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 •Mechanism/Reactivity Piericidin A1 •Scope/Limitations •Utility/Application III. Cyclopropenone Ketals Rubrolone Aglycon IV. Intramolecular [4+2]/[3+2] Cascades Vindoline II. Heteroaromatic Azadiene
1 R R R N R N 3 N N N N R N R R R R
EDG 1,3,5-triazine N N 1,2,4-triazine
R R pyridine 2 R pyrimidine
N N N N
R
1,2,4,5-tetrazine O O R R R2 N N Zn/HOAc N 2 NH N N R N R R1 R R1 1,2-diazine R pyrrole 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 R N + ! N N N
R R 1,2,4-triazine pyridine
Mechanism
N 1 N R1 N R N –N N N + 2 R1 N N N R1 N loss of R2 R2 2 N R 2 H R N Reactivity
CO2Et
CO2Et N N •Highly functionalized pyridines > > N N N N N •Rxns run at 25-80 ºC N N •Aromatization is slow step, not initial [4+2] and loss of N CO2Et 2 CO2Et 1,2,4-Triazines
CO2Et R1 CO2Et N N + N N N R2 CHCl3, 45 ºC R1 R CO Et 2 R2 1,2,4-triazine Dienophile Conditions product yield (%)
EtO2C N CO2Et
N CHCl3, 60 ºC, 18 h 79 EtO2C Ph Ph
EtO2C N CO2Et N CH3 CHCl3, 45 ºC, 8 h 73 EtO C CH Ph 2 3 Ph
TMSO EtO2C N CO2Et CHCl3, 60 ºC, 22 h 84 Ph EtO2C Ph TMSO CH 3 CHCl3, 60 ºC, 16 h No Product 0 Ph
EtS CH3 CHCl3, 80 - 160 ºC, 16 h No Product 0 Ph Catalytic 1,2,4-Triazines Diels Alder
H N O R1 N + R2 R1 N N N 2 CHCl3, 45 ºC R 1,2,4-triazine R –N2
Ketone time (h) equiv of product yield (%) pyrollidine O
22 0.2 N 52
O 58 0.2 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
N CO2H H2N N
N CO2H O H2N N CH3 H2N O OH CH3 H2N 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 CO2CH3 R EDG R N N N + N N N R R
CO2CH3 CO2CH3
Mechanism
CO2CH3 CO2CH3 CO2Et N R EDG CO2CH3 R R N N N R N N + N R EDG N N ! N N EDG N N R -N2 R -H-EDG H3CO2C CO2CH3 CO2CH3 CO2Et
Reactivity
CO2CH3 SCH3 SCH3 NHCOR
N N N N N N N N > > > R = CH3, OCH3 N N N N N N N N
CO2CH3 SCH3 NHCOR NHCOR 1,2,4,5-Tetrazines
Utility
CO2CH3 CO2CH3 CO2CH3 R EDG R R N N N Zn/HOAc + N N N NH R R R
CO2CH3 CO2CH3 CO2CH3 1,2,4,5-Tetrazine 1,2-Diazine Pyrrole
Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D.; J. Org. Chem. 1984, 4405;
Mechanism
CO2Et CO2Et CO2Et CO2CH3 CO2CH3 R R R R R N Zn N H+ O -H2O H N NH NH N HN N 2 H2N R R CO2CH3 CO2CH3 CO2Et CO2Et CO2Et
Kornfield, E. C. et. al.; J. Med. Chem. 1980, 23, 481. 1,2,4,5-Tetrazines!1,2-Diazine!Pyrrole
CO2CH3 CO2CH3 CO2CH3 R EDG R R N N N Zn/HOAc + 25 ºC N N N NH dioxane 25 ºC R R R
CO2CH3 CO2CH3 CO2CH3
Dienophile Diazine Yield Pyrrole Yield
Et3SiO H CO C CO CH 87 H CO C 63 3 2 2 3 3 2 N CO2CH3 N N H
N
H CO C CO CH 85 52 3 2 2 3 H CO C 3 2 N CO2CH3 N N H
O Ph Ph
N H3CO2C CO2CH3 87 65 H CO C CO CH N N 3 2 N 2 3 H Ph
O O OCH OCH3 3 OCH3
H CO C CO CH O OCH3 3 2 2 3 71 H CO C 56 3 2 N CO2CH3 N N H Total Synthesis of Roseophilin
Retrosynthesis
SEMN RCM N Acyl Radical SEMN O Alkene Cyclization CO2Me O N OMe + SEM O OMe O
HN HN Cl Cl Wittig
N N OBn MeO2C CO2Me OBn N N
CO Me + MeO2C N 2 MeO2C CO2Me SEM [4+2] N N OMe 1,2,4,5-tetrazine Reductive Ring Contraction OBn Total Synthesis of Roseophilin
1. TiCl , (iPr) NH, 1. TPAP, NMO O O 4 2 BnOCH2Cl, 99% 100% OMe 2. LiAlH , 54% 2. CH3OCH=PPh3 N 4 HO OBn OBn
Bn
N N
MeO2C CO2Me OBn Zn/TFA, 25 ºC, OBn N N 1 h, 52% 25 ºC, 60 h MeO2C CO2Me 91% for 2 steps MeO C CO Me N N 2 N 2 H
1. Pd/C, H2 2. CSA, PhH 1. SEMCl, 92% 1. ClCO2Et, Et3N 77% for 2 steps 2. LiI, 74% 2. NaBH4, 90% O O O MeO2C HO2C N N HOH2C H O SEM O N SEM O Total Synthesis of Roseophilin
1. MnO2 BnO + - 1. Pd/C, H2, 97% 2. BnO(CH2)4PPh3 Br , NaHMDS, 2. TPAP, NMO 96% for 2 steps 3. CH2=PPh3 67–85% for two steps O O O HOH C 2 N N SEM N SEM O SEM O O
1. LiOH O + - 2. TMSCHN2 CH2=CH(CH2)2PPh3 Br , 3. TPAP, NMO NaHMDS
CO Me 91% for 4 steps N 2 SEM CO Me N 2 SEM
PCy3 Cl Ru CHPh Cl 1. NaOH, 49% 2. (EtO) P(O)Cl; PCy3 2 PhSeNa, 83% Bu3SnH, AIBN CH2Cl2, 40 ºC, 72 h 83% SEMN 72–88% SEMN CO2Me SEMN (1:1 E:Z) COSePh O Intramolecular Acyl Radical Cyclizations
(EtO)2P(O)C, PhSeNa Bu3SnH, AIBN 83% 83% SEMN SEMN SEMN CO2H COSePh O Other Examples 5-exo-dig
Bu3SnH, AIBN COSePh 80% O
SEMN CN H H O Bu3SnH, AIBN
COSePh 62% O CH2CN O
O Bu3SnH, AIBN O ( )n SePh 46 - 74% n = 2 - 11 ( )n Boger Isr. J. Chem. 1997, 37, 119 O O Total Synthesis of Roseophilin
1. n-BuLI, -78 ºC 2.CeCl , –55 ºC 30 min PtO , H 3 SEMN 2 2 3. -78 C OH 100% OMe OMe SEMN SEMN O O O O TIPSN Cl Cl TIPSN
1. Bu4NF 2. HCl
ClH•N
OMe O
HN Cl
ent–Roseophiline•HCl Intramolecular Diels-Alder: Preperation of Indoles and O Indolines O R2 2 N R N –N2 N
N N
N 1 R R1 1,2-Diazine Conditions Product Yield CH3 N N 230 ºC, 12 h 85% N N CO CH 2 3 CO2CH3
H3C CH3 N N 230 ºC, 18 h 77%
N N CO2CH3 CO2CH3
CH OTBS TBSOH2C 2 N N 230 ºC, 18 h 92%
N N CO2CH3 CO2CH3 Et Et
H3COS N • N 120 ºC 50 -55% N N CO2CH3 CO2CH3 Intramolecular Diels-Alder: Preperation of Indoles and Indolines
Utility
NH2 N N
HO2C O HO2C O O OH O OH OMe OMe
PDE-I PDE-II
H2N
N O
Me OH
HN OMe NH N N O O O O OH OMe
(+)-CC-1065 1,3,5-Triazines
R N R N R EDG N N + N
R R 1,3,5-triazine pyrimidine
Ynamines Diels-Alder
R N R CH3 N Me N R R R –RCN N N + Me N N N Bn2N Bn N R NBn2 2 R R pyrimidine 1,3,5-triazine R = H, 40 - 90 ºC, 81% Amidine Diels-Alder R = CO2Et, 40 - 90 ºC, 95% R = SCH3, 160 ºC, 93% R R = S(O)CH , >25 ºC, 50% NH2•HCl 3
HN H2N Me N N R R R N R Me N R N -NH3 R -RCN N N + H2N N N N R H N R 2 NH2•HCl NH N R 2 R R
H2N N R = H,125 ºC, 64% H2N N R R = CO2Et, 100 ºC, 85% N R R = SCH3, 150 ºC, 0% 1,3,5-Triazine
H N O H N O 2 2 NH2 NH2 H H N N CONH2 CONH2
N N O CH3 N N H N H2N N CO2H H2N CO2H H Me O Me N
NH (–)-Pyrimidolblamic Acid P-3A
H O N H2N O S NH2 H N N CONH2 O S H HO N N N O NH N H N H2N N HO S H H bleomycin A2 Me O N O OH HO O NH O OH OH O OH
OCONH OH 2 Heteroaromatic Azadiene Diels-Alder Reactions
1 R R R N R N 3 N N N N R N R R R R
EDG 1,3,5-triazine N N 1,2,4-triazine
R R pyridine 2 R pyrimidine
N N N N
R
1,2,4,5-tetrazine O O R R R2 N N Zn/HOAc N 2 NH N N R N R R1 R R1 1,2-diazine R pyrrole R indole I. 1-Aza-1,3-Butadiene Diels-Alder Background R H R N R R N R + R X 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 OR R N R OR + R R R R R R R
•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)
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 H R N OR R N R OR + R R R R R R R
Reactivity/Scope 60 - 100 ºC 25 ºC <25 ºC SO2Ph
SO2Ph SO2Ph SO2Ph N
N EtO2C N N < < < O O
Ph Ph CO2Et OEt
SO2Ph
SO2Ph SO2Ph SO2Ph N OEt
N OEt EtO2C N OEt N OEt O
O
Ph Ph CO2Et
72% (>1:20) 80% (>1:20) 82% (>1:20) 89% (>1:20) 1-Aza-1,3-Butadiene Diels-Alder
SO2Ph H R N R OR R N OR + R R 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
EtO OEt SO2CH3 SO2CH3 OEt EtO2C N EtO2C N EtO C N OEt OEt 2 CO2Et DBU
25 ºC, 95% CO Et 2 70 ºC, 91-94% CO2Et CH CH 3 3 CH3 Total Synthesis of Piericidin A1
Retrosynthesis
OH MeO OMe OH MeO OR MeO Stille [4+2] MeO OMe + MeO N Br MeO N NSO2CH3 Piericidin A1, R = H Piericidin B1, R = Me + CO2Et OR N-sulfonyl-1-azadiene
Bu3Sn
Julia Olefination
O O Ph O OTBS I S N + N H N N Total Synthesis of Piericidin A1
Synthesis of Pyridine Fragment
O O O
NH2OH•HCl MeSOCl, Et3N EtO EtO EtO 96% O N 0 ºC, 20 min N HO H3CO2S
Mechanism O Homolytic 3 OH Et N Cleavage SO2R N 3 O S N O N + R3SOCl N + Cl S 2 1 R2 R1 R R O Cl R2 R1 R2 R1
Not Stable Total Synthesis of Piericidin A1
Synthesis of Pyridine Fragment MeO OMe O O O SO2Me NH OH•HCl MeSOCl, Et N OMe 2 3 MeO OMe EtO2C N EtO EtO EtO OMe 96% 0 ºC, 20 min O N N PhCH3, 50 ºC, 18 h OMe HO H CO S 64% for 2 steps 3 2 OMe
1. 5 equiv BuLi OH EtO2C N OMe 1. DIBAL, 92% BF3•OEt2 N OMe 2. 6 equiv. B(OMe)3 N OMe 2. TIPSCl, Imid., 95% TIPSO 3. AcOOH, 88% TIPS CH Cl , 0 ºC, 1 h 2 2 OMe 88% OMe OMe OH Mechanism OH N OMe N OMe TIPSO 1. Bu4NF, 96% N OMe TIPS Br Bu4NF, 30 min 2. CBr4, PPh3, 84% OMe OMe OMe OH OH OH Fragment 1 36 h •Initial Brook Rearrangement
N OMe HO
OMe OH Total Synthesis of Piericidin A1
Fragment 2 Ph OH Ph O HS N ((NH4)6Mo7)O24 O Ph I PPH3, DEAD S + I H2O2 S N N I N N N N 71% N 89% N N N PTSH N Fragment 2 Fragment 3
O O O O OH iPr2NEt, Bu2BOTf 1. MeNH(OMe)•HCl 2. TBSCl, 66% 2 steps CH2Cl2 O OTBS N N 3. DIBAL, 86% O O O H
67% CO2Et O NaH 1. P (OEt)2 2. DIBAL, 72% 2 steps 3. (COCl)2, DMSO, 99%
O OTBS
H
Fragment 3 Total Synthesis of Piericidin A1
1. KHMDS, DME, O O OTBS O Ph –78 ºC, 18 h, 60% OTBS S I N + 2. BuLi, (Bu) SnCl H 3 N (Bu)3Sn N N Fragment 2 Fragment 3 N OMe Br
OMe OH Fragment 1
Pd2(dba)3, t(Bu)3P, OH LiCl, 74% MeO OTBS
MeO N
Bu4NF, 93%
OH MeO OH
MeO N
Piericidin A1 III. Cyclopropenone Ketals
RO OR RO OR OR !
OR
R R EWG EWG [4+2] [1+2] [3+2] [3+4]
OR EWG RO RO CH2CO2R OR R GWE OR 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] Cyclopropenone Ketals
Diels-Alder
O •High reactivity due to strain olefin O R conditions R •Reacts with electron deficient, + electron rich, and electron neutral O O dienes •exo products exclusively Diene Conditions Yield Transition State Model
neat, 25 ºC, 40 h 65% CO2CH3
R R 72% neat, 25 ºC, 60 h O OCH3 O O H
neat, 25 ºC, 62 h 69% H O exo endo
Tropone Introduction
CO CH CO2CH3 2 3 H3CO2C H3CO2C O O tBuOK O H+ 25 ºC O 25 ºC O O O
OCH3 Cyclopropenone Ketals
[4+3] O O 70 ºC O RO OR RO OR O O benzene H2SO4 O O O O MeOH
Transition State MP2/6-31++G(d)//6-31++G(d) OH OH HO HO •High temp., [3+4] cycloaddition H H with electron-deficient dienes O •Room temp or high pressure, [4+2] singlet H cycloaddition O H 0.00 kcal 1.40 kcal OH OH HO HO HO H H HO H H H triplet 9.22 kcal 8.73 kcal [1+2] CN 75 ºC O O RO OR RO OR benzene CN 80% yield O 9:1 cis:trans O
•High temp., exclusive [1+2] cyclopropanation with olefins having a single electron withdrawing group Cyclopropenone Ketals [3+2]
80 ºC O O H3CO2C •High temp., exclusive [3+2] H3CO2C CO2CH3 benzene O + H3CO2C cyclopropanation with olefins having O 95-100% two electron withdrawing group H3CO H CO 3 •Dienes with two EWG will undergo [3+2], not [3+4] at high temps O 80 ºC O O heptane O O + H3C O 22% Accounts for: NO2 CH3 1. partial loss of olefin geometry
O2N 2. lack of solvent dependency 3. lack of pre-rearrangement intermediates Mechanism 4. lack of inhibition by radical traps
RO OR RO OR GWE EWG
O ! EWG O R + O EWG O single e– EWG EWG RO OR transfer R R Total Synthesis of Rubrolone Aglycon
Retrosynthesis
O O Electrocylcic O N H O N Rearrangement N OH OH OH OH O O H O O OH HO O OH H O OH Rubrolone Rubrolone Aglycon
[4+2] Cyclopropenone Ketal
MeO O OMe O RO N O N + N O
O O Intramolecular Diels-Alder 1-aza-1,3-butadiene Total Synthesis of Rubrolone Aglycon
OH 1. DHP, PPTS, 99% OTHP CH3(CH2)2C!CLi 2. Bu NF, 99% OHC OTBS OTBS 4 OH 90%
1. PDC, 77%
O O 1. BnONH2, 96% 2. 2. Amberlyst, MeOH P(OMe)2 OTHP 99% 3. DMSO, (COCl) , O O 2 NaH, 96% Et3N, 86–95% N OBn
triisopropylbenzene 185 ºC, 48 h, 70%
O
N Total Synthesis of Rubrolone Aglycon
MeO
O 1. PhI(OAc)2, KOH, MeOH 2. (CF3CO)2O, Et3N MeO
N 65% N
HO
MeO MeO O PhI(OAc) , KOH, MeOH (CF CO) O, Et N 2 MeO 3 2 3 MeO
N 65% N -H2O N
I O MeO
MeO MeO N N Total Synthesis of Rubrolone Aglycon Br MeO MeO O 1. PhI(OAc)2, KOH, MeOH 1. Br2 2. (CF3CO)2O, Et3N MeO 2. t-BuOK MeO N 65% N 91% N
O SnBu3 O O H O O O O O MeO O (PPh3)4Pd O H MeO 95% MeO 25 ºC. 45 min, 97% MeO N exo 1 diastereomer N
Transition State Model O O O O
MeO MeO N OMe N O OMe Pr Pr O O H
H O exo endo Total Synthesis of Rubrolone Aglycon
HO O H O H O O O O O 1. NBS, MeOH O OH 80% O Br O 1. DBU H 2. aq. TFA, quant. H MeO OMe 2. aq. TFA O O 72% O MeO
N N N
LiOH, 99%
HO O HO HO OR OH OH O O O Zn, NH4Cl NBS, DMSO O O 48% HO N N N R = Br ! R = H Rubrolone Aglycon TMSBr, 99% O H O O H O MeO
MeO
N O H O O H O MeO
MeO
N
1. NBS, MeOH 80% 2. aq. TFA, quant.
O H O O H Br O OMe O
N O H O HO O O O OH H Br O OMe O O O
N N DBU
–HBr
O H O O O O OH H O O OMe OH O O
N N
aq. TFA
O H OH O O H O OH O H O O O O O H O OH H H OH O O O
N N N Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
General Reaction Goal •Facile approach to vinca alkaloids R R R1 R1 OH N O O N Et Vinblastine, R = CH3 N Vincristine, R = CHO R1 R1 R1 R1 N H N R R MeO2C FAST MeO [4+2] [3+2] Et SLOW OH R R N O R1 1 R R CO Me N O 2 O N R1 R1 R R N MeO •1,2,4-oxadiazoles behave as electron-deficient azadienes Vindoline OH Et N O Boger, D. L. et. al. J. Am. Chem. Soc. 2006, 128, 10589 H CO2Me
O O N N MeO Et Et O N O MeO N N N OBn Me H CO2Me BnO CO2Me Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Mechanism O O O
N N N [4+2] -N2 N O N endo O RZ O R N N N N Z N R Me Me E Me RE CO2Me RZ RE CO Me 2 CO2Me O
N [3+2]
endo O R Analogous Reaction N z H RE Me CO2Me N O O
Rh(II) N N O MeO MeO O N O Et [3+2] Et N 2 OMe O N O N H H O CO Me O 2 CO2Me Et O
Padwa J. Org. Chem. 1995, 60, 6258 Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Transtion State O O O N N vs. RZ E N E RZ Me RE N Me O RE
endo exo Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
O O
N N
O N O N RE N N Me H RZ CO2Me RZ RE CO2Me
RE RZ Conditions Yield 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 0-DCB = orthodichlorobenzene Ph o-DCB, 175 ºC, 19 h 61 H TIBP = triisopropylbenzene 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 Intramolecular Diels-Alder/1,3-Dipolar Cylcoaddition Cascade
Key Requirements/Limitations
1. N-Acylation 2. Oxadiazole Substitution O X N O N N N O N Me CO Me N 2 N X = NCO, 87% Me X X = CON, 61% X = NCH2, 0% X =EWG •Rate increases as EWG increases •Must stabilize 1,3-dipole 3. Tether Length 4. Dipolarphile •Dienophile O •Dipolarphile O O
N N N ( )n ( )n O N O N N O N X N N Me N X N CO Me Me X 2 n = 0, 68% X = NMe, 87% n = 1, 72% n =1, 87% X = NBn, 83% n = 2, 43% n = 2, 89% n = 3, 26% X = NCO2Me, 74% X = O, 63% X = S, 62% Total Synthesis of (–)- and ent-(+)-Vindoline
Retrosynthesis Intramolecular O [4+2]/[3+2] O Cylcloaddition N N Cascade N MeO MeO Et Et Et OH O O N N N N MeO H OAc OBn N H Me CO Me CO2Me BnO 2 CO2Me
NH NH2
O N N MeO N MeO N Me Me CO2Me +
HO2C Et
Boger, D. L. et. al. J. Am. Chem. Soc. 2006, 128, 10596 BnO Total Synthesis of (–)- and ent-(+)-Vindoline
NH NH NH 1. CDI, 90% 2 TsCl, Et3N 2. H2NHNCOCO2Me, 78% HN O O N N 81% N MeO HN O MeO MeO N N Me Me CO Me Me 2 CO2Me
EDCI, DMAP O HO2C Et O
N 1,3,5-triisopropylbenzene N BnO 230 ºC, 90 min MeO Et 96% O N 53% O Et MeO N N N Me H OBn CO2Me BnO 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 S OTIPS N 1. LDA, (TMSO) N OTIPS 2 Lawesson N MeO 2. TIPSOTf MeO Reagent MeO O Et O Et 64% 70% O Et N N H OBn H OBn N H OBn CO2Me CO2Me CO2Me
OTIPS OTIPS N N 1. Ra-Ni, 91% MeO MeO 2. Ac2O, 97% H2, PtO2 Et O Et OH 98% N N OAc H OAc H CO2Me CO2Me
N 1. Bu4NF, 89% MeO 2. Ph3P, DEAD, 75% OH Et N H OAc CO2Me (–)- and ent-(+)-Vindoline N MeO
OH Et N H O CO2Me Vindoline Analogs
N N N N MeO
Et OH Et OH Et OH Et N N N OAc N Me Me Me Me CO2Me CO2Me CO2Me CO2Me
Minovine Desacetoxyvindorosine Dihydrovindoline 4-Desacetoxyvindorosine- 6,7-dihydrovindorisine
N N N N MeO MeO
OH Et OH Et OH Et Et N OAc N N N Me Me Me H CO2Me CO2Me CO2Me Me
Vindoline Desacetoxyvindoline 4-Desacetoxyvindoline- N-Methyl- 6,7-dihydrovindorisine 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 O CO Et O OEt 2 O EtO O CO Et Et2NH N H 2 1 H2N 2 4 H2N N OEt OEt O NC OEt H2S N N S N H2N 25 ºC CO2Et
CO2CH3 CO2Et 2 CO2CH3 NH N R CO2CH3 -N R + N N N 2 N -HX N N R R X N N N NH N N ! N N X H H3CO2C CO2CH3 CO2Et CO2CH3
1,2,4,5-Tetrazine X = SCH3, OEt Synthesis CO2CH3 CO2Na CO2CH3 O 1. HCl, H2O NaOH Nitrous gases N N N NH 2. SOCl2, MeOH N NH OEt N N H O HN N HN N 2 CH2Cl2 N2 CO2CH3 CO2Na CO2CH3 1-Aza-1,3-Butadiene Diels-Alder
Preperation of N-sulfonyl-1-aza-1,3-butadienes
1 RSO NH SO2R O 2 2 N
1 R H MgSO4, TiCl4 R1 H 4Å MS
2 O
OH S OSOR SO2R N R Cl N N
Et N R1 R2 3 R1 R2 R1 R2
Mechanism O Homolytic 3 OH Et N Cleavage SO2R N 3 O S N O N + R3SOCl N + Cl S 2 1 R2 R1 R R O Cl R2 R1 R2 R1
Not Stable
3 O R S CN OH OSOR SO2R N O N N Et N R1 R2 3 R1 R2 R1 R2 Cyclopropenone Ketals
Synthesis
OH OH Cl KNH , NH O 1 equiv. NBS, cat. H2SO4 2 3 Cl O O -50 ºC 12-15% O Cl Br 68%
Boger J. Am. Chem. Soc. 1986, 108, 6695
O OH OH 3.5 equiv NaNH O cat. TsOH O O 2 O O O O NH4Cl
liq. NH3 O Cl Cl Cl Cl Cl Na
Nakamura Tetrahedron 1992, 48, 2045 1. NaOH, MeOH OMe 2. TBSCl NMe2 O 3. K2CO3, MeOH/H2O/THF MeO OMe O Cl MeO OMe OTBS OTBS 52% HO Cl O O
OMe 1. nBuLi, -78 ºC Cl O Cl 2. ZnCl2, -78 ºC to 0 ºC MeO OMe 3. Pd(PPh3)4 OTBS PPTS, MeOH O
Br O NTs N MeO OMe 76% Cl Ts TIPSN OTBS Cl