Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
Prof. Dr. Johann Mulzer, born August 5th, 1944 in Prien/Chiemsee (Germany)
Education
1969: Diploma in chemistry, University of
Munich (LMU)
1969- Ph.D., University of Munich (LMU),
1974: (with Rolf Huisgen)
1974- Postdoc, Harvard University,
1975: (with E. J. Corey)
The early days in Munich:
Decarboxylative dehydration of β-hydroxycarboxylic acids
Angew. Chem. Int. Ed. 1977, 16 , 255–256.
O
O
+ Li
R1
R2
OLi
Publications (as of December 2013)
321 publications
49 reviews
13 patents
many 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.
OLi
R3
O
R1
R2
R4
R1
R3
R2
R4
OH
R3 R4
PPh 3
DEAD
→ methodology expanded to synthesis of 1,3-dienes: Tetrahedron Lett. 1978, 19 , 2953–2954.
2-thietanimines from α-deprotonated β-lactones and phenyl isothiocyanate
Angew. Chem. Int. Ed. 1980, 19 , 466–467.
O LDA
O
i-Pr
-78 °C
Ph
i-Pr
Me
O
S O
O
O
Ph
NPh
i-Pr
Ph
F
O
-78 °C
O
O
O
O PhN=C=S
S
Ph
NPh
i-Pr
MeS
20 °C
i-Pr
Ph
H 2O
CO2 –
Ph
i-Pr
- CO2
S
Me
S O
CO2Me
Ph
i-Pr
O
S
NPh
N-phenylthietanimine
i-Pr
O
F
S
NPh
NPh
i-Pr
- CO2
i-Pr
Ph
Ph
Ph
SMe
MeI
H 2O
PhN
SH
S
PhHN
"Die Guad'n haltens aus!" (Mulzer)
OH
H 2O
new olefin synthesis
1996- Full Professor,
2012: University of Vienna (Austria)
Selected Awards and Memberships
1981: Grant for a University Lecturer in Chemistry, Chemical Industry Fund (FCI)
1983: Jost Henkel Memorial Prize
1994: Leibniz Prize, German Research Foundation (DFG)
1997: Ernst Schering Prize, Ernst Schering Research Foundation
1999: Erwin Schrödinger Prize of the Austrian Academy of Science
2002: Member of the Austrian Academy of Science
2010: Emil-Fischer-Medaille, Gesellschaft Deutscher Chemiker (GDCh)
O
- mild conditions
- easy workup
- low cost of reagents
1980- Assistant Professor,
1982: University of Munich
1982- Associate Professor,
1984: University of Düsseldorf
1995- Full Professor,
1996: University of Frankfurt
R1
R2
R3 R4
Academic Career
1984- Full Professor,
1995: Free University of Berlin
OLi
PhN
A
+
i-Pr
Ph
S
A:B = 63:37
PhN
B
Me
Some work from the Düsseldorf, Berlin and Frankfurt period:
concrete example:
Diastereo- and enantioselective synthesis of chrysanthemic acid methyl ester
Angew. Chem. Int. Ed. 1983, 22, 63–64.
NaH,
H
MeO 2C
O
O
O
P OEt
OEt
H
H
O
CO2Me
95%
PPh 3
quant.
64%
ozonolysis
O
O
O
multigram quantities,
d.r. = 91:9
First total synthesis of (–)-ACRL Toxin III B
Angew. Chem. Int. Ed. 1993, 32, 1452–1454.
H
CO2Me
O
+
CO2Me
O
O
Retrosynthesis:
O
CH2N 2, Et 2O
- ACRL toxin III A present in a fungus which causes brown spot disease on citrus
- unknown mechanism of action
O
OH
quant.
OH
OH
O
KOH, MeOH
THF
OR
H
CO2H
O
CO2Me
3
O
(1R,3R)-chrysanthemic acid
methyl ester
O
separation
Me
OTr
O
1
2
OBn 1) H 2SO 4
R
O
O
2) Pb(OAc) 4
OBn
H
O
1) RM
2) NaH, BnCl
R
O
(S)
i-BuMgCl
[Cp 2TiCl2]
then 2
alcohol
acid
1
O
PPh 3
Me
3
Total Synthesis:
Synthesis of optically active building blocks from (R)-2,3-isopropylidene glyceraldehyde
Tetrahedron Lett. 1983, 24, 2843–2846.
O
OTHP
CBr2
Me
Me
- related to the family of pyrethroid insecticides
- (1R)-configuration important for physiological activity
6 steps
24% overall yield
Me
R = H: ACRL toxin III A
R = Me: ACRL toxin III B
CO2H
O
crystalline
99% ee
H
+
O
1
Me
H
H
OMe
5
4
1) NaH, PMBCl
2) ZnBr2, DCM
3) Swern
4) CBr 4, PPh 3, Zn
5) n-BuLi
OH
OTr
78%
OPMB
Me
(d.r. = 1:1)
diol
OBn
O
R = Ph, Me, n-butyl, allyl
M = Li, MgBr, Zn, Ti(Oi-Pr) 3
R
O
1) H 2SO 4
2) Pb(OAc) 4
O
separated by column chromatography
OBn
H
R
O
(R)
alcohol
TBDPSO
1) TBDPSCl
2) p-TsOH
3) Swern
H
acid
diol
1) 4
2) LiAlH 4
57%
PMBO
O
Me
6
Me
Li
52%
Me
H
O
O
O
O
THF
H
H
OBn H
60%
O
H 2SO 4, THF
NaIO 4
OBn
OBn
PPh 3
CO2Me
O
95%
O
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
OPMB
OH
OTHP
73%
Me
(d.r. = 1.8:1)
Me
Forward Synthesis:
O
1) 5, KHMDS
-100 °C
2) DDQ then TBAF
6
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
OH
OH
OH
OPMB
O
Li
O
36%
OMe
Me
16 steps LLS
1.3% overall yield
OPMB
OEt
P OEt
O
O
OPMB
O
Li
O
OEt
OTr
O
H 2O
P
O
(–)-ACRL toxin III B
O
H
O
Me
3
TrO
58%
OEt
3
see THL, 1996,
37, 9177–9178.
O
1) MeMgCl
2) KH, Bu 3SnCH2I
Synthesis of a Vitamin B 12 A–B-semicorrin
J. Am. Chem. Soc. 1997, 119 , 5512–5518.
1) n-BuLi
2) TBSCl
3) DDQ
OH
Retrosynthesis:
OTr
H 2NOC
H 2NOC
N
Me
Me
H
H 2NOC
MeO 2C
CONH2
Me
OH
MeO OMe
MeO 2C
see
Eschenmoser
N
A
Me
N
N
CN N
D
MeO 2C
Me
N
CO2Me
Me
OTr
C
Me
OH
Me
NC
FG
FG
FG
FG
FG
A
FG
NH
Me
Me
O
Me
HN
Me
FG
B
O
38%
N
NC Me
HN
O
HO
TrO
OTr
Me
N
NC Me
HN
OTr
Me
A
1) A, (PhCOO) 2
2) P(OEt) 3
A
99%
90%
Me
TrO
2) NH 3
3) 110 °C
Me
B
O
OTr
OTr 1) MsCl, DIPEA TrO
N
H
TrO
A
TrO
88%
S
N
H
1) TBAF
2) PDC
O
67%
1) KCN
2) Lawesson
Me
cobyric acid
FG
OTr
OTBS
OTr
CO2Me
SnBu3
Me
OTBS
TrO
O
1) mCPBA
2) LAH
3) TrCl
4) Pb(OAc) 4
N
CN
CONH2
O
98%
CONMe2
Co
OTr
Me
see THL, 1994,
35, 9021–9024.
NMe 2
B
O
PMBO
81%
OTBS
E/Z > 100:1
Me
CONH2
Co
N
CONMe2
74%
- cobyric acid
- siroheme
- factor 430
B
O
vitamin B12 A–B semicorrin
16 isolated intermediates
7% overall yield
O
O
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
(±)-desamino huperzine A
Tetrahedron Lett. 2000, 41, 9229–9232
The Vienna Era:
(–)-Morphine
Angew. Chem. Int. Ed. 1996, 35, 2830–2832.
Retrosynthesis:
Me
O
O
Total Synthesis:
1) Cl2, AcOH
2) (COCl) 2
3) SnCl 4
MeO
MeO
b) KOH, dioxane
MeO
70%
CO2H
Cl
OMe
≡
O
MeO
13
Br
H
MeO
O
H
O
H
O
CO2Me
1) LiOH, DMF, Δ
CO2Me 2) Ph 3P=CH 2
OH
O
O
O
85%
O
H
O
H
O
HO
(–)-morphine
O
O
H
75%
NMe
NMe
H
N
(–)-dihydrocodeinone
O
O
11 steps
11.5% overall yield
N Me
SO2Ph
CO2Me
O
Me
H
N
76%
Me
O
O
OH
O
CN
1) H 2SO 4
2) Ph 3P=CHMe
3) PhSH, AIBN
PhMe
MeO
1) Li, NH 3
2) 3N HCl
Me
CN
42%
O
68%
DBU, DMF
2) LiBr, DMF
O
Me
Rapoport,
Rice etc.
CO2Me
O
1)
O
1) NH 3, MeOH
2) SO2Cl2, DCM
OH
MeO
O
CO2Me
Me
O
HO
OH
69% over
3 steps
Pd/C, H 2
EtOH
53%
O
O
MeO 2C
1) PhSO 2NHMe
ADDP, Bu 3P
2) NBS, (PhCOO) 2
CCl 4, reflux
63%
O
O
O
enantiomers resolved
by chromatography
on cellulose triacetate
DMF, 140 °C
Cl 1) TMSCl, (CH 2OH)2 MeO
2) a) BH 3·Me 2S, THF
b) H 2O2, OH –
3) Ra-Ni, MeOH, KOH
- huperzine A is a AChE inhibitor and a potential lead for
treatment of Alzheimer's disease
- great potential in synthetic derivatives of huperzine A
EtONa, EtOH
O
O
Total Synthesis:
H
84%
(d.r. = 3:1)
MeO
Cl
O
O
R = NH 2: huperzine A
R = H: desamino huperzine A
O
Br
quant.
R
MeO
O
O
73%
(H 2C=CH)2CuMgCl
-78 °C to 0 °C then
TMSCl, Et 3N then
NBS, THF, -78 °C
Cl
O
O
Me
O
MeO
OMe
H
N
1) HCO Me, NaOMe
2
Cl 2) a) MVK,
Et 3N
MeO
R
10 steps LLS
13% overall yield
one protecting group
E/Z = 1:1
(±)-desamino huperzine A
→ synthesis and biological activity of more derivatives: BMCL 2001, 11 , 2627–2630.
O
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
Epothilone B
Angew. Chem. Int. Ed. 2000, 39, 581–583.
Wittig
O
S
S
Horner
Me
O
Me
O
Me
Me
OH
Me
N
OEt
O
OH
aldol addition
O
TBSO
OPMB
TBSO
OH
(d.r. = 9:1)
n-Bu
O
O
O
+
N
TBSO
1) MsCl, Et 3N
2) K 2CO 3, MeOH
91%
O
84%
S
Cl -
TBSO
CO2Me
N
S
OH
Me
N
40%
O
epothilone B
Me
O
OH
O
1) DDQ
2) Swern ox.
O
AD-mix-β
TBSO
OH
OH
CO2Et
Me
CO2Et
OTBS
1) L -selectride, then
MeI, HMPA
2) a) TBAF, THF
b) TESCl, Et 3N, DMAP
3) DIBAL-H
TBSO
O
91%
O
X*
O
1) Yamaguchi
2) Zn, NH 4Cl
3) HF·pyridine
CO2Et
OTBS
S
N
N
S
86%
Me
OPMB
n-Bu
S
O
OH
95%
C
TBSO
O
Et
KHMDS
1) DIBAL-H
2) LiOH,
O
,
OH
O
(EtO)2(O)P
N
O
P+
O
OEt
xylene, 140 °C (cat.)
(78–85%)
1) MsCl, Et 3N
2) K 2CO 3, MeOH; H 2O; 1 N HCl
Me
n-Bu
N
B:C = 3:1
B
Me
HO
S
O
EtO
OPMB
84%
O
A
EtO
1) TBSCl, im
2) O3
3) isopropenyl-MgBr
92%
Me
HO
- 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
Me
DIBAL-H; MgBr 2·OEt2
then allyl-MgBr
S
OPG
H
epothilone B
OPMB
CO2Et
O
Me
OPG
O
macrocyclization
N
62%
O
S
N
TESO
1) a) OsO4, NMO
b) NaIO 4, EtOH
2) HF·pyridine, py
3) Pinnick oxidation
S
N
OTr
HO
HO 2C
63%
O
(d.r. > 99:1)
Me
86%
S
N
OTr
TESO
TBSO
O
H
Me
O
Me
Me
TBSO
→ 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.
O
O
1) LDA, A
2) Troc-Cl, py
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
Laulimalide
JACS 2001, 123 , 10764–10765.
1) BH 3·Me 2S
2) DMP
Me 3) (–)-Ipc B-allyl
2
- laulimalide is a metabolite from marine sponges that promotes abnormal tubulin polymerization
- displays unusually high activity against multidrug resistant cancer cell lines
HO
allyl transfer
Retrosynthesis:
OH
O
O
O
HO
83%
OH
Me
O
TMS
MgBr
2) K 2CO 3, MeOH
3) DMP
laulimalide
O
85%
OMOM
O
O
O
O
O
Me
P
O
O +
MeO P
MeO
O
B
OTBDPS
OMOM
O
O
O
O
B
Me
O
TMS
O
Me
OH
O
O
O
H
Me
O
H
Me
40%
OTHP
1) DMP
2) OH OH
O
KHMDS, then B
O
O
prepared in 6 steps
prepared 5 steps
Me
OMOM
O
H
1) LiOH
2) NaBH 4, CeCl 3
3) MOMCl, DIPEA
4) HCl, MeOH
5) Red-Al
O
CONMe2
EtO
82%
Me
H
Grubbs
(4 mol%)
A
TMS
H
A
O
H
A
O
87%
60%
Me
H
Total Synthesis:
O
O
OTES
TMS
Me
O
F 3CH2COC
H
EtO
90%
1)
, LiClO 4
2) NaBH 4
OTf
3) TESCl, py
4) MeLi
Me 5) KHMDS, PhNTf
2
1) Pd(PPh 3)4, LiCl
H
3
Still-Gennari
coupling
H
Me
O
H
2
O
1) Et 2NH
Me 2) acrolein-diethyl
-acetal, TsOH
OTBS
O
F 3CH2COC
CONMe2
COOEt
COOEt
O
OMOM
H
OTBDPS
OH
laulimalide
P(O)(OCH 2CF 3)2
*
O
F 3CH2CO P
F 3CH2CO
O
OH
H
Me
3) TBAF
4) *
76%
O
O
Me
H
1) EtAlCl 2
2) DMP
3) TsOH
4) Me 2BBr
5) SAE
31%
19 steps LLS
21% overall yield
1st fully stereocontrolled synthesis
O
Cl
→ 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.
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
OMe
Elisabethin A
JACS 2003, 125 , 4680–4681.
Me N
O
- isolated from the Carribean gorgonian Pseudopterogorgia elisabethae
- some members of the elisabethane class show significant activity agains Mycobacterium tuberculosis
TrO
Retrosynthesis:
H
O
H
O
O
OH
Me
O IMDA
Me
Me
Me
O
MeO
HO
94%
OMe
69%
ZnBr2
PdCl 2(o-tol3P) 2
71%
OMe
Me
OTBS
O
Me
Me
Me
86%
OMe
(de: 86%)
TBSO
Me
TBSO
OMe
O
O
OTBS
PivCl then
N
1) Pd/C, H 2
2) NaOH
3) BBr 3
O
H
OTBS
TBSO
OMe
Me
OMe
O
17–20 steps LLS
7% overall yield
O
Me
OH
Me
Me
elisabethin A
Me
Me
Me
O
O
OMe
Me
Me
O
A
Me
O
Me Me
Me
Me H
Bn
H
O
27%
OMe
Me
Me
Me H
OTBS
TBAF then
FeCl 3
91%
OTBS
Me
O
Me
1) TBSCl
2) NBS
Br
Me
Li
N
Ph 3P
*X
OEt
TBSO
91%
Me
Me
2) Swern
Me
3)
OMe
97%
Bu 3Sn
O
Bn
Me
Me
OTBS
Me
Me
TBSO
O
OMe
NaHMDS
then B
OH
Me
TBSO
TrO
77%
Me 1) LIBH 4
2) Na 2S2O4
Me
HO 2C
Me
B
OMe
OH 1) CAN
1) mCPBA
H 2) NaOH
1) DIBAL-H
2) Swern
3) Pinnick
76%
1) BCl 3
2) I 2, PPh 3
Me
O
EtO
2) Ph 3P=CHMe
Me
O
A
97%
OMe 1) DIBAL-H
O
I
Total Synthesis:
OMe
TrO
93%
Me
elisabethin A
MeO
O
N
OMe
Me Me
Me
Me
Me
Me H
Me
Me
O
EtO P
EtO
Me
Me
Me H
H
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
(–)-Ovalicin
Angew. Chem. Int. Ed. 2007, 46, 2690–2693
O
- ovalicin and the structurally closely related fumagillin show potent antiangiogenic activity
- ovalicin is also a promising agent against microsporidiosis
OH
76%
OMe
Retrosynthesis:
O
B, t-BuLi
Et 2O, toluene
O
OMe
OTBS
O
O
OTBS
OH
1
OMe
4
OHC Br
OPG 2
OPG 2
2
3
O
CHO
OMe
OH
OH
71%
OMe
OMe
O
Total Synthesis:
O
[VO(acac) 2]
t-BuOOH, benzene
O
OPG 2
OPG1
(–)-ovalicin
1) TBAF
2) DMP
Br
O
O
85%
O
(–)-ovalicin
Br
CHO
OMe
O
BF 3·OEt2, DCM OHC
-78 °C
Ph
OPMB
BH 3·NH 3
O
Ph
75%
O
O
OMe
Br
O
OPMB
84%
OH
O
O
OH
78%
92%
OTBS
Ph
N
OH
1) NBS
2) DMP
N
N N
O
SnBu3
A
O
S
O
HO 2C
OH
OMe
Me
O
O
N
H
platensimycin
O
O
Me
Me
Nicolaou's key
intermediate
LHMDS, -78 °C
70%
93%
- 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
OH
O
OMe
OTBS
Formal synthesis of platensimycin
Angew. Chem. Int. Ed. 2007, 46, 8074–8075.
Retrosynthesis:
O
DMP
OMe
15 steps LLS
15% overall yield
OH
89%
1) p-MeOC6H 4CH(OMe)2
CSA, DCM
2) DIBAL-H, DCM
Br
90%
1) TBSCl, im
2) NaH, MeI
3) DDQ
Br
(d.r. = 8:1)
1) NaH, THF
2) OsO4 (1 mol%) HO
NMO
OH
HO
Br
Br
B
O
Formal synthesis of (–)-platencin
Angew. Chem. Int. Ed. 2008, 47, 6199–6200.
Total Synthesis:
1) NaBH 4, EtOH
- isolated along with platensimycin
- exhibits broad-spectrum antibacterial activity against many pathogens that show resistance to current
antibiotics
OMe 2) POCl 3, DMF
3) AgNO3, NaOH, EtOH
4) Pd/C, H 2, EtOH
O
85%
OMe
Retrosynthesis:
HOOC
$2/g
59%
6-methoxy-1-tetralone
Me
via:
OH
O
1) SOCl2
2) TMSCHN2
3) TFA, -20 °C
HO 2C
OMe
O
H+
O
N
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
O
common
intermediate
O
H
HO
Rawal diene
Me
H
80%
HO
Ph 3PMeBr
t-BuOK
O
O
Grubbs II
DCM, Δ
H
H
O
HIO 3·DMSO
60%
O
O
Me
A
Br
H
CrCl 3
LAH
48% (over 3 steps)
O
O
H
Me
B
C
A
+
5 steps
26% overall yield
protecting-group free
7 steps
(1:3 mixture)
OH
O
HO 2C
(see Nicolaou:
ACIE 2008, 47, 1780–1783)
B:C = 1.3:1
5 steps from A
20% overall yield
protecting-group free
(d.r. = 20:1)
78% (brsm)
O
Me
CHO
(–)-perillaldehyde
commercially available
NBS
t-BuOH
H
Me
O
68%
O
O
Me
H
80%
[Ir(cod)Py(PCy 3)]PF6
H 2 (1 bar), DCM
NaOMe
toluene, Δ
then HCl
TBSO
know intermediate, multigram quantities
sequence to A requires only one column
Br
CHO
+
Br
O
O
H
B
C
O
1) MeMgI, THF, -78 °C
2) NBS, (BzO) 2, CCl 4
O
A
B
Total Synthesis:
53%
A
O
O
H
H
NMe 2
O
O
O
platencin
N N
N
N
H
OH
O
Me
OH
N
H
platencin
Me
H
O
Total synthesis of (–)-platencin
J. Org. Chem. 2009, 74, 2937–2941.
O
Me
O
1) TFA, DCM
then aq. KOH
2) Martin's sulfurane
H
Me
KHMDS, MeI
HMPA, THF
H
15
77%
previous
intermediate
Me
N
H
OH
O
1) NaOH, THF
2) B, DCC, DMAP
Et 3N, MeCN
H
9 steps
10% overall yield
protecting-group free
MeO 2C
OH
HO 2C
NH 2
O
O
O
Bn
OMe
3
N
MOMO
O
6
OMe 5
O
O
Total Synthesis:
H
O
Me
TMSCHN2
n-BuLi, THF
-78 °C to rt
H
Me
Me
[CpZrHCl]
benzene, I 2
I
(d.r. = 4:1)
83%
76%
OH
A
Me
TBDPSO
O
OMOM
Photo-Fries approach:
Me
Me
Me
67%
Br
OR
80%
MOMO
RO
OMOM
OMe
MOMO
OMe
Me
Me
O
JACS, 2004,
126 , 14720
Me
HO
Me
1) DMDO
2) Pd(OAc) 2
PBu 3, t-BuOH
OMe
OH
HO
[Pd(PPh 3)4]
t-BuLi, ZnCl2
R = MOM
Me
O
OTBDPS
OTBDPS
OTBDPS
OTBDPS
- antitumor macrolide first isolated in 2000 from the bacteria Streptomyces violaceoruber
- potent endothelin receptor antagonist and antiosteoperotic compound with remarkable antibacterial
and cytostatic activity
Me
Me
O
Kendomycin
Angew. Chem. Int. Ed. 2009, 48, 6032–6036.
Me
O
4
Me
Evans O
56%
B:
Me
O
Me
52%
Me
TBDPSO
Me
8
O
OH
O
OH
16
Me
9
87%
t-BuOK
methyl acrylate
OH
ClaisenIreland
Me
O
H
O
HO 2C
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
O
O
HO
1) TfOH, 4Å MS
2) MOMCl
3) TBAF
HO 2C
Me
HO
80%
O
Me
1) IBX
2) Pinnick
O
96%
O
HO
OMe
kendomycin (1)
2
Photo-Fries
MOMO
MOMO
OMe
OMe
5
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
O
CrCl2, NiCl 2
Br
Me
Me
EDCI, DMAP
5
85%
OTBDPS
Me
Me
1) MsCl, Et 3N
2) LiAlH 4
3) TBAF
4) IBX
Me
O
O
O
OMe
Me
OH
16
Me
OTBDPS
81%
71%
2
OH
RCM approach:
Me
OH
OH
Me
Me
O
Me
6, Sn(OTf)2
87%
Et 3N
Me
Me
O
69%
O
N
O
O
OMe
(d.r. = 6:1)
Me
Me
CO2H
O
O
Me
MOMO
O
O
OMe
Total Synthesis:
MOMO
OMe
1) 3M HCl
2) Me 2C(OMe)2,
CSA
3) LiOH
5
9
O
Sn(OTf)2, DCM
Et 3N, -20 °C, -78 °C
O
then
O
O
N
O
Me
6
OH
Bn
O
O
Me
Me
9
O
O
N
Me
1) Me 2C(OMe)2
CSA
2) LiAlH 4
Me
3) pyr·SO 3
H
HO
O
H
91%
O
OMe
O
Me
O
O
O
7
Me
O
O
OMe
71%
Me
O
MOMO
Me
(d.r. = 20:1)
Me
55%
OH
O
Me
HO
MOMO
EDCI, DMAP
reflux
O
1) Me 4NBH(OAc) 3
2) LiOH, H 2O2
OH
Me
8
2
OMe
(d.r. = 4:1)
Me
Me
RCM
MOMO
OMe
3
O
HO
OMe
3
MOMO
O
1) NaBH 4
2) p-TsOH
O
O
75%
O
84%
O
Me
O
O
1) LHMDS
HMPA
TBSCl
2) LiAlH 4
hν (254 nm)
cyclohexane
Me
O
MOMO
4
Me
Me
O
Me
TBDPSO
(d.r. = 1.4:1)
Me
Me
O
86%
Me
O
A
H
Me
Me
OH
86%
O
Me
(d.r. = 5:1)
Bn
1) Me 4NBH(OAc) 3
2) LiOH, H 2O
O
50%
HO
O
Me
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
Ph
Ph
O
O
O
O
(–)-Penifulvin A
J. Am. Chem. Soc. 2009, 131 , 452–453.
Ti
Cl
OH
Ph Ph
then methacrolein
MgBr
- shows strong insecticidal activity against the fall armyworm, one of the most significant pest of corn
5, DMAP
EDCI
Me
1) (R,R)-NMPE
DIC, DMAP
2) LiCl, LDA
Total Synthesis:
81%
52%
8
(d.r. = 50:1)
Me
Me
1) LHMDS, HMPA
TBSCl, µw
2) LiAlH 4
3) MsCl
4) LiAlH 4
Me
O
O
Me
OMe
94%
OH
H
H
HO
HO
H
Me
H
Me
Me
Grubbs II
(20 mol%)
OH
O
HH
Me
HH
Me
Me
OH
O
O
HO
(d.r. = 3.2:1)
MOMO
OMe
Me
7
Me
(E) only!
1) N 2(COOK) 2, AcOH
2) 3M HCl, MeOH
Me
Me
OH
O
O
1) TESOTf, Et 3N
2) IBX
3) 0.1M HF
25%
Me
H
Me
H
Me
Me
A:B = 45/55
O
B
Photo-Fries route: 29 steps
RCM route: 23 steps
H
Me
Me
HO
OMe
Me
O3
O
8 steps
8% overall yield
protecting-group free
OH
Me
Me
Me
A
H
O
92%
O
Me
Me
Me
HO
O
OH
Me
HO
Me
HO
Me
59%
IBX/DMSO
then NaClO 2
H
H
OMe
OH
Me
Me
H
O
MOMO
H
HO
H
OH
kendomycin
EtNH 2, Li
72%
Me
62%
O
Me
hν
pentane
OMe
Me
O
57%
(95% ee)
MOMO
Me
LDA
BH 3·NH 3
OH
HO 2C
O
MOMO
O
N
O
79%
90%
(d.r. = 4:1)
Ph
Br
Me
n-BuLi, TMEDA
then 9
Me
O
O
H
O
H
PDC
O
Me
penifulvin A
78%
82%
O
H
Me
Me
H
O
OH
Me
(+)-Lycoflexine
J. Am. Chem. Soc. 2010, 132 , 14338–14339.
transannular
O Mannich
H
H
Me
Retrosynthesis:
O
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
Me
O
O
H
Grubbs II
O
FGI
N
O
then H 2
N
Boc
O
O
Sakurai
H
O
H
O
O
O
Boc
N
I
HCl
HCHO
O
H
H
O
BH 3·THF
then IBX
H
O
H
N
O
HO
O
H
Boc
B: prepared in 2 steps
N
Boc
N
Boc
N
H
aldol
O
O
H
Me
Me
52%
NBoc
H
Me
H
L nRuH 2
BocN
N
Boc
lycoflexine
O
tandem
catalysis
H
N
O
H
64%
N
Total Synthesis:
TiCl4
TMS
Me
then CH 3CHO
H
Me
1) IBX
2) Cs2CO 3, B
70%
68%
O
O
O
OH
BocN
H
Me
H
Me
Cl
N
pyridine
O
BocN
99%
N
H
H
Me
NTf 2
KHMDS
O
BocN
OTf
85%
O
fawcettimine
lycoflexine
8 steps
13% overall yield
4 tandem/one-pot reactions
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
A selection of further completed targets by the Mulzer group:
O
Me
Me
Me
O
Me
OH
O
Me
O
O
O
Me
O
exo- and endo-brevicomin
Liebigs Ann. Chem. 1986, 825–838.
Me
Me
OH
OH
HO
HO
O
OH
MeO
OH
NH
Me
rolipram
erythronolide B
ACIE 1992, 31, 870–872.
Me
HO 2C
O
H
OH
H
HO
OH
H
OH
OMe
O
H
O
OH
O
O
Me
O
OH
O
O
OH
Me
OH
H
O
MeO
OR
CO2H
valerenic acid
OL 2009, 11, 1151–1153.
Me
efomycine M
ACIE 2007, 46, 5791–5794.
O
H
H
O
OL 2009, 11, 5306–5309.
OMe
CO2Me
OH
O
Me
H
OH
OMe
branimycin
ACIE 2010, 49, 2050–2053.
Me
O
O
OH
O
Me
OH
OH
O
echinopine A: R = H
echinopine B: R = Me
Me
Me
O
Me
H
O
Me
Me
H
O
OH
O
Me
H
O
tartrolon B
JACS 1999, 121, 8393–8394.
Me
OH
O
pasteurestin A and B
ACIE 2007, 46, 9320–9322.
cyoctol
TH 2004, 60, 9599–9614.
B
Me
Me
OH
Na +
O
(+)-detoxinine
JOC 1996, 61, 566–572.
OH
H
Me
O
O
HO
H
O
O
O
N
H
JACS 1991, 113, 910–923.
O
O
O
O
OH
11-gorgiacerol
OL 2012, 14, 2834–2837.
Group Meeting
12/07/2013
Johann Mulzer
Christian A. Kuttruff
Some studies towards:
HO
AcO
Me
BzO
OH OAc Me
NicO
Me
H
AcO
AcO
AcO
O
Me
pepluanin A and euphosalicin
Synlett 2004, 2258–2562.
H
OAc
ONic
O
OH
HO
O
OH
O
H
H
O
O
H
OAc
bielschowskysin
OL 2012, 14 , 2195–2197.
OL 2013, 15 , 3098–3101.
O
Me
O
OH
H
OH
O
N
lemonomycin
Synlett 2008, 2443–2446
Me H
H
O
N
O
CO2Me
OH
OH
H
N
MeO
H
AcO
AcO
ONic
AcO
AcO
O
O
OAc
O
providencin
Synlett 2009, 1357–1366.