total synthesis of (+)- pleuromutilin · total synthesis of (+)-pleuromutilin neal j. fazakerley,...
TRANSCRIPT
Total Synthesis of (+)-Pleuromutilin
Neal J. Fazakerley, Matthew D. Helm
and David J. Procter
University of Manchester UK Chem. Eur. J. 2013, 19, 6718–6723
O
OH
OO
OH
H
Introduction – Pleuromutilin
3
• Fungal secondary metabolite (+)-Pleuromutilin was first
isolated from Clitopilus passeckerianus in 1951 by
Kavangh and co-workers
• Antibacterial acitivity through a novel mode of action
involving binding to the prokaryotic ribosome
• First enantiospecific total synthesis of natural compound
by David Procter
• Two racemic synthesis by Gibbons (JACS 1982) and
Boekman (JACS 1989)
• Two elegant routes to the trycyclic core by Zard (Org.
Lett. 2003) and Sorensen (Chem. Commun. 2011)
Introduction – Pleuromutilin Analogues
4
• Analogues derived by semi-synthesis from pleuromutilin, including tiamulin (2; Denegard® by Novartis Animal Health) and retapamulin (3; Altargo® by GlaxoSmithKline)
O
OH
OO
R
H
1, R = OH
3, R =
2, R =S
N
N
S
à Abstract of INN register (International Nonproprietary Names) by WHO
Key Step of Racemic Total Synthesis by Boeckman and co-workers
5
Sterically demanding oxy-Cope re-arrangement of tricyclic vinyl carbinol which could arise via a stereoelec- tronically controlled 1,6-addition/alkylation of a suitable derivative of dienone
R. K. Boeckman et al. J. Am. Chem. Soc. 1989, 111, 8284.
OHbase O- O- O
99%
racemic Pleuromutilin
O
OTs
Route to Tricyclic Core of Pleuromutilin by Samir Z. Zard
6
CO2H
CO2Et CO2Et
O SePh Radical InitiatorSnBu3
H
CO2Et
O
OO
OS
S
OEt
Radical Initiator
OO
O
SS
EtO
O
OH
OO
OH
H
O
OOH
OHO
Org. Lett. 2003, 5, 325-328.
Synthesis of the Cascade Cyclisation Substrate
8
(a) S. L. Schreiber J. Am. Chem. Soc. 1980, 102, 6163.
O
ref. (a)
O
1) TBSO MgBrCuCN 2LiClthen TMSCl
2) Pd(OAc)2, O2
85% (95% ee, chiral HPLC)
OTBSO
TBSO
TMS
3) CuI then Comins' reagent 85%
MgBrTMS
4) Pd(OAc)2, PPh3, Et3N, MeOH, DMF, CO 85%
CO2Me
d.r. 2.5:1TBSO O
BF3 Et2O
TBSOCO2Me
TBSO OH
d.r. 1:1
OCO2Me
OPivO5) PivCl, DMAP6) HF7) DMP
88% for 3 steps73%
d.r. 2.5:2.5:1:1
4)
SmI2-mediated Cyclisation Cascade
9
OCO2Me
OPivO
SmI2 (2.5 equivalent)
88%
MeO2C OHHHO
OPiv
HO
OMe
OPivO
O
H
SmIIIO
OPivO
OOMe
SmIII SmIIIO O
OPiv
H
O OMeSmIII
anti radical cyclisation selective enolate formation chelation-controlledaldol-cyclisation
Procter et al. ACIE 2009, 48, 9315.
Protection/Deprotection, Reduction of Double Bond
10
MeO2C OHHHO
OPiv1) TBSOTf
MeO2C OTBSHTBSO
OPiv
76%
d.r. 2.5:2.5:1:1
2) LiAlH4, rt3) DMP
63%
MeO2C OTBSHTBSO
O
(> 98% ee, chiral HPLC)
4) Pd/C, H2
MeO2C OTBSHTBSO
O
d.r. 3:1, but major was isolatedin 75% yield
Reduction of C5 Methyl Ester
11
Reduction of hind. esters with SmI2: D. J. Procter Chem Commun 2011, 47, 10254.
MeO2C OTBSHTBSO
O
MeO2C OTBSHTBSO
O
O ethanediol, HC(OCH3)3, amberlyst 15 (cat.)
99%
1)
2)LiAlH4reflux
OHHHO
O
O
HOOTBSHHO
O
O
HO
3)MeO OMe
, CSA4) TBSOTf5) PPTS
54% for 4 steps
1st generationMeO2C OTBSHTBSO
O
MeO2C OTBSHTBSO
O
O ethanediol, HC(OCH3)3, amberlyst 15 (cat.)
99%
1)
2)LiAlH4reflux
OHHHO
O
O
HOOTBSHHO
O
O
HO
3)MeO OMe
, CSA4) TBSOTf5) PPTS
54% for 4 steps
MeO2C OTBSHHO
O
O
6) ethanediol, HC(OCH3)3, amberlyst 15 (excess)
96%
7) SmI2/pyrrolidine/H2O95%
1st generation 2nd generation
8) LDAthen MBzCl
OTBSHR1O
O
O
R2OR1 = MBz, R2 = H, 77%R1 = H, R2 = MBz, 20%
9) NaOMe99% OTBSHMBzO
O
O10) TCDI11) nBu3SnH, AIBN
66%
S
NNNN
TCDI = 1,1'-Thiocarbonyldiimidazole
Elaboration of the Eight-Membered Ring
12
OTBSHMBzO
O
O
OTBSHMBzO
O1) FeCl3 SiO2
99%
2) HMDS, TMSI3) NaHCO3, mCPBA4) TBAF
94 %
OTBSHMBzO
OOH
5) HF(aq)
OHHMBzO
OOH
78%6) MOMCl
75%
OMOMHMBzO
OOMOM
OMOMHMBzO
OMOM
OH
7) SnBu3EtO
nBuli, then addition of ketone
8) FeCl3 SiO29) NaBH4
63% for 3 steps
10) NCS, DMS97%
OMOMHMBzO
OMOM
Cl 11) CuCN, ZnMe271%
OMOMHMBzO
OMOM
single diastereoisomer at C12
12
OHHO
OH12) LiAlH413) DMP14) AcCl
69% for 3 steps
(+)-mutilin
Completion of the Synthesis
13
OHHO
OH
(+)-mutilin
O
OHO
OF
FFN
HN
O
F F
F
OHHO
O
CF3O
EDCI, DMAP
then MeOH, Et3N
OHO
OH
O
OH
(+)-Pleuromutilin
75% for 2 steps
Conclusion
14
• First entantiospecific total synthesis (but long)
• Key Steps including SmI2: 1) SmI2-mediated cyclisation cascade 2) SmI2/pyrrolidine/H2O-based ester reduction
• Efficient conversion of (+)-mutilin to (+)-pleuromutilin
• This approach is currently being used to expand the pleuromutilin class of antibiotics through the synthesis of novel analogues that are inaccessible from the natural compound
S. L. Schreiber J. Am. Chem. Soc. 1980, 102, 6163.
16
i)Transfer of an electron from Fe2+to peroxide to form oxy-radical ii) Fragmentation to form carbon-radical iii) Oxidative coupling with Cu(OAc)2 iv) β-elimination
O OO
OOHMeOO3, MeOH Cu(OAc)2, FeSO4
Fe2+
Fe3+
O
OMeO
O O
[Cu]
i)
ii) iii)
iv)