Synthesis of the Stenine Ring System from Pyrrole

NH N

O

H

O

H

Current Literature Presentation Igor Opsenica06/18/2011

Bates, R. W.; Sridhar, S. J. Org. Chem., 2011, 76, 5026–5035

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Stemona sessilifolia

The Stemonaceae family is still the only source of the Stemona alkaloids

The Stemona alkaloids are:

•structurally characterized by the presence pyrrolo[1,2-a]azepine corepyrido[1,2-a]azepine core

•currently comprises 139 alkaloids

The Stemona alkaloids can be organize into eight groups: •stenine (I), •stemoamide (II), •tuberostemospironine (III), •stemonamine (IV), •parvistemoline (V), •stemofoline (VI) (all of which contain the pyrrolo[1,2-a]azepine core)

•stemocurtisine (VII) displaying the pyrido[1,2-a]azepine nucleus, •miscellaneous group

N12

35678 9

9a

A

N

R

N

O

O

N

OO

N

O

I

II

III IV

V

N

N

NO O

VI

VII

N

O

HH

H

O

HH

Stenine

Nat. Prod. Rep., 2010, 27, 1908

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N

O

HH

H

O

HH

( )-Stenine

N

O

I

O

OH

H

H CO2MeN

OH

H

H CO2Me

O

Me2N

N

OH

H

H CO2MeOH N

OH

H

H CO2Me O

O

Chen, C.; Hart, D. J. J. Org. Chem., 1990, 55, 6236

O

O

O

O

H

H

EtAlCl3

CHCl3, 85 °CO

NNMe3

H

H

OAc

NHCO2Me

H

H

OAc

1. Mesytilene, Δ

2. MeOH

NHCO2Me

H

H

OAc

OMsMeLi, THFN

OH

H

H CO2Me

intramolecular Diels-Alder reaction

Curtius rearrangement

A

B

C

D

N

O

O

ring D: Claisen–Eschenmoser rearrangement and iodolactonization

ring B: intramolecular lactam formation

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N

O

HH

H

O

HH

(-)-Stenine

N

O

O

H

H Cbz

TIPSO

N

H

H CO2Bn

O

Me2N

TIPSO

N

H

H CO2BnOH

CO2MeOH

NHCO2Bn

CO2H

Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117, 11106Wipf, P.; Spencer, S. R. J. Am. Chem. Soc. 2005, 127, 225

OH

NHCO2Bn

CO2H N

OH

H CO2BnO

CO2MePhI(OAc)2, NaHCO3

MeOH, 21-40 °C

N

H

H CO2BnOH

CO2Me

N

H

H CO2Bn

O

Me2N

CO2MeH3CC(OMe)2NMe2

130 °C

N

O

HH

H

O

HH

OH

H

O

Tuberostemonin

N

H

HO

CO2Me

Ph

OH

NHCbz

CO2HN

O

PhSe

O

H

HOH

H

O

A

B

C

D

N

O

O

ring D: Claisen–Eschenmoser rearrangement and iodolactonization

ring B: intramolecular lactam formation

N-benzyloxycarbonyltyrosine

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S

S

OTHP

MPMO

Cl

N O

O

Ph

O

(EtO)2PO

MPMO

S S

N

O

O

O

Ph

H

H

O

NHCO2MeMPMO

N

O

HH

H

O

HH

(-)-Stenine

N

O

I

O

H

H CO2Me

MPMO

OH

Morimoto, Y.; Iwahashi, M.; Nishida, K.; Hayashi, Y.; Shirahama, H. Angew. Chem. Int. Ed. Engl., 1996, 35, 904

H

H

OTMS

NHCO2MeMPMO

N

O

I

O

H

H CO2Me

MPMO

OH1. MCPBA, hexane, DCM, -15 °C-rt

2. H5IO6, THF, H2O, rtI2, NaHCO3, rt

A

B

C

D

N

O

O

ring B: intramolecularnitrogen alkylation

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N

O

HH

H

O

HH

NHH

BnO H

O

N3

O

BnO

H

HO

BnON3

OTBS

BnO

( )-Stenine NHH

H

O

O N3

O

TMSO

H

H

TMSO

N3

O

Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.; Aube, J. J. Am. Chem. Soc. 2008, 130, 6018

O

BnON3

MeAlCl2

CH2Cl2, 45 °C NHH

BnO H

O

H

OBn

N3O

HH

H

RH

HN

N2

OH

-N2

H

RH

HNO

Tandem Diels-Alder/Schmidt reaction

A

B

C

D

N

O

O

ring D: iodolactonization

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N

O

HH

H

O

HH

( )-Neostenine

N

O

HH

H

O

HH

OO

OH

O

H

N

O

OO

O

OO O

CO2H

HO2C

OCl

OCl

O

Lainchbury, M. D.; Medley, M. I.; Taylor, P. M.; Hirst, P.; Dohle, W.; Booker-Milburn, K. I. J. Org. Chem., 2008, 73, 6497

O

O

OOO

CO2H

HO2C O+H

CO2H

OH

O

HO2C

OH

OO

N

O

HH

H

O

HH

OO

OH

O

H

N

O

OOH

O

H

N

O

O

ring C / D:

ring A / B:

hν

[5+2]

A

B

C

D

N

O

O

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N

O

HH

H

O

HH

( )-Stenine

N

OH

O

HH

ON

O H

O

CO2Me

MeS

N

O

O

CO2Me

OHMeS

MeS Et

Padwa, A.; Ginn. J. D. J. Org. Chem. 2005, 70, 5197

N

O H

O

CO2Me

MeS

N

O

O

CO2Me

OHMeS

MeS Et N O

CO2Me

OOHEt

MeSDMTSF

Et3N N O

CO2Me

OMeS

Et

N

H

O

CO2Me

SMeO

N

H

O

CO2MeO

MeS

S S BF4

intramolecular [4+2] cycloadditionrearrangement cascade reaction

A

B

C

D

N

O

O

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The Stemona alkaloids are attractive synthetic targets due to the diversity of structures found in this family of alkaloids

Recently, it has been reported that neostenine, a stereoisomer of stenine,has antitussive activity comparable to that of codeine

Using pyrroles in natural product synthesis is challenging:•highly electron-rich nature of the pyrrole ring promote certain productive reactions,but it can also cause some problems

Additional synthetic strategies has been used to construct the pyrrole moiety in pyrrole-containing natural products

Bates, R. W.; Sridhar, S. J. Org. Chem., 2011, 76, 5026–5035

NH N

O

H

O

H

NH

O

O

H

NO

R

OH

H

NOHC

NH

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NH

O

O

H

NO

R

OH

H

NOHC

NH

NH

N N

CHO

NOHC H

N

HOH

OMs CHO

NH

NO

BnMcMillan's

catalyst

THF, -20 oC

NaOH, DMSO, rt

87%

Grubbs II, DCM, Δ

86%

NaBH4, EtOH, rt

75%, 95% ee(two steps)

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N

HOH

N

HO

O

CF3

F3C

O

I

N

HTBSO

O

CF3

I

ii)i)

i) 1) (CF3CO)2O, Et2O, rt, 83%; 2) ICl, DCM, rt, 88%ii) 1) PVP, MeOH, rt, quant.; 2) TBSCl, imidazole, DCM, rt, quant.

N

HOH

N

HO

O

CCl3

Cl3C

O

I

N

HTBSO

O

OMe

I

ii)i)

i) 1) CCl3COCl, Et2O, rt, 95%; 2) ICl, DCM, rt, 90%ii) 1) NaOMe, MeOH, rt, 90%.; 2) TBSCl, imidazole, DCM, rt, 80%

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NH

O

O

H

NO

R

OH

H

NOHC

NH

N

HTBSO

O

CF3

I

N

HTBSO

O

CF3

OHPd/C, CuI, K2CO3

Ph3P, DME, 85 °C

87% N

HTBSO

O

CF3

Br

N

HOH

O

CF3

Br

Ambrelyst-15i-PrOH, 24h, rt

90%

N

HO

O

CF3

Br

DMP, DCM, rt

84%N

O

CF3

OH

HIn, AcOH, DMF, -40 °C

52%

CBr4, PPh3, CaCO3: 60%CBr4, PPh3, Et3N: no reaction

Ambrelyst-15, MeOH, 14h, rt: 0%PPTS, MeOH, 10h, rt: 0%TBAF, THF, 14h, rt: 48% corresponding fluoride

no diastereoselectivity using zinc (Zn)

slight improvement with stannous chloride (SnCl2)

CBr4, PPh3

collidine, DCM, 0 °C

83%

OH

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NH

O

O

H

NOHC

NH

NO

R

OH

H

NO

CF3

OH

H NO

CF3H

O

O

NaOH, H2O, DMSO, rt

99%

Ru3(CO)12, dioxane, Et3NCO, 100 °C, 100 psi

87% NO

OHH

O

O

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Possible Mechanism of Ruthenium-Catalyzed Cyclocarbonylation

J. Org. Chem. 2003, 68, 8571-8576

NO

CF3

OH

H NO

OH

OH

H

NaOH, H2O, DMSO, rt

90% NO

OH

O

HNO

OHH

O

O

Ru3(CO)12, dioxane, collidineCO, 100 °C, 100 psi

68% 14%

Cyclocarbonylation of Allenol - Ru3(CO)12, CO

reagent and solvent

catalyst loading /

mol%

yield of butenolid

(%)

yield of enone

(%) dioxane, Et3N (6 eq) 4 40 30a

Et3N (neat) 4 20 40b

2,4,6-collidine (neat) 4 50 5c

dioxane, collidine (6 eq) 4 68 14c a A ca. 2:1 mixture of E/Z isomers. b A ca. 10:1 mixture. c One isomer.

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NH

O

O

H

NOHC

NH

NO

R

OH

H

NO

CF3

OH

H NO

OH

OH

H

NaOH, H2O, DMSO, rt

90% NO

OH

O

HNO

OHH

O

O

Ru3(CO)12, dioxane, collidineCO, 100 °C, 100 psi

68% 14%

NH

O

O

CF3CO2HDCM / 40 oC

90%

Mg, MeOH, rt

NH

O

O

NH

O

O

H

NH

O

O

H 2

45% <5% 22%

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N

CHO

NOHC H

NH

McMillan'scatalyst

N

HO

O

CF3

Br

NO

CF3

OH

H

Intramolecular Propargylic Barbier Reaction

NO

OH

OH

HNO

OHH

O

O

Ru-Catalyzed Cyclocarbonylation

ring B

ring C

ring D

CONCLUSION

Additional contribution to the synthesis of the stemona alkaloids using an new synthetic approach

The high electron density of the pyrrole ring can complicate some reactions but can be controlledby using the trifluoroacetyl group, that can easily and rapidly be removed

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