Asymmetric adical eactions Zhen Liu 08/30/2018
Contents Introduction eactions Using Chiral Auxiliary Chiral Lewis Acid-diated eactions Transition tal-catalyzed eactions eactions Using Chiral rganocatalysts Miscellaneous 2
Contents Introduction eactions Using Chiral Auxiliary Chiral Lewis Acid-diated eactions Transition tal-catalyzed eactions eactions Using Chiral rganocatalysts Miscellaneous 3
Introduction adical Chemistry 1 2 adical Features: Very reactive early planar (slight pyramidal) adicals Stability: 1 2 > 1 > 1 hyperconjugation effect 3 2 Et Cl 2 C (+)-1 Cl 2 hυ Et Cl 2 C Cl (±)-2 E π* Electrophilic ucleophilic Brown,. C. et. al. J. Am. Chem. Soc. 1940, 62, 3435. n (long pair) i Pr Et ( )-3 C DTBP Δ i Pr Et (±)-4 adical SM 1 2 Doering, W. von E. et. al. J. Am. Chem. Soc. 1952, 74, 3000. Parsons, A. F. An Introduction to Free adical Chemistry, xford: Blackwell Science 2000. 4
Introduction adical Chemistry adical Precursor Initiation adical-1 Propagation adical-2 Termination eutral Species Chain Process ne example: Common radical initiators: Br Et DTBP Et chanism: hυ or Δ 2 Br + Br Br initiation steps C C AIB The Fate of adicals Et 3 B Et Et + Br Br Br Et Et Br propagation steps Br + Br Atom Transfer Addtion to eutral Molecule Fragmentation 10 4 10 8 dm 3 mol 1 s 1 10 4 10 8 dm 3 mol 1 s 1 10 5 10 9 s 1 Br Br Br 2 Br Br Et Br Et termination steps Br Coupling 10 9 dm 3 mol 1 s 1 Sibi, M. P. et. al. Chem, ev. 2003, 103, 3263. 5
Contents Introduction eactions Using Chiral Auxiliary Chiral Lewis Acid-diated eactions Transition tal-catalyzed eactions eactions Using Chiral rganocatalysts Miscellaneous 6
eactions Using Chiral Auxiliary Porter, Giese and Lindner, 1989 gcl ab 4, 25 ºC + 40 : 1 vs. X X Favored Unfavored Porter,. A. et. al. J. Am. Chem. Soc. 1989, 111, 8311. Giese, 1990 gcl abd 4, 25 ºC D + D 13 : 1 Giese, B. et. al. J. Am. Chem. Soc. 1990, 112, 6741. 7
eactions Using Chiral Auxiliary aito, 2000 S 2 Bn I (5 eq.), BF 3 Et 2 (2 eq.) Bu 3 Sn (2.5 eq.), BEt 3 (5 eq.) DCM, 78 ºC S 2 Bn S 2 Entry I Yield (%) d.r. 1 EtI 80 Bn 95:5 2 PrI S 80 A 96:4 3 Attack BuI from si face is 83 preferred >98:2 Bn Mo(C) 6 (0.7 eq.) 1 Li 2 i Pr 2 /C, reflux S 2 i Pr TF i Pr 2 D-Valine 55% over 4 steps S Bn S Bn Bn S B C D aito, T. et. al. J. rg Chem. 2000, 65, 176. 8
eactions Using Chiral Auxiliary Sibi, 2002 C 2 Et i PrI (10 eq.), Sm(Tf) 3 (1 eq.) Bu 3 Sn (6 eq.), BEt 3 (3 eq.) 2, DCM/TF, 78 ºC Tf Tf Sm Tf C 2 Et x i Pr i Pr i Pr C 2 Et 95%, d.r. = 29:1 C 2 Et Br (10 eq.) Sm(Tf) 3 (1 eq.) Bu 3 Sn (6 eq.), BEt 3 (3 eq.) 2, DCM/TF, 78 ºC 71% C 2 Et I amds, TF 50% C 2 Et Li, 2 2 88% Sibi, M. P. et. al. J. rg. Chem. 2002, 67, 1738. 9 C 2 Et 1. B 3 /TF, 15 ºC 2. PPTS, reflux 3. BBr 3 (4 eq.) 69% for three steps ( )-Enterolactone
Contents Introduction eactions Using Chiral Auxiliary Chiral Lewis Acid-diated eactions Transition tal-catalyzed eactions eactions Using Chiral rganocatalysts Miscellaneous 10
Chiral Lewis Acid-diated eactions ydrogen Atom Transfer Bn I Bn (S)-L1 MgI 2 /Et 2 Bu 3 Sn, DCM, 78 ºC 5a, = C 2 5b, = C 2 Et 5c, = C 2 Bn 5d, = Entry Substrate Yield (%) ee (%) 1 2 3 4 5a 5b 5c 5d 88 62 () 84 65 () 89 58 () 78 30 (S) Conjugate adical eaction Murakata, M. et. al. Tetrahedron1999, 55, 10295. 2-aph C 2 Mg(Cl 4 ) 2 /L2 (1.3 eq.) X, BEt 3 / 2 Bu 3 Sn, DCM, 78 ºC 2-aph C 2 L2 Entry X Yield (%) ee (%) 1 2 3 4 AcBr C 2 Br EtI i PrI 76 80 71 65 72 85 () 62 83 () 5 I 54 27 () Sibi, M. P. et. al. Angew. Chem. Int. Ed. 2001, 40,1293. 11
Chiral Lewis Acid-diated eactions Cyclization eaction Et Br L3 (1.1 eq.) Mg(Cl 4 ) 2 (1 eq.) BEt 3,toluene, 4Å MS, 78 ºC Br C 2 Et 67% (94% ee) Et Mg Yang, D. et. al. J. Am. Chem. Soc. 2001, 123, 8612. Allylation eaction Br 1 + Z 2 2 3 3 MX 2, BEt 3 / 2 DCM, 78 ºC 1 + Z Br X M X vs. Entry 1 2 Config. MX 2 Z Yield (%) ee (%) 1 2 3 4 5 3 (, ) (, ) Zn(Tf) 2 SnBu 3 84 42 (S) Zn(Tf) 2 Si(Et) 3 65 60 (S) 88 90 () (, ) Zn(Tf) 2 Si 3 86 68 (S) -(C 2 ) 2 - (S, S) MgI 2 Si 3 65 88 () (, ) MgI 2 Si 3 X M X Porter,. A. et. al. J. rg. Chem. 1997, 62, 6702. 12
Chiral Lewis Acid-diated eactions Addition-Trapping eaction MgI 2 /L2 (30 mol%) I, BEt 3 / 2 + SnBu 3 DCM, 78 ºC = i Pr, 93%, 37:1 d.r., 93% ee =, 84%, 99:1 d.r., 97% ee Sibi, M. P. et. al. J. rg. Chem. 2001, 123, 9472. L2 Cycloaddition eaction + Eu(Tf) 3 (10 mol%) L4 (20 mol%) [u(bpy) 3 Cl 2 ] (5 mol%) i Pr 2 Et, C, rt., hυ trans-6 (92% ee) 71%, 7:1 d.r. L4 ab 4 n Bu Eu(Tf) 3 (10 mol%) L5 (30 mol%) [u(bpy) 3 Cl 2 ] (5 mol%) i Pr 2 Et, C, rt., hυ cis-6 (95% ee) 78%, 4.5:1 d.r. L5 n Bu *L n M u(bpy) 2+* 3 hυ i Pr 2 Et *L n M u(bpy) 2+ 3 u(bpy) + 3 [2+2] trans-6 or cis-6 Yoon, T. P. et. al. Science 2014, 344, 392. 13 e
Chiral Lewis Acid-diated eactions ggers, 2014 Λ-Ir (2 mol%) 1 a 2 P 4 (1.1 eq.) + Br EWG 2 visible light, 40 ºC 2 7 8 9 2 2 C 2 i Pr 1 EWG Br S Ir S Λ-Ir C C + PF 6 97%, 99% ee 87%, 97% ee 86%, 91% ee [Ir] EWG Br Λ-Ir [Ir] Asymmetric Catalysis [Ir] EWG SET [Ir] 9 PS PS + toredox Catalysis SET Br PS* Br EWG EWG 7 EWG ggers, E. et. al. ature 2014, 515, 100. 14 Visible light
Contents Introduction eactions Using Chiral Auxiliary Chiral Lewis Acid-diated eactions Transition tal-catalyzed eactions eactions Using Chiral rganocatalysts Miscellaneous 15
Transition tal-catalyzed eactions Cross-Coupling eactions Bn 1 + 2 ZnX Br racemic icl 2 glyme (10 mol%) ()-( i Pr)-Pybox (13 mol%) DMI/TF, 0 ºC Bn 2 1 up to 96% ee up to 90% yield i Pr ()-( i Pr)-Pybox i Pr Fu, G. C. et. al. J. Am. Chem. Soc. 2005, 127, 4594. Bpin X racemic 1 icl 2 glyme (10 mol%) (S, S)-L6 (13 mol%) 2 ZnBr (1.8 eq.) DMA/TF, 0 ºC Bpin 2 1 up to 95% ee up to 86% yield Ar Ar (S, S)-L6 (Ar = o-tolyl) Fu, G. C. et. al. Science 2016, 354, 1265. 2 1 2 Cl + racemic (1.2 eq.) X cat. CuCl/(S)-L7 hυ (blue LED) Li (1.5 eq.) toluene, 40 ºC 2 1 2 up to 99% ee up to 98% yield X P (S)-L7 Fu, G. C. et. al. Science 2016, 351, 681. 16
Transition tal-catalyzed eactions Alkene Difunctionalization eactions n Ar n = 1, 2 + I CF 3 Cu(C)4 PF 6 (7.5 mol%) (S, S)-L3 (7.5 mol%) MTBE, rt. Buchwald, S. L. et. al. Angew. Chem. Int. Ed. 2013, 52, 12655. n Ar CF 3 up to 83% ee up to 88% yield L3 n n = 1, 2 ', Cu(C) 4 PF 6 /L3 n ' n 3 n Ar S 2 n Ar Ar' I(Ac) 2, TMS 3 Ag 2 C 3, TsCl DTBP, Ar' 2 BF 4 Buchwald, S. L. et. al. J. Am. Chem. Soc. 2015, 137, 8069. Ar + I CF 3 Cu(C) 4 PF 6 (1 mol%) L2 (1.5 mol%), TMSC C, rt. Ar CF 3 C up to 99% ee L2 Liu, G. et. al. J. Am. Chem. Soc. 2016, 138, 15547. 17
Transition tal-catalyzed eactions C Functionalization Ar cat. CuAc/L* TMSC (2 3 eq.) C FSI (1.5 eq.) Ar C 6 6, rt., 2 2 2 3 L* 3 C 71%, 97% ee C 3 73%, 97% ee Cl C S 2 76%, 98% ee Liu, G. et. al. Science 2016, 353, 6303. S C 80%, 96% ee 2 i Pr Co i Pr 2 C 2 2 S 2 Cat-1 (2 mol%) Benzene, rt. 92%, 96:4 d.r. 2 C 2 S i Pr Cat-1 i Pr 2 C 2 S 2 Ar Cat-1 2 C 2 S [Co] Ar 2 C -abstraction 2 S [Co] Substitution Ar 2 C 2 S Ar Zhang, X. P. et. al. Chem. Sci. 2015, 6, 1219. 18
Contents Introduction eactions Using Chiral Auxiliary Chiral Lewis Acid-diated eactions Transition tal-catalyzed eactions eactions Using Chiral rganocatalysts Miscellaneous 19
eactions Using Chiral rganocatalysts ydrogen-bonding rganocatalysts (2.5 eq.) I Bu 3 Sn, BEt 3, toluene, 78 ºC 81%, 84% ee Bach, T. et. al. Angew. Chem. Int. Ed. 2004, 43, 5849. PET catalyst (30 mol%) toluene, 40 ºC, hυ 64%, 70% ee Bach, T. et. al. ature 2005, 436, 1139. Si 3 SnBu 3 P (10 mol%) 2 Si 3 2 [Ir(ppy) 2 (dtbpy)]pf 6 (2 mol%) dioxane, rt., hυ Et 2 C C 2 Et 90%, 92% ee P 2 * Knowles,.. et. al. J. Am. Chem. Soc. 2013, 135, 17735. 20
eactions Using Chiral rganocatalysts Chiral Brønsted Acids Bn I (5 eq.), QP (2 eq.) BEt 3 (0.5 eq.)/ 2 DCM/ 2, rt. Bn Bn I (5 eq.), QDP (2 eq.) BEt 3 (0.5 eq.)/ 2 DCM/ 2, rt. Bn Entry I Yield (%) :S 1 n cti 50 40:60 2 i PrI 83 21:79 Entry I Yield (%) :S 1 n cti 50 58:42 2 i PrI 83 62:38 3 I 60 1:>99 3 I 60 >99:1 2 P 2 Si-face attack 2 P 2 Quinine, QP 2 P 2 Quinidine, QDP Jang, D.. et. al. Chem. Commun. 2006, 5045. 21
eactions Using Chiral rganocatalysts Chiral Amine Catalysts SM Activation + ' Si 3 CA (2 eq.), ac 3 DME, 20 ºC CF 3 C (20 mol%) ' 70 88%, 87 95% ee IP 9.8 ev 3 Si IP 8.8 ev 3 Si CA oxidation t Bu IP 7.2 ev SM-activated CA oxidation Si 3 MacMillan, D. W. C. et. al. Science 2007, 316, 582. 22
eactions Using Chiral rganocatalysts Chiral Amine Catalysts SM Activation + FeCl 3, a 2, 2 (20 mol%) 49 78%, up to 90% ee Sibi, M. P. et. al. J. Am. Chem. Soc. 2007, 129, 4124. + TMS ' CA (2 eq.), DTBP, 2 Acetone, 20 ºC (20 mol%) ' 55 92%, 86 96% ee MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 2007, 129, 7004. + KF 3 B ' CA (2 eq.), ac 3, 2 DME, 50 ºC (20 mol%) ' 61 93%, 89 96% ee MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 2008, 130, 398. 23
eactions Using Chiral rganocatalysts rge otoredox with rganocatalysis 2+ n Bu + Br Fluorescent light rganocatalyst, u(bpy) 3 Cl 2 2,6-lutidine, DMF, rt. ex 84%, 96% ee Tf u 2Cl rganocatalyst u(bpy) 3 Cl 2 Si-face open u(bpy) 3 2+* hυ u(bpy) 3 2+ Br u(bpy) + 3 Br MacMillan, D. W. C. et. al. Science 2008, 322, 77. 24
eactions Using Chiral rganocatalysts + CF 3 I Ir(ppy) 2 (dtb-bpy)pf 6 (0.5 mol%) 2,6-lutidine, DMF, 20 ºC TFA CF 3 90 99% ee (20 mol%) MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 2009, 131, 10875. + fac-ir(ppy) 3 (0.5 mol%) Br Ar Ar 2,6-lutidine, DMS, rt. 87 97% ee Tf Bn (20 mol%) MacMillan, D. W. C. et. al. J. Am. Chem. Soc. 2010, 132, 13600. 25
Contents Introduction eactions Using Chiral Auxiliary Chiral Lewis Acid-diated eactions Transition tal-catalyzed eactions eactions Using Chiral rganocatalysts Miscellaneous 26
Chiral rganotin ydride or Chiral Thiols Chiral rganotin ydride Br Et lewis acid (1 eq.) stannane (1.1 eq.) 9-BB, toluene, 78 ºC Et Mn Cl men = 2 Sn(men) 2 75%, 96% ee Schiesser, C.. et. al. Chem. Commun. 1999, 1665. Chiral Thiol C 2 Bn C 2 Bn + S Si (4-CF 3 C 6 4 ) 2 = 10-Bu-9-anthryl (3 mol%) Benzoyl peroxide, toluene, rt., hυ C 2 Bn C 2 Bn Bn 2 C Bn 2 C S Ar Ar Si Bu 95%, 95:5 d.r., 86% ee Maruoka, K. et. al. ature Chem. 2014, 6, 702. 27
Solid-State otochemistry tochemistry in Chiral Crystals i Pr 2 C C 2 i Pr hυ, solid i Pr 2 C C 2 i Pr P2 1 2 1 2 1 (chiral) 95% ee Scheffer, J..; Trotter, J. et. al. J. Am. Chem. Soc. 1986, 108, 5648. Bn S P2 1 (chiral) hυ, solid S Bn S Bn 81% ee, 100% conv. Sakamoto, M. et. al. J. Am. Chem. Soc. 1996, 118, 10664. 28
Enzyme-catalyzed eactions Biocatalysis n asad (1 mol%) ADP + (1 mol%) GD-105, glucose, TIS Glycerol, DMS 460 nm hυ, rt. Br n acemic LKAD (0.25 mol%) ADP + (0.4 mol%) kpi, i Pr, DMS 460 nm hυ, rt. n P 2 F as-ad 47%, e.r. 97/3 LKAD 91%, e.r. 2/98 as-ad 79%, e.r. 3/97 LKAD 56%, e.r. 4/96 as-ad 29%, e.r. 80/20 LKAD 80%, e.r. 4/96 as-ad 82%, e.r. 81/19 LKAD 74%, e.r. 9/91 P 2 AD + yster, T. K. et. al. ature 2016, 540, 414. 29
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