chemistry from the boger research group
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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
Chemistry from the Boger Research Group
Cycloaddition Reactions
I. Heteroaromatic Azadienes
Roseophilin
II. N-Sulfonyl-1-Azadienes
Piericidin A1
III. Cyclopropenone Ketals
Rubrolone Aglycon
IV. Intramolecular [4+2]/[3+2] Cascades
Vindoline
•Mechanism/Reactivity•Scope/Limitations•Utility/Application
Research Interests
•Total synthesis
•New synthetic methods
•Bioorganic and medicinal chemistry
•Combinatorial chemistry
•DNA-agent interactions
•Chemistry of antitumor antibiotics
II. Heteroaromatic Azadiene
EDG
N N
N RR
R
N
N N
R
R
R
N
N N
N
R
R
1,2,4-triazine
1,2,4,5-tetrazine
1,3,5-triazine
N
N
N
N
N
R
R
N
N
R
R
R
N
R
R
R
pyridine
1,2-diazine
pyrimidine
N
OO
R2
R1
R1
R
R2
indole
Zn/HOAc
NH
R
R
pyrrole
1
2
3
•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
Utility
1,3,5-Triazines
N N
N RR
R
Ynamines Diels-Alder
+
CH3
NBn2
NN
NR
Me
Bn2N
–RCN
N
NMe
Bn2N
R
R
1,3,5-triazinepyrimidine
R
R
R = H, 40 - 90 ºC, 81%R = CO2Et, 40 - 90 ºC, 95%R = SCH3, 160 ºC, 93%R = S(O)CH3, >25 ºC, 50%
N
NMe
H2N
R
R
N N
N RR
R
Amidine Diels-Alder
+
NH2•HCl
H2N Me
NH2•HCl
H2N
N
NN
NH2
H2N
R
R
R
N
NNHN
R
R
R
-NH3
N
NNH2N
R
R
R
-RCN
R = H,125 ºC, 64%R = CO2Et, 100 ºC, 85%R = SCH3, 150 ºC, 0%
+N N
N RR
R
1,3,5-triazine
EDG
N
N
R
R
pyrimidine
1,3,5-Triazine
N N
H2N
Me
CO2H
HN
OH2N
CONH2
NH2
(–)-Pyrimidolblamic Acid
bleomycin A2
N N
H2N
Me
HN
OH2N
CONH2
NH2
O
HN
O
NH
CO2H
CH3
NH
N
P-3A
N N
H2N
Me
HN
OH2N
CONH2
NH2
O
HN
O
NH
NH
NO
HOHN
HOH
NH
O
S
N
S
N
HN
O
S
OO
O
HO
OH
OH
OHOCONH2
OH
OH
Heteroaromatic Azadiene Diels-Alder Reactions
EDG
N N
N RR
R
N
N N
R
R
R
N
N N
N
R
R
1,2,4-triazine
1,2,4,5-tetrazine
1,3,5-triazine
N
N
N
N
N
R
R
N
N
R
R
R
N
R
R
R
pyridine
1,2-diazine
pyrimidine
N
OO
R2
R1
R1
R
R2
indole
Zn/HOAc
NH
R
R
pyrrole
1
2
3
Background
R N
R
R
R
+
R
HN
R
R
R R
•!,"-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)
•Dienophile geometry conserved
•C-3 EWG substantially accelerates reaction
•Noncomplementery C-2 or C-4 EWG accelerates
reaction
Utility - Synthesis of Pyridines
N
SO2CH3
CH3
EtO2COEt
OEt
CO2Et
DBU
70 ºC, 91-94%
N
CH3
CO2Et
OEtEtO2CN
SO2CH3
CH3
EtO2C
EtO
CO2Et
OEt
25 ºC, 95%
Stille
N
Bu3Sn
OR
OH
MeO
MeO
+
Br
[4+2]
OMe
MeO
MeO
OMe
+
NSO2CH3
CO2Et
N-sulfonyl-1-azadiene
N
OR
OH
MeO
MeO
Piericidin A1, R = HPiericidin B1, R = Me
Retrosynthesis
Total Synthesis of Piericidin A1
NN
N
NS
Ph
I
OOOTBS
H
O
+
Julia Olefination
EtO
O
O
NH2OH•HCl
96%
EtO
O
NHO
MeSOCl, Et3N
EtO
O
NH3CO2S
0 ºC, 20 min
Synthesis of Pyridine Fragment
Total Synthesis of Piericidin A1
R1
NOH
R2
+ R3SOCl
R1
NO
R2
S
Cl
O
R1
N
R2
+
OS
O
Cl
Et3N
Not Stable
HomolyticCleavage
R1
N
R2
SO2R3
Mechanism
EtO
O
O
NH2OH•HCl
96%
EtO
O
NHO
MeSOCl, Et3N
EtO
O
NH3CO2S
0 ºC, 20 min
Synthesis of Pyridine FragmentOMe
MeO
MeO
OMe
PhCH3, 50 ºC, 18 h64% for 2 steps
NEtO2C
OMe
OMe
OMe
OMe
SO2Me
BF3•OEt2
CH2Cl2, 0 ºC, 1 h88%
N OMe
OMe
EtO2C 1. DIBAL, 92%2. TIPSCl, Imid., 95%
N OMe
OMe
TIPSO
1. 5 equiv BuLi2. 6 equiv. B(OMe)33. AcOOH, 88%
N OMe
OMe
TIPS
OH
OH
1. Bu4NF, 96%
2. CBr4, PPh3, 84%
N OMe
OMe
Br
OH
Fragment 1
Mechanism
N OMe
OMe
TIPS
OH
Bu4NF, 30 min
N OMe
OMe
TIPSO
OH
N OMe
OMe
HO
OH
OH
•Initial Brook Rearrangement36 h
Total Synthesis of Piericidin A1
IOH
NN
N
NHS
Ph
PTSH
+
Fragment 2
PPH3, DEAD
71% NN
N
NS
Ph
I((NH4)6Mo7)O24
H2O2
89%N
N
N
NS
Ph
I
OO
Fragment 2Fragment 3
N
O
O
O
O
N
O
O
O OH
67%
iPr2NEt, Bu2BOTfCH2Cl2
1. MeNH(OMe)•HCl2. TBSCl, 66% 2 steps3. DIBAL, 86%
H
O OTBS
1. P(OEt)2
CO2Et
O NaH
2. DIBAL, 72% 2 steps3. (COCl)2, DMSO, 99%
OTBS
H
O
Fragment 3
Total Synthesis of Piericidin A1
NN
N
NS
Ph
I
OO OTBS
H
O
+
Fragment 2 Fragment 3
1. KHMDS, DME,–78 ºC, 18 h, 60%
2. BuLi, (Bu)3SnCl
OTBS
(Bu)3Sn
NBr
OH
OMe
OMe
Pd2(dba)3, t(Bu)3P,LiCl, 74%
OTBS
N
MeO
MeO
OH
Fragment 1
Bu4NF, 93%
OH
N
MeO
MeO
OH
Piericidin A1
Total Synthesis of Piericidin A1
[4+2]
R
OR
OR
R
[1+2]EWG
CH2CO2R
H
EWG
[3+2]EWG
GWEOR
RO
[3+4]
R
OR
RO
•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
Total Synthesis of Rubrolone Aglycon
Retrosynthesis
N
O
O
O
O
OH
OH
H
OH
OH
Rubrolone
N
OH
O
O
OH
Rubrolone Aglycon
N
O
O
O
HOO
OH
H
H
ElectrocylcicRearrangement
N
O
O
OO
+
[4+2]Cyclopropenone Ketal
OMeMeO
N
O
N
O
RO
Intramolecular Diels-Alder1-aza-1,3-butadiene
Total Synthesis of Rubrolone Aglycon
OTBSOHCCH3(CH2)2C!CLi
90%
OH
OTBS
1. DHP, PPTS, 99%2. Bu4NF, 99%
OTHP
OH
O
P(OMe)2
O
NaH, 96%
1. PDC, 77%
2.OTHP
O
1. BnONH2, 96%2. Amberlyst, MeOH 99%3. DMSO, (COCl)2, Et3N, 86–95%
N
O
OBn
triisopropylbenzene185 ºC, 48 h, 70%
N
O
N
O 1. PhI(OAc)2, KOH, MeOH2. (CF3CO)2O, Et3N
65% N
MeO
MeO
Total Synthesis of Rubrolone Aglycon
N
O
65% N
MeO
MeO
HO
PhI(OAc)2, KOH, MeOH
N
MeO
MeO
I
N
MeO
O
(CF3CO)2O, Et3N
-H2O N
MeO
MeO
N
O 1. PhI(OAc)2, KOH, MeOH2. (CF3CO)2O, Et3N
65% N
MeO
MeO
Total Synthesis of Rubrolone Aglycon
1. Br22. t-BuOK
91%N
MeO
MeO
Br
O
O SnBu3
(PPh3)4Pd
95%
N
MeO
MeO
O
O
O
O
25 ºC. 45 min, 97%
N
MeO
MeO
O
OO
O
H
H
exo
1 diastereomer
N
Pr
MeO
OMe
O
O
O
O
H
H
exo
N
Pr
MeO
OMe
O
O
O
O
endo
Transition State Model
N
MeO
MeO
O
OO
O
H
H
Total Synthesis of Rubrolone Aglycon
1. NBS, MeOH80%
N
O
OO
O
H
H Br
OMe2. aq. TFA, quant.
O
1. DBU2. aq. TFA
72%
N
O
O
OOH
O
HO
NBS, DMSO
48%
N
O
O
OHHO
Rubrolone Aglycon
LiOH, 99%
N
O
O
OOR
HO
TMSBr, 99%
R = Br ! R = H
Zn, NH4Cl
N
HO
O
OHHO
N
O
OO
O
H
H Br
OMe
O
DBU
N
O
OO
O
H
H
OMe
O
–HBr
aq. TFA
N
O
OO
O
H
HOH
O
N
O
O
H
H
O
O
O
OH
N
O
O
H
H
O
OH
O
OH
N
O
OH
OOH
O
O
N
O
O
OOH
O
HO
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
•1,2,4-oxadiazoles behave as electron-deficient azadienes
N
NO
R
RR1 R1
O
R1
R1
R1
R1
R
R
N
NO
R1
R1
R
R
O
R
R
R1
R1
[4+2][3+2]
SLOW
FAST
General Reaction Goal
•Facile approach to vinca alkaloids
N
N
OH
O
CO2Me
Et
MeO
N
OH
Et
NHMeO2C
R
Vinblastine, R = CH3Vincristine, R = CHO
N
NH
OH
O
CO2Me
Et
MeO
Vindoline
N
NH
O
OBn
CO2Me
Et
O
MeO
N
Me
N
MeO
O
N
N
CO2Me
O
Et
BnO
Boger, D. L. et. al. J. Am. Chem. Soc. 2006, 128, 10589
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Mechanism
N
Me
N
O
N
N
CO2Me
O
RZ
[4+2]
endoN
Me
N
N
N
CO2Me
O
RERE
RZ
O
-N2
N
Me
N
CO2Me
O
RE
RZ
O
[3+2]
endo
N
NH
ORz
CO2Me
O
RE
Analogous Reaction
N
Me
O
NO
O
N2
O
OMe
Et
Rh(II) N
NH
O
CO2Me
Et
O
MeO
O
[3+2]
N
NH
O
O
CO2Me
Et
O
MeO
Padwa J. Org. Chem. 1995, 60, 6258
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
N
O
RE
RZ
N
Me
O
E
vs.
N
O
RE
RZ
N
Me O
E
endo exo
Transtion State
N
Me
N
O
N
N
CO2Me
O
RZ RE
N
NH
O
RZ
CO2Me
O
RE
RE RZ Conditions Yield
Me
CH2OTBS
Ph
OBn
OBn
CO2Me
CO2Me
CN
CN
H
H
H
H
H
H
H
H
H
H o-DCB, 180 ºC, 3 h
o-DCB, 180 ºC, 24 h
o-DCB, 180 ºC, 24 h
o-DCB, 175 ºC, 19 h
TIPB, 230 ºC, 19 h
TIPB, 230 ºC, 38 h
TIPB, 230 ºC, 46 h
TIPB, 230 ºC 60 h
TIPB, 230 ºC, 22h
H
TIPB, 230 ºC, 22h
87
65
86
61
88
41
71
62
79
74
0-DCB = orthodichlorobenzeneTIBP = triisopropylbenzene
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Key Requirements/Limitations
N
Me
X
O
N
N
CO2Me
X = NCO, 87%X = CON, 61%X = NCH2, 0%
1. N-Acylation
•Rate increases as EWG increases
2. Oxadiazole Substitution
N
Me
N
O
N
N
X
O
X =EWG
•Must stabilize 1,3-dipole
3. Tether Length
•Dienophile
N
Me
N
O
N
N
X
O
( )n
n = 0, 68%n =1, 87%n = 2, 43%
•Dipolarphile
N
Me
N
O
N
N
X
O
( )n
n = 1, 72%n = 2, 89%n = 3, 26%
4. Dipolarphile
X
N
O
N
N
CO2Me
O
X = NMe, 87%X = NBn, 83%X = NCO2Me, 74%X = O, 63%X = S, 62%
Total Synthesis of (–)- and ent-(+)-Vindoline
Retrosynthesis
N
NH
OH
OAc
CO2Me
Et
MeO
N
NH
O
OBn
CO2Me
Et
O
MeO
N
Me
N
MeO
O
N
N
CO2Me
O
Et
BnO
Intramolecular[4+2]/[3+2]
Cylcloaddition Cascade
N
Me
NH
MeO
O
N
N
CO2Me
EtHO2C
BnO
+
N
Me
NH2
MeO
Boger, D. L. et. al. J. Am. Chem. Soc. 2006, 128, 10596
Total Synthesis of (–)- and ent-(+)-Vindoline
N
Me
NH2
MeO
1. CDI, 90%2. H2NHNCOCO2Me, 78%
N
Me
NH
MeO
OHN
HN O
CO2Me
N
Me
NH
MeO
O
N
N
CO2Me
TsCl, Et3N
81%
EDCI, DMAP
EtHO2C
BnO
N
Me
N
MeO
O
N
N
CO2Me
O
Et
BnO
96%
N
NH
O
OBn
CO2Me
Et
O
MeO
53%
1,3,5-triisopropylbenzene230 ºC, 90 min
enantiomers seperated on Chiralcel OD column (30% IPA/Hexanes, ! = 1.70, tR = 15.1 and 25.6 min, 10 mL/min) - up to 200 mg/injection
N
NH
O
OBn
CO2Me
Et
O
MeO
1. LDA, (TMSO)22. TIPSOTf
64%
N
NH
O
OBn
CO2Me
Et
O
MeO
OTIPS
Total Synthesis of (–)- and ent-(+)-Vindoline
N
NH
O
OBn
CO2Me
Et
S
MeO
OTIPSLawessonReagent
70%
1. Ra-Ni, 91%
2. Ac2O, 97%
N
NH
O
OAc
CO2Me
Et
MeO
OTIPS
H2, PtO2
98%
N
NH
OH
OAc
CO2Me
Et
MeO
OTIPS
1. Bu4NF, 89%2. Ph3P, DEAD, 75%
N
NH
OH
OAc
CO2Me
Et
MeO
(–)- and ent-(+)-Vindoline
Vindoline Analogs
N
N
CO2Me
Et
Minovine
N
N
OH
CO2Me
Et
Me Me
Desacetoxyvindorosine
N
N
OH
CO2Me
Et
Me
OAc
Dihydrovindoline
N
N
OH
CO2Me
Et
Me
4-Desacetoxyvindorosine-6,7-dihydrovindorisine
N
N
OH
CO2Me
Et
Me
OAc
Vindoline
N
N
OH
CO2Me
Et
MeO
Me
MeO
Desacetoxyvindoline
N
N
OH
CO2Me
Et
MeO
Me
4-Desacetoxyvindoline-6,7-dihydrovindorisine
N
N
Et
MeH
N-Methyl-aspidospermidine
Chemistry from the Boger Research Group
Conclusion
•Use natural products as inspiration for new reactions
•Form highly fuctionalized ring structures (in particular heterocylces) efficiently
•Methods allow ready access to valuable analogs as well
Cycloaddition Reactions
I. Heteraromatic Azadiene ! Pyridines, Pyrimidines, 1-Diazines, Pyrroles,
Indoles
Roseophilin
II. N-Sulfonyl-1-Azadienes ! Cyclic Enamines and Pyridines
Piericidin A1
III. Cyclopropenone Ketals - [4+2], [3+2], [1+2], [3+4], tropones
Rubrolone Aglycon
IV. Intramolecular [4+2]/[3+2] Cascades - vinca alkoloids
Vindoline
1,2,4-Triazines
Synthesis
NC OEt
O Et2NH
H2S
S
H2N
O
OEt1 N2H4
N
H2N
H2N
O
OEt
EtO
O
OEt
O
25 ºC
N
N N
CO2Et
CO2Et
CO2Et
2
R
NH
X
N
N N
N
CO2CH3
CO2CH3
+
!
1,2,4,5-Tetrazine
N NH
NN
N
X
R
CO2CH3
H3CO2C
N
N NH
R
CO2CH3
CO2CH3
-N2 N
N N
R
CO2Et
CO2Et
-HX
X = SCH3, OEt
N
N N
N
CO2CH3
CO2CH3
Synthesis
O
OEt
N2
N
HN N
NH
CO2Na
CO2Na
N
HN N
NH
CO2CH3
CO2CH3
NaOH
H2O
1. HCl, H2O2. SOCl2, MeOH Nitrous gases
CH2Cl2
1-Aza-1,3-Butadiene Diels-Alder
Preperation of N-sulfonyl-1-aza-1,3-butadienes
R1 H
O1 RSO2NH2
MgSO4, TiCl44Å MS
R1 H
NSO2R
2
R1 R2
N RS
Cl
O
Et3NR1 R2
NOSOR
R1 R2
NSO2ROH
R1
NOH
R2
+ R3SOCl
R1
NO
R2
S
Cl
O
R1
N
R2
+
OS
O
Cl
Et3N
Not Stable
HomolyticCleavage
R1
N
R2
SO2R3
Mechanism
3
R1 R2
N
Et3NR1 R2
NOSOR
R1 R2
NSO2ROH
R S
O
O
CN
Cyclopropenone Ketals
Nakamura Tetrahedron 1992, 48, 2045
Cl
Cl1 equiv. NBS, cat. H2SO4
OH OH
12-15%
Cl Br
OOKNH2, NH3
-50 ºC
68%O
O
O
O
Cl
O
Cl
OH OH
cat. TsOH
Cl Cl
OO3.5 equiv NaNH2
liq. NH3
O O
Cl
O O
Na
NH4Cl
Synthesis
Boger J. Am. Chem. Soc. 1986, 108, 6695
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