Angewandte Chemie International Edition Methodologies

Angewandte Chemie International Edition thodologies 2010-2016 Maximilian äfner Konstanz, 12.07.2017

ACIE 2010-2016 Cyclobutanes and -butenes Cross-Couplings eptacycles ing contractions or expansions Various methods 97014 pages published More than 1000 methods Azomethin- Ylides Allylic manipulations C - oxidation otochemistry 2 12.07.2017

Synthesis of heptacycles Gold-catalysis 1 1 = Ac > Piv > Bz [( t Buos)AuTf 2] (1 mol%) 1 1 2-15 examples, up to quant. yield - high diastereoselectivity PAu ipr ipr Tf 2 3 ipr G [Au] G G [Au] G 11 12 13 14 Ac 4 81 % d.r. 1.4 : 1 Ac = C 2 42 % = C= 63 % Ac 5 6 = 99 % = C 2 Bn 61 % = C 2 92 % 1 4 Au-cat./AgTf 2 (5 mol%) DCM, 28 C 4 2 1 15 16 17 23 examples up to 83 % yield retention of stereochemistry 1-4 = (substituted) aryl, (cyclo) alkyl = alkyl,, Bn = Ms, Ts Ac 1 [( t Buos)AuTf 2] (1 mol%) Ac DCM, 0 C to 40 C 7 1 2 8 [( t Buos)AuTf 2] (1 mol%) DCM, 0 C to 40 C 9 10 only acceptable yields if 1 / = alkyl not for = or cyclo-alkyl 1,2 - - shift = 57 % = 42 % Gagosz and Cao, Angew. Chem. Int. Ed. 2013, 9014 9018. ipr ipr ipr Au Cl ipr 18 Ms Ms 19 20 63 %, no loss of ee 62 % Liu et al., Angew. Chem. Int. Ed. 2012, 8722 8726. 3 12.07.2017

Synthesis of heptacycles via Diazo-intermediates 1 C 2 1 [h2(s-btcpc) C 2 2 4] TBS (1 mol%) 2 pentane r.t. or TBS TIPS TIPS hexanes, rflx 21 22 23 TIPS C 2 C 2 TBS TBS TIPS TIPS 24 25 26 C 2 TBS Ts [h2(adc)4] Ts (1 mol%) h CCl, 60 C h 35 36 37 4 TIPS TIPS 1 1 C C 2 2 conditions 2 TBS TBS TIPS 2 27 28 29 C 2 C 2 DIBAL, DCM TBS TBS 21 % TIPS 85 % eetips 30 31 32 Br - 9 examples, up to 92 %yield - diastereoselective reaction - gram scale Ts Ts 2 =, Ts, (2C) 2C, 2 C =,, p- 2 -, p-- [h2l 4] Ts [3,3] 38 39 40 41 Sarpong et al., Angew. Chem. Int. Ed. 2014, 9904 9908. Ts 10 examples up to 80 % yield d.r. > 20:1 86 to 99 % ee 34 h h 4 Davies et al., Angew. Chem. Int. Ed. 2014, 13083-13087. 4 12.07.2017

Synthesis of heptacycles other methodologies 1 C C C (1 atm) 24 examples, up to 92 %yield 5 mol% Pd(Ac)2 20 mol% DMS 1.5 eq BQ DCE, rt, 6h 42 43 1 / = Alkyl = Alkyl, yl, Alkynyl, Allyl 1 C 2 Bäckvall et al., Angew. Chem. Int. Ed. 2016, 14406 14408. [4 3] - 53 54 55 TiCl 4, DCM, S - 78 to -10 C S 56 ' 57 2 h 58 S = 2- or Benzo 2 eq ' /' =, Et,, 2 6 examples, > 70% yield D Bn 1 TIPS [e(c)5i] (2.5 mol%) MS 4A 1,4-Dioxan 100 C, 4h 44 45 4 46 22 examples, up to 93 % yield average yield ~ 80 % Bn [e] TIPS 1 1 / =, Alkyl, Cycloalkyl / 4 = Alkyl, yl, etyl [e] Bn [1,5-] C 47 [e] D 48 49 D TIPS TIPS D - C [e] D 50 51 D 52 4 TIPS Iwasawa and Sogo, Angew. Chem. Int. Ed. 2016, 10057 10060. 82 % 4:1 59 72 % 10:1 60 96 % 61 97 % 62 TiCl S 4, DCM, - 78 to - 10 C S dienes 63 ' 2 h S = 2- or ' 4 64 2 or 3 eq /' = 2, 2, 7 examples, 25 to 85% yield 60 % 65 57 % 66 69 % 67 Winne et al., Angew. Chem. Int. Ed. 2011, 11990 11993. 5 12.07.2017

ing contraction Synthesis of ᵞ-quat. Acyclcyclopentenes 1) C Allyl C 2 Allyl (S)--P (6.25 mol%) LDA, TF, -78 C [Pd2(pmdba)3] (2.5 mol%) 2) base, electrophile, 30 C 68 61 to 88 % yield 69 70 = alkyl, allyl, propargyl, benzyl yields 89 to 99 % ee 80 to 92 % P 2 71 hard electrophilic site quaternary stereocenter 80 nucleophilic site soft electrophilic site 1 reduction conditions 1 reduction conditions - LA, Et 2, 0 C then 10% Cl - DIBAL,, -78 C then oxalic acid, - CeCl 3 * 7 2, ab 4,, 0 C, then 10% Cl Li, TFA, TF, 60 C 72 73 74 1 1 = alkyl, allyl, propargyl, benzyl, etbenzyl = allyl, crotyl, cyclohexenyl overall yields o2s 80 to 95 % functional group handle variable group many possible further manipulations 1 1 1 2 1 2-2 75 76 77 78 79 1 Stoltz et al., Angew. Chem. Int. Ed. 2011, 2756 2760. 6 12.07.2017

ing expansion Cyclohexyne Cycloinsertion BF 4 I KCEt 3, TF -78 C to rt then p 7 buffer 81 82 83 84 85 86 87 Ac KCEt 3, TF -78 C to rt 74 % 94 95 steps 96 97 Guanacastepenes and [Fe2(C)9],, 90 C then DBU 51 % Carreira and Gampe., Angew. Chem. Int. Ed., 2011, 2962 2965. SEM SEM SEM K, I-comp, 2, K, [18]crown-6, -78 C to rt TF, rt TMS 1 1 only if 1 = 88 89 90 1 K K K SEM K, I-comp, SEM 2, KMDS, [18]crown -6, TMS -78 C to rt TF, rt 83 % SEM 76 % brsm 91 92 93 98 99 100 101 Carreira et al., Angew. Chem. Int. Ed., 2010, 4092 2095. 7 12.07.2017

4-membered ings (asymm.) allylic alkylation 2) 1, K 2 C 3, acetone p-absa, Et 3, C, rt, 12 h 86 % 1 2 1 [Pd2(dmba)3] (5 mol%) (S) - L 2 (12.5 mol%), 20 C F 1) µwave,, 180 C, 1 h 102 103 104 105 P 2 L 2 1 106 107 C hν, Et 2 1) C 2 a, Pd(P3)4, TF 1 1 C 2 quant. 2) SCl 2, C 2 112 113 114 = alkyl, Bn 1 =, alkyl, allyl, propargyl, Bn, (C2)C2 Et = alkyl ester or diphenylamide [Pd(P3)4] (5 mol%) Et 3, TF, 0 C 113 115 116 = alkyl, Bn, allyl =, p--c 6 4, (3,5)-CF3 -C 6 3, p- 2 -C 6 4 12 examples up to 92 % yield C 2 10 examples up to 68 % yield d.r. > 90:10 dialkyl γ lactones 109 15 examples, 62 to 98 % yield, 86-99 % ee Bn 2 2, 1 M a,, 23 C 80 % 1) TMSC 2, BF 3 *Et 2, Et 2 2) Cl (aq), DCM 69 % o2s 1 = Alkyl, (et)benzyl, Allyl, Propargyl = Vinyl,, Cl,, Alkyl, yl Grubbs-oveyda II, 1 97 % 108 TMS 110 α 111 -quaternary F cyclopentanones 1) 2 *Cl, pyr, Et 2) ptscl, Et 3, DMAP, DCM 22 % o2s 112 Bn quaternary spirocycles dialkyl γ lactams C2 Et C2 Et cat. s C2 4, Et M,, C 2 Et PIDA, DIPEA,, C C MTBE, Et, 0 C to rt 2 Et 2 Et 2 = = 2 C 2 73 % 56 % Et 118 117 119 C 2 Grubbs II (20 mol%) C2 ethylene (1 atm), DCM, rt 50 % 120 121 2 C C 2 1) IS, C/ 2 2) TFA, DCM 34 % C 2 I C 2 122 123 C 2 Stoltz et al., Angew. Chem. Int. Ed. 2013, 6718 6721. Maulide et al., Angew. Chem. Int. Ed. 2010, 5672 5676. 8 12.07.2017

4-membered ings asymm. allylic alkylation [{Pd(allyl)Cl}2] (2.5 mol%) C 2 1 L1a (7.5 mol%) C 2 1 1 1 TF, 0 C, 1h C 2 124 125 127 1 =, Et = Alkyl, Allyl, Propargyl, (C2)3 Bn, (C2)3 Cl, (C2)2C 9 examples up to 85 % yield d.r. > 95:5 ee 90 to 96 % P L 1a = [{Pd(allyl)Cl}2] (2.5 mol%) C 2 L1b (7.5 mol%) TF, 0 C, Et 3, 6 h 124 128 129 = p- 2 -C 6 4 = alkyl, allyl, benzyl, benzyl, p-brbn (C)2 Bn 7 examples up to 76 % yield d.r. > 91:9 ee 94 to 98 % 2 C [{Pd(allyl)Cl}2] (2.5 mol%) 2 1 1 1 C2 L2a (7.5 mol%) 1 TF, 40, 1h 124 125 130 C 2 1 =, Et = alkyl, allyl, (C)2 C 2 Et, (C2)3 Bn, Bn, p- 2 -Bn 10 examples up to 82 % yield d.r. > 95:5 ee 92 to 99 % P P 2 L 2a L 1b nbu C2 Et nbu C 2 Et C 2 Et C 2 Et 134 135 C 2-96 % ee nbu C2 Et C 2 Et C 2 137 96 % ee L1a ent-l1a 124 L2a ent-l2a C 2-98 % ee nbu C 2 Et C 2 Et C 2 98 % ee 136 Et 2 C Et 2 C 2 C 131 C 2 C 2 C 2 132 133 55 % 63 % 50 % d.r. 80:20 d.r. 71:29 d.r. 55:45 ee 87 % ee 91 % ee 83 % Maulide et al., Angew. Chem. Int. Ed. 2011, 12631 12653. 9 12.07.2017

4-membered ings asymm. allylic alkylation h ν not stable compound 138 139 C 2 C 2 2 M Cl, Et 2 bench-stable compounds Cl Cl rac - cis rac - trans 139 140 141 C 2 Cl rac - cis C 2 Cl rac - trans C 2 1 C 2 2 1 140 142 C 2 1 C 2 1 141 142 [{Pd(allyl)Cl}2] (2.5 mol%) L1a (7.5 mol%) C, 0 C [{Pd(allyl)Cl}2] (2.5 mol%) L2 (15 mol%) TF, 40 C [{Pd(allyl)Cl}2] (2.5 mol%) L1a (7.5 mol%) C, 0 C [{Pd(allyl)Cl}2] (5 mol%) L2 (30 mol%) TF, 30 C 1 2 C 1 2 C 1 2 C 1 2 C C 2 C 2 1 C 2 C 2 1 C 2 C 2 1 C 2 143 144 145 146 C 2 1 P 2 P L 1a L 2 15 examples up to 76 % yield d.r. > 95:5 ee 81 to 96 % enantiomeric approach: 8 examples up to 95 % yield d.r. > 90:10 ee 65 to 96 % 10 12.07.2017 Maulide et al., Angew. Chem. Int. Ed. 2012, 7314 7317.

otochemical methods n m 93 %; 75 % ee hν (300 nm) LA (50 mol%), -70 C 20 mm in DCM then Et 3, r.t. 147 148 86 %; 82 % ee Br 3 Al F B Bach and Brimioulle, Angew. Chem. Int. Ed. 2014, 12921 12924. 93 %; 94 % ee 149 150 151 158 LA LA 1M Cl DCM 72 % 1) BF 3 *Et 2, Et 3 Si, DCM 2) IB, C 63 % 2 154 155 F 9 examples up to 94 % yield ee 75 to 94 % n,m = 1 or 2 = alkyl, F 152 153 TMS BF 3 *Et 2, DCM 76 % 156 157 F LA Ts Ts 88 % d.r. 3:1 159 [Ir( F ppy) 2( t Bubpy)]PF6 (1 mol%) DMS, visible light Ts 89 % 160 Tf (C2)3 Ts 161 81 % 162 93% 163 d.r. > 10:1 d.r. 1:1 Ts I C 2 Et 80 % 98 % 71 % 164 d.r. > 10:1 165 d.r. 2:1 166 d.r. 5:1 Ts 168 Ts 169 Cl 2, Pd/C, 90 % Cl (2M in Et 2), DCM, rt 99 % Ts 167 1) 3, DCM, -78 C 2) DMS 16 examples up to 98 % yield d.r. varies, but mostly > 5:1 98 % Ms, DCM, rt 86 % Ts Ts C P Et Et irrad. cond. 172 nbuli, 84 % 98 % 173 C C 174 Grubbs II (/-)-epiraikovenal 42 % overall yield 175 Yoon et al., Angew. Chem. Int. Ed. 2014, 8991 8994. Ms 170 171 11 12.07.2017

otochemical methods 6 W g lamp (254 nm) C, 6 h 176 177 178 Et 2 C C Et 2 C C 41 % 179 40 % 180 44 % 181 12 % 182 9 % 183 14 examples up to 44 % yield of aziridine and up to 29 % cyclobutane formation clean reaction 6 W g lamp (312 nm) C, 2h C 2 Et C 2 Et Et 2 C 184 185 55 % 8 % 186 C 2 Et [2 2] C 2 Et C 2 Et Et 2 C 187 188 189 190 C 2 Et 12 mm in C 9.5 ml/min, 1 h 254 nm flow reactor Et 2 C 191 192 0.91 g, 51 % Productivity 21.8 g/d Milburn et al., Angew. Chem. Int. Ed. 2013, 1499 1502. 12 12.07.2017

C-C-bond activation synthesis of tropane systems [{h(cd)cl}2] (2.5 mol%) L (6 mol %) 1,4-dioxane, 130 C, 12 h 1 4 1 3 5 193 194 5 4 P 2 P 2 L = 204 [h I ] 200 15 examples up to 96 % yield ee 95 up to >99 % Tolerant to (protected) functional groups esters, prot. alcohols, nitriles C 2 Bn F 195 196 197 198 199 Cramer et al., Angew. Chem. Int. Ed, 2014, 3001 3005. 203 [h III ] 202 [h III ] [h I ] 201 [{h(cd)cl}2] (2.5 mol%) L (6 mol %) 1,4-dioxane, 110 C, 12 h 1 1 2 205 206 F 3 C C 2 Et 13 examples up to 89 % yield ee 95 up to >99 % 2 C TIPS 207 208 209 210 with higher temperatures: Cramer et al., Angew. Chem. Int. Ed, 2014, 9640 9644. [{h(cd)cl}2] (5 mol%) L (6 mol %) 1,4-dioxane, 130 C, 12 h C 2 I 2, ac 3, 1,4-dioxane, r.t. 211 212 I 213 81 % o2s, ee > 99 % 13 12.07.2017

Azomethin Ylides Dearomatization and [6 3]-Cycloaddition C 2 Bn TMS cat. TFA (5 mol%) Bn DCM 214 2 215 85 % 2 2 Bn Bn 216 2 2 217 Bn 14 examples up to 95 % yield only single products formed [Cu(C)4]BF4 (5 mol%) L (5 mol%) Et 3, 1,4-dioxane, r.t., 0.5 h * 1 1 2 C 225 226 ( epimer at C * 227 ) dienophile, 3 major product r.t., 3 h * S 1 2 C P 2 ( epimer at C * Fe ) = L 228 major product 229 218 2 24 examples up to 96 % yield d.r. 75:25 up to >95:5 36 up to 97 % ee generation of 8 stereocenters 1 = substituted aryl, when alkyl no reaction = substituted aryl, when alkyl low ee =, Bn 2 Bn 2 2 Bn Bn Bn Cl S C 2 Ts 2 Cl Bn 9 eq., 23 h, 81 % 3 eq., 21 h, 95 % 4 eq., 22 h, 94 % 9 eq., 24 h, 62 % 2 2 225 219 220 221 222 Bn Bn DCM 66 % 2 eq. 2 6 eq. 2 Bn DCM 57 % 2 2 223 224 Bn Bn Piettre et al., Angew. Chem. Int. Ed. 2011, 472 476. C 2 [CuL*] [6 3] [4 2] exo 1 2 C 1 230 231 232 2 C 1 234 2 C F 2 C 58 %, ee 87 % 62 %, ee 94 % 235 236 Waldmann et al., Angew. Chem. Int. Ed. 2012, 9512 9516. Br 14 12.07.2017

Azomethin Ylides Cyano Group as a traceless activator C 1 AgAc (10 mol%) Cs 2 C 3 (20 mol%) C ab 4 (20 mol%) B 3 *TF (1.2 eq.), 0 C to r.t. 1 TF, r.t. 237 238 239 240 2 1 25 examples up to 96 % yield [3 2] and in gram scale and up to 94 % yield in decyanation and in gram scale endo/exo 10:1 up to >20:1 = substituted aryls, heteroaryls, alkyl 1 =, =, = C 2, C 2, C, S 2 Boc C C 2 2 TBDPS C 2 C 2 56 % o2s 70 % o2s 52 % o2s 76 % o2s 80 % o2s 241 242 243 244 245 246 C C 2 2 C LA, TF, rflx 80 % AgAc (20 mol%) DBU (20 mol%) 2 C 75 % 247 C 248 251 (/-)-isoretronecanol C 2 B 3 *TF, ab 4 (20 mol%) 2 C 84 % 249 2 C 250 C 2, rflx quant. 15 12.07.2017 Zhang et al., Angew. Chem. Int. Ed. 2015, 6306 6310.

Allylic transformations [{Ir(cod)Cl}2] (2.5 mol%) ()-L (10 mol%) ' mcba ' (0.5 eq.) DCE, 50 C, 24 h 252 253 P ( )-L 16 examples up to quant. yield 63 to 99 % ee = (substituted) aryl, heteroaryl, (substituted) alkyl ' =, Et, ipr, PMB, Bn Carreira and oggen, Angew. Chem. Int. Ed. 2011, 5568 5571. alkyl 1) [{Ir(cod)Cl}2] (2.5 mol%) 2) Protection (S)-L (10 mol%) 2 e.g. 4 eq. Et 3, 1,2 eq. 3 S 3 2 eq. BzCl,4 h, r.t. PG 254 5 eq. DMF, 2--TF, 24 h, r.t. 255 256 1) [{Ir(cod)Cl}2] (2.5 mol%) (S)-L (5 mol%) 1,2 eq. 3 S 3 DMF, 24 h, r.t. alkyl 2 2) Protection e.g. 4 eq. Et 3, 2 eq. BzCl,4 h, r.t. alkyl PG 257 258 259 : 20 examples up to 85 % yield 80 to 99 % ee alkyl: 7 examples up to 87 % yield 68 to 99 % ee = (substituted) aryl, heteroaryl PG = Bz, Ts, Fmoc, 3 Cl alkyl = (substituted) (cyclo)alkyl PG = Bz, Ts, Fmoc, 3 Cl Carreira et al., Angew. Chem. Int. Ed. 2012, 3470 3473. [{Ir(cod)Cl}2] (2.5 mol%) (S)-L (10 mol%) S' P()(Bu)2 (0.5 eq.) 'S DCE, 50 C, 24 h 260 261 BnS = el.-poor aryl [{Ir(cod)Cl}2] (2.5 mol%) (S)-L (10 mol%) P()(Bu)2 (0.5 eq.) DCE, r.t, 72 h S' 1 : 1 P ( S)-L 12 examples up to 92 % yield 86 to 97 % ee = el.-rich (substituted) aryl, heteroaryl ' = Bn,, PMB, Cy, p--c 6 4 Carreira et al., Angew. Chem. Int. Ed. 2012, 8652 8655. ' [{Ir(cod)Cl}2] (4 mol%) ' (S)-L (12 mol%) KF 2 (1.5 eq.), TFA (2.5 eq.) KF 3 B nbu 4 Br (10 mol%), 262 263 1,4-dioxane, 25 C, 6h 264 26 examples up to 99 % yield 95 to >99 % ee = (substituted) aryl, heteroaryl ' = aryl, heteroaryl, (cyclo)alkenyl/alkyl Carreira et al., Angew. Chem. Int. Ed. 2013, 7532 7535. 16 12.07.2017

Allylic transformations [{Ir(cod)Cl}2] (3 mol%) 4 ()-L (12 mol%) 1 Sc(Tf)3 (10 mol%) TMS 1,4 - dioxane, r.t., 12 h 265 266 1 267 P ( )-L 21 examples up to 95 % yield 91 to >99 % ee 1 = (substituted) aryl, heteroaryl =, = Br,, (substituted) alkyl Carreira et al., Angew. Chem. Int. Ed. 2014, 10759 10762. Boc [{Ir(cod)Cl}2] (1 mol%) alkyl (S)-L (4 mol%) BrZn-alkyl, r.t., 12 h 268 269 270 22 examples up to 81 % yield 80 to >99 % ee alkyl = (substituted) alkyl, cycloalkyl = (substituted) aryl, heteroaryl, vinyl, propargyl P ( S)-L 17 12.07.2017 Carreira et al., Angew. Chem. Int. Ed. 2015, 7644 7647.

Cross Coupling reactions i(cd)2 (5 mol%) Et 3 (1.1 eq.), Zn (2 eq.) 12 examples up to I C, 23 C 95 % yield 271 1 272 1 4 conditions I 1 Bn 4 1 93 % 40 % 273 274 275 276 i(cd)2 (5 mol%) Et 3 (1.1 eq.), Zn (2 eq.) 1 C, 23 C 277 278 C 2 C 2 2C C2 12 examples up to 98 % yield C 2 C 2 1 C 2 C 87 % 76 % 98 % 61 % 279 280 281 282 = ester, amide, nitrile = Br, I 1, =,, LG Cl Cl [{Pd(allyl)Cl}2] (5 mol%) Et 2 Zn, L1 (30 mol%) TF TMS 289 290 C 2 78 % 90 295 % 88 % ee 86 % ee 296 80 % 76 % ee P TF C 2 C 2 rac 291 292 [{Pd(allyl)Cl}2] (5 mol%) ' 2 Zn (2.4 eq.), L1 (15 mol%) [{Pd(allyl)Cl}2] (5 mol%) ' 2 Zn (2.4 eq.), L2 (15 mol%) C 2 52 % 80 % ee 1 L1 L2 TF 1 293 294 Ts 82 % 80 % ee TMS 3 examples up to 67 % yield and up to 87 % ee 11 examples up to 92 % yield and up to 90 % ee = ester,, Weinreb - amide, C, C() 1 =, Et, ipr LG = Cl, Ac, 2 C 297 298 299 Stoltz et al., Angew. Chem. Int. Ed. 2016, 7437 7440. Maulide et al., Angew. Chem. Int. Ed. 2014, 7068 7073. 18 12.07.2017

Cross Coupling reactions I I or II (15 mol%) ipr 2 Et (1.5 eq.) blue LEDs C, r.t. 24 h 300 301 15 examples up to 91 % yield [PdCl2(P3)2] (0.2 mol%) antphos (0.24 mol%) ()4biphenol (1 mol%) 1 Ac 2, 132 C, 2 h 1 310 311 11 examples up to 77 % yield no loss of stereochemistry II, 91 % 302 I, 83 % 303 I, 83 % 304 Boc Co I: = Sn 3 Ts II: = ipr I, 89 % II, 91 % py 305 306 Ac 41 % 312 69 % 313 C 2 nbu 60 % 51 % P 2 P 2 315 316 317 314 TBS TBS 1) Allyl alcohol, IS, DCM, 90 % 2) I (15 mol%), ipr 2 Et (1.5 eq.) (/-)-samin blue LEDs, C, 24 h, r.t., 97 % 307 308 309 C 2 [PdCl2(nbd)] (1 mol%) antphos (1.2 mol%) MP, 132 C, 93 % 318 319 320 (-) and ()-10-epi-Aspewentin C Carreira et al., Angew. Chem. Int. Ed. 2011, 11125 11128. Grubbs, Stoltz et al., Angew. Chem. Int. Ed. 2015, 11800 11803. 19 12.07.2017

Cross Coupling reactions [Ir(cod)Cl]2 (2 mol%), L (4 mol%), TBD, LiCl, proton sponge Cl TF 25 C 321 322 323 12 examples up to >99 % yield b:l > 90:10, up to 98 % ee 2 2 324 325 =, 2, 2, Br,, = ester, nitrile, C() P L 332 C 2 Et 327 3S()I, a, DMS 82 % C 2 Et Grubbs-oveyda II DCM allylmgcl, TF, -78 C 71 % K 2 s 4, M, 326 TF/ 2 65 % 331 81 % C 2 Et DIBAL, TF, -78 C 43 % 330 C 2 Et 328 K 2 s 4, M, TF/ 2 59 % 329 C 2 Et 20 12.07.2017 Stoltz et al., Angew. Chem. Int. Ed. 2016, 16092 16095.

C- xidation Ts 333 I 2 (2.5 mol%), I(mCBA)2 (1 eq.) DCM, r.t., 12 h 334 Ts Ts Ts Ts Ts Ts 335 99 % 336 95 % 337 72 % 338 77 % Ts 2 S 82 % 90 % 339 340 31 examples up to 99 % yield selectivity >95 % 2.2. eq. nbuli, 0 C, 2 h; then 1.1 eq. ZnCl 2, 1 h; then 1.3 eq. I 2, 2 h to r.t. 64 % 348 349 350 18 examples up to 75 % yield 5-, 6- and 7-membered rings = C 2, C= = (cyclo) alkyl, aryl, amide Sarpong et al., Angew. Chem. Int. Ed. 2013, 2194 2197. 74 % Bu 351 I I(mCBA) 2 347 Ts 341 Ts I(mCBA) I(mCBA) Ts mcba Ts I 346 Ts I Ts 343 344 Ts 345 1) 2 eq. nbuli; then 1 eq. I 2 TF, -78 C 90 % 352 2) aset ()-lyconadin A 353 76 % 342 Muniz and Martínez, Angew. Chem. Int. Ed. 2015, 8287 8291. Sarpong et al., J. Am. Chem. Soc. 2009, 11187 11194. 21 12.07.2017

Various thods Se, rflx, 12 h Se (TMS)3 Si, AIB isooctane or, rflx, 1 h 354 355 356 357 enylselenoacrylate as ethylene equivalent 12 examples up to to 97 % yield (Diels-Alder) and up to 99 % yield (reduction) Jung et al., Angew. Chem. Int. Ed. 2013, 2060 2062. 1 TMS C 4 TBAT (2 eq.), TF, 40 C, 8-12 h Tf 358 359 360 361 1 2 4 = (cyclo) alkyl,, (substituted) aryl 4 =, cyclic 1 TMS Tf C 4 362 TBAT (2 eq.), TF, 40 C, 8-12 h 1 363 4 2, 4 =, C 2, Three component aryne reactions 32 examples up to 96 % yield 1 `= (substituted) aryl = alkyl, (substituted) aryl Stoltz et al., Angew. Chem. Int. Ed. 2011, 4488 4491. 1 Y 364 365 C Tf (1.1 eq.) DCM, 0 C to r.t. = (substituted) aryl, heteroaryl, (cyclo) alkyl, vinyl, Cl, Br, I 1 = (substituted) aryl, heteroaryl, (cyclo) alkyl 1 Y = C 2,, (C2)2, (C2)3, benzannulated Y = S, PG 36 examples up to 88 % yield tal-free formal 366 [222]-Cycloaddition Maulide et al., Angew. Chem. Int. Ed. 2016, 12864 12867. 22 12.07.2017

Various thods Ligand (20 mol%) P()3 (40 mol%) 2 Zn (3 eq.), 367 368 369 370 Asymm. alkynylation of acetaldehyde 11 examples up to 98 % yield = aryl, alkenyl, silyl, alkyl, C 2, highly functionalized residues Trost and Quintard, Angew. Chem. Int. Ed. 2012, 6704 6708. n 371 1 1 372 n 373 20 examples up to 90 % yield Tf 2, collidine DCM, µwave Tf 2, collidine DCM, µwave Tf 2, collidine DCM, µwave 1 1 n n 374 376 C C 2 375 =,, C2 Et, C 2 PG, C, Br, C 2 Cl 1 =, n = 1, 2 = alkly, (C2)3 Cl n = 1, 2 48 % 78 % 377 378 Tf 2, collidine 379 380 C [3,3] 2 381 382 383 Maulide et al., Angew. Chem. Int. Ed. 2010, 1583 1586. 1) Br 2 (2.6 eq.), Et 2 (5.2 eq.) 1 2) Et 2 Zn (2.6 eq.) 2 C C 2 Br 3) CBr 3 (2.6 eq.) 4) substrate, L (1.1 eq.) DCM, -42 C to r.t., 4 h B L 384 385 1 Bu 15 examples up to 92 % yield d.r. > 20:1 94 up to 98 % ee 1 =, = (substituted) aryl, (cyclo) alkyl =, alkyl, (if alkyl low yield) Enantioselective Bromocyclopropanation Charette et al., Angew. Chem. Int. Ed. 2015, 14108 14112. 23 12.07.2017