Polycyclic cycloheptane synthesis Methodologies

Polycyclic cycloheptane synthesis Methodologies

Polycyclic cycloheptane synthesis
Methodologies
Literature review presentation
Grenning Group
Fabien Emmetiere
Our journey
✴  Direct formation of 7-membered ring
✴  [4+3] cycloaddition
✴  [5+2] cycloaddition
✴  Conclusion
Natural products
Example of natural products with pharmaceuticals interest
O
H
OH
OH
OH
HO
OH H
HO
CHO
(+)-frondasin A
O
(+)-allocyathin B 2
(+)-dictamnol
Manicol
MeO
NHAc
OH iPr
OH
MeO
CH2OH
Aphanamol I
OMe
O
OMe
Colchicine
and a lot more!
Kai E. O. Ylijoki, Jeffrey M. Stryker, Chem. Rev. 2013, 113, 2244−226634.
OH
Widdrol
Lasidiol
Direct formation of 7-membered ring
Dieckmann condensation
CO2Et
CO2Et
O
NaH
CO2Et
Ether, 15h
Mechanism
O
OEt
O
CO2Et
CO2Et
Jacob, T. M.; Vatakencherry, P. A.; Dev, S. Tetrahedron 1964, 20, 2815.
80-90%
Direct formation of 7-membered ring
Ruzicka cyclization
H
O
H
H
Fe
CO2H
CO2H Ba(OH)
2
pyrolysis
O
O
24%
H
Mechanism
O
OH
H
H
H
H
OH
O
Krapcho, A. P.; Mundy, B. P. J. Org. Chem. 1967, 32, 2041.
OH
O
O
O
O
O
O
H
Δ - CO2
H
Direct formation of 7-membered ring
Thorpe-Ziegler reaction
Ph(Me)N Li
PhBr, ether
rt, 48h
CN
CN
HCl, 30min
H
H
H
O
58%
H
Mechanism
. N
N
N
H
N
B-H
B
N
N
Δ O
O
OH
HCl
NH
O
- CO2
Allinger, N. L.; Zalkow, V. B. J. Am. Chem. Soc. 1961, 83, 1144.
N
- 2NH3
Direct formation of 7-membered ring
Acid-mediated olefin cyclization
CHO silica gel
OH
80%
2%-5% ether-C6H 6
Mechanism
O
O
H
H+
OH
OH
- H+
H
Marshall, J. A.; Anderson, N. H.; Johnson, P. C. J. Org. Chem. 1970, 35, 186.
Direct formation of 7-membered ring
Ring expansion
TsO
OH
O
O
KOH, tBuOH
rt, 6h
H
O
61%
Ac2O, Py
CH2Cl2
2 days
OH
O
O
AcO
Mechanism
TsO
OH
TsO
O
O
O
KOH
O
O
O
O
O
OH
OH
Heathcock, C. H.; Delmar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907.
TsO
HO
Direct formation of 7-membered ring
Ring expansion
O
O
Bn
CO2tBu
O
CO2tBu
BF 3 OEt2
Bn +
+
N2
tBu
CH2Cl2
-78°C
30min
H
91% dr 20:1
Bn
tBu
tBu
CO2tBu
H
Tiffeneau-Demjanov type ring expansion
BF 3
tBu
O
eq. attack
BF 3
Bn
O
CO2tBu
N2
BF 3
O
N2
tBu
Bn
CO2tBu
F 3B
Bn
tBuO
Hashimoto T.; Naganawa Y.; Maruoka K. J. Am. Chem. Soc. 2009, 131, 6614–6617.
CO2tBu
N2
tBu
Bn
F 3B
O
N2
O
O O
N2
O tBu
Bn
Direct formation of 7-membered ring
Ring expansion
5mol% [Rh(OH)(cod)]2
(PhBO)3
3eqArB(OH)
H 2O
O O
O
2
Et
Ph
dioxane, 100°C, 6h
[Rh]-OH
Et
[Rh]-Ar
Et
H 2O
Et
O
Ph
O
[Rh]
[Rh]
O
Et
Ar
Et
Ar
H
[Rh]
[Rh]
O [Rh]
multiple B-hydride
elimination/readdition
O
Et
Ar
O
Et
Hashimoto T.; Naganawa Y.; Maruoka K. J. Am. Chem. Soc. 2009, 131, 6614–6617.
Ar
Et
Ar
Direct formation of 7-membered ring
Radical-induced cyclisation
Bu 3SnH
cat. AIBN
I
7-endo
O
O
O
C6H 6, rt-0°C
4h
O
O
93%
O
98%
O
6-exo
7%
O
Mechanism
O
7-endo
O
6-exo
O
O
O
O
Duffault, J. M.; Tellier, F. Synthetic Communication. 1998, 28, 2467.
O
O
Direct formation of 7-membered ring
Ring Closing Metathesis
N
Mo
O
[CH 3(CF 3)2CO]2
O
Schrock catalyst
Ph
95%
1h
Mechanism
R
O
M
O
R
M
O
M
O
M
+
O
M
Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W.; Schulz, G. R.; Wagener, K. B. J. Am. Chem. Soc. 1992, 114, 10978.
[4+3] cycloaddition
Concept
+
Electron rich diene + allylic cation
First example of [4+3]
O
O
O
Ph 2,6-lutidine
Ph
Cl
DMF, rt
96h
Fort, A. W. J. Am. Chem. Soc. 1962, 84, 4979.
Ph
Ph
O
Ph
18%
Ph O
[4+3] cycloaddition
Allylic cation precursors
TMS
R
N
O
OTMS
O
RO
OR
oxallyl
2-aminoallyl
allyl acetal
unsaturated carbonyl
Example of oxallyl cation
O
O
Br
Br
O
O
O
+
O
O
+
O
Mixture of products, could be controlled by LA used
Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1984, 23, 1.
[4+3] cycloaddition
Intramolecular [4+3]
OEt
pTolSO 2 Et
TiCl4
O
O
Et
74%
O
CH2Cl2, -78°C
only! Mechanism
E
OEt
pTolSO 2 Et
OEt
OEt
Et
O
O
+
OEt
O
8.4
O
TS2
TS1
TS2
Et
TS1
Et
Et
OEt
0
2.2
-0.4
O
-3.5
Harmata, M.; Gamlath, C. B. J. Org. Chem. 1988, 53, 6156.
Harmata, M.; Schreiner, P. R. Org. Lett. 2001, 3, 3663.
4.0
-3.4
[4+3] cycloaddition
Allylic acetal as precursor
O
OTES
O
O
O
O
TMSOTf
-95°C, 10min
O
O
+
Ph
O
Ph
Ph
major
minor
TS
O
O
O
SiEt 3
O
H
H
O
Et 3Si O
H
H
favored
Stark, C. B. W.; Eggert, U.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. 1998, 37, 1266.
H
H
H
H
disfavored
O
[4+3] cycloaddition
Unsaturated carbonyl compounds
1. SnCl 4
O
OH
SiMe 3
O
2. H 2O
Mechanism
O
SiMe 3
O
SnCl 4
SiMe 3 SnCl 4
O
Sasaki, T.; Ishibashi, Y.; Ohno, M. Tet. Lett. 1982, 23, 1693.
O
OSiMe3
OH
32%
H 2O
[4+3] cycloaddition
2-Amino allyl cation
R
N
R
N
nBuLi
R
N
LA
methyleneaziridine
X
Mechanism
R
N
LA
R
N
LA
N
R
LA
N
R
R
N
LA
Example
Bn
N
O
BF 3 OEt2
CH2Cl2, rt, 16h
Bn
N
H
O
Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem. Int. Ed. 2004, 43, 6517.
67%
[5+2] cycloaddition
Concept: discovery 1885
OAg
O
O
O
O
OH
OH
EtBr
+
O
O
O
OH
O
H
H
silver salt of perezone
pipitzol
Mechanism: intramolecular perezone type cycloaddition
LA
H
O
O
LA
HO
O
OH
OH
BF 3 OEt2
0°C, CH2Cl2
O
O
+
O
H
Anschütz, R.; Leather, W. Chem. Ber. 1885, 18, 715.
Joseph-Nathan, P.; Garibay, M. E.; Santillan, R. L. J. Org. Chem. 1987, 52, 759.
O
O
H
H
98% 9:1
[5+2] cycloaddition
First intermolecular [5+2]
O
O
O
Ph
O
O
Ph
HClO 4
O
O
O
CH2Cl2
Mechanism: intermolecular perezone type cycloaddition
O
O
O
O
Ph
O
OH
O
O
O
O
O
O
Ph
O
Ph
OH
O
O
H
O
O
Ph
O
O
O
O
Mamont, P. Bull. Soc. Chim. Fr. 1970, 1557.
Ph
O
O
O
[1,3]
hydride shift
O
Ph
O
O
[5+2] cycloaddition
Intermolecular Lewis-Acid mediated [5+2]
O
O
O
O
O
i
R TiCl4/Ti(O Pr) 4
Ph
CH2Cl2, -78°C
O
Ph
R
H
Ph
O
Ph
O
[Ti]
H
O
[Ti]
O
OH
O
R
Ph
O
OH
[Ti]
O
O
R
Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K. O., Jr.; Ray, J. E. J. Org. Chem. 1994, 59, 6567.
Ph
O
O
R
[5+2] cycloaddition
Oxidopyrilium Ylid [5+2]
O
O
O
O
O
O
O
O
Intramolecular [5+2]
OH
O
OH
O
O
N
O
PhH
reflux
O
OAc
O
Ac2O
O
N
O
N
Garst, M. E.; McBride, B. J.; Douglass, J. G., III. Tetrahedron Lett. 1983, 24, 1675.
H
O
55%
[5+2] cycloaddition
Vinylcyclopropane cycloaddition
R
R
Ru cat.
Catalytic cycle
Example
R
R
[Ru]
R
10mol%
[CpRu(MeCN) 3]PF6
R
[Ru]
[Ru]
CH2Cl2, 0°C
HO
HO
TIPSO
OH
H
TIPSO
HO
(+)-frondosin A
R
[Ru]
Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781.
[3+2+2] cycloaddition
Alkenylidenecyclopropanes with Activated Alkynes
cat. Rh{I)
X
X
R2
R1
E
+
E
R1
X
R2
R1
R2
E
Mechanism
X
Pdt
Rh(I)L n
Pdt
Rh(I)L n
RhL n
E
X
X
RhL n
X
RhL n
X
E
E
X
Rh
E
Evans P.A.; Inglesby P.A. J. Am. Chem. Soc. 2008, 130, 12838–12839
Rh
E
X
Rh
E
[3+2+2]/[4+2] cycloaddition
One pot
CO2Et
CO2Et
O
1. cat. Ni(0)
PhN
+
Me 3Si
SiMe 3
Ph
N
O
O
O
TiCl2(Oi-Pr) 2
toluene, rt
Mechanism
Ni
CO2Et
O
+
Me 3Si
PhN
SiMe 3
Ni(0)
SiMe 3
O
CO2Et
O
Ph
N
O
[4+2]
Saito S. et al; J. Org. Chem. 2009, 74, 3323–3329
CO2Et
EtO 2C
CO2Et
Ni
Ni
SiMe 3
SiMe 3
SiMe 3
Aphanamol I – 3 approaches
Via ring opening
O
H
OH
Sequence
O
hv
H
OBz
+
+
[2+2]
OBz
H H O
H OBz O
1:1
O
S
7%
H
O
H
O
OH
H H
Hansson, T.; Wickberg, B. J. Org. Chem. 1992, 57, 5370.
KOH/MeOH
O
reflux, 2h
OBz
H H
O
Aphanamol I – 3 approaches
Via [4+3] cycloaddition
O
H
Sequence
OH
CN
CHO +
O
Ph
CN
OMOM
O
MeMgI
P
Ph
85%
58%
Li
OMOM
OMOM
1. LDA
EtO
2. LAH
O OEt
P
69%
O
EtO
OEt
EtO
O
1. Tf2O, CH2Cl2, 2,6-lutidine, -78°C, 32%
H
OH
OH
2. .H 3O+, 42%
OMOM
Harmata, M.; Carter, K. W. Tet. Lett. 1997, 38, 7985.
Aphanamol I – 3 approaches
Via [5+2] cycloaddition
O
H
OH
Sequence
O
0.5mol% [Rh(CO) 2Cl]2
Toluene, 110°C, 30min, 93%
H
OBn
OBn
RE
OA
RhL n
strain-driven
cyclopropane cleavage
H
Ln
Rh
OBn
Wender, P. A.; Zhang, L. Org. Lett. 2000, 2, 2323.
H
OBN
H
OH
Conclusion
Ring expension
reactions
O
R
CO2tBu
+
N2
Radical
cyclizations
Condensation
reactions
CO2Et
CO2Et
R
O
O
O
O
+
Ring Closing
Metathesis
[5+2] cycloaddtion
+
[4+3] cycloaddtion
+
[3+2+2] cycloaddtion
Acknowledgements
✴  Grenning Group
✴  University of Florida
✴  Chemistry Department
✴ Thank you all for your attention