The Staunton-Weinreb Annulation SED Group meeting | Guanqun Zhang | 2015.04.21
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The Staunton-Weinreb Annulation SED Group meeting | Guanqun Zhang | 2015.04.21
Steven M. Weinreb • Brooklyn, NY – May 10, 1941 (Age 73) • Cornell University, A.B. – 1963 • University of Rochester, Ph.D. – 1967
• Advisor: Marshall Gates
• NIH Postdoc Fellow • Columbia; Gilbert Stork: 1966-1967 • MIT: George Buchi: 1967-1970
• Fordham University – 1970 • Associate professor - 1975
• Penn State University – 1978 • Professor of chemistry – 1980 • Russell and Mildred Marker Professor of Natural
Products Chemistry – 1987
Weinreb, S. M. Acc. Chem. Res. 1985, 18, 16. Weinreb, S. M. Acc. Chem. Res. 2002, 36, 59.
Short, P. C&EN 2005, 83, 65. Weinreb, S. M. Heterocycles 2006, 70, 5.
Early synthetic targets
Franck, R. Heterocycles 2006, 70, 1.
Steve Weinreb
O
ONH
HHO
OMecephalotaxine (1972)
N
NHHO2C
OO
CO2H
CO2H
methoxatin (1981)
N N
OMeMeO
HOH2N
CO2H
O
O
MeO
H2N
streptonigrin (1982)
HN H
N H
HH
HH H
HH
papuamine (1994)
O
O N H
OH
OH
pancracine (1997)
N
OMeMeO
MeOOMe
H
tylophorine (1979)
HO
OH OH OOH
OH
O
OMe OHHolivin ("1984")
MeO
OMe OMe OOH
OH
O
OMe OHH
tri-O-methylolivin (1984)
Tri-O-methylolivin
Convergent synthesis: let’s take the naphthalene apart...
MeO
OMe OMe OOH
OH
O
OMe OHH
OMe
MeO
OMe
O
O
OTHP
OMe OH
O
MeO+
OMe
MeO CO2H
Hatch, R. P.; Shringarpure, J.; Weinreb, S. M. JOC 1978, 43, 4172. Todd, J. H.; Starrett, J. E.; Weinreb, S. M. JACS 1984, 106, 1811.
Initial plan:
MeO
OMe OMe OOH
OH
O
OMe OHH
tri-O-methylolivin
MeO
OMe OMe O
CHO MeO
OMe O
CHO MeO
OMe
Cl
linear synthesis: too many steps
Dodd, J. H.; Weinreb, S. M. Tetrahedron 1979, 20, 3593. Hauser, F. M.; Rhee, R. P. JOC 1978, 43, 178.
Kraus, G. A.; Sugimoto, H. TL 1978, 19, 2263.
Weinreb was inspired by four other people:
LDA, THFmethyl acrylate
-78 oC68%
O
O
SOPh
OH
OH
CO2Me
H
LDA (3.3 equiv)MVK (3 equiv)
THF, -78 oCO
O
CN
O
O
O
85%H
Hauser, 1978 Kraus, 1978
Dodd, J. H.; Weinreb, S. M. Tetrahedron 1979, 20, 3593. Wildeman, J.; Borgen, P. C.; Pluim, H.; Rouwette, P. H.F.M.; van Leusen, A. M. TL 1978, 19, 2213.
Parker, K. A.; Kallmerten, J. L. TL 1979, 20, 1197.
(1) NaH, -56 oC(2) KOH, EtOH, H2O
(3) TFA, TFAA (2:3)(4) HOCH2CH2OH, TsOH, HC(OEt)3
47% over 4 steps
OMe
OMe CN
OMe
OMe
O
CN O O
EtO2C
O O+
NaH (2-3 equiv)
1,2-dimethoxyethane-78 oC78%
O
HTs Ph
Ph
O
+ Ph
O
Phvan Leusen, 1978
Parker, 1979
Dodd, J. H.; Weinreb, S. M. Tetrahedron 1979, 20, 3593. Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 205 and 406.
Jim Staunton
And this brings us to the Staunton-Weinreb annulation
LDA, THF
-78 oC35%
O
OMe
OMe
MeO
+
OMeO
OMe
FSO3
OMe
MeO O
OOMe
O
OEt
OMe
+ O
O
MeO48% over two steps
(1) LDA, THF, -78 oC
(2) H2CN2
OMe
O
OOMe
Staunton-Weinreb annulation general scheme
• R1 = R2 = alkyl, Bn, MOM, MEM • X = usually H or OMe • Y = CH2 or O
• o-toluate is preformed with base • o-toluate anion is bright yellow • electrophile is added later • Michael acceptor can be acyclic
or cyclic, esters or ketones
OR1
Me
OR2
O
Y
O
X
+
OR1 OH
Y
OLDATHF
-78 oC rt
It’s a stepwise sequence involving Michael addition followed by Dieckmann condensation and subsequent aromatization
OMe
MeO
OMe
O
O
OMe
O
O
O
MeO
+
- MeOH
Staunton-Weinreb annulation general mechanism
Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 205 and 406.
LDA-78 oC
OMe
MeO
OMe
OOMe
MeO
OH
OMe
O
O
can be isolated if quenched at -78 oC
can be isolated if quenched at 0 oC
OMe
Me
OMe
O O
MeO
+
OR1 OH OLDATHF
-78 oC rtMeO
Staunton-Weinreb annulation general mechanism
if a leaving substituent is absent, tetralones will be isolated
Evans, G. E.; Leeper, F. J.; Murphy, J. A.;Staunton, J. JCS Chem. Comm. 1979, 406. Mahidol, C.; Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. TL 1989, 30, 3861.
OMe
Me
OMe
O O
+
OMe O
OMe
OLDATHF
-78 oC rt
RR
OMe
OMe
Me
OMe
O O
+
OMe
MeO
OH
O
OLDATHF
-78 oC rtMeO
if the alpha position is saturated, decarboxylation can be done to aromatize
The reaction works great with... variety of o-toluates
N
OBnCO2Ph
N
CO2Ph
Br
NMe2
OBocCO2Ph
OBocCO2Ph
OMeMeO
OBocCO2Ph
N
OBocCO2Ph
S
N
EtO2C
OEtCO2Et
O
O NMe
CO2Et
O
O
Donnor, C. D. Tetrahedron 2013, 69, 3747.
α,β-unsaturated esters/ketones
MeO
O H
H OO
OO
MeO
O H
H OO
OTBS
O H
H OO
OO
8
O OMe
OOH
H
OTMS
OO
OMe
SPh
O
O
MeO
O
O
O
O
Essentials in the nucleophile
CO2Me
OMe
O
OMe
O
OMe
LDA, THF
-78 oC+ S S 34%67% without Ph2S2
Hauser, F. M.; Rhee, R. P.; Prasanna, S.; Weinreb, S. M.; Dodd, J. H. Synthesis 1980, 72, 74.
A methyl ether ortho to the ester group is necessary to stabilize the anion
CO2Et LDA, THF
-78 oC+ S S CO2Me
SPh87%
OMe OMe MeO
OMe
O
MeO
Li
Aryl Substituent effects
CO2MeR
LDA (2 equiv)
-65 oC, THF
CO2MeR + O
O
MeO OTBS
6 steps from aspartic acid
slow warm to rt
30 minO
OTBS
OOH
R
CO2Me0%
CO2MeOMe
46%
CO2MeOMe
MeO<5%
CO2MeOMe
PivO0%
CO2MeO
O0%
CO2MeOMEM
MeO0%
CO2MeOMe
MeO41%
CO2MeOMEM
MeO49%
CO2MeOTBS
MeO0%
CO2MeOMe
OMe
20%
CO2MeOMe
Br"10%"
Tan, N. P.H.; Donner, C. D. TL 2008, 49, 4160.
It’s a three-way balance between steric interactions, electron density on the toluate and the stabilization offered by chelation
Skipping the preformed “enolate”
N
CO2Ph
(1) E(2) LDA, HMPA
-95 -50 oCN
O
OH O OBn
NMe2H
OTBS
N
O76%
CO2Ph
Br(1) E(2) n-BuLi
-100 -70 oCN
O
OH O OBn
NMe2H
OTBSO81%
CO2PhOMe
Br (1) E(2) n-BuLi
-100 -0 oC
NO
OH O OBn
H
OTBSOOMe
NMe2
75%
NO
O O OBn
NH
OTBS
E =
Charest, M. G.; Lerner, C. D.; Brubaker, J. D.; Siegel, D. R.; Myers, A. G. Science 2005, 308, 395.
Two additional enolate generation methods...Sn
Hill, B.; Rodrigo, R. OL 2005, 7, 5223.
OMeCO2Et (1) LDA, THF, -78 oC
(2) Bu3SnCl
OMeCO2Et
SnBu3
(1) n-BuLi, -78 oC
(2) E, -78 25 oC (75%)
OMe OH O
60%
O OMe
OOH
H
OTMS 51%
OO
OMe
SPh
47%
O OMe
OOH
H
OTMS 71%
O OMe
OOH
H
OTMS 62%
O
75%
O
74%
O
83%
Two additional enolate generation methods...Si
Aono, M.; Terao, Y.; Achiwa, K. Chem. Lett. 1985, 339.
CO2Me
TMS
CO2Me
R+
CsF, HMPA
60 oC, 3 h
OCO2Me
R
CO2Me
CO2MeR+
CO2Me CO2Me
MeO2C
CO2Me
CO2Me
CO2Me
O
OHCO2Me
17%
CO2Me
CO2Me21% CO2Me
CO2Me
15%CO2Me
CO2Me
CO2Me
28%CO2Me
OHCO2Me
41%
CO2Me
OCO2Me
41%
CO2Me 0%CO2Me
OH
14%O CO2Me
33%O
CO2MeMeO2C
Ph
OCO2Me
0%PhCO2Me
CO2Me 70%CO2Me
CO2MePh
O OH
0%
O CO2Me
26%
O
OHCO2Me43%
CO2Me
Two additional enolate generation methods...Si
Xiang, J.-N.; Nambi, P.; Ohlstein, E. H.; Elliott, J. D. Bioorg. Med. Chem. 1998, 6, 695.
CO2Me
TMS
MeO2C CO2Bn
OO
one step+
O
O
OCO2Me
CO2Bn
CO2Me
TMS
MeO2C CO2Bn
OO
CsF, HMPA
60 oC+
CO2Me
O
OCO2Me
CO2Bn
60%
(1) H2, Pd/C
(2) 150 oC
CO2Me
O
O
CO2Me
96%overtwosteps
NaOMe, MeOH, THF
O
O
OCO2Me
quant.
Acyclic Michael acceptor are hit/miss and generally don’t work well
Characteristics of electrophiles
CO2MeOMe
MeO MeO R
OMe
O
+LDA, THF
-78 oC
OMe
MeO
OH
R
O
OMe R = Me 50%R = OMe 0%
Dodd, J. H.; Garigipati, R. S.; Weinreb, S. M. JOC 1982, 47, 4045. Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Synthesis 1986, 785.
CO2MeOMe
R2
OMe
O
+(1) LDA, THF, -78 0 oC
(2) HCl, MeOH, reflux
OMe
R1
O
R2
R1 = R2 = H 41%R1 = H, R2 = Me 40%R1 = Me, R2 = H 52%R1 = R2 = Me 51%R1
Yields aren’t so great
A “cyclic” Michael acceptor
Mahidol, C.; Tarnchopoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. TL 1989, 30, 3861.
OH OH
OHOH
CO2MeOMe
CO2MeMeO2C + 2 eq.
OH OMe
OHOMe
LDA (2 equiv)
THF, -78 oC
CO2MeMeO2CCO2Me
OMe
CO2MeCO2Me
OMe OLDA, -78 oC rt
80%
CO2MeCO2Me
OMe O60%
DDQ, dioxane
reflux
(1) NaOH, EtOH, THF
(2) Me2SO4, K2CO3CO2Me
OMe OMe48% over two steps
500 oC, 0.01 torrCO2Me
OMeOMe 92%
CO2MeOMe
LDA, -78 oC rt74%
O OMe
OMeOMe
CO2Me(1) NaOH (aq.), MeOH, dioxane(2) (MeO)3CH, TsOH, MeOH
(3) DDQ, PhH(4) BCl3, DCM 57% over 4 steps
Applications of this annulation in natural product synthesis
O
MeO
OH OH O
CO2Me
semiviriditoxin
MeO
OH OH O
(R)-atrochrysone
OH
O
OO
O
OO
neojusticidin B
FtsZ inhibitor; broad spectrum antibiotic activity against gram-positive pathogens
A family of anthranoids, which has displayed anti-bacterial, anti-malarial, and insect antifeedant activities
Interesting skeleton for organic synthesis
Synthesis of semiviriditoxin
O
MeO
OH OH O
CO2Me
HO2C CO2H
TBSO
CO2Me
OH
OTBS
NH2O(1) NaNO2, H2SO4, KBr, H2O, 0 oC, 4 h (91%)
(2) BH3-Me2S, THF, -30 oC to rt, 18 h (97%)
(3) K2CO3, DCM, 72 h (96%)(4) TBSCl, imidazole, DCM, 4 h (98%)
methyl propiolaten-BuLi, BF3-Et2O
THF, -78 oC, 30 min (72%)
O
O
MeO OTBS
NaOMe, MeOH, 16 h
(80%)
OMe
MeO
OMe
O
+LDA, THF, -60 oC, 30 min
(36%)
O
MeO
OMe OH O
OTBS
(1) THF, 10% HCl, 16 h(2) PhI(OAc)2, TEMPO, DCM, 20 h(3) NaClO2, tBuOH, H2O, NaH2PO4, 3 h
(4) MeOH, conc'd H2SO4, 16 h(5) BCl3, DCM, 6 h44% over 5 steps
Donner, C. D.; Tan, N. P.H. Tetrahedron 2009, 65, 4007.
Synthesis of atrochrysone
OH
MeO2C CO2Me
OH
MeO2C CO2H
OTBDMS
MeO2C CO2TBDMS
pig liver esterase
pH 8, 92 %
TBDMS-OTf, lutidine
DCM, 0 oC to rt86%
Muller, M.; Lamottke, K.; Low, E.; Magor-Veenstra, E.; Steglich, W. JCS Perkin Trans 1 2000, 2483.
MeO
OH OH O
OH
+OMe
MeO
OMe
O(1) LDA, THF, -78 oC (25%)
(2) HF, MeCN (78%)
OTBDMS
CO2TBDMSMeO
OMeO
OTBDMS Tebbe reagent, THF
-78 oC, 30 min, then rt, 1 h61-85%
(1) K2CO3, MeOH(2) Tf2O, DMAP, DCM
40-80% over two steps
Synthesis of neojusticidin B
Kobayashi, K.; Maeda, K.; Uneda, T.; Morikawa, O.; Konishi, H. JCS Perkin Trans 1 1997, 443.
CO2Et
+ O
O
O
O (1) LDA, THF, -78 oC
(2) p-cymene, 10% Pd/C, reflux
OH
O
OOH
OO
O
O
CO2Et
+ O
O
O
O
OO
notattempted
The molecule in hand...
Feng, Y.; Majireck, M. M.; Weinreb, S. M. ACIE 2012, 51, 12846.
NH
N
CO2Me
N
H
OH
O
TMSEO2C Ts
NH CO2Me
TMSEO2CO 2 equiv LiHMDS, THF, -78 oC
NCO2Me
TMSEO2CO
TsN
NHO
Cl-HCl
NCO2Me
TMSEO2CO
NH CO2Me
TMSEO2CO
TsN
NO
+
NH
NH
CO2Me
HO
H
O
alstilobanine A
Staunton-Weinreb Annulation
• Discovered Independently by Staunton and Weinreb in 1979 for synthesizing linear polycycles
MeO
OMe OMe OOH
OH
O
OMe OHH
OMe OMe
MeO
OHCO2Et
OMe
MeO
OMe
O
O
OMe
O OMe
MeO
O
OMe
O
O
OMe
MeO
OMe
O O
O NMe
CO2Et
O
O
CO2MeMeO2CO
O
MeO
• Tandam Michael addition, Dieckmann condensation followed by optional aromatization
• ortho-toluates
• Generally requires an ether group ortho to ester for anion stabiliztion
• ...unless the Anion is generated in situ by lithium-halogen exchange
• cyclic esters and ketones are generally better electrophiles
OMeCO2Et
CO2Ph
Br
still acyclic
What happened to Hauser, Kraus, van Leusen, and Parker?
Supposingly, this should be the beginning of this part of history
Frank Hauser
O
OMe
OH
O OMe OOMe
OH
O
CO2H
LDACO2, THF
-78 oC
(1) Ac2O, py(2) NaOH, H2O
(3) Ac2O, HClO4
ethyl bromoacetateZn, PhH
refulx
90% 68% over 3 steps
73%
OMe OH
OEt
O (1) KOH, Me2SO4(2) H2O
OMe OMe
OH
O
then on and on for longer polycyclic chains
Hauser, F. M.; Rhee, R. JACS 1977, 99, 4533.
(Stabilized) phthalide nucleophiles
Frank Hauser
O
O
SO2Ph
CO2H
O
(1) PhSH, PhH, reflux
(2) mCPBA, DCM87% over two steps
Hauser, F. M.; Rhee, R. JOC 1978, 43, 178.
One oxidation state higher than the Staunton-Weinreb version
LDA, THFmethyl acrylate
-78 oC68%
O
O
SOPh
OH
OH
CO2Me
LDA, THFmethyl acrylate
-78 oC86%
OH
OH
CO2Me
OCO2Me
O
SO2Ph
Synthesis of neojusticidin B
Kobayashi, K.; Maeda, K.; Uneda, T.; Morikawa, O.; Konishi, H. JCS Perkin Trans 1 1997, 443.
+O
O
O
O
OH
OO
O
O
not attempted
CO2EtO
O
OO
LDA, THF, -78 oC
O
OOMe
OO
O
O
O
OO
O
OO
O
+LDA, THF,
-78 oC
O
OOH
OO
O
OOH
50% over two steps
I2, CHCl3
CH2N2, 0 oC
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