Chemistry from the Boger Research Group
A Synergy of Target-Oriented Synthesis
and
New Reaction Development:
Cycloadditions for the Formation of Highly-Functionalized
Ring Structures and Applications in Total Synthesis
Troy E. Reynolds
January 8, 2007
Dale L. Boger
Education
B.S. University of Kansas, 1975
Ph.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 1979-1985
Associate Professor/Professor, Purdue University, 1985-1991
Professor, The Scripps Research Institute, 1991-present
Awards
Searle Scholar Award 1981-1984
NIH Career Award 1983-1988
Alfred P. Sloan Fellow 1985-1989
ACS Arthur C. Cope Scholar Award, 1988
Japan Promotion of Science Fellow, 1993
ISHC Katritzky Award in Heterocyclic Chemistry, 1997
Honorary Member, The Lund Chemical Society (Sweden), 1998
ACS Aldrich Award for Creativity in Organic Synthesis, 1999
A. R. Day Award, POCC 1999
Honorary Ph.D. Degree: Laurea Honors Causa, Univ. of Ferrara, 2000
Smissman Lecturer, Univ. of Kansas, 2000
Yamanouchi USA Faculty Award, 2000
Paul Janssen Prize for Creativity in Organic Synthesis, 2002
oss Lecturer, Dartmouth College, 2002
Fellow, American Association for the Advancement of Science, 2003
Adrien Albert Medal, Royal Society of Chemistry, 2003
ISI Highly Cited (top 100 chemists)
Alder Lecturer, University of Köln, 2005
Chemistry from the Boger Research Group
Research Interests
•Total synthesis
•New synthetic methods
•Bioorganic and medicinal chemistry
•Combinatorial chemistry
•DNA-agent interactions
•Chemistry of antitumor antibiotics
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
II. Heteroaromatic Azadiene
R
1
R
N
N
R
R
R
3
N
R
R
N
N
N
R
EDG
1,2,4-triazine
N
N
1,3,5-triazine
R
N
R
R
pyridine
R
2
pyrimidine
N
N
N
N
R
1,2,4,5-tetrazine
O
R
R
N
Zn/HOAc
NH
R2
O
N
N
pyrrole
1,2-diazine
R2
N
N
R
R
N
R1
R
R1
R
indole
•Electron-deficient azadienes ideally suited for inverse-demand Diels Alder reactions
•Introduction of highly substituted heterocylcic systems
I. Heteroaromatic Azadienes: 1,2,4-Triazine
R
R
R
N
N
N
+
N
R
!
N
R
R
1,2,4-triazine
pyridine
Mechanism
N
N
N
N
R1
N
N
+
N
N
R2
N
–N2
R1
R1
R1
N
R2
loss of
R2
H
N
N
R2
Reactivity
CO2Et
CO2Et
N
N
N
CO2Et
>
N
N
N
>
N
N
N
CO2Et
•Highly functionalized pyridines
•Rxns run at 25-80 ºC
•Aromatization is slow step, not initial
[4+2] and loss of N2
1,2,4-Triazines
CO2Et
N
N
R1
CO2Et
N
+
N
R1
CO2Et
1,2,4-triazine
Dienophile
R
R2
Conditions
product
EtO2C
N
CHCl3, 60 ºC, 18 h
N
yield (%)
CO2Et
79
EtO2C
Ph
Ph
EtO2C
N
N
R2
CHCl3, 45 ºC
CH3
CHCl3, 45 ºC, 8 h
Ph
N
CO2Et
73
EtO2C
CH3
Ph
EtO2C
TMSO
N
CHCl3, 60 ºC, 22 h
Ph
CO2Et
84
EtO2C
Ph
TMSO
CH3
CHCl3, 60 ºC, 16 h
No Product
0
CHCl3, 80 - 160 ºC, 16 h
No Product
0
Ph
EtS
CH3
Ph
Catalytic 1,2,4-Triazines Diels Alder
H
N
N
N
+
N
R2
R1
CHCl3, 45 ºC
1,2,4-triazine
Ketone
R1
O
–N2
time (h)
equiv of
pyrollidine
22
0.2
58
0.2
O
N
R2
R
yield (%)
product
52
N
O
86
N
O
96
2.0
93
N
O
84
4.0
36
N
O
36
1.0
N
19
I. Heteroaromatic Azadienes: 1,2,4-Triazine
Utility
O
MeO
O
H2N
H2N
N
N
CO2H
N
N
O
CH3
H2N
O
H2N
CO2H
OH
CH3
OMe
OMe
Lavendamycin
Streptonigrin
Lavendamycin (J. S. Panek, S. R. Duff, M. Yasuda), J. Org. Chem. 1985, 50, 5782-5789, 5790-5795
Streptonigrin (J. S. Panek), J. Am. Chem. Soc. 1985, 107, 5745-5754
1,2,4,5-Tetrazines
CO2CH3
N
N
N
N
CO2CH3
R
R
EDG
N
+
N
R
R
CO2CH3
CO2CH3
Mechanism
CO2CH3
R
EDG
+
R
N
N
N
N
N
N
!
CO2CH3
N
N
H3CO2C
CO2CH3
CO2CH3
R
R
N EDG
R
N
R
R
N
EDG
N
-N2
CO2Et
N
-H-EDG
CO2CH3
CO2Et
Reactivity
CO2CH3
N
N
N
N
CO2CH3
SCH3
>
N
N
N
N
SCH3
SCH3
>
N
N
N
N
NHCOR
NHCOR
>
N
N
N
N
NHCOR
R = CH3, OCH3
1,2,4,5-Tetrazines
Utility
CO2CH3
N
N
N
N
CO2CH3
R
R
EDG
CO2CH3
NH
R
CO2CH3
1,2,4,5-Tetrazine
CO2CH3
N
R
R
Zn/HOAc
N
+
R
CO2CH3
Pyrrole
1,2-Diazine
Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D.; J. Org. Chem. 1984, 4405;
Mechanism
CO2Et
CO2Et
R
N
N
Zn
R
N
HN
CO2Et
CO2Et
H+
H2N
CO2Et
R
O
H
N
R
-H2O
CO2CH3
N
CO2CH3
NH
NH2
R
CO2Et
R
R
CO2CH3
Kornfield, E. C. et. al.; J. Med. Chem. 1980, 23, 481.
CO2CH3
1,2,4,5-Tetrazines!1,2-Diazine!Pyrrole
CO2CH3
N
N
N
N
CO2CH3
R
R
EDG
25 ºC
+
dioxane
R
R
N
Zn/HOAc
N
25 ºC
CO2CH3
R
NH
R
CO2CH3
CO2CH3
Dienophile
Et3SiO
N
Pyrrole
Yield
Diazine
H3CO2C
CO2CH3
CO2CH3
87
CO2CH3
85
H3CO2C
N
Yield
N
H
CO2CH3
N
H
CO2CH3
N
H
CO2CH3
63
N
H3CO2C
N
N
H3CO2C
Ph
O
Ph
H3CO2C
N
52
CO2CH3
N
87
N
H3CO2C
Ph
65
O
O
OCH3
O
OCH3
H3CO2C
OCH3
CO2CH3
N
N
OCH3
71
H3CO2C
N
H
CO2CH3
56
Total Synthesis of Roseophilin
Retrosynthesis
SEMN
N
+
OMe
O
RCM
Acyl Radical SEMN
Alkene Cyclization
N
SEM
O
OMe
O
CO2Me
O
HN
HN
Cl
Wittig
Cl
N
N
MeO2C
CO2Me
N
OBn
OBn
N
+
[4+2]
1,2,4,5-tetrazine
OMe
OBn
MeO2C
CO2Me
N
N
MeO2C
Reductive
Ring Contraction
N
SEM
CO2Me
Total Synthesis of Roseophilin
O
1. TiCl4, (iPr)2NH,
BnOCH2Cl, 99%
2. LiAlH4, 54%
O
N
1. TPAP, NMO
100%
2. CH3OCH=PPh3
HO
OMe
OBn
OBn
Bn
N
N
MeO2C
OBn
CO2Me
N
N
25 ºC, 60 h
91% for 2 steps
MeO2C
CO2Me
N
OBn
Zn/TFA, 25 ºC,
1 h, 52%
MeO2C
N
N
H
CO2Me
1. Pd/C, H2
2. CSA, PhH
77% for 2 steps
O
MeO2C
N
H
1. SEMCl, 92%
2. LiI, 74%
O
HO2C
O
N
SEM
O
1. ClCO2Et, Et3N
2. NaBH4, 90%
O
HOH2C
N
SEM
O
Total Synthesis of Roseophilin
1. MnO2
2. BnO(CH2)4PPh3+Br-,
NaHMDS,
96% for 2 steps
BnO
1. Pd/C, H2, 97%
2. TPAP, NMO
3. CH2=PPh3
67–85% for two steps
O
HOH2C
N
SEM
N
SEM
O
1. LiOH
2. TMSCHN2
3. TPAP, NMO
O
N
SEM
Cl
Cl
O
O
N
SEM
O
CH2=CH(CH2)2PPh3+Br-,
NaHMDS
CO2Me
91% for 4 steps
N
SEM
CO2Me
PCy3
Ru CHPh
1. NaOH, 49%
2. (EtO)2P(O)Cl;
PhSeNa, 83%
PCy3
CH2Cl2, 40 ºC, 72 h
72–88%
(1:1 E:Z)
SEMN
Bu3SnH, AIBN
83%
CO2Me
SEMN
COSePh
SEMN
O
O
Intramolecular Acyl Radical Cyclizations
(EtO)2P(O)C, PhSeNa
Bu3SnH, AIBN
83%
SEMN
83%
SEMN
CO2H
SEMN
COSePh
O
Other Examples
5-exo-dig
Bu3SnH, AIBN
COSePh
80%
O
H
CN
H
SEMN
O
Bu3SnH, AIBN
COSePh
62%
CH2CN O
O
( )n
Bu3SnH, AIBN
O
SePh
O
46 - 74%
n = 2 - 11
O
Boger Isr. J. Chem. 1997, 37, 119
( )n
O
Total Synthesis of Roseophilin
1. n-BuLI, -78 ºC
2.CeCl3, –55 ºC 30 min
3. -78 C
PtO2, H2
100%
SEMN
O
SEMN
OMe
OMe
SEMN
O
OH
O
O
TIPSN
TIPSN
Cl
Cl
1. Bu4NF
2. HCl
ClH•N
OMe
O
HN
Cl
ent–Roseophiline•HCl
Intramolecular Diels-Alder: Preperation of Indoles and
O
O
Indolines
R2
N
N
N
R2
–N2
N
N
N
1,2-Diazine
R1
Conditions
R1
Product
Yield
CH3
N
N
230 ºC, 12 h
85%
N
CO2CH3
N
CO2CH3
H3C
N
CH3
N
77%
230 ºC, 18 h
N
CO2CH3
N
CO2CH3
CH2OTBS
TBSOH2C
N
N
CO2CH3
N
Et CO2CH3
H3COS
N
N
92%
230 ºC, 18 h
N
•
N
CO2CH3
Et
50 -55%
120 ºC
N
CO2CH3
Intramolecular Diels-Alder: Preperation of Indoles and
Indolines
Utility
N
NH2
N
O
HO2C
O
O
HO2C
O
OH
OH
OMe
OMe
PDE-I
PDE-II
H2N
N
O
OH
Me
HN
NH
N
N
O
O
O
O
OH
OMe
(+)-CC-1065
OMe
1,3,5-Triazines
R
N
R
N
R
EDG
N
+
N
N
R
R
pyrimidine
1,3,5-triazine
Ynamines Diels-Alder
R
N
N
CH3
R
Me
–RCN
Bn2N
R
R
pyrimidine
R = H, 40 - 90 ºC, 81%
R = CO2Et, 40 - 90 ºC, 95%
R = SCH3, 160 ºC, 93%
R = S(O)CH3, >25 ºC, 50%
Amidine Diels-Alder
R
NH2•HCl
R
N
N
HN
Me
R
R
N
+
H2N
NH2•HCl
H2N
NN
NN
R
N
R
-NH3
R
R
N
Bn2N
1,3,5-triazine
H2N
N
N
N
NBn2
R
R
Me
+
N
N
R
R
N
R
-RCN
N
H2N
R
NH2 N
R
Me
R
H2N
NN
N
R
R
R = H,125 ºC, 64%
R = CO2Et, 100 ºC, 85%
R = SCH3, 150 ºC, 0%
1,3,5-Triazine
H2N
H2N
O
NH2
H
N
N
O
NH2
H
N
CONH2
CONH2
N
N
H2N
N
H2N
CO2H
Me
Me
CONH2
N
H2N
Me
O
OH
O
HO
OH
O
H
N
CO2H
NH
O
S
NH2
H
N
N
O
H
N
O
CH3
N
H
N
P-3A
(–)-Pyrimidolblamic Acid
H2N
O
H
N
H
N
HO
N
H
N
O
HO
NH
O
OH
O
OH
OH
OCONH2
N
O
S
NH
N
S
H
bleomycin A2
Heteroaromatic Azadiene Diels-Alder Reactions
R
1
R
N
N
R
R
R
3
N
R
R
N
N
N
R
EDG
1,2,4-triazine
N
N
1,3,5-triazine
R
N
R
R
pyridine
R
2
pyrimidine
N
N
N
N
R
1,2,4,5-tetrazine
O
R
R
N
Zn/HOAc
NH
R
pyrrole
R2
O
N
N
R2
N
N
R
1,2-diazine
N
R
R1
R1
R
indole
I. 1-Aza-1,3-Butadiene Diels-Alder
Background
R
R
N
R
R
X
+
R
H
N
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
1-Aza-1,3-Butadienes
SO2Ph
SO2Ph
R
N
R
OR
R
N
R
+
R
R
R
OR
R
R
R
•EWG substitution at N1 or C3 should accelerate potential [4+2] with electronrich diene - Inverese Demand Diels-Alder
•Bulky EWG at N1 should preferentially decelerate 1,2-imine additon as well
as stabilize cycloaddition product (deactivated enamine)
Boger, D. L.; Corbett, W. L.; Curran, T. T.; Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713
1-Aza-1,3-Butadiene Diels-Alder
SO2Ph
R
N
R
R
OR
H
N
OR
R
+
R
R
R
R
R
R
Reactivity/Scope
60 - 100 ºC
25 ºC
<25 ºC
SO2Ph
SO2Ph
N
EtO2C
SO2Ph
SO2Ph
N
N
<
<
N
O
<
O
Ph
CO2Et
Ph
OEt
SO2Ph
SO2Ph
N
OEt
SO2Ph
SO2Ph
EtO2C
N
OEt
N
N
OEt
OEt
O
O
Ph
72% (>1:20)
Ph
80% (>1:20)
CO2Et
82% (>1:20)
89% (>1:20)
1-Aza-1,3-Butadiene Diels-Alder
SO2Ph
R
N
R
R
OR
H
N
R
+
R
OR
R
R
R
R
R
Transition State Model
N
•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
SO2CH3
EtO2C
EtO
OEt
EtO2C
N
CO2Et
SO2CH3
OEt
N
OEt
25 ºC, 95%
CH3
CO2Et
CH3
DBU
EtO2C
N
70 ºC, 91-94%
OEt
CO2Et
CH3
Total Synthesis of Piericidin A1
Retrosynthesis
OH
MeO
MeO
OH
OR
MeO
Stille
N
MeO
Piericidin A1, R = H
Piericidin B1, R = Me
[4+2]
MeO
OMe
MeO
OMe
+
Br
N
NSO2CH3
CO2Et
+
OR
N-sulfonyl-1-azadiene
Bu3Sn
Julia Olefination
O
I
O
S
Ph
N
N
+
N
N
O
H
OTBS
Total Synthesis of Piericidin A1
Synthesis of Pyridine Fragment
O
O
O
MeSOCl, Et3N
NH2OH•HCl
EtO
EtO
96%
O
HO
EtO
0 ºC, 20 min
N
H3CO2S
N
Mechanism
N
R2
O
OH
+
R1
Et3N
N
R3SOCl
R2
O
S
Cl
R1
Not Stable
Homolytic
Cleavage
N
R2
O
+
R1
O
S
N
Cl
R2
SO2R3
R1
Total Synthesis of Piericidin A1
Synthesis of Pyridine Fragment
O
O
MeSOCl, Et3N
NH2OH•HCl
EtO
EtO
BF3•OEt2
EtO
96%
O
HO
EtO2C
N
OMe
CH2Cl2, 0 ºC, 1 h
88%
MeO
OMe
MeO
OMe
SO2Me
OMe
N
OMe
O
N
0 ºC, 20 min
H3CO2S
1. DIBAL, 92%
2. TIPSCl, Imid., 95% TIPSO
N
OMe
EtO2C
PhCH3, 50 ºC, 18 h
64% for 2 steps
N
OMe
OMe
OH
1. 5 equiv BuLi
OMe 2. 6 equiv. B(OMe)3
3. AcOOH, 88%
TIPS
N
OMe
OMe
OH
Mechanism
OH
1. Bu4NF, 96%
2. CBr4, PPh3, 84%
Br
N
OMe
TIPS
N
Bu4NF, 30 min
Fragment 1
TIPSO
N
OMe
OMe
OMe
OMe
OH
OMe
OMe
OH
OH
36 h
•Initial Brook Rearrangement
HO
N
OMe
OMe
OH
Total Synthesis of Piericidin A1
Fragment 2
Ph
OH
I
+
HS
N
N
PPH3, DEAD
N
N
S
I
71%
N
PTSH
Ph ((NH4)6Mo7)O24
H2O2
N
N
89%
N
O
O
O
N
N
N
Fragment 2
O
O
iPr2NEt, Bu2BOTf
CH2Cl2
O
O
Ph
N
N
Fragment 3
O
O
S
I
N
OH
1. MeNH(OMe)•HCl
2. TBSCl, 66% 2 steps
3. DIBAL, 86%
O
OTBS
H
CO2Et
67%
O NaH
P
(OEt)2
1.
2. DIBAL, 72% 2 steps
3. (COCl)2, DMSO, 99%
O
OTBS
H
Fragment 3
Total Synthesis of Piericidin A1
O
I
O
S
+
N
N
Fragment 2
O
Ph
N
N
OTBS
1. KHMDS, DME,
–78 ºC, 18 h, 60%
OTBS
2. BuLi, (Bu)3SnCl
H
(Bu)3Sn
Fragment 3
N
Br
OMe
OMe
OH
Fragment 1
OH
Pd2(dba)3, t(Bu)3P,
LiCl, 74%
MeO
OTBS
MeO
N
Bu4NF, 93%
OH
MeO
MeO
OH
N
Piericidin A1
III. Cyclopropenone Ketals
!
OR
RO
OR
RO
OR
OR
R
[4+2]
OR
R
EWG
[1+2]
EWG
CH2CO2R
R
EWG
[3+2]
RO
GWE
OR
H
•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]
[3+4]
RO
OR
OR
Cyclopropenone Ketals
Diels-Alder
O
R
+
conditions
O
Diene
Conditions
CO2CH3
Yield
•High reactivity due to strain olefin
•Reacts with electron deficient,
electron rich, and electron neutral
O
dienes
•exo products exclusively
Transition State Model
O
R
65%
neat, 25 ºC, 40 h
R
R
OCH3
72%
neat, 25 ºC, 60 h
O
neat, 25 ºC, 62 h
69%
O
H
O
H
O
exo
endo
Tropone Introduction
CO2CH3
CO2CH3
OCH3
H3CO2C
O
tBuOK
O
O
25 ºC
O
H3CO2C
O
H+
O
25 ºC
O
Cyclopropenone Ketals
[4+3]
O
70 ºC
benzene
O
O
RO
OR
RO
OR
O
O
O
H2SO4
O
Transition State
O
O
MeOH
MP2/6-31++G(d)//6-31++G(d)
OH
OH
HO
HO
•High temp., [3+4] cycloaddition
with electron-deficient dienes
•Room temp or high pressure, [4+2]
cycloaddition
H
H
O
singlet
H
O
H
1.40 kcal
0.00 kcal
OH
OH
HO
HO
HO
H
H
HO
H
H
9.22 kcal
[1+2]
O
O
75 ºC
benzene
CN
RO
OR
RO
OR
triplet
H
8.73 kcal
O
CN
O
80% yield
9:1 cis:trans
•High temp., exclusive [1+2] cyclopropanation with olefins having a single electron withdrawing group
Cyclopropenone Ketals
[3+2]
O
+
H3CO2C
O
CO2CH3
80 ºC
benzene
H3CO
80 ºC
heptane
O
O
•High temp., exclusive [3+2]
cyclopropanation with olefins having
two electron withdrawing group
O
H3CO2C
95-100%
H3CO
+
H3CO2C O
•Dienes with two EWG will undergo
[3+2], not [3+4] at high temps
O
O
O
H3C
22%
O
NO2
Accounts for:
1. partial loss of olefin geometry
2. lack of solvent dependency
3. lack of pre-rearrangement intermediates
4. lack of inhibition by radical traps
CH3
O2N
Mechanism
RO
OR
RO
GWE
O
!
R
O
RO
OR
OR
EWG
single e–
transfer
EWG O
+
EWG
EWG
EWG
R
R
O
Total Synthesis of Rubrolone Aglycon
Retrosynthesis
O
O
Electrocylcic
Rearrangement
N
N
OH
O
H
N
O
OH
OH OH
O
H
O
O
OH
O
O
H
HO
O
OH
OH
Rubrolone Aglycon
Rubrolone
[4+2]
Cyclopropenone Ketal
MeO
O
RO
N
O
OMe
N
+
N
O
O
O
Intramolecular Diels-Alder
1-aza-1,3-butadiene
O
Total Synthesis of Rubrolone Aglycon
OHC
OTBS
CH3(CH2)2C!CLi
OH
OTBS
1. DHP, PPTS, 99%
2. Bu4NF, 99%
90%
1. PDC, 77%
2.
O
O
P(OMe)2
NaH, 96%
OTHP
1. BnONH2, 96%
2. Amberlyst, MeOH
99%
3. DMSO, (COCl)2,
O
Et3N, 86–95%
O
N
OBn
triisopropylbenzene
185 ºC, 48 h, 70%
O
N
OTHP
OH
Total Synthesis of Rubrolone Aglycon
MeO
1. PhI(OAc)2, KOH, MeOH
2. (CF3CO)2O, Et3N
O
MeO
65%
N
N
HO
MeO
O
PhI(OAc)2, KOH, MeOH
MeO
(CF3CO)2O, Et3N
MeO
65%
N
N
I
O
MeO
MeO
MeO
N
N
-H2O
MeO
N
Total Synthesis of Rubrolone Aglycon
Br
MeO
1. PhI(OAc)2, KOH, MeOH
2. (CF3CO)2O, Et3N
O
O
MeO
MeO
65%
N
91%
N
SnBu3
MeO
1. Br2
2. t-BuOK
N
O
O
O
O
(PPh3)4Pd
95%
H
O
O
O
MeO
O
MeO
25 ºC. 45 min, 97%
exo
1 diastereomer
N
O
H
MeO
MeO
N
Transition State Model
O
O
O
O
MeO
MeO
O
OMe
Pr
H
O
N
OMe
Pr
O
H
O
exo
endo
N
Total Synthesis of Rubrolone Aglycon
O
H
O
O
1. NBS, MeOH
80%
2. aq. TFA, quant.
O
O
H
MeO
HO
H
O
O
O
O
Br
H
O
OMe
1. DBU
2. aq. TFA
O
O
72%
MeO
N
OH
O
N
N
LiOH, 99%
HO
HO
HO
OH
O
OH
O
O
O
NBS, DMSO
O
48%
Zn, NH4Cl
O
HO
N
N
N
R = Br ! R = H
Rubrolone Aglycon
TMSBr, 99%
OR
O
H
O
O
O
H
MeO
MeO
N
O
H
O
O
O
H
MeO
MeO
N
1. NBS, MeOH
80%
2. aq. TFA, quant.
O
H
O
O
H
Br
O
OMe
O
N
O
H
HO
O
O
O
Br
H
O
O
OMe
OH
O
O
O
N
N
DBU
–HBr
O
H
O
O
O
O
H
OH
O
O
OMe
OH
O
O
N
N
aq. TFA
O
H
O
O
O
O
OH
H
O
H
O
O
H
OH
O
O
O
H
O
N
OH
O
OH
H
O
N
N
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
General Reaction
Goal
•Facile approach to vinca alkaloids
R
R
R1
N
O
R1
R
R1
R1
R1
R
O
R1
FAST
[3+2]
N
N
O
R
CO2Me
O
N
Et
OH
R1
N
Vinblastine, R = CH3
Vincristine, R = CHO
Et
N
H 2C
MeO
MeO
R
R
R1
N
O
N
[4+2]
SLOW
OH
R1
R1
R
N
R
•1,2,4-oxadiazoles behave as electron-deficient azadienes
MeO
Et
OH
N
H
Boger, D. L. et. al. J. Am. Chem. Soc. 2006, 128, 10589
O
CO2Me
O
O
N
N
MeO
N
O
MeO
N
N
Me CO Me BnO
2
Et
Et
O
N
H
OBn
CO2Me
Vindoline
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Mechanism
O
O
N
N
O
N
O
N
[4+2]
N
endo
N
N
Me CO Me
2
RZ
N
N
O
RZ
O
N
RE
CO2Me
Me
RE
-N2
RZ
RE
CO2Me
Me
O
N
[3+2]
endo
O
Analogous Reaction
Rz
RE
CO2Me
N
H
Me
O
N
N
N
Rh(II)
O
O
N
MeO
O
Et
N2
O
OMe
O
MeO
Et
O
N
H
O
CO2Me
Padwa J. Org. Chem. 1995, 60, 6258
[3+2]
Et
O
N
H
O
CO2Me
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Transtion State
O
O
O
N
N
vs.
RZ
N
E
E
Me
RZ
RE
N
Me
endo
O
exo
RE
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
O
O
N
N
N
O
N
N
Me CO Me
2
O
RZ
N
H
RE
RE
RZ
CO2Me
RE
RZ
Conditions
H
H
o-DCB, 180 ºC, 3 h
87
Me
H
o-DCB, 180 ºC, 24 h
65
CH2OTBS
H
o-DCB, 180 ºC, 24 h
86
Ph
H
o-DCB, 175 ºC, 19 h
61
OBn
H
TIPB, 230 ºC, 19 h
88
H
OBn
TIPB, 230 ºC, 38 h
41
CO2Me
H
TIPB, 230 ºC, 46 h
71
H
CO2Me
TIPB, 230 ºC 60 h
62
CN
H
TIPB, 230 ºC, 22h
79
H
CN
TIPB, 230 ºC, 22h
74
Yield
0-DCB = orthodichlorobenzene
TIBP = triisopropylbenzene
Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Key Requirements/Limitations
1. N-Acylation
2. Oxadiazole Substitution
O
X
N
O
N
N
N
Me CO Me
2
O
N
N
Me X
X = NCO, 87%
X = CON, 61%
X = NCH2, 0%
N
X =EWG
•Rate increases as EWG increases
•Must stabilize 1,3-dipole
3. Tether Length
4. Dipolarphile
•Dienophile
•Dipolarphile
O
O
O
N
N
O
Me X
n = 0, 68%
n =1, 87%
n = 2, 43%
( )n
( )n
N
N
N
O
Me X
n = 1, 72%
n = 2, 89%
n = 3, 26%
N
N
N
N
X
O
N
CO2Me
X = NMe, 87%
X = NBn, 83%
X = NCO2Me, 74%
X = O, 63%
X = S, 62%
N
Total Synthesis of (–)- and ent-(+)-Vindoline
Retrosynthesis
Intramolecular
[4+2]/[3+2]
Cylcloaddition
Cascade
O
N
N
MeO
O
N
MeO
Et
OH
N
H
Et
O
N
H
OAc
CO2Me
OBn
N
MeO
O
N
Me CO Me BnO
2
CO2Me
NH
NH2
MeO
N
N
MeO
O
N
Me CO Me
2
Me
+
HO2C
Boger, D. L. et. al. J. Am. Chem. Soc. 2006, 128, 10596
Et
N
Et
BnO
N
Total Synthesis of (–)- and ent-(+)-Vindoline
NH
NH2 1. CDI, 90%
2. H2NHNCOCO2Me, 78%
TsCl, Et3N
HN
N
MeO
N
MeO
NH
Me
Me
HN
O
O
81%
N
MeO
O
N
N
Me CO Me
2
CO2Me
EDCI, DMAP
HO2C
Et
1,3,5-triisopropylbenzene
230 ºC, 90 min
N
BnO
96%
O
O
MeO
N
O
N
N
Me CO Me BnO
2
Et
N
MeO
53%
Et
O
N
H
OBn
CO2Me
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
Total Synthesis of (–)- and ent-(+)-Vindoline
O
O
N
Et
O
N
H
64%
O
N
H
OBn
MeO
70%
OBn
N
H
Et
O
N
H
98%
OAc
MeO
Et
OH
N
H
OAc
CO2Me
CO2Me
N
MeO
Et
OH
N
H
OTIPS
N
H2, PtO2
OAc
CO2Me
(–)- and ent-(+)-Vindoline
OBn
CO2Me
OTIPS
MeO
Et
O
CO2Me
N
1. Bu4NF, 89%
2. Ph3P, DEAD, 75%
Et
OTIPS
N
Lawesson
Reagent
MeO
CO2Me
1. Ra-Ni, 91%
2. Ac2O, 97%
OTIPS
N
1. LDA, (TMSO)2
2. TIPSOTf
MeO
S
N
MeO
Et
OH
N
H
O
CO2Me
Vindoline Analogs
N
N
N
N
MeO
Et
OH
N
Me
Et
N
Me
CO2Me
Minovine
N
N
N
Me
CO2Me
Vindoline
CO2Me
4-Desacetoxyvindorosine6,7-dihydrovindorisine
N
MeO
Et
OAc
Me
N
MeO
N
N
CO2Me
Dihydrovindoline
Et
OH
OAc
Me
CO2Me
Desacetoxyvindorosine
OH
Et
OH
OH
Et
N
Me
OH
Et
N
CO2Me
Desacetoxyvindoline
Me
Et
N
CO2Me
4-Desacetoxyvindoline6,7-dihydrovindorisine
Me
H
N-Methylaspidospermidine
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
O
Synthesis
O
1
NC
O
O
Et2NH
H2S
OEt
N2H4
H2N
H2N
OEt
S
H2N
EtO
N
N
+
R
X
N
N
N
N
CO2CH3
1,2,4,5-Tetrazine
N
25 ºC
CO2Et
CO2Et
CO2CH3
N
NH
CO2Et
N
O
OEt
CO2CH3
2
CO2Et
OEt
!
N
N
N
H3CO2C
CO2CH3
R
N
H
X
-N2
R
N
N
NH
CO2CH3
-HX
R
N
N
N
CO2Et
X = SCH3, OEt
Synthesis
CO2Na
O
NaOH
OEt
N2
H2O
N
HN
NH
N
CO2Na
CO2CH3
CO2CH3
1. HCl, H2O
2. SOCl2, MeOH
N
HN
NH
N
CO2CH3
Nitrous gases
N
N
N
N
CH2Cl2
CO2CH3
1-Aza-1,3-Butadiene Diels-Alder
Preperation of N-sulfonyl-1-aza-1,3-butadienes
1
RSO2NH2
O
R1
N
MgSO4, TiCl4
4Å MS
H
2
R1
SO2R
H
O
N
R1
OH
S
R
Cl
N
Et3N
R2
R1
OSOR
N
R2
R1
SO2R
R2
Mechanism
N
R2
O
OH
+
Et3N
N
R3SOCl
R1
O
S
Homolytic
Cleavage
Cl
R2
R1
R2
N
O
+
R1
O
S
N
Cl
Not Stable
O
3
N
R1
OH
R2
R
S
CN
O
Et3N
N
R1
OSOR
R2
N
R1
SO2R
R2
R2
SO2R3
R1
Cyclopropenone Ketals
Synthesis
Cl
Cl
OH
OH
1 equiv. NBS, cat. H2SO4
O
O
KNH2, NH3
O
-50 ºC
12-15%
Cl
O
68%
Br
Boger J. Am. Chem. Soc. 1986, 108, 6695
OH
OH
cat. TsOH
O
O
O
3.5 equiv NaNH2
O
O
O
liq. NH3
Cl
Cl
Cl
Cl
O
NH4Cl
O
O
Cl
Nakamura Tetrahedron 1992, 48, 2045
Na
OMe
1. NaOH, MeOH
2. TBSCl
3. K2CO3, MeOH/H2O/THF
52%
O
O
N
Ts
O
MeO
Br
Cl
O
MeO
OMe
OTBS
HO
1. nBuLi, -78 ºC
2. ZnCl2, -78 ºC to 0 ºC
3. Pd(PPh3)4
Cl
NMe2
OMe
OTBS
O
MeO
Cl
OMe
OTBS
Cl
Cl
O
MeO
NTs
OMe
OMe
OTBS
PPTS, MeOH
O
76%
TIPSN
Cl