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

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


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


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


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


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+


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


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


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


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


[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


R R

Tropone Introduction

O

O

CO2CH3

OCH3

tBuOK

O

O

CO2CH3

25 ºC25 ºC

O

O

H3CO2C

H+

H3CO2C

O


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


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


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


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


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


N

MeO

MeO

O

OO

O

H

H


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

MeO

MeO

O

OO

O

H

H

N

O

OO

O

H

H Br

OMe

O

N

MeO

MeO

O

OO

O

H

H

1. NBS, MeOH80%

2. aq. TFA, quant.

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


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


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



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


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


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

N

NH

OH

O

CO2Me

Et

MeO

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


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


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


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

OO

OMe

HO

OMeO OMe

OTBS

NMe2

Cl

1. NaOH, MeOH2. TBSCl3. K2CO3, MeOH/H2O/THF

52% Cl

OMeO OMe

OTBS

NTs

Cl

Br

1. nBuLi, -78 ºC2. ZnCl2, -78 ºC to 0 ºC3. Pd(PPh3)4

Cl

OMeO OMe

OTBS

OMeO OMe

OTBS

NTs

Cl

PPTS, MeOH

76%

O

TIPSNCl

OMe

Chemistry from the Boger Research Group

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