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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 ...
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