Comparative Syntheses of Gelsemine

Comparative syntheses of Gelsemine

! Historical context ! Approaches to Racemic Gelsemine ! Asymmetric Synthesis of Gelsemine H O N

Joel Austin N O

MacMillan Group Meeting Me January 9, 2002

H Historical Background of Gelsemine O N

! Isolated as an amorphous base from the roots of the Gelsemium Sempervirens N O (Carolina or Yellow Jasmine) in 1870 by Wormley. Me

! Obtained in crystalline form by Gerrard in 1883.

! Molecular formula elucidated in 1910 by Moore.

! 80 years of largely inconclusive degradative studies still had not produced a structure.

! Structure determined independently by the groups of Conroy and Wilson in 1959 via NMR and X-ray crystallography.

! Unique hexacyclic cage structure.

! Strychnine like activity, strong CNS stimulant as well as antihypertensive activity.

Saxton, JE.; In The Alkaloids; Manske, R.H.F., Ed.; Academic Press: New York, 1965; Vol 8, pp 93-117 Gerard, A. Pharm. J. 1883, 13, 641 Moore, C.W. J. Chem. Soc. 1911, 99, 1231 Conroy, H.; Chakrabarti, J.K.; Tet. Lett. 1959, 6 Lovell, F.M.; Pepinsky, R.; Wilson, A.J.C. Tet. Lett. 1959, 1 H O Stork's approach to Gelsemine Core N

! Key steps include mixed acetal radical cyclization and a sequential N O transannular alkylation - Claisen rearrangement sequence. Me ! No further work on gelsemine is reported from the Stork lab beyond synthesis of model core.

i) LDA/ PhSeSePh O O O ii) mCPBA O AIBN DIBAL OEt OEt 95% yield OEt 93% yield OEt 95% yield MeO2C Br MeO2C MeO2C HO Radical Cyclization OH 1) DCC, DMAP 95% yield O 2) Hydrolysis / esterification 77% yield

O OH O O O H LDA / TMSCl TMSOTf OBOC

96% yield 67% yield O

O O OH O O O Ireland Claisen

Stork, G.; Krafft, M.E.; Biller, S.A.;Tet. Lett. 1987, 28, 10, 1035-1038

H O Stork's approach to Gelsemine Core N Stereochemical Rationale

N O Me

! Mixed acetal radical cyclization ! Transannular Alkylation

EtO O O H

MeO2C H O OTMS O O H OBOC O AIBN O O TMSOTf OEt OEt

MeO2C Br MeO2C O O O

! Ireland Claisen O O H H O LDA / TMSCl

O O OTMS O OH

Stork, G.; Krafft, M.E.; Biller, S.A.;Tet. Lett. 1987, 28, 10, 1035-1038 Fleming's approach to Gelsemine Core H O N ! Key steps are the use of a Diels-Alder to make bicycle core, bicycle rearrangement, addition of an allylsilane to an acyliminium ion. ! No further work on gelsemine is reported from the Fleming lab after N O considerable work to install the oxindole. Twenty steps. Me

CO H OTHP OTHP OH 3 OH

O2N 81% yield O2N O N O 43% yield 2 1) Al/Hg, MeOH 85% yield EtO2CHN EtO2CHN CO2Et 2) EtCO2CCl, Et3N OAc OAc CO2Et 3) LiAlH4 4) AcCl, Et3N 5) PhH+ TsO-, EtOH MgBr2 78% yield

OH OEt 1) PhNMe3Br3 O 1) PCC / OEt + Al O 2) DHP, H OEt 2 3 HO OEt HO 2) 3) K2CO3, H2O EtO CHN MgBr EtO CHN 2 O EtO2CHN O 4) PyH+ TsO- EtOH 2 OAc

82% yield 62% yield

Clarke, C; Fleming, I; Fortunak, J.M.D; Gallagher, P.T. Tetrahedron 1988, 44, 13, 3931-3944

Fleming's approach to Gelsemine Core H O and approach to introduction of oxindole N

N O ! Key allylsilane construction of quaternary carbon. Me

Me3Si

OH OEt Cl OEt OEt O (Me Si) CuLi (CH2O)3 OEt SOCl2 OEt 3 2 OEt

97% yield 84% yield HCO2H EtO2CHN O EtO2CHN O EtO2CHN O N O 85% yield EtO2C

! Devoped three new methods for introduction of oxindole moiety. two of these go in very low yield. Third approach NO2 works decently on adamantyl system but not as NO2 Ph3Al well on model with ether bridge. No further work 1) NaOMe is reported. X=CH2 91% yield 2) AcCl X X=O 35% yield X 66% yield OMe H O N O N 1) t-BuOCl MeOHNOC 1) H2SO4 ONC Na / Hg 2) Zn(OAc)2 2) Na2CO3

100% yield 85% yield 69% yield

Clarke, C; Fleming, I; Fortunak, J.M.D; Gallagher, P.T. Tetrahedron 1988, 44, 13, 3931-3944 Fleming, I; Moses, R.C.; Tercel, M.; Ziv, J. J. Chem. Soc. Perkin Trans 1 1991 617-626 Fleming's approach to Gelsemine Core H O Stereochemical Rationale N

OH O N O ! Bicycle rearrangement. MgBr2 Me HO O 78% yield EtO CHN 2 EtO2CHN OAc OAc

OH O Cl3AlO AlCl3 NHCO2Et CO2Me EtO CHN 2 OH OH CO2Me 35% yield O EtO2CHN Br CO2Me OH O MgBr2 HO Migration HO EtO CHN 2 EtO2CHN CO2Me CO2Me

44% yield 39% yield

Clarke, C; Fleming, I; Fortunak, J.M.D; Gallagher, P.T. Tetrahedron 1988, 44, 13, 3931-3944

Fleming's approach to Gelsemine Core H O Stereochemical Rationale N

N O ! Pyran formation via intramolecular SN2 Me

1) PhNMe3Br3 2) DHP, H+ O OEt O

3) K2CO3, H2O Br HO OEt DHPO HO 4) PyH+ TsO- EtOH EtO CHN EtO CHN EtO CHN 2 OAc 62% yield 2 O 2 OH

! Allylsilane addition to acyliminium ion

Me3Si Me3Si

OEt O O (CH O) OEt 2 3

EtO CHN HCO2H N N 2 O O EtO C O 84% yield EtO2C 2

Clarke, C; Fleming, I; Fortunak, J.M.D; Gallagher, P.T. Tetrahedron 1988, 44, 13, 3931-3944 Johnson's synthesis of Gelsemine H O N ! Key steps are the use of a photoinduced intramolecular cycloaddition, retro- Claisen condensation, intramolecular Mannich, novel oxindole synthesis. ! Stops synthesis at racemic imino-ether of 21-oxogelsemine; this natural product N O has previously been shown to be readily converted to gelsemine. 28 steps. Me

MeO2C CO2Me MeO2C CO2Me MeO2C CO2Me pyridine h" H O Cl 73% yield O 53% yield

1) LiAlH4 2) AgOAc, I2, AcOH 44% yield

1) (i) RuCl3, NaIO4 O CO2Me PhSeSiMe , O CO2Me (ii) CH N O 3 2 2 OH ZnI2, PhMe H H 2) K CO , MeOH H OTMS O 2 3 reflux O TBDMSO TBDMSO 3) TBDMSOTf, lutidineAcO 94% yield 85% yield

SePh

Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764

Johnson's synthesis of Gelsemine H O N

N O O CO2Me O CO2Me mCPBA 1) K2CO3, MeOH, THF Me H H OTMS 92% yield OTMS 2) Me2SO, TFAA, –70°C TBDMSO TBDMSO 92% yield

SePh

O CO2Me O H O H 1) LiBH CO Me 4 CHO MeNH2, MeOH 2 H H 2) CrO3, pyridine H O THF TBDMSO TBDMSO CONHMe TBDMSO CONHMe 86% yield 95% yield crude

K2CO3, MeOH 88% yield

Br O H O Br , MeOH O TsOH, DCM OMe 2 OH H H H N 97% yield N N TBDMSO Me from hydroxy TBDMSO Me TBDMSO Me O lactam O O

Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764 Johnson's synthesis of Gelsemine H O N

Br Br O 1) TBAF O OMe OMe N O 2) Swern TIPSOTf, Et3N H H Me N N TBDMSO Me O Me 96% yield O O 97% yield

O Br O N O TFA, reflux Bu3SnH N OMe O benzene O H N N O N N O TIPSO Me 74% yield Me reflux OMe Br 70% yield Me TMS O i) LDA ii) nBuLi 65% yield iii) then cage structure imino-ether of 21-oxogelsemine MeO MeO N h! N N N N 1:2 36% yield O O O OMe N N O O N O Me Me Me

Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764 Dutton, J.K.; Steel, R.W.; Tasker, A.S.; Popsavin, V.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 765-766

Johnson's Synthesis of Gelsemine H O Stereochemical Rationale N

" Photochemical [2+2] N MeO2C O CO2Me Me MeO2C CO2Me O h! H O CO2Me MeO C O 53% yield 2

" Pyran formation

1) LiAlH4 MeO2C CO2Me 2) AgOAc, O OH I2, AcOH H 44% yield H O O AcO O Me Me OH OAc O O Me O O O O I O O O I OH HO HO OH OH HO OH

Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764 Johnson's Synthesis of Gelsemine H O Stereochemical Rationale N

! Methoxy bromination

N O O Me Br2, MeOH H N TBDMSO Me 97% yield from hydroxy O lactam OTBDMS OTBDMS Br O O H O OMe Me H N O H Br Me N N O TBDMSO Me Br O MeO MeOH

! Intramolecular Mannich cyclization

O Br OTIPS O O TFA, reflux OMe O O O H N N N O O N Me O TIPSO Me 74% yield Me Me Br Br Br O

Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764

Johnson's Synthesis of Gelsemine H O Stereochemical Rationale N

! Oxindole synthesis

N O Me

MeO MeO N N N N h" N

O 36% yield O O OMe N N N O O O Me Me Me 1:2

MeO MeO MeO N N N N N

O O O N N O N O O Me Me Me N2

Sheikh, Z; Steel, R; Tasker, A.S.; Johnson, A.P. J. Chem. Soc., Chem. Commun. 1994, 763-764 Speckamp and Hiemstra's synthesis H O of Gelsemine N ! Key steps are the use of a Diels-Alder, intramolecular Mannich, Overman oxindole synthesis. N ! Completes gelsemine in racemic form, enzymatic route to enantiopure starting O Me material is known. 19 steps.

toluene HO HO OH reflux NaBH4 O O N H H H H Me EtOH, H+ 95% yield O O OEt N O N Me Me

TPAP / NMO 45% yield from D–A

TIPSO TIPSO OHC 1) LDA PhSeCH2CHO TIPSOTf, Et3N H H H H H 2) MsCl, Et N O OEt 3 O OEt O OEt N N N Me 70% yield Me 98% yield Me

Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768 Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166 (+) enantiomer of intermediate Koot, W.J.; Hiemstra, H.; Speckamp, W.N. J. Org. Chem. 1992, 57, 1059-1061 (-) enantiomer of intermediate Dijink, J.; Cintrat, J.C.; Speckamp, W.N.; Hiemstra, H. Tet. Lett. 1999, 40, 5919-5922

Speckamp and Hiemstra's synthesis H O of Gelsemine N

TIPSO N O BF3·OEt2 NaBH4 Me H 70% yield O 90% yield O OEt N N CHO Me Me

OTf O L-selectride Pd(OAc) , PPh , Et N, 1) TDSCl, imidazole 2 3 3 O then Tf NPh O 2 O CO, DMF N OH N Br 2) CrO3 N OTDS OTDS Me 65% yield 3,5-dimethylpyrazole Me Me 45% yield NH2 70% yield

O O

N N H SEM Br NAH, SEMCl Br O O N OTDS 90% yield N OTDS Me Me

Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768 Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166 (R) enantiomer of intermediate Koot, W.J.; Hiemstra, H.; Speckamp, W.N. J. Org. Chem. 1992, 57, 1059-1061 (S) enantiomer of intermediate Dijink, J.; Cintrat, J.C.; Speckamp, W.N.; Hiemstra, H. Tet. Lett. 1999, 40, 5919-5922 Speckamp and Hiemstra's synthesis H O of Gelsemine N

N O Me

O SEM SEM O N O N N SEM Pd (dba) , Et N Br 2 3 3 O PhMe O TBAF O N OTDS N OTDS 60% yield N OH Me Overman conditions Me over 2 steps Me and 30% yield of epimer oxindole 1) HgO, Tf2O PhNMe2, CH3NO2 2) NaBH4, NaOH 50% yield H H SEM O N O N O N

O O AlH3, THF TBAF N O N O N O 50% yield Me Me 90% yield Me

Newcombe, N.J; Ya, F.; Vijn, R.J.; Hiemstra, H.; Speckamp, W.N. J. Chem. Soc., Chem. Commun. 1994, 767-768 Speckamp, W.N.; Newcombe, N.W.; Hiemstra, H.; Ya, F.; Vijn, R.J.; Koot, W.J. Pure & Appl. Chem. 1994, 66, 10, 2163-2166 (R) enantiomer of intermediate Koot, W.J.; Hiemstra, H.; Speckamp, W.N. J. Org. Chem. 1992, 57, 1059-1061 (S) enantiomer of intermediate Dijink, J.; Cintrat, J.C.; Speckamp, W.N.; Hiemstra, H. Tet. Lett. 1999, 40, 5919-5922

Speckamp and Hiemstra's synthesis H O of Gelsemine, Stereochemical Rationale N ! Appendage of vinyl group

TIPSO TIPSO N 1) LDA O Me PhSeCH2CHO H H H 2) MsCl, Et N O OEt 3 O OEt N N Me 70%yield Me

OTIPS OTIPS OTIPS OEt OEt OEt

NH NH NH

H H H OLi O O

Se Se OH Se OMs O Cl

! Intramolecular Mannich cyclization

TIPSO

BF3·OEt2 H 70% yield O O O OEt N N N CHO Me Me Me OTIPS

! Overman Intramolecular Heck for Oxindole synthesis

N O O SEM O N Me N SEM Pd (dba) , Et N Br 2 3 3 O PhMe O N OTDS N OTDS Me Overman conditions Me

olefin coordination O SEM ox add O N N SEM O Br NSEM O O L Pd L N PdL OTDS 2 N O Br Me Me N Pd OTDS Br Me L OTDS

SEM SEM O N O N

migratory insertion

N L N L Pd L Me Me H Pd Br Br Et3N·HBr OTDS OTDS L "-hydride elim

Hart's synthesis of Gelsemine H O N

! Key steps are two free radical cyclization and an isomerization / cyclization. ! Completes 21-oxogelsemine in racemic form. 23 steps. N O CO2Et Me BnO R1 O BnO O 6 steps O free radical 2 steps cyclization MeN O O 65% yield 65% yield MeN H functional 17% yield R2 R = CHO, R = OEt H O group manip 1 2 PhS 65% yield Br BnO O Ac BnO Ac BnO O N Acylation of N isocyanate and Free Radical O O O protection cyclization N Me O Me N N 79% yield OAc 40% yield Me OAc Ph2(MeO)C Ph (MeO)C Ph2(MeO)C 2

! Overman Intramolecular Heck for Oxindole synthesis

N O O SEM O N Me N SEM Pd (dba) , Et N Br 2 3 3 O PhMe O N OTDS N OTDS Me Overman conditions Me

olefin coordination O SEM ox add O N N SEM O Br NSEM O O L Pd L N PdL OTDS 2 N O Br Me Me N Pd OTDS Br Me L OTDS

SEM SEM O N O N

migratory insertion

N L N L Pd L Me Me H Pd Br Br Et3N·HBr OTDS OTDS L "-hydride elim

Hart's synthesis of Gelsemine H O N

Ac Ac BnO O N BnO O N Elimination / Epimerization 4 steps ozonolysis to 21-oxogelsemine O and cyclization O 39% yield 90% yield N 64% yield Me OAc N O OHC Me OH Kuzmich, D.; Wu, S.C.; Ha, D.C.; Lee, C.S.; Ramesh, S.; Atarahi, S.; Choi, J.K.; Hart, D.J. JACS 1994, 116, 6943-6944 Atarahi, S.; Choi, J.K.; Ha, D.C.; Hart, D.J.; Kuzmich, D.; Lee, C.S.; Ramesh, S.; Wu, S.C. JACS 1997, 119, 6226-6241 Overman's synthesis of Gelsemine H O N ! Key steps are Aza-Cope rearrangment, Mannich cyclization, intramolecular Heck, base promoted reorganization of oxindole. This synthesis is of note in that the mannich cyclization was demonstrated well in advance of the other syntheses. N O ! Completes gelsemine in racemic form. 26 isolated intermediates. Me

OH KH OK 18-c-6 OK N ClCO2Me HN N 81% yield H CN

i) KHMDS, Et3SiCl ii) (PhIO)n, BF3•OEt2 OH O TFA O iii) KHMDS, Comins' reagent MeO CN 2 61% yield 67% yield MeO2CN over 2 MeO2CN H steps Br Br X X=H Br2 X=Br O NMOM OTf 1) Carbonylation N Heck MOM I 2) Amidation / protection O EtO2CN OMe EtO2CN OMe 61-78% yield EtO2CN O 74% yield Br Br Br 11:1

Earley, W.G.; Jacobsen, E.J.; Meier, P.; Oh, T.; Overman, L.E. Tet. Lett. 1988, 29, 31, 3781-3784 Madin, A.; Overman, L.E. Tet. Lett. 1992, 33, 34, 4859-4862 Madin, A.; O'Donnell, C.J.; Oh, T.; Old, D.W.; Overman, L.E.; Sharp, M.J. Angew. Chem. Int. Ed. 1999, 38, 19, 2934-2936

Overman's synthesis of Gelsemine H O N

1) HCl N O NMOM 2) (iBu)3Al NMOM Me 3) Ethyl vinyl ether 1) MeOTf, NaCN O 4) NaCN, DMSO O 2) p-TSA 150°C OEE EtO2CN O N Br 59% yield 84% yield

H O N NMOM DBU H NMOM O H O 80% yield O OH N N HNR N H 3 O Me Me CN CN Me CN

MOM H MOM O O O N N 1) HCl N 2) DIBAL 3) Et3SiH, TFA

N N O 60% yield N O CN OH Me Me Me O

N O ! Aziridine formation Me

NMOM NMOM NMOM NMOM NaCN, DMSO O O O OEE OEE OEE 150°C O HN HN HN OEE N Br CN Br CN

! New Heck conditions

L O [Pd2(dba)3] NMOM Pd NMOM N CHCl3, Ag3PO4 L MOM I Et3N O O N EtO2CN OMe 61-78%yield EtO2CN O OMe Br Br 11:1 Me OTDS

Fukuyama's synthesis of (+)-Gelsemine H O N ! Key steps are an epoxide rearrangment and a divinylcyclopropane rearrangement. ! Completes gelsemine enantioselectively. Shorter endgame than racemic N O synthesis. 21 steps. Me

Single Isomer OH O O SiMe2H SiMe2H

Et2AlCl H2O2 Cl N O Cl –78°C 53% yield Cl 88% yield Bn CO2Me X O X=Aux Sm(OTf)3 X= OMe MeOH VO(acac)2 99% yield t-BuOOH 100% yield

a) TESOTf OH I CHO OSiEt NH 4-I-oxindole 3 lutidine piperidine MAD, PhMe b) t-BuOK Cl O O O CO2Me 65-78% yield 99% yield 95% yield Et3SiO CO2Me CO2Me CO2Me

Et3SiO

Fukuyama, T.; Liu, G. JACS 1996, 118, 7426-7427 Fukuyama, T.; Liu, G. Pure & Appl. Chem. 1997, 69, 3, 501-505 Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075 Fukuyama's synthesis of (+) Gelsemine H O N

N O Me

O I O NH I i) Wittig i) TBAF NH ii) MOMCl ii) CrO3, H2SO4 NH O ii) Tol/ACN Heat iii)nBu3SnH, AIBN O MeO C 72% yield 2 54% yield CO2Me I CO2Me Et3SiO O

CO2tBu H CO tBu 2 CO tBu O MOM 2 O N O MOM N H H NMOM MeNH2 A) AllocCl MeOH B) LiBEt3H MeO2C MeHN AllocN H H 94% yield 100% yield Me OH CO2Me

Fukuyama, T.; Liu, G. JACS 1996, 118, 7426-7427 Fukuyama, T.; Liu, G. Pure & Appl. Chem. 1997, 69, 3, 501-505 Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075

Fukuyama's synthesis of (+)-Gelsemine H O N

CO tBu 2 CO2tBu O MOM MOM N a) [Pd(Ph ) ] O 3 4 N N O pyrrolidine KHMDS H H Me

b) ICH2CN NC 62% yield AllocN N iPr2NEt Me OH 78% yield Me OH

OH MOM MOM O O MOM t-BuO2C N N O N

o-NO2PhSeCN, 1) PhCOCl mCPBA, Et N NC NC 3 O N N OH 2) Hydrolysis OCOPh 97% yield N reduction OX Me Me Me 71% yield

MOM H O N O N Hg(OTf) 1) TMSCl, NaI K CO X=COPh 2 2 3 PhNMe , NaOH 2) DIBAL MeOH 2 O 96% yield 61% yield N X=H O 57% yield N O Me Me

OSiEt3 CHO N O MAD, PhMe O Me CO Me 65-78%yield 2 CO2Me Et3SiO

OSiEt3 OSiEt3 OSiEt3 OSiEt3 CHO O O OMAD O MAD MAD CO2Me

CO2Me CO2Me CO2Me H CO2Me H Et3SiO

! Condensation by oxindole, Iodine at 4 position helps with olefin geometry.

O CHO 4-I-oxindole I I NH NH NH piperidine HO HO

CO2Me 99%yield O O

Et3SiO I

CO2Me CO2Me CO2Me

Et3SiO Et3SiO Et3SiO

Meinwald, J.; Labana, S.S.; Chadha, M.S. JACS, 1963, 85, 582 Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075

Fukuyama's synthesis of (+)-Gelsemine H O N ! Divinyl cyclopropane rearrangement.

O O N O I NH NH Me

O MeO2C I

CO2Me O O H O H O N O N H

MeO2C H MeO2C I I

Meinwald, J.; Labana, S.S.; Chadha, M.S. JACS, 1963, 85, 582 Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Angew. Chem. Int. Ed. 2000, 39, 22, 4073-4075 Danishefsky's synthesis of Gelsemine H O N ! Key step is a divinylcyclopropane rearrangement, new oxindole synthesis from an Eschenmosr Amide acetal Claisen. ! Completes gelsemine in racemic form. Not completely published. ? steps. N O H Me H NO2 rearrangement 5 step process t-BuO then unknown N elaboration NO2 MeO2C 24%yield OPiv

O CbzHN NCbz NCbz

2 steps CH3C(OMe)2NMe2 OH N N N MeO C 30-40%yield 2 MeO2C 24%yield MeO2C OPiv OPiv OH Dihydroxylation protection and Cbz oxidation O N sequence CbzN CbzN (5 steps) 18%yield NMe2 NMe2 O O N

EtO2C N N OTES

MeO2C MeO2C OPiv OPiv Ng, F.; Chiu, P.; Danishefsky, S.J. Tet. Lett 1998, 39, 767-770 Lin, H.; Ng, F.W.; Danishefsky, S.J. Tet. Lett fast 2002

H Conclusion O N

! Lots of synthetic work on this molecule with two basic premises dominating: N O cyclisation onto an iminium and rearrangements to build core. Me

! Oxindole synthesis at end is problematic but solved.

! This molecule is SCREAMING for a faster synthesis along a novel strategy.