Total Synthesis of Reserpine by L3Yaq6O

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									Total Synthesis of Reserpine
                       MeO    A
                                  B   C
                                  N   3 N
                                  H H   D           H
                                                            O
                                        H       E
                                  MeO                                 OMe
                                                        O
                                            H     H
                                        O       OMe                   OMe
                                                                OMe

                                            Reserpine


 Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. J.Am.Chem.Soc.1956,78,
                                          2023, 2657
            Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W.
                                    Tetrahedron 1958, 2,1
                            For other completed total syntheses see
                    Pearlman, B.A. J.Am.Chem.Soc.1979, 101, 6398, 6404
  Wender, P.A.; Schaus, J.M.; White A.W. ibid. 1980, 102, 6157; Heterocycles 1987, 25, 263
 Martin, S.F.; Rüeger, H.; Williamson, S.A.; Grzejszczak, S. J.Am.Chem.Soc. 1987, 109, 6124
                        Stork, G. Pure and Appl.Chem. 1989, 61, 439
 Reserpine - Isolation, Biological and Physical
                   Properties
1.      Isolated in 1952 by Schlitter et al. from
        the extracts of Indian snakeroot                                       MeO

        Rauwolfia serpentina                                                             N
                                                                                         H
                                                                                                   N


2.      Belongs to the alkaloid family of which                                          MeO

        yohimbine is the prototype                                                             O       OH


3.      Weak base with Pk 6.6 and sparingly                                             Yohimbine


        soluble in water but soluble in glacial
        acetic acid and alcohol
4.      Effective in the treatment of
        hypertensive, nervous and mental
        disorders
5.      Induces a period of sedation when
        intravenously injected into animals
Plummer, A.J.; Earl, A.; Schneider J.A.; Trapold, J.; Barrett, W. Annals of New York Acad.Sci.1955,59,1-21
Scriabine,A. In Pharmacology of Antihypertensive Drugs; Scriabine A., Ed., Raven Press : New York, 1980, p.119
                   Effect of Reserpine on Animals




Plummer, A.J.; Earl, A.; Schneider J.A.; Trapold, J.; Barrett, W. Annals of New York Acad.Sci.1955,59,1-21
Retrosynthesis
                DA of Methyl Vinyl Acrylate / Vinyl Acrylic acid with
                                 p-Benzoquinone




For leading discussions on secondary orbital interactions and other mechanistic aspects see
Garcia,J.I.; Mayoral,J.A.; Salvatella,L. Acc.Chem.Res 2000, 33, 658-664
Sauer, J.; Sustmann, R. Mechanistic Aspects of Diels Alder Reactions: A Critical Survey. Angew.Chem.Int.Ed.Engl.1980,
19, 779-807
          Chemoselective reduction of Ketone
Concave and Convex Faces in cis - decalin
             Concave Face


                                                            O                                     BH4
                                                            H                                 H
                                                                                      H           O
                                                  O
                                                    H                          O2 C       H
                                                 HO2C                            O
                                                        H
                                                       10                     BH4



                Convex face                      BH4
       Fig 1

                                                                                                                   H
                                                                                                                       OH
                                                                                                                       H
                                                                                                        O
                                                                                                           H
                                                                                                        HO2C
                                                                                                               H

                                                                                                               11

                                                                        BH4
                                        MM2 energy minimized structure
                                        showing electrostatic repulsion

                                                   Fig 2

  Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
                               Lactonization to 12




I) Formation of lactone indicated that hydroxy acid most likely posesses the depicted sterochemistry

II) Lactonization was a slow process due to the predominance of the more favored conformation A
in which the bulky substituents are in a pseudo-equatorial conformation



        Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
                MVP Reduction and Cycloetherification
            H                              H
                OH                             OH
                                               H                                    OH
                H                                                                                          O                   O        O
                     CH2 N2                                i                        H                           O
O                              O                                                         Br2              c       H                c
   H                              H                                     O                                H
                                                                                                        a    HO
HO2C                          MeO2C                                         H                                                  a
       H                              H
                                                                       O      H                                H
       11                             13                                     14                                            H
                                                                                                   Br     b                            b H     OH
                                                                            73 - 85 %                                          Br
                                                                                                              15a                        15b
                                                               i
                                   O H
                                               H
                                                                                i


                                    H                  O                            O
                                                   O                                H
                                                                       O
                                        12                               H                                         H
                                                                     MeO2C                     H         O         H
                                                                               H
                                                                                               O
                                                                            6                       H
                                                                                                                       H
                                                                                               O         H
                                      i) Al(O i - Pr)3 , i - PrOH                                             Br

                                                                                                         16
                                                                                                         46 %


                                                                    Scheme 4



                Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
                  Synthesis of Bromohydrin 19
                           H
                                                                      H                                      H
      H           O        H
                                       NaOMe             H        O    H                      H        O      H
       O
              H                                                                               O
                                       MeOH              O
                               H                             H                                     H
      O           H                                                                                               H
                      Br                                                   H
                                                     O                                    O            H
                                                                                                           OMe
                  16                                                                              17       83 %
                                                                      OMe


                                                                                                           NBS
                                                                                                           H2SO4, H2O



                                                                                                           OH2
                      Br                             O                                    O
                                                             O HO          H                       O
          HO                   H
                                                                            H                                     Br
           H          O        H                 H                                    H
                                                                               Br
           O                                             O                                    O
                  H                                          H                                    H
                                   H           MeO                                  MeO
          O           H
                           OMe                                   H                                     H
                  19                                         19                               18


                                                         Scheme 5


Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
              Zinc mediated Cleavage to 6
             Br                                   Br
                                                                                          Zn            Br
    HO             H                      O                H
                                                                                               O                 H
     H       O     H                      H       O        H
                            H2Cr2O7                                     Zn                     H        O        H
     O                                    O
         H                                    H                    glacial acetic acid         O
                             AcOH                                                                  H
                        H                                      H
    O        H                         O          H                                                                  H
                  OMe                                  OMe                                  O           H
                                                                                                             OMe
         19                                       20 60 %                                              21




                                                                                            Zn
                                                                                                   Br
                                      O                                                    O                H
                                                       H
                                                                                                   O         H
                                         H
                                                                                         H    H
                                      HO2C                 OH
                                              H     H                                     HO2C H                 H
                                                  OMe                                                   OMe

                                                  6     79 %                                            22




                                                       Scheme 6




Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
          Preparation of Intermediate 2
      O                                                    OH
                  H            1. CH2 N2             O           OH                                   H        O
                               2. Ac2O                           H                                             H
     H                                                                    1. HIO4
                                                                                            MeO2C
  HO2C                OH       3. OsO4, NaClO3     H                      2. CH2 N2              H
          H     H                                                                                                   OAc
              OMe                 H2O          MeO2C                OAc                      MeO2C
                                                           H  H                                       H         H
                                                            OMe                                               OMe
              6                                                                                           5
                                                           23 41%

                                                                                                               CO2 Me
                                                                                              MeO2C
                                                                                            MeO                 CHO
                                                                                              AcO
                       NH 2                                                                           5
                                           H    O
                                                                                      MeO      A
                                                H              1. PhH                               B
                           +                                                                          O        N
                  N              MeO2C                                                              N
MeO                                    H
                  H                                            2. NaBH 4, MeOH                      H                   H
                                   MeO2C             OAc
                                           H     H
                                               OMe                                                        H         E
                                                                                                    MeO
                                                                                                                            OAc
          4                                5                                                                   H      H
                                                                                                          O         OMe
                                                                                                      2        81 %

                                                     Scheme 7




 Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
      Synthesis of (±)-Methyl-O-Acetyl-Reserpate
            Cl
       Cl        Cl
             P
MeO         O
                                                        MeO                                              MeO
                 O       N
        N                                                                                                                          N
        H                        H         POCl3
                                                                            N RO      N                                N Cl
                                                                        H                     H                    H                       H
                     H       E
        MeO                                                              Cl                                                   H
                                     OAc                                     H            E                                            E
                                                                         MeO                                       MeO
                         H     H                                                                  OAc                                          OAc
                     O       OMe                                                                                                   H     H
                                                                                      H     H                                 O
                                                                                 O        OMe                                          OMe
                 2
                                                                            R = POCl2
                                                                                   24                                             25




                                                                                                        MeO
                                           MeO
                                                                                                                              N
                                                                                              NaBH 4               N
                                                        N       3 N                                            H                       H
                                                    H       H               H                 MeOH
                                                                                                                         H         E
                                                                                                               MeO
                                                                H       E                                                                  OAc
                                                      MeO                                                                     H      H
                                                                                OAc                                      O         OMe
                                                                    H H
                                                                O   OMe
                                                                27 71 %                                                  26

                                             (±)-Methyl-O-Acetyl-Reserpate


                                                                    Scheme 8

                      Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
      Synthesis of (±)-Reserpic Acid Lactone
                                                                                        OMe
MeO                                                       H                                                              H
                                                 H                                                                                 N
             N       3 N                                                     NH                                    H                   H
                                 H         H          N      3
         H       H
                                                     CO2Me                                                                X
                     H       E                                                                               MeO          Y
          MeO                                                                                                                    HN
                                     OAc
                         H     H
                     O       OMe                                                                               X = CO2Me
                                           MeO
                      27                   OAc
                                                                                                               Y = OAc
                                                       27a                                                                27b
  (±)-Methyl-O-Acetyl-Reserpate                                                                                                        OMe


                                                                                                                             1.KOH, MeOH
                                                                                                                              2. DCC, Pyridine

                                                              H
                                                                         N                                               H
                                                      H                                                                            N
                                                                                                                   H                   H
                                                                 O                            Pivalic acid
                                               MeO                       HHN                                              O
                                                                     O                        xylenes
                                                                                                             MeO
                                                                                                                              O HN


                                                                                  OMe
                                                                     29 79 %                                             28 67 %
                                                                                                                                       OMe
                                               (±)-Reserpic Acid Lactone

                                                     Scheme 9

        Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
Mechanism of Acid Induced Epimerization

           H
                                            H                            H
MeO
                           MeO
                                                             MeO                   H
               3 N
      N                                          3 N                           N
      H H                              N
                                       H H                          N
                                                                    H 3

      30                                    31                      32




                     MeO                                            H
                                       3 N                  MeO
                                 N                                       3 N
                                 H H                               N
                                                       -H          H H

                                       34                          33

                                  Scheme 10
                      Preparation of (-)-Reserpine
           H
                     N                                            MeO
       H                                                                         3 N
                                                                           N
            O                                                              H H              H
                                     1. NaOMe, MeOH,
MeO                  H                                                                              O
                      HN
                O                                                                H
                                     2. 3,4,5 - (MeO)3C 6H2COCl            MeO                                  OMe
                                                                                                O
                                          Pyridine                                   H     H
                                                                                 O       OMe                    OMe
                           OMe                                                                           OMe
                29
                                                                        (±) - 1 (±) Reserpine            44 %
(±)-Reserpic Acid Lactone
                                                                                         1. MeOH / CHCl3 (3 / 1)
                                                                                           (+) - CSA
                                                                                         2. Resolution
                                                                                         3. 1N NaOH


                                                                  MeO
                                                                                 3 N
                                                                          N
                                                                          H H              H
                                                                                                    O
                                                                                 H
                                                                          MeO                                   OMe
                                                                                                O
                                                                                     H     H
                                                                                 O       OMe                    OMe
                                                                                                         OMe
                                                                           1 ( - ) - Reserpine


                                                 Scheme 11

      Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J.; Kierstead, R.W. Tetrahedron 1958, 2,1
Asymmetric Diels-Alder Reaction with
          Benzoquinone




      White, J.D.; Choi,Younggi Org.Lett. 2000, 15, 2373-2376
                    Conclusions

1.   The foremost example in synthesis that demonstrates the
     use of substrate stereocontrolled reactions

2.   Use of Lactone formation as an remarkable way of
     epimerizing the C-3 stereocenter

								
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