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
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