Polycyclic cycloheptane synthesis Methodologies Literature review presentation Grenning Group Fabien Emmetiere
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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
and a lot more!
Kai E. O. Ylijoki, Jeffrey M. Stryker, Chem. Rev. 2013, 113, 2244−226634.
OHHO OH H
HOH
CHO
O OHHO
O
CH2OH
MeO
MeOOMe
OMeO
NHAc OH
OH
OH iPr
Widdrol LasidiolAphanamol I
Manicol(+)-dictamnol (+)-allocyathin B2(+)-frondasin A
Colchicine
Direct formation of 7-membered ring
Jacob, T. M.; Vatakencherry, P. A.; Dev, S. Tetrahedron 1964, 20, 2815.
CO2EtCO2Et
NaH
Ether, 15h
O
CO2Et 80-90%
Dieckmann condensation
Mechanism
O OEt
CO2Et
OCO2Et
Direct formation of 7-membered ring
Krapcho, A. P.; Mundy, B. P. J. Org. Chem. 1967, 32, 2041.
Ruzicka cyclization
Mechanism
O CO2HCO2H
H
H
Fe
Ba(OH)2O
H
H
O 24%
pyrolysis
O
H
H
OOH
OOH
O
H
H
O
OHO
O
H
H
O
- CO2
Δ
Direct formation of 7-membered ring
Allinger, N. L.; Zalkow, V. B. J. Am. Chem. Soc. 1961, 83, 1144.
Thorpe-Ziegler reaction
Mechanism
CNCN
H
H
Ph(Me)N Li
HCl, 30min
PhBr, etherrt, 48h
H
H
O 58%
N
N
H
BN
N
N
N
B-H
NH
N
O
HClOH
O
- 2NH3- CO2
O
.
Δ
Direct formation of 7-membered ring
Marshall, J. A.; Anderson, N. H.; Johnson, P. C. J. Org. Chem. 1970, 35, 186.
Acid-mediated olefin cyclization
CHO silica gel
2%-5% ether-C6H6
OH 80%
Mechanism
O
H+
OH
OH
H- H+
OH
Direct formation of 7-membered ring
Heathcock, C. H.; Delmar, E. G.; Graham, S. L. J. Am. Chem. Soc. 1982, 104, 1907.
Ring expansion
Mechanism
O
OTsO OH
OH
KOHO
OTsO O
OH TsO HO
O
O
O
O
OTsO OH
OH
KOH, tBuOHrt, 6h
O
OO
AcO
H61%
Ac2O, PyCH2Cl22 days
Direct formation of 7-membered ring Ring expansion
Hashimoto T.; Naganawa Y.; Maruoka K. J. Am. Chem. Soc. 2009, 131, 6614–6617.
Tiffeneau-Demjanov type ring expansion
CO2tBu
N2
Bn
+
O
tBu
BF3 OEt2
CH2Cl2-78°C30min
O
tBuH
CO2tBu
Bn
O
HtBu
CO2tBu
Bn+ 91% dr 20:1
N2O
OtBuO
F3B
Bn N2
OF3B
OtBu
O
Bn
OtBu
BF3
CO2tBu
N2
Bn
eq. attack tBu
OBF3
CO2tBuBn
N2 tBu
OBF3
N2CO2tBu
Bn
Direct formation of 7-membered ring Ring expansion
Hashimoto T.; Naganawa Y.; Maruoka K. J. Am. Chem. Soc. 2009, 131, 6614–6617.
Et
O
5mol% [Rh(OH)(cod)]2(PhBO)33eq H2O
dioxane, 100°C, 6h
Et PhO[Rh]-OH [Rh]-Ar
H2O
Et PhO ArB(OH)2
Et
O
O
ArEt
[Rh]
EtAr
O [Rh]
ArEtO
[Rh]
ArEtO
[Rh]H
ArEtO
[Rh]
multiple B-hydride elimination/readdition
Direct formation of 7-membered ring
Duffault, J. M.; Tellier, F. Synthetic Communication. 1998, 28, 2467.
Radical-induced cyclisation
Mechanism
O O
IBu3SnHcat. AIBN
C6H6, rt-0°C4h O O
7-endoO
O
6-exo O
O
98%
93%
7%
O O O
O
O
O
O
O7-endo 6-exo
Direct formation of 7-membered ring Ring Closing Metathesis
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.
Mechanism
O
NMo
Ph[CH3(CF3)2CO]2
1h
O
95%
O MR
O MR
O
M
O
M
O
M +
Schrock catalyst
[4+3] cycloaddition Concept
Fort, A. W. J. Am. Chem. Soc. 1962, 84, 4979.
First example of [4+3]
+
Electron rich diene + allylic cation
PhO
Ph
Cl
2,6-lutidine
DMF, rt96h
PhO
Ph
OO
OPh
Ph18%
[4+3] cycloaddition Allylic cation precursors
Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1984, 23, 1.
Example of oxallyl cation
Mixture of products, could be controlled by LA used
O
BrBr
O O
O
O
O
O
O+ +
ONR
OR
RO
TMSOTMS
O
oxallyl 2-aminoallyl allyl acetal unsaturated carbonyl
O
OEtEtpTolSO2
O
OEtEt
+O
OEtEt
OEt
O
Et OEt
O
Et
[4+3] cycloaddition Intramolecular [4+3]
Harmata, M.; Gamlath, C. B. J. Org. Chem. 1988, 53, 6156. Harmata, M.; Schreiner, P. R. Org. Lett. 2001, 3, 3663.
Mechanism
only!
O
OEtEtpTolSO2TiCl4
CH2Cl2, -78°C74%
O
O
Et
TS1
TS2
-3.5
2.2
-3.4
-0.4
8.4
4.0
E
0
TS1 TS2
[4+3] cycloaddition Allylic acetal as precursor
Stark, C. B. W.; Eggert, U.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. 1998, 37, 1266.
OTES
O
O
Ph
O
TMSOTf-95°C, 10min
O
O O
Ph
O
OO
Ph
+
major minor
TS
OHH
HH
OSiEt3
O
O
HHH H
Et3SiO
O
favored disfavored
[4+3] cycloaddition Unsaturated carbonyl compounds
Sasaki, T.; Ishibashi, Y.; Ohno, M. Tet. Lett. 1982, 23, 1693.
Mechanism
OSiMe3
1. SnCl4
2. H2O
OOH
OSiMe3 SnCl4
OSiMe3 SnCl4
OOSiMe3
OOH
H2O32%
[4+3] cycloaddition 2-Amino allyl cation
Prie, G.; Prevost, N.; Twin, H.; Fernandes, S. A.; Hayes, J. F.; Shipman, M. Angew. Chem. Int. Ed. 2004, 43, 6517.
Mechanism
NR nBuLi
NR
LAN
R
X
NR
LA
NRLA N
RLANRLA
NR
Example
O
NBn
BF3 OEt2
CH2Cl2, rt, 16h
NBnH
O67%
methyleneaziridine
[5+2] cycloaddition Concept: discovery 1885
Anschütz, R.; Leather, W. Chem. Ber. 1885, 18, 715. Joseph-Nathan, P.; Garibay, M. E.; Santillan, R. L. J. Org. Chem. 1987, 52, 759.
Mechanism: intramolecular perezone type cycloaddition
O
OOAg
EtBrO
OH
HO
OOH
HO
+
silver salt of perezone pipitzol
O
OOH
O
OH LA
H
HO OLA
O
OOH
HO
OOH
HO
+BF3 OEt2
98% 9:10°C, CH2Cl2
[5+2] cycloaddition First intermolecular [5+2]
Mamont, P. Bull. Soc. Chim. Fr. 1970, 1557.
Mechanism: intermolecular perezone type cycloaddition
O
O
O
O
Ph
HClO4
CH2Cl2
O OO
Ph O
O
O
O
O
OO
O
HOH
Ph
O
O
O OHPh
Ph
O
O
O O
O
Ph
O
O
OO
Ph
O
O
OO
Ph
O
O
O[1,3]
hydride shift
[5+2] cycloaddition Intermolecular Lewis-Acid mediated [5+2]
Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K. O., Jr.; Ray, J. E. J. Org. Chem. 1994, 59, 6567.
O
OO R TiCl4/Ti(OiPr)4
PhCH2Cl2, -78°C
Ph
O
OO [Ti]
O
O
O[Ti]
R
R
PhH
O
O
O[Ti]
R
PhH
Ph
O
OHO
O
OH
ORPh
[5+2] cycloaddition Oxidopyrilium Ylid [5+2]
Garst, M. E.; McBride, B. J.; Douglass, J. G., III. Tetrahedron Lett. 1983, 24, 1675.
O
O
O
O
O
O O
O
Intramolecular [5+2]
N
O O
OOH PhH
refluxN
O O
OHO Ac2O
N
O OAc
OO
H
55%
[5+2] cycloaddition Vinylcyclopropane cycloaddition
Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007, 129, 11781.
Catalytic cycle
TIPSOHO
10mol%[CpRu(MeCN)3]PF6
CH2Cl2, 0°CHO H
TIPSO HO
OH
(+)-frondosin A
R
R
[Ru]
[Ru]
R
[Ru]R
R
[Ru]
R Ru cat.
R
Example
[3+2+2] cycloaddition Alkenylidenecyclopropanes with Activated Alkynes
Evans P.A.; Inglesby P.A. J. Am. Chem. Soc. 2008, 130, 12838–12839
X
R1R2 E
cat. Rh{I)X
R1
E
R2
X
R1
R2
E
+
X
RhLn
E
X Rh EXRh
E
XRh E
XRhLn
EX
RhLn
E
Rh(I)Ln Rh(I)Ln
XPdt Pdt
Mechanism
[3+2+2]/[4+2] cycloaddition One pot
Saito S. et al; J. Org. Chem. 2009, 74, 3323–3329
Mechanism
CO2Et
Me3Si
1. cat. Ni(0)
TiCl2(Oi-Pr)2toluene, rt
PhN OO
+ PhN
O
OSiMe3
CO2Et
+
Me3Si Ni(0)
Ni SiMe3
CO2Et
NiSiMe3
CO2Et
Ni
SiMe3
EtO2C
SiMe3
CO2EtPhN OO
[4+2]
PhN
O
OSiMe3
CO2Et
Aphanamol I – 3 approaches Via ring opening
Hansson, T.; Wickberg, B. J. Org. Chem. 1992, 57, 5370.
Sequence
O
H OH
+
O
OBz
hv
[2+2]OH
OBz
H OH
H
OBz
+
SO
H
OBz
H O
KOH/MeOH
reflux, 2hH
O
H O
HO
H OH
1:1
7%
Aphanamol I – 3 approaches Via [4+3] cycloaddition
Harmata, M.; Carter, K. W. Tet. Lett. 1997, 38, 7985.
Sequence
O
H OH
CN
CHO + P
Li
OMOMPhPh
O
58%
CN
OMOM
MeMgI
85%
OMOM
O
P
OEtO
OEtEtOEtO
O
1. LDA 2. LAH
69%
OMOM
EtO
OH1. Tf2O, CH2Cl2, 2,6-lutidine, -78°C, 32%
2. .H3O+, 42%
O
H OH
Aphanamol I – 3 approaches Via [5+2] cycloaddition
Wender, P. A.; Zhang, L. Org. Lett. 2000, 2, 2323.
Sequence
O
H OH
OBn
0.5mol% [Rh(CO)2Cl]2
Toluene, 110°C, 30min, 93%H OBn
O
H OH
H
RhLn
OBnH
LnRh
OBN
OA RE
strain-driven
cyclopropane cleavage
Conclusion
CO2EtCO2Et
Condensationreactions
Ring expensionreactions
CO2tBu
N2
R
+
O
RRadical
cyclizations
O O
O
Ring Closing Metathesis
[4+3] cycloaddtion
+
+O
[5+2] cycloaddtion
+
[3+2+2] cycloaddtion
Acknowledgements
✴ Grenning Group ✴ University of Florida ✴ Chemistry Department
✴ Thank you all for your attention
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