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Nucleophilic Heterocyclic carbene Organocatalysis

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Nucleophilic Heterocyclic carbene  Organocatalysis Powered By Docstoc
					  N-Heterocyclic carbenes :
Comprehensive Organocatalysis
        Review 2010
            Seminar Presentation
               April 1st, 2010

                Francis Barabé

               University of Ottawa
                Dept. of Chemistry
   Center for Catalysis Research and Innovation
               Prof. Louis Barriault
The Program                                                      R
                                                                 N
                                                             Y
Introduction                                                     X                                                  O
                                                                  R                                             R
Thiamine
History-Properties                                                                                      O                                O
                                                                                                                NHC
Asymetric Catalysis (Benzoin Condensation and Stetter Reaction)                                     R       H
                                                                                                                E+
                                                                                                                                    R        E


Homoenolate Chemistry
                                       H
                                                  NHC                    E       Nu
                         R1                O
                                               Strong base       R1                  O



Internal Redox Reaction
                                           O                         X       O                O                         H       O
                                                   NHC                                                NHC
                              R1               H             R1                  Nu      R1       H weak base R1                    Nu
                                       X                                 E                                                  E



 Diels-Alder Reaction                      O                         H       O
                                                   NHC
                              R1               H             R1                  X
                                                      X



 Activation of ketene              O
                                                         O       Nu
                                               NHC
                                                      R1
                              R1       R2               R2 E
 Thiamine diphosphate (TPP) - Nature’s NHC
   The first water soluble vitamin isolated and described by Casimir Funk in 1912

Thiamine                 O
                              O       Important coenzyme in a number of biochemical reactions
Vitamin B1             O P O P
                         O O O
        N                              pyruvate dehydrogenase (glycolysis)
                   S
    N         N
                                       acetolactase synthesis (amino acids)
        NH2   Cl




                                                                                              terpenes
                                                                     OPP




                                  O                 O                            O    O
    C6H12O2                                   TPP                                         O
                                          O
    Glucose                                             SCoA                                  SCoA
                                      O                                           n

                                                                           fatty acids and poly acetates
Pyruvate Dehydrogenase complex
                                                                                                   O
                                                                                                        O
 Three enzymes complex                                                                           O P O P
                                                                                                   O O O
                                                                  N
                                                                                        S
 E1- pyruvate dehydrogenase      N                                              N                    Thiamine
 E2- dihydrolipoyl transacetylase NH2                                           Cl
                                                                                                                                    CoA(SH)
 E3- dihydrolipoyl dehydrogenase

                                  O
                                                                        HO O
                                            O                                                                                    HO
                                                                                    O
                                       O                           R                                                            R
                                                                        N   S                                                       N
                     R                                                                   S                                              S            S
                         N   S                                                          S
                                        S                                                                                                           S
                                       S                                                              FAD                                                     FAD
                                                FAD


                                                                                O

                     H                                                              SCoA
                 O                                                                                                                          R
     R                                          R           O                                R                                                  N
                                                    N                                            N    S                                              S         S
         N           S                                  S     S                                              HS
             S                                                                                                                                                S
                                                            HS                                              HS
                 HS                                                                                                   FAD                                                  FADH2
                                                                  FAD
                                 FAD




                                                                                                                                                                   OH N         N
                                                                                                                                                         HO
                                                                                                                  O         O                                                       NH2
                                                                                                                                            O O                        N
                                                                                                                                             O
Chem. Rev, 2007, 107, 12- 5609                                                                   HS           N        N                    P P                    O        N
DeTar, D. F.; Westheimer, F. H. J. Am. Chem. Soc. 1959, 81, 175                                               H        H        OH          O O
Notes de cours Substances Naturelles de Pr. Claude Spino                                                                                                       AcetylCoenzym A
 Brief History
                 O                         O                                                                       O
                           NaCN                                                     O
 1832                                 Ph
                                                   Ph
                                                               1943                             Thiamine                Ph
            Ph       H     EtOH                                                                  base      Ph
                                               OH                           Ph          H
                                                                                                                       OH

Wohler, F. Liebig. J. Ann. Pharm. 1832, 3, 249-282             Ugai, T.; and al. J. Pharm. Soc. Jpn. 1943, 269


                                                                                                    OH
                                                                                                               H                           D
            O                                                                   N
                                               O                                                                            D 2O
                    O      Thiamine                                                             S          N       S                   N       S
 1954                                                           1958        N               N
                O           base                                                                                       t1/2 20min
                                                   OH                           NH2                        Br-                         Br-

Mizuhara, M.and al. J. Am. Chem. Soc, 1954, 76, 571             Breslow, R.; J. Am. Chem. Soc. 1958, 3719-3726




                                           Ph N         N Ph     1991               N       N            NaH
 1960-1980          Ph N   N Ph                                                                                              N     N
                                           Ph N         N Ph                        H
                                                                                 Cl-

 Debate on active specie and stability                            Isolation and caracterization of first NHC
 more studied in organometallic chemistry                         by Arduengo and co worker
Wanzlick, H.W.; Angew. Chem. Int. Ed. 1962, 75-80                 Arduengo, J. Am. Chem. Soc. 1991, 113, 361-363
Lemal, D. M.; J. Am. Chem. Soc. 1964, 2518-2519
Wanzlick, H.W Angew. Chem. Int. Ed. 1968, 7, 141-142
Kind of NHC and his property
                                                                                         R                         R                         R
                                                                                         Y    R                    Y       R                 Y       R
    RN     S               R N NR                            R N    NR
                              N                                                          X X                    X X                       X X
      R     R                   R                             R      R                  R    R                 R    R                    R    R
  Thiazolium salt         Triazolium salt              Imidazolium salt                                     singlet sp2
                                                                                                      uncharged divalent carbon



                 H
          MeO
                               H                H                         H                     H                      H                 H
          Me N            HN            Me N        N Ph           Me N       N Me       Me N       N Me      HN           NH    IPr N       N IPr
                      S            S

           Me                                                                                                                      Me        Me

 pKa             14            19.9             19.7                 22.0                     23.0                  23.8                 24

                                                                                                                       Richard JACS 2004 126 4366

                                                                                     Elimination     Substitution

                               IPr N                    Br
                                        N IPr                                                        IPr N    N IPr
                                                                                                     Br-
                                   Me   Me                                                             Me      Me

                                                                                        20%                  80%

 More nucleophilic than basic, but remains one of the strongest neutral base known
D. Bourissou, O. Guerret, F. P. Gabbai, G. Bertrand. Chem. Rev. 2000, 100, 39-91.
  Insight in The Catalytic Cycle
                                                                    Y
                                                                     N R         O
                                                                 RX
                                                                             H       R
                                        Leaving Group                                    Nucleophilic Addition
                                        O
                                    E       R
            E   O       R
                                                    OH R                                     O       R
        R               N                       E
                          Y                     R       N                                H           N
       Nu           X                                     Y                              R             Y
                R                                     X                                          X
                                                    R                                        R




                                 Enamine Reactivity                                      Acidification
                                                                         OH R
                                                                  E+   R     N
                                                                               Y
                                                                           X
                                                                         R
                                                              Breslow's Intermediate


                                                                 E+      OH R
                                                                   R         N
                                                                               Y
                                                                           X
                                                                         R
Nolan, S. P.; et al. Angew. Chem. Int. Ed. 2007, 2988-3000
Evolution of Asymetric Version : The
Benzoin Condensation
                                                                                   R                                                       R           R
                           O                  NHC                   O
                                                                                                                     N      N                  N   N
                                 H            Base                                                                                    Ph                   Ph
                                                                        OH
           R                                                R



               NHC                                   Years, Prof.         yields         ee%              NHC                    Years, Prof.      yields         ee%

     Me                                                                                                  Ph
                   -O3S              H                                                                N N
       N                                        1974, Sheehan                78%        8% ee                                   1998, Leeper       67%          88% ee
                                         Br                                                               N
           S                         O                                                            O             Ph
                   Me
                       N                                                                          O       N
                                                                                                           N
                             S                  1974, Sheehan             6%           52% ee         N                         2002, Enders       50-83% 80-95% ee
                   Br-                                                                                    BF4-

                                                                                                                     O
               S
                       TfO-
           N                                                                                                         N    N
                                                 1997, Leeper            34%           19.5% ee                                  2002, Rovis     60-83% 82-97% ee
      O             OTBS                                                                                                 N
                                                                                                              BF4-        Ar    both enantiomer commercially available

                                                                                                                   N
       O                                                                                                            N
                         N                                                                                     N
                   N                             1996, Enders           22-72%     20-88% ee                                     2002, Rovis        8-83%       82-95% ee
       O                 N                                                                                           BF4-
                             Ph                                                                       Ph
               ClO4-


Sheehan, J.; et al. J. Am. Chem. Soc. 1966, 3666-3667; Sheehan, J.; et al. J. Org. Chem. 1974, 1196-
1199 ; Enders, D.; et al. Helv. Chim. Acta 1996, 1217-1221 ; Leeper, F. J.; et al. J. Chem. Soc., Perkin
Trans. 1 1998, 1891-1893 ; Enders, D.; et al. Angew. Chem. Int. Ed. 2002, 1743-1745
Efficient Catalyst Design : Triazolium Salt
                                                                                                R
                                                    O            5-10 mol% NHC   O
                                                                                     
                                                        H        Base, THF
                                                                                     OH
                                         R
                                                                             R
                                   Triazolium salts improved efficiency and enantioselectivity
                                               Ph                                O       N
                                          O                 ClO4-
                                                        N                                 N
                                                  N                                  N
                                          O             N                                BF4-
                                                            Ph
                                             22-72%                                      50-83%
                                             20-88% ee                                   80-95% ee




Houk, K. N.; et al. Proc. Natl. Acad. Sci. U. S. A.2004, 5770-5775
Enders, D.; et al. Acc. Chem. Res. 2004, 534-541
Benzoin Condensation : Intramolecular version
 Intramolecular
                                              -
                           MeO               Br
                                                  N S                         O N      OMe
                        O N                        5-20 mol%
                                             DBU, 10-70 mol%
               R1            O                    tBuOH, 40 C           R1
                                 O                                            HO
                        R2                          79-96%                   R2 O
                                                     dr 20:1            Suzuki et al. J. Am. Chem. Soc. 2003, 125, 8432-8433

                                                                                                                           O
                                                                                                                               OH
                                                                                                                                         OAc
 Asymetric
                                                                                          Ph                   HO                        OAc
       O                 10 mol% NHC                         O                             N                            (+)-sappanone B
                                                                  R2           NHC =           N
                         9 mol% KHMDS                              OH
           H                                                                               N       BF4-               OH O
                   R2    THF, rt, 18-72h                     X                                                                 OH
       X                                                R1
R1             O        24-93%, 71-99% ee
                                                                                                                HO         O              OMe
                                                                                                                        S-eucomol
                                                                 Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2006, 124, 10298-1
                                                                 Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem. Int. Ed. 2006, 45, 1463-
 Macrocyclization
                                                -
                                           N BF4
                                         N N Ar
       OBn O                                                        OBn O
                                      1 eq
                                     2 eq DBU, DCM, rt                                 low yields : product is unstable, not selectivity
 BnO                                                   BnO
               O    O                      21%                          OH O
                                                                                                   Miller, T and al.. J. Org. Chem. 2007, 72, 5260
The Stetter Reaction : Michael Addition
         Y                                   O       R                          O       OH R                               HO OH R                     O
          N R         O
   RX                                   H            N                      R       H R     N                              R      N            R
                                                                                                                                                           R
                  H       R              R             Y                                      Y                              R      Y
                                                 X                                        X                                     X                  OH
                                             R                                          R                                     R
                                                                                                                                        -hydroxyketone

                                                                      R                 OH R                                 OH R                          O
                                                                                            N                      O             N
                                                                  O             R     R                                                    R
                                                                                              Y                             R      Y                           R
                                                                                          X                            R       X
                                                                                                                             R                 O       R
                                                                                        R

                                                                       Micheal Addition                                                  1,4 dicarbonyle


         O
   R1                                            O                                         O                        O
             H    Thiamine, Et3N        R1                     NaOH             R1                                                                 O
                                                                                                                                          R                R
          O                                                O   62-68%
                                                               for 2 steps                                        cis-jasmone                          R

                                                                                                                                                   H
                                                                                                                                           R       N       R
                  O                                                             O O
         BzO                      O                                   BzO
                              H                  Thiamine,                                     3       Grubb's                                         R
                                                   Et3N                                                H2, Pd/C


                                                      H                                 Cl
             OO                                       N                                                OMe
   BzO                                       O
                                  NH3                                                                    N
                                                                                       N           O
                                                                                       H
                                                                                    Rosephillin
Stetter, H. Angew. Chem. Int. Ed. 1976, 15, 639
Tius, M. A.; Harrington, P. E. Org. Lett. 1999, 1, 649
     Stetter Reaction with unactivated olefin
                                                                                                        ClO4-                BF4
                                                                                                                                   -
                                                                              NHC =            N
                                                              O                                    N Ph                       N
       O                   20 mol% NHC                                                     N                                      N Ar
                           Base                                    CO2R                                             O        N
           H                                                                                       44-73%                                  63-94%
                                                                                 O                 56-74% ee
                           THF, rt, 18-72h                    X                        O
                                                                                                                                           92-97% ee
       X           CO2R                              R1
R1
                                                                                                   Enders                         Rovis




                                                                                  ClO4-
                                                                                N Mes                     O
                                             O                    20 mol% S                                     R
                                                 H                DBU 40 mol%
                                             X                 1,4-dioxane, 2h, 120°C          R1
                                                                                                          X
                                   R1                R                 57-94%




               H                                          H
           O                                                                         Mes                                    Mes
                                                     O
                                                                                 N                                      N
                                                                                               O    H                                       O
                                                                                                                                       R        H
                                                                                 S         R                            S


               Conia-ene


Glorius, F.; et al. J. Am. Chem. Soc. 2009, 191, 14190-14191
Stetter Reaction with unactivated olefin : Conia-ene
                                                -
                                         ClO4
                                      N Mes          O      R1
         O
                        20 mol% S
             H   R1     DBU 40 mol%                             R2
         X        R2   1,4-dioxane, 2h, 120°C        X


         R1               R2                        yield
                                                                                O                O
         H                 CH3                      trace                                            OBn

         H                 Ph                       25%                                          O
                                                                                O

         CH2CH3                                     trace                     94%           93%
                          H

         CH2OCH2Ph        H                         93%


 Quaternary center formation is tolerated but, substitution of the terminal carbon
 of the alkene diminishes the reactivity

                                                                                        S   N Mes


                                                            S        N Mes
                                                                                             O H
                                                                          H
                                                                     O
                                                                                    X
                                                    X
                                                                                            Ar
                                                                     Ar
 Homoenolate Chemistry
                                                        R2       O                                                      Ph CF3
                                                                                      Product                                O
                                                                          O
                                                        R1                                                              R1       O
                                  SO2Ar
                           R2    N                                                                                                                  O
                                    O                                             O                 O                                      GP
                           R1                                                                                                                   N              R1
                                                                             R2       H        Ph       CF3
                                                                                                                                                          R2
                                               ArO2S                                                            GP
MeO                                                          N                                                          N
                                                    R2           H                                                  H        R2
                 NH O
                                                                     O                                          OH Ar
                                                                                                                                                               H    O
            R1             OMe                 O
                                                        R1               H
                                                                                   Ar                   R1         N                                      R1            Nu
                                               N                                   N
                                                                                                                    N                HNu
                                                                               N                               Ar                                   Internal Redox Acylation
                  O                       R2                              Ar
                                                                                                             Homoenolate
       R1         O
            HN
                                                        O                                                     ArO2S
                      R2                                                                  O                              N
                                                   R3                R2
                                                                                   R3           CO2Me            Ar3             Ar2

                                                                                                                                                 SO2Ar
                                                                                                                                           O    N
                                           R3                                         Electrophile                                                Ar3
                                                                                                                                           H
                                                                                                                                           R1
                                   R1                                                          R3                                                   Ar2
                                           R2

                                                                                          R1
                                                                                               CO2Me

Nolan, S. P.; et al. Angew. Chem. Int. Ed. 2007, 2988-3000
Homoenolate Chemistry                            E+
               O
                            Ar       OH Ar                  OH Ar                                            OH Ar
          R1       H                                                                                            N
                            N    R      N          R1          N                                   R1
                        N                 N                      N                                                N
                   Ar                Ar                     Ar                                               Ar
                                                                                                            E+


                                                             E       O        Ar
                                                                                                             E        Nu
                                                        R                     N
                                                                                                         R                O
                                                        Nu                N
                                                                     Ar



                                                                                       O
                                                                          R                H            N         S
                                                                                                              -
                                                                                               Ph           Br


                                                                     O                                                O
                                                                                   R                    R                         R
                                                        R
                                                                         OH                                                   O
                                                        Benzoin Product                                 Stetter Product
                                                                                               O

                                                                                               O
                                                                                       R

                                                                                                    R
                                                                          Homoenolate Product

 Glorius and Bode have both shown that it is necessary to carefully adjust the steric
  bulk of the NHC for selective activation of homoenolate
 Synthesis of g-Butyrolactones
                                             8 mol% NHC
                                            7 mol% DBU                                           NHC
    R2                    Bodes         1 : 2, THF/tBuOH, rt         R2                                            Cl-                                  Cl-
             O                                                            O
                                              79%, dr 4:1                       O                                                                       N     N
         H                                                                                                      N        N
                 O                                                   R1
                          Glorius          5 mol% NHC
   R1                H                                              g-butyrolactone
                                          10 mol% tBuOK
                                           1 : 1, THF, rt
                                            49%, dr 4:1

                                                                                                           O        Ar
                                                                                                 R1                 N
             O                        O                                                                    H
                                                                            O                                 N
         O                        O                                                                        Ar
                                                                     R1         H
   O                       O
                     R1                   R1
                           RN
                                                                                                                                  OH Ar                           OH Ar
       dr 10:1                      dr 1:1                                                                                           N
                                                                           Mes N         N Mes                               R1                             R1       N
                                                                                                                                       N                               N
                                                                                                                                  Ar                              Ar
                                    O                      O
                                O                      O
                                                                                                      H                                         O
                           Ph                                                                    R2       O
                                                  Ph           Ph                                             OH Ar                        R2       H
                          MeO2C                        CF3
                                                                                                 R1              N
                                dr 7:3                 dr 3:2                                                   N
                                                                                        O                  Ar
                                                                                    O
                                                                              R2
                                                                                        R1             H
                                                                                                  R2       O
                                                                                                               O        Ar
Glorius, F.; et al. Angew. Chem. Int. Ed. 2004, 6205-6208                                         R1                    N
Bode, J.; et al. J. Am. Chem. Soc. 2004, 14370-14371                                                                N
                                                                                                              Ar
Synthesis of g-Butyrolactames
   Dimerization, if imine isn’t enough reactive                                             Inhibition, if imine is too much reactive
                                              Cl-                                   O                                                  Cl-
                    Ar            Mes N            N Mes                                                                                            TsN   Ar
            O             N                                                 O
                                                                                                          O       Ts
                                                                                                                       N
                                                                                                                               Mes N       N Mes          N
    R1
                                          15 mol%                                                                                      1 eq    R2
                H    R2       H                                                                                                                   H
                                  DBU, tBuOH, 60 °C                                 R1         R1             H   R2       H                         N
                                                                                                                                 DBU, MeOH d-4    Ar
                                                                     R1




    With the good balance
                                                                           OMe

                                                                                                    Cl-
                                                                                                                                           O
                                                                                          Mes N       N Mes                    ArO2S
                                                                                                                                       N
                                                          O
                                                                          O2S
                                                                                N
                                                                                                     15 mol%
                                              R1              H                            DBU, tBuOH, 60 °C                      R2
                                                                           R2       H                                                      R1
                                                                                         50-75%, dr 1.5 : 1 to 10 : 1


                                                                  Cl-
                                                                     N                     O     O O                                         O
                                          O                           N
                      O           O
                                      S                           N                             N S                                 NH
                                  N                                 1 mol%                                        Na, Naphtalide
                                                    R3
              R1          H                                 DBU,DCM, rt                                           DME, 90 sec
                                                                                  R1 R2                   R3                     R1 R2             R3
                                  R2                     50-95%, dr 3 : 1 to 6: 1                                      60%



M. He, J. W. Bode, Org. Lett. 2005, 7, 3131 – 3134.
Bode, J. W.; et al. J. Am. Chem. Soc. 2008, 130, 17266
Synthesis of b-Amino Acid Esters
                                        Cl-
                                    iPr N     N iPr              R2                                                    -
                                                      MeO                                                         N BF4                O
            O                        10 mol%                                                                    N N Mes                        OH
                               O                                                                                               R1          N
                                                                        NH O                                   10 mol%
  R1            H              N 1) KOtBu, DCM
                                                                R1             OMe                      t-BuOK, THF
                                    2) H+, MeOH
                          R2                                                                               60-85%                              R2
                                       60-85%



                                                                                               O       Ar
                                                            O                        R1                N
                                                                                               H
                                                      R1        H                                 N
                                                                                               Ar



                                                                                                                     OH Ar                          OH Ar
                                                                                                                        N                              N
                                                            Mes N        N Mes                                  R1                     R1
                                                                                                                          N                              N
                                                                                                                     Ar                             Ar



                                                                                     R2        O                                   O
                                                                                          N        OH Ar                           N
                                                                                                      N                       Ar
                                                                                     R1
                                                                                                    N
                                                                                               Ar
                                                                        O
           R1 O
                               Bamberger rearrangement              O
  Ar                                                                N
       N            OMe                                     Ar
       H                                                                R1                Ar       O
                                                                                               N       O       Ar
                                                                                          R1                   N
                                                                                                           N
Ying, G.Y., and al. Org. Lett. 2008, 10, 953-956                                                    Ar
Bamberger Rearrangement :Annulation

                                                                      OMe
                                            OMe                  O                            OMe
           O                         O                                                   O                            OMe
                                     OH                                                                       O
      O
                H+, MeOH                          -H2O       N
                                     N                                                   N
      N                                                              R1                                       N
                                          R1                                                 R1
           R1                                                                                                     R1


                                                                                         MeOH


                                                                                              OMe
                                                                                         O                    O
                                                                                         H
                                                                                         N          R1            O
                                                                                             R1          HN
                                                                                   MeO
                                                                                                                  R2


                                      Cl-                                 O
                O             O       N     N               R1            O
      R1            H         N           20 mol%                HN

                         R2       DBU 20 mol%, THF, -5 °C
                                                                              R2




Ying, J.Y. and al., Org. Lett. 2008, 12, 2333-2336
Synthesis of trans-Substituted Cyclopentene
                                                         Cl
                                                              -                                                            O
                                                                                                          R3
          O                 O                Mes N            N Mes                                            Ar              H                                     Ar
                                                     6 mol%
 R1           H        R3              R2                                                                              O                                                   S
                                             DBU 12 mol%, THF, rt                               R1
                                                                                                          R2                            S
           R1, R2, R3, mostly aryl                                                                                                                                   H

                                                                                                                    substrate                              product

                                                                                                                                                  O
                                                                                                                                             R3

                                                                                             O       Ar                     OH Ar                     R2     OH Ar
                                                                                    R1               N                         N
                                                                                           H                    R1                                    R1        N
                                                                                              N                                 N
                                                                                           Ar                              Ar                                    N
                                                                                                                                                            Ar
                                                                            O
                                                                  R1            H

                                                                                                                                        R3    O
                                                                                                                                   R2
                                                                                                                                             OH Ar
                                                                           Mes N     N Mes                                                      N
                                                                                                                                   R1
                                                                                                                                                  N
                                                                                                                                             Ar
                                                                                                                                                                 O
                                 R3                  R3 O              O                                                   R3                                             O
                                            - CO2                                   R3 O O          Ar                          O
                                                                                                    N                                                      R1             R3
                                                                                                                R2                                               R2
                            R2                      R2                                                                     O        Ar
                                  R1                      R1                                    N
                                                                                                                R1                  N
                                                                                    R2   R1Ar
                                                                                                                                N
                                                                                                                           Ar


Nair, V.; et al. J. Am. Chem. Soc. 2006, 8736-8737
Synthesis of cis-Substituted Cyclopentene
                                                       O                                                                                O
                                                                       Cl-
                                                                   N                           R3                                                H
                                                           N                                                                      Ar3
                                                                   N
            O                 O                                        Mes
                                                                                                                                                 Ar
                                                      10 mol%                                                                  s-trans configuration
   R1           H       R3            CO2Me                                             R1
                                  H         DBU 15 mol%, DCE, rt                               CO2Me                           chair TS for oxy-cope
                                                                                                                               lowest enantioinduction


                s-cis configuration                                                                      O
                                                                                                    R3
                boat TS for oxy-cope
                high enantioinduction                                                                         E
                                                                                         OH R                           OH R
                                                                                            N                 R1           N
                                                                       O           R1
                                                                                             N N                           N N
                                                           R1              H            Ar                           Mes



                                                                                                                   HO      R
                                                                                                                   O       N
                                                       Mes N N R                                         R1
                                                            N                                            E             N N
                                                                                                                    R3 Mes



                        R3                    R3 O     O
                                                                                                             HO       R                      H
                                      - CO2                     R3 O O         R                                                            H         O   R
                                                                                                                      N
                                                                               N                    R1        O                                           N
                                              E                                                                                      R1              O
                    E                             R1                                                 E              N N
                         R1                                               N N                                      R3Mes                               N N
                                                                                                                                    R2                R3Mes
                                                               E       R1 Mes



Bode, J. W.; et al. J. Am. Chem. Soc. 2007, 3520-3521
Synthesis of b-lactames
                                                 O
                                                        N
                                                      N N Mes                           SO2Ar
                                                         Cl-                  O        N
           O       ArO2S                                                                 Ar3
                           N                         10 mol%                  H
  R1           H     Ar3         Ar2        DMAP AcOEt, rt
                                                                              R1
                                            up to 90%, 99% ee                           Ar2
                    Ar : still 4-MeOPh        dr 10:1 to 20:1


                                                                                                      ArO2S
                                                                                                                 N
                                                                                                           Ar3              Ar2
                                                                      O                        OH R                               OH R
                                                           R1             H            R1         N                                  N
                                                                                                                       R1
                                                                                                    N N                               N N
                                                                                              Mes                               Mes


                                                           Mes N N R                                                     HO           R
                                                                N                                                      TsN            N
                                                                                                              R1
                                                                                                             Ar2                N N
                                                                                                                             R3 Mes

                                                      Ts
                                                      N    O
                                                R3                                                               HO         R
                                                                 R3 NTsO           R
                                                                                                                            N
                                                                                                                                                 O   R
                                                                                   N                  R1         TsN                                 N
                                                                                                                      N N                   R1   NTs
                                               Ar2    R1                      N N                    Ar2                                           N N
                                                                                                                     R3Mes                  R2
                                                                Ar2       R1 Mes                                                                  R3
                                                                                                                                                     Mes



Bode, J. W.; et al. J. Am. Chem. Soc. 2008, 418-419
The Program                                                      R
                                                                 N
                                                             Y
Introduction                                                     X                                                  O
                                                                  R                                             R
Thiamine
History-Properties                                                                                      O                                O
                                                                                                                NHC
Asymetric Catalysis (Benzoin Condensation and Stetter Reaction)                                     R       H
                                                                                                                E+
                                                                                                                                    R        E


Homoenolate Chemistry
                                       H
                                                  NHC                    E       Nu
                         R1                O
                                               Strong base       R1                  O



Internal Redox Reaction
                                           O                         X       O                O                         H       O
                                                   NHC                                                NHC
                              R1               H             R1                  Nu      R1       H weak base R1                    Nu
                                       X                                 E                                                  E



 Diels-Alder Reaction                      O                         H       O
                                                   NHC
                              R1               H             R1                  X
                                                      X



 Activation of ketene              O
                                                         O       Nu
                                               NHC
                                                      R1
                              R1       R2               R2 E
Internal Redox Reaction
      Y                                                                                                       O       R
                  O                       H+   OH R                        OH R
       N R
RX                                                                             N                     R                N                  O
              H        R                   R       N                   R                                                Y
                                                     Y                           Y                   ROH          X
                                                 X                           X                                                  R             OR
                                                                           R                                  R
                                               R

            Y
                           O                                  OH R
             N R                                                                                     O
         RX                                                      N
                                                                                                              R
                                                                                                                                     O
                       H              R                  R         Y                                          N
                                                                                               R                Y
                               X                             X X
                                                              R                   -X-           Nu        X                 R            Nu
                                                                                                      R



                           N                                                                       Cl-
                                Cl-                                                           Mes N N Mes
         O                 N                                 O                          O                                                 O
                        5 mol%                                                                             5 mol%
R1           H DBU, BnOH, tol, 100 °C             R1             OBn                        H DBU, EtOH, tol, 100 °C            R1            OEt
                                                                             R1

 Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905-908                      Zeitler, K., Org. Lett. 2006, 8, 636


                                                                                                      Bn
                        N                                                                            N Cl-
                         N                                                                                                           XH O
         O            N                                      O                       XO            10 mol%
                                                                                                     S
                          Cl-         10 mol%
                                                  R1                         Ph       H iPr2NEt, BnOH, DCM,                     Ph             OBn
R1           H Et3N, BnOH, tol, 100 °C                           OBn
                                                                                 Me                                                      Me
       Br             60-90%                                                               89%, dr 10:1
                                                                             X= O or NTs

     Rovis, T. And al. J. Am. Chem. Soc. 2004, 126, 9518-9519              Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-81
Catalytic Enolate for Mannich Reaction
                             O
                                     N BF4-
                                   N N Mes             Ts                     Ts
         O        Ts                                         NH O                  NH O
                       N          10 mol%
  ArO                         Ph                       Ar           OAr       Ar           NHBn
             H    Ar           THF, DCM rt
                                                                                   BnNH2
                             O2N          ONa

                             60-75%, 90-95% ee



                                                                                            O     R
                                                                                    ArO           N
                                                                                            H
                                                                    O                          N N
                                                             ArO                           Mes
                                                                        H                                          OH R
                                                                                                           ArO        N
                                                                                                                       N N
                                                                                                                 Mes
                                                                   Mes N N R
                                                                        N
                                                                                                           NTs

                                                                                    ArO_              R2          OH R
                                                                                                                     N
                                                                                   R2 O
                                                                                           R                           N N
                                                          O
                                                       NHTs                                N                     Mes
                                                                            TsHN
                                                  R2          OAr                         N N
                                                                                    Mes



Scheidt,K. A. al. J. Am. Chem. Soc. 2009, 128, 18028-18029
Other Applications of Internal Redox Reactions
                                                                       Ar
                                                                       N    -
                                                                         Cl
                                                                       N                                O       O
                                                O       O
                                                                        Ar 10 mol%
                                                                                                    R           n
                                            R       n H               DBU, DCM, rt
                                                                        60-90%

                                                             OH Ar                         OH Ar
                                                     O          N                 O           N
                                                                  N                             N
                                                            Ar                             Ar
Gravel, M., and al,, T. Org. Lett. 2009, 11, 891-
893
                                                                                                                O
                                                                        Ar
                                                         O              N                                           R2
                                                                          Cl-
                                                             R2       N N
                                     R1                                                     R1
                                                             H           Ar 10 mol%
                                                    O                                                       O       O
                                                         O             DBU, ACN, rt
                                                                         60-90%

                                                                             OH Ar
                                                                                  N                         R2
                                                O
                                                                                    N                   O
                                                                                N                                        O       Ar
                                                    R2                       Ar
                              R1                                                                                                 N
                                                    OH                            O              R1
                                        O                                                                                    N
                                                                                                                    O Ar
                                      Ar N          N Ar                              R2
                                                                      R1
                                                                             O
Scheidt,K. A. and al.. Org. Lett. 2009, 11, 105-108
Internal Redox with Formylcyclopropanes :
Synthesis of 3,4-Dihydro--pyrone Derivatives
                                _
                            BF4
                           N                     R1
        R1                  N Mes
   O                   N
              H            5 mol%                     O
                    DBU, tol, 100 °C        R2             O
              O
       R2             60-90%


                                                                             O      O     R
                                                                        R1                N
                                                      R1                             H          R
                                                 O                                     N N
                                                               H                  RMes
                                                                                   2

                                                               O
                                                     R2



                                                                                                    O     OH R
                                                           Mes N N R                          R1             N
                                                                                                                     R
                                                                N                                              N N
                                                                  R                                     RMes
                                                                                                         2




                                                                              O      OH R
                                                                                                                          O     O     R
                                                               R1        R1             N
                                                                                                   R                 R1               N
                                                                                          N N                                              R
                                                                O                                                                    N N
                                                                                   RMes
                                                                                    2
                                                                                                                              RMes
                                                                                                                               2
                                                     R2             O



You. S-L., and al,, T. Org. Lett. 2009, 11, 1623-1625
Synthesis of b-lactones
                                    Cl-
     O            O         Mes N       N Mes            Ph CF3
                                      5 mol%                  O
R1       H   Ph       CF3    Et3N, tol, 60 °C       R1            O
                               48% dr 3:2




                                                                      O      Ar
                                                            R1               N
                                            O                         H
                                                                         N                                         +
                                   R1                                 Ar                                       H
                                                H
                                                                                        OH Ar                          OH Ar
                                                                                  R1       N                              N
                                                                                                               R1
                                                                                             N                              N
                                                                                        Ar                             Ar

                                            Mes N   N Mes


                                                                                             OH Ar
                                                                                   R1           N
                                                                                                 N
                                   Ph CF3             F3C O O             Ar             Ar
                                                                                                     O
                                        O              Ph                 N
                                                                      N                       Ph         CF3
                              R1            O             R1     Ar
Azadiene Diels-Alder Reaction
                                                 O
                                                              BF4-
                                                          N
                      Ar                              N   N                        O
                    O2S                                       Mes    ArO2S                      R1
            O           N                                                      N
  R1
                                                 10 mol%
                H                                                                         O
                     H        R2        DIPEA, tol/THF, rt                              R2
       O                                up to 90%, 99% ee




                                                                          high diastereoselectivity : endo TS
                                                                          cis stereoselectivity : Z-enolate


                                                                                            O    R
                                                                                   R1            N
                                                                                         H           R
                                                          O                                 N N
                                                                                        Mes
                                                 R1           H


                                                                                                                                  H+
                                                                                                                   OH R                     OH R
                                                                                                                      N                        N
                                                          Mes N N R                                      R1                 R         R1               R
                                                               N                                                     N N                         N N
                                                                 R                                             Mes                         Mes


                                                                          R1
                                         O
                                                                     R2                                               N PG
                                                 PG                            OH R                           R2
                                 R1          N                                                                         OH R
                                                                                 N                                      H
                                   R2                                      N            R                                 N
                                                                             N N                               R1                 R
                                                                          GP
                                                                             Mes                                            N N
                                                                                                                      Mes
Bode et al. J. Am. Chem. Soc. 2006, 128, 8418-8420
Oxodiene Diels-Alder Reaction
                                     O                                                                                  O
                   O                                                                               OH
                                           Cl-            O                                                                       Cl-
                                     N N                                              R1               SO3Na             N  N                       O
    R1                 H
                                      N               O            R1                         Cl                           N                    O        R1
              Cl                1 mol% Mes                                                                          1 mol% Mes
                                                 R2           R3
          O                   Et3N, AcOEt, rt                                                     O              K2CO3 aq., tol, rt        R2           R3
                            70-95%, 83-99% ee                                                R2          R3     70-95%, 83-99% ee
     R2                R3         dr 20:1                                                                            dr 20:1


                                                                                                         O      R
                                                                                                  R1            N
                                                                                                         H                              OH R
                                                                             O                          Cl N N
                                                                                                        Mes                  R1            N
                                                              R1                 H
                                                                                                                                    Cl N N
                                                                        Cl                                                          Mes


                                                                                                                                           OH R
                                                                        Mes N                NR                                     R1        N
                                                                             N                                               O               N N
                                                                                                                        R2          R3     Mes


                                                                                 R2
                                                                                                               O R1 O    R
                                                                                     O                                   N
                                                                                                         R2
                                                                   R3                    O                            N N
                                                                                                                 R3 Mes
                                                                                     R1


Bode et al., Org. Lett. 2008, 10, 3817-3820
   [4 + 2] Cycloaddition of Ketenes with Enones
                                         Ph             Cl-                  O
                                        Ph    N  N                               R2
         O                                                                        R1
                     O                 TBSO     N                        O
                                         10 mol% Ph
    R1       R2 R3             CO2Et     Cs2CO3,THF, rt R3                        CO2Et
                                       70-95%, 83-99% ee
                                           dr 16-24:1



                                                                O        R
                                                       R1                N
                                                                           Y                       R1R2
                                                                                                      O                     R1R2
                                                            R2       X                     E                  R
                                                                 R                                                      E             O
                                                                                                              N
                                                                                                      O         Y              O
                                                                                                         X
                                                            O                                       R3 R
                                                                                                                             R3
                                                       R3                CO2Et
             Mes
          N N         O
      R      N
             R   R1       R2
                                                            O       R
                                                  R1                N
                                                                      Y                                                                   R3
                                                       R2       X                              O          O    R
                                                            R                                        R1                                    O
                                                                                                               N
                                                                                          R3                        R
                                                       O                                              R2 N                        E            O
                                                                                                           N                          R1 R2
                                                                                                    EMes
                                                  R3                CO2Et


Song, Y., and al. J. Org. Chem. 2009, 74, 7585-7587
[4 + 2] Cycloaddition of Ketenes with N-Benzoyldiazenes
                                        Ph       Cl-                                  Ph        Cl-
                                       Ph     NN                                     Ph      NN
      O                  O     Ar2                           O   O    Ar2                                      O   O     Ar2
                                      TMSO    N                                        HO    N
                         N
                           N           10 mol% Ph           R NN                     10 mol% Mes               R NN
Ar1       R1                           Cs2CO3,THF, rt       Ar1                      Cs2CO3,THF, rt            Ar1
                         Ar3                                    Ar3                                                Ar3
                                      50-95%, 63-99% ee                           50-95%, -63 to -99% ee
                                                                                Switching enantioselectivity




               O     O       Ph                           Ph O
                                  MeONa, MeOH        N
          Ph     N                             BzHN       OMe
               N                    10 min, rt      Ph Et
            Et
               Ph
                   97% ee                           99%, 97% ee




L. He, X. Wu, P. L. Shao, S. Ye,, T. Angew. Chem. Int. Ed. 2009, 48, 192-195.
Formal [2+ 2] Cycloaddition of Ketenes
                                            Ph        BF4-
                                           Ph       NN
        O                 O       R
                                          TMSO     N          O        E
                              N             20 mol% Ph             N
                          N                                        N
  Ar1       R1                             Cs2CO3,THF, rt     R
                                                              Ar       E
                      O       R          50-95%, 63-99% ee



                                                                                                     O
            Electrophile                     Product                                                       R
                                                                                                   N N
                      Boc                   O       Boc                                        O
                  N                             N                                                              O        R
                                                                                                   R Ar1                N
            Ar2       H                    R        Ar2                      O                                            Y
                                           Ar                                                              R1       X
                                                                                                                R
                                       60-90%, 90-99 %ee               Ar1       R1
                                        dr 4:1 to 10:1, cis

                                           O
                 O                              O                            Mes N     N Mes
                                                                                                                              R
        Ar2          CF3                        CF
                                          Ar R Ar 3
                                                 2
                                                                                                                         O        N   O    R
                                      60-90%, 90-99 %ee                                                                           N        N
                                                                                                                              E              Y
                                      dr 5:1 to 16:1, trans                                                                       R1 1 X
                                                                                                                                   Ar
                                                                                                                                     R


                                                                                  O        E
                                                                                       N
L. He, X. Wu, P. L. Shao, S. Ye,, T. J. Org. Chem. 2009, 19, 7585-7589                 N
                                                                                  R        E
L. He, X. Wu, P. L. Shao, S. Ye,, T. Org. Lett. 2008, 10, 277-280                 Ar
L. He, X. Wu, P. L. Shao, S. Ye,, T. Org. Lett. 2008, 10, 4029-4031
The Program                                                      R
                                                                 N
                                                             Y
Introduction                                                     X                                                  O
                                                                  R                                             R
Thiamine
History-Properties                                                                                      O                                O
                                                                                                                NHC
Asymetric Catalysis (Benzoin Condensation and Stetter Reaction)                                     R       H
                                                                                                                E+
                                                                                                                                    R        E


Homoenolate Chemistry
                                       H
                                                  NHC                    E       Nu
                         R1                O
                                               Strong base       R1                  O



Internal Redox Reaction
                                           O                         X       O                O                         H       O
                                                   NHC                                                NHC
                              R1               H             R1                  Nu      R1       H weak base R1                    Nu
                                       X                                 E                                                  E



 Diels-Alder Reaction                      O                         H       O
                                                   NHC
                              R1               H             R1                  X
                                                      X



 Activation of ketene              O
                                                         O       Nu
                                               NHC
                                                      R1
                              R1       R2               R2 E
Acknowledgements
Group members:
Prof. Louis Barriault
Geneviève Bétournay
Kassandra Lepack
Daniel Newbury
Jason Poulin
Boubacar Sow

My students
Gabriel Bellavance
Patrick Levesque

Past members
Steve Arns               My sponsors            and all of you….
Marie-Christine Brochu   CRSNG
Éric Beaulieu            University of Ottawa
Christiane Grisé-Bard    Family
                         Rockstar
                         Hooley’s
                         Chartwell’s
Other Applications of Internal Redox Reactions




                                                   N
                                                    N -                  TMSO         H
                                OO               N   Cl                               N    N3
                                                           20 mol%        R1
                          R1          H                                            R2 O
                                R2          Et3N 15 mol%, tol, rt
                                            TMSN3, NaN3, EtOH                    2.5 : 1 : 0

                                                                            TMSN3
                                                                                                                O
                               OH O       Ar               OH O                         OH                  O
                                                                                                                NH
                         R1               N NaN                        Curtius                 N
                                               3      R1          N3               R1                  R1
                                                                                                   O            R2
                                R2 N                        R2                            R2
                                 Ar
                                                                                                        1:1:1
Rovis, T. And al. J. Org. Chem. 2008, 73, 9727
     Exploring the Scope
 Cyclohexanones and cyclopentanones can be accessed and formation of quaternary
c center is tolerated
                                                              O                O                   20 mol% NHC                         O
        O                        20 mol% NHC
                                 Base                               CO2R               O           20 mol% KHMDS
             H                                                                                                                               CO2R
                                                                                            OR
                                                                                                   PhMe, rt, 18-72h
        X             CO2R
                                THF, rt, 18-72h       R1
                                                              X
                                                                                                    95%, 99% ee
R1

                        ClO4-                     BF4
                                                        -                  O                     20 mol% NHC                       O
     NHC =       N                                                                               20 mol% KHMDS
                     N Ph                         N                                O
                 N                                    N Ar                                       PhMe, rt, 18-72h                          CO2R
                                            O                                          OR
                     44-73%                       N          63-94%                               90%, 84% ee
       O             56-74% ee
            O
                                                             92-97% ee
                                                                                             Enders, D.; et al. Helv. Chim. Acta 1996, 1899-1902
                     Enders                           Rovis                                  Rovis, T.; et al. J. Am. Chem. Soc. 2002, 124, 10298
                                                                                             Rovis, T.; et al. Synlett 2009, 1189-1207

 Diasteroselective reaction
                                                                                                                           N
                                         20 mol% NHC                       O                          NHC =                    N           CF3
                        O                                                      H                                       N
                                         20 mol% KHMDS                             CO2R
                            H                                                                                     Bn
                                         PhMe, rt, 18-72h                                                                  BF4-
                                                                           X
                        X          CO2R
                                        94%, 95% ee, dr 30 : 1




Rovis, T.; et al. J. Am. Chem. Soc. 2005, 127, 6284
Imine as Electrophile
         O                                                              O         R                           Ar R
                                                                                                           Ar3 1 O R                        O   O         Ar2
                    Mes N N R                                   Ar1               N                           N              - NHC
                                                                                    Y                                N
 Ar1          R1         N                                             R1     X
                                                                                                             N
                                                                                                                 O       R                  R NN
                           R                                                R                                      N N                      Ar1
                                                                              O                              Ar2                                Ar3
                                                                                                                   Mes
                                                                                   Ar2
                                                                        N N
                                                                      Ar3


                                                                 OH

                                                      N     S 10 mol%                                                                                     O
                                                                                                                                     NPG
                                                            -                                     R2       O                                                      R2
                                                 Bn    Br
                                                                                                                                                     R1
                               R2       O                                                                                       R1      H
                                                      DBU, 10-70 mol%                    R1
     O                                                                                                 N       R3                                             NPG
                          Ts        N       R3                                                         H
                                                                                              O
R1       H                          H                     Et3N, DCM
                                                          60-96%



                                                                                                                                                     R2       O
                                                                                                                                    O
                                                                                                                                                Ts        N       R3
                                                                                                                               R1       H                 H
                                                                                                       O
                                             O                                                                 R2
                                                                N     S 10 mol%                   R1
              O                              P Ph
                                            N Ph                 Br-                                   HN        Ph
                                                                                                               P Ph
         R1        SiR3
                                    R2       H                                                                 O
                                                                DBU, CHCl3
                                                                50-96%
     You. S-L., and al,, T. Org. Lett. 2009, 11, 3182-3185
 Generation of ,b,-Unsaturated Acyl Imidazolium
                               Cl-                                                                                                        Cl-
             R1   R2   Mes N       Mes            R1   R2                                              R1           R2        Mes N           Mes                         R1       R2
                                 N                                                                                                          N
                                  10 mol%                                            R3            F                                         20 mol%
        R3        O                          R3        O                                                            OTMS                                         R3                O
                         KOtBu, tol, 60 °C                                                                                        KOtBu, tol, 60 °C
                                                                                                   O
                  O         50-90%                     O                                                                              50-80%                                       O




                                                                                                        O            R
                                                                        R1    R2                                     N                                   O
                                                                                              R3
                                                                                                        O
                                                                                                                X
                                                                   R3        O                              R                                   R1       R2
                                                                                              R1       R2
                                                                             O                                                                       O           R
                                                                                                                                                                 N
                                                                                                                                           R3
                                                                                                                                                             X
                                                                                                                                                         R


                                                                             Mes N        R
                                                                                     N

                                                                                      R                                                                  R2
                                                                                                                                                                 R1
                                                                                                                                                     O                O        R
                                                                                                                                                                               N
                                                                                                                                                     R3
                                                                                                                                                                          X
                                                                        R1   R2                                                                                       R
                                                                                                                R2
                                                                   R3        O
                                                                                                                         R1
                                                                                                            O                 O       R
                                                                             O                                                        N
                                                                                                            R3
                                                                                                                                  X
                                                                                                                              R




Ryan, S. J. Candish, L. Luton, D. W..; et al. J. Am. Chem. Soc. 2009, 131, 14176-14177
Si-attack O

                   H
                        Ph
                             N       N
R                  HO
                                 N
                                                                    O


                        Ph                    O               Ar1       R1
                                                                                                                              O        R
                                         O                                                                         Ar1                 N
                                                                                                                                         Y
                                                                                                                         R1        X
                                                                                                                               R
                                                                                                                                   O
                                                                             Mes N              R                                        Ar2
                                                                                            N
                                                                                                                              N N
                                                                                  N
                                                                                                                         Ar3
                                                                                            R




                             Re- attack block
                                                      OH                          R3
                              R3                                                                           R3
                                                                                 N                     Ar R
                             N                                                                      Ar3 1 N
                                              N   S 10 mol%                                                 OH R
                                                                                                       N
           O                             Bn   Br-                   O        O        Ar2                      N
                                                                                                      N             R
                                                                                                          O
                                                                    R O N
                                                                           N           R2                    N N
      R1       H                   R2     Cs2CO3, ACN                                                 Ar2     R2
                         Ts                                          Ar1                                     Mes
                                            60-96%                       Ar3
                                                                                 R1
                                                                                                                         SO2Ar
                                         ArO2S                                                                 O        N
                                                  N                                                                       Ar3
                                E+ =                                                                           H
                                            Ar3                      Ar2
                                                                                                               R1
                                                                                                                            Ar2
        Y                                  E+            OH          R
                   O                                                                         E   O       R
    X    N R                                                         N                                              E       Nu
R                                           R                                                            N
               H           R                                           Y                R
                                                                 X                                         Y   R              O
                                                             R                          Nu           X
                                                                                                 R


                                                                                                                        R
                                                                                                                                  O
                                                         O
                                                                                                                                      O
                                         E+ =
                                                  H                   R                                                      R




                                                     -
                                                Cl
                                    O   Mes N         N Mes
                   O
                                                       15 mol%                           O
                           Ph   H                                          O
                                         THF, tBuOK, 60 °C                          O
                       O                                                       Ph
                                                           Ar
                                                             N  BF4-
                                                            N N
                                OH                O                                      O
                          Br         Br                        O
                                          R1           H                       R1            OBn
                                               Cl Cl       KH, BnOH, tol, rt        Cl
                                                            79%, 93% ee

Rovis, T. And al. J. Am. Chem. Soc. 2005, 127, 16406

				
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