Carreira DOLEFIN Ligands

Aldrich ChemFiles 2006, 6.10, 4.

Aldrich ChemFiles 2006, 6.10, 4.

For the past years, the Carreira group has been employing chiral [2.2.2]bicyclooctadienes derived from (R)- or (S)-carvone in Ir(I)-catalyzed kinetic resolution of allylic carbonates1 and Rh(I)-catalyzed conjugate addition reactions of boronic acids.2 More recently, Carreira has developed the ligand 1 (Figure 1), which exhibited substantially improved enantioselectivity in the 1,4-addition of arylboronic acids to α,β-unsaturated carbonyls.3 This new ligand facilitates selective preparations of diarylmethine stereogenic centers, even when there is little differentiation between the two aryl groups. Heretofore, the stereoselective synthesis of this motif had been a challenge, with rather limited methods for its preparation.4

Figure 1

In one report, tert-butyl cinnamate was converted to (S)-tert-butyl 3-(4-methoxyphenyl)-3-phenylpropanoate in the presence of the Rh(I)-1 complex in excellent yield and selectivity. Furthermore, from a single enantiomer of the ligand, access to both enantiomers of a product can be achieved simply by switching the aryl acceptor and donor. In this manner, the (R)-isomer was prepared from phenylboronic acid and tert-butyl 4-methoxycinnamate (Scheme 4). Similarly, other 3,3-diaryl- and 3-aryl-3-heteroarylpropanoates were prepared in good to excellent yields and with consistently high enantioselectivity (89–94% ee).

Scheme 4

The preparation of chiral 3,3-diarylpropanals has recently been achieved by other researchers via an amine-catalyzed addition of aromatic nucleophiles to 3-substituted acrolein derivatives.5 Unfortunately, this method does not work well with electron-poor aromatics. However, the Rh(I)-1- catalyzed conjugate addition offers a general route independent of the electronic nature of the aryl groups. The addition of 4-fluorophenylboronic acid to cinnamaldehyde provided the 1,4-adduct in 90% yield and 93% ee (Scheme 5). Again, other substrates maintained high enantioselectivity in the conjugate addition (89–93% ee).6

Scheme 5

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  1. Fischer, C. et al. J. Am. Chem. Soc. 2004, 126, 1628.
  2. Defieber, C. et al. Org. Lett. 2004, 6, 3873.
  3. Paquin, J.-F. et al. Org. Lett. 2005, 7, 3821.
  4. (a) Mauleón, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195.
    (b) Bolshan, Y. et al. Org. Lett. 2004, 6, 111.
    (c) Duursma, A. et al. Org. Lett. 2003, 5, 3111.
    (d) Lautens, M.; Rovis, T. J. Org. Chem. 1997, 62, 5246.
  5. Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894.
  6. Paquin, J.-F. et al. J. Am. Chem. Soc. 2005, 127, 10850.

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