a b b c a c Ally anion type Propargyl/allenyl anion type a b c a b c a b c a b c a b c a b c b =,, or C a b c a b c b = Gothelf, K. V.; Jørgensen, K.

(1)

1,3-Dipolar Cycloaddition Reactions

of Nitrones with Alkenes

2009,12,05

(2)

The basic resonance structure of 1,3-dipoles

a

b

c

_a

b

_c

a

b

c

a

b

c

a

b

c

a

b

c

b = N, O, or C

Ally anion type

a

b

c

a

b

c

b = N

a

b

c

a

b

c

Propargyl/allenyl anion type

(3)

Allyl anion type

Nitrogen in the middle

C N O C N N C N C N N N N N O O N O Nitrone Azomethine Imines Azomethine Ylides Azimines Azoxy Compounds Nitro Compounds C O C C O N C O O N O N N O O O O O Carbonyl Ylides Carbonyl Imines Carbnyl Oxides Nitrosimines Nitrosoxides Ozone Oxygen in the middle

C N O C N N C N C N N O N N N N N C Nitrile Oxides Nitrile Imines Nitrile Ylides Diazoalkenes Azides Nitrous Oxide Nitrillium Betaines Diazonium Betaines

Propargyl/allenyl anion type

Classiﬁcation of the Parent 1,3-Dipoles

(4)

Mechamisms for the 1,3-DC reaction

a

b

c

b

a

b

c

b

a

b

c

Ar

C

N

O

D

O

N

D

Ar

(5)

The classiﬁcation of the 1,3-DC reactions on

the basis of the FMOs

Dipole Alkene Dipole Alkene Dipole Alkene

LUMO

HOMO

Type I Type II Type III

C N N C N C C N O C N O N O O O O O

(6)

The change in frontier orbitals by coordination

of a Lewis acidーType I and III

Dipole Alkene _{Lewis acid}Alkene- _{Lewis acid}Dipole- Dipole Alkene

LUMO

HOMO

Type I _{Type III}

(7)

The change in frontier orbitals by coordination

of a Lewis acidーType II

Dipole Dipolarophile Dipolarophile-_{Lewis acid} _{Lewis acid}Dipole- Dipole Alkene

LUMO HOMO N H O OR1 O R2 Lewis acid _N H O OR1 O R2 _LA N X O _O R Lewis acid N X O _O R LA

(8)

Mechamisms for the 1,3-DC reaction

N O R1 R2 X O N O N R2 R3 R2 R3 N O R1 R2 R3 O OR4 R1 R1 OR4 O OR4 O endo (trans) exo (cis) X endo exo X O _N R1 R2

Endo-transition state for the

Diels-Alder reaction

Transition state for 1,3-dipolar cycloaddition

(9)

1,3-DC Reactions of nitrones with Alkenesー

General Application

N

O

R

1

R

2

O

N

O

N

R

2

R

4

R

3

R

2

R

4

R

3

R

3

R

4

R

1

R

1

endo

(trans)

exo

(cis)

O

N

R

2

R

4

R

3

R

1

isoxazolidine

Reduction

•H

₂

/Pd

•H

₂

/Raney Ni

•Zn, acid

and more...

OH

NHR

1

R

2

R

4

R

3

β-amino alcohol

R

1

is removed in Reduction step.

OH

NH

₂

R

2

R

4

R

3

primary amine

(10)

Methods for asymmetric 1,3-DC reactions of

Nitrones with Alkenes

N

O

R

1

R

2

O

N

O

N

R

2

R

4

R

3

R

2

R

4

R

3

R

3

R

4

R

1

R

1

endo

(trans)

exo

(cis)

• Chiral Nitrones (acyclic and cyclic)

• Chiral Alkenes

• Intramolecular Reactions

• Metal-Catalyzed Reactions

• Organo-Catalyzed Reactions

(11)

Acyclic Chiral Nitrones

Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F.; Pardo, C.; Sáez, E. Torres, M. R. J. Org. Chem. 2002, 67, 7004-7013

N O H N O Ar H H OCH₃ Ph O N O O Ph Si-face N O _PMP H₃CO H H N O H H R H NH O O O N O O Ph endo-approach Re-face _O N _PMP H₃CO H H N O N O O Ph H H R H O N O O Ph exo-approach Re-face N O PMP H₃CO H H N O N O O Ph H H R H O Si-face N O _PMP H₃CO H H N O H H R H NH O O N O O Ph N O PMP H₃CO H H N R O N O O Ph Toluene, 110 ˚C N O PMP H₃CO H H N O N O O Ph H H R H 2; R=Bn : 95% (dr=100:0:0:0) 3; R=Me : 80% (dr=73:9:9:9) major

(12)

Cyclic Chiral Nitrones

Cordero, F. M.; Pisaneschi, F.; Gensini, M.; Goti, A.; Brandi, A. Eur. J. Org. Chem. 2002, 1941-1951

N t-BuO O toluene, 60 ˚C, 1 day, 77% N O H₃CO₂C _H OtBu OH sole adduct CO₂CH₃ OH 4 5 6 OH H₃CO₂C N tBu O O H H H

N

O

H

₃

CO

₂

C

_H

OtBu

OH

₆

1) MsCl, TEA

2) H

₂

, Pd/C

N

H

OtBu

H

₃

CO

₂

C

HO

N

H

OH

HO

enantiopure

indolizidine

8

(13)

Chiral Alkenes

Stecko, S.; Paśniczek, K.; Jurczak, M.; Urbańczyk-Lipkowska, Z.; Chmielewski, M. Tetrahedron: Asymmetry 2006, 17. 68-78

N O t-BuO O OAc O OAc O OAc O OAc O O N O O N OAc OAc O H Ot-Bu O AcO _OAc H t-BuO H H 10; 62%; de = 100% 9; 81%; de = 100% 4 N O t-BuO O O O OAcOAc O O O OAc OAc

(14)

Intramolecular Reactions

Shing. T. K. M.; Zhong, Y. L. Tetrahedron 2001, 57, 1573-1579

O HO HO O OH OH O HO HO O OH OH 11 13 MeNHOH•HCl, NaHCO₃ MeNHOH•HCl, NaHCO₃ OH HO OH O HO N Me O OH HO OH O HO N O Me 12 O O N Me HO OH OH HO O O N Me HO OH OH HO OH OH HO O HO N Me O 14 15

(15)

Intramolecular Reactions

O HO HO O OH OH MeNHOH•HCl, NaHCO₃ OH HO OH O HO N Me O OH HO OH O HO N O Me 11 12 O OH R N O Me O O N Me HO OH OH HO O OH R N O Me O O N Me HO OH OH HO O OH R N O Me O OH R N O Me R = OH OH OH

(16)

O OH R N O Me O OH R N O Me O OH R N O Me O OH R N O Me 14 15

Intramolecular Reactions

Shing. T. K. M.; Zhong, Y. L. Tetrahedron 2001, 57, 1573-1579

O O N Me HO OH OH HO O O N Me HO OH OH HO OH OH HO O HO N Me O 14 15 O HO HO O OH OH MeNHOH•HCl, NaHCO₃ 13

(17)

Metal-Catalyzed Reactions

N N O O O O Co SbF₆ Co(III)-SbF₆

Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 15, 2457-2460

N Ph O H Cl Cl Co(III)-SbF₆ (5 mol%) -40 ˚C, CH₂Cl₂ 60 h, quant. NaBH₄ EtOH O N H OH Ar Ph O H endo:exo= >99:1 87% ee (endo) 16 17 18

(18)

Metal-Catalyzed Reactions

Mita, T.; Ohtsuki, N.; Ikeno, T.; Yamada, T. Org. Lett. 2002, 15, 2457-2460

N Ph O H Cl Cl Co(III)-SbF₆ (5 mol%) -40 ˚C, CH₂Cl₂ 60 h, quant. NaBH₄ EtOH O N H OH Ar Ph O H endo:exo= >99:1 87% ee (endo) 16 17 18 Ar N Ar N O O Ar O Ar O CoCo O N Ph O Ar H favored N Ph O Ar H disfavored (S) (R) O N H O Ar Ph endo adduct (S) (S) O N H OH Ar Ph endo adduct

(19)

Organo-Catalyzed Reactions

Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874-9875

N O Bn O H O N Bn CHO Me O N Bn CHO Me N N H O Me Me Me Ph •HClO₄ 20 mol% 70% (endo:exo=99:1) 99% ee (endo) 19 20 N N O Me Me Me N N H O Me Me Me Ph O H N O Bn H Re-face O N Bn CHO Me 21 endo

(20)

Organo-Catalyzed Reactions

Karlsson, S.; Högberg, H. Eur. J. Org. Chem. 2003, 2782-2791

N O Me O H O N Me Ph _CH 2OH H 24 endo 25 exo O N Me Ph _CH 2OH H DMF-H₂O, -10 ˚C 120 h N H H H N •2HCl 10 mol% NaBH₄ MeOH 50% (exo:endo=97:3) 90% ee (exo) 23 ₁₇ CHO N O Me O N Me Ph _CHO H 24 endo N O Me 25 exo O N Me Ph _CHO H

(21)

Organo-Catalyzed Reactions

Karlsson, S.; Högberg, H. Eur. J. Org. Chem. 2003, 2782-2791

N NH 2Cl N NH 2Cl H N NH 2Cl H _H N NH 2Cl H s-cis s-trans _s-cis _s-trans

nitrone _nitrone nitrone nitrone (E)-iminium isomers (Z)-iminium isomers

attack from sterically lowest hindered side

attack from sterically hindered side

N H N N OH Me O H O N Me Ph _CH 2OH H 24 endo 25 exo O N Me Ph _CH 2OH H DMF-H₂O, -10 ˚C 120 h •2HCl NaBH₄ MeOH 23 ₁₇