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					Enantioselective Formation of
 Quaternary Carbon Centers



        Cory C. Bausch
       November 18, 2004
                  Outline
• Introduction
• Types of Reactions
  – Alkylations
  – Diels-Alder
  – Cyclopropanation
  – Pd Catalyzed Reactions
  – Chiral Transfer Reactions
• Summary
               Introduction
• Chiral quaternary center: Carbon with four
  different non-hydrogen substituents
                            A
                     D
                                    B
                      C
• Quaternary Center in this context: Carbon with
  four non-equivalent carbon substituents
                                1
                             C
                     4
                    C
                         3
                                    C2
                        C
                             Synthetic Targets
                                                                                           O
                               O                                                                 Me
                                Me                                    N
        Me       H
HO                   O   O
                                                                                Me
                                       HO                                             HO
                                                                                            Me
                                 H                                N                                    OH
        H        H
                                                                      CO2Me
                                                                                                      OH
        Ivalin                 (-)-Reiswigin A                (+)-Tabersonine              Cassiol




                                                                 Me H                   Me H
                                                                   H                      H
                                                                 N   N                  N   N
      Me     H                         O
                 Me                          Me


                                                        O
     Me Me     Me
             Me                        O          O              N   N                  N   N
                                                                 H H Me                   H H
                                                                                        Me
     Modhephene 1                    (+)-Xestoquinone       (-)-Chimonanthine        Meso-Chimonanthine
                   Outline
• Introduction
• Types of Reactions
                                        Chiral Aux.
  – Alkylations            O
                              R    1
                                           PTC
                                       T.M. Catalyst
                                                       O
                                                           R1

  – Diels-Alder             R  2            E+         E   R2

  – Cyclopropanation
  – Pd Catalyzed Reactions
  – Chiral Transfer Reactions
• Summary
                 a,a-Alkylated Ketones


             R              O                                     O
                        H           O                         H         O
         H2N C CO2tBu                                                                           O
O                       R       N                             R       N Li                          Ph
    Ph       H                          Ph     LDA                           Ph   1) R'X, THF
                                                                                                     R'
                                                                                  2) H3O+




                            R’               Isolated Yield       Optical Yielda
                            Me                   62%                    94 (S)
                                a) Based on optical rotation of pure enantiomer




                  Shun-ichi Hashimoto and Kenji Koga Tetrahedron Lett. 1978, 6, 573
Tandem Michael Addition/Aldol
     t
     Bu
                                                    CHO                                 CHO
N C CO2tBu                                   Me                                  Me
                                                             R       +                        R
         H                                                  H                                H




    RMgBr                                                                                   1) KH, THF
                                                       1)MeI-HMPA                           2) MeI
                                                       2)H3O+


t                                             t
    Bu       H                                 Bu      H
                  t
                                                                                            O
                 O Bu                                            t
                                                            O Bu      H3O+          H
N                                             N
        O                                               O                                        R
     Mg                                           Mg                                            H
     R Br                                          R
                                                       Br
                                                  H




         Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron Lett. 1980, 21, 4005
     Scope of Addition/Alkylation
                                                                                CHO
                                               1)MeI-HMPA              Me
             t
                 Bu       H                    2) H3O+                           R
                                                                                H
                                t
                               O Bu                                      Method A
            N
                           O
                  Mg
                          Br                                                    CHO
                  R                                                    Me
                 H                              1)H3O+                          R
                                                2)KH                           H
                                                                        Method B
                                                3)MeI

Entry            Method                 R              Trans (yield)   Cis (yield)         %ee
 1                    A                C6H5                 55             0               82
 2                    A               CH2=CH                62             0               92
 3                    B                C6H5                 0              65              82
 4                    B               CH2=CH                0              61              92




        Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron Lett. 1980, 21, 4005
        Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron 1981, 37, 3951
                  Alkylation of b-Keto Esters
                                                                                                                 O           O

                                                                                                            R1                   OR3
                                                                                                                     2       4
                                                                                                                 R       R

                                                                                                     R4X
                                                                                                     HMPA

                                       OtBu                          OtBu
                                           O                             O

                                               H                             Li
     O        O          (S)-valine        N        O                    N            O
                           ester                              LDA
                                                                                           3
R1                OR3                 R1                OR3         R1                    OR
                                                                                  2
         R2                                    R2                            R



                                                                                               R4X
                                                                             THF, NMe3, dioxolane

                                                                                                                 O       O

                                                                                                            R1                   OR3
                                                                                                                     4   2
                                                                                                                 R       R


 •Achieve both enantiomers with the same chiral species
 •Binding properties of ligand affect orientation of enamine
                        Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. J. Am. Chem. Soc. 1984, 106, 2718
    Orientation of Addition
          L = THF                                        RX



                                 t
                               O Bu                                  L        L
                N
                    Li   O                                               Li       O
                O                                                 N
   MeO                                                                                OtBu
                     L
                                                                 O
                                                     MeO

                                                            L = HMPA
          RX


•THF is poor coordinating ligand
•HMPA is strong coordinating ligand


Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. Tetrahedron Lett. 1984, 25, 5677
                              Scope of Alkylation
                 OtBu
                     O
                                                            O     O                     O   O
                         Li
                     N        O
                                                       R1             OR3     +   R1             OR3
                                                                                             2
                R1                 OR3                      R2 R4                       R4 R
                         R2                                   A                           B


Entry   R1,R2                 R3         R4X                Ligand (equiv)    Product       Yield (%)   % ee

1       (CH2)4                Me         MeI                HMPA (1.0)        A             57          >99 (R)

2       (CH2)4                Me         MeI                THF (2.0)         B             63          92 (S)

3       (CH2)4                Me         CH2=CHCH2Br        HMPA (1.0)        A             71          76 (S)

4       (CH2)4                Me         CH2=CHCH2Br        Dioxolane (1.2)   B             56          56 (R)

5       Me                    Et         CH2=CHCH2Br        HMPA (1.0)        A             68          94 (S)

6       Me                    Et         CH2=CHCH2Br        Dioxolane (2.0)   B             20          47 (R)

7       Me                    Et         PhCH2Br            HMPA (1.0)        A             90          92 (S)

8       Me                    Et         PhCH2Br            Dioxolane (2.0)   B             83          90 (R)




        Tomioka, K.; Ando, K.; Takemasa, Y. Koga, K. J. Am. Chem. Soc. 1984, 106, 2718
Chiral Phase Transfer Catalysis
                CO2Et          O                              CO2Et
                                       Catalyst
                        +
                O                       25 °C
                                                                   O       O

                               OCH3               OCH3                 H
            H           OR                               RO
                N                                                 N
                Me                                               Me
                 -             N                  N           -
                   OH                                           OH
           Quinine Methohydroxide            Quinidine Methohydroxide
                        A                                B
 Entry     Catalyst          Solvent     Reaction        Yield (%)             % Optical
                                          Time                                  Purity
  1             A            Dioxane       67 h               99                 5 (R)
  2             A            CH2Cl2        43 h               89                 8 (R)
  3             A            Benzene       74 h               99                10 (R)
  4             A            Toluene       18 h               90                10 (R)
  5             A             CCl4          1h                98                17 (R)
  6             B             CCl4          1h                99                 9 (S)

         Hermann, K. and Wynberg, H. J. Org. Chem. 1979, 44, 2238
                   PTC, cont.
         Cl   O                                            Cl       O
    Cl                         1) LDA                 Cl
                                                                        Me
                               2) MeI                                   Ph
  H3CO                                  H           H3CO

                              HO
                                        N
                                                R
                         N




                                            H
                                 H
                             Cl O O
                  Cl                        N
                                                                R
                  N
              H3CO


•Reaction gives up to 95% yield, 92% ee

  Dolling, U.H.; Davis, P.; Grabowski, E.J. J. Am. Chem. Soc. 1984, 106, 446
                                    PTC, cont.
                               30 mol %   OCH3

                          H         OR                               O                          O
                               N
      Cl   O        O                                     Cl   O                           Cl
 Cl                                       N         Cl                                Cl
                              Br-                                            H2SO4
               +
MeO                                                MeO                               MeO




• Convenient, efficient Robinson annulation.
• Product can be obtained in 78% ee and 99% yield.



                   Dolling, U.H., et al. Angew. Chem. Int. Ed. Engl. 1986, 25, 476
Nucleophilic Chiral Pd Enolates
               H
  *   P        O        P   *                 P        OH
          Pd       Pd                     *
                                                  Pd
      P        O   P                          P
               H 2 TfO-                            TfO-

      *    P                                      A
                   = (R)-Tol-BINAP
           P




                                                            t-Bu   1)         O      O
      O        O                                                                          O
                                              P        O
                                  A       *                                                    t-Bu
                                                  Pd
                                THF, rt       P                         2) TfOH
                                                       O
                    t-Bu                                                                         O

                                                                                  97% ee (100 mol % A)
                                                                                  90% ee (10 mol % A)



•Works for b-keto esters as well
•Reaction scope gives 69-92% yield and 89-93% ee
                   Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240
    Salen-Al Catalyzed Michael Additions

     O       O                                                                                  O       O
                                   R'
         N       Ph                                             [(salen)Al]2O                       N       Ph
                      +                                                                             H
         H                    NC        CO2Me                                              R'
R                                                            t-BuOH (1.2 equiv)                  R
     1.0 eq                    1.2 eq
                                                               Cyclohexane, rt             NC CO2Me




    Entry                 R                 R’       Time            Yield (%)     %ee           d.r.
     1                n-Pr                  Ph       19 hr               98         97           14:1
     2                n-Pr              m-CF3C6H4    15 hr               96         98           35:1
     3                n-Pr              p-MeOC6H4    38 hr               94         95           6:1
     4                n-Pr               2-thienyl   4d                  76         91           14:1
     5                 Me                   Ph       24 hr               95         86           5:1
     6                i-Bu                  Ph       24 hr               96         96           16:1




                      Taylor, M.S. and Jacobsen, E.N. J. Am. Chem. Soc. 2003, 125, 11204
                  Outline
• Introduction
• Types of Reactions
  – Alkylations           R1              *
                                           L.A.       R1
                                                           EWG
                                EWG
                                      T.M.(*Ligand)
  – Diels-Alder
                          R2                          R2
  – Cyclopropanation
  – Pd Catalyzed Reactions
  – Chiral Transfer Reactions
• Summary
 Enantioselective Diels Alder
       Cycloadditions
 OMe O       COOR                                         OMe O        COOR
                COOH                       CH2Cl2                         O
         O              +    BH3·THF                              O
                                                                               B X
              OH
    OMe                                                         OMe O      O

     (2R, 3R)                                                      A



                                   10 mol % A                      85% yield
                   +
         CHO                                                CHO    96% ee



                                   H
                                       O
                              O           B
                                         O O        Me
                               H            H
                            HOOC       O  RO
                                       O RO



•Reaction scope gives 40-91% yield and 82-96% ee
   Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamota, H. J. Org. Chem. 1989, 54, 1481
         Cr(III)-Salen Catalyzed
       Enantioselective Diels-Alder
TBSO                                                      TBSO                       TBSO
                                            5 mol% 1
                                                                           Me                         Me
                           +                                                     +
                                   CHO        4Å MS                       CHO                        CHO
           N                                  CH2Cl2                 N                          N
       R       CO2Me                                             R       CO2Me              R       CO2Me
                                                                 Favored




           N        N
               Cr
           O        O
               X



1a: X=Cl, b: X=BF4, c: X=SbF6




                        Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843
Cr(III)-Salen Catalyzed, cont.
        TBSO                                                                      TBSO
                                                             5 mol % 1
                                                                                                    Me
                                +
                                              CHO                4Å MS                             CHO
                   N                                             CH2Cl2                      N
               R        CO2Me                                                            R        CO2Me




                                                   N         N
                                                       Cr
                                                   O         O
                                                       X



                                         1a: X=Cl, b: X=BF4, c: X=SbF6



Entry              R            Catalyst          Temp (°C)               Time           Yield (%)        % ee
 1              Allyl               1b                 -40                2d                 93            90
 2              Me                  1b                 -40                2d                 89            78
 3             Benzyl               1b                 -40                2d                 95            95
 4             Benzyl               1c                 -40                2d                 93            97
 5             Benzyl               1b                  rt                8 hr               80            93
 6             Benzyl               1c                  rt                16 hr              92            91

         Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843
Cr(III)-Salen Catalyzed, cont.
TBSO                                                              TBSO
                                                 5 mol % 1c
                                                                                    R
                          +
                              R      CHO          4Å MS                            CHO
  Ph     N                                        CH2Cl2             Ph       N
             CO2Me                                                                CO2Me


Entry           R                 Temp (°C)            Time       Yield (%)        % ee
 1             Me                    -40               2d            93             97
 2              Et                   -40               2d            91             97
 3           Isopropyl               -40               5d            92             >97
 4         TBSO(CH2)2                -40               2d            93             95
 5            TBSO                   -40               2d            86             >97



                TBSO
                                                              O
                                    R         1) LAH
                                   CHO        2) HF                  R
                     Ph       N
                                  CO2Me                               OH




        Huang, Y.; Iwama, T.; Rawal, V.H. J. Am. Chem. Soc. 2000, 122, 7843
     Advances of Cr(III)-Salen
      Catalyzed Diels-Alder
                             5 mol % 1c                             1) LAH
                                                             Me                         Me
                 +
                     CHO      rt, 4Å MS                     CHO                          OH
     N                          CH2Cl2                 N                          N
Bn       CO2Me                                 Bn          CO2Me             Bn       CO2Me
                                                                              99% yield
                                                                              >99 de
                                                                              99% ee



                                                            SbF6-
                                          N        N
                                              Cr
                                          O        O



                                              1c



                 •Preserves second stereocenter
                 •Possesses more functionality
                 •General reaction scope
                 •Mild and convenient conditions
             Huang, Y.; Iwama, T.; Rawal, V.H. Org. Lett. 2002, 4, 1163
            Rare-Earth Metal Catalyzed
               Quinone Diels-Alder
•New effective chiral lewis acid in quinone Diels-Alder reactions
•Sm, Gd are optimal metals from lanthanide metal screen
                                          O   O             Me                                       O       Me
                                                                                                         X
                                                  OMe                  10 mol % Catalyst
                                                        +
                                                                  R1 CH2Cl2, -78 °C                               R1
                                                                                                         H
                                          O                 R2                                       O       R2




        O       N        O
   R'                          R'
            N   M      N
                                                                   O            N           O
        R TfO OTf   OTf    R                                 R'                                 R'
                                                                        N       M       N
        1a: R = Ph, R' = H                                                  O (Y) O         R
                                                                   R                n
        1b: R = Me, R' = Ph
            M = Sm, Gd                                                                  OMe


                                                                            O



                         Evans, D.A. and Wu, J. J. Am. Chem. Soc. 2003, 125, 10162
        Quinone Diels-Alder Reaction
        O                       O                O     O              Me                                          O       Me
                  N                                                                                                   X
  R'                                R'
            N     M    N                                   OMe                        10 mol % Catalyst
                   OTf                                           +
        R TfO OTf          R
                                                                              R1 1:1 THF/Toluene                                R1
                                                                          2           -78 °C                          H
        1a: R = Ph, R' = H                       O                    R                                           O       R2
        1b: R = Me, R' = Ph
            M = Sm, Gd

Entry           Quinone              Catalyst   R1         R2                     Product                 Yield (%)        % ee
 1                                   1a-(Sm)    Me         H                                                 87                97
                                                                              O       Me
              O       O                                                           E
 2                                   1a-(Gd)    Me         H                                                 99                98
                          OMe
 3                                   1a-(Gd)     H         H                                                 99                98
                                                                                               R1
 4                                   1a-(Gd)     H         Me                     H                          99                97
              O                                                               O       R2
 5                                   1a-(Gd)    n-Pr       H                                                 96                98
 6                O       O          1a-(Sm)    Me         H                  O       Me                     91                >99
                                                                                  E
                              OMe
 7                                   1a-(Gd)     H         H                                                 88                >99
         Me                                                          Me                        R1
 8                                   1a-(Sm)     H         Me                     H                          84                98
                  O                                                           O       R2
                  O       O                                                       O       Me
 9                                   1b-(Gd)    Me         H                          E                     >99                91
                              OMe

 10                                  1b-(Gd)     H         H                                    R1           91                91
                  O                                                                   H    2
                                                                                  O       R



                          Evans, D.A. and Wu, J. J. Am. Chem. Soc. 2003, 125, 10162
 Application of Enantioselective
           Diels-Alder
       P                                                     P                                      P
            N                        endo-selective              N           olefin                     N
                                 CHO  Diels-Alder        P           CHO   metathesis           P
   P
                    +

TBSO                                                  TBSO                                  TBSO



                                      Hal                                               N
                                                N
                regioselective                           intramolecular
                 indolization                               alkylation                          Me
                                                                                 N
                                            N                                           CO2Me
                                                                             (+)-Tabersonine


  •        Key step in the synthesis of Aspidosperma alkaloids
  •        Generates two key stereocenters in one step
  •        Synthesis gives >95% ee in 12 overall steps
  •        Can be completed on >1 g scale

           Kozmin, S.A.; Iwama, T.; Huang, Y.; Rawal, V.H. J. Am. Chem Soc. 2002, 124, 4628
                    Further Applications
                                                 O                                    OTIPS

    CHO
                O
                             1) (86%)                              1) LDA
           +
O    O                       2) I2 (90%)                             2) TIPSOTf
                      PPh3                                                                              O
                                                               O       (>99%)

                                                           O                                       O


                                                                                                            H
                                                                                                            N
                                                                                    Me

                                                                                       CHO         Me           O
                                                                                                    H                 O
                                                                                  83% yield                             O
                                                                                  97 % ee               H           N B
                                                                                                                    H   H


                                                                                          OTIPS
                                           O
                                                                                              Me
                                                Me
                                                                   1) NaBH4 (99%)
                                                                                                   H
                                                                   2) DDQ             H
                                  HO                               3) TBAF                    Me
                                           Me                                                                   O
                                                      OH            (63%)                 O
                                                                                                        O
                                   Cassiol           OH            4) HCl (96%)

                                    40% overall yield
                                    97% ee

          •Diels-Alder sets stereocenter in high ee
          •Efficient synthesis of 6-membered ring backbone
          Corey, E.J.; Guzman-Perez, A.; Teck-Peng, L. J. Am. Chem. Soc. 1994, 116, 3611
                   Outline
• Introduction
• Types of Reactions
  – Alkylations                2
                             R         ":CH2"        R2
  – Diels-Alder           R1
                               R   3            R1
                                                          R3

  – Cyclopropanation
  – Pd Catalyzed Reactions
  – Chiral Transfer Reactions
• Summary
 Enantioselective Cyclopropanation
• Asymmetric Modified Simmons-Smith Reaction
  – Reported in 1985 by Yamamoto, et al. and Mash, et al.

                     R2                                           R2
               R1                                       R1
                          CHO                                      CHO
                                                             85-89% ee




                R2
                                                         R2
          R1             O          Et2Zn-CH2I2
                                                   R1             O
                             CO2R
                     O                                                 CO2R
                                                              O
                         CO2R
                                                                  CO2R




          Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254
          Mash, E.A. and Nelson, K.A. J. Am. Chem. Soc. 1985, 107, 8256
        Cyclopropanation, cont.
                                Temp (°C),
Entry   Acetal                                    Product                 Yield (%)   % de
                                 Time (hr)

                 O                                         O
 1                    CO2iPr      -20, 1                         CO2iPr      81        89
         O                                             O
                 CO2iPr                                    CO2iPr


                 O                                         O
 2          O
                        CO2Et     -20, 7               O
                                                                  CO2Et      61        88
                 CO2Et                                     CO2Et


                 O                                         O
 3          O
                        CO2Et     -20, 7               O
                                                                  CO2Et      50        85
                 CO2Et                                     CO2Et



             O                                         O
 4                   CO2Et        30, 4                        CO2Et         63        95
        O                                          O
             CO2Et                                     CO2Et



             O                                         O
 5                   CO2Et        30, 4                        CO2Et         75        93
         O                                         O
                CO2Et                                  CO2Et

         Arai, I.; Mori, A.; Yamamoto, H. J. Am. Chem. Soc. 1985, 107, 8254
         Mash, E.A. and Nelson, K.A. J. Am. Chem. Soc. 1985, 107, 8256
Cyclopropanation in Total Synthesis
• Cyclopropanation in 84% yield, 89% ee
• 15% overall yield in 14 Steps
                                                OMe                                  OMe
             MeO             OMe
   O
                                 MeO                                     MeO        O
                                                O
                   HO   OH                  O                   Zn(Cu)         O
                   TMS-OTf                                      CH2I2




                   O                                O                               Me   H
                                                                                             Me
       HCl                          TMS-I
   MeOH                              CCl4
                                                            I                  Me Me       Me
                                                                                         Me
                                                                               Modhephene 1



             Mash, E.A.; Math, S.K.; Flann, C.J. Tetrahedron Lett. 1988, 29, 2147
Cyclopropanation of Allylic Alcohols
• General substrate scope
• No stoichiometric chiral source necessary
• Order of addition of reagents is important
                                                NHSO2CH3
                              1)                           (0.1 eq)
                                                NHSO2CH3
                                                Et2Zn (0.1 eq)
           R1                                                                  R1
                                                ZnI2 (0.1 eq)
      R2             OH                                                   R2            OH
                                                                                    3
                R3           2)             "Zn(CH2I)2"                           R
                                                                               88-98% yield
                                                                               26-81% ee

                                                     I
                                                    Zn

                                        O           NR O

                                   Me   S       N   Zn   Zn           I
                                            O          I



                 Denmark, S.E. and O’Connor, S.P. J. Org. Chem. 1997, 62, 584
                   Outline
• Introduction
• Types of Reactions
  – Alkylations              R
                                                   R
                           X     Pd(II), *Ligand
  – Diels-Alder
  – Cyclopropanation
  – Pd Catalyzed Reactions
  – Chiral Transfer Reactions
• Summary
 Pd-Catalyzed Heck Reactions
• Thoroughly explored pathway to quaternary carbons
• Reaction is enantioselective and catalytic

                                                    R
                     R

                                                             H
          L*nPd-I                                          H
                                                    H*
                                                     L nPd-I

                                             Base




                                                                        R
                                    *
                                 PdL n

                     R
                                                                        H
             I
                                                Base:HI




        Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738
                           Heck Reactions
• Cis-decalin derivatives among first systems studied

        CO2H                           CO2Me                                         CO2Me                        R
               1) Na, EtOH, NH3                1) LDA, THF
                                                                             I                           I
               2) CH2N2                             I
                                               2)
                                                               I

                                           R                                     R
                                                Pd(OAc)2 (5 mol %)
                                   I            *
                                                    Ligand (5.5 mol %)
                                                                                 H
                                                     Ag2CO3 (2 eq)




Entry   R                         Ligand        Temp (°C)                Time (hr)           Yield (%)       % ee
1       CO2Me                     (DIPHOS)      60                       5                   68              --
2       CO2Me                     (R)-BINAP     60                       37.5                74              46
3       CH2OTBDMS                 (R)-BINAP     40                       44                  70              44
4       CH2OAc                    (R)-BINAP     40                       88                  66              36




                   Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738
                              Heck Reactions
• Improvements using vinyl triflates
    – No silver salt needed
    – Higher enantiomeric excess obtained
CO2Me                                            CO2Me                                   CO2Me                  R
         1) LDA, THF                                         1) TsOH, Acetone
                              MeO
                                    OMe                      2) Tf2O, base         OTf                    OTf
                        OMe
        2) I
                        OMe



                                             R                                       R
                                                    Pd(OAc)2 (5 mol %)
                                OTf                 *
                                                        Ligand (5.5 mol %)
                                                                                     H
                                                        K2CO3 (2 eq)


Entry          R                    Ligand              Temp (°C)            Time (hr)   Yield (%)   % ee
1              CO2Me                (R)-BINAP           60                   31          54          91
2              CH2OTBDMS            (R)-BINAP           60                   30          35          92
3              CH2OAc               (R)-BINAP           60                   30          44          89
4              CH2OPv               (R)-BINAP           60                   27          60          91

                   Sato, Y.; Watanabe, S.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2589
                   Heck Reactions
• Synthesis of hydrindans

                        OTBDMS                          OTBDMS

                                  Pd0Ln*                     63% Yield
                                    AgY                      3% ee
                   I
                                                   H


           CO2Me        Pd(Cl)2[(R)-BINAP] (10 mol %)        CO2Me
                               Ag3PO4 (2 eq)                             78% Yield
                              CaCO3 (2.2 eq)                             82% ee
       I                    NMP, 60 °C, 49 hr                H


           R           Pd(OAc)2[(R)-BINAP] (10 mol %)            R
                               K2CO3 (2 eq)                              63% Yield
                                                                         73% ee
       OTf                  C6H6, 60 °C, 64 hr
                                                                 H



       Sato, Y.; Honda, T.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2593
               Heck-Type Reactions
• Palladium catalyzed polyene cyclizations of
  trienyl triflates

                                               M


     M



                                     OTf
                                                   Pd(II)
                                                   Ligand
                                       n            Base            n
                                O                               O

         OTf
                               Pd(OAc)2 (10 mol %)
                              (R,R)-DIOP (10 mol %)                     >90% Yield
                                                                        45% ee (unoptimized)
                                  Et3N (2 eq)
     O                           CH3CN, 2 hr, rt
                                                            O




               Carpenter, N.E.; Kucera, D.J.; Overman, L.E. J. Org. Chem. 1989, 54, 5846
 Application of Polyene Cyclization
• Enantioselective total synthesis
• Heck reaction unsuccessful, polyene cyclization
  works well

          OMe                                                           OMe
                 OTf                   Pd2(dba)3((S)-(+)-BINAP)4               Me
                                              (10 mol %)                                    TBS
                                 TBS          82% yield                                 O
                         O
                                              68% ee
          OMe       O                                                   OMe         O


                                                                    O     Me
                 OMe    Me
                                       TBS
                                                                                    O
                                   O
                                                                    O          O
                 OMe         O
                                                                   (+)-Xestoquinone



  Maddaford, S.P.; Anderson, N.G.; Cristofoli, W.A.; Keay, B.A. J. Am. Chem. Soc. 1996, 118, 10766
             Heck Reaction, cont.
• Form enantioenriched spirocycles
• Achieve either enantiomer with same catalyst
                                                              O
                             Pd2(dba)3 (5 mol %)                     NR
                           (R)-(BINAP) (11 mol %)
                                                                          86% yield
                                Ag3PO4 (2 eq)                             70% ee
                                 80 °C, 26 hr
              O
                                                               (S)
                  NR
                       I


                                                              O
                             Pd2(dba)3 (5 mol %)                     NR
                           (R)-(BINAP) (22 mol %)
                                                                          71% yield
                                 PMP (5 eq)
                                                                          63% ee
                                 100 °C, 8 hr
                                                               (R)


    Ashimori, A.; Bachand, B.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6477
    Enantioenriched Spirocycles
• Silver salt works better than amine base
• Scope is fairly general
        O                                   O                           O                        O
              NMe                                NBn                         NSEM                     NMe
                                                                                            Me
                               O                             O
     n                             O                             O
    n = 1-3
                                                                     78% yield                   88% yield
   70-96% yield                        91% yield
                                                                     58% ee                      59% ee
   56-95% ee                           50% ee



        O                               O                                                               O
                                                                            NCO2Me
               NMe                              NMe
   Me                           t-Bu
                                                         O                              O

  OHC                          OHC                           O                              O

     88% Yield                     41% yield                     90% Yield                   91% Yield
     45% ee                        72% ee                        64% ee                      55% ee



            Ashimori, A.; Bachand, B.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6477
 Enantioenriched Natural Products
• Heck cyclization can obtain either enantiomer

                                                           Me            OTIPS                                 Me
 MeO   I             OTIPS   10% Pd2(dba)3 CHCl3                                                                         CHO
           O                                       MeO                                                   MeO
                               23% (S)-BINAP                                         1) HCl, 23 °C
                                                                     O                                                   O
       N                                                        N                                                   N
       Me      Me                 N                             Me                                                  Me
                                          DMA
                                         100 °C        (84% yield, 95% ee
                                                     (>99% ee after recryst.)



                                                                                          Me
                                                                         MeHNO2C
                                                                                                     NMe
                                                                                              N H
                                                                                              Me
                        Me                                                       (-)-Physostigmine
               MeO                CHO
                                  O
                             N
                             Me                                                            Me
                                                                          MeHNO2C
                                                                                                     O
                                                                                                N H
                                                                                                Me
                                                                                  (-)-Physovenine




       Matsuura, T.; Overman, L.E.; Poon, D.J. J. Am. Chem. Soc. 1998, 120, 6500
   Synthesis of Vicinal Stereogenic
     Quaternary Carbon Centers
MeO2C                                                                                                          BnO   OBn
             CO2Me                                    BnO   OBn
         +               LDA, THF/HMPA                                        Me3Al                    I                      I
                                                                                                              Bn         Bn
   BnO       OBn              LDA, I2                                      2-iodoaniline                      N          N
                                                 MeO2C      CO2Me                                               O    O
   I           I



                            TBDMSO      OTBDMS
                                                                                       TBDMSO              OTBDMS

                         I    Bn            Bn    I         10% (Ph3P)2PdCl2
                              N             N               Et3N, DMA, 100 °C
                                                                                           BnN                NBn
                                   O    O                         71% yield                          O O



                                   O    O                                                        O        O
                                                                                             O
                        I                         I         10% (Ph3P)2PdCl2
                              Bn            Bn
                              N             N               Et3N, DMA, 100 °C          BnN
                                                                                                              NBn
                                O       O                      90% yield                              O




                   Overman, L.E.; Paone, D.V.; Stearns, B.A. J. Am. Chem. Soc. 1999, 121, 7702
Vicinal Quaternary Centers, cont.
                                                      Bn                      Me H
                                                      N                         H
                                                                              N   N
  TBDMSO           OTBDMS                        O
                                            HO

                                            HO
                                                 O
   BnN                 NBn                            N
             O O                                                              N   N
                                                      Bn                        H
                                                                              Me H
                                                                          Meso-Chimonanthine


                                                                                 Me H
         O         O                                                               H
                                                     Bn                          N   N
         O                                           N
                                                 O
   BnN                                     HO
                       NBn                                 O
               O                           HO
                                                          NBn                    N   N
                                                                                 H H Me

                                                                            (-)-Chimonanthine



•Both products formed with complete stereocontrol
•Variation in protecting group allows access to both
stereogenic products

             Overman, L.E.; Paone, D.V.; Stearns, B.A. J. Am. Chem. Soc. 1999, 121, 7702
Further Expansion of Heck Coupling
                                                                 NMeTs                                   Bn
                                                      O                                                  N    O
                     OTf Bn      SnBu3                                                                              NMeTs
 I                                                   N           H H Me
     H H Me              N                                                                                        H H Me
     N   N                                       OTf Bn          N   N                                            N   N
                             O                                                 Pd(OAc)2, (R)-Tol-BINAP
                                     NMeTs                                       PMP, MeCN, 80 °C
                  Pd2(dba)3 CHCl3, P(2-furyl)3                                     62% Yield, 90% ee
                         CuI, NMP, rt                                              (21% meso isomer)
     N   N                                       OTf Bn           N   N                                           N   N
                             71%                                  H H Me
 I   H H Me                                          N                                                            H H Me
                                                                                                                    NMeTs
                                                          O                                              N    O
                                                                 NMeTs
                                                                                                         Bn


                                                                 H H Me
                                                                 N   N

                                                                         H H Me
                                                                         N   N




                                                                          N   N
                                                                          H H Me

                                                                 N   N
                                                                 H H Me

                                                              Quadrigemine C




       Lebsack, A.D.; Link, J.T.; Overman, L.E.; Stearns, B.A. J. Am. Chem. Soc. 2002, 124, 9008
       Pd-Catalyzed Allylation
• Chiral ferrocenylphosphine ligands among
  first used
• Works for wide array of b-diketones
                                X




             Pd(0)
                                                  Pd(II)                         PPh2
                                                                           Fe     PPh2
                           Nu                Nu                                     NR2
                                                                                H Me

                                                                          yield: 74-96%
         O     O                                  O       O                 ee: 3-81%
                            1) Base                   *
                           (-C3H5)PdCl/L*
                      2)
                                      OAc



      Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113
         Pd-Catalyzed Allylation
                                     1.2 mol%
                                           O                 O
                                                 NH HN

O   O                                                                        O       O
                                               PPH2   Ph2P
                          R                                                                      91% Yield
        OBn       +                     0.5 mol % [(3-C3H5PdCl)2]                       OBn
                               OAc                                                               99% ee
                                      TMG (1.2 eq), Toluene, 0 °C
                                                                                 R



                                     5 mol%
                                           O                 O
                                                NH HN

    O                                                                       O
                                               PPH2   Ph2P
                      R                                                                        99% Yield
              +                        2.5 mol % [(3-C3H5PdCl)2]                              88% ee
                              OAc
                                     LiTMP (2 eq), (CH3)3SnCl, DME
                                                                                 R




        Trost, B.M.; Radinov, R.; Grenzer, E.M. J. Am. Chem. Soc. 1997, 119, 7879
        Trost, B.M.; Schroeder, G.M. J. Am. Chem. Soc. 1999, 121, 6759
Enantioselective Tsuji Allylation
                                           O

         O                       PPh2 N
                       6.25 mol %           t
                                                Bu       O
     O       O
                        2.5 mol % Pd2(dba)3                          90% Yield
                             THF, rt                                 89% ee




                             O                       O           O
             O



                         O       O


                  O                    O                     O
                                           Bn




                                     85-96% Yield
                                      85-91% ee


         Behenna, D.C. and Stoltz, B.M. J. Am. Chem. Soc. ASAP
         Tsuji Allylation, cont.
• Catalytic cycle of racemic allylation
                                             O
               O                         O       O   Pd
           O       O                                 Ln
                                                                  -CO2




                       PdLn                                       O     Pd
                                                                         Ln



           O




               Behenna, D.C. and Stoltz, B.M. J. Am. Chem. Soc. ASAP
               Tsuji, J. and Minami, I. Acc. Chem. Res. 1987, 20, 140
                   Outline
• Introduction
• Types of Reactions
  – Alkylations            OH                     O   OH

  – Diels-Alder                  2   Lewis Acid
                         M      R                        R2
                             1O
                            R                     M R1

  – Cyclopropanation
  – Pd Catalyzed Reactions
  – Chiral Transfer Reactions
• Summary
           Chiral Transfer Reactions
• Chirality transfer based on thermodynamic
  stability

                O
   O                                 Ph Me                                        Me      O             Me
                         nBuLi      HO     O                     TsOH                                        O
   S tol   +        Me                                                       Ph           S tol   Ph
                                           S tol            C6H6, reflux

 99% ee                                                                                                94% ee
                                       3:2 dr




                                                Me       O                   Ph       O
                                         Ph              S tol    +     Me            S tol


                                                     A                            B




               Hiroi, K.; Nakamura, H.; Anzai, T. J. Am. Chem. Soc. 1987, 109, 1249
 Pinacol-Type Rearrangement
• Lewis acid promoted migration forms
  quaternary carbon center
• Larger group migrates
• 87-100% Yield, 95-100% retension of
  stereochemistry
                                 R                              R M
                                     M        Lewis Acid
                                                (1 eq)
                                 O
                                     OH                       OH O
                      M: Migrating Group


                            Me                               Me    Tol
                       O
                                 Tol      (i-PrO)2TiCl2    HO            R

                            R OH                                  O
                           87% ee                            87% ee
                                                            100% Yield

     Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987, 28, 5891
Lewis Acid Cat. Rearrangement
• Form b-siloxy aldehydes from epoxy silyl ethers
• Can use catalytic L.A., but decreases yields


    Me                     MLn           Me MLn                                    Me         OSiMe2tBu
      O                                    O
R         OSiMe2tBu                    R      OSiMe2tBu                            R      CHO



                                   2 eq

                                  Br           O      O          Br
                                                   Al
                                                   Me
                                                                                                  t
                O                                                                         OSiMe2 Bu
                                              (MABR)
                      OSiMe2tBu                                                         CHO
           (90% ee)                                                              (90% ee)




            Maruoka, K.; Ooi, T.; Nagahara, S.; Yamamota, H. Tetrahedron 1991, 47, 6983
                 Summary
                             Chiral Aux.
         O                      PTC                  O
                  R1        T.M. Catalyst                         R1

             R2                  E+                      E    R2



    R1                                *                            R1
                                    L.A.                                EWG
                      EWG
                               T.M.(*Ligand)


    R2                                                             R2




                 R2              ":CH2"                      R2
    R1                                          R1
                      R3                                          R3



             R
                                                              R
         X                    Pd(II), *Ligand




    OH                                               O        OH
                   2           Lewis Acid
M                 R                                                R2
             O
     R1                                              M R      1
Acknowledgements
       Advisor:
     Jeff Johnson

    Johnson Group

				
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