6 October 2004 Guerrero Prenylated Alkaloids Baran Group Meeting

O H Me HO Me Syntheses Discussed: O N NH O H Me N NH Me N N H H O H O N NH H H O Me N Me NMe Me M e O Me N H Me Austamide Okaramine J H N O Corey, JACS, 2002, 7904 Ganesan, OL, 2003, 2825 Me Me Me Me O H Me H HO Me O ent–Breviananmide B ent–Debromoflustramine B NH H Williams, JACS, 1990, 808 Crich, JOC, 1994, 5543 H N NH Me H OH N H H O N Me OH H Me Me Me O Me Me H H Me Me H O Okaramine C Penitrem D H N N N H H H H Ley, OBC, 2004, 2415 Smith, JACS, 2000, 11254 N N N N H H O N H O Me Me O For your consideration: Me Me Me

O O OH Ardeemin Amauromine MeO O O H NMe N Danishefsky, JACS, 1999, 11953 Danishefsky, JACS, 1999, 11953 O N N NH N N H O Me H H O OH N O O H Me O Me O Me O Me HO H Me H Me HN N N N N Ergotamine Fumitremorgin A H H N O N H Me H OH H Me O OMe Cl O N Me Me Me Me H Me Me H H O H Me OH NCH Me N O N H Me O Spirotryprostatin B N N OH Me Me MeO H Me Williams, JACS, 2000, 5666 Gypsetin H Me N O HN Me H Danishefsky, ACIEE, 2000, 2175 Danishefsky, JACS, 1999, 11964 N N Me Carreira, ACIEE, 2003, 694 Me Oxaline Ambiguine D Echinulin Horne, ACIEE, 2004, 5357 isonitrile Note: the references given do not necessarily refer to communications. Williams, Top. Curr. Chem., 2000, vol. 209, 97 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

Synthesis: NH H O N O O O 1. K2CO3, Me MeO CH2NHLi O BrCH2COBr Me 2. aq. NaOH H N NpMB O O N approx. 100% NHpMB 79–85% N N H tBu O ent–Breviananmide B 1. O3, DMS 2. Me Williams, JACS, 1990, 808 69–99% for 1; 87–92% for 2 and 3 Ph3P CHO Biosynthesis: Most of the brevianamides are comprised of a - 3. NaBH diketopiperazine and a single prenyl unit. Usually, the prenyl unit is attached 4 Me Me Me to the indole in a reversed sense to C2 of indole. A set of events that TBSO TBSO HO explains both the abundance and results of feeding experiments is outlined O O O below: 1. TBSCl, Et3N, DMAP n-Bu P, D 2. n-BuLi, ClCO2Me NpMB 3 NpMB NpMB CO2H 71% H N NMe2 N N O CO2Me CO2Me NH2 cyclase H O O O H NH N N H CO2H N N N H N H H H H 62% O deoxybrevianamide E 1. LiCl, HMPA, H2O, 100 °C reverse 85% 2. KOt-Bu, Boc2O prenyl 3. TBAF transferase Me Me HO Cl Me Me O NH O O H O H H O O N N MsCl, LiCl, collidine conditions R N NpMB NpMB O N N NBoc 100% NBoc Me N N H H N N Me H H Me H N H IMDA H O O O Me O O brevianamide B R-selective pinacol indole 1,2-shift oxidase

O BocN BocN O H O conditions exo:endo yield (%) OH H pMB pMB H O HO N O O N N NaH, DMF, 25 °C 2:1 63 N N N R R NaH, benzene, 80 °C 3:97 82 H H N N N NaH, benzene, 18c6, 80 °C 3.9:1 56 Me Me Me H irreversible H NaH, benzene, 18c6, 25 °C 6:1 14 Me N H Me H O Me NaH, warm THF, 18c6 3-4.9:1 64 H H N Me closure O N N O Me O O (combined yields) brevianamide A brevianamide E desired (anti or exo undesired (syn or endo diastereomer) diastereomer)

Williams, Top. Curr. Chem., 2000, vol. 209, 97 Williams, JACS, 1990, 808 Diels Alder hypothesis: Porter, JCS CC, 1970, 1103 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

Me

Me H H H CO Me CO Me 1. NaIO , CO Me BocN Br 2 2 4 2 n-Bu3Sn(allyl), OsO4 (cat.) pMB pMB benzene, 80 °C 2. Ph PCMe O O NCO Me NCO Me 3 2 NCO Me N 12 M aq. HCl HN N 2 2 2 N H 80% N H 83% for 1, N H Me SO Ph SO Ph 64% for 2 SO Ph Me 72% 2 2 2 H Me N H N O O 1. MeOH, KOH 89% for 1, r.t. Me 61% for 2 2. Barton desired (anti or exo decarboxylation diastereomer) m-CPBA 63% then NaOMe Me Na, NH3 Me Me then 1. MeOH, KOH, Me Br NMe Me reflux Me 2. AcOH, CH2O NH NH Na(CN)BH H O pMB O N H Me 3 N t-BuLi, –100 °C N then dry 3O gas NMe 99% for 1, NCO2Me O 2 O 57% Me Me N H 79% for 2 N H Me H 40% Me Me Me SO2Ph SO2Ph N H N O O ent–Debromoflustramine B ent–Breviananmide B Me Me Me Me Me Me H O H N N N H H H N N N N H H O NMe N H O N H Me O Me Me Ardeemin Amauromine Me Me Danishefsky, JACS, 1999, 11953 ent–Debromoflustramine B Crich, JOC, 1994, 5543

CO2Me H N-PSP, cat. TsOH, SePh SePh NHBoc Na2SO4; 78% H H H H H CO Me CO Me CO Me H 2 H 2 Br 2 OR N N CO2Me N N CO2Me NBS, CCl , H H 4 N N-PSP, Boc Boc Boc Boc PhSO2Cl, py reflux Boc NCO Me NCO2Me NCO2Me PPTS; 2 93% N H 85% N H 60—70% N H major minor H SO2Ph SO2Ph Rationalize the realtive product distributions. Hint: the cyclization is irreversible under the reaction conditions.

Williams, JACS, 1990, 808 Crich, JOC, 1994, 5543 Crich, JOC, 1994, 5543 Danishefsky, JACS, 1999, 11953 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

CO Me 2 Br Me H Me Me SePh Me H N CO2Me TMSI, 0 to N Boc H 23 °C Boc H H SePh N Boc N N N CO2Me 83% H H N N CO2Me Br Boc Boc Boc H H H

SePh SePh 78% A, BOPCl, Et3N H H Me Me N N CO2Me N N CO2Me Me Me H H Boc Boc Boc Boc H H O O MeOTf, prenyl n-Bu Sn, 60% 3 N N TMSI, 0 to N N 2,6-lut, —78 to 40 °C H H H H 23 °C H H H H N N Boc Boc N N O H 58% MeO2C Me Me Me Me Me Me MeOH, NaOH, relux Me Me H H 98% Amauromine N N CO2H N N CO2Me H A H Boc Boc Boc Boc O O cyanuric fluoride, HN N 71% py, D-Ala-OMe•HCl, NaHCO , H O N 3 2 Me Me Me H H Me O TMSI, 0 °C then Me H Me NH3, MeOH, DMAP O H N N O 76% H H N N NH H O Boc Boc HN CO2Me Spirotryprostatin B Me Me Williams, JACS, 2000, 5666 K(TMS)2N, —78 °C, 80% COCl Ph Ph OMe Ph Ph Me Ph O N3 O CHO Ph Me O O Me Me HN toluene, N Me Me O 3 Å MS, r.t. R N O n-Bu3P, R O benzene H H H 82% O O N3 CO2Et N 72% O CO2Et N N N N CO2Et HN H H H H HN N N O O HN Me O Me O

Ardeemin

Danishefsky, JACS, 1999, 11953 Danishefsky, JACS, 1999, 11953 Williams, JACS, 2000, 5666 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

O Ph H H H CO2Me CO Me O HN 2 Ph OH N O 1. D-Pro-OBn, BOP, Et3N Me Me H NH HN H2, PdCl2, N 2. H2, Pd/C N NH R N R Me O 60 psi O 3. BOP, Et3N O CO Me CHO H O O H MeO O H 2 O H H Me 99% 74% for 1, Me Me CO Et CO2Et 94% for 2 and 3 CO2Et NH2•HCl Et N, 3 Å MS, py HN 2 HN HN 3 Me Me O 73% for 2 steps N H O H H CO2Me CO2Me TsOH, mixture at C3 HN 82-89% toluene, reflux HN NH NH O H Me 1. DCC, DMAP, H H Me O O O N-hydroxy-2- Me Me Me N thiopyridinone, Me N Me N bromochlorform LiI, py (solvent), N N N Boc-Pro-OH, 2. MeOH, NaOMe reflux 90% O O O BOPCl, Et N Me O H Me O H Me O H 3 34–43% combined 70–74% CO H CO Et HN yield of a 2:1 epimeric HN 2 HN 2 mixture O H H CO2Me CO Me HN 2 Spirotryprostatin B N HN N H N N O O 1. Li(TMS)2N, 0 °C then Boc O PhSeCl, 0 °C Boc O Me Me O 2. DMDO Me Me HN N N O H H H CO Me CO2Me O 2 HN Me HN N Me N N O H N Spirotryprostatin B O O Boc Boc Danishefsky, ACIEE, 2000, 2175 Me Me Me Me

O O O CO2Me HN HN N TFA then Et3N N N CO2Me CO2Me H H H N 86% H H AcOH, DMSO, 12 M aq. HCl, O O NH2•HCl 5 mol % PhOH, 25 °C NH2•HCl Boc Me Me Me Me 95% O N N 40% of a three component mixture H H Spirotryprostatin B mixture at C3

Williams, JACS, 2000, 5666 Danishefsky, ACIEE, 2000, 2175 Danishefsky, ACIEE, 2000, 2175 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

O O O O HN N HN N N N H H H O O Me Me Me Me Spirotryprostatin B Spirotryprostatin B Carreira, ACIEE, 2003, 694 Horne, ACIEE, 2004, 5357

Me MgI2, CO2Me CO2Me CO2Me H H MgSO , H N Me 4 NH2 NH2 Me N N2 {Rh(OAc)2}2, benzene, NCS, AcOH, CHO reflux, slow adition of S.M. HCO2H, r.t. Me TIPS O Cl Cl 68% yield of N O N O Nallyl N 70% N 95% N H Me H stereoisomers HN H H H Me Me H 1. Troc-Pro-Cl 2. TFA

TIPS O O O O O O H CO2Me H Me Me cat. Pd(PPh3)4, HN N HN N HN N N Li(TMS)2, 0 °C; Zn, MeOH no yield N N given N PhSeCl, 0 °C reflux N O O H H H H H Troc O 20% O 37% for O Me Me 3 steps Me Me Me Me Me Me CHO O O O 37% (other diastereomers produced 1. cat. OsO4, Spirotryprostatin B during reaction ) N N NMO N N Boc-Pro-Cl, NH HN Boc 2. Pb(OAc)4 HN Boc Et3N HN H H H Me O 97% O 45% O HO H Me H N N TIPS TIPS TIPS N resolution N H Me H OH 1. NaClO , 2-methyl-2-butene, buffer O 89% 2 1. Li(TMS)2N, O Me 2. CH N O 2 2 Ph O O N S HN N i-Pr Gypsetin N N CO2Me CO2Me N Danishefsky, JACS, 1999, 11964 O 1. TBAF O N H H 2. Lindlar cat, Quin, H 2. Li(TMS) N, O 2 2 CO2Me N N 3. cat. OsO , NMO N N PhSeCl; H CO2Me CO2Me HN Boc 4 HN Boc Me H H 4. Pb(OAc)4 DMDO Me H H NPhth O O NPhth NPhth 69% CHO 3. TFA; Et3N Spirotryprostatin B Cl THF, —78 °C, 78% for 1, THF, –78 °C, t-BuOCl prenyl 9-BBN Me 74% for 2, Me TIPS 95% 74 for 3 N N N H H

Carreira, ACIEE, 2003, 694 Horne, ACIEE, 2004, 5357 Danishefsky, JACS, 1999, 11964 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

CO2Me CO2Me Me H H O H Me NPhth H2NNH2, NH FmocN H O N 65 °C 2 140 °C N H NH NH Et NH then Me Me MeO C O 2 O O m-CPBA O H 2 benzene, reflux then NaOMe H Me 69% Me 30% HN HN H N H N N O N N Me H 95% 54% H H O N Me H Me Me Me Me DMDO, 40% N Me N Me —78 to 0 °C H H Bz O , 72% brsm 2 2 THF, 3O Me 2 O HO H Me H N N O N O N O H O H N OH N MsCl, Et N H H OH N 3 N Me O O O Me N 63% N H H Gypsetin Me Me Me Me Austamide

O N O O H H Me Me HO NH N O N NH N H N H H Me Me H O

Austamide Me M e Corey, JACS, 2002, 7904 Okaramine J Ganesan, OL, 2003, 2825

Me 1. 10 mol % CuCl, H CHO i-PrEt N, 2 H HO CO2t-Bu CO Me MeO C O Br CO t-Bu 2 Me 2 FmocN H H HO 2 H then NaBH H Fmoc Me O 4 Pd(OAc) , CO2t-Bu N then Schotten- N 2 MeO2C O HO O NH2 N N TFA, 16 h S O Baumann acylation THF, AcOH, H2O, H N O Me H H 3 S O N with Fmoc-Pro-Cl O2, r.t. N H Anth S O N H 2. H2, Lindlar cat. Anth 84% N H 65% for 1, 98% 29% Anth N N H 95% for 2 Me M e Me H H Me Me N Me Me Me H

Danishefsky, JACS, 1999, 11964 Corey, JACS, 2002, 7904 Corey, JACS, 2002, 7904 Ganesan, OL, 2003, 2825 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

Me H H Me CO2t-Bu CO2H H H H HO HO O CO2Me CO2Me CO2Me CO2Me H PhSe HO HO O O A, PyBop, wet m-CPBA, 1. aq. H PO N TMSOTf, N HO NH 3 4 S O 2,6-lut S O Et3N N NCbz K2CO3 NCbz 2. H2, Pd/C NCbz H N H N H N H Anth 75% H Anth 82% N H 85% N H 93% N H SO2 Boc Boc Boc N H CO2Me H Anth H Me Me Me Me NH CO2H 2 H Me Me Me NHTroc HATU, Et N, Me 73% Al/Hg 3 Me 95% N H Me A N Me H Me 1. i-PrEt2N, CuCl, O O CO2Me O O H Me H H Me Me Me H Me NH Me HO HO N HO HO NH 1. MeOH, KOH NH Br NH 2. HBTU, i-PrEt N H N NH 2 NH N NH N N H H 49% N H N H H 2. Lindlar cat., N H H H O H O 1% py H O 70% for 1 Me Me 95% for 2 Me N Me H Me M e Me Me Okaramine J Okaramine C Me Me O Me H H O HO Me H NH H N NH Me H OH N H H O N Me OH H Me Me O Me H H

Okaramine C Penitrem D Ley, OBC, 2004, 2415 Smith, JACS, 2000, 11254

CO2Me 1. Me2NNH2, AcOH H 1. Me C(CH OH) , CSA, 2. LDA, 65 °C, B then C Li(TMS)2N, H 2 2 2 2. i-Bu AlH, —78 °C 3. BzCl, DMAP NHCbz PhSe CO2Me —10 °C; PhSe CO2Me 2 OMTM N-PSP, PPTS, MeOH, O Me 3. aq. HCl, MeOH O Me 4. NaOAc, AcOH O Me Me Na2SO4 NCbz —78 to 0 °C NCbz 85% (brsm) for 1, 33-40% for O Me MeO Me MeO Me N 89% N H 100% N H 83% for 2, 4 steps OBz Boc Boc Boc O 43-53% for 3 O O B OMTM Me O C NMe2 N

Ganesan, OL, 2003, 2825 Ley, OBC, 2004, 2415 Ley, OBC, 2004, 2415 Smith, JACS, 2000, 11254 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

1. NaOH, OMOM OMOM D OMOM OMTM 1. HClO , H O OMTM 2. H2, Pd(OH)2, O Me 4 2 O Me BnO H Me NH OH•HCl, BnO H Me CSA TIPSO H Me Me 2. PDC Me 2 Me NaOAc, D; Me 3. TBSCl, Et3N, Me Bz2O, D DMAP MeO Me 74—90% for 1, O Me H H H OBz 78% for 2 OBz Me Me Me O O 60% 76% for 3 steps

O NHBz NH2 54% for 1. TfOH, Et3SiH 3 steps 2. K2CO3, MeOH 3. EDC, DMAP OTMS a. n-BuLi OTMS b. TMSCl 1. DMP TIPSO H Me TIPSO H Me 2. SiO , air c. s-BuLi O Me 2 O Me H Me d. D Me OH 3. PPh3 O OH H e. SiO2 H Me Me OH 60% Me O Me O Me 81% from D Me H O O OH H H H H N NH2 Me OH H Me O similarly prepared H H 76% for 1. L-Selectride 2 steps 2. TESOTf, 2,6-lut 1. SO3•py, DMSO 47% for 2. 1 M aq. HCl 3 steps 3. Sc(OTf)3

O2N O Me H OTES Se Me Me Me Me O H TIPSO H Me OH O Me O 1. Ac2O, DMAP, Et3N O H 2. TBAF H O H H H H 3. Greico's reagent, n-Bu3P Me H Me H OAc OH D 54% for N Me OH 3 steps N Me OH H Me H Me OBn OBn O O - + H H H H 1. i Bu2AlH; H base, BOMCl 2. H2, Pd/C

52% for 1. m-CPBA, NaHCO3 80 for O OEt O OEt O 2 steps 2. MeOH, K2CO3 2 steps

Me Me 1. Scalemic , H ca. 60% n-BuLi; TMSCl O 1 H 2. O2; PPh3 H 1. Me acrylate, Me H uranium OH OMOM OH filter, hn BnO 1. MOMCl, i-Pr EtN BnO 2. ketalization OBn N Me OH H Me 2 H Me H Me 2. Robinson 3. MeMgBr O Me annulation Me 4. hydrolysis H H H H Me 71% for 2 steps Penitrem D O 49% O

O

Smith, JACS, 2000, 11254 Smith, JACS, 2000, 11254 6 October 2004 Guerrero Prenylated Indole Alkaloids Baran Group Meeting

Other notable syntheses:

O Me Me O Me O O Me HN H N N H HN O HO O

Me N Me N Me Me O O Me Me Me

Paraherquamide B Paraherquamide A Williams, JACS, 1996, 557 Williams, ACIEE, 2000, 2540

O H O O H N HN N H Me N N N H H H Me O Me Me Me

VM5599 Spirotryprostatin B Williams, JACS, 2002, 2556 Ganesan, JOC, 2000, 4685

O Me H Me NH N NH N N H O

Isoroquefortine C Joullie, JOC, 2002, 620 Joullie, PNAS, 2004, 11971