Index

References to tables are given in bold type. acetals 23 symmetrical cyclic 209210 acetylenes see alkynes Achilles Heel strategy 6364 acids, halogenation 47 acyl anion equivalents 167170, 187189 acylation by ketene dimers 254 Friedel-Crafts 89, 209 acyloin reaction 180182 adipic acid 199 adrenaline 50 AIDS drugs 119120 alcohols C-C disconnections 6976 dehydration to alkenes 107 derivatives 2728 oxidation 72 protecting groups for 6566 symmetrical 7880 synthesis 7071, 7475 1,2 C-C disconnections 7374 examples 7475 aldehydes from alcohols 72 synthesis by acylation 9396 aldol reaction 134, 321322 alkaloids 275 alkenes cyclisation by carbene insertion 231234 from alkynes by reduction 116117 hydration synthesis of 1,2-difunctionalised compounds 170171 by elimination 107108 by Wittig reaction 108112 alkylation reactions amination 5657 aromatic compounds 910, 1011 alkynes in anti-AIDS drug 119120 reduction to alkenes 116117 allylic carbons 177179 amides, as protecting groups 6264 amines overview 5354 primary 55, 5657 secondary 55, 57 tertiary 56 from nitro compounds by reduction 161162 monomorine I synthesis 5759 reductive amination 5556 amino acids 3132 Aphox 306 Arndt-Eistert procedure 237238 aromatic compounds acylation 89 disconnection 78 functional group addition, general strategy 1722 functional groups, and reactivity 18 reduction 273277 aspartame 64 axial attack 8990 azides 56 Baeyer-Villiger reaction 203204, 253 Beckmann rearrangement 253 benzene rings, Birch reduction 274275 benzocaine 78 benzoin condensation 174175 biotin 177179 Birch reduction 274275 aromatic carboxylic acids 276277 brevianamide 194 bromohexanoic acid 47 t-butyloxycarbonyl group 64 carbenes metal complexes 233 synthesis by -elimination 232233 carbobenzyloxy (Cbz) groups 63 carbon acids 131132 carbon nucleophiles 70
Stuart Warren and Paul Wyatt

Organic Synthesis: The Disconnection Approach. Second Edition 2008 John Wiley & Sons, Ltd

CO

PY R

IG

HT

ED

MA

TE

RI

AL

326

Index

carbonyl compounds 1,2 di- 173174 1,3 di- 136137 1,4 di- 190191 1,5 di- 151159 1,6 di- 199204 and amination 54 -hydroxy 133135 by conjugate addition 98100 cyclisation to ve-membered rings 255256 derivatives 2325 dicarbonyl 129132 intramolecular reactions 140141 nucleophilicity 129 ,-unsaturated 135136 -functionalisation 172173 carbonyl condensations, compounds which cannot enolise 141144 carboxylic acids C-C disconnection 7273 reduction 276277 Cbz group 63 chemoselectivity 2934 chirality see stereochemistry chloroacetyl chloride 47 cis-chrysanthemic acid 230 citronellal 196197 Claisen rearrangement 265267 clopirac 302303 columbiasin A 271272 conformational control 8990 conjugate addition 36, 3738, 321322 of acyl anion equivalents 187189 carbon nucleophiles 104106 nitro-alkanes 163 convergence 314318, 319 copaene 293295 Cope rearrangement 265 coriolin 292, 292293 cyanide ion 169170, 187 cyclisation 4849, 217219 three-membered rings 219 cyclopropanes 229231 sulfonium ylids 234235 four-membered rings 220221, 245, 280282 by ionic reactions 248 ve-membered rings 221223, 255258 six-membered rings 223224, 270271 Diels-Alder reaction 201202 seven-membered rings 224226 disconnections for small rings 280282 general considerations 217219 ketenes 251254 kinetic and thermodynamic factors 218 ring expansion and contraction 238240 Robinson annelation 156157 salbutamol 5051 and selectivity control 279280 cyclomethycaine 3031

cyclopentanes 257258 by conjugate addition 258 cyclopropanes 229231 damascenone 262 darifenacin 75 dendrimers 267 diarylketones 182183 diastereoisomers 8385 diazoalkanes 237238, 238240 dicarbonyl compounds 193196 dichlorocarbene 232 dicyclomine 273274 Diels-Alder reaction 121127, 269, 271273, 320321 1,6-dicarbonyl compounds 201202 functional group interconversion (FGI) of products 126 molecules with several chiral centres 291 nitroalkene synthesis 164165 regioselectivity 124125 in water 126127 dienes stereospecicity 122123 synthesis 117 by Wittig reaction 112 dienoestrol 180 difunctionalised compounds 1,1-difunctionalised 4143 1,2-difunctionalised 3941 1,3-difunctionalised 37, 38 see also disconnections, two-group dihydropyran 63 dimedone 230 disconnections 1,5-difunctionalised compounds 151158 overview 12, 80 symbol 7 example 24 guidelines 80 order of events 1718 C-C one-group 1, 1 7073 1, 2 7375 other 7576 simplication 7778 starting materials 7879 symmetry 78 two-group 1,2-difunctionalised compounds 167176 1,3-difunctionalised compounds 133138 1,4-difunctionalised compounds 185192 1,5-difunctionalised compounds 151159 1,6-difunctionalised compounds 199205 Diels-Alder reactions 129132 C-heteroatom 301303 polarity reversal 4546

Index

327

carbonyl compounds 207214 heterocyclic compounds 301304 two functional groups as analytic preliminary 4344 overview 3536 recognition 36 see also Diels-Alder reactions; disconnections, C-C, two-group disparlure 111 DMF 9497 electrocyclic reactions 261263 elm bark beetle 2 enamines 147148 enantiomers 8385 enolates 1,3-dicarbonyl compounds 9798 alkylation to cyclopropanes 229231 anionic 131132, 132 lithium 9697, 145146 enols alkylation 9698 specic 144148 enones, spiro 210211 epoxides 4546 rearrangement reactions 241 equilibrium reactions 148149 esters lithium enolates 145146 synthesis by acylation 9396 ethers as protecting groups 62 synthesis 2526 Favorskii rearrangement 242243 fencamfamin 164 fentiazac 303304 uconazole 40 uoxetine 1213 folded molecules 90 stereochemistry 292293 formaldehyde, Mannich reaction 143144 Friedel-Crafts reactions 89, 209 functional group addition (FGA) 1,4-difunctionalised compounds 196197 aromatic compounds 1011 carbonyl compounds 191 order of events 1718 functional group interconversion (FGI) 78 Diels-Alder products 126 functional groups choice and yields 33 functionalisation, allylic and benzylic 177179 interaction 1718 and reactivity 18 two-group disconnections 3536 see also protecting groups

furans, electrophilic substitution 309310 furfural 119 gingerol-6 146 grandisol 168 guanacastetepenes 272273 halicholactone 235 halogenation acids 47 ketones 4647 Henry reaction 163 heterocyclic compounds 1,5-dicarbonyl compounds 158 aromatic 301311 indoles 307 saturated 217227 substitution reactions 308311 homoenolates 189190 4-hydroxyketones 187 indoles, electrophilic substitution 309310 indomethacin 307308 intramolecular reactions, cyclisations 217226 jasmone 116117 juvabione 295298 ketenes 251254 ketones alkylation, regiospecic 101103 cyclopentyl 256257 from alcohols 7172 halogenation 4647 synthesis 95 by acetylene hydration 118 by acylation at carbon 9396 by alkylation of enolates 9698 by conjugate addition 98100 by oxidation of alcohols 72 unsaturated 133149 Knoevenagel reaction 144 lactones 148149, 208209 laulimalide 65 LHASA program 2 lithium enolates 9697, 145146 -lycorane, stereochemistry 323324 Mannich reaction 143144 maritidine 275 metal carbenoids 233234 metaproterenol 172 methoxatin 315318 methylenomycin 186187

328

Index

Michael reactions acceptors suitable for conjugate addition 155156 enol equivalents suitable for conjugate addition 155156 MIV-150 319 monomorine I 5759 multistriatin 24, 8385, 8788 Nazarov reaction 261263 nitro compounds 161, 162164, 165, 188189 Novartis PKI 166 anti-cancer drug 310311 oblivon 115 Palanil 111 paracetamol 2930 pentalenoactone 201 permethrin 230 pH, and chemoselectivity 3031 Pharaohs ant 5758 phenaglycodol 169 phensuximide 188 photochemistry, cycloadditions 245248 pinacol reaction 179180, 240242 piquindone 212214 pKa of bases and carbon acids 132 polarity, synthons 130131 Prelog-Djerassi lactone 289291 propanil 24 protecting groups 31, 6162, 67 for alcohols 6566 for amines 6264 literature 6667 pyrazoles 313318 pyridines 304306 nucleophilic substitution 310 pyrimidines 306, 310 pyrroles 302303 electrophilic substitution 309310 radical reactions C-C bond formation 179182 strategy 177183 reactivity, functional groups, and selectivity 2930 rearrangement reactions 238240 Claisen 265267 Cope 265 Favorskii 242243 pinacol 240242 sigmatropic 263267 reconnection 193197 denition 194

regioselectivity 101106, 124125 of cyclisation reactions 283 in photochemical cyclisations 247248 enones 103106 Reissert synthesis 317, 318 Reppe process 116 reserpine 19 Robinson annelation 156157, 269, 270271 saccharine 15 salbutamol 20, 5051 sarracenin 4344, 284286 sigmatropic rearrangements 263267 silyl groups, as protecting groups 65 spiro-enones 210211 starting materials 7880 1,2-dicarbonyl 173174 1,4-dicarbonyl 190191 enantiomeric purity 8384 steganone 233234 stereochemistry 45 -lycorane 323324 conformational control 89 folded molecules 90, 292293 molecules with many chiral centres 289291 ortho- and para- product mixtures 1415 stereoselectivity 8889 Claisen rearrangment 266267 stereospecicity 8588, 86 Diels-Alder reaction 122123 stereoselectivity 8889, 266267 stereospecicity 8588, 86, 266267 substitution reactions difcult-to-add substituents 19 electrophilic aromatic compounds 1920 reagents 11 nucleophilic allylic halides 26 aromatic compounds 1112, 1315, 2021 suldes, synthesis 27 surfynol 115116 symmetrical compounds, alcohols 7880 synthesis design, general strategy 4 synthons 910 denition 9 polarity 130131 t-butyldimethylsilyl (TBDMS) group 65 tandem processes 313 Taxol 283284 thiazoles 303304

Index

329

thiols 32 tri-iso-propylsilyl groups 65 triethylsilyl group 65 tropinone 12 vernolepin 207208 vinyl cyclopropane 263264 vinyl halides 105106 vulpinic acid 169170

Wittig reaction 108112 and lithium enolates 146147 X-506 antibiotic 194 ylids stabilised, Wittig reaction 110112 sulfur 234235 Z group 63