an interrupted vinylogous iso nazarov reaction: of ...ccc.chem.pitt.edu/wipf/current...
TRANSCRIPT
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Mart ín J . R i ve i ra and Mir ta P. Mischne .
J . O r g . C h em . , 2 0 1 4 , 7 9 ( 1 7 ) , pp . 8 2 4 4 ‐ 8 2 5 4
( N a t i o n a l U n i v e r s i t y o f R o s a r i o , S a n t e F e , A r g e n t i n a )
An Interrupted Vinylogous Iso‐Nazarov Reaction: Cycloisomerization of Conjugated Trienones to
Cyclopenta[b]furan Derivatives
A. Manos‐Turvey,Wipf Group Current Literature
October 11th, 2014
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New Scaffolds via Cycloisomerisation
The Mischne group is interested in synthesis of new carbo‐ and heteropolycyclic molecular scaffolds, through the use of efficient and innovative methodology
This work resulted from an unexpected cyclopenta[b]furan product obtained from a Knoevenagel‐type condensation, leading to a stereoselective annulation cascade reaction of 1,3‐dicarbonyl substrate, dimedone, with an α,β,ϒ,δ‐unsaturated aldehyde
M.J. Riveira, C. Gayathri, A. Navarro‐Vázquez, N.V. Tsarevsky, R.R. Gil, M.P. Mischne, Org. Biomol. Chem., 2011, 9, 3170‐3175M.J. Riveira, M.P. Mischne, Chem. Eur. J., 2012, 18, 2382‐2388
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New Biologically Active Scaffolds
Cyclopenta[b]tetrahydrobenzofurans are of interest as they can have antileukemic, insecticidal and cytostatic biological properties
The cyclopenta[b]furan motif alone has also been shown to be of clinical significance
N. Ribeiro, F. Thuaud, C. Nebigil, L. Désaubry, Bioorg. Med. Chem., 2012, 20, 1857‐1864N. Li, L. Di, W.‐C. Gao, K.‐J. Wang, L.‐B. Zu, J. Nat. Chem., 2012, 75, 1723‐1728
O
Br
Aplysin
-hepatoprotective effect-anti-tumour activity,resensitising agent
O
HO
OMe
CONMe2HO
MeO
MeOPh
O
H
H
OH
HO2C
ROH
Rocaglamide
-insecticidal activity-anti-proliferativecancer activity
Benzoprostacyclins
-active against pulmonaryvascular and diseases
OHC
O
H
H
OGlcH
Iridoid glucosides
-cytotoxicity against cervicaland gastric carcinomas
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New Scaffolds via Cycloisomerisation
Further experimental investigations revealed:
substituted dienals at the α‐ and ϒ‐position (R1 and R2 resp.) result in cyclopenta[b]furan derivatives
unbranched dienals (R1 and R2 = H) give trienedione products, stable in solid form alternate dicarbonyl substrates are tolerated
Suggested that steric effects may contribute to destabilisation of the expected Knoevenagel condensation open form product
M.J. Riveira, M.P. Mischne, Chem. Eur. J., 2012, 18, 2382‐2388
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Stalled Cycloisomerisation Products
O
O
50%
O
O
90%
O
O
60%
O
O
70%
O
O
50%
O
O
90%
M.J. Riveira, M.P. Mischne, Chem. Eur. J., 2012, 18, 2382‐2388
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Proposed Mechanism for Alternate Products
X
O
OH
R3OHC
R2
X
HO
O
R3
R2
+1,2-addition
X
O
O
R3
R2R1
R1
OH+ H+, - H2O
X
O
O
R3
R2R1
X
OH
OR1
R3
R2
isomerisation- H2O
X
O
O
R3
R2R1
(R1 = H)
4 conrotatoryring closure
X
O
O
R3
R2 R1
H
R1
H- H+
(R1 H)
CA
B
DEM.J. Riveira, M.P. Mischne, Chem. Eur. J., 2012, 18, 2382‐2388
A.F. Kluge, C.P. Lillya, J. Org. Chem., 1977, 36, 1971‐1988
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The Nazarov Cyclisation
O
R2R1
O
R2R1
O
R2R1
A A
A
O
R2R1
A
a4
O
R2R1
AO
R2R1
AO
R2R1
deprotonation+ H+
R2R1
O
+/or
C. Santelli‐Rouvier, M. Santelli, Synthesis, 1983, 429‐442E.A. Braude, J.A. Coles, J. Chem. Soc., Abstracts, 1952, 1430‐143
D.N. Kursanov, Z.N. Parnes, I.I. Zaretskaya, I.N. Nazarov, Chem. Sci, 1953, 103‐107
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The Iso‐Nazarov Cyclisation
nBu
O
AuL+O
nBu
a4
nBu
O
nBu
H
O
nBu
H
OAuL AuL
HAuL
AuL
OLA
OLA O
LA1357 135
7
2468
8
64 2
13572468
O LA
34
567 8
21
O
34
567 8
21
W.T. Spencer III, T. Vaidya, A.J. Frontier, Eur. J. Org. Chem., 2013, 3621‐3633G.R. Elia, R.F. Childs, G.S. Shaw, Can. J. Chem., 1992, 2065‐2069
N.C. Baird, Tetrahedron, 1972, 2355‐2360
Could electrophilic activation of the stable unsaturated 1,3‐dicarbonyl substrates allow for cation rearrangement followed by intramolecular cation trapping via a related mechanism?
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Reaction Condition Screening
O
O
acid catalyst,solvent 0.1 M,
reflux
O
O
H
H
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Screening of FeCl3 as Catalyst
O
O
acid catalyst,solvent 0.1 M,
reflux
O
O
H
H
c = reaction carried out at rt d = only distilled, not dried, CH2Cl2 was used
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Substrate Scope
O
O
O
O
H
H
0.5 mmol substrate in CH2Cl2 (0.1 M) at reflux with FeCl3 (0.5 eq)
substrate time (h) product yield
O
O
O
O
H
H
O
O
H
H+
3 80%
4 85% (0.6:1)
4 80% (insep dias.)
4 80%
O
O
O
O
O
O
H
H
O
O
H
H
O
O R
R = H, 7R = OMe, 4R = F, 3
R = H, 85%R = OMe, 85%R = F, 75%
O
O
H
H
R
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Substrate Scope and Limitations
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Proposed Mechanism
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Substrate Limitation?
spon. 60%
O
O
O
O
H
H
spon. 65%
O
O
O
O
H
H
spon. 60%
O
O
O
O
H
H OO
CDCl3 at rt for 2 weeks
substrate time (h) product yield
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ε‐Branched Compound Reactivity
The compounds that had undergone “spontaneous” cyclisation in initial testing were subjected to the actual reaction conditions, to give different tricyclic products greater efficiency with 1 eq of FeCl3
O
O
PhO
O
H
H Ph
O
O
O
O
H
H
O
O
Ph
H
O
OH
FeCl3 (1 eq),CH2Cl2 (0.1 M),reflux, 2 h
CDCl3NMR tube
60% 60%
85%65%
O
O
R3
R2
R4R1 O
O
R4R3
R2
R1
HFeCl3 (0.5 eq),CH2Cl2 (0.1 M),
reflux
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Further Labeling Studies
Three alkyl‐branched deuterated substrates were synthesised and products assessed
ζ‐D retention was quite low in the alternate cycloisomerisation, suggesting a new mechanism an elimination step was considered likely
O
O
Ph
D D
O
O
D
D
PhDCDCl3
NMR tube
Ac/d/e
Dc (60%)Dd (67%)De (65%)
DFeCl3 (1 eq.)CH2Cl2 (0.1 M)reflux, 1 h
Fc (73%)Fd (62%)Fe (65%, 0.15:1 D:H)*
O
O
Ph
D DH/D
*Fe = 55%, 1.5:1 D:H if reaction carried out in D2O-saturated CH2Cl2
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New Mechanistic Insight
The authors suggest that the ε‐branched substrates can lead to a preference for the tertiary cyclopentenyl cation intermediate
O
O
R4
R3
A B
R5 Lewis acidactivation
R1 O
O
R5
Cl3Fe
R4
R3
R1
O
O
R5R4
R3
R1
H
R2
R2O
O
R5
Cl3Fe
R4
R3
R1
R2
elimination-R5
intram. cationtrapping
(when R3 = H)
O
O
Cl3Fe
R4
R3
R1
R2O
O
HR2R1
R4 HB
R3i) stereoselectiveprotonation
ii) intram. cationtrapping
O
O
H
H
R
FeCl3 (2 eq),CH2Cl2 (0.1 M),reflux, 8 h
O
O
H
R
R = Me (65%)R = Et (65%)
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Conclusions
Successfully demonstrated an unusual cascade reaction leading to the formation of cyclopenta[b]furan derivatives in one pot good yields, mild conditions restrictions in substrate reactivity potential for further scaffold expansion courtesy of “re‐rearranged” product discovery
The exact utility of this synthetic strategy on non‐diketal substrates is of interest reach structures of greater similarity to the cyclopenta[b]tetrahydrobenzofurans?
More detailed mechanistic studies are in the works Can these reactions be carried out asymmetrically?
Alexandra Manos-Turvey @ Wipf Group Page 18 of 18 10/12/2014