A Synergy of Target-Oriented Synthesis and New Reaction Development: Cycloadditions for the Formation of Highly-Functionalized Ring Structures and Applications in Total Synthesis Chemistry from the Boger Research Group Troy E. Reynolds January 8, 2007
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
A Synergy of Target-Oriented Synthesis
and
New Reaction Development:
Cycloadditions for the Formation of Highly-Functionalized
Ring Structures and Applications in Total Synthesis
Chemistry from the Boger Research Group
Troy E. Reynolds
January 8, 2007
Dale L. BogerEducation
B.S. University of Kansas, 1975Ph.D. Harvard University, 1980 - E. J. Corey"Part I: New annulation processes, Part II: Studies directed toward a biomimetic synthetic approach to prostaglandins"
Professional Career
Assistant Professor/Associate Professor, University of Kansas 1979-1985Associate Professor/Professor, Purdue University, 1985-1991Professor, The Scripps Research Institute, 1991-present
Awards
Searle Scholar Award 1981-1984NIH Career Award 1983-1988Alfred P. Sloan Fellow 1985-1989ACS Arthur C. Cope Scholar Award, 1988Japan Promotion of Science Fellow, 1993ISHC Katritzky Award in Heterocyclic Chemistry, 1997Honorary Member, The Lund Chemical Society (Sweden), 1998ACS Aldrich Award for Creativity in Organic Synthesis, 1999A. R. Day Award, POCC 1999Honorary Ph.D. Degree: Laurea Honors Causa, Univ. of Ferrara, 2000Smissman Lecturer, Univ. of Kansas, 2000Yamanouchi USA Faculty Award, 2000Paul Janssen Prize for Creativity in Organic Synthesis, 2002oss Lecturer, Dartmouth College, 2002Fellow, American Association for the Advancement of Science, 2003Adrien Albert Medal, Royal Society of Chemistry, 2003ISI Highly Cited (top 100 chemists)Alder Lecturer, University of Köln, 2005
•Electron-deficient azadienes ideally suited for inverse-demand Diels Alder reactions•Introduction of highly substituted heterocylcic systems
N
N N
R
R
R
1,2,4-triazine
N
N
R
R
R
pyridine
+!
Mechanism
N N
N+
N R1
R2
N
N
N
R2
R1
N
NR2
R1N–N2
N
R1
R2
HN
loss of
•Highly functionalized pyridines•Rxns run at 25-80 ºC•Aromatization is slow step, not initial [4+2] and loss of N2
Reactivity
N
N N
CO2Et
CO2Et
CO2Et
>N
N N> N
N N
CO2Et
I. Heteroaromatic Azadienes: 1,2,4-Triazine
1,2,4-Triazines
N
N N
1,2,4-triazine
N
R1
R2
R
+ N
R1CHCl3, 45 ºC
R2
CO2Et
CO2Et
CO2Et
Dienophile Conditions product yield (%)
CHCl3, 60 ºC, 18 h 79
CHCl3, 45 ºC, 8 h 73
Ph
N
N CO2Et
Ph
EtO2C
EtO2C
Ph
NCH3
N CO2Et
Ph
EtO2C
EtO2C
CH3
Ph
TMSO
CHCl3, 60 ºC, 22 h
N CO2Et
Ph
EtO2C
EtO2C
84
Ph
TMSOCH3 CHCl3, 60 ºC, 16 h No Product 0
Ph
EtSCH3
CHCl3, 80 - 160 ºC, 16 h No Product 0
Catalytic 1,2,4-Triazines Diels Alder
N
N N
1,2,4-triazine
N
R1
R2
R
+
O
R1
HN
CHCl3, 45 ºC
R2
–N2
Ketone time (h) equiv ofpyrollidine
product yield (%)
O
22 0.2 52N
O
58 0.2N
86
O
96 2.0 93
N
O
84 4.0
N
36
O
36 1.0 19N
I. Heteroaromatic Azadienes: 1,2,4-Triazine
N CO2H
CH3H2N
Streptonigrin
N
O
O
MeO
H2N
OMe
OMe
OH
N CO2H
CH3H2N
Lavendamycin
N
O
O
H2N
Utility
Lavendamycin (J. S. Panek, S. R. Duff, M. Yasuda), J. Org. Chem. 1985, 50, 5782-5789, 5790-5795Streptonigrin (J. S. Panek), J. Am. Chem. Soc. 1985, 107, 5745-5754
1,2,4,5-Tetrazines
Reactivity
N
N N
N
CO2CH3
CO2CH3
>N
N N
N
SCH3
SCH3
>N
N N
N
SCH3
NHCOR
N
N N
N
NHCOR
NHCOR
> R = CH3, OCH3
N
NR
R
CO2CH3
CO2CH3
N
N N
N
CO2CH3
CO2CH3
R
R
EDG
+
Mechanism
R
N
N N
N
CO2CH3
CO2CH3
+
N N
NN
N
EDG
R
CO2CH3
H3CO2C
N
N
R
CO2CH3
CO2CH3
N
N
R
CO2Et
CO2Et
-H-EDG-N2!
EDGR
R
R
EDG
N
NR
R
CO2CH3
CO2CH3
N
N N
N
CO2CH3
CO2CH3
R
R
EDGZn/HOAc
NH
R
R
CO2CH3
CO2CH3
+
Utility
1,2,4,5-Tetrazine 1,2-Diazine Pyrrole
1,2,4,5-Tetrazines
Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D.; J. Org. Chem. 1984, 4405;
Kornfield, E. C. et. al.; J. Med. Chem. 1980, 23, 481.
Mechanism
N
N
R
CO2Et
CO2Et
Zn N
HN
R
CO2Et
CO2Et
O
HN
R
CO2Et
CO2Et
H2N
N
R
R
CO2CH3
CO2CH3
-H2O
NH2 NH
R
R
CO2CH3
CO2CH3
H+
1,2,4,5-Tetrazines!1,2-Diazine!Pyrrole
N
NR
R
CO2CH3
CO2CH3
N
N N
N
CO2CH3
CO2CH3
R
R
EDGZn/HOAc
NH
R
R
CO2CH3
CO2CH3
+ 25 ºC
dioxane 25 ºC
Dienophile Diazine PyrroleYield Yield
Et3SiO
N N
CO2CH3H3CO2C87 63
NH
H3CO2C CO2CH3
N
N N
CO2CH3H3CO2C85
NH
H3CO2C CO2CH3
52
Ph
N
O
N N
Ph
CO2CH3H3CO2C 87 65NH
H3CO2C CO2CH3
Ph
O
OCH3
OCH3
N N
CO2CH3H3CO2C
O OCH3
71NH
H3CO2C CO2CH3
O
OCH3
56
Total Synthesis of Roseophilin
Retrosynthesis
N
O
OMe
HN
Cl
SEMN
O
O
OMe
HN
Cl
+
SEMN
O
Acyl RadicalAlkene Cyclization N
SEM
CO2Me
RCM
NSEM
CO2MeMeO2C
OBn
Wittig
N N
OBn
CO2MeMeO2C
ReductiveRing Contraction
N N
NN
CO2MeMeO2C
OBn
OMe
+
[4+2]1,2,4,5-tetrazine
N
O O
Bn
Total Synthesis of Roseophilin
1. TiCl4, (iPr)2NH,BnOCH2Cl, 99%
2. LiAlH4, 54%HO OBn
1. TPAP, NMO100%
2. CH3OCH=PPh3
OBn
OMe
N N
NN
CO2MeMeO2C
25 ºC, 60 h91% for 2 steps
N N
OBn
CO2MeMeO2C
Zn/TFA, 25 ºC, 1 h, 52%
NH
CO2MeMeO2C
OBn
1. Pd/C, H2
2. CSA, PhH77% for 2 steps
NH
MeO2C
O
O
1. SEMCl, 92%2. LiI, 74%
NSEM
HO2C
O
O
1. ClCO2Et, Et3N2. NaBH4, 90%
NSEM
HOH2C
O
O
Total Synthesis of Roseophilin
1. Pd/C, H2, 97%2. TPAP, NMO3. CH2=PPh3 67–85% for two steps
NSEM
O
O
1. LiOH2. TMSCHN2
3. TPAP, NMO
NSEM
CO2Me
O CH2=CH(CH2)2PPh3+Br-,
NaHMDS
91% for 4 steps
NSEM
CO2Me
Ru CHPh
PCy3
PCy3Cl
Cl
CH2Cl2, 40 ºC, 72 h72–88% SEMN
CO2Me(1:1 E:Z)
Bu3SnH, AIBN
83%SEMN
O
NSEM
HOH2C
O
O
1. MnO22. BnO(CH2)4PPh3
+Br-, NaHMDS, 96% for 2 steps
NSEM
O
O
BnO
1. NaOH, 49%2. (EtO)2P(O)Cl; PhSeNa, 83%
SEMNCOSePh
SEMNCO2H
(EtO)2P(O)C, PhSeNa
83%
SEMNCOSePh
Bu3SnH, AIBN
83%SEMN
O
5-exo-dig
SEMN
O
Boger Isr. J. Chem. 1997, 37, 119
COSePh
Bu3SnH, AIBN
Other Examples
O
COSePh
Bu3SnH, AIBN
CNH
H
O
62%
CH2CN
O
SePh
O
O
( )nBu3SnH, AIBN O
O
( )n46 - 74%n = 2 - 11
80%
Intramolecular Acyl Radical Cyclizations
PtO2, H2
100%SEMN
O
SEMN
O
1. Bu4NF
2. HCl
ClH•N
O
OMe
HN
Cl
ent–Roseophiline•HCl
Total Synthesis of Roseophilin
O
TIPSNCl
OMe
1. n-BuLI, -78 ºC2.CeCl3, –55 ºC 30 min3. -78 C
SEMN
O
OMe
TIPSN
Cl
OH
Intramolecular Diels-Alder: Preperation of Indoles and Indolines
N
N
N
N
N N
R2
OO
R2
R1 R1
–N2
1,2-Diazine Conditions Product Yield
NN
NCO2CH3
NCO2CH3
230 ºC, 18 h 77%
H3C CH3
NN
NCO2CH3
TBSOH2C
NCO2CH3
CH2OTBS
230 ºC, 18 h 92%
NN
NCO2CH3
NCO2CH3
CH3
230 ºC, 12 h 85%
NN
NCO2CH3
•120 ºC
H3COS
NCO2CH3
Et Et
50 -55%
N
O
O
OH
OMe
HO2C
PDE-II
N
O
O
NH2
OH
OMe
HO2C
PDE-I
N
O
O
OH
OMe
NH
N
H2N
O
OH
OMe
N
O
HN
Me
O
(+)-CC-1065
Intramolecular Diels-Alder: Preperation of Indoles and Indolines
•!,"-unsaturated imines in [4+2] rarely observed •Suffers from low conversion, complementary imine addition and/or imine tautomerization precluding DA•Diels-Alder occurs through enamine tautomer (2#) •Where tautomerization is not accessible [2+2] can occur
X
•EWG substitution at N1 or C3 should accelerate potential [4+2] with electron-rich diene - Inverese Demand Diels-Alder•Bulky EWG at N1 should preferentially decelerate 1,2-imine additon as well as stabilize cycloaddition product (deactivated enamine)
I. 1-Aza-1,3-Butadiene Diels-Alder
Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713
R N
R
R
SO2Ph
ORR
R
N
R
R
R OR
R
R+
1-Aza-1,3-Butadienes
SO2Ph
1-Aza-1,3-Butadiene Diels-Alder
R N
R
R
SO2Ph
ORR
R
HN
R
R
R OR
R
R+
Reactivity/Scope
N
SO2Ph
Ph
N
SO2Ph
Ph
EtO2C N
SO2Ph
CO2Et
N
SO2Ph
OEt
O
O
N
Ph
OEt
SO2Ph
N
Ph
OEt
SO2Ph
EtO2C N
CO2Et
OEt
SO2Ph N
SO2Ph
O
O
OEt
72% (>1:20) 89% (>1:20)80% (>1:20) 82% (>1:20)
60 - 100 ºC 25 ºC <25 ºC
< < <
R N
R
R
SO2Ph
ORR
R
HN
R
R
R OR
R
R+
1-Aza-1,3-Butadiene Diels-Alder
N
Transition State Model
•Regiospecific
·Endo specific
Secondary overlap (C-2 diene/OR)
n-!* stabilization (transition state anomeric effect)
•Strained olefin react with both electron-rich and electron-deficient dienes at ambient temperatures
•Thermal generation of !-delocalized singlet carbene - [1+2], [3+2], [4+3]
III. Cyclopropenone Ketals
OR
OR! RO OR RO OR
Cyclopropenone Ketals
O
O
O
O
R
Diels-Alder
R
+conditions
Diene Conditions Yield
CO2CH3neat, 25 ºC, 40 h 65%
OCH3neat, 25 ºC, 60 h
72%
neat, 25 ºC, 62 h 69%
•High reactivity due to strain olefin•Reacts with electron deficient, electron rich, and electron neutral dienes•exo products exclusively
O
O
H
H
exo
O
O
endo
Transition State Model
R R
Tropone Introduction
O
O
CO2CH3
OCH3
tBuOK
O
O
CO2CH3
25 ºC25 ºC
O
O
H3CO2C
H+
H3CO2C
O
Cyclopropenone Ketals
O
O
[4+3]
70 ºC
benzeneRO OR RO OR O
O
O
O O
OH2SO4
MeOHO
[1+2]
O
O75 ºC
benzeneRO OR RO OR
CN
CNO
O
80% yield9:1 cis:trans
•High temp., exclusive [1+2] cyclopropanation with olefins having a single electron withdrawing group
HO
OH
H
H
HO
OH
H
H
HO
OH
H
H
HO
OH
H
H
MP2/6-31++G(d)//6-31++G(d)
singlet
triplet
0.00 kcal 1.40 kcal
9.22 kcal 8.73 kcal
O
O
HO
HO
H
Transition State
•High temp., [3+4] cycloaddition with electron-deficient dienes•Room temp or high pressure, [4+2] cycloaddition
[3+2]
O
O
+CO2CH3H3CO2C
H3CO
OO
H3CO
H3CO2C
H3CO2C
95-100%
80 ºCbenzene
O
O
+
O
H3C
NO2
80 ºCheptane
22%
OO
O
CH3
O2N
•High temp., exclusive [3+2] cyclopropanation with olefins having two electron withdrawing group
•Dienes with two EWG will undergo [3+2], not [3+4] at high temps
Cyclopropenone Ketals
Mechanism
O
O
RO OR
RO OR
!
single e–
transfer
EWGGWE
R
RO OR
+
EWGEWG
R
OO
R
EWG
EWG
Accounts for:1. partial loss of olefin geometry2. lack of solvent dependency3. lack of pre-rearrangement intermediates4. lack of inhibition by radical traps