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Cyclization of Cross-Conjugated Trienes: The Vinylogous Nazarov Reactions
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504-7505
Nazarov Cyclization Initiated by Peracid Oxidation: The Total Synthesis of (±)-Rocaglamide
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560-7561
Antoinette NibbsShort Literature Presentation
2 February 2010
Frederick G. West
B.S. (1980): University of Arizona Chemistry, Summa cum Laude (Victor Hruby)
Ph.D. (1986): University of Wisconsin (Edwin Vedejs)1981-1984: NSF Predoctoral Fellow
Post Doc (1986-1988): Columbia University (Gilbert Stork)1986-1988: NIH Postdoctoral Fellow
Professor (1988-1989): University of Utahresearch areas: 4-pyranone photochemisty, Stevens rearrangement,
Nazarov cyclizations, taxane synthesis
Professor (2002 to present): University of Alberta
Frederick G. West
c Dr. John Andraos, 2002
Frederick G. WEST(Wisconsin, 1986) [Utah, Alberta]
Edwin VEDEJS(Wisconsin, 1966; Harvard)
Andrew J. VREUGDENHIL(McGill, 1996) [Trent]
William D. LUBELL(Nagoya) [McGill]
Ryoji NOYORI(Kyoto, 1967; Harvard)
John F. BECK (UBC, 1971) [St. Francis Xavier]
Edward PIERS (UBC) [UBC]
Donald C. WIGFIELD (UBC) [Carleton]
Andrew G.H. WEE(Stanford) [Regina]
George JUST(Stanford) [McGill]
Robert MCCRINDLE(Stanford) [Guelph]
James P. KUTNEY(Wayne State, 1958)[UBC]
Carl DJERASSI(Wisconsin, 1945)
Alfred L. WILDS(Michigan, 1939)
Frank E. SMITH(McGill) [Laurentian]
Robert A. GOSSAGE(Victoria, 1996) [Acadia]
Stephen R. STOBART(McGill) [Victoria]
Mihai SCARLETE(McGill, 1995) [Bishop's]
Yining HUANG(McGill, 1992) [Western]
Pierre D. HARVEY(McGill, 1985) [Sherbrooke]
Ann M. ENGLISH(McGill, 1980) [Concordia]
Ian S. BUTLER(Northwestern) [McGill]
Fred BASOLO(Illinois, 1943)
John C. BAILAR(Michigan, 1928)
Moses GOMBERG(Michigan, 1894)
Albert B. PRESCOTT(Michigan, 1886)
John C. SHEEHAN(Michigan, 1941)
Elias J. COREY(MIT, 1951) Chemistry Nobel 1990)
Werner BACHMANN(Michigan, 1926)
Tony DURST(Harvard) [Ottawa]
Livain BREAU(Ottawa, 1991)[UQAM]William OGILVIE(Ottawa, 1989) [Ottawa]
David E. CANE(Harvard, 1971)
Youla S. TSANTRIZOS(Brown) [Concordia]Paul H.M. HARRISON(Brown) [McMaster]
Norman A. NELSON(Wisconsin, 1952)
Leo PAQUETTE(MIT, 1959)
Louis BARRIAULT(Ohio State) [Ottawa]Peter D. WILSON(Ohio State) [SFU]
Robert W. PARRY(Illinois, 1947)
Duward F. SCHRIVER(Michigan, 1961)
Ivor WHARF(Northwestern)[McGill]RabinBISSESSUR(Northwestern)[UPEI]
Cornelius K. CAIN(Johns Hopkins, 1939)
Edward C. TAYLOR(Cornell, 1949)
Charles W. JEFFORD(Princeton, 1962)
F.Y. WISELOGLE(Michigan, 1936)
James MCNULTY(Geneva) [Brock]
John BOUKOUVALAS(Warwick) [Laval]
Nazarov Cyclization
O
R2
R1 R3
R4
O
R3R1
R2 R4
4π ERC stereocontrol?O
LA
R2
R1 R3
R4
"acid"
O
R3R1
R2 R4
LA
H
O
R3R1
R2 R4
LA
loss of stereocenter
O
R4R2
conrotatory
R1R3
LA
New Approaches to Stereocontrol: Employing Bridged Bicyclic Dienones
Mazzola, R. D., Jr.; White, T. D.; Vollmer-Snarr, H. R.; West, F. G. Org. Lett. 2005, 7, 2799
Me Me
Me
H O
Me
SiMe3
BF3·OEt2–78 → 0 °C
Me Me
Me
H
HH
O
70%, 19:1 dr
–78 → –40 °CBF3·OEt2
Me MeMe O
Me
SiMe3
Me MeMe H
H
Me
O 81%, >33:1 dr
New Approaches to Stereocontrol: Chiral Auxiliaries for the Allene Ether Nazarov
Banaag, A. R.; Tius, M. A. J. Am. Chem. Soc. 2007, 17, 5328
NO
O
MePh
OOTBSOTBS
TBSO OLi
HH
OOO
OTBS O
Ph
Li
HH
O
Me
OH
Ph
4/96 er
OH
Me
O
Ph
95/5 er
Interrupted Nazarov Cyclization
Rieder, C. J.; Fradette, R. J.; West, F. G. Chem. Commun. 2008, 1572
OBF3·OEt2
O
OH
H H
O OH
H H
OO
O
R3R1
R2 R4
LA
H
elimination trapping
Nu O
R3R1
R2 R4
NuO
R3R1
R2 R4
Alternatives to Carbonyl Precursor
Grant, T. N.; West, F. G. J. Am. Chem. Soc. 2006, 128, 9348–9349; Grant, T. N.; West, F. G. Org. Lett. 2007, 9, 3789–3792
R3R2
R1
OTIPS CHCl350% aq. NaOH
BnEt3NCl R3R2
R1
TIPSO ClCl
O
R1
R2 Cl
R3
O inherent limitations of dienone substitution pattern
LA
R2
R1 R3
R4
O
R2
R1 R3
R4
R
R2
R1 R3
R4
substrate initiation?
AgBF4, rt
CH2Cl2Cl
R3R1
R2
O
Cl
R3R1
R2
O
Alternatives to Carbonyl Precursor: Imino Nazarov
PhMe
CN
OMOM
Li
H
H
PhMe
N
OMOM
H
H
Li
Me
NH2Ph
O
73%
Vinylogous Nazarov?
R2
R1 R3
R4
O
R5
Tius, M. A.; Chu, C. C.; Nieves-Colberg, R. Tetrahedron Lett. 2001, 42, 2419
MXn
R2
R1 R3
R4
O
R5
MXn
4π ERCR1
R2
R3
R4
O
R5
MXn
H+ transferR1
R2
R3
R4
O
R5
Preparation of Cross-Conjugated Trienes
Bradford, T. A.; Payne, A. D.; Wilis, A. C.; Paddon-Row, lM. N.; Sherburn, M. S. Org. Lett. 2007, 9, 3789
Plan A: metal-catalyzed cross couplings
Plan B: homologation of cross-conjugated dienonesO
R2
R1 R3
R4
MgBr
X R
R
X
Zn R
X
Zn
BrMg R
X R
Ni(dppp)Cl2
THF, —20 to 25 °C
Pd(PPh3)4,
THF, —78 to 25 °C
Ni(dppp)Cl2
THF, —20 to 25 °C
Pd(PPh3)4,
THF, —78 to 25 °C
Negishi cross-coupling
Tamao-Kumada-Corriu cross-coupling
unreactive to standard olefination reagents
Preparation of Cross-Conjugated Trienes
homologation of cross-conjugated dienones O
R2
R1 R3
R4
Meyer-Schuster rearrangement of bis-allylic propargyl carbinols:
OH
PhPh
Ph
H+ Ph
Ph
Ph
Ph Ph
O
HOH
Ph
Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71, 429See also: Engel, D. A.; Lopez, S. S.; Dudley, G. B. Tetrahedron 2008, 64, 6988
Ramon, Ruben S.; Marion, N.; Nolan, S. P. Tetrahedron 2009, 65, 1767
OH
R2R1
OEt
AuCl3 (5 mol %) R2
R1 OEt
O
HR1,2 = alkyl, aryl
Preliminary Experiments
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504
OOEtLi
THF, —78 °C99%
HO
OEt
SiO2
94%
CO2Et
O
Ph
Me Me
Ph
OEtLi
THF, —78 °C99% Ph
Me Me
Ph
HO
OEt
Ph
Me Me
Ph
CO2Et
SiO2
Au(III)
X
X
O
Ph
Me Me
Ph
OEtLi
THF, —78 °C99% Ph
Me Me
Ph
HO
OEt
VO(acac)2
PhMe, 80 °C84% Ph
Me Me
Ph
CO2Et
Meyer-Schuster Homologation of DienonesO
R2
R1 R3
R4
OEtLi
VO(acac)2, PhMe, 80 °C
,THF, —78 °C
R2
R1 R3
R4
CO2Et
O
R2
R1 R3
R4
OEtLi
THF, —78 °CR2
R1 R3
R4
HO
OEt
VO(acac)2
PhMe, 80 °CR2
R1 R3
R4
CO2Et
5 1
CO2Et
99%61%
Ph
Me Me
Ph
99%84%
i-Pr
Me Me
i-Pr
98%76%
Ph
Me Me
H
92%81% (1:1 mixture)
93%80% (7:3 E/Z)
H
Me
96%78%
Me
Me Me
Me
36%75%
CO2Et CO2EtCO2EtCO2Et
CO2Et CO2Et
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504
Reactivity of Other Carbonyl Groups
i-Pr
Me Me
i-Pr
CO2Et
1. DIBAL
2. MnO297% yield over two steps
Me Me
i-Pr i-Pr
O
H
(MeO)NHMe·HCl
i-PrMgCl 82%
O
N(OMe)MeMe Me
i-Pr i-Pr
MeMgCl
74% over two steps
O
MeMe Me
i-Pri-Pr
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504
O
R2
R1 R3
R4
OEtLi
2. VO(acac)2, PhMe, 80 °C
,THF, —78 °C
R2
R1 R3
R4
CO2Et1.
Evaluation of Activation Conditions
Bronsted acids (HCl, H3PO4, CF3CO2H) and Lewis acids (FeCl3, SnCl4) provided minimal conversion
Ph
Me Me
Ph
CO2Et
Me
Ph
Me
Ph
CO2Et
mixture of regioisomers
conditions
DCE 55 °C 55 %Sc(OTf)3 5 mol %
Lewis acid solvent temp yieldamount
BF3·OEt2 –78 °C → rt 70%CH2Cl21.1 equiv–78 °C → rtCH2Cl2 76%TiCl4 1.1 equiv
TiCl4 substoichiometric partial conversion–78 °C → rtCH2Cl2
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504
Cyclization and Modifications
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504
R2
R1 R3
R4
Method A: TiCl4, CH2Cl2, –78 °C
Method B: Sc(OTf)3 (cat)., DCE 55 °C R1
R2
R3
R4
O
XX
O
O
OEt
83%79%
Me
Ph
Me
Ph
O
OEt
75%93%
OEt
O
H
MeOEt
O
OEt
O
75%0 % 0%
Me
Me Me
Me
Cyclization and Modifications
R2
R1 R3
R4
Method A: TiCl4, CH2Cl2, –78 °C
Method B: Sc(OTf)3 (cat)., DCE 55 °C R1
R2
R3
R4
O
XX
O
Me
i-Pr
Me
i-Pr
O
N(OMe)Me
76% (at 0 °C)
Me
i-Pr
Me
i-Pr
O
Me
74% (yield over two steps from Weinreb amide dienone)
MeMgCl
Me
i-Pr
Me
i-Pr
O
H
Me
i-Pr
Me
i-Pr
OH
86%
NaBH4, CeCl3
EtOH
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504
Conclusions
R2
R1 R3
R4
Method A: TiCl4, CH2Cl2, –78 °C
Method B: Sc(OTf)3 (cat)., DCE 55 °C R1
R2
R3
R4
O
XX
O
replacement of carbonyl with enoate, enamide, enone, or enal functionality affords viable substrates
substoichiometric amounts of Sc(OTf)2 are sufficient
all examples (except for Me-Ph-Me-Ph) afford single diene regioisomer
exocyclic alkene formed as a single stereoisomer
Rieder, C. J.; Winberg, K. J.; West, F. G. J. Am. Chem. Soc. 2009, 131, 7504
Alison J. Frontier
B.S. (1992): Harvard University, Chemistry (Yoshito Kishi)
(1992-1994): Research Scientist, Basic Medicinal Chemistry Division, Merck
(1997-1998): Division of Organic Chemistry Fellowship
Ph.D. (1999): Columbia University (Samuel Danishefsky)
Post Doc (1999-2001): Stanford University (Barry Trost)NIH Postdoctoral Fellow
Professor (2002 to present): University of Rochesterresearch program: organometallic strategies, pericyclic reactions
asymmetric catalysis, total synthesis
Rocaglamide
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
cyclopenta[b]tetrahydrobenzofuran-containing heterocycleisolated from the root and stems of Aglia elliptifolia by King in 1982
rocaglamide and related compounds demonstrated cytostatic and cytotoxic activity against a number of human cancer cell lines:
IC50 = 1.0–6.0 ng/mL
synthetic challengefive contiguous stereocenters
cis aryl groups on adjacent carbonshighly oxygenated system
before this paper, seven total syntheses, two affording enantioenriched products (Trost and Porco)
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
[3+2] Cycloaddition Strategy
Gerard, B.; Sangji, S.; OʼLeary, D. J.; Porco, Jr., J. A. J. Am. Chem. Soc. 2006, 128, 7754
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
O
OOMe
MeO
OH
OMe
CO2MePh
MeOH, 0 °C,uranium filter
hυTADDOL der.
OMe
MeO O
HO
Ph
CO2Me
O
PMP
NaOMeMeOH
O
O
CO2MeHO
OMe
MeO
OMe
Me4NBH(OAc)3
O
OH
CO2Me
PhPMP
HOOMe
MeOO
OH
CO2Me
PhPMP
HOOMe
MeO
exo methyl rocaglate endo methyl rocaglateO
OHOMe
MeO
O
OMe
MeO
O
Ph
Oxidative Cyclization
OH
CO2R
OMe
MeO
OMe
CO2R
O
CO2R
OMe
MeO
OMe
CO2RDDQ
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
Trost, B. M.; Greenspan, P. D.; Yang, B. V., Saulnier, M. G. J. Am. Chem. Soc. 1990, 112, 9022
O
CO2R
OMe
MeO
OMe
CO2R
Original Synthetic Plan
O
OMe
O
OMe
OOMe
MeO
δ- δ+ O
OOMe
MeO
OMe
OMe
Oelectro-
cyclization
M
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
H2O
O
O
PhPMP
HOOMe
MeO OMe
O
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
Lewis acid
O
OMe
O
OMe
OOMe
MeO
M
The Best Laid Plans of Mice and Men...
OPMP
OR
OMe
MeOLewis acid
H2O
M
Ph
OPMP Ph
O
OMe
O
δ- δ+
OMe
MeO Lewis acid
H2OO
PMP Ph
O
OMe
OOMe
MeO
M
OPMP Ph
OR
OMe
MeO
δ-δ+δ- δ+
R = EDG, reestablishes complementary polarizationand stabilizes oxyallyl cation
O
O
R
PhPMP
OMe
MeO
M
R = CO2Me, both termini electron deficient
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
Complementary Polarization
δ-δ+
OPMP
OR
OMe
MeOLewis acid
H2O
M
PhO
PMP Ph
OR
OMe
MeO
δ-δ+
R = EDG, reestablishes complementary polarizationand stabilizes oxyallyl cation
OPMP
OROMe
MeO
H
Ph
Testing This Hypothesis
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
O
O
R
PhPMP
OMe
MeO
M
OPMP
OROMe
MeO O
Ph
[O]
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
Synthesis of Propargyl Ethers
O
O
OMe
MeO
PMP
O
OMe
MeO
PMP
OR
Ph
1. phenylacetylene, n-BuLi, THF;
2. KH, EtI, THF, 64% or KH, NaI, PMBCl, THF 69% over three steps
R = Et or PMB
1. CeCl3, MgBrthen 1.0 M HCl, 65%
2. OsO4, NMO, acetone/t-BuOH/H2O; then NaIO4, THF/H2O
CHO
O
OMe
MeO
PMP
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
Key Bond-forming Step
O
OMe
MeO
PMP
OROH
PhSnBu3
O
OMe
MeO
PMP
OR
SnBu3
Pht-BuLi, Bu3SnCl
Et2O
no hydridoalkoxyallene
O
OMe
MeO
PMP
OR
Ph
R = Et or PMB
O
OR
O
PhPMP
OMe
MeO
single diastereomer
m-CPBA
DMF, 23 °C40-50% over
two steps
oxidation/Nazarov cyclization cascade
O
OMe
MeO
PMP
OR
SnBu3
PhO
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
Completion of Synthesis
O
OEt
O
PhPMP
OMe
MeO
all attempts to functionalize ethyl enol ether failed
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
Backup Plan
Pd(PPh3)4, CO, MeOH
DIPEA, THF, 65 °C (79%)
O
O
CO2Me
PhPMP
OMe
MeO
HO
O
OPMB
O
PhPMP
OMe
MeO
1. DDQ, CH2Cl2 (71%)
2. KHMDS, PhNTf2, THF, 0 °C (83%) O
O
OTf
PhPMP
OMe
MeO
HO
enol ether cleavageinstallation of OH under oxidative conditions
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
Mission Accomplished
oxidation/Nazarov cyclization as key bond-forming step pentadienyl cation generated through the peracid oxidation of an allenol ether
O
O
CO2Me
PhPMP
OMe
MeO
HO
O
O
CO2Me
PhPMP
OMe
MeO
HOPtO2, H2
EtOH 65%
11 steps
NaHB(OAc)3
MeCN/AcOH 56% O
OH
CO2Me
PhPMP
OMe
MeO
HO
aglafolin
O
OH
CO2Me
PhPMP
OMe
MeO
HO
aglafolin
O
OH
PhPMP
OMe
MeO
HONMe2
O
rocaglamide60%
Me2NH·HCl, DCC, DMAP
LiOH, THF/H2O
82%
O
OH
PhPMP
OMe
MeO
HOOH
O
rocagloic acid
Malona, J. A.; Cariou, K.; Fronteir, A. J. J. Am. Chem. Soc. 2009, 111, 7560
O
OH
PhPMP
HOOMe
MeO R
O
R = NMe2, rocaglamideR = OMe, aglafolin
