-96% ee 5 6 Cat. 5 mol% 5 Tf 7 4-Me-Ph 1 2 1 CCl 3, 2,6-lutadine 3 455 nm LEDs, rt, 24 h 3 Tf 2 28 examples 35-77% 1.7:1 dr to 16:1 dr 6 7 BF 4 - Mes Ph Cat. 1 2 2 Br X 1 Pd 2 (dba) 3 (2.5 mol%) CPhos (5 mol%) or L LitBu 2 toluene:t-amyl- 2 3 110 C, 24 h 20 example 20-94% dr 19:1 to 49:1; 63-73 % ee X 3 Me PCy 2 L rg. Lett. 2013, 15, 2502-2505; AC Catal., 2016, 6 (10), pp 7183 7187 James Johnson @ Wipf Group Page 4 of 19 3/4/2017
5 Wolfe Group Chemistry Boc 1 -Br Pd 2 (dba) 3 (2.5 mol%) ()-iphos-pe (7.5 mol%) atbu toluene, 90 C 23 examples 61-80% 72-94% ee Boc 1 -Br 1 2 PMP -Tf Pd(Ac) 2 (4 mol%) CPhos (10 mol%) LitBu tbu, 82 C, 16 h 9 examples 45-89% 5:1 to 13:1 dr 1 2 PMP C 2 mol% [Pd 2(dba) 3 ] 6 mol% ()-iphos-pe atbu xylenes, 115 C 56-89% (77-95% ee) C C 4 9 Br TM Pd 2 (dba) 3 P(2-furyl) 3 atbu, xylenes tbu 140 C C 4 9 68% >20:1 dr tbu 1) TFA 2) PMBC TM 72% C 4 9 PMP Pd 2 (dba) 3 PCy 3 BF 4 atbu, toluene 110 C 91% >20:1 dr C 4 9 Et PMP C 4 9 C 4 9 James Johnson @ Wipf Group Page 5 of 19 3/4/2017
6 Cyclic ulfamides 2 F Active against gram-positive methicillin and vancomycin resistant bacteria Ac 2 Low µm inhibition of norovirusus Me 2 F β-secretase-1 inhibitor Biologically active Enantioselective synthesis usually multi-step starting from amino acids 5 steps 2 2 nly one previous asymmetric metal-catalyzed synthesis rg. Lett., 2013, 15 (4), pp 796 799 Pd 2 (dba) 3 (2.5 mol%) 10 mol% L toluene, 65 C, 3 h 14 examples, 66-98% 90-93% ee Ph P L Ph James Johnson @ Wipf Group Page 6 of 19 3/4/2017
7 Anti-aminopalladation Tf Pd(Ac) 2 (2 mol%) u-phos(5 mol%) LitBu PhCF 3, 100 C 14 examples 51 to 92 % Anti-aminopalladation Chem. Eur. J. 2014, 20, 8782 8790 D James Johnson @ Wipf Group Page 7 of 19 3/4/2017
8 ptimization of Cyclization with -Tf James Johnson @ Wipf Group Page 8 of 19 3/4/2017
9 James Johnson @ Wipf Group Page 9 of 19 3/4/2017
10 James Johnson @ Wipf Group Page 10 of 19 3/4/2017
11 James Johnson @ Wipf Group Page 11 of 19 3/4/2017
12 yn vs Anti-aminopalladation D Ph PhBr Pd(Ac) 2 (2 mol%) X-Phos(5 mol%) atbu toluene, 100 C 47%, 4:1 dr yn-aminopalladation D PhBr Pd(Ac) 2 (2 mol%) C-Phos(5 mol%) atbu PhCF 3, 100 C 90%, >20:1 dr Anti-aminopalladation Ph D Mechanism highly solvent and ligand dependent Chem. Eur. J. 2014, 20, 8782 8790 James Johnson @ Wipf Group Page 12 of 19 3/4/2017
13 Title Paper -Br Pd 2 (dba) 3 (1 mol%) ()-iphos-pe (5 mol%) atbu xylenes 120 C, 18 h yn-aminopalladation D Chem. Eur. J. 2016, 22, 5919 5922 James Johnson @ Wipf Group Page 13 of 19 3/4/2017
14 ptimization of Protecting Groups James Johnson @ Wipf Group Page 14 of 19 3/4/2017
15 eaction cope Ph Me 2 Me 96% (93:7 er) X = Br 95% (94:6 er) X = I 75% (75:25 er) 85% (95:5 er) 89% (94:6 er) 75% (96:6 er) Me 74% (92:8 er) 74% (90:10 er) Ph 77% (88:12 er) CF 3 69% (90:10 er) F 72% (92:8 er) 58% (68:32 er) 21% (62:38 er) F 3 C 34% (95:5 er) TM 44% (94:6 er) Me James Johnson @ Wipf Group Page 15 of 19 3/4/2017
16 Anti-aminopalladation yn-aminopalladation lefin substitution not tolerated James Johnson @ Wipf Group Page 16 of 19 3/4/2017
17 Deuterium Labeling tudies EWD groups decrease dr anti-aminopalladation pathway Addition of water (4b) improved yield. o effect on dr or er James Johnson @ Wipf Group Page 17 of 19 3/4/2017
18 Deprotection James Johnson @ Wipf Group Page 18 of 19 3/4/2017
19 Conclusions Developed enantioselective Pd-catalyzed alkene carboamination with good to high enantio selectivity Example of controlling syn vs anti-aminopalladation Expansion to intermolecular variant? James Johnson @ Wipf Group Page 19 of 19 3/4/2017