Université René Descartes – Paris 5 UFR Biomédicale des Saints-Pères UFR Biomédicale des Saints-Pères Ecole Doctorale du Médicament Ecole Doctorale du Médicament Strategic investigations for the Strategic investigations for the design of a library of design of a library of liposidomycins analogs, natural liposidomycins analogs, natural antibiotics dedicated to the MraY antibiotics dedicated to the MraY translocase translocase Maryon GINISTY Direction : Pr. Yves Le Merrer aboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques Direction : Dr. Daniel Mansuy - UMR 8601 – CNRS 45, rue des Saints-Pères - 75270 Paris Cedex 06- France
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Université René Descartes – Paris 5 UFR Biomédicale des Saints-PèresUFR Biomédicale des Saints-Pères
Ecole Doctorale du MédicamentEcole Doctorale du Médicament
Strategic investigations for the Strategic investigations for the design of a library of design of a library of
liposidomycins analogs, natural liposidomycins analogs, natural antibiotics dedicated to the MraY antibiotics dedicated to the MraY
translocasetranslocase
Maryon GINISTY
Direction : Pr. Yves Le Merrer
Laboratoire de Chimie et Biochimie Pharmacologiques et ToxicologiquesDirection : Dr. Daniel Mansuy - UMR 8601 – CNRS45, rue des Saints-Pères - 75270 Paris Cedex 06- France
2
ANTIBACTERIAL RESISTANCE : ANTIBACTERIAL RESISTANCE : A MAJOR OBSTACLE FOR A MAJOR OBSTACLE FOR
ANTIBIOTHERAPYANTIBIOTHERAPY 1940’s : development of penicillin and appearance of the concept of antibiotics
« Agents with specific antibacterial action and with toxicity selectively directed against bacteria in low concentrations »
► Bacteriostatic effect (decrease or stop of bacterial growth)
► Bactericid effect (destruction of bacteria)
● Complexity and adaptability of bacterial world
► Therapeutic failure► Development of a large number of antibiotics classified according to various
criteria : site of action, origin, administation route, structure
⇒ Eight major families : -lactams, aminosides, macrolides, sulfamides, poly- et glyco-peptides, cyclins, (fluoro)quinolons…
3
● Two types of resistance :
► Natural resistance (intrinsic property related to the bacterial genetic program)
► Acquired resistance (property resulting from genetic modifications of the bacterial cells)
● Five major mechanisms of resistance :
- Overproduction of antibiotic target- Metabolic bypass of inhibited reaction - Inactivation of antibiotic by enzymatic modification - Modification of target eliminating or reducing antibiotic
binding to target
RESISTANT STRAINS AND MECHANISMSRESISTANT STRAINS AND MECHANISMS
⇒ Resistant strain : strain able to develop in the presence of an antibiotic concentration notably higher than that which inhibits development of other strains of same species
antibiotic « modifying »enzyme
modified antibiotic
antibiotic
X
modifiedreceptor
antibiotic
receptor resistancegene
pump
- Decrease of cellular permeability to antibiotic
4
⇒ Four sites of action specific to procaryote bacterial cells
- ribosomes responsible for protein synthesis
- metabolism of nucleic acids⇒ inhibition of DNA synthesis⇒ inhibition of DNA transcription into messenger RNA
- oxydoreduction (5-nitro-imidazoles) via formation of superoxides and nitro radicals responsible of irreversible damage on bacterial DNA- cell wall biosynthesis
SITES OF ACTION OF ANTIBIOTICS AND SITES OF ACTION OF ANTIBIOTICS AND POTENTIAL TARGETSPOTENTIAL TARGETS
Gram (-) cell
Gram (+) cell lipopolysaccharide
periplasm
cytoplasmic membranecytoplasmic membrane
external membrane
peptidoglycancytoplasmcytoplasm
mRNA
ribosomeDNA
DNA-gyrase
RNA-polymerasemRNA
Bacterial wall
N
N
R
CH3O2N
5-nitro-imidazoles
BACTERIA
aminoacid
5
OHN
O
NH2
D-Cycloserin
PERIPLASM
ANTIBIOTICS AND BACTERIAL
PEPTIDOGLYCAN BIOSYNTHESIS
UDP-GlcNAc
UDP-GlcNAc-enolpyruvate
UDP-MurNAc
UDP-MurNAc-L-Ala
UDP-MurNAc-dipeptide
UDP-MurNAc-tripeptide
PEP
NADPH
L-Ala D-Ala
D-Glu L-Glu
meso-A2pm
D-Ala-D-Ala D-Ala
MurA
MurB
MurC
MurD
MurE
MurF
Alr
MurI
Ddl
-O2C OPO32-
PEP
PO32-
O
Fosfomycin
UDP-MurNAc-pentapeptide
bacitracin
vancomycinmoenomycinpenicillin
cephalosporin
D-cycloserin
D-cycloserin
fosfomycin
tunicamycinmuraymycinmureidomycinliposidomycin
MraY
O
O-
NH3+
D-Alanine
CYTOPLASM
UMP
PiUDP-GlcNAc
UDP
BacA MurG
PBPs
PBPs
Lipid I
Lipid II
AcceptorPolymer
Peptidoglycan
Undecaprenyl-PP
Undecaprenyl-P
MEMBRANE
N-acetylmuramic acid
N-acetylglucosamine
tétrapeptide
pentapeptide
O
O
NHCOCH3
OO
O
NHCOCH3
CHH3C
C
NH
O
tetrapeptide
N-acetylmuramic acid N-acetylglucosamine
6
INHIBITORS AND NATURAL SUBSTRATE INHIBITORS AND NATURAL SUBSTRATE OF MraY TRANSLOCASEOF MraY TRANSLOCASE
OO
OH
HO
NH
CH2
OOH
NHN
O
OO
OHOHO
HOAcHN
HO OH
Tunicamycins
n
A : n=9
B : n=10
C : n=8
D : n=11
OOH2N
HO OCH3
O
HO OH
NH
N
O
O
CO2HHN
HN
NH
HNHO2C
O
OOR
HN
NH
HN
O
Muraymycins
A1: R=COC11H22N(OH)C(NH2)=NH
A3: R=COC11H22NHC(NH2)=NH
C1: R=H
NHN
O
O
O
OH
O
HN
CH3
N
NH
R1
O
HO
HN
ONH
R2
HN
O
R3
OH
O
H3C
R1=H, glycinylR2= CH3S(CH2)2-R3= m-hydroxyphenyl
Mureidomycins
O
NHN
O
ON
N
CH3
HO2C
O
O
CH3R
O
O
HO2C
O
O
O
NH2
A: R=
B: R=
C: R=
Liposidomycins
OH OH
OHHO3SOO
OH
HOO
AcHN
O
pentapeptide-HNO
PO
PO
-O O
O
HO OH
N
NH
O
O
O O-
Me
UDP-Mur-NAc-pentapeptide
7
N
N
CH3
HO2C O
CH3
12
345
67
N
N
CH3
HO2C O
CH3
12
345
67
O O
OHH O3S O
NH2
O O
OHH O3S O
NH2
NHN
O
O
O
HO OH
H1'
2'3'4'
STRUCTURE OF LIPOSIDOMYCINSSTRUCTURE OF LIPOSIDOMYCINS
A: R=
B: R=
C: R=
O
R
O
O
HO2C
O
5'NHN
O
O
O
HO OH
H1'
2'3'4'
S
S
S S
8
N
NCH3
CH3O
PhCOO
O
EtON Boc
CH3
PhCOO
O
EtON H
CH3
PhCOO
O
EtON
N CH3
H3C O
PhCOO
O
EtO
Z
N
N CH3
H3C O
PhCOO
O
EtO
O
Z
SYNTHETIC APPROACHES DESCRIBED IN SYNTHETIC APPROACHES DESCRIBED IN LITTERATURELITTERATURE
OHCacrolein
N
HO
O
CH3Z
N-Z-sarcosine
EtO2C NBoc
CH3
N-Boc-sarcosine ethyl ester
⇖
⇖⇖
1,4-diazepan-2-one moiety
N
NCH3
CH3O
PhCOO
O
EtO 1 23
456
7
Knapp et coll. Tetrahedron Lett. 1992, 33, 5485.Knapp et coll. J. Org. Chem. 2001, 66, 5822.
9
BnO
NH
OMPM
OTBDMSO
OBn
R
N3BnO
NH
OH
OTBDMSO
OBn
R
N3BnO
NH
O
OTBDMSO
OBn
R
N3
Ribosyl-diazepanone Isono et coll. Heterocycles 1992, 34, 1147.
OMPM
OTBDMSN3
BnO
(S1)
HO2C
N3 OBn
(S2)
O OCH3
O O
OH
OH
OMPM
OH
RHO
OtBuOOH, Ti(OiPr)4
L-DET
78%
OMPM
OH
OD-DET
tBuOOH, Ti(OiPr)4
88%
OMPM
OHN3
HO
50%
NaN3
RHO
N3 OH
RHO
NaN3
O OCH3
O O
R :
NH
N
O
BnO OBn
TBDMSO O OCH3
O O
O OCH3
O O
OHC
DCC / HOBt
NH
N
O
BnO OBn
TBDMSO O OCH3
O O
Pd/C, H2
36%
SYNTHETIC APPROACHES DESCRIBED SYNTHETIC APPROACHES DESCRIBED IN LITTERATUREIN LITTERATURE
10
O O
OTBDMSO
HO2C
OH
N3
H O O
OTBDMSO
HO2C
OH
N3
H
NHCH3
PhCOO
CO2Et
O O
OTBDMSO
OH
NH2
O
O NCH3PhCOO
CO2EtEEDQH
NHCH3
PhCOO
CO2Et
O O
OTBDMSO
OH
N3
O
NCH3PhCOO
CO2EtEEDQH
NHCH3
PhCOO
CO2Et
O O
OTBDMSO
OH
N3
O
O NCH3PhCOO
CO2EtEEDQH
Nucleosidyl-diazepanone Knapp et coll. Org. Lett. 2002, 4, 603.
O O
OHO
O H
OH
O O
OTBDMSO
HO
O
O
OTBDMSO
N
N
OH3C
CH3
EtO2C
OHH
O
O
OHHO
NH
N
O
ON
N
OH3C
CH3
EtO2C
OHdeprotection, acylation
thenglycosylation
1/ Oxidation
2/ NaN3
1/ Ozonolysis
2/ Azidereduction
3/ Reductive amination
SYNTHETIC APPROACHES DESCRIBED SYNTHETIC APPROACHES DESCRIBED IN LITTERATUREIN LITTERATURE
FORMATION OF PREFUNCTIONALIZED FORMATION OF PREFUNCTIONALIZED RIBOFURANOSIDESRIBOFURANOSIDESO OH
HO OH
HO D-Ribose
* 2 NaN3 + H2SO4 2 HN3 + Na2SO4H2O
0°C
50%(= 3,4)
O OAc
AcO OAc
N3
AcOH, Ac2O,H2SO4,RT, 2h.
35%
O OH
O O
N3
40%a
O OH
O O
PhtN
a 25%
a : 1/ H2SO4 (0,1N), 65°C, 4h; 2/ Me2C(OMe)2, CSA, Me2CO, 50°C, 30 min.
22
R= Boc, Cbz, FmocR= BocR= CbzR= Fmoc, Cbz
SYNTHESIS OF SYNTHESIS OF LL-SERINYL ACCEPTORS-SERINYL ACCEPTORS
BnOCO2H
NHBoc
BnOCO2tBu
NHBoc
Cl3C OtBu
NH
BF3.OEt2,cyclohexane, CH2Cl2,
TA, 17 h.
96%
HOCO2tBu
NHBoc
H2, Pd(OH)2/ C,
EtOH abs., AcOH,TA, 72 h.
99%
HOCO2H
NH2
L-serine
HOCO2tBu
NHR
N-carbamoyl-L-serine tert-butyl ester
HOCO2H
NHR
tBu-Br, BnEt3NCl,
K2CO3, CH3CN,
50°C, 24h.
88%
HOCO2tBu
NHZR= Cbz
Cl3C OtBu
NH
AcOEt,cyclohexane,
20°C, 24h.
84%
HOCO2tBu
NHFmoc
R= Fmoc
23
O OP2
OP1P1O
Y
O X
OP1P1O
Y
O O
OP1P1O
Y
CO2tBu
NHP3
HOCO2tBu
NHP3
activation glycosylation STRATEGY 1 (riboses not functionalized )
STRATEGIE 2 (prefunctionalized riboses)
PP11 PP22 YY ActivationActivation XXX = Br, Cl, FX = Br, Cl, F
ZZ
AgOTf, DCM, -15°C, 15 h.AgOTf, DCM, -15°C, 15 h.
: 100%: 100% 3232
ZZ : 100%: 100% 9292
BocBoc 0,30,3 6969BocBoc 0,30,3 6969
AcAc AcAc OAcOAc
TMSBr, DCM, -40°C à TATMSBr, DCM, -40°C à TA
BrBr
BzBz AcAc OBzOBz BrBr
BnBn AcAc OBnOBn BrBr
CMeCMe22 HH NN33
DAST, THF, -30°C à TA, DAST, THF, -30°C à TA,
2h.2h.
FF
CMeCMe22 HH NN33 FF
BnBn HH OBnOBn FF
O OH
OO
Y
O F
OO
Y
O O
OO
Y
CO2tBu
NHP
DAST, THF, -30°C à TA, 1h.
HO CO2tBu
NHP
activateur
SnCl2/ AgClO4
BocBoc
SnClSnCl22, AgClO, AgClO44, -15°C à TA, , -15°C à TA,
48 à 72 h.48 à 72 h.
2,152,15 6464
FmocFmoc 1,71,7 100100
BocBoc 1,21,2 4444
HOCO2tBu
NHP
O OAc
RO OR
RO
O
RO OR
ROX O O
RO OR
RO
CO2tBu
NHP
activator
SELECTION OF ACTIVATORS AND OPTIMIZATION SELECTION OF ACTIVATORS AND OPTIMIZATION OF GLYCOSYLATION CONDITIONSOF GLYCOSYLATION CONDITIONS
Ginisty M., Gravier-Pelletier C., Le Merrer Y., Tetrahedron: Asymmetry 2004, 15, 189-193.Ginisty M., Gravier-Pelletier C., Le Merrer Y., Tetrahedron: Asymmetry 2006, 17, 142-150 .
Hg(CN)2
AgClO4
TMS-OTf BF3.OEt2
AgOTf SnCl2/ AgClO4
PP33 GlycosylationGlycosylationRatio Ratio
))Yield Yield (%)(%)
24
O O
P1O OP1
P1O
NHR3
R2O2C
O O
P2O OP2
R1HN
NH2
R2O2C
N3
PO O
azido-epoxide
O X
P2O OP2
R1HN
NHR3
R2O2C
glycosylation OH
prefunctionalizedribofuranose
O X
P1O OP1
P1O
NHR3
R2O2C
glycosylationOH
O O
P2O OP2
R1HN
NHR3
R2O2C
functionalizedL-serinyl-O-ribofuranoside
O O
P1O OP1
P1O
NHR3
R2O2C
O
P1O OP1
R1HN
O
NHN3
HO2C
HO
TBDPSO
O O
P1O OP1
P1O
NH2
R2O2C
N3
PO Oazido-epoxide
⇗
⇘
O X
P1O OP1
P1O
NHR3
R2O2Cglycosylation OH
STRATEGY 1
STRATEGY 1
STRATEGY 2
aminedeprotection
aminedeprotection
functionalization of ribosyl moiety
ACCESS TO THE SCAFFOLD BY « CHAIN ACCESS TO THE SCAFFOLD BY « CHAIN EXTENSION »EXTENSION »
25
PhtNK, DMF,
160°C, 12h.O O
O O
PhtN
tBuO2C
NHZ
1'
2'3'
4'5'
1 2 3
O OHO
HO OH
1'
2'3'
4'5'
12
3tBuO2C
NHR
CH3C(OMe)2, MeOH, APTS, (CH3)2CO. O O
HO
O O
1'
2'3'
4'5'
12
3tBuO2C
NHR
O O
AcO OAc
AcO
tBuO2C
NHZ
O O
HO OH
HO
tBuO2C
NHZK2CO3, MeOH/ H2O,
TA, 1h.
70%
1'
2'3'
4'5'
12 3 1
2 3
1'
2'3'
4'5'
O O
O O
HO
tBuO2C
NHZ
1'
2'3'
4'5'
1 2 3
O O
BzO OBz
BzO
tBuO2C
NHZ
O O
HO OH
HO
tBuO2C
NHZK2CO3, MeOH/ H2O,
TA, 1h.
1'
2'3'
4'5'
12 3 1
2 3
1'
2'3'
4'5'
O O
BzO OBz
ZHN H
BzOOtBu
O
O O
BzO OBz
BzO
NHZ
OtBu
O
+O OBnO
BnO OBn
1'
2'3'
4'5'
12
3tBuO2C
NHBoc
O OHO
HO OH
1'
2'3'
4'5'
12
3tBuO2C
BocHN
Pd(OH)2/C, H2, EtOH abs., CH3CO2H,
TA, 24h.
100%
TsCl, DMAP, Et3N, CH2Cl2,
0°C to TA, 6h.
81%
O O
O O
TsO
tBuO2C
NHZ
1'
2'3'
4'5'
1 2 3
O O
HO OH
HO
NHR3
R2O2C
1'
2'3'
4'
5'
12 3
FUNCTIONALIZATION OF RIBOSYL MOIETYFUNCTIONALIZATION OF RIBOSYL MOIETY
O O
P2O OP2
R1HN
NHR3
R2O2C
1'
2'3'
4'5'
1 32
O O
P2O OP2
HO
NHR3
R2O2C
1'
2'3'
4'
5'
12 3
O O
P1O OP1
P1O
NHR3
R2O2C
1'
2'3'
4'5'
12 3
functionalizationat C-2’ and C-3’
positions
substitutionof the
5’-OH function deprotection
C-2’ and C-3’protection
substitutionof the5’-OH
function
P1 = Ac, Bz, BnP2 = C(CH3)2
OMe
X
MeO
MeOH
O OH
BzO OBz
BzO
MeOCO2tBu
NHZ
major product
+R = Z 82%
Boc -
Maryon Ginisty
diapo plan 3
26
O O
P2O OP2
R1HN
NH2
R2O2C
O
P1O OP1
R1HN
O
NHN3
HO2C
HO
TBDPSO
O O
P1O OP1
P1O
NHR3
R2O2C
O X
P2O OP2
R1HN
NHR3
R2O2C
glycosylation OH
prefunctionalizedribofuranose
O X
P1O OP1
P1O
NHR3
R2O2C
glycosylationOH
O O
P2O OP2
R1HN
NHR3
R2O2C
functionalizedL-serinyl-O-ribofuranoside
O O
P1O OP1
P1O
NHR3
R2O2C
O O
P1O OP1
P1O
NH2
R2O2C
⇗
⇘
O X
P1O OP1
P1O
NHR3
R2O2Cglycosylation OH
STRATEGY 1
STRATEGY 1
STRATEGY 2
aminedeprotection
aminedeprotection
functionalizationof the ribosyl moiety
N3
PO O
azido-epoxide
N3
PO Oazido-epoxide
ACCESS TO THE SCAFFOLD BY « CHAIN ACCESS TO THE SCAFFOLD BY « CHAIN EXTENSION »EXTENSION »
27
O O
O O
H2N
tBuO2C
NHFmoc
1'2'3'
4'5'
21
3
O O
O O
H2N
tBuO2C
NH2
1'2'3'
4'5'
21
3
HCO2NH4
Pd/C 10%
MeOH, TA.
O O
O O
N3
NH2
tBuO2C
N3
PO
O
O O
O O
N3
N3
HO
PO
tBuO2C
NH
azidoreduction
O O
O O
H2N
tBuO2C
NHFmoc
1'2'3'
4'5'
21
3
O O
O O
Y
tBuO2C
NHFmocprotection
of C5'-amino group
1'2'3'
4'5'
21
3
O O
RO OR
RO
tBuO2C
NHZ
O O
RO OR
RO
tBuO2C
NH2
1'2'3'
4'5'
21
3
1'2'3'
4'5'
21
3
AMINE DEPROTECTIONAMINE DEPROTECTION
STRATEGY 1
H2, Pd(OH)2/ C, CH3CO2H, EtOH abs., RT, 24h.
H2, Pd(OH)2/ C, CH3CO2H, EtOH abs., RT, 48h.
H2, Pd black, CH3CO2H, RT, 48h.
R = Ac, Bz
X
STRATEGY 2
O O
O O
N3
tBuO2C
NHFmoc
1'2'3'
4'5'
21
3
Y= PhtN-, ZHN-
O O
O O
Y
tBuO2C
H2N
1'2'3'
4'5'
21
3deprotection
of C2-amino group
X
Maryon Ginisty
diapo 3
28
O OY
O O
tBuO2C
NH2
1'2'
4'5'
1 2 3
A
B
3'
Powerful glycosylation conditions for the diastereoselective formation of Powerful glycosylation conditions for the diastereoselective formation of serinyl-5’-amino-serinyl-5’-amino--D-ribofuranoside derivatives-D-ribofuranoside derivatives
⇒ ⇒ unfinished strategy because of difficult functionalization of the unfinished strategy because of difficult functionalization of the ribosyl moiety and amine deprotection. ribosyl moiety and amine deprotection.
PerspectivePerspective : : ⇒ ⇒ strategy 2 : glycosylation of 2,3-strategy 2 : glycosylation of 2,3-OO-isopropyliden--isopropyliden-DD-ribofuranoside -ribofuranoside derivatives differently derivatives differently NN-protected, -protected, whose synthesis was already carried out. whose synthesis was already carried out.
. .
O OMeN3
O O
123
45O OH
HO
HO OH
123
45
functionalizationof the
ribosyl moiety O XY
O O
123
45
ACCES TO THE SCAFFOLD BY « CHAIN ACCES TO THE SCAFFOLD BY « CHAIN EXTENSION » : CONCLUSION AND EXTENSION » : CONCLUSION AND
PERSPECTIVESPERSPECTIVES
1) glycosylation
2) aminedeprotection
HOCO2tBu
NHFmoc
123
Y = PhtN-, ZHN-X = activated group
29
ACCESS TO THE SCAFFOLD BY DIRECT COUPLINGACCESS TO THE SCAFFOLD BY DIRECT COUPLING
O
PO OP
HN
NH
O
PO
O
PO
H2N
1
2
3
45
67
1'
2'3'
4'5'
1''
C B
A
O
PO OP
H2N
O O
H2N 1'
2'3'
4'5' A
HO
HN
NH
O
PO
OH
PO
1
2
3
4
5
67
C B
O
PO OP
H2N1'
2'3'
4'5'
X
5'-amino-ribose
NH2
PO
H2N
O OH
HO
L-sérine
HO
amino-dihydroxy-
butane
Y
O
PO OP
H2N
1'
2'3'
4'5'
X
5'-amino-ribose
NH2
O OH
HO L-serine
GLYCOSYLATION
N-ALKYLATION
PEPTIDECOUPLING
GLYCOSYLATION
NH2
POamino-dihydroxy-butane
HO Y
30
1,4-diazépan-2-one
NH
NH
O
PO
POC B
OH1 2
3
45
6
7
1,4-diazépan-2-one
NH
NH
O
PO
POC B
OH1 2
3
45
6
7
1,4-diazepan-2-one
NH
NH
O
PO
POC B
OH1 2
3
45
6
7
NH2
PO
amino-butanol
PO
Y
O OHO
HO
HO OHL-ascorbic acid
NH
H2N
O
PO
OH
1
2
34
5
6 7
Y
PO
N-alkylation
peptidecoupling
N-alkylationNH2
CO2H
NHPO
PO
OH
12
34
5
6
7
peptidecoupling
H2N
O
OH
HO
L-serine
CAG STRATEGY
ACGSTRATEGY
ACCESS TO THE SCAFFOLD BY DIRECT COUPLINGACCESS TO THE SCAFFOLD BY DIRECT COUPLING
Maryon Ginisty
diapo plan 5
31
CO2Et
OHO
O OTBDPS
N3O
O
azido-acetonide
FORMATION OF NFORMATION OF N11-C-C22 LINKAGE BY PEPTIDE LINKAGE BY PEPTIDE COUPLINGCOUPLING
- FIRST STEP OF THE CAG STRATEGY -- FIRST STEP OF THE CAG STRATEGY -
FORMATION OF NFORMATION OF N44-C-C55 LINKAGE BY LINKAGE BY NN-ALKYLATION :-ALKYLATION : NUCLEOPHILIC ATTACK OF AN ACTIVATED PRIMARY NUCLEOPHILIC ATTACK OF AN ACTIVATED PRIMARY
FORMATION OF NFORMATION OF N44-C-C55 LINKAGE BY LINKAGE BY NN-ALKYLATION :-ALKYLATION : NUCLEOPHILIC ATTACK OF AN ACTIVATED PRIMARY NUCLEOPHILIC ATTACK OF AN ACTIVATED PRIMARY
CARBONCARBON
40
« -stacking »interactions
O
Si
O
HN
OO
NH2H
Primary carbon atomof epoxide ring
Amine functioninvolved in
epoxide ring opening
MOLECULAR MODELING OF AMINO-EPOXIDEMOLECULAR MODELING OF AMINO-EPOXIDE
« -stacking » interactions
41
O CO2P
NHPO
O
OP
N3
CHOPO
PO
CO2P
H2N
OP
L-serineazido-aldehyde
1
3
2
4
1
23
4N3
CHOPO
POazido-aldehyde
1
23
4
OTBDPSO
OLiBH4, MeOH,Et2O, 0°C, 4h.
83%
HO
NH
NH2CHO
OPO
PO
PO
NHP
CHOPO
PO
NH2
OPO
PO
Reductive amination
NH2CO2P
NHPO
PO
OP21
34
NN-ALKYLATION BY REDUCTIVE AMINATION-ALKYLATION BY REDUCTIVE AMINATION
NH
NHPO
PO
OP
O
target diazepanone
O
CHOPO
O4
3
21
acetonide-aldehyde
CO2P
H2N
OP
L-serine
reductive amination
reductive amination
functionalizationof the diol moiety
functionalization of the diol moiety
peptidecouplingCO2Et
OTBDPSO
O(ClCO)2, DMSO, Et3N,
CH2Cl2, -78°C, 2h.
93%
CO2Et
OTBDPSN3
OTBDPS DIBAL-H (1M in toluene),CH2Cl2, -78°C, 2h.
96%
SYNTHESIS OF PRECURSORS INVOLVED IN REDUCTIVE AMINATION
1/ Aldehyde derivatives
P= TBDPS
O
CHOPO
O4
3
21
acetonide-aldehyde
42
YYARAR
8484
5858
2727
4747
YYARAR
8484
5858
2727
4747
YYZClZCl
8484
9595
YYTFATFA
7676
8383
O CO2R1
NRTBDPSO
OBn
O
O
NRTBDPSO
OBn
O
CO2R1
FUNCTIONALIZATION OF THE DIOL FUNCTIONALIZATION OF THE DIOL MOIETYMOIETY
Cl3C-C(NH)-OtBu,cyclohexane, CH2Cl2,
50°C, 3h.
100 %
BnOCO2tBu
NHFmoc
H2N
OBn
L-serine
R1O2C
N3
CHOTBDPSO
TBDPSO azido-aldehyde
1
23
4
NN-ALKYLATION BY REDUCTIVE AMINATION-ALKYLATION BY REDUCTIVE AMINATION
TFA, CH2Cl2,RT, 30 min.
100 %
TFA, CH2Cl2,RT, 30 min.
100 %
BnBr, K2CO3,DMF, RT, 3h
100 %
BnOCO2Bn
NHBoc
EtI, Cs2CO3,CH3CN,
reflux, 1h30
100 %
BnOCO2Et
NHBoc
Aldehyde Aldehyde derivativederivative
RR11
BnBn
ttBuBu
ttBuBu
EtEt
O OP
CHOOBnO
CO2Bn
NH2.CF3CO2H
BnOCO2Et
NH2.CF3CO2H
BnOCO2tBu
NH2
reductive amination
BnOCO2H
NHBoc
2/ Serinyl derivatives
N3CO2R1
NHTBDPSO
TBDPSO
OBn21
34
O
CHOTBDPSO
O4
3
21
acetonide-aldehyde
H2N
OBn
L-serineR1O2C
reductive amination
R = H
R = Z
ZCl, K2CO3, DMF, TA, 1h.
OH CO2R1
NZTBDPSO
OBn
R'O
TFA, H2O, THF,
0°C, 3h.
R’ = H
R’ = TBDPS
TBDPSCl, ImH, DMF,
0°C to RT, 15h.
1/ Tf2O, 2,6-lutidine, CH2Cl2, -78°C, 2h.
2/ NaN3, DMF, 0°C to RT, 15h.
N3 OP
CHOPO
YYN3N3
8585
--
1/ Step 12/ NaBH3CN, EtOH abs., 18 h.
1/ Step 12/ NaBH3CN, EtOH abs., 18 h.
BnOCO2H
NHFmoc
DBU, THF, RT, 2h.
100 %
SYNTHESIS OF PRECURSORS INVOLVED IN REDUCTIVE AMINATION