Photochemicalkeystepsinthe synthesisof+alkaloids...17 Indole Photochemistry intramolecular: N O hυ...

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Photochemical keysteps in the synthesis of alkaloids

Ruben Eckermann Gaich-‐Group Seminar December 10, 2012

Gaich-‐Group Seminar Ruben Eckermann

Overview

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1) Enamide 6π – Photocyclization 2) ortho – Quinodimethanes 3) Pyridinium salts 4π – Photocyclization 4) Phthalimide/Maleimide Photochemistry 5) Indole - Photochemistry

NR

hυ

HNu

NR

H H

Nu

RN O hυ

RN O

HH

H

NaBH4

Ohυ

OH

NR

O

O

hυ

NR

O

O

NH

CO2H

NH

O

ClNH

O

NH

CO2Hhυ


Enamide 6π – Photocyclization

3 T. Naito, Chem. Pharm. Bull., 2008, 56, 1367-1383

RN O

hυ (256 nm)

conrotatory

RN O

HH

1 2

I2

NaBH4MeOH

RN O

H

H

RN O

RN O

H

H H5

4

3


4

(±) – Yohimbine

O. Miyata, Y. Hirata, T. Naito, I. Ninomya, J. Chem. Soc., Chem. Comm., 1983, 1231-1232

NH

N MeO

Cl

O

85% NH

NO

OMe

hυ (254 nm)NaBH4, (MeOH)

90%

6 7

NH

NO

OMe

HH

8

NH

N

HH

(±) - yohimbine (9)

H

MeO2C OH


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(±) – Methyl lysergate

I. Ninomya, C. Hashimoto, T. Kiguchi, T. Naito, J. Chem. Soc., Perkin Trans. 1, 1985, 941-948

NBz

O1) MeNH2

2) 3-furoyl chloride NEt3

96% NBz

NMe

OO

hυ (256 nm)

NaBH4, MeOH81%

NBz

NMe

OO HH

HH

H

NH

NMe

O

H

CO2Me

(±) - dimethyl lysergate (13)

10 11

12


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ortho – Quinodimethanes

O

O

O

Diels Alder+

ortho-Quinodimethan

O

O

O

H

H

Mechanism:

ClCl

hυ (266 nm) ClCl

T1

- Cl

hυ (308 nm)

Cl - Cl

M. A. Miranda, J. Pérez-Pietro, E. Font-Sanchis, J. C. Scaiano, Chem. Comm., 1998, 1541-1542


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ortho – Quinodimethanes

R

OH

R

R

hυ

R

R

ClCl

hυ

X

XR

Rhυ

X = S, Se

hυXPhXPh

R

R

X = O, S, Se

OR

Rhυ

N2

R

hυ

O

R

R

hυ

O

R

R hυ

Photochemical generation

J. L. Segura, N. Martín, Chem. Rev., 1999, 99, 3199-3246


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(±) – Alpinigenine

S. Prabhakar, A. M. Lobo, M. R. Tavares, J. Chem. Soc., Perk. Trans. 1, 1981, 1273-1277

N

O OMe

OMe

OOMeMeO hυ (> 280 nm)

34°C, tBuOHN

O OMe

OMe

OHOMeMeO

N

OMe

OMe

OMeO

MeO

HO

H

HN

OMe

OMe

OMeO

MeO

HO

H

H

+

28%

(±) - cis-alpinigenine (16) (±) - alpinigenine (17)

14 15


Pyridinium salts 4π – Photocyclization

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NMe

hυ NMe

H H

OH

Cl

KOH

cis

cis

Observation of Kaplan, Wilzbach &

Pavlik in the late 1960s

L. Kaplan, J. W. Pavlik, K. E. Wilzbach, JACS, 1972, 94, 3283-3284 J. Zou, P. S. Mariano, Photochem. Photobiol. Sci., 2008, 7, 393-404 T. Damiano, D. Morton, A. Nelson, Org. Biomol. Chem., 2007, 5, 2735-2752

Mechanism:

NMeCl

Me

hυ (254 nm)

KOH, H2O

π

NMeCl

Meπ∗

NMeCl

Me

NMe

Me

Cl NMe

Me

Cl


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L. Kaplan, J. W. Pavlik, K. E. Wilzbach, JACS, 1972, 94, 3283-3284 J. Zou, P. S. Mariano, Photochem. Photobiol. Sci., 2008, 7, 393-404 T. Damiano, D. Morton, A. Nelson, Org. Biomol. Chem., 2007, 5, 2735-2752

Pyridinium salts 4π – Photocyclization

NMe

Me

ClN

N

N

Me NH

H

OHKOH

Me

NH

H

OH

Me

Me

NH

H

Me

HOMe

+

+

NR

O

NR

O

NR

NR2

hυ

hυ

hυ

NR

O

NR

O

NR

NR2

RN HH

Nu1

HNu2SN2'

HNu2SN2

Nu2

Nu1

NHR

Nu1

NHRNu2


(-) – Allosamizoline & (+) – Mannostatin

11 R. Ling, P. S. Mariano, JOC, 1998, 63, 6072 H. Lu, P. S. Mariano, Y. Lam, Tet. Lett., 2001, 42, 4755 - 4757

N1) hυ (254 nm) aq. HClO4

2) Ac2O, pyr

42%

NHAc

OAcAcOEEACE

pH = 6.968%

NHAc

OHAcO

Burgess reagent

18 19 20

HN

OAcO

O

S NO O

CO2MeAcO O

N HCl

then K2CO3

NHAc

OHAcO

21 22 23

NHAc

OHAcO

23

NHAc

OHMeS

(+) - mannostatin (24)

OHHO

HO ON

NMe2

HO OH(-) - allosamizoline (25)


(-) – Cephalotaxine

12 Z. Zhao, P. S. Mariano, Tetrahedron, 2006, 62, 7266-7273 N. Isono, M. Mori, JOC, 1995, 60, 115-119

NClO4 hυ (254 nm)

aq. KOH

NH

OH

1) HOAc

2) Boc2O

50%

BocNOHAcO

1) Ac2O

2) TFA76%

26 27 28

EEACE

90% ee

HNOAcAcO

HNOHAcO

MeO

MeO

Cl

O

80%

29 30

NOHAcO

O

MeO

MeO

31

O

ON

OMe

HHO

(-) - cephalotaxine (32)


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Phthalimide/Maleimide Photochemistry

N

O

O

hυ (256 nm)

MeCN, -20 °C+

N

O

O

Mechanism:

N

O

O

N

O

O

hυor N

O

O radical

N

O

O

concerted

N

O

O

N

O

O

N

O

O

P. H. Mazzochi, P. Wilson, F. Khachik, L. Klingler, S. Minamikawa, JOC, 1983, 48, 2981-2989


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Phthalimide/Maleimide Photochemistry

N

O

O

hυhυ

N

O

O

N

O

Otrans/cis = 2:1 cis/trans = 2:!

NMeO

O

O

hυN

MeO

O

O

1-hexene

NMeO

O

O

Bu

N

O

O

Me

hυ (256 nm)

MeCN, -20 °C

63%

N

Me

O

O

P. H. Mazzochi, P. Wilson, F. Khachik, L. Klingler, S. Minamikawa, JOC, 1983, 48, 2981-2989


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(±) – Neostenine

M. D. Lainchbury, M. I. Medley, P. M. Taylor, P. Hirst, W. Dohle, K. I. Booker-Milburn, JOC, 2008, 73, 6497-6505

OCOCl

ClOC+

1) 0°C (THF) then LiAlH4

61%

O

NCCN

2) MsCl, NEt3 (THF) then KCN (DMSO), 100°C

H2SO4 (6 M)100°C

45%O

O

O

O

32 33 34 35

1) EtMgCl, CuBr SMe2 (THF), -20°C

82%

O

O

2) EtOCOCl, NEt3 then NaBH4

OH

NHCl

Cl

O

O

PPh3, DEAD(THF), -78°

71%

O

O

NO

O

ClCl

36 37

400 W Hg lampPyrex FEP flowreactor, (CH2Cl)

63%N

O

ClCl

O

O

O

H H

H

H

H

N

O

O

H H

H

H

H

(±) - neostenine (39)38


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Indole Photochemistry

2+2 – Cycloaddition:

N

PhO

R1

R2X

+hυ

NX

O

R1

R2

X

NX

O

R1

R2

X

+

R1 = H, Me, CHO, Ac, OAc, SMe, CN, ClR2 = H, Me, CNX = OAc, CO2Me

N

R1

R2

R1 = alkylR2 = H, alkyl

CO2Me

CO2Me

+hυ

N

R1

R2

CO2Me

CO2Me

Δ

hυ N

R1 CO2Me

CO2Me

R2

M Ikeda et al.: Synth. Commun., 1980, 110, 437; Tet. Lett., 1980, 21, 3403; J. Chem. Soc., Perkin Trans. 1, 1982, 741 & 1984, 405 P. D. Davis, D. C. Neckers: Tet. Lett. 1978, 2979; JOC, 1980, 45, 456 & 462

exo-product preferred


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Indole Photochemistry

intramolecular:

N

O

hυ

92%N

H

O

H

H

NBoc

NH CO2EtEtO2C

hυ

NBoc

NH

HCO2EtCO2Et

82% NBoc

N

CO2Et

CO2Et

Paternó-Büchi:

NAc Ph R

O+

hυ

NAc

O

Ph R

R = Ph, CONH2, CO2Me

D. L. Oldroyd, A. C. Weedon, J. Chem. Soc., Chem. Comm., 1992, 1491-1492 D. R. Julian, G. D. Tringham, J. Chem. Soc., Chem. Comm., 1973, 13


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Vindorosine

J. D. Winkler, R. D. Scott, P. G. Williard, JACS, 1990, 112, 8971-8975

NH

NHCbz

CO2H OHO

DCC, DMAP(Et2O)

84%NH

NHCbz

OO O

1) BF3*OEt2, -4°C (CH2Cl2)2) H2, Pd/C (EtOH)

Cl O

NEt3, (THF)71%

3)

NH

NH

OO O

O

40 41 42

1) nBuLi, benzyl chloroformate (THF), -78°C

2) 450 W Hg lamp (MeCN)

74%NCbz

N

H

OBO

O

1) LDA, TBSOTf (THF)

2) nBu4NF, (THF)51% N

Cbz

TBSN

H

OBO

O

N

N

HOH

OAcEt

CO2Me

vindorosine (45)43 44


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Photo-Fries reaction

NH

O

O Me hυ (EtOH)

paraNH

OOH

Me

60%

hυ (EtOH)

metaNH

OOH

Me

30%hυ (EtOH) ortho

NH

OOH

Me

NH

O

Me

OH

+

55% 30%

N

OR

hυ (EtOH)

NH

RO

+

NH

O R

NH

O

R

+

main productR = OEt, Me, Ph

M. Somei, M. Natsume, Tet. Lett., 1973, 27, 2451-2454 A. Weedon, Advances in Photochemistry – The Photochemistry of IIndoles, (Edited by D. C. Neckers, D. H. Volman, G. Bünau), Vol. 22, 229-279, John Wiley & Sons, 1997, New York


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Photo-Fries reaction

intramolecular:

N

O

R

R = alkyl

hυ (EtOH)

N

RO

20%

Y. Ban, K. Yoshida, J. Goto, T. Oishi, E. Takeda, Tetrahedron, 1983, 39, 3657 – 3668 M. A. Mirande in CRC Handbook of Organic Photochemistry and Photobiology, (Edited by W. M. Horspool, P.-S. Song), CRC Press, Boca Raton, FL, 1994, 570 - 578

mechanism:

O

O

R

hυ O

R+

Me

O

Me O

R+

O

MeMe

HO

O

R

N

OR

hυ O

R+

N

O

R+

NN

RO

very instable!


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(±) – Condifoline & (±) – Tubifoline

Y. Ban, K. Yoshida, J. Goto, T. Oishi, JACS, 1981, 103, 6990-6992 D. Schumann, H. Schmid, Helv. Chim. Acta, 1963, 6, 1996-2003 B. A. Dadson, J. Harley-Mason, G. H. Foster, Chem. Comm., 1968, 1233

N

O

NH2hυ (EtOH)

N

OH2N

N

HN OH

46 47 48

NH

NHO

80%

1) LiAlH4

Cl

O

Cl

2)

3) I2O5 (THF/H2O)

65%

NH

N

O

OCl 1) NaO-tAm, (THF)

reflux

2) Wolf-Kishner3) LiAlH4

49 50

NH

N

H

51

O2

N

N

HH

(±) - condyfoline (52)

O2

PtN

N

HH

(±) - tubifoline (53)


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Witkop Cyclization

first observed by Witkop and coworkers

in 1966

mechanism:

-HNH

NH

O CO2Me

Cl hυ

SET

NH

NH

O CO2Me

Cl

-Cl

NH

NH

O CO2Me

O. Yonemitsu, P. Cerutti, B. Witkop, JACS, 1966, 3941-3945 K. S. Feldman, P. Ngernmeesri, Synlett, 2012, 23, 1882-1892

NH

CO2HNH

O

Cl hυ

40%

NH

NH

O CO2H

53 54

NH

CO2MeNH

O

Cl

Cl

hυ (254 nm)

(MeCN)

SET NH

CO2MeNH

O

Cl

Cl

-Cl

NH

CO2MeNH

O

Cl

55


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(±) – Dragmacidin E

NH

NH

O CO2Me

-H

NH

NH

O CO2Me

53%

+

NH

NH

O

CO2Me

8%

K. S. Feldman, P. Ngernmeesri, Synlett, 2012, 23, 1882-1892

NH

NH

O CO2Me1) Boc2O, DMAP (MeCN)

2) N-Selectride (THF), -78°C

NBoc

O

BocNO

H

59%

1) LiOH, H2O (THF), 0°C

2) NH4Cl, NH3 (MeOH), 85°C then TMSCN

71%

NBoc

MeH2N

CN NHBoc

56 57 58

1) ClCO2Me, K2CO3 (THF), reflux2) CoCl2, NaBH4 (MeOH), 0°C

3) CsOH, H2O (THF), MW, 150°C

50% NBoc

Me

NHBoc

HN

HN

O

NH

MeNHN

H2N

HO NH

N

O

NH

Br

(±) - dragmacidin (60)59


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Indole Synthesis

demonstrated by Burgess and

coworkers in 1968

E. M. Burgess, R. Carithers, L. McCullagh, JACS, 1968, 90, 1923 P. A. Wender, C. B. Cooper, Tetrahedron, 1986, 42, 2985-2991

NN

N

hυ

NH

61 62

NN

N

NH

hυ (254 nm)(cyclohexane)

25%

63 64

NN

Nhυ (254 nm)(cyclohexane)

NH

44%

65 66

NN

Nhυ (254 nm)(cyclohexane)

NHCO2Et

CO2Et

MeMe

72%

67 68


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Gelsemine

Z. Sheikh, R. Steel, A. S. Tasker, A. P. Johnson, J. Chem. Soc., Chem. Commun., 1994, 763-766

O

CO2MeMeO2Chυ (MeOH)[AcOH]

53% O

H CO2MeCO2Me

O CO2Me

OH

TBSO

69 70 71

MeNH2(MeOH/THF)

86%

O

HTBSO

CO2Me

NHMe

ON

O

TIPSOO

BrOMe

HO

OTIPS

NO

Br

O

N

72 73


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Gelsemine

Z. Sheikh, R. Steel, A. S. Tasker, A. P. Johnson, J. Chem. Soc., Chem. Commun., 1994, 763-766

1) TFA, reflux2) BU3SnH, (PhH) reflux

52% ONO

ON

NN

OMeMe3Si

2 eq LDA2 eq nBuLi

65%ON

O

NMeO NN

74 75

O

OTIPS

NO

Br

O

73

hυ (MeCN)

36%ON

O

NMeO1) HCl, H2O (THF)2) DIBAL-H

63%ON

HNO

1 : 2 for otherregioisomer gelsemine (77)76

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Thank you for your attention! Questions?


Photochemicalkeystepsinthe synthesisof+alkaloids...17 Indole Photochemistry intramolecular: N O hυ...

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