total synthesises of ( atrop -) abyssomicin c
DESCRIPTION
Total Synthesises of ( atrop -) Abyssomicin C. Pusheng Wang 2012/05/12. Contents. 1. Introduction 2. Sorensen’s Total Synthesis 3. Nicolaou’s Total Synthesis 4. Saicic’s Total Synthesis. 1. Introduction. - PowerPoint PPT PresentationTRANSCRIPT
Total Synthesises of (atrop-) Abyssomicin C
Pusheng Wang2012/05/12
• 1. Introduction• 2. Sorensen’s Total Synthesis• 3. Nicolaou’s Total Synthesis• 4. Saicic’s Total Synthesis
Contents
1. Introduction
HO
O
O O
OO
HO
O
O O
OO
abyssomicin C atrop-abyssomicin C
HO
O
O O
OO
Natural polycyclic polyketides isolated from the bottom (depth 289 m) of the
Japanease Sea, as secondary metabolites(次级代谢产物 ) of the Gram-
positive(革兰氏阳性 )actinomycete(放线菌 ). Antibiotic activity against Gram-positive bacteria
2. Sorensen’s Total Synthesis
E. J. Sorensen, Angew. Chem. Int. Ed. 2005, 44, 6533 – 6537.
O
O O
O
O
OMe
LiIntermolecularcarbonyl additions
HO
O
O O
OO
abyssomicin C
O
O O
OMeO
O
O
O
OMeO
IntramolecularDies-Alder
1. Stereoselective epoxidation
2. Demethylation3. Intramolecular epoxide opening
Retrosynthetic analysis
2. Sorensen’s Total Synthesis
O
Me
Me
O
O
Me MeOMe
O
MeO
O
Me MeOMe
O
HO
O
O
Me
Me O
Me MeOTESMe
O
Me MeOTES
OO
Me
TBS
Me
CHO
Me
OO
Me
TBS
1) MeOH, reflux, 24 h2) MeOH, H2SO4 (cat.), benzene, reflux, 18 h
87%, 2 steps
a-chymotrypsin, 23oC, 4 d,phosphate buffer pH 7.8
96%
LiBH4 (2 equiv), THF, 50 oC, 5 h;then HCl, H2O, 23 oC, 15 h
60%, 93% ee
1) MeLi (1.3 equiv), THF, -78oC, 1.5 h2) TESCl(1.1 equiv), imidazole (2 equiv), DMF, 0oC, 1.5 h
1) LDA, THF, -78oC, 2.5 h; then trans,trans-2,4-hexadienal(1.1 eq.), 1.5 h (94%, d.r.=1:1);2) TBSOTf (1 equiv), 2,6-lutidine (2 eq.), CH2Cl2, 0oC, 0.5 h (85%);
(COCl)2 (5 eq,), DMSO (10 eq,), Et3N(10 eq,), DCM, -40 ~ -78 oC, 5 h
60-70%
2. Sorensen’s Total Synthesis
Me
CHO
Me
OO
Me
TBS
O
OMe
OMe Me
OO
Me
TBSOH
OO
OMe
Me Me
OO
Me
TBSO
OO
OMe
LDA, toluene, -78oC, 6 min; then aldehyde, 1.5 h35–55%, d.r.=1:1
DMP (1.5 equiv),CH2Cl2, 0-23oC, 1.5 h
84%
Sc(OTf)3 (5 mol%), DCM, 0oC, 40 min
Me Me
O
Me
O
OO
OMe
65%
2. Sorensen’s Total Synthesis
Me Me
O
Me
O
OO
OMe
Me Me
O
Me
O
OO
OMeOTBS
Me
MeO
O
O
OMe
OMe
Sc(OTf)3 (5 mol%), DCM, 0oC, 40 min 65%
toluene, 100oC, 4 h
79%
HO
O
O O
OO
abyssomicin C
O
O O
OMeO
one-pot process
La(OTf)3 (10 mol%),toluene, 100oC, 4 h 50%
1) DMDO (1 eq.), acetone, 0-23oC, 18 h 2) LiCl(10 eq.), DMSO, 50oC, 2 h
67%O
O O
OHO
O
p-TsOH (1.2 eq.),LiCl(5 eq.),CH3CN, 50oC, 2 h
DMDO = dimethyldioxirane = OO
15 steps, 0.3% yield
3. Nicolaou’s Total Synthesis
HO
AcO O
HO
O
O O
OO
abyssomicin CSPh
MgCl
Ac2O
O
OMe
K. C. Nicolaou, Angew. Chem. Int. Ed. 2006, 45, 3256 – 3260.
Retrosynthetic analysis
3. Nicolaou’s Total Synthesis
N
O
MeMeO
MeMePhS
OH1) PhSCH2Li
2) (R)-CBS, catecholborane
OH
N
OMe
O
+ MeMgBr
Me
OPhS Mg
OOMe
OMg
R2N
++++
++
OO
Me
H
H
PhSLiHMDS(EtO)3P, O2
OO
Me
OH
H
PhSLi, (4-tBu-C6H4)2K2CO3, MeIMeO2C
Me
OH1) VO(OEt)3 tBuOOH
2) Ac2O, Et3N DMAP
MeO2C
Me
O
O
1) LiHMDS aq. NH4Cl2) TESCl, imid.
Me O
Me
O
O
O
TES
O
OO
Me
Me1) tBuLi;
2) (CH2SH)2, TMSOTf O Me
O
O
O
Me
MgCl
TES
Me
HOS
S
1) IBX
2) O Me
O
O
O
Me
TES
Me
HOS
S
3. Nicolaou’s Total Synthesis
HO Me
O
O
O
MeMe
HOS
SN NMes Mes
RuCl
Cl
PCy3Ph
1)
2) IBX
PhI(OTFA)2
HO Me
O
O O
OO
MeMe
atrop-abyssomicin C
HO
O
O
OO
MeMe
S
S
HO
O
O O
OO
MeMe
abyssomicin C
CHCl3, 25oC, 24h,
HO
O
O O
OO
MeMe
atrop-abyssomicin C
HO
O
HO O
OO
MeMe
O
O OH
OHO
MeMe
HO
1:2
4. Saicic’s Total Synthesis
Radomir N. Saicic, Angew. Chem. Int. Ed. 2012, 51, 1 – 6.
Retrosynthetic analysis
HO
O
O O
OO
abyssomicin C
Nozaki–Hiyama–Kishi coupling
organometallic addition
PGO
O
O
O
Intramolucularetherification
Dieckmann condensation
PGO
O
O
OH
OH
PGO
Enolate-hydroxylation
CO2EtIntramolucularalkylation
OPGPGO
CO2Et
OPG
X
Wittigolefination
AldolAdditon
OHCO N
OO
OPGBn
+
4. Saicic’s Total Synthesis
O OBn
O
N O
OOTBDMS
OBnOH
OH
OBnN O
O O
OTBDMS
OBn
CO2EtOTBDMS
OBnBr
OTBDMS
OBnBr
OHC
CHO
OTBDMSBnO
OTBDMSBnO
NL2Pd
+
1) nBu2BOTf, Et3N, DCM, -78oC;2) H2O2, MeOH, phosphate buffer
77%
1) TBDMSOTf, DCM, sym-collidine, 0oC; 2) NaBH4, THF, H2O
86%
DMP, DCM, RT, then Ph3P=CHCO2Et 82%
1) DIBAL-H, Et2O, -40oC; 2) CBr4, Ph3P,DCM, 0oC
81%
1) mCPBA, DCM, RT; 2) H5IO6, Et2O
[Pd(PPh3)4],THF, pyrrolidine, RT
sym-collidine :
N
4. Saicic’s Total Synthesis
CHO
OTBDMSBnO
OTBDMSBnO
OTIPS O
OTBDMSBnO
OTBDMSBnO
HO
C(OEt)3
OHBnO
O
O
OMe
BnO
O
O
O
TIPSOTf, Et3N, DCM, reflux
99%
mCPBA, DCM ; then H5IO6, Et2O
87%
88%
Nafion-Hg, MeOH, H2O then: HF, MeCN, 60oC
74%
C(OEt)3
Li
OH
BnOMe
O
OOMe
TBDMSO OBn O
)( Nu
Nu
4. Saicic’s Total Synthesis
OTBDMSBnO
HO
C(OEt)3
BnO
O
O
OHF, MeCN, 60oC
OHBnO
HO
C(OEt)3
85%
1) [(PPh3)AuNTf2] (10 mol%), iPrOH, 70oC;2) hv (254 nm), iPrONa
60%
O OBn
OH(EtO)3C
HO OBn
OH(EtO)3C
HLAu
O OH
OBn
HEtO2C
hv O OH
OBn
CO2EtH
254nm
HO O
OBn
AuLEtO2C
PT, -LAu+
LAu+
H
4. Saicic’s Total Synthesis
BnO
O
O
O
CHOTBDMSO BnO
O
O
O
OMOM
TBDMSO
BnO
O
O
O
OMOM
TBDMSO
I
BnO
O
O
O
OMOM
O
IO
O OH
OHO
+
1) tBuLi, THF, -78oC;2) aldehyde, -78oC to -40oC;3) MOMBr, -40oC to -25oC
O3, DCM, -78oC; then Me2S; then DBU (30 mol%)
44%
BnO
OO
O
O
OMOM
TBDMSO
CrCl2, CHI3,THF, RT to 50oC
1) HCl, MeOH2) DMP, DCM, RT
CrCl2, NiCl2, DMF,RT to 45oC
BnO
4. Saicic’s Total Synthesis
BnO
O
O O
OO
O
O OH
OHO
BnO
HClaq, MeOH, RT; then DMP, DCM
HO
O
O O
OO
HO
O
O O
OO
BBr 3, DCM, RT
atrop-Abyssomicin C Abyssomicin C
H2 , Pd/C, EtOAc
SO
Cl O
OCl SO O
OCl
ClS
ClCO2 CO Cl+ ++
ROH
SO
Et3N
R1 R2
HSO
H R2
R1
O
R1 R2Me2S+
Swern Oxidation
OO
OMe
OO
Stereoselectiveepoxidation
H
MeO
PhS
OO O
P(OEt)3
OO
Me
OH
H
PhSLi, (4-tBu-C6H4)2K2CO3, MeIMeO2C
Me
OH
Li LiO
O
Me
OH
H
PhS+
OO
Me
OH
H
Li
LiO2C
Me
OHK2CO3, MeI
MeO2C
Me
OH
SS
R1
R2
I
R1 R2
O
S S
R1R2
Ph IOTFA
OTFA OTFAPh OTFA
IS S
R1R2
OTFAPh OTFA
H2O
IS S
R1R2
OTFAPh OTFA
OH2
O OBn
O
N O
O
Bn
OH
OBnN O
O O
Bn
+
1) nBu2BOTf, Et3N, DCM, -78oC;2) H2O2, MeOH, phosphate buffer
77%
R =
OBn
O
NO
O
Bn
OBBu2
NO
O
Bn
OBn
OBBu2
N
OOBn
OBn
RO+
OH
OBnN O
O O
Bn
O
BO
OBn
R'
nBu
nBu
R
Me
H
R' = N O
O
Bn
TBDMSO OBn
N
L2Pd
TBDMSO OBn
NL2Pd
VS
Thank you for your attention!