Research summary - 2011 updated
Transcript of Research summary - 2011 updated
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
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)