Chemistry in Germany - The Young Generation
Baran Group Meeting
Dirk Trauner
- born: April 17th 1967, Linz, Austria
- studies in biology and biochemistry, University of Vienna
- 1997 PhD with Johann Mulzer, Free University of Berlin
- 1998-2000 Postdoc with S. Danishefsky, New York
- 2000-2006 Assistant Professor, UC Berkeley
- 2006-2010 Associate Professor, UC Berkeley
- since 2008 Professor of Chemical Biology and
Chemical Genetics, LMU Munich, Germany
- 113 publications (15 PhD and Postdoc)
"I f ind it amazing that … I am getting paid f or sitting in my of f ice and
playing with toys and that my
imagination occasionally corresponds to the material world."
"In a nutshell, my research involves … natural products and neurons."
(T otal synthesis of bioactive natural products,
synthetic methodology, and chemical neurobiology)
MeO
HO
MeO
O
two atropisomers
at low temp.
MeO
5
O
MeO
NMe
OMe
OMe
(-)-hasubanonine
Angew. Chem., Int. Ed. 1997, 35, 2830.
Synlett 1997, 5, 441.
Synthesis 1998, 653.
J. Org. Chem. 1998, 63, 5908.
Chirality 1999, 11, 475.
CO2H
MeO
2. HCOOMe, NaOMe,
toluene
3a. MVK, NEt3, MeOH
3b. KOH, dioxane, H2O
77%
resolution w/ cellulose
triacetate on 10 g scale
H
Cl
71%
MeO
1a. (COCl)2,
toluene,
1b. SnCl4, 0 °C
Cl
MeO
O
4a. (H2C=CH)2CuMgCl, THF
4b. (TMS)Cl, Et3N
5. NBS, THF
MeO
Cl
MeO
Cl
6. DMF,
O
O
99%
O
Cl
7. TMSCl,
(CH2OH)2
92%
H
H
O
(-)-morphine
99%
H
Br
H
HO
Cl
MeO
N
H
CO2H
MeO
MeO
MeO
Cl2, AcOH
MeO
81%
Total Synthesis of Morphine and Hasubanan Alkaloids:
The Hydrophenanthrenone Approach
Daniel Goetz
O
H
O
O
3:1 mix. of epimers,
recycling possible
-haloketone ef f ect
-bromocyclohexanones prefer a
conformation with axial bromine in
order to minimize electrostatic
interaction of the dipolar
C–Br and C=O bonds or
maximize overlap between the
corresponding * and p- orbitals
Baran Group Meeting
MeO
Chemistry in Germany - The Young Generation
MeO
Cl
8a. BH3*SMe2, THF
8b. H2O2, OH-
O
70%
H
O
10. PhSO2NHMe,
ADDP, Bu3P
O
O
67%
O
O
OH
98%
9. Raney-Ni,
MeOH, KOH
O
12. Li, NH3, THF,
t-BuOH
13. 3N HCl, 90 °C
H
O
O
4a. NsCl, Et3N, DCM
4b. SiO2
4c. NaN3, DMF
O
OH
76%
- only 13 isolated intermediates
- all of which are crystalline
- total yield: 11.5%
- inexpensive and readily available sm
- recycling of undesired isomers
2. (CH2OH)2, H+
3. TBAF, THF
Cl
MeO
O
N3
OH
O
5. benzene,
reflux
MeO
Cl
Cl
MeO
6. pyridine, reflux
MeO
O
N
75%
N SO Ph
2
OTIPS
MeO
55%
H
MeO
O
Cl
O
11. NBS, (PhCOO)2,
CCl4, Et3N, reflux
H
MeO
OTIPS
MeO
N SO Ph
2
H
O
76%
MeO
H
O
MeO
H
81%
H
O
1a. KHDMS, TMSCl, THF
1b. Pd(OAc)2, MeCN
Cl
70%
H
MeO
MeO
Cl
MeO
O
Mitsunobu w/
N-methylbenzenesulfonamide,
1,1'-(azodicarbonyl)dipiperidine
H
MeO
O
O
MeO
Cl
Daniel Goetz
H
H
O
N
N
N
MeO
NH
73%
O
O
(-)-hasubanonine
(-)-morphine
Baran Group Meeting
Chemistry in Germany - The Young Generation
Total Synthesis of Halichlorin
H
Daniel Goetz
phenylglycinol
Meyer's lactam
NH2
N
O
Ph
O
1. toluene,
O
+
Angew. Chem., Int. Ed. 1999, 38, 3542.
T etrahedron Lett. 1999, 40, 6513.
H
Cl
Ph
OH
O
N
95%
O
HO2C
2. allylSiMe3,
TiCI4, DCM
99%
OH
Sakurai
halichlorin
5. LiHMDS,
THF,
MeI
H
HO2C
Helv. Chim. Acta 2000, 83, 2344.
Angew. Chem., Int. Ed. 2001, 40, 4450.
Angew. Chem. Int. Ed. 2001, 40, 4453.
HN
H
Cl
HO
Boc
N
O
90%
(structure elucidated by combination
of spectroscopy, total synthesis,
and degradation experiments)
N
H
7a. ClCOOEt, Et3N
7b. NaBH4, MeOH
8. TBDPSCI, Et3N
N
89%
H
- halichlorin exhibit considerable structural homology (e.g. quinolizidine
subunit), but act upon different biological targets (VCAM-1 vs. cPLA2)
- VCAM-1 has recently emerged as a potential target for drug discovery since
it is supposed to be involved in regulating leukocyte trafficking
- derivatives for SAR studies
H
TBDPSO
CO2Me
H
HN
10a. TFA, DCM
10b. H2O, K2CO3
BocHN
72% over
two steps
OTBDPS
BocHN
78%
HO2C
MeO2C
bioactivity conformational change
Ph
O
88%
6. LiOH,
THF/H2O BocHN
O
cisoid/ transoid invertomers
HO
H
Boc
OH
pinnaic acid
3. Na, NH3,
THF/EtOH
4. Boc2O, DMAP
TBDPSO
H
9a. 9-BBN, THF
9b. ICH=CH-COOMe,
Pd(dppf)Cl2, AsPh3,
Cs2CO3, DMF/H2O
H
excellent review on -alkyl Suzuki-Miyaura cross-coupling reactions:
Angew. Chem., Int. Ed. 2001, 40, 4544
Baran Group Meeting
Chemistry in Germany - The Young Generation
11. tBuOAc, LiHMDS,
THF
12. H2CO, EtOH
H
MeO2C
HN
H
O
H
N
O
63%
Daniel Goetz
N
O
OtBu
H
N
O
18. TBSOTf
19. TBAF
OtBu
OH
66%
TBDPSO
TBDPSO
Cl
Cl
17
O
H
P OMe
OMe
15. TPAP, NMO, MeCN
16. Seyferth-Gilbert,
O
KOtBu, THF
N
OtBu
H
- 21 steps
- 1.3% overall yield
H
17c. A, -65 to -30 °C
17d. B, -30 to rt
O
H
Me
O
TBSO
OH
OMe
9,10-deoxytridachione
TBSO
B
O
H
N
Ph
Ph
OH
Soai's
aminoalcohol
h
H
in vivo
or
in vitro
17
Cl
halichlorin
Biomimetic Syntheses applying Electrocyclization Cascades
OtBu
Cl
ZnMe
H
N
O
67%
4:1 mix. of epimers
N
O
O
key steps:
- use of Meyer's lactam to install core structure
Cl
- -alkyl-Suzuki coupling
- Claisen-Mannich sequence
- hydrozirconation-transmetalation-asymmetric addition
OH
H
A
OTBS
N
17a. Cp2Zr(H)Cl, DCM
17b. Zn2Me, heptane, -78 °C
OtBu
HO
H
OtBu
57%
N
OH
20. EDCI, DMAP,
CHCl3/THF
21. HF*pyridine
HO
O
17
TBSO
51%
N2
H
O
86%
13a. LiHMDS, THF, 0°C
13b. Cp2Zr(H)CI, rt
14. HF*pyridine, THF
Me
O
H
OMe
Me
O
photodeoxytridachione
biosynthetic relationship
via triplett state, diradical mechanism: Org. Lett. 2005, 7, 4959.
Chemistry in Germany - The Young Generation
Baran Group Meeting
Angew. Chem., Int. Ed.
2003, 42, 549.
Me
O
O
H
Me
H
O
H
H
Me
OMe
6. Weinreb
7. EtMgBr
Me
OMe
H
Daniel Goetz
55%
CO2Et
H
Me
Me
O
H
O
LiHMDS,
photodeoxytridachione
9,10-deoxytridachione
59%
(95% brsm)
4a+ 2s
6
O
H
Me
O
H
O
OMe
O
O
Me
DBU, ,
benzene
H
OMe
Me
O
H
78%
CO2Me
FSO2OMe,
77%
DCM
O
1. Still-Gennari
2. DiBAlH, DCM
H
73%
OH
43%
H
single
diastereomer
CO2Et
Me
3. TPAP/NMO
4. HWE
Me
O
H
H
Me
O
photodeoxytridachione
CO2Et
5. Me2AlCl cat.,
DCM
Me
single
diastereomer
H
H
CO2Et
Me
mechanism?
Me
O
H
OMe
Me
(-)-crispatene
95%
divergent access
to both
frameworks
see also:
OMe
benzene,
73%
O
Me
OH
MeO
O
O
O
Cl
common
synthetic
precursor?!
O
Me
E. crispata,
the ‘‘lettuce slug’’...
O
PNAS 2004, 101, 12019.
Baran Group Meeting
OH
Chemistry in Germany - The Young Generation
Daniel Goetz
Biomimetic Synthesis of Rubicordif olin
O
O
O
H
"several hundred
milligram prepared"
CO2Me
H OH
OH
O
hetero-DA
Me
J. Am. Chem. Soc. 2005, 127, 2870.
O
Org. Lett. 2010, 22, 5162.
(theoretical investigations)
+
O
rubicordifolin
PhB(OH)2,
toluene,
rubicordifolin
+
OH
OH
CO2Me
CO2Me
MeO2C
10%
OH
67%
1. stannane,
n
BuLi, CuCN
2. deprotection
O
CO2Me
OH
CO2Me
66%
+
O
O
Bu3Sn
O
O
O
OH
OTMS
A
HO
Ph
OH
B
O
OMe
HO
Ph
OH
B
O
OMe
O
O
OH
H OH
THF, rt
O
OH
O
CO2Me
-H2O
OH
23%
direct conversion of A
yields 45% rubicordifolin!
CO2Me
O
OH
+
O
O
OH
furomollugin
O
HO
Ph
B
O
O
O
H
H OH
OH
CO2Me
24%
-MeOH
mechanism
MeO2C
B
OH
2+4
O
C
rubicordifolin
Chemistry in Germany - The Young Generation
Baran Group Meeting
J. Am. Chem. Soc. 2006, 128, 11022 (with I. Seiple).
OMe
Me
Total Synthesis of Guanacastepene E
Me
OMe O
H
key disconnection
HO
MeO
+
O
MeO
HOH2C
guanacastepene E
Tf 2O, 2,6-DTBP,
MeNO2
aromatic Nazarov
cyclization - trif lation
OMe
OMe O
OTf
Me
I
SO2CF3
O
TBDPSO
+
-H+
70%
Me
O
OHC
MeO
taiwaniaquinoids
building block A
Ph
O
O
also: Friedel-Crafts triflation
R'
O
R
O
+
1. SnCl4, DCM,
-78 °C
O
1.5 eq Tf 2O,
1.01 eq 2.6 DTBP,
MeNO2, 0 °C
40-80%
intramolecular
N
J. Am. Chem. Soc. 2006, 128, 17057.
I
4
MeO
OAc
H
O
Daniel Goetz
OTf
O
64%
O
2. NaH, BnBr
85% 3. DiBALH
asymmetric carbonyl ene-reaction
H
4. vinyl-MgBr
5. DMP
6. Grubbs-II
OTf
OBn
O
building block B
N
OH
10:1 dr
R
67%
Org. Lett. 2006, 8, 5429.
+
R'
1.5 eq Tf 2O,
1.01 eq 2.6 DTBP,
MeNO2, 0 °C
intermolecular
H
Ph
61%
OBn
H
O
I
Chemistry in Germany - The Young Generation
Baran Group Meeting
Me
A
I
1a. tBuLi, Et2O
1b. cuprate
1c. BF3*OEt2, B
RO
O
Me
HO
O
S
B
Cu
CN
O
O
OBn
Me
RO
O
1a. allylSnBu3, BF3*Et2O
1b. TBSOTf, 2,6-lutidine
2a. K2OsO4, NaIO4
2b. NaClO2, NaH2PO4
Me
RO
OBn
O
TBSO
Me
OH
rubioncolin B
O
Me
anodic
oxidation
Biomimetic Total Synthesis of
Rubioncolin B
H
MeO2C
2. KHMDS,
18-cr-6,
TBSOTf
94%
Me
O
54%
R = TBDPS
"cuprate in a bottle”
J. Am. Chem. Soc. 2008, 130, 9230-9231.
O
OBn
O
Li
O
MeO2C
Me
RO
+
Daniel Goetz
CO2H
16%
CO2Me
OBn
OTBS
CO2Me
O
TBSO
OTBS
Me
Me
Me
MeOH
H
RO
OBn
H
O
MeO2C
H
RO
O
O TBS
OBn
H
O
MeO
70%
OMe
TBS
MeO2C
O
O
3a. (COCl)2,
DMF/DCM
3b. A, Et3N,
DCM
O
TBSO
MeO2C
OMe
OTBS
Me
Me
H
H
RO
HO
O
HO
Me
Me
OAc
H
O
guanacastepene E
O
MeO
OBn
H
O
O
A
(see synthesis
of rubicordif olin)
Baran Group Meeting
MeO2C
MeO2C
O
O
Chemistry in Germany - The Young Generation
MeO2C
OMe
O
MeO2C
TASF
O
O
OMe
O
MeO2C
PhI(OAc)2
O
TBSO
Daniel Goetz
MeO2C
O
OTBS
N
O
F
S
O
O
OTBS
N
O
TBS
Si F
N
TASF
tris(dimethylamino)sulfonium difluorotrimethylsilicate
(anhydrous fluoride source)
MeO2C
MeO2C
HO
O
O
O
O
MeO2C
ortho-quinone methide
4+2
O
O
O
MeO2C
HO
HO
O
O
O
MeO2C
H
MeO2C
O
BBr3
95%
OMe
O
O
O
MeO
endo
transition state
O
O
MeO2C
60%
OMe
racemate in nature!
H
MeO2C
rubioncolin B
OH
O
OMe
Chemistry in Germany - The Young Generation
Baran Group Meeting
O
H2N
Biomimetic Synthesis of Exiguamines
N
O N
BocHN
R = H: exiguamine A
R = OH: exiguamine B
OH
O
9. Pd black, HCO2NH4
10a. salcomine, O2, MeCN
10b. 1% aqu. formic acid
Nature Chem. Bio. 2008, 4, 535-537.
O O
N
H
Daniel Goetz
A
OMe
OMe
N
Boc
72%
O
O
R
N
Me2N
+ ortho-isomer (1:2.5)
mechamism?
name reaction?
1. BnCl, K2CO3
2a. N3CH2CO2Me, NaOMe,
MeOH
2b. o-xylene, 160 °C
OH
OHC
O
N
O
O
O
N
H
O
11. LiHMDS, THF
12a. BBr3
12b. MeOH,
2% formic acid
OH
N
Boc
Br
N
N
N
OH
MeO2C
39%
Br
H2N
OBn
O
29%
O2N
BocHN
OBn
N
Boc
OBn
6. LiAlH4
7. Boc2O, DMAP
Br
80%
3a. NaOH
3b. decarbox.
4. POCl3, DMF
5. MeNO2
Me2N
AgO (20 eq.),
MeOH/2% formic acid
N
H
Br
H2N
O
H2N
N
O N
O O
71%
OBn
A
O
HO
N
Boc
Me2N
OMe
N
O O
OH
N
H
OMe
OMe
NMe2
exiguamine A
O
BocHN
OMe
Me3Sn
46%
exiguamine B
O N
8. Pd(PPh3)4, CuCl,
LiCl, DMSO, 60 °C
47%
AgO (10 eq.),
MeOH/2% formic acid
OH
N
H
O
N
- two oxidations
- amine ring closure
- tautomerization
- oxa-6 -electrocyclization
N
Baran Group Meeting
Chemistry in Germany - The Young Generation
HO
Br
Org. Lett. 2005, 7, 2837
Daniel Goetz
J. Org. Chem. 2009, 74, 1581.
Org. Lett. 2005, 7, 5207.
MeO
O
Br
H
OH
Me
N
H
S-(+)-frondosin B
Angew. Chem., Int. Ed. 2002, 41, 1569.
SNF4435
O2N
H
O
N
O
amathaspiramide F
Angew. Chem., Int. Ed. 2002, 41, 4556
O
H
O
Me
OMe
REVIEW: "Biosynthetic and Biomimetic Electrocyclizations."
Chem. Rev. 2005, 105, 4757.
Org. Lett. 2002, 4, 2221.
Org. Lett. 2005, 7, 4475.
Org. Lett. 2005, 7, 5865.
J. Am. Chem. Soc. 2005, 127, 6276.
elysiapyrone A
Org. Lett. 2002, 4, 4109.
Org. Lett. 2005, 7, 2901.
Angew. Chem., Int. Ed. 2005, 44, 4602.
Baran Group Meeting
Chemistry in Germany - The Young Generation
Daniel Goetz
Studies Toward the Haouamines: Org. Lett. 2006, 8, 23.
Studies Toward Maoecrystal V: Org. Lett. 2010, 12, 5656-5659.
Org. Lett. 2006, 8, 345.
Org. Lett. 2006, 8, 5901.
newbouldine
T etrahedron 2010, 66, 6626-6631.
shimalactone A
Org. Lett. 2008, 10, 149.
smenochromene B
T etrahedron 2007, 63, 6529.
pycnanthuquinone C
Org. Lett. 2008, 10, 149
halenaquinone
J. Am. Chem. Soc. 2008, 130, 8604-8605.
(Vinyl Quinones as Diels-Alder Dienes)
Angew. Chem. Int. Ed. 2010, 49, 2619-2621.
Angew. Chem. Int. Ed.
2010, 49, 6199–6202.
Baran Group Meeting
Chemistry in Germany - The Young Generation
Daniel Goetz
loline
Nat. Chem. 2011, 3, 543-545.
A-74528
Org. Lett. 2011, 13, 1386-1389.
variecolortide A
Angew. Chem. Int. Ed. 2011, 50, 1402-1405.
not covered: "Chemical Neurobiology"
excellent review: Introduction: Chemical Approaches to Neurobiology,
Chem. Rev. 2008, 105, 1499.
Angew. Chem. Int. Ed. 2009, 48, 9097-9101.
NEt3
R
R
HN
O
380 nm
N
N
O
N
H
NEt3
500 nm
N N
crocipodin
T etrahedron 2011, 67, 1536-1539.
... don't miss the zebra-f ish experiment!
(Nature 2009, 461, 407-410.)
Baran Group Meeting
Chemistry in Germany - The Young Generation
Daniel Goetz
Thorsten Bach:
- born: 1965, Ludwigshafen, Germany
- studies in chemistry, University of Heidelberg / USC LA
- 1991 PhD with Manfred Reetz, University of Marburg
("Enantioselective C-C Coupling Using Chiral Catalysts")
- 1991-1992 Postdoc with D. Evans, Harvard University
("Histidine Analogs by Pd-mediated C,C Bond Formation")
- 1992-1996 Habilitation, University of Münster
- 1997-2000 Full Professor, University of Marburg
- since 2000 Chair of Organic Chemistry I, TU Munich
- 188 publications
chiral host A
Angew. Chem. Int. Ed. 2000, 39, 2302-2304.
J. Org. Chem. 2006, 71, 5662-5673.
Synlett 2004, 2588-2509.
Synthesis 2001, 1395-1405 (preparation of host).
main research interests:
- photochemistry
- catalysis
- chemistry of heterocycles
- total synthesis
Boc
Bn N MeO2C OTMS
Total Synthesis of Meloscine
N
H
Angew. Chem. Int. Ed. 2008, 47, 5082-5084.
Chem. Eur. J. 2009, 15, 3509-3525.
H
N
H
N
H
O
O
Boc
Bn N
OH
O
2. K2CO3
H
98%
N
H
3. AcCl
4. TFA
5. H2, Pd(OH2)/C
6, Boc2O
(+)-meloscine
Bn
N
Boc
CO2Me
OTMS
Boc
Bn N MeO2C OTMS
N
H
O
Boc
N
A, h (370 nm),
toluene, -60 °C
87%,
98% A recovered
74%
enantioselective [ 2+2]
photocycloaddition
OH
H
H
N
H
H
O
79% ee
>99% ee (after HPLC)
N
H
O
7. K2CO3
8. IBX
9. Ph3PCHCO2Et
10. DiBALH
60%
Boc
N
O
H
OAc
H
N
H
O
Chemistry in Germany - The Young Generation
Baran Group Meeting
OH
Boc
H
N
H
N
H
H
Johnson-Claisen
11. MeC(OMe)3,
12. TFA
13. K2CO3,
Br
H
N
17. TsCl, NEt3
18. NaBH4,
+
O
1. LDA, THF, -78°C;
then B
O
MeO
MeO
OMe
SeCN
OMe
99%
(dr 94:6)
OH
N
N
H
O
H
61%
H
N
H
O
O
O
O
(+)-meloscine
H
H
Overman intermediate
OH
O
OMe
Total Synthesis of Podophyllotoxin
H
O
O
OH H
H
MeO
OMe
O
OMe
OMe
H
O
O
79%
(dr 98:2)
Angew. Chem. Int. Ed. 2008, 47, 7557-7559.
O
H
3. Tf 2O, NEt3, DCM
4. Pd(OAc)2, PPh3,
K2CO3, MeCN
52%
MeO
2. sesamol, rt,
FeCl3, DCM or
Bi(OTf)3, MeNO2
O
H
19. TFA, mCPBA
O
OMe
OMe
NO2
N
H
94%
(dr 52:48)
B
14. Grubbs-II
67% 15. DiBALH
16. NaBH4
O
HO
CHO
H
N
H
O
H
O
A
CO2Me
55%
Daniel Goetz
H
MeO
O
J. Org. Chem. 2009, 74, 312-318.
(chiral carbocations, theoretical investigations)
OMe
Synlett 2011, 1235-1238.
(enantioselective FC with chiral Broensted acids)
OMe
(-)-podophyllotoxin
OH
H
O
O
O
H
- lignane class of natural products
- antiviral properties
- several total syntheses (e.g. 1st synthesis by Meyers, 24 steps)
5. OsO4, NMO, DCM;
then NaIO4
6. LiAlH(OtBu)3, Et2O
H
MeO
O
OMe
OMe
- 6 steps
- 35% overall yield
- enantiomerically pure material
- clever use of carbenium ion with adjacent
stereogenic center
Baran Group Meeting
OH
Chemistry in Germany - The Young Generation
FSO3H:SbF5 1:1,
-60 °C
Chiral Carbenium Ions
mechanism?
S
OH
CO2Me
H+,
-H2O
Wagner-Meerwein
OAc
t
J. Org. Chem. 2009, 74, 4747-4752.
HBF4*OEt2,
rt, DCM
Bu
R
chiral propargylic
acetates
S
FG
S
CO2Me
R
nucleophile,
Bi(OTf)3,
rt, MeNO2
70-97%
(dr < 95:5)
Nu
t
Bu
R
anti
S
H
anti
S
HBF4*OEt2,
rt, DCM
92%
(dr 64:32)
ring opening
OH
Daniel Goetz
FG
H
+
FG
simple model
f or predicting
the outcome
syn
Angew. Chem. Int. Ed. 2008, 47, 10106-10109.
diastereoselective Ritter reactions:
O
OH
syn
CO2Me
RCN,
TfOH,
0 °C, DCM
R
NH
CO2Me
84-96%
(dr < 94:6)
simple model
f or predicting
the outcome
anti
anti
Chem. Commun. 2009, 2130-2132.
Chemistry in Germany - The Young Generation
Baran Group Meeting
Total Synthesis of Cystothiazole E
O
OMe
Angew. Chem. Int. Ed.
2001, 40, 3184-3185
N
N
Br
2nd coupling
N
S
Br
S
Br
N
+
B(OH)2
S
S
Br
nd
2
coupling
S
Br
Br
O
Br
Br
R
N
H
Br
ClZn
Pd(PPh3)4, THF
2. H2, Pd/C, EtOH
N
O
T etrahedron 2005, 61, 2245-2267.
Br
A
Br
1 coupling
review:
1.
O
Thiazoles: T etrahedron Lett. 2000, 41, 1707-1710.
J. Org. Chem. 2002, 67, 5789-5795.
Synthesis 2011, 199-206.
Pyrroles: Synlett 2005, 1957-1959.
Heterocycles 2007, 74, 569-594.
N
Br
st
regioselective cross-coupling
on polyhalogenated heterocycles
OPG OMe
Br
Br
R
R
S
cystothiazole E
Br
Daniel Goetz
4 steps
Br
N
O
Br
eupomatenoid-6
Br
68%
Br
O
S
T etrahedron Lett. 2002, 43, 9125-9127.
Synlett 2001, 1284-1286.
Synthesis 2003, 925-939.
1st coupling
4. Pd(PPh3)4, CsOH,
benzene/EtOH/H2O,
95 °C
97%
OH
54%
3. t BuLi, Et2O, -78 °C;
ZnCl2, 25 °CTHF;
A, PdCl2(PPh3)2,
THF, 60 °C
Br
4 steps
rosefuran
OPG OMe
MeO2C
B(OH)2
cystothiazole E
Br
N
O
Br
43%
N
O
Eur. J. Org. Chem. 1999, 2045-2057.
S
94% for
Suzuki coupling
S
- 10 steps
- 21% overall yield
- three sequential couplings as key sequence
- usually bithiazole core established by classical Hantzsch thiazole methodology
(e.g. Boger's bleomycin synthesis; Angew. Chem. Int. Ed. 1999, 38, 448-476.)
WS 75624A
OMe
OMe
HO2C
N
N
S
Synlett 2002, 2089-2091.
OH
Baran Group Meeting
Chemistry in Germany - The Young Generation
Daniel Goetz
H
Regioselective C,C Coupling Reactions on
Polyhalogenated Heterocycles
H
HH
Synlett 2002, 1305-1307.
T op. Curr. Chem. 2005, 243, 1-42.
OH
O
Stereoselective [2+2] Photocycloadditions
(e.g. Paterno-Büchi Reactions)
kelsoene
H
Synlett 2005, 511-513.
J. Org. Chem. 2001, 66, 3427-3434.
HO
O
Ph
O
H
+
H
O
C9H19
N
H
Ph
(+)-preussin
N
CO2Me
furanocembranes
Angew. Chem. Int. Ed. 1998, 37, 3400-3402.
AcO
O
TIPSO
O
h , iPrOH,
-75 °C
O
AcO
HH
O
TIPSO
O
67%
H
GE2270 A
... a potent antibiotic thiazolylpeptide
Angew. Chem. Int. Ed. 2008, 47, 6189-6191.
Chem. Eur. J. 2010, 16, 6015-6032.
O HO
HO2C
HH
O
H
H
O
HO
punctaporonin C
wailupemycin
Chem. Eur. J. 2008, 14, 2322-2339.
Angew. Chem. Int. Ed. 2007, 46, 4771-4774.
Angew. Chem. Int. Ed. 2003, 42, 4685-4687.
Chem. Eur. J. 2005, 11, 7007-7023.
O
Baran Group Meeting
Chemistry in Germany - The Young Generation
Light-Driven Organocatalysis
Stefan Bräse:
- born: November 30th 1967, Kiel, Germany
- studies in chemistry, University of Göttingen
- 1995 PhD with Armin de Meijere
- 1995-1996 Postdoc with J. Bäckvall, University of Uppsala
- 1996-1997 Postdoc with K.C. Nicolaou, TSRI, La Jolla
(T otal synthesis of vancomycin)
- 1997-2001 Habilitation, RWTH Aachen (mentor: D. Enders)
- 2001-2003 Full Professor, University of Bonn, Germany
- since 2003 KIT, Karlsruhe, Germany
- around 110 publications
ratio 79:21
h (366 nm),
-25 °C, PhCF3,
10 mol% catalyst
O
N
H
O
78%
O
H
O
H
N
H
H
+
O
94% ee
N
H
Daniel Goetz
O
94% ee
main research interests:
- combinatorial chemistry
- solid-phase chemistry
- nanostructures
- total synthesis
"If I were a car... I would be an Audi RS6."
Angew. Chem. Int. Ed. 2009, 48, 6640-6642.
My motto is... "I know!".
Chiral Lewis Acids in
Enantioselective Photochemistry
O
Hobbies: Chemistry...
O
Total Synthesis of Diversonol
h (366 nm),
-35 °C, ClCH2CH2Cl,
20 mol% catalyst
87%
Angew. Chem. Int. Ed. 2006, 45, 307-309.
OH
O
OH
OH
- isolated from Penicillium diversum
- absolute configuration unknown
H
N
H
O
R = CF3, R' = Me
78% ee
Angew. Chem. Int. Ed. 2010, 49, 7782-7785.
O
diversonol
OH
Chemistry in Germany - The Young Generation
Baran Group Meeting
OMe
O
OMe
1. imidazole,
dioxane/H2O
CHO
+
O
61%
OH
O
OH
A Novel Protecting Group f or RCOOH
R
Domino Oxa-Michael Aldol
OMe O
Br
OMe OH O
Br
Br
11%
O
O
OMEM
H
OMEM
7. t BuLi, NaHCO3
53%
8. MMPP, EtOH
H
O
OH
OH
9. BBr3
10. NaBH4
O
26%
O
OH
N-Me-imidazole,
dioxane/H2O 1:2,
sonication
R
OH
O
+
cis
R1
R3
2
H R
cis preferred!
O
H
N
Cu(OTf)2 or FeCl3,
MeOH
- stable towards: reductions,
fluoride sources,
bases, weak acids,
click reactions with copper, ...
- easily removed in >95% yield
Cu(OTf)2 or FeCl3,
Ba(OH)2
O
R
O
OMe
R
OH
Angew. Chem. Int. Ed. 2011, 50, 6175-6177.
R
Balz-Schiemann
reaction
F
perfluorohexanes C6F14 as magic solvent:
- suppression of side product formation
- mild reactions conditions (80 °C)
- applicable to solid phase and in solution
O
usually around
60-70%
H
R
N
HBF4*OEt2,
C6F14
O
(Eur. J. Org. Chem. 2006, 1535-1546.)
N
O
N
bispicolylamine
(bpa)
N
Domino Oxa-Michael Aldol Reaction
CHO
NH
N
OH
OH
OMEM
1
+
standard amide
coupling reagents
Solid Phase Synthesis
diversonol
OMe O
OH
2. MEMCl
39% 3. nBu4NBr3,
THF/H2O
4. DABCO
5. TPAP, NMO
6. MeLi, CuCN
OH
N
O
H
cis/trans 1.5:1 OH
separation of diastereomers
af ter DABCO step
Daniel Goetz
N
N
Wallach
reaction
R
N
HBF4*OEt2,
C6F14
Angew. Chem. Int. Ed. 2010,
49, 5986-5988.
R3
2
+ R
... also worth reading:
O
trans
R1
O
H
R3
R2
Angew. Chem. Int. Ed. 1999, 38, 1071 (C,C couplings w/ immobilized subtrates).
Angew. Chem. Int. Ed. 2008, 47, 8120-8122 (solid phase synthesis of simple NP).
Eur. J. Org. Chem. 2009, 4494-4502 (f luorinating cleavage f rom solid support).
Chemistry in Germany - The Young Generation
Baran Group Meeting
Frank Glorius:
- born: XX. XX. 1972, XX, Germany.
- studies in chemistry, University of Hannover
- 1995-1996 Research with Paul A. Wender, Stanford
- 2000 PhD with Andreas Pfaltz, MPI/University of Basel
- 2000-2001 Postdoc with D. A. Evans, Harvard University
- 2001-2004 Habilitation, MPI Mühlheim (mentor: A. Fürstner)
- 2004 Associate Professor, University of Marburg, Germany
- since 2007 Full Professor, University of Münster, Germany
- 91 publications
main research topics:
- sterically demanding NHCs
- functional MOFs
- challenging cross-couplings
- CH activation
- asymmetric organocatalysis
- heterocyclic chemistry
"W hen I wake up I… can't believe it's that time already."
Indoles f rom Enamines by CH Activation
Angew. Chem. Int. Ed. 2008, 47, 7230-7233.
Pd(OAc)2, Cu(OAc)2,
K2CO3, DMF, 80 °C
CO2Me
N
H
N
H
CO2Me
- very wide substrate scope
- steric demand determines outcome, not electronic influence; rarely regioisomers
- good yields, scalable
- one-pot reaction possible (see below)
1. InBr3 (1 mol-%), rt
2. Pd(OAc)2, Cu(OAc)2,
K2CO3, DMF, 140 °C
NH2
+
O
CO2Me
O
72%
OMe
N
H
Daniel Goetz
Chemistry in Germany - The Young Generation
Baran Group Meeting
proposed mechanism:
Initial mechanistic investigations unambiguously support a -bond
metathesis or deprotonation pathway and not an electrophilic
aromatic palladation of the aniline ring.
NHC-Catalyzed Hydroacylation of Unactivated Double Bonds
(cp. Stetter reaction)
J. Am. Chem. Soc. 2009, 131, 14190-14191.
Org. Lett. 2008, 10, 4243-4246 (synthesis of NHC A).
S
O
R
N Mes
DBU, 1,4-dioxane,
120 °C
R2
H
1
proposed mechanism:
ClO4
A
O
R3
R1
R3
O
R2
O
- very wide substrate scope
- good yields (70-96%)
- scalable
- formation of quartenary centers possible
- useful disconnection
A
DBU, 1,4-dioxane,
120 °C, 1h
O
H
R1
94%
O
Ph
O
Ph
R1
O
Daniel Goetz
Chemistry in Germany - The Young Generation
Baran Group Meeting
Mathias Christmann:
- born: XX. XX. 1972, Peine, Germany.
- studies in chemistry, University of Braunschweig
- 2000 PhD with M. Kalesse, University of Hannover
(T otal Synthesis of (+)-Ratjadone)
- 2001-2002 Postdoc with C. J. Forsyth, Univ. of Minnesota
- 2003-2007 Habilitation, RWTH Aachen (mentor: D. Enders)
- since 2008 Associate Professor, TU Dortmund, Germany
- 36 independent publications
Intramolecular Direct Arylation of Benzoic Acids
by Tandem Decarboxylation/ C-H Activation
J. Am. Chem. Soc. 2009, 131, 4194-4195.
CO2H
1
R2
R
Pd((TFA)2, Ag2CO3,
5% DMSO/1,4-dioxane,
150 °C, 14 h
R1
R2
51-85%
O
Daniel Goetz
O
dibenzofurans
A Sterically Demanding Chiral NHC Ligand
J. Am. Chem. Soc. 2009, 131, 8344-8345.
O
7 steps
(-)-menthone
[Pd(allyl)Cl]2, A,
NaOt Bu, DME,
50-100 °C
X = Cl, Br
X
O
Ar
N
R1
R2
IBiox[(-)-menthyl]*HOTf
80-99%
intramolecular
main research topics:
- total synthesis
- method development
- organocatalysis
- catalytic transformations of renewable ressources
W e have recently initiated a program that is aimed at making larger
substructures within natural products available f rom terpene f eedstock. Using
simple bulk terpenes such as geranyl and neryl acetate or nepetalactone we
are aiming to f ind ef f icient ways to modif y the carbon skeleton using
oxidations, organocatalytic and metal-catalyzed reactions such as
hydrof ormylations.
The Concept - e.g. (-)-Englerin A f rom (-)-Nepetalactone:
2
R Ar
81-97% ee
Angew. Chem. Int. Ed. 2009, 48, 9105 (1st generation synthesis).
Angew. Chem. Int. Ed. 2011, 50, 3998 (2nd generation synthesis).
O
O
N
-arylation
Ph
R1
H
HO
H
O
O
- rigid geometry of NHC leads to excellent ee's
- high yields
- aryl chlorides (X = Cl) can be used for the first time
- N-benzyl give higher ee's than N-methyl
- highest ee's for ortho-substituted aryls (Ar)
H
(-)-nepetalactone
i
Pr
O
H
Me
O
H
i
Pr
O
OTBS
key intermediate
H
Me
OH
O
(-)-englerin A
- multigram quantities of key intermediate available
- route allows for various late stage modifications for SAR studies
- derivatives with improved activity against renal cancer cell lines
O
Chemistry in Germany - The Young Generation
Baran Group Meeting
The Concept - continued...
Chem. Commun. 2011, 47, 394-396.
AcO
epoxygeranyl acetate
O
5
HO
CO2H
O 1
Ph
OH
20
ripostatin B
... the end!
not covered:
selected examples of prepared building blocks:
MgBr
20 mol-% CuI,
THF/Me2S, -30 °C
O
f ull retention of
DB conf iguration
O
88%
O
A
NMe
t
95% ee
Bu
N
H
A*TFA, K2S2O8,
LiCl,Cu(TFA)2,
MeCN/H2O;
then NaBH4;
then NaOH
56%
77%
NaIO4,
THF/H2O
O
O
1. 2-methyl-1,3-dithiane, nBuLi, THF
2. PhI(TFA)2, CaCO3, MeOH/MeCN
62%
- valuable building blocks on multigram scale
HO
C5-C14 f ragment (see above)
O
OH
92% ee
C12-C20 f ragment (see above)
O
13
AcO
Ph
70%
11
O
3 steps
O
AcO
Daniel Goetz
- Magnus Rüping, RWTH Aachen
- Dirk Menche, University of Heidelberg
- Armino Studer, University of Münster
- Benjamin List, MPI Mühlheim
- Christian Hertweck, HKI Jena
- Lutz Ackermann, University of Heidelberg
- ...
... part II to come ...