Baran Group Meeting Isoquinoline Alkaloids 10/18/2006 Jun Shi

5 4 4a 3 6 MeO HO isoquinoline O N 7 2 8a N N 8 1 MeO O -isoquinoline first isolated from coal tar in 1885, sweetish odour O NMe -isoquinoline alkaloids, large familiy,until now over 400 members OMe -Biological activities: HO antimalarial, anti-HIV, insect growth retarding OMe antitumor, antimicrobial, antileukmic OMe antibacterial, Parkinson's disease Papaverine OMe Morphine Berberine

CHO OMe OMOM HO Me NHBoc OMe O Me OAc H O HO Me H MeN Me R Br O N Me MeO H O Cl O N O COOEt H2N Me O H N S HO O OH RO NH HO OMe MeO NH O 2 SCAr3 NAc MeO OMe NH COOH HO MeO cryptaustoline curicyleatjehine HO NHTroc Ecteinascidin 743 Jieping Zhu et al, J. Am. Chem. Soc., 128, 87-89, 2006

MeO OH

NMe HO HO HO OH R3O O OH H O OMe NMe N O MeN N N O OMe O R1 O NH O R2 Chaetoindicin B neocaryachine labrandine chaetoindicin A roebramine Guo-Lin Zhang et al. Org. Lett. 2006, 8, 3613-3615 R OMe

For a comprehensive review see: K.W. Bentley, Natural Product Report, 8, 365-391, 1992 1 Baran Group Meeting Isoquinoline Alkaloids 10/18/2006 Jun Shi

5 4 Zhen Yang et al, Org. Lett., 6, 3155-3158, 2004 4a 6 3 NH2 R1NC N R R2 7 2 2 8a planar, 10 electron deficient aromatic symtem 8 1 ! MeOH I O Pd(0) O electrophilic attack: C4 and C8 CHO CO2H O O nucleophilic attack: C1 and C3 I N N isoquinoline R R3 3 R R3 HN HN 2 R 5 4 5 4 R1 1 3 6 3 6 NH N NH 7 7 R1NC 2 R2 R2 8 1 2 8 1 2 MeOH O I CO H Pd(0) H tetrahydroisoquinoline dihydroisoquinoline CHO 2 N O N R I N 1 R3 O R3 R2 HN O R Synthesis of core 1 R3 Classic: 5 4 C8a-C1: Bischler-Napieralski reaction 4a 3 Pictet-Gams reaction Ronald Grigg et al, Angew Chem Int Ed, 44, 7570-7574, 2005 6 C1-N2: Pictet-Spengler reaction O C4-C4a: Pomeranz-Fritsch reation 7 N 8a 2 Novel: Formation of C -C and N -C 8 1 3 4 2 3 O N O Ring expansion of other ring system I Me NH2

NH2OH R CO Me James W. Herndon et al, Org. Lett., 5, 4261-4263, 2003 OMe CN Pd(0), base 2 NH2NHR Cr(CO) Pd(0), base Bu 5 Bu Pd(0), base Me MeO CN N O Me Me + O N O N O O O NC H CHO N H H H H H H R Jungha Chae et al, J. Org. Chem., 10172-10174, 2005 O H NR H Pd(0), N N tBu N N CO Me N Na2CO3 N 2 F3C R1 +

I R2 R1 R2 CF3 R2 CF3 R1 2 J. A. Joule and K. Mills, Heterocyclic Chemistry, P121-P143 Baran Group Meeting Isoquinoline Alkaloids 10/18/2006 Jun Shi

Biosynthesis of isoquinoline alkaloids

Biosynthesis pathway to berberine in Berberis cell cultures

HO HO H CO 3 H3CO

NH2 NH NH NMe HO HO HO H HO H coclaurine CHO H from zizyphus

OH OH OH Coclaurine HO Norcoclaurine

H3CO H3CO H3CO

NMe NMe N HO HO HO H H H OH OH OH reticuline OH OMe OMe from siparuna reticuline scoulerine

H3CO O N O N HO O H N OMe H O OMe OMe OMe OMe canadine OMe Berberine Heinz G. Floss et al, J. Am. Chem. Soc, 117(5), 1995 Berberine from Berberis

3 Baran Group Meeting Isoquinoline Alkaloids Jun Shi 10/18/2006

Photochemical Synthesis of Isoquinoline alkaloids

1. G. R. Lenz et al, J. Am. Chem. Soc, 88, 5369, 1966 5. K. Fukumoto et al, Tetrahedron, 27, 5993, 1971 h! HO O NCO2Et N O

NCO2Et NCO2Et MeO h! MeO hv MeO Br MeO NCO2Et hv MeO MeO [o] NCO2Et OH OH 2. T. Mori et al, Tetrahedron Lett., 3643, 1963 HO HO H NMe MeO Br h! NMe h! MeO H NR NR N

O O HO O 3. P. D. Gardner et al, Tetrahedron Lett., 2493, 1967 6. Patrick S. Mariano et al Tetrahedron Lett., 26, 5867-5870, 1985 R R Me N N h! ClO4 N h! O Br N + TMS R R TMS 4. Gregorio Torres et al, Tetrahedron Lett., 36, 1315-1318, 1995 N CN CN ClO + N 4 hv MgCl h! NR MeO O NH R MeO MeO O O TMS OH OH TMS

for more see Jeremy's group meeting materials

4 Baran Group Meeting Isoquinoline Alkaloids Jun Shi 10/18/2006

Aymmetric Synthesis of Isoquinoline Alkaloids

1. Esther Leter et al, J. Org. Chem. 70, 10368-10374, 2005 4. Ihara, M. Heterocycles, 59, 51, 2003

MeO MeLi OR Me MeO Lewis acid N OR MeO O N O Me N MeO N O 2 HCl H MeO NHCOMe N 1 MeLi OR H R R protic acid N N MeO O Me MeOH-H2O 3 MeO O CHO 2. Marine Boudou and Dieter Enders, J. Org. Chem, 70, 9486-9494, 2005 1 OMe O OMe 2 5. Tomioka, K., Tetrahedron Lett. 41, 5533, 2000 O NEt2 O SAMP, MS 4 A N N N Ph H N OMe Me N O H 2 R LDA, AlMe3 R H 55%, 96%ee N N MeLi OMe Me OMe 2 3. Jiang, L et al, Tetrahedron Lett., 36, 715, 1995 1 O S 1. CH2O/NaBH3CN C6H4NO2 R R R NH 2. Raney Ni NMe NH 2 TFA Me O S 3 R R NH N C H NO 1 6 4 2 Me OMe 3 Me 2 3

For more about SAMP-Hydrazone Methodology see Review: Dieter Enders et al, Angew Chem Int Ed, 44, 1304-1325, 2005 5 Baran Group Meeting Isoquinoline Alkaloids Jun Shi 10/18/2006

Aymmetric Synthesis of Isoquinoline Alkaloids

6. Michiko Miyazaki and coworkers, Org. Lett, 8, 1295-1297, 2006 10. Hoye, T. R. and Chen, M. Tetrahedron Lett. , 37, 3099, 1996 HO

MeO MeO NaBH4 CuCl, (R)-tol-BINA, TBAT or H2/Pd-C NH HO N NH MeO MeO Si(OMe)3 H OH N 67%, 97%ee

OH HO 7. Mikiko Sodeoka et al, J. AM. CHEM. SOC, JA065646R, 2006 LiAlH4, AlMe3 NH Chiral Pd cat. OH N NBoc CO2R 11. Ligong Liu, Synthesis, 11, 1705-1707, 2003 * MeO CO R Me 2 MeO CO2R 2 n-BuLi, PhMe + N O O MeO NH (-)-sparteine 8. Joanna Szawkalo and Zbigniew Czarnocki, Monatashefte fur Chemie, MeO 136, 1619-1627, 2005 N R1 R2 berine

12. Eric N. Jacobson et al, Angew. Chem. Int. Ed, 44, 6700-6704, 2005 Chiral Ru complex R1 R1 N Et N/HCOOH NH 1. RCOCl tBu S 3 iBuN N R 2 N N 2. OTBS R2 R2 N O H H Ph chiral thiourea Me O 9. Takashi Itoh et al, Synlett, 10, 1595-1597, 2006 OR' R'O2C

HCN, Jacobson catalyst 13. Karl Anker Jrgensen et al, Angew. Chem. Int. Ed, 44, 6058-6063, 2005 R1 R1 N TFAA N CF3 10% Catalyst OMe N MeO CN O N Et3N CH2Cl2 N H H H

O O

6 Baran Group Meeting Isoquinoline Alkaloids Jun Shi 10/18/2006

Total synthesis of isoquinoline alkaloids natural product

Toshio Honda and Hiroki Shigehisa, Org. Lett, 8, 657-659, 2006 MeO NO MeO NHAc MeO CHO MeO CHO 2 Pd(OAc)2, PPh3, Na2CO3 1. BnBr MeO MeO MeO 1. LiAlH4 MeO 2. CH3NO2, NH4Ac 2. AcCl, NEt , Br 3 3 3.Pd(OH)2, H2 B(OH)2

Bn OH OH HO 2 1 POCl3, ACN

MeO MeO MeO MeO

HCHO, NaBH3CN NTFA TFAA NMe NH PIDA, Then NaBH4 NH MeCN MeO MeO MeO MeO Cl OAc I OAc OH 4 O O OH Pronuciferine Stepharinine 5

Toshio Honda and Hiroki Shigehisa, Tetrahedron Lett, 47, 7301-7306, 2006 OMe OMe OMe OMe MeO Pd(PPh)2Cl2 PIDA, Then NaBH4 MeO MeO MeO NaBH3CN, HFIP Bu3SnH, AcOH N O O N O N O N O O O HO

1 3 O O Annosqualine O OTBS 2

7 Baran Group Meeting Isoquinoline Alkaloids Jun Shi 10/18/2006

Total synthesis of isoquinoline alkaloids natural product

Albert Padwa and M. Diana Danca, Org. Lett., 715-717, 4, 2002

MeO MeO MeO MeO O O O O O O 1. H+, MeOH CHO MeO NH2 SEt SEt SEt 2. TBSCl, DMAP MeO N MeO N MeO N O NaIO4 TBSO CO2Me CO2Me CO2Me CO2Me 3. LDA 1. CBr , PPh then EtSCH2COCl 4 3 HCO2Et 2 TBSO HO 2. NaIO4, Br 1 3 4 5 CSA

MeO MeO MeO MeO MeO H H H H NaH H N N N NaIO N N MeO MeO S MeO O 4 MeO O MeO O

MeO2C MeO2C Lawesson's reagent MeO2C MeO2C SEt MeO2C SEt Meerwein's salt Br NaBH4 6 8 Jamtine 9 7

Miwako Mori et al, Org. Lett., 5, 2323-2325, 2003

O NHBoc O O NO2 NHBoc TMS O CHO O NH LiAlH4, (Boc)2O 1. CO2, Ni(cod)2, DBU O O O 1. TMSCCH, O O Br 2. CH2N2 TFA, MeOH, PdCl2(PhCN)2 TMS TBAF CO Me TMS ZnCl COOMe 2 2. CH3NO2 3 5 1 2 4

8 Baran Group Meeting Isoquinoline Alkaloids Jun Shi 10/18/2006

Total synthesis of isoquinoline alkaloids natural product

1. LiAlH4 O 2. (COCl)2, DMSO, TEA O O O Grignard HCl, Grubbs' reagent 1 Allyl bromide K2CO3 N N N N O O O O

3. Ac2O, TEA, DMAP AcO HO CO2Me OAc Erythrocarine 6 8 7

Michiko Miyazaki and coworkers, Org. Lett, 8, 1295-1297, 2006; Tietze, L. F et al, Angew. Chem. Int. Ed., 42, 4254, 2003 MeO MeO MeO O MeO

(Boc)2O Grubbs'1 NH NH NBoc MeO N MeO MeO H MeO H H pyrrolidine H H ethyl acrylate H TMSOTf H 1 O O 2 CO2Et 4 MeO EtOOC N MeO 3 H H Me Ph3PCH3Br, LiPh H O then MeOH EtOOC

MeO

N MeO MeO MeO 1. AlMe3 H H N 2. POCl3 N Pd/C MeO MeO H H H H H MeO 3. Ru catalyst NH HCO2H/Et3N H H 6 5 MeO EtOOC EtOOC emetine

9 Baran Group Meeting Isoquinoline Alkaloids Jun Shi 10/18/2006

Total synthesis of isoquinoline alkaloids natural product Christopher J. Bungard and Jonathan C. Morris, J. Org. Chem., 7345-7363, 2006 Yamamoto, H. J, J. Am. Chem. Soc., 124, 5365-5375, 2002 O O O MeO CHO MeO CHO OMe OH MeO MeO MeO 1,2-ethanediol O O O I BuLi, Bu3SnCl Pb(OAc)4 pyridine, H2SO4 I Bu3Sn (AcO)3Pb OMe OMe OMe OH Me 1 OMe OMe OMe 1. MOMCl, NaH 2 3 4 5 Me 2. NaH, (EtO)2POCH2CO2Et O 3. DIBAL-H O MeO MeO MeO Me OMe OMOM OTs MeO OMe OMOM OH OMe OMOM OMe OMOM OH OH LiAlH4 TsCl i TI(O Pr)4, D-(-)-DIPT OMe OMe OMe Me OMe TBHP 9 Me Me 8 Me 7 6 1. phthalimide, DEAD, PPh3 2. MeNH2, MeO Me MeO Me MeO Me OMe OH OMe OMOM OMe OMOM N NHAc NH2 OMe Me POCl OMe CH3COCl OMe 3 Me Me Me 2,4,6-collidine Ancistrocladidine 10 11

MeO Me MeO Me

N N MeO Me MeO CHO Bu3Sn (OAc)3Pb OMe Me OMe Me N I I MeO Me MeO Me OMe OMe Me NH NH Bu3Sn (OAc)3Pb OMe Me OMe Me

10 Baran Group Meeting Isoquinoline Alkaloids Jun Shi 10/18/2006

Total synthesis of isoquinoline alkaloids natural product Brian M. Stoltz et al, J. Am. Chem. Soc., 125, 15000-150001, 2003 O OH OTIPS OTIPS Bn N O N-Me-morpholine Bn I Bn Bn NaBH4 N 1. TIPOTf N Pd(PPh3) N HN Br O N HN HN HN 2. ICl O O O S O B TsO O O O O 1 O 5 4 O 2 3 OTs Pd/C, H2 O O OTIPS O OTIPS OH Cbz N H 1. (Boc) O N O N Cbz 2 O HN 1.CbzCl HN O 2. NaBH NH2 4 2. KOTMS TsO 3. HCl HO 6 O HO 7 O OH 8 O O O OH O O O O O 1. HCl O 1.Red Al, PhCH3 OsO4, NaIO4, TFA EA, LDA 2. (MeO)2CH2 OH OH O N N O E t TMSOTf 2.CH2O, O SO2Ph SO2Ph 3. DIBAL O NaBH3CN N 13 N 9 4. MsOH, PhO2SN 10 allyl alcohol 12 11 O O OH OH N H N Cbz O O N OH O O EtOH NH 1. H2, Pd /C O O Cbz TsO 2. (COCl) , TEA, then OH N OH 2 O O OH O HCl, CAN NH 2 O 14 OH OH O HO N 8 OH O 13 Lemonomycin N N

11