johann mulzer group meeting - scripps research...cl 1) cl 2, acoh 2) (cocl) 2 3) sncl 4 70% 1)...
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Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
Prof. Dr. Johann Mulzer, born August 5th, 1944 in Prien/Chiemsee (Germany)Education1969: Diploma in chemistry, University of Munich (LMU)1969-1974:
1974-1975:
Academic Career1980-1982:1982-1984:1984-1995:1995-1996:1996-2012:
Postdoc, Harvard University,(with E. J. Corey)
Assistant Professor, University of MunichAssociate Professor, University of DüsseldorfFull Professor,Free University of BerlinFull Professor, University of FrankfurtFull Professor, University of Vienna (Austria)
Selected Awards and Memberships1981: Grant for a University Lecturer in Chemistry, Chemical Industry Fund (FCI)1983: Jost Henkel Memorial Prize1994: Leibniz Prize, German Research Foundation (DFG)1997: Ernst Schering Prize, Ernst Schering Research Foundation1999: Erwin Schrödinger Prize of the Austrian Academy of Science2002: Member of the Austrian Academy of Science2010: Emil-Fischer-Medaille, Gesellschaft Deutscher Chemiker (GDCh)
Publications (as of December 2013)
321 publications49 reviews13 patentsmany books and book chapters
Disclaimer: this presentation represents a presonal selection of the published work of Johann Mulzer and is not intended to be comprehensive by any means.
The early days in Munich:
2-thietanimines from α-deprotonated β-lactones and phenyl isothiocyanateAngew. Chem. Int. Ed. 1980, 19 , 466–467.
OO
i-Pr
LDA-78 °C O
O
i-PrPh
PhN=C=S-78 °C O
O
i-PrPhPh
SNPh
Ph.D., University of Munich (LMU),(with Rolf Huisgen)
OSFO
OMe
OO
i-Pr Ph
MeSNPh
20 °C
SNPh
i-Pr CO2–
PhH2O
- CO2SNPh
i-Pr PhOSFO
OMe
SNPh
i-Pr CO2MePh
- CO2
Phi-Pr
SHPhN
H2OPhi-Pr
SPhHN
MeI
Phi-Pr
SMePhN
+Phi-Pr
PhNS
Me
N-phenylthietanimine
A
B
A:B = 63:37
Decarboxylative dehydration of β-hydroxycarboxylic acidsAngew. Chem. Int. Ed. 1977, 16 , 255–256.
LiOLi
OO
R1 R2+
OLi
O
R1
OLi H2O
R3 R4 R2R3 R4
OH
O
R1
OH
R2R3 R4
PPh3DEADR1
R2 R4
R3- mild conditions- easy workup- low cost of reagents
new olefin synthesis
→ methodology expanded to synthesis of 1,3-dienes: Tetrahedron Lett. 1978, 19 , 2953–2954.
"Die Guad'n haltens aus!" (Mulzer)
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
Some work from the Düsseldorf, Berlin and Frankfurt period:Diastereo- and enantioselective synthesis of chrysanthemic acid methyl esterAngew. Chem. Int. Ed. 1983, 22, 63–64.
O
H
OO
NaH,MeO2C P
O
OEtOEt
H
OO95%
CO2MePPh3
THF
60%
H
OO
CO2MeH
OO
CO2Me+
KOH, MeOH
H
OO
CO2HH
OO
CO2H+
crystalline
separation
quant.CH2N2, Et2Oquant.
OH
CO2Me
H
H2SO4, THFNaIO4
95%
PPh3
THF64%
HCO2Me
H(1R,3R)-chrysanthemic acid
methyl ester
13
6 steps24% overall yield
Synthesis of optically active building blocks from (R)-2,3-isopropylidene glyceraldehydeTetrahedron Lett. 1983, 24, 2843–2846.
H
O
OO
1) RM2) NaH, BnCl
R = Ph, Me, n-butyl, allylM = Li, MgBr, Zn, Ti(Oi-Pr)3
R
OBn
OO
R
OBn
OO
R
OBn
O
H1) H2SO42) Pb(OAc)4
alcohol
acid
diol
separated by column chromatography
(S)
R
OBn
O
H
alcohol
acid
diol(R)
concrete example: OBn
OOmultigram quantities,
d.r. = 91:9
OBn
O
ozonolysis O
OBn
OO
H
- related to the family of pyrethroid insecticides- (1R)-configuration important for physiological activity
First total synthesis of (–)-ACRL Toxin III BAngew. Chem. Int. Ed. 1993, 32, 1452–1454.
- ACRL toxin III A present in a fungus which causes brown spot disease on citrus- unknown mechanism of action
Retrosynthesis:
OH
Me
OH OH
Me
O
O
OR
R = H: R = Me:
ACRL toxin III AACRL toxin III B
Me Me
O
Me
OTrCBr2
PPh3
O
Me
OTHPO
O
OMe
Total Synthesis:
1 2 3 4 5
1
i-BuMgCl[Cp2TiCl2]
then 2OH
OTrMe
78%
OPMB
Me
Li
1) NaH, PMBCl2) ZnBr2, DCM3) Swern4) CBr4, PPh3, Zn5) n-BuLi
52%
(d.r. = 1:1) 1) 42) LiAlH4
57%
OPMB
Me
OH
OTHPMe
(d.r. = 1.8:1)
PMBO
Me
TBDPSO
OMe
1) TBDPSCl2) p-TsOH3) Swern
73%
H
6
99% ee
1) H2SO42) Pb(OAc)4
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
OH
Me
OH OH
Me
O
O
OMe
1) 5, KHMDS -100 °C2) DDQ then TBAF
6
(–)-ACRL toxin III B16 steps LLS1.3% overall yield
36%
Synthesis of a Vitamin B12 A–B-semicorrinJ. Am. Chem. Soc. 1997, 119 , 5512–5518.
N
N
N
NMe
H
Me
Me
Me
O OH
CONH2
CONH2H2NOC
H2NOC
H2NOC
CONH2
Co
OH
CN
N
N
N
N
Me
Me
Me
CN
CONMe2MeO2C
MeO2C
MeO2C
CO2Me
Co CO2Me
Retrosynthesis:
A B
CD
cobyric acid
N HNONC Me
FG
Me
FG FG
Me
FG
A BHN
O
FG
Me
FG
BNH
OMe
FG
FG
A
Forward Synthesis:
O
OO
OPMBLi P
O
OEtOEt
O
O
OPMB
LiOP
OEtOEt
O
O
OPMBOTr
3
TrOO
H3
H2O
58%see THL, 1996, 37, 9177–9178.
1) MeMgCl2) KH, Bu3SnCH2I
74%
OPMBO
Me OSnBu3
OTr
1) n-BuLi2) TBSCl3) DDQ
81%
OH
OTr
OTBSE/Z > 100:1see THL, 1994, 35, 9021–9024.
NMe2
MeO OMe98%
OTr
OTBS
CONMe2
Me
1) mCPBA2) LAH3) TrCl4) Pb(OAc)4 O
OTr
OTBS
OTrMe 1) TBAF
2) PDC
O O
TrO
Me
OTr
HO
1) MsCl, DIPEA2) NH33) 110 °C
99%
90%
NH
O
TrO
Me
OTr1) KCN2) Lawesson
88%NH
S
TrO
Me
OTr
NCMe
1) A, (PhCOO)22) P(OEt)3
38%
N HNONC Me
TrO
Me
TrO TrO
Me
OTr
A B
67%
- cobyric acid- siroheme- factor 430
16 isolated intermediates7% overall yield
vitamin B12 A–B semicorrin
seeEschenmoser
A
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
(–)-MorphineAngew. Chem. Int. Ed. 1996, 35, 2830–2832.
Total Synthesis:
MeO
MeO
CO2H
MeO
MeO
O
Cl1) Cl2, AcOH2) (COCl)23) SnCl4
70%
1) HCO2Me, NaOMe2) a) MVK, Et3N b) KOH, dioxane
73%
MeO
MeO Cl
O
H
enantiomers resolvedby chromatography
on cellulose triacetate
(H2C=CH)2CuMgCl-78 °C to 0 °C then TMSCl, Et3N thenNBS, THF, -78 °C
84%
MeO
H
O
MeOBr
ClOMe
OMe
Cl
Br
O≡
DMF, 140 °Cquant.
MeO
HO
O
Cl 1) TMSCl, (CH2OH)22) a) BH3·Me2S, THF b) H2O2, OH–
3) Ra-Ni, MeOH, KOH
MeO
OH
HO
O
O
1) PhSO2NHMe ADDP, Bu3P2) NBS, (PhCOO)2 CCl4, reflux
63%
MeO
HO
O
ON MeSO2Ph
1) Li, NH32) 3N HCl
53%
75%
MeO
NMe
HO
O(–)-dihydrocodeinone
Rapoport, Rice etc.
HO
NMe
HO
HO(–)-morphine 11 steps
11.5% overall yield
The Vienna Era: (±)-desamino huperzine A Tetrahedron Lett. 2000, 41, 9229–9232Retrosynthesis:
HN O
Me
Me
R = NH2: huperzine AR = H: desamino huperzine A
R
O
O
O
O
O
O OO
Total Synthesis:
O
O O
EtONa, EtOH
OCO2MeMeO2C
O
OHO
O CO2Me
CO2Me1) LiOH, DMF, Δ2) Ph3P=CH2 OH
O
O CO2Me
Pd/C, H2EtOH
Me
OHO
O CO2Me
1) DBU, DMF2) LiBr, DMF
CNMe
OO
OCN
HN O
Me
O
O
1) NH3, MeOH2) SO2Cl2, DCM
1) H2SO42) Ph3P=CHMe3) PhSH, AIBN PhMe H
N O
Me
MeR E/Z = 1:1
(±)-desamino huperzine A
69% over3 steps
68%
42%85%
76%
10 steps LLS13% overall yield one protecting group
- huperzine A is a AChE inhibitor and a potential lead for treatment of Alzheimer's disease- great potential in synthetic derivatives of huperzine A
→ synthesis and biological activity of more derivatives: BMCL 2001, 11 , 2627–2630.
13
(d.r. = 3:1)
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
Epothilone BAngew. Chem. Int. Ed. 2000, 39, 581–583.
O
O OH OMe
OHMe
O Me
S
N
epothilone B
aldol additionmacrocyclization
Me
OPG
OMe
O Me
S
NMe
TBSO O
H
Wittig HornerO
CO2EtOPG
O
OEtOPMB DIBAL-H; MgBr2·OEt2
then allyl-MgBr
92%OH
OPMB1) TBSCl, im2) O33) isopropenyl-MgBr
(d.r. = 9:1)
84%TBSO
OPMB
OH95%
EtO OEtEtO , Et
O
OH(cat.)xylene, 140 °C
OTBS
OPMB
CO2Et1) DDQ2) Swern ox.91%
OTBS
O
CO2EtAD-mix-β
TBSO
O
CO2EtOH
OH
P+n-Bu
n-Bun-BuS
NCl-
KHMDS
(78–85%)
TBSO
S
N
OHO
Me
O
TBSO
S
N
OHO
Me
O
+
1) MsCl, Et3N2) K2CO3, MeOH; H2O; 1N HCl
84%
B CB:C = 3:1
1) MsCl, Et3N2) K2CO3, MeOH
91%
TBSO
S
N
OMe 1) DIBAL-H
2) LiOH,N
SO O
O(EtO)2(O)P
86%TBSO
S
N
OMe
O
X*
TESO
S
N
OMe
O
H
A
1) L-selectride, then MeI, HMPA2) a) TBAF, THF b) TESCl, Et3N, DMAP3) DIBAL-H
Me62%
(d.r. > 99:1)
TESO
S
N
OMe
CO2Me
OTBSO
1) LDA, A2) Troc-Cl, py86%
HO
S
N
OMe
OHO2C
TBSO
1) a) OsO4, NMO b) NaIO4, EtOH2) HF·pyridine, py3) Pinnick oxidation
63%
1) Yamaguchi2) Zn, NH4Cl3) HF·pyridine
epothilone B
O
O OH OMe
OHMe
O Me
S
N 40%
- epothilones are antitumor compounds that inhibit microtubule function- aza-epothilone B (ixabepilone) was FDA-approved in 2007 for the treatment of aggressive metastatic breast cancer
→ subsequent work about epothilones and derivatives: THL 2000, 41, 7635; JOC 2000, 65, 7456; Chem. Eur. J. 2001, 7, 2261; OL, 2005, 7, 1311; JOC, 2006, 15 , 3372.
OTrOTr
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
OOH
O O
OH
Me
O
OHH
OOMOM
O O O
O Me
MePO
F3CH2COC
F3CH2COC
OH
MeH
TMS
H
O
allyl transfer
Still-Gennaricoupling
COOEt
HO
O
Me1) BH3·Me2S2) DMP3) (–)-Ipc2B-allyl
83%
COOEt
HO
Me1) Et2NH2) acrolein-diethyl -acetal, TsOH
90%
CONMe2
O
Me
EtO
Grubbs(4 mol%)87%
CONMe2
O
Me
EtO
1) , LiClO42) NaBH43) TESCl, py4) MeLi5) KHMDS, PhNTf2
O
Me
OTf
OTES
O
Me
O
TMS
H
60%
1) Pd(PPh3)4, LiCl
OTBS
TMS MgBr2) K2CO3, MeOH3) DMP
85%
B
prepared 5 steps
OO
HH O
PMeOMeO
O
OTHPOTBDPS
prepared in 6 steps
1) LiOH2) NaBH4, CeCl33) MOMCl, DIPEA4) HCl, MeOH5) Red-Al
OH
OH
OMOM
OTBDPS
40%
OH
OMOM
O O
P(O)(OCH2CF3)2
O
O1) DMP2) OH OH
3) TBAF4) *
OP
F3CH2COF3CH2CO
O
Cl
*
76%
LaulimalideJACS 2001, 123 , 10764–10765.
laulimalide
A B
Retrosynthesis:
Total Synthesis:
A
AKHMDS, then B
O
Me
OMOM
O O
OH H
O
O Me
MeTMS
Me
O
Me
OH
O O
OH
Me
O
OHH
laulimalide
1) EtAlCl22) DMP3) TsOH4) Me2BBr5) SAE
2
3
31%
19 steps LLS21% overall yield1st fully stereocontrolled synthesis
- laulimalide is a metabolite from marine sponges that promotes abnormal tubulin polymerization- displays unusually high activity against multidrug resistant cancer cell lines
82%
→ subsequent work about laulimalide and analogs: THL 2002, 43, 3381; JOC 2003, 68, 3026;OL 2008, 10 , 4701; Chem. Eur. J. 2009, 15 , 5979; THL, 2009, 50, 5790.
+
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
Me
O
OMe
OH
Me
Me
Me
H H
elisabethin A
Me
O
OMe
OMe
Me H H
Me Me
O
OMe
OMe
MeMe
Me
MeIMDA
H
O
MeOMe
OMe
1) mCPBA2) NaOH
97%
OH
MeOMe
OMe
1) CAN2) Na2S2O4
OH
HOMe
OMe
1) TBSCl2) NBS
94%
97%
OTBS
TBSOMe
OMe
Br
O
OEtBu3Sn
ZnBr2PdCl2(o-tol3P)2
71%
OTBS
TBSOMe
OMe
EtO O
1) DIBAL-H2) Swern3) Pinnick
OTBS
TBSOMe
OMe
HO2C
O
LiN OBn
PivCl then
OTBS
TBSOMe
OMe
N O
OO
Bn91%
TrO O
H
Me
NO
OMeMe
PO
EtOEtO
93% TrOMe
O
NOMeMe 1) DIBAL-H
2) Ph3P=CHMe
76%
TrOMe Me
1) BCl32) I2, PPh3
77%I
Me Me
A
B
A
NaHMDSthen B69%
OTBS
TBSOMe
OMe
O
*X Me
Me
(de: 86%)
OTBS
TBSOMe
OMe
Me
Me
MeMe
1) LIBH42) Swern3)
Ph3PMe
Me
86%
TBAF thenFeCl3
91%
O
OMe
OMe
MeMe
Me
Me
Me
O
OMe
OMe
Me H H
Me Me
1) Pd/C, H22) NaOH3) BBr3
27%
Me
O
OMe
OH
Me
Me
Me
H H
elisabethin A
Elisabethin AJACS 2003, 125 , 4680–4681.
Retrosynthesis:
- isolated from the Carribean gorgonian Pseudopterogorgia elisabethae- some members of the elisabethane class show significant activity agains Mycobacterium tuberculosis
Total Synthesis:
17–20 steps LLS7% overall yield
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
(–)-OvalicinAngew. Chem. Int. Ed. 2007, 46, 2690–2693
Retrosynthesis:
O
OOMeOH
O
(–)-ovalicin
O
OPG1OMe
OPG2BrOHC
OPG2 CHO
Br
OPG2
Total Synthesis:
O
OPh
OMeCHO
Br
BF3·OEt2, DCM-78 °C
BrOHCO
75%O
OMe
Ph
BrOH
HOBH3·NH3
89%
1) p-MeOC6H4CH(OMe)2 CSA, DCM2) DIBAL-H, DCM
84%
BrOPMB
HOO
OHOH
OPMB1) NaH, THF2) OsO4 (1 mol%) NMO
90%
1) TBSCl, im2) NaH, MeI3) DDQ
78%
O
OTBSOMe
OHDMP
92%
O
OTBSOMe
O
A
OH
SnBu3
1) NBS2) DMP
93%
O
Br
NN N
NPh
SO
O
LHMDS, -78 °C
70%
BrB
O
OTBSOMe
O B, t-BuLiEt2O, toluene
76%
O
OTBSOMeOH
1) TBAF2) DMP85%
O
OOMeOH
O
OOMeOH
O
(–)-ovalicin
[VO(acac)2]t-BuOOH, benzene
71%
15 steps LLS15% overall yield
- ovalicin and the structurally closely related fumagillin show potent antiangiogenic activity- ovalicin is also a promising agent against microsporidiosis
OH
HO2COH
NH
OMe
O
O
Meplatensimycin
Formal synthesis of platensimycinAngew. Chem. Int. Ed. 2007, 46, 8074–8075.
O
O
MeNicolaou's keyintermediate
OMe
O
Retrosynthesis:
- originally isolated by a Merck group from a strain of Streptomyces platensis- inhibits β-ketoacyl-ACP synthase I/II (Fab F/B) which is involved in fatty acid biosynthesis- its novel scaffold and extraordinary antibacterial activity have drawn great attention
123
4
(d.r. = 8:1)
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
O
O
OMe
O
NN
H+
O
O
NN
Mevia:
know intermediate, multigram quantitiessequence to A requires only one column
O
O
1) MeMgI, THF, -78 °C2) NBS, (BzO)2, CCl4
O
HO
Br
HMe
O
HO
Br
HMe
53%
NaOMe
80% O
O
Me
[Ir(cod)Py(PCy3)]PF6H2 (1 bar), DCM
O
MeO
MeO
O
H
78% (brsm)
B CB:C = 1.3:1
HIO3·DMSO
60%O
O
Me
A
5 steps from A20% overall yieldprotecting-group free
OMe
O
Total Synthesis:
$2/g
OMe
HOOC6-methoxy-1-tetralone
1) NaBH4, EtOH2) POCl3, DMF3) AgNO3, NaOH, EtOH4) Pd/C, H2, EtOH
85% 1) SOCl22) TMSCHN23) TFA, -20 °C
59%
Formal synthesis of (–)-platencin Angew. Chem. Int. Ed. 2008, 47, 6199–6200.
OH
HO2COH
NH
OMe O
H
Retrosynthesis:
platencin
OH
AB
C
Total Synthesis:
CHO
(–)-perillaldehydecommercially available
+
TBSO
NMe2
Rawal diene
toluene, Δthen HCl H
CHO
O
O
HB
68%
(d.r. = 20:1)
Ph3PMeBrt-BuOK80%
HO
Grubbs IIDCM, Δ
OHNBS
t-BuOH
OH
BrCrCl3LAH
48% (over 3 steps)
+
OH
A
(1:3 mixture)
OH
HO2COH
NH
OMe O
H7 steps
A
5 steps26% overall yieldprotecting-group free
(see Nicolaou: ACIE 2008, 47, 1780–1783)
platencin
commonintermediate
- isolated along with platensimycin- exhibits broad-spectrum antibacterial activity against many pathogens that show resistance to current antibiotics
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
Total synthesis of (–)-platencin J. Org. Chem. 2009, 74, 2937–2941.
OH
previous intermediate
1) TFA, DCM then aq. KOH2) Martin's sulfurane
77%
OH KHMDS, MeI
HMPA, THF
87%
OHMe
t-BuOKmethyl acrylate 52%
O
H
MeMeO2C
1) NaOH, THF2) B, DCC, DMAP Et3N, MeCN
56%
OH
HO2COH
NH2
B:
OH
HO2COH
NH
OMe O
H
9 steps10% overall yield
Kendomycin Angew. Chem. Int. Ed. 2009, 48, 6032–6036.
- antitumor macrolide first isolated in 2000 from the bacteria Streptomyces violaceoruber- potent endothelin receptor antagonist and antiosteoperotic compound with remarkable antibacterial and cytostatic activity
O
Me Me
HOO
O
OHMe
Me
HOMe
kendomycin (1)
JACS, 2004,126 , 14720
O
Me Me
HOOMe
O
Me
Me
HO
Photo-Fries
Me Me
OOMe
O
Me
O
O
O
Me
Me
1516
8
9
Claisen-Ireland
Evans
Me
OH
TBDPSO 4
N
OO
O
OMe
Bn
6MOMO
OMe
O
Me
O
OH
5
Photo-Fries approach:
Total Synthesis:
H
OMe
OTBDPS
TMSCHN2n-BuLi, THF-78 °C to rt
83%
Me
OTBDPS
[CpZrHCl]benzene, I2
76%
Me
OTBDPS
I
MOMOOMe
MeTBDPSO
[Pd(PPh3)4]t-BuLi, ZnCl2
Br
OMOM
MOMOOMe
MeOTBDPS
OMOM
OR
ROOMe
R = MOM
67%
O
1) DMDO2) Pd(OAc)2 PBu3, t-BuOH
80%
MOMOOMe
O
MeHO2C
MOMOOMe
O
MeHO1) TfOH, 4Å MS
2) MOMCl3) TBAF
80%
5
1) IBX2) Pinnick
96%
A
3
2
protecting-group free(d.r. = 4:1)
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
A
CrCl2, NiCl2Br
86% Me
O
TBDPSO
MOMOOMe
O
MeO
OHMe
OTBDPS4
(d.r. = 1.4:1)
EDCI, DMAP5
85%
Me
OMe
O
Me
MOMO
OH
OTBDPS
1) LHMDS HMPA TBSCl2) LiAlH4
84%
(d.r. = 4:1)
16
Me Me
OMe
O
Me
MOMO
OH
1) MsCl, Et3N2) LiAlH43) TBAF4) IBX
81%
Me
OMe
O
MOMO
OH
Me Me
OMe
O
MOMO
O
ON
OO
Me
Me
6, Sn(OTf)2Et3N
87%
OMe
HO OMe
1) Me4NBH(OAc)32) LiOH, H2O2
69%
(d.r. = 20:1)(d.r. = 6:1)
Me Me
OMe
O
HO
OMe
OCO2H
Me
1) 3M HCl2) Me2C(OMe)2, CSA3) LiOH
71%EDCI, DMAP
reflux
55%3
Me Me
OOMe
O
Me
O
O
O
Me
Me
3
hν (254 nm)cyclohexane O
Me Me
HOOH
O
Me
Me
O75% O
1) NaBH42) p-TsOH
71%
2
RCM approach:
2RCM
Me Me
MOMOOMe
O
Me
O
O
OH
MeOH
MOMOOMe
O
Me
O
OH
57
8
OMe
Me
O
O
9
Total Synthesis:
N O
OOO
MeBn6
Sn(OTf)2, DCMEt3N, -20 °C, -78 °C
O
H
91%
then
MeN O
OOO
MeBn
OH
O
O
Me
HOMe
OO
O
H
Me Me
1) Me4NBH(OAc)32) LiOH, H2O
50%
1) Me2C(OMe)2 CSA2) LiAlH43) pyr·SO3
86%
9
(d.r. = 5:1)
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
MgBr
O
O
O
OTi
Cl
Ph Ph
Ph Phthen methacrolein Me
OH
52%
(d.r. = 50:1)8
MeO
MOMOOMe
O
MeO
5, DMAPEDCI
81%
1) LHMDS, HMPA TBSCl, µw 2) LiAlH43) MsCl4) LiAlH4
79%
Me Me
OMe
O
Me
MOMO
n-BuLi, TMEDAthen 9
(d.r. = 4:1)
90%
Me Me
MOMOOMe
O
Me
O
O
OH
7(d.r. = 3.2:1)
Grubbs II(20 mol%)
62%OH
Me Me
MOMOOMe
O
Me
Me
OO
(E) only!
O
Me Me
HOO
O
OHMe
Me
HOMe
1) N2(COOK)2, AcOH2) 3M HCl, MeOH
Photo-Fries route: 29 stepsRCM route: 23 steps
O
Me Me
HOOMe
O
Me
Me
HO
59%
1) TESOTf, Et3N2) IBX3) 0.1M HF
25%
kendomycin
(–)-Penifulvin AJ. Am. Chem. Soc. 2009, 131 , 452–453.
HO2C
1) (R,R)-NMPE DIC, DMAP2) LiCl, LDA
Br
O
NPh
OH
Me
57%(95% ee)
OH
LDABH3·NH3
94%
hνpentane
H
HHO
H
HHO
H
HHO
MeH
Me
HMeMe
OH
H
H
HHO
MeH
Me
OH
MeMe
H
BA A:B = 45/55
EtNH2, Li
72% OHH
MeMe
Me
- shows strong insecticidal activity against the fall armyworm, one of the most significant pest of corn
Total Synthesis:
IBX/DMSOthen NaClO2
H
MeMe
Me
O
OH
92%
O3 78%
O
OH
OH
MeMeH
OMe
O
OH
OH
MeMeH
OHMe
PDC
82%
penifulvin A
8 steps8% overall yieldprotecting-group free
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
(+)-LycoflexineJ. Am. Chem. Soc. 2010, 132 , 14338–14339.
Retrosynthesis:
OO
NH
lycoflexine
transannular Mannich O
O
H
NBoc
FGI
O
MeH
NBoc
tandemcatalysis
O
MeH
NBoc
O
MeH
OH
IBocN
Sakurai
O
Me
Total Synthesis:
O
MeTiCl4
then CH3CHO
TMS
70%
O
MeH
OHO
MeH
O
1) IBX2) Cs2CO3, B
BocN
prepared in 2 stepsB:
68%
N
Cl
NTf2
KHMDS
85%O
MeH
OTf
BocN
O
MeH
BocN
pyridine
99%
aldol
O
MeH
BocN
Grubbs II
then H2 LnRuH2
OH
NBoc
OH
NBoc
52%
BH3·THFthen IBX
OO
H
NBoc
HHClHCHO
OO
NH
H
OO
NH
H HOO
H
N
fawcettimine
OO
NH
lycoflexine
64%
8 steps13% overall yield4 tandem/one-pot reactions
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
A selection of further completed targets by the Mulzer group:
O
OMe O
OMe
exo- and endo-brevicominLiebigs Ann. Chem. 1986, 825–838.
O
Me
Me
OHMe
MeOH
MeO
OMe
OH
OH
erythronolide BJACS 1991, 113, 910–923.
MeONH
O
rolipramACIE 1992, 31, 870–872.
NH
HO
HO
HO2C
(+)-detoxinineJOC 1996, 61, 566–572.
OOH
O
Me
MeO O
Me
O
Me
O
O
Me
MeO OH
OO
O
OBNa+
tartrolon BJACS 1999, 121, 8393–8394.
O
OHHO Me
O
O
Me
OHMe
OH
Me Me
O
OMe
O
O
Me
OH
Me
O
OH
Me
O
O
MeOH
OHefomycine M
ACIE 2007, 46, 5791–5794.
OH H
HOH O
OH
H
HOH O
OH
HO
pasteurestin A and BACIE 2007, 46, 9320–9322.
O
H H
OMecyoctol
TH 2004, 60, 9599–9614.
HMe
CO2Hvalerenic acid
OL 2009, 11, 1151–1153.
OR
HH HO
echinopine A: R = Hechinopine B: R = Me
OL 2009, 11, 5306–5309.
OH
OMeH
OH
O
O
OMeO
Me
OHOMe
H
H
branimycinACIE 2010, 49, 2050–2053.
O
CO2Me
O
O OH11-gorgiacerol
OL 2012, 14, 2834–2837.
Johann MulzerChristian A. KuttruffGroup Meeting
12/07/2013
Some studies towards:
O
CO2MeOH
O
O
O
OAc
O
H
Me
H
providencinSynlett 2009, 1357–1366.
MeAcO
BzO
OH
H
OAcMe
AcOAcO
AcOONic
MeNicO
AcO
AcO
H
OMe
AcOAcO ONic
OAc
pepluanin A and euphosalicinSynlett 2004, 2258–2562.
O
OMeO
NN
O
OOH
N
H
OH
HOOH
H
lemonomycinSynlett 2008, 2443–2446
O
O H
OH
OH
OAcH
OO
MeHO H
H
bielschowskysinOL 2012, 14 , 2195–2197.OL 2013, 15 , 3098–3101.