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Litterature Meeting Enantioselective Total Enantioselective Total Synthesis of Synthesis of Avrainvillamide Avrainvillamide and and Stephacidins A and B Stephacidins A and B Aspergillus ochraceus

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Litterature Meeting. Enantioselective Total Synthesis of Avrainvillamide and Stephacidins A and B. Aspergillus ochraceus. Aspergillus : A source of complexe prenylated indole alkaloids. - Isolation from Aspergillus ochraceus WC76466: 2002 – Bristol Myers Squibb - PowerPoint PPT Presentation

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Page 1: Litterature Meeting

Litterature Meeting

Enantioselective Total Enantioselective Total Synthesis of Synthesis of

Avrainvillamide Avrainvillamide

andand

Stephacidins A and BStephacidins A and B

Aspergillus ochraceus

Page 2: Litterature Meeting

N

N

ON

O

O

Stephacidin B

N

N

O

HN

OO

O

HO

51

20 21

39

62

55

N

N

ON

O

O

Stephacidin B

N

N

O

HN

OO

O

HO

51

20 21

39

62

55

N

N

ON

O

O

Stephacidin B

N

N

O

HN

OO

O

HO

51

20 21

39

62

55

N

N

O

NH

OO

O

Avrainvillamide (CJ-17665)

N

N

O

NH

OO

O

Avrainvillamide (CJ-17665)

NH

N

O

NH

OO

Stephacidin A

N

N

O

NH

OO

O

Avrainvillamide (CJ-17665)

Aspergillus: A source of complexe prenylated indole alkaloids

N

N

Spirotryprostatins A and B

OHN

O

O

H3CO

N

N

O

NH

OO

O

Aspergamide A

OH

NH

N

O

NH

OO

Stephacidin A

N

N

O

NH

OO

Aspergamide B

NNMe

O

CH3

HN

O

OParaherquamide F

N

O

NH

O

Brevianamide A

HN

O

- Isolation from a fungal species found in an Indian clay sample (Sirsaganj, Uttar Pradesh, India) - Sources: 1/ Marine fungal strain Aspergillus: 2000 - Fenical and coworkers 2/ Fermentation broth of Aspergillus ochraceus: 2001 – Sugie and coworkers

- Isolation from Aspergillus ochraceus WC76466: 2002 – Bristol Myers Squibb-In vitro citotoxic activity (human tumor cell lines) ⇒ SPC B: 5-30 fold more active than SPC A (testosterone-dependent prostate LNCaP cell line: IC50=0.06 µM)

98

2021

Page 3: Litterature Meeting

N

O

NH

O

Brevianamide A

HN

O

N

N

O

O

HN

Deoxyaustamide

Biosynthesis of Stephacidin B: a lesson for the chemist

HN HN

N

O

O

Brevianamide FHN HN

N

O

O

Tryprostatin B

N

N

O

O

Demethoxyfumitremorgin C

NH

[O]

Prenylation Reverse Prenylation

2 [O]

N

N

Spirotryprostatin B

OHN

O

O

HN HN

N

O

ODeoxybrevianamide E

N

N

O

OAustamide

NH

O

[O]

N

O

NH

O

Brevianamide A

HN

O

N

N

O

OH

2 [O]2 [O]

Diels-Alder *

bicyclo[2.2.2]diazaoctane

* Birch and coworkers, J. Chem. Soc. Perkin I, 1974, 50.

Sammes and coworkers Chem. Comm., 1970, 1103.

.

Page 4: Litterature Meeting

NH

N

O

NH

O

HN N

N

O

OH

O

HN HN

N

O

O

Brevianamide F

O

HN HN

N

O

O

HN N

N

O

OH

Presumed biosynthesis of Stephacidins A and B

N

N

O

NH

OO

O

Avrainvillamide

NH

N

O

NH

OO

Stephacidin A

N

N

ON

O

O

Stephacidin B

N

N

O

HN

OO

O

HO

51

2021

39

62

55

[O]

Prenylation

IntramolecularDiels-Alder

[O]

[O]

HN NH2

O

OH

Tryptophane

HN

O

HO

Proline

Page 5: Litterature Meeting

Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus

Williams’ approaches

PMBN

N

O

ONH

H

Cl

NaH

SN2’

PMBN

N

O

ONH

N

N

OMe

ONH

HN

N

OMe

ONH

H

2:1 mixture

Diels-Alder

J. Am. Chem. Soc. 1990, 112, 808.Acc. Chem. Res. 2003, 36, 127.Tetrahedron Lett. 2004, 45, 4489.

Page 6: Litterature Meeting

Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approachPMBN

N

O

ONH

NH

O

OH

L-Proline

OHC

1.

2. LDA, THF, hexane, -78 °C

then

, THF,

-78 °C to -30 °C, 87 %Br

N O

OTFA, pentane, 92 % MeO CH2NHLi

THF, -78 °C

quant.

NH

NH

O

OMe

1. BrCH2COBr

DCM/ K2CO3

2. 50 % aq. NaOH,

DCM

85 %

N

NPMB

O

O

N

NPMB

O

O

O

O3 / MeOH,Me2S

99 %N

NPMB

O

O

1. 2. NaBH4, EtOH

3. TBDMSCl, Et3N, DMAP, DCM

85 %

MePh3P

Me

CHOTBDMSO

N

NPMB

O

O

Me

TBDMSO

1. nBuLi, THF

2. ClCO2Me71 %

4:1 mixture

CO2Me

N

NPMB

O

O

Me

CO2Me

TBDMSO

Bu3P, MeCN,

62 %

NH

NMe2

NH

Seebach and coworkers, J. Am. Chem. Soc. 1983, 105, 5390.

Somei and coworkers, Heterocycles 1981, 16, 941.

Page 7: Litterature Meeting

SolventTemperature

(°C)Base

Ratio

anti:synYield (%)

Benzene 80 NaH 3:97 82

DMF 85 NaH 2:1 63

Benzene 25 NaH/18-crown-6 6:1 14

Benzene 80 NaH/18-crown-6 3.9:1 56

Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach (2)PMBN

N

O

ONH

N

NPMB

O

O

Me

CO2Me

TBDMSO

NH

1. LiCl, HMPA, H2O,100°C

2. Boc2O, tBuOK, THFthen

Bu4NF, THF, rt

85 % N

NPMB

O

O

Me

H

HO

NBoc

N

NPMB

O

O

Me

H

Cl

MsCl, LiCl, DMF,

collidine

quant.

NBoc

Base / Solvant

N

N

OBocN

Me

HH

H

pMB

N

N

OBocN

Me

HH

H

pMB

OO

SYNANTI

+

Brevianamide B

Page 8: Litterature Meeting

N

N

O

OMe

O

N

O

(Me)3CO

Me

Cl

"OPEN" transition state

N

N

O

OMe

O

N

O

OC(Me)3

Me

Cl

HH

"CLOSED transition state

Synthesis of the bicyclo[2.2.2]diazaoctane by SN2’ approach (2)PMBN

N

O

ONH

O

O

O

O O

O

Na NaH, benzene, 80 °C

NO

OMe

O

N

O

(Me)3CO

Me

H

SYN

NO

OMe

O

N

O

(Me)3CO

H

ANTI

Tightion pair

NaH, DMF

NaH, benzene, 80 °C18-crown-6Na

Page 9: Litterature Meeting

N

HN

O

OH

HN

NaOH, MeOH, rtthen

dioxane, 65 °C

82 %

Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder approach N

N

OMe

ONH

H

N

HNO

O

MeO2C

H

H

1. SOCl2, benzene,

2. (MeO2C)2-CHNH2, Et2O, 0 °C

thenNa2CO3, H2O, 15 °C

69 %

CbzN

HO

NHMeO2C

MeO2C1. H2, Pd/C, MeOH, 70 °C

2. , 70 °C 93 %

N OH

NH

NHNH2 NH

NMe2

1. 6M aq. HCl, NaNO2, 0°C

2. SnCl2, 10M aq. HCl, 0 °C

3. 10M aq. NaOH 45 %

1.

toluene,

2. ZnCl2, diglyme, 170 °C

O

H2CO, MeNH, AcOH, rt

83 %

NaH, DMF, 60 °C

77 %

N

HN

O

OH

HN

MeO2C

N

N

OMe

ONH

HN

N

OMe

ONH

H

2.5:1

CbzN

HO2C

H

N-Z-L-Proline

NH2

2.5:1

Page 10: Litterature Meeting

Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder Approach N

N

OMe

ONH

H

N

HN

O

OH

HN

epi-deoxybrevianamide E

N

HN

O

OH

HN

deoxybrevianamide E

2.5 : 1

Me3OBF4, DCM, 0 °C

79 %

N

N

O

OMeH

HN

DDQ, toluene, -78 °C

31 %

N

N

O

OMe

HN

N

N

O

OMe

HN

KOH, MeOH, H2O

NN

HN

O

OMe

NN

HN

O

H

OMe

+

2 : 1

90 %

Williams et al. Bioorg. Med. Chem., 1998, 6, 1233.

S R

Page 11: Litterature Meeting

Synthesis of the bicyclo[2.2.2]diazaoctane by Diels-Alder Approach N

N

OMe

ONH

H

N

N

O

OMe

HN

KOH, MeOH, H2O

N

N

O

OMe

HN

N

N

OMe

O

H

H3C

H3C

HN

NN

HN

O

OMe

NN

HN

O

H

OMe

+

2 : 1

N

N

OMe

O

H

HN

R

R

"EXO" "ENDO"

N

N

OMe

O

H

H3C

CH3

HN

N

N

OMe

O

H

H3C

CH3

HN

S

S

90 %

Page 12: Litterature Meeting

William’s synthesis of bicyclo[2.2.2]diazaoctane nucleus

PMBN

N

O

ONH

H

Cl

NaH

SN2’

PMBN

N

O

ONH

N

N

OMe

ONH

HN

N

OMe

ONH

H

2:1 mixture

Diels-Alder

16 steps in 12 % yield overall

High stereoselectivity of alkylation based on the presence or absence of metal chelation

4 steps in 17 % yield overall from and

Medium stereoselectivity of cycloaddition based on steric effects

NH

NMe2

N

HNO

O

MeO2C

H

H

Page 13: Litterature Meeting

Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus

Liebscher’ approach

HN

N

O

ON

H

MOMDiels-Alder

AcCl HN

N

O

ONH

H

Based on intermolecular Diels-Alder model reactions

⇒ acidic conditions such as HCl and BF3.OEt2 not as effective as AcCl or HCO2H

⇒ high pression and temperature

⇒ slow rates (6-20 days)

HN

N

O

R1

O

A

N

N

O

R1

OCOR

B

N

N

O

R1

O

H

R3R2

H

N

N

O

R1

O

H

R3R2

H

R1 = iPr, PhR2 = H, PhR3 = Ph, (CH2)4

N

N

O

R1

X

+ +

major

R = Me, CH2Br, Ph

X = OCOR Cl OH

R3

R2

P = atm, 10 kbarT = rt, reflux

AcCl or HCO2H or DCM, BF3.OEt2

Liebscher and coll. J. Org. Chem. 2001, 66, 3984.

Page 14: Litterature Meeting

HN

N

O

O

PMeO

MeOO

Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus

Liebscher’ approach (2)

NH

CHO

ClHC=NMe2Cl, DCM,

then aq. NaOH, EtOAc

NH

NH2

1. 6M aq. HCl, NaNO2, 0°C

2. SnCl2, 10M aq. HCl, 0 °C

3. 10M aq. NaOH NHNH2

1.

toluene,

2. ZnCl2, diglyme, 170 °C

O

Et3N9-BBN

NH

Cl

NCS, DMF, rt

NH

HN

N

O

ON

H

MOMNH

CHO

HN

N

O

O

PMeO

MeOO

+

ZHN

N

O

PMeO

MeOO

O

O H2, Pd/C, AcOH, MeOH

95 %

ZHN

OH

O

PMeO

MeOO

DCC,

DCM, rt

92 %

HN

O

O+

Lieberknecht and coll. Tetrahedron Lett. 1987, 28, 4275.

Williams and coll. Tetrahedron Lett. 2005, 46, 9013.

Z-Admpa

Page 15: Litterature Meeting

N

N

OAc

O

H

H3C

H3C

HN

N

N

OAc

O

H

H3C

CH3

HN

N

N

OAc

O

H

HN

N

N

OAc

O

H

H3C

CH3

HN

Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus

HN

N

O

O

PMeO

MeOO

NMOM

CHO

tBuOK

78 %

HN

N

O

ON

H

MOM Diels-Alder

AcClHN

N

O

ONH

H

48 %

rt, 20 daysone stereoisomer !

"EXO"

"ENDO"

Liebscher’ approach (3)R

minimal steric repulsion

defavoring steric repulsion

R

S

Page 16: Litterature Meeting

Liebscher’s synthesis of bicyclo[2.2.2]diazaoctane nucleus

HN

N

O

ON

H

MOMDiels-Alder

AcCl HN

N

O

ONH

H

2 steps in 37 % yield overall from and

Stereospecificity of cycloaddition based on steric effects due to presence of acetoxy group

BUT

Cycloaddition step achieved in 20 days and in only 48 % yield !!

NMOM

CHOHN

N

O

O

PMeO

MeOO

Page 17: Litterature Meeting

Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus

Myers’ approach

HN

RN

OHPhS

TBDPSOH

HN

N

OH

TBDPSOH

O

t-amylO

O Ph

O

tBuPh

R =

O Acyl radical approach

HN

RN

OHPhS

TBDPSOH

H3C

H3C

O O

O

NBoc

OH2CS

O

O

iPr

NBoc

Abrams and coll. Tetrahedron 1991, 47, 3259.

J. Am. Chem. Soc. 2005, 127, 5342.

Page 18: Litterature Meeting

H3C

H3C

O O

H2BO H

H3C

H3C

O O

HO H

HCl, MeOH

Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach

H3C

H3C

O O

O

LiHMDS, TMS-Cl,

Pd(OAc)2, CH3CN, rt

98 %

or

IBX, MPO, DMSO,

60°C

70 %

H3C

H3C

O O

O

H3C

H3C

O O

OH

R

BH3.DMS,

(S)-CBS catalyst,

THF, 0 °C

94 %, >95 % ee

R1 R2

O

N B

O

H PhPh

CH3

S(0.1 equiv)

BH3.THF (0.6 equiv), THFR1

HO

R2

H

(S)-CBS

84-97.6 % eeR1 > R2

N B

O

H PhPh

R

N B

O

H PhPh

R

BH3.DMS

H3B

H3C

H3C

O O

O

BO

N

R

CH3H3C

O

O

O

H2B H

Ph

PhB

O

N

R

CH3H3C

O

O

OH2B

Ph

Ph

H

BH3

N B

O

H PhPh

RH2B

CH3H3C

O

O

O

HHB

HH

O O

OH

OTBS

(92 % ee)

Corey and coworkers, Tetrahedron Lett. 1991, 32, 5025.

Corey E. J., Bakshi R. K., Shibata S. J. Am. Chem. Soc. 1987, 109, 5551.

Page 19: Litterature Meeting

Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach

H3C

H3C

O O

OH

R

1. TBDPSOTf, 2,6-lutidine,

DCM, rt

2. 1N H2SO4,

Me2CO/H2O/THF,

0 °C rt

91 %

H3C

H3COTBDPS

O

1. KHMDS, -78 °C

2. -35 °C,

70 %

BocN

CH2O S

O

O

iPr

H3C

H3COTBDPS

ONBoc

H3C

H3COTBDPS

ONBoc

NC

H3C

H3COTBDPS

ONBoc

NC

(65 %) (16 %)

TMS-CN,

HFIPA, 0 °C

4:1 dr, 81 %

KHMDS, PivOH, -78 °C

88 %

H3C

H3COTBDPS

ONBoc

NC

H3C

H3COTBDPS

ONBoc

EtOH, H2O, 70 °C

85 %

O

H O

P

PtP

H

P OH

O

H2N

SR

Page 20: Litterature Meeting

Pt

PMe2

Me2P

Me2PO

O

OH

OTBDPS

O

NBoc

NC

H

H3C

H3COTBDPS

ONBoc

EtOH, H2O, 70 °C

85 %

O

H O

P

PtP

H

P OH

O

H2N

Ghaffar T., Parkins A. W. J. Mol. Cat. A 2000, 160, 249.

H3C

H3COTBDPS

ONBoc

NC

Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach

Pt

PMe2

OH

Me2P

Me2PO

O

OHH

Pt

PMe2

S

Me2P

Me2PO

O

OHH

H2O

H2

Pt

PMe2

Me2P

Me2PO

O

OH

N C

R

Pt

PMe2

Me2P

Me2PO

O

OH

N C

RHH

H2O

O

H

R

O

NH2

Pt

PMe2

Me2P

Me2PO

O

OHH

R-CN

NC

R

Pt

PMe2

Me2P

Me2PO

O

O

H

OTBDPS

O

NBoc

NC

X

7-membered ring !

Pt

PMe2

H

Me2P

Me2PO

O

OHH

S = H2O

Page 21: Litterature Meeting

H3C

H3COTBDPS

ONBoc

O

H2N

Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach

PhSH, Et3N, THF, 70 °C

95 %

H3C

H3COTBDPS

NHOH

N

SPh

OBoc

1. TMSOTf, 2,6-lutidine,DCM,

DCM, -78 °C 0 °C

98 %

2. , DIPEA, DCM, rt

92 %

H3C

H3COTBDPS

NH

N

SPh

O

Cl

O

O

Jackson L. V., Walton J. C. Chem. Commun. 2000, 2327.

H3C

H3COTBDPS

N

t-amylO

O Ph

O

tBuPh, 120 °C

62 %

O

NO

H

N

NH

O

TBDPSO

O

N

OR

Ph

In

Me +

O

NR

Ph

O

NR

Ph

+ MePh

X

Page 22: Litterature Meeting

Formation of the bicyclo[2.2.2]diazaoctane nucleus: Myers’ approach

N

OR

Ph

N O

Ph

R =

InN O

Ph

- MePhN O

Ph

NH

O

Ph+NO

PhNO

Ph minor product

X

major product

5-exo-trig

N Ph

O

6-endo-trig

N

NH

O

TBDPSO

O

PhS

N

NH

O

TBDPSO

O6-exo-trig favored

vs

7-membered ring closure

N NH

O

TBDPSO

SPh

O

H

H

MeN

HN

OOTBDPS

SPh

OH

HMe

minor conformation

N

HN

OOTBDPS

SPh

O

H

BUT

62 %

Page 23: Litterature Meeting

Myers’ synthesis of bicyclo[2.2.2]diazaoctane nucleus

H3C

H3C

O O

O

H3C

H3COTBDPS

N O

N

O

H

N

NH

O

TBDPSO

O

Enantioselective synthesis of the desired nucleus

12 steps in 19 % yield overall from and

Product used as precursor for synthesis of Stephacidin B

H3C

H3C

O O

O

NBoc

OH2CS

O

O

iPr

Page 24: Litterature Meeting

Synthesis of Stephacidin A: formation of the bicyclo[2.2.2]diazaoctane nucleus

Baran’ s approach

Three steps:

1/ Synthesis of a model of the bicyclo[2.2.2]diazaoctane nucleus

2/ Application of the strategy to a functionalized system for eventual elaboration into Stephacidin A

3/ Formation of Stephacidin A

HN

N

O

ONH

H

HN

N

O

ONH

HO

HN

N

O

ONH

HO

J. Am. Chem. Soc. 2006, 128, 8678.

Page 25: Litterature Meeting

- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -

HN

N

O

ONH

H HN

N

O

O

NH

HN

N

O

O

NH

Br

N

N

O

O

NBoc

MeO

O

PG

IntramolecularDiels-Alder

Intramolecular vinyl radical cyclisation

Intramolecular oxidative enolate heterocoupling

Page 26: Litterature Meeting

- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -

First strategy: Ring closure by intramolecular Diels-Alder reaction

HN

N

O

O

NH

HN

N

O

O

NH

NH

NHBoc

CO2HH

NH CO2Me

+

Dehydrogenation Peptide coupling

NBoc

CO2Me

HLHMDS, THF, -78 °C

83 %

Br

NBoc

CO2Me

p-TsOH, toluene,reflux

84 %

NH

CO2Me

Boc-L-Trp-OH, BOP-Cl,DIEA, DCM, rt

48 %

N

CO2Me

O

NH

NHBoc

HHN

N

O

O

NH

190 °C, neat

54 %

N-Boc-L-Trp

Dehydrogenation

Page 27: Litterature Meeting

HN

N

O

O

NH

X

YH

HN

N

O

O

NH

HN

N

O

O

NH

First strategy: Ring closure by intramolecular Diels-Alder reaction (2)

NH

NHCO2Me

CO2MeH

NO

ZrCl4NH

NHCO2Me

CO2MeH

N

O

N

NHCO2Me

CO2Me

H

N

O H

NHOH

N

NHCO2Me

CO2MeH

NH

NHCO2Me

CO2Me

Path A

NH

NHCO2Me

CO2MeH

NO

ZrCl4N

NHCO2Me

CO2Me

Path B

H

O

N H

Dehydrogenation:

- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -

R1

O

R2

PhN

O

+ R1

O

R2

ONH

PhMLn

Yamamoto and coll. J. Am. Chem. Soc. 2004, 126, 5962.

92 %

PhNO, ZrCl4, DCM

0 °C rt

⇒ Study of direct dehydrogenation of simplified Trp derivatives

Y

X

Page 28: Litterature Meeting

First strategy: Ring closure by intramolecular Diels-Alder reaction (3)

HN

N

O

O

NH

Diels-Alder

conditions

HN

N

O

O

NH

H

X

Conditions: - Reflux in toluene, xylenes...

- Use of Lewis Acids: AlCl3, TiCl4, ZrCl4 - Use of Rh(I) catalyzer

- Heating of the substate neat at high temperature (300 °C)

N

N

OAc

OAc

NH

Diels-Alder

Liebscher method

HN

N

O

O

NH

H

X

- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -

Page 29: Litterature Meeting

Second strategy: Ring closure by intramolecular vinyl radical cyclization

NBoc

CO2Me

H

1. LHMDS, THF, -78 °C,

2.

3.p-TsOH, toluene, reflux

71 %

NH

CO2Me

BrBrBr

Boc-L-Trp-OH, BOP-Cl,DIEA, DCM, rt

54 %

N

CO2Me

O

NH

NHBoc

HBr

p-TsOH, toluene, reflux

46 %

NO

NH

HBr

O

PhNO, ZrCl4, DCM, rt

79 %

HN

N

O

O

NH

Br

AIBN, nBu3SnHHN

N

O

ONH

H

X

HN

N

O

O

NH

BrHN

N

O

ONH

H HN

N

O

ONH

H

- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -

Page 30: Litterature Meeting

Third strategy: Ring closure by intramolecular oxidative enolate coupling

N

N

O

O

NH

MeO

X

HN

N

O

ONH

HPG

HN

N

O

O

NH

MeO

O

PG

X = O

X = CH2

Intramolecular Oxidative Coupling

1. LHMDS, THF, -78 °C,

2.

3. 9-BBN, H2O2, NaOH

78 %

NZ

CO2Me

OH

Br

NZ

CO2Me

H

1. TBSCl, ImH, DCM, rt

2. H2, Pd/C, MeOH, rt

96 %

NH

CO2Me

OTBS

NBoc

CO2H

NHZ

H

HATU, DIEA, DMF, rt

79 %

N

CO2Me

O

NBoc

TBSO

ZHNHN

N

O

O

NBoc

TBSO

1. H2, Pd/C, MeOH, AcOEt, rt

2. toluene, reflux

74 %

N

N

O

O

NBoc

TBSO

PMB

NaH, PMB-Cl, DMF,0 °C

74 %

N

N

O

O

NBoc

MeO

O

PMB1. TBAF, THF

2. DMP, DCM, rt

3. NaClO2, NaH2PO4.H2O, THF, H2O, rt

4. CH2N2, MeOH, 0 °C

72 %

- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -

Baran and coll. Angew. Chem. Int. Ed. 2005, 44, 609.

Page 31: Litterature Meeting

Third strategy: Ring closure by intramolecular oxidative enolate coupling

N

N

O

O

NBoc

MeO

O

PMB

N

N

O

O

NBoc

MeO

O

PMBH

N

N

O

O

NBoc

MeO

O

PMB

LDAN

N

O

O

NBoc

OMe

O

PMB

LnFe

"chelated"

N

N

O

MO

NBoc

PMB

MO

OMe

"non-chelated"

Diastereoselectivity

N

N

O

O

NBoc

OMe

O

PMB

LnFe

A (ionic/ concerted)

N

N

O

O

NBoc

OMe

O

PMB

LnFe

C (initial amide oxidation)

Mechanism ?

N

N

O

O

NBoc

OMe

O

PMB

B (diradical)

N

N

O

O

NBoc

OMe

O

PMB

LnFe

D (initial ester oxidation)

1. MeMgBr, toluene, 0 °C

2. Burgess reagent, benzene, 50 °C

41 %

N

N

O

O

NBoc

Me

PMBH

- Baran’s Synthesis of Stephacidin A –- First step: Preparation of a model of the bicyclo[2.2.2]diazaoctane nucleus -

NS

NEt3

O O O

Burgess reagent

4 4

6

6R

LDA, -78 °C, then Fe(acac)3, THF, -78 °C rt

65 %

7

Page 32: Litterature Meeting

- Baran’s Synthesis of Stephacidin A –- Second step: Application to the elaboration of a suitable functionalized system -

HN

N

O

ONH

HO

Stephacidin A

HN

N

O

ONH

H

OMe

O

O

O NH

NHZ

CO2H

OMe

O

NH

CO2Me

+

Benzopyran

Tryptophan

Proline-derived

Ester

I

TsO NH2

+NZ

CO2MeHOPd(OAc)2, DABCO, TBAI, DMF, 105 °C

75 %NH

NHZ

CO2Me

TsO

X

TsO NH

NHZ

CO2Me Pd

TsO NH

NHZ

CO2Me

Ln

N

NHZ

CO2Me

TsO

PdLn

Ha

migratory

insertion Hb

N

N

N

N.HI

-hydride

elimination

Benzopyran Tryptophan Synthesis:

Amide bondformation

X = I

X = PdI

Reider and coll. J. Org. Chem. 1997, 62, 2676.

Page 33: Litterature Meeting

- Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A -

NH

NHZ

CO2Me

TsO

1. Boc2O, DMAP, DCM/MeCN, rt, 95 %

2. Mg(0), MeOH, 0 °C rt

3. A, CuCl2 (O.1 mol%), DBU, DCM/MeCN, 0°C

75 %

NBoc

NHZ

CO2Me

O

OCO2Me

A

o-dichlorobenzene,190 °C

95 %NH

NHZ

CO2Me

O

NBoc

NHZ

CO2H

O

1. Boc2O, DMAP, DCM/MeCN, rt,

77 %

2. LiOH, THF/H2O, 0°C

100 %

Benzopyran Tryptophan Synthesis (2):

Proline Synthesis:

NZ

CO2Me

OMe

O

NZ

CO2Me

NZ

CO2Me

OTBS

1. PhI(OAc)2, TEMPO, MeCN/H2O, rt

2. CH2N2, AcOEt, rt

86 %

9-BBN, THF, rtthen

3M aq. NaOH/ 35 % aq. H2O2

92 %

TBSCl, ImH, DCM, rt

96 %NH

CO2Me

OTBSH2, Pd/C, toluene, rt

100 %

NH

CO2Me

OMeH2, Pd/C, toluene, rt

97 %

O

Page 34: Litterature Meeting

- Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A -

Union of Tryptophan and Proline Fragments

NBoc

NHZ

CO2H

O

R1

NH

CO2Me

1 2a: R= CH2OTBS2b: R= CO2Me

2a or 2b, HATU, DIEA, DMF,rt MeO

N

O

ONBoc

R1

O

ZHN

3a: R= CH2OTBS 62 %3b: R= CO2Me 81 %

Pd2dba3.CHCl3, Et3SiH, Et3N, DCM, rt

thenMeOH, reflux

thentoluene,reflux

N

O

ONBoc

R1

O

4a: R= CH2OTBS 53 %4b: R= CO2Me 85 %

HNH

N

O

ONBoc

R1

O

5a: R= CH2OTBS; Base = NaH 65 % 5b: R= CO2Me ; Base = NaHMDS 63 %

MOMN

Base, MOMCl, THF,-78 °C rt

Conditions

1. TBAF, THF, rt2. DMP, DCM, rt3. NaClO2, NaH2PO4.H2O, THF, rt4. CH2N2, MeOH, rt

69 %

Conditions

N

O

O

BocN

O MOMN

LDA, THF, -78 °Cthen

Fe(acac)3, -78 °C

61 %

MeOO

6

Ohfune and coll. J. Org. Chem. 1990, 55, 870.

Page 35: Litterature Meeting

- Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A -

Union of Tryptophan and Proline Fragments (2)

N

O

O

BocN

O MOMN

MeOO

6

1. BCB, DCM, 0 °C

63 %

2. MeMgBr, toluene, rtthen

Burgess reagent, benzene, 50 °C

88 %

N

O

O

BocN

O HN

Me

7

200 °C, sulfolane

28 - 45 %

N

O

O

HN

O HN

8

N

O

O

BocN

O HN

Me

7

N

O

O

HN

O HN

MeN

O

O

N

O HNH

Yield: 4.5 % from 1 in 8 steps

Comparison with natural Stephacidin A (spectra and optical data)

Page 36: Litterature Meeting

- Baran’s Synthesis of Stephacidin A –- Third step: Final formation of Stephacidin A -

Determination of absolute configuration

CO2Me

NH

CO2MeNH

CO2H

H

L-Proline

MeO

N

O

ONBoc

R1

O

ZHN

CO2Me

NH

CO2MeNH

CO2H

H

D-Proline

MeO

N

O

ONBoc

R1

O

ZHN

HN

N

O

ONH

HO

HN

N

O

ONH

O

+

+

NBoc

NHZ

CO2H

O

1

Stephacidin A

R

S

1H and 13C NMR: identical in all respects to natural Stephacidin A Optical properties

HN

N

O

ONH

HO

?

R

S

Page 37: Litterature Meeting

N

O61

9 8

2021

N

HO

55

5150

39

62

HN O

Synthesis of Stephacidin B

N

N

ON

O

O

Stephacidin B

N

N

O

HN

OO

O

HO

51

2021

39

62

55N

N

O

NH

OO

O

Avrainvillamide

DIMERIZATION

N

N

OHN

O

O

O

N

N

O

HN

OO

O61

9 8

2021

5652

5150

3839

62

H

Stephacidin A

N

O61

9 8

2021

N

O

52

5150

3839

62

H

HN O

a

N

O61

9 8

20 21

N

HO

55

5150

39

62

N O

nitrone

N-hydroxyindole

b

N

O61

9 8

2021

N

O

52

5150

3839

62

H

HN O

nitrone

nitrone

Double Michael addition pathway

c

N

O61

9

2021

N

O

52

5150

3839

62

N O

N-hydroxyindole

nitrone

H

H

d

cd

Cationic pathway

Page 38: Litterature Meeting

Synthesis of Stephacidin B

Myers’ approach:

Three steps:

1/ Preparation and reactivity study of a model of Avrainvillamide

2/ Enantioselective synthesis of Avrainvillamide from bicyclodiazaoctane nucleus

3/ Formation of Stephacidin B

N

N

ON

O

O

Stephacidin B

N

N

O

HN

OO

O

HO

51

2021

39

62

55

N

N

O

NH

OO

O

Avrainvillamide

2 XOxidation

N

N

O

NH

OO

O

Avrainvillamide

N

O

Model of Avrainvillamide

J. Am. Chem. Soc. 2005, 127, 5342.

J. Am. Chem. Soc. 2003, 125, 12041.

Page 39: Litterature Meeting

-Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide -

H3C

H3C

H3C CH3

OI2, DMAP,

CCl4-pyridine,50°C H3C

H3C

H3C CH3

O

I

A, Pd2(dba)3, Ba(OH)2.8H2O, 2-(di-t-butylphosphino)biphenyl,

H2O, THF, 38 °C

73 %

or

B, Pd2(dba)3, Cu (powder), DMSO,70 °C

70 %

H3C

H3C

H3C CH3

OO2N

I

O

Pd

O

I

L

L

I

NO2

Cu

NO2

Cu

Pd

O L

L

O2N

PdL4

OO2N

X

NO2

A: X= B(OH)2

B: X= I

Oxidative addition

Formation of

aryl copper derivative

1,1-reductive elimination

Shimizu and coworkers, Tetrahedron Lett. 1993, 34, 3421.

Page 40: Litterature Meeting

Zn (dust), 1M NH4Cl, EtOH, 48°C

64 %

HN

CH3

H3CH3C

H3C

HEtO

NCH3

H3CH3C

H3C

OH

O

NCH3

H3CH3C

H3C

O

(48 %) (9 %) (7 %)

5-exo-trig 5-endo-trig

-Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide (2) -

H3C

H3C

H3C CH3

OO2N

Identification of the Mickael acceptor group

NCH3

H3CH3C

H3C

O

NCH3

H3CH3C

H3C

OH

NuH

Nu

Base or acid

A B

T = 23 °C A:B = 2:1T = -20 °C A:B = 10:1

h

HN

O

H3CH3C

, EtOH 67 %

Nu: OCD3, SPh, SC6H4OCH3

Page 41: Litterature Meeting

N

O

N

ON

O

N

O

OH

O

H

NO

NO

H

-Myer’s Synthesis of Stephacidin B –- First step: Preparation and reactivity study of a model of avrainvillamide (2) -

NCH3

H3CH3C

H3C

O

NCH3

H3CH3C

H3C

OH

NuH

Nu

BaseX

Nu: nPrNH2, , ,NH

O

N

HO

OH2NHN O

Si,

!!!

N

N

OHN

O

O

O

N

N

O

HN

OO

O61

9 8

2021

5652

5150

3839

62

H

N

ONH

O

N

O

OH3C CH3

N

O

O

H

NO

NO

H

H3C CH3

N

H3C

H3CO

H3CCH3

Page 42: Litterature Meeting

-Myer’s Synthesis of Stephacidin B –- Second step: Synthesis of Avrainvillamide from bicyclodiazaoctane nucleus -

H3C

H3COTBDPS

N O

N

O

H

N

NH

O

TBDPSO

O

1. HF, CH3CN, 35 °C93 %

2. DMP, DCM, 23 °C85 %

3. I2, DMAP, Pyr-CCl4,, 60 °C91 %

N

NH

O

O

O

I

N

NH

O

O

O

A, Pd2(dba)3, Ba(OH)2.8H2O, 2-(di-t-butylphosphino)biphenyl,

H2O, THF, 38 °C

56 %

or

B, Pd2(dba)3, Cu (powder), DMSO,70 °C

72 %

O

O2N

NO2

I

OH

NO2

I

OCH3

CH3

TBAI, K2CO3,Me2CO, 65 °C

91 %Cl

CH3

H3C

NO2

X

OCH3

CH3

, m-xylène,

140 °C.

CH3

tBu tBu

OH

(BHT)

78 %

NO2

X

OCH3

CH3

A: X =

B: X =

O

B

O

I

B: X =

A: X =O

B

O

I

PhMgCl, -40 °C

O

B

O

iPrO

44 %

Knochel and coll. Angew. Chem. Int. Ed. 2002, 41, 1610.

Page 43: Litterature Meeting

-Myer’s Synthesis of Stephacidin B –- Second step: Synthesis of Avrainvillamide from bicyclodiazaoctane nucleus -

N

NH

O

O

O

O

O2N

Zn, NH4Cl, EtOH, 40 °C

49 %

NO

O

N O

NO

H

Avrainvillamide

OHN

OH

NHO

HO

N

O

O

NHOH

OH

N

OH

O

N

OH

Nicolaou and coll. Angew. Chem. Int. Ed. 2005, 44, 3736.

Page 44: Litterature Meeting

-Myer’s Synthesis of Stephacidin B -- Third Step: Final Formation of Stephacidin B -

NO

O

N O

NO

H

Avrainvillamide Optical property:

Synthetic D25 = -35,1 (c 1,0; CHCl3)

Natural D25 = + 10,6 (c 1,0; CHCl3)

Comparison 1H and 13C NMR spectra:

1H NMR: lack of correspondence in the region 2.45-2.6013C NMR: identical spectra

NO

O

N O

NO

H

N

O

N

ON

O

N

O

HO

O

H

NO

NO

H

Et3N, CH3CN, rt

> 95 %

Optical property:

Synthetic D25 = +91,0 (c 1,0; CHCl3)

Natural D25 : unknown

Comparison 1H and 13C NMR spectra:

⇒ Exact correspondence

Stephacidin B

Interconversion in various solvent-acetonitrile systems:

T = 38 °C AVR : SPC B = 2 : 1T = 23 °C AVR : SPC B = 1 : 2 after 48h

Page 45: Litterature Meeting

-Synthesis of Stephacidin B -

Baran’s approach:

HN

N

O

ONH

HO

Stephacidin A

HN

N

O

ON

HO

HN

N

O

ON

HO

Aspergamide B Aspergamide A

O

HO

HN

N

O

ON

HO

Avrainvillamide

O

HN

N

O

ON

O

O

NH

N

O

O

N

O

O

H

Stephacidin B

Increasing Oxidation State

J. Am. Chem. Soc. 2006, 128, 8678.

Page 46: Litterature Meeting

-Synthesis of Stephacidin B -

Baran’s approach: HN

N

O

ON

HO

Aspergamide A

O

HO HN

N

O

ON

HO

Avrainvillamide

O

-H2O (occured gradually

during storage/shipping)

100 %

KMnO4

X

HN

N

O

ONH

HO

Stephacidin A

HN

N

O

ON

HO

Aspergamide B

DDQ,

IBX,

or

Pd/C/O2

HN

N

O

ON

HO

OH

1. O2 (g), MeOH, hv,

2. Me2S

80 %

X

p-TsOH

or

Burgess reagent

X

HN

N

O

ON

HO

OH

Page 47: Litterature Meeting

-Synthesis of Stephacidin B -

Baran’s approach:

1/ Initial oxidation studies performed on simplified Stephacidin A models

2/ Total synthesis of Stephacidin B starting from Stephacidin A via Avrainvillamide

3/ Biological evaluation of Avrainvillamide and simplified mimics

HN

N

O

ON

H

O

HN

N

O

ONH

HO

Stephacidin A

HN

N

O

ON

HO

Avrainvillamide

ON

N

O

ON

O

OH

NH

N

O

ON

O

O

Stephacidin B

J. Am. Chem. Soc. 2006, 128, 8678.Angew. Chem. Int. Ed. 2005, 44, 3892.

Page 48: Litterature Meeting

-Synthesis of Stephacidin B -- First Step: Initial Oxidation Studies performed on Simplified Stephacidin A models -

NBoc

NHZ

CO2H

CO2Me

NH

CO2Me

HATU, DIEA, DMF,rt

74 %

MeO

N

O

O

NBoc

R

ZHN

R= CO2Me

H

H

N

O

ONBoc

R

MOMN

1. H2, 10% Pd/C, toluene, rtthen

toluene, reflux

87 %

2. NaHMDS, MOMCl, THF,-78 °C rt

86 - 92 % R= CO2Me

H

LDA, THF, -78 °Cthen

Fe(acac)3, -78 °C

53 %

N

O

ONBoc

R

MOMN

R= CO2Me

(single diastereomer)

BCB, DCM, 0 °C

68 %N

O

ONBoc

R

HN

R= CO2Me

MeMgBr, toluene, rtthen

Burgess reagent, benzene, 50 °C

59 %

N

O

O

BocN

HN

Me

R= CO2Me

p-TsOH, toluene, reflux

68 % N

O

O

HN

HN

Stephacidin A model

Synthesis of a Stephacidin A model :

Page 49: Litterature Meeting

-Synthesis of Stephacidin B -- First Step: Initial Oxidation Studies performed on Simplified Stephacidin A models -

Oxidation of Stephacidin A models:

NaBH3CN, AcOH, rt

N

O

O

HN

RN

1a: R = PMB1b: R = H

N

O

O

HN

RN

2a: R = PMB2b: R = H

H

HNa2WO4.2H2O, aq. 35% H2O2,

MeOH,H2O, rt

N

O

O

N

RN

N

O

O

N

PMBN

3a: R = PMB (non isolable) 3b: R = H (isolable) 54 % over 2 steps

HOO

N

O

O

N

PMBN

O

spontaneous

16 % over 2 steps

N

O

O

N

HN

O

p-chloranil, THF, reflux

88 %

Page 50: Litterature Meeting

- Synthesis of Stephacidin B -- Second Step: Formation of Stephacidin B starting from Stephacidin A via Avrainvillamide -

NaBH3CN, AcOH, rt

95 %

HN

N

O

ONH

HO

1: Stephacidin A

HN

N

O

ONH

HO

2

HN

N

O

ON

HO

3: Avrainvillamide

O

4: Stephacidin B

N

N

O

ON

O

OH

NH

N

O

ON

O

O

Conditions

Preparative TLC (SiO2, AcOEt) 15 - 20 % (70 - 80 % recovered 3) Et3N, MeCN, rt, 45 min. 95 %

DMSO, drying in vacuo, 30 min - 1h 2 : 1 (4 : 3)

Conditions

Synthetic Compound Natural Compound

3 []D = +11 (c 0.1, CHCl3) []D = + 10.7 (c 0.1, CHCl3)

4 []D = -33 (c 0.1, MeCN) []D = -21.1 (c 0.19, CDCl3)

Identical in all respects to the natural Stephacidin B:

LCMS TLC in several solvent mixtures 1H NMR Optical rotation

SeO2, 35% aq. H2O2,

1,4 - dioxane, rt

27 %(50 % recovered 2)

Na2WO4.2H2O, aq. 35% H2O2, MeOH,H2O, rt

X

Page 51: Litterature Meeting

HN

N

O

ONH

H

- Synthesis of Stephacidin B -- Third Step: Biological Evaluation of Avrainvillamide and Simplified Mimics

Biological assays of simplified analogues using the human colon HCT-116 cell line

HN

N

O

ONH

HO

(+)-Stephacidin A

HN

N

O

ON

H

OH

N

N

O

ON

OH

NH

N

O

O

N

O

(±)-Stephacidin B Model

N

N

O

ON

OH

NH

N

O

O

N

O

(-)-Stephacidin B

Stephacidin AModel

HN

N

O

ON

H

O

(±)-Avrainvillamide Model

(+)-Avrainvillamide

HN

N

O

ON

HO

O

Activity (µg/mL)

9.36

5.47

2.0

no significant activity

10.4

Activity (µg/mL)

3.95

0.41

Essential for anti-cancer activity

Low activity

Activity restored

Best candidate for in vivo studies

Page 52: Litterature Meeting

HN

N

O

ON

HO

O

HN

N

O

ON

HO

O

- Conclusions -

Avrainvillamide (2) Stephacidin B (3)

Myers - 17 steps 4.2 % overall 1 step from 2 95 %

Baran 8 steps 4.5 % overall 3 steps from 1 26 % overall 1 step from 2 15 – 95 %

NO

O

N O

NO

HN

O

N

ON

O

N

O

HO

O

H

NO

NO

H

HN

ON O

NO

H

Stephacidin A (1)

Page 53: Litterature Meeting

The End