0035

							0035
    THE “BIP METHOD” FOR ASSIGNMENT OF THE ABSOLUTE
   CONFIGURATION OF β-AMINO ACIDS: ICD IN THE BIPHENYL
               CORE OF BIP-β-XAA* DIPEPTIDES
   Laurence Dutot1, Anne Gaucher1, Karen Wright1, Michel Wakselman1, Jean
     Paul Mazaleyrat1, Cristina Peggion2, Fernando Formaggio2 and Claudio
                                    Toniolo2
  1
   ILV, UMR CNRS 8180, University of Versailles, F-78035, Versailles, France and 2Department of
                   Chemistry, University of Padova, I-35131, Padova, Italy
Introduction
The Cα-tetrasubstituted α-amino acid residue Bip possesses non isolable (R) and (S) conformationally labile
atropoisomers [1]. We have previously reported that in the linear dipeptides Boc-Bip-α-Xaa*-OMe with α-Xaa* =
L-Ala, L-Val, L-Leu, L-Phe, L-(αMe)Val and L-(αMe)Leu residues (Fig. 1), the onset of an equilibrium between
two diastereoisomers could be observed by CD and 1H NMR [2]. The phenomenon of induced circular dichroism
(ICD) represents the basis for the "Bip method", an easy and fast configurational assignment of chiral α-amino
acids. We have now investigated the Boc-Bip-β-Xaa*-OMe dipeptide series with β-Xaa* = L-β3-HAla [3], L-β3-
HVal, L-β3-HLeu, L-β3-HPro and the cyclic β2,3-amino acids (1S,2S)/(1R,2R)-ACHC and (1S,2S)/(1R,2R)-ACPC
(Fig. 1).


                               (S)                                             (R)

                                                    14 kcal/mol




                    Boc-HN           CO-Xaa*-OMe                      Boc-HN         CO-Xaa*-OMe

                                               Boc-Bip-Xaa*-OMe



              R     H       L-Ala (R= Me)
      Xaa* =                L-Val (R= iPr)                                               (1S,2S)-ACHC
            -HN      CO-    L-Leu (R= iBu)
                                                                      -HN        CO-

                           R    H        L-3-HAla (R= Me)
                                         L-3-HVal (R= iPr)                              (1S,2S)-ACPC
                                            3
                        -HN          CO- L- -HLeu (R= iBu)                        CO-
                                                                       -HN


  Fig. 1. Chemical structures and diastereoisomer equilibrium of the Boc-Bip-Xaa*-OMe dipeptides
                                           discussed in this work.
Result and Discussion
The terminally protected dipeptides were prepared in solution by coupling Boc-Bip-OH with the β-amino ester
hydrochlorides HCl.β-Xaa*-OMe. The EDC/HOAt activation method was generally used for coupling at the
sterically demanding C-terminus of Bip. In the same manner as previously observed [2], two sets of signals,
corresponding to the presence of two diastereoisomers with unequal populations and exchanging slowly on the
NMR time scale, were usually seen at low temperature. Significantly high d.r. values (ranging from 60:40 to
74:26) were observed at 233 K in CD3OD for all combinations of Bip with both β3- and cyclic β2,3-amino acids.
 Fig. 2. Comparative CD spectra (200-300 nm range) of the terminally protected Boc-Bip-Xaa*-OMe
                                      dipeptides in MeOH solution.
Our analysis in MeOH solution allowed us to conclude that the ICD resulting from the induced axial chirality in
the biphenyl core of the Bip residue gives clear information on the β-Xaa* configuration, for both β3- and cyclic
β2,3-amino acids (Fig. 2). In all dipeptides, a P torsion of the biphenyl axial bond of Bip is preferentially induced
by the L-β3-Xaa* as well as by the cyclic (1S,2S)-β2,3-Xaa* C-terminal residues. In conclusion, a substantial
central-to-axial induction of chirality from the C-terminal β3-Xaa*-OMe (β3-HAla, β3-HVal, β3-HLeu, β3-HPro) or
cyclic β2,3-Xaa*-OMe (ACHC, ACPC) amino ester residues to the Nα-Boc protected, pro-atropoisomeric, Cα-
tetrasubstituted α-amino acid Bip has been unraveled in simple linear dipeptides, thus demonstrating that the Bip
residue may be used as a convenient CD probe for the determination of the absolute configuration not only of α-
amino acids, as previously reported [2], but of β-amino acids as well.
References
1.   Formaggio F., Crisma M., Toniolo C., Tchertanov L., Guilhem J., Mazaleyrat J. P., Gaucher, A. and M. Wakselman,
     Tetrahedron, 56 (2000) 8721.
2.   Mazaleyrat J.-P., Wright K., Gaucher A., Toulemonde N., Dutot L., Wakselman M., Broxterman Q.B., Kaptein B., Oancea
     S., Peggion C., Crisma M., Formaggio F. and C. Toniolo, Chem. Eur. J., 11 (2005) 6921.
3.   Dutot L., Gaucher, A. Wright K., Wakselman, M. Mazaleyrat, J.-P., Oancea S., Peggion C., Formaggio F. and C. Toniolo,
     Tetrahedron: Asymmetry, 17 (2006) 363.