《有机合成设计导论》课程教学资源（案例）合成实例 2 The Total Synthesis of Strychnine

The Total Synthesis of strychnine(1954) strychnine Poison isolated in 1818 Used as a pestcide and in medicine as a stimulant for the central nervous system Structure elucidation in 1946 X-ray crystallographic confirmation in the early 1950s Absolute configuration in 1956 Challenge: 6 chiral centers and 7 rings or its molecular size it is the most complex substance known Sir robert robinson

The Total Synthesis of Strychnine (1954) strychinine · Poison Isolated in 1818 · Used as a pestcide and in medicine as a stimulant for the central nervous system · Structure elucidation in 1946 · X-ray crystallographic confirmation in the early 1950¶s · Absolute configuration in 1956 · Challenge: 6 chiral centers and 7 rings ³For its molecular size it is the most complex substance known.´ ------ Sir Robert Robinson N O O N H H H H

Retrosynthesis I C-12-O cleavage 11H:0-23 Conjugate addition 1: strychnine allylic rearrangement 3: isostrychnine I formation HO Organometallic addition 6: dehydrostrychninone convex face Nb.C-20 cleavage concave face CIS

Retrosynthesis I

Retrosynthesis II NAc H 9 Dieckmann NAC condensation OH 14OMe CO2 Me NAc C-16 epimerization co,Me CO,Me CO,Me COmE NSO,A NSO,Ar Et CO2Et CO,M Lactam 13a formation Ar= C6H4-P-Me NSO,Ar NSO,Ar CO2Et CO,Me CO. Meo,c 1011 Ac 12 CO2 Me 15

Retrosynthesis II

Retrosynthesis III Et C-C bond NSOzA CO2Et OMe 18b C6Ha-p-Me Eto Imine formation CHO 21: ethyl glyoxylate 20: 2-veratry tryptamine C-C bo OMe 23: 2-veratrylindole NHNH2 OMe 24: phenylhydrazine 25: acetoveratrone

Retrosynthesis III

Synthesis of Intermediate 19 polyphosphoric NHNH OMe Fischer indole OMe synthesis 24: phenylhydrazine 25: acetoveratrone OMe [3,3] H2N OMe OMe OMe OMe.NH3 OMe H④ OMe 23: 2-veratrylindole CH2o, Me2NH H2O-dioxane,(92% AcOH 1. Mel 2. NaCN. DMF OMe (97% overall) LAH4,THF,△(85% NH? CHO 21: ethyl glyoxylate OMe 20: 2-veratryltryptamine

Synthesis of Intermediate 19

Synthesis of Intermediate 13a p-TsCl, pyr. CO2Et OMe OMe B: NSO,Ar CO2Et O2Et OMe 18a 18b Ar CsHa-D-Me CO,Et 1. NaBH4, EtoH Co pyr. 10 OMe (84% for 2 steps) 17 NSO2Ar NSO,Ar ACOH H,O MeO2C 16a 16b NSO2Ar NSO2Ar MeOH,Hcl,△ (75%) MeO2C. 15 lactamization NSO2Ar NSO.Ar o,Et isomerization CO,Et CO Me

Synthesis of Intermediate 13a

Epimerization of Intermediate 13a epimerization at C-16 CO2E Ar= CsH4 p-Me 13b NSoA HI, red phosphorous CO,Me △(72% CO2H 1. Ac2o, pyr. 2.CH2N2, MeOH(79%) NaOMe MeOH, O2Me 15 CO,Me OMe CO,Me 11 NaOMe(881 NAc = OMe CO Me 10 Synthesis of Intermediate 10b

Synthesis of Intermediate 10b Epimerization of Intermediate 13a

Synthesis of Intermediate 9 OTs P-TsCI,pyr. (95%) CO Me 10 28 NaSCH? Ph MeOH,25°C (77% NAC NAc SCH, Ph SCH2Ph CO, Me 29 Ra EtoH,△(84%) H2, Pd-C COMe COM 30 cis-31 KOH H2O-MeOI reflux(87%) CH2N COH Et2O trans-31

Synthesis of Intermediate 9

Synthesis of Intermediate 35 AC2O, pyr. COH reflux (42%) b NAc 33 AC,O 35 Ac2O 34

Synthesis of Intermediate 35

Synthesis of intermediate 6 b Hc,AcOH,H2O,Δ OAc Seo EtoH CHO CHO CHO cis-glyoxal 7 trans-glyoxal 36 cyclization oxidation 6: dehydrostrychninone

Synthesis of Intermediate 6