33 ans • PACSé • 1 enfant Domicilié à Sannois (95 - Val d’Oise)

DEA - Université Cergy-Pontoise (Prof. J. Ardisson/DR A. Pancrazi)

“Contribution à la Synthèse Totale du (+)-Discodermolide”

Doctorat - RWTH Aachen (Prof. D. Enders)

“Synthèse Totale du (+)-Altholactone”

Ingénieur R&D - Faculté de Pharmacie Paris V (Prof. J. Ardisson)

“Contribution à la Synthèse Totale du Salinosporamide A, Nouvel Inhibiteur nM du Protéasome” (Programme ANR)

Ingénieur R&D - BayerCropScience Lyon (Dr. J.-P. Vors)

“Synthèse d’Hétérocycles Trifluorométhoxylés”

Julien BarbionDocteur en Chimie - Ingénieur Chimiste R&D

Research Summary (last update 2011) I - (+)-Discodermolide

II - (+)-Altholactone

III - Salinosporamide A

IV - OCF3-Heterocycles

Studies Towards the Total Synthesesof Bioactive Products

(+)-Discodermolide(DEA, 2002-2003)

Synthesis, 2004, 3017-3022.Angew. Chem., Int. Ed. 2007, 46, 1917-1921.

Chem. Eur. J. 2008, 14, 11092-11112.

Isolated from a marine sponge (Discodermia dissoluta)

Low extraction yield (0.002%)

Biological activity Cytotoxic IC50 = 2.5 nM Microtubule stabilisation

Target = tubuline active in vivo

Structural features Polypropionate 13 chiral centres 3 double bonds (Z)

(+)-Discodermolide

OMe

Me

O

HOMe

OHMe

Me

OH

Me

O

Me

NH2

O

Me

(+)-Discodermolide

HO

21 15

24

1

5

8

7

14

(+)-Discodermolide - Retrosynthesis

OO

OH

HO

OH OCONH2

OH

O"Cu"

Me

12

14

dyotropicaltransposition

13

OR4

X

14

8

CbO

R

crotyltitanation

O N

OiPr

iPr

OCb =OH

11

118

R5O OR6

15

24

X

R2O OR3

NR1O

OOMe

Me1 7

Fragment C Fragment A

(+)-Discodermolide - Strategies

CO2CH3HO

12

Crotylation antiTransposition

FBW

13

ORCbO

8

OHOR'

OMe

14

TMS

O

TMS

14OR4

SnBu3

14

8Dihydrofuraneformation

Transposition of cuprates

8

8

O

12

HOMe

SnBu3

14

12

13

CbO

8

OH

Transposition of cuprates SnBu3Crotylation anti

Transposition FBW

Difficult obtention of DHF

Route 1

Route 2

63% over 4 stepsde=94%

58% over 6 steps

15% over 3 steps

OCb

(E)

(+)-Altholactone(PhD, 2003-2006)

defended in Aachen, the 10/27/2006

Chem. Eur. J. 2008, 14, 2842-2849.

Isolated from the stark of little trees(Goniothalamus giganteus)

Goniothalamus is known as a source of natural products presenting biological activities

(5-hydroxy-5,6-dihydro-2H-pyran-2-one)

Biological activityCytotoxic IC50 = 0.7 µMAntitumoral and antibacterial properties

Structural features4 chiral centres in a rowBicyclic cis-junction

Cycle 1: 5-hydroxy-5,6-dihydro-2H-pyran-2-one

Cycle 2: disubstituted tetrahydrofurane

(+)-Altholactone

O

O

OPh

OH

233a

7a

(+)-Altholactone

(+)-Altholactone - Retrosynthesis

lactonisation

SN2 ring-closure

aldol reaction

OO

O

OH

Ph

O O

O

XRO

2

3

3a7a

4

6

2

3

3a

7a

4

6

H

O

= 2,2-Dimethyl-1,3-dioxan-5-one

(+)-Altholactone - Synthesis (1/2)

Chirality Introduction

OBn

OO

O

OO

ORAMP

Benzene

90% OO

NN

OMe

1) t-BuLi, THF Br-(CH2)3-OBn2) Oxalic acid, Et2O

ee > 98%

OBn

OO

O

Ph

OH

ee > 98%de > 98%

1) Cy2BCl, NEt3, Et2O2) PhCHO, Et2O

68%

82% over 2 steps

NH2

NOMe

RAMP = (R)-1-Amino-2-MethoxymethylPyrollidine

(+)-Altholactone - Synthesis (2/2)

(18 steps, 13.7% overall yield)

O

O O

OBnPh

OH OBn

O O

OBnPh

OH

O

OO

O

OTBS

Ph OO

OPh

OH

(+)-altholactone

1) TBSOTf2) (L)-Selectride®

3) KH, BnBr4) TBAF

68% over 4 stepsde > 96%

1) 2,2-DMP2) TBSOTf3) H2, Pd/C4) IBX, DMSO5) TPAP/NMO

72% over 5 steps

1) LDA, PhSeCl2) H2O2, CH2Cl23) TBAF4) TsCl, DMAP5) Amb.® 15, MeOH

56% over 5 steps

Salinosporamide A(Research Scientist, 2006-2008)

ANR Program

ʺstill under investigationʺ

HN

OO

O

H

Cl

OHHH

12

13

14

151

3

68

10

Salinosporamide A

Isolated from a novel microbial source (2003)

(marine bacterium of the new genus Salinospora)

Biological activity

IC50 = 10 nM (in vitro) - Human colon carcinoma

Inhibition of the 20S proteasome

Structural features

5 chiral centres in a row

cis-fused c-lactam-b-lactone bicyclic ring structure

2 side chains: cyclohexenylcarbinol and chloroethyl chains

Salinosporamide A

The b-lactone is recognized as a key pharmacophor (its forms a covalent adduct with the N-terminal Thron proteasome 20S)

HN

OO

O

H

Cl

OHHH

12

13

14

15

13

68

10

H2NNH

OH

O HN

OHO

O

H

Cl

OHHH

12

13

14

15

13

68

10

O

NH2

HN

O

Salinosporamide A

N-terminal Thron proteasome 20S

HN

O

O

H

OHHH

1213

14

15

13

68

10

O

NH2

HN

O

covalent adduct

O

Salinosporamide A - SAR

NGP

OH

O

OH

1

23 OH

NH2 OH

OHOH

3GPO

CH3

OCb2

1GPO

"Ti"

OH

NHO

OO

H

1

32

13

4

5

8 10

6

4

1

23

NHGP

OGP

OGP

OH

CbO

GPO

12

13

13

Allylation

4

4

13

ONH

O

O OGPO

1

32

13

54

Lactonisation

OH

Allylationor Aldol reaction

Cl

Salinosporamide A - Retrosynthesis

OO

Boc2O (1.3 eq.)t-BuOH/MeOH (3:2)

RT, 24h2,2-DMP (3.0 eq.), TsOH (0.05 eq.)

DCM, RT, 30min

90% over 2 steps

NH2

OH

HO

HO

NHBoc

OH

HO

HO

NHBocHO

TRIS

OO

MeLi (5.2 eq.)CeCl3

.7H2O (2.6 eq.)THF, -78°C, 30min

93%

NHBoc

OO

NHBocOHC

OH

(COCl)2 (2.0 eq.)DMSO (3.0 eq.)NEt3 (6.0 eq.)

DCM, RT, 30min

OO97%

NHBocO

97%

(COCl)2 (2.0 eq.)DMSO (3.0 eq.)NEt3 (6.0 eq.)

DCM, RT, 30min

TRIS = Tris(hydroxymethyl)aminomethane 99+%, 43€/500g (ACROS Organics)

Salinosporamide A Synthesis of the Methyl Ketone

Salinosporamide A Synthesis of the II-Carbamate

94% over three steps

1) Im. (1.7 eq.), TPSCl (1.5 eq.) DMAP (0.05 eq.), THF, RT, overnight2) n-BuLi (1.1 eq.), CH3CHO (2.5 eq.) THF, RT, 1h

HO TPSO

OH

Red-Al (65% in toluene) (1.6 eq.)THF, 0°C, 4h

TPSO OH94%

KH (1.4 eq.)CbCl (1.1 eq.)THF, RT, 30min

TPSO OCb

Overall yield = 88% (over 4 steps) - Racemic version of the II-carbamate

Salinosporamide A Hoppe‘s Allylation with a II-Carbamate (1/2)

OCb

Li

O

NNn-BuLi

TMEDA

Ti(OiPr)3

OCb

Ti(OiPr)4

OCbO

Me

R

L

H

R

O

ROCb

TiL

L

Z-anti

retention of configuration

Si face attack

O N

OiPr

iPrOCb =

PGO PGO

N(iPr)2

O(S)

PGO

OGP

OH

PGO

OO

(+/-)-carbamate II (1.1 eq.)n-BuLi (2.2 eq.)/TMEDA (2.2 eq.)

Ti(OiPr)4 (3.3 eq.)Et2O, -78°C

No reaction

NHBoc

OO

NHBoc

OCb

(+/-)

OTPS

OO

(+/-)-carbamate II (1.1 eq.)n-BuLi (2.2 eq.)/TMEDA (2.2 eq.)

Ti(OiPr)4 (3.3 eq.)Et2O, -78°C, 2h

76%

NHBoc

OO

NHBocOHC

OCb

(+/-)

HO

OTPS

OHO

Salinosporamide A Hoppe‘s Allylation with a II-Carbamate (2/2)

Salinosporamide A Attempts on Assymetric methylation (1/2)

OO

NHBoc

OCb

(+/-)

HO

OO

NHBoc

OCb

(+/-)

O

OO

NHBoc

OCb

HO

OO

NHBoc

OCb

HO

+

MeLi (5.0 eq.)THF, -78°C, 4hMeLi (13.2 eq.)

CeCl3.7H2O (6.6 eq.)

THF, -78°C, 1.5h

(easily separableon silica gel)

DMP (1.2 eq.)DCM, RT, 2h

95%

20%14%

62%78%

OTPSOTPS OTPS OTPS

(+/-) - mino (+/-) - majo

1) O3, DCM, -78°C, 1h then Me2S (40.0 eq.) RT, overnight2) CrO3/H2SO4 (1.05 eq.) Acetone, 0°C, 5min

60-70%over two steps

OO

(+/-)

NBoc

O

HO

OO

(+/-)

NBoc

O

HO

Expected diastereomer

(confirmed by NOESY on bothone diastereomers)

TPSO TPSO

Salinosporamide A Attempts on Assymetric methylation (2/2)

OO

NHPMB

OCb

O

OTPS

OO

NHBoc

OCb

OTPS

OO

NHBoc

OTPS

O

OTBS

OO

NBocO

TPSO

OO

NHO

TPSO

OTBSTBSO

NBoc

TPSO

O

Acyclic form

Bicyclic form

Asymmetric oxidation of C=C

degradation never obtained91% mixture (63:37)80% mixture (70:30)

41% only unexp. dia. + SM65% only unexp. dia. + SM

degradation degradation + SM

OO

NHBoc

OCb

O

OTPS

82% mixture (76:24)92% mixture (85:15)

OCF3-Heterocycles(Research Scientist, 2009-2010)

BayerCropScience, Lyon

ʺstill under investigationʺ(BCS-Patent in press)

Trifluoromethoxy Group- OCF3 group is more & more important in agrochemical and pharmaceutical industries because of its unique properties.

- OCF3 is referred as "pseudo- or super-halogen" (close to F or Cl):highly electron-withdrawing by induction ( =3.7) slightly positive mesomeric effect +Mand hydrophobic R=+1.04 compared to R(CF3)=+0.88 and R(OMe)=-0.02

O

NN

NO

OCF3

CO2Me

CO2Me

Indoxacarb(proinsecticide)

Cl

O

NH

NH

OOCF3

Triflumuron(insecticide)

S

NNH2

F3COF3CO N

N

OH

Riluzole(amyotrophic lateral

sclerosis)

Flurprimidol(plant growth regulator)

Þ Few methods are described in literature

Þ Use of quite drastic conditions and/or large excess of reagents

Þ limited to aromatic substrates or simple aliphatic ones

TFMT as OCF3 Generator

Reactivity of TFMT:Contrary to alkyltriflates, which are powerful alkylating agents, TFMT is a CF3O

-

generator (and not a CF3+)

TFMT (trifluoromethyl triflate) is known since 1965.

Different synthesis have been reported(for a review see Taylor, Martin, J.Org.Chem. 1987, 52, 4147-4156 )

Now commercially available from ABCR.

F3C S

O

O

O CF3

S

O

O

O

F

F

F

F

F

FF-

SF

O

O

F

F

F O-F

F

F

F F

O

F-+ +

Trifluoromethoxylation Reaction

Marrec, O.; Billard, B.; Vors, J.-P.; Pazenok, S.; Langlois, B.R. J. Fluorine Chem. 2010, 131, 200-207.

S OCF3O

OE OCF3+ +

-30°C, 2h -30°C then rt 24h

E+

in situ

CH3CNAgFCF3 CF3SO2F Ag+ -OCF3

O OCF3

OAcAcO

OAc

AcO

OCF3

NO

O

Ph

O

OCF3

O

OCF3

O

OCF3 OCF3 OCF3

O

OCF3

O

O

OCF3

O

OCF3

AgOCF3 is an efficient reagent for trifluoromethoxylation of primary bromides and iodides but also secondary reactive bromides and tolerates a lot of functional groups.

Access to OCF3-Heterocycles (patent in preparation)

Solid knowledge in multi-steps synthesis of natural products

Real autonomy in work

Good capacity of communication (in 3 different languages)

Team-worker and team leader (organisation)

Almost always in a good mood

Julien Barbion - Conclusion