DSM MonoPhos™ Family

By: William Sommer and Daniel Weibel, Aldrich ChemFiles 2008, 8.2, 51.

Aldrich ChemFiles 2008, 8.2, 51.

Feringa and co-workers have developed a diverse array of chiral, monodentate phosphoramidites based on the privileged BINOL platform.1 The MonoPhos™ family has exhibited high levels of enantiocontrol in synthetic transformations ranging from metal-catalyzed asymmetric 1,4‑additions of organometallic reagents to allylic alkylations to desymmetrization of meso-cycloalkene oxides.2

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Asymmetric 1,4‑Additions of Organometallic Reagents

Feringa and co-workers showcases the high activity of the (S,R,R)-phosphoramidite ligand in copper-catalyzed 1,4‑additions of organozinc reagents to cyclohexenones.1 Interestingly, the in situ formed zinc species originating from the cyclohexenone is readily trapped via a palladium-catalyzed allylation. It was followed by a formal annulation process through a palladium-catalyzed Wacker oxidation, and finally by an aldol cyclization. The high (96%) enantioselectivity of this methodology is completely retained throughout this synthetic strategy (Scheme 1).

Scheme 1

Scheme 1

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Highly Asymmetric Rhodium-Catalyzed Hydrogenation

Feringa has also gone to great lengths to develop structurally varied MonoPhos ligands in industrially useful transformations such as asymmetric hydrogenation.3 Impressively, the (S)-N-benzyl-N-methyl- MonoPhos derivative shown has been utilized in highly selective hydrogenations of (E)-N-acylated dehydro-β-amino acid esters, affording the corresponding enantiopure β-amino acid derivatives (Scheme 2).3a The authors found that this ligand, after being screened versus related chiral phosphoramidites, afforded the highest enantiocontrol in hydrogenations, albeit at slightly slower reaction times. 

Scheme 2

Scheme 2

The Feringa research group has broadened the substrate scope of the asymmetric hydrogenation reaction by generating another chiral center on the amine moiety of the phosphoramidite ligand. Amazingly, this fine ligand tuning produces a very active and productive catalyst, which efficiently hydrogenates a wide range of acetamido derivatives in less time than the corresponding Me-DuPhos analogs.3a Note that the chiral (S,R)-phosphoramidite ligand is the only ligand known to afford greater than 90% enantioselectivies for the substrate shown (Scheme 3)


Scheme 3

Scheme 3

Recently, Feringa's R&D group prepared additional structurally varied phosphoramidite ligands for rhodium-catalyzed asymmetric hydrogenations. The aptly named PipPhos and MorfPhos ligands contain piperidinyl and morpholinyl amine subunits, respectively, and are examples of easily synthesized chiral ligands for highly effective enantioselective transformations. Under mild reaction conditions including low H2 pressure, this catalyst system yields unprecedented enantioselectivities for several substrates such as dimethyl itaconate and α-dehydroamino ester derivatives (Scheme 4).4


Scheme 4

Scheme 4

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Asymmetric Regioselective Allylic Aminations

Hartwig and co-workers have succeeded in developing highly selective iridium catalysts with the (R,R,R)-phosphoramidite L.2g The allylic aminations of a wide variety of achiral allylic esters proceeded with total conversion and superb regioselectivity in many cases. The reaction clearly shows the power of this methodology; wherein, cinnamyl acetate was converted to the allylic benzyl amine in excellent yield and enantiopurity (Scheme 5). The authors mentioned that these valuable amination reactions were mediated by air-stable Ir complexes at ambient temperatures, which should lead to wide acceptance of this catalyst in bench-top organic synthesis.

Scheme 5

Scheme 5

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Materials

     

References

  1. (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Minnaard, A. J. et al. Acc. Chem. Res. 2007, 40, 1267.
  2. (a) Feringa, B. L. et al. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620. (b) Martina, S. L. X. et al. Tetrahedron Lett. 2005, 46, 7159. (c) Malda, H.et al. Org. Lett. 2001, 3, 1169. (d) Alexakis, A. et al. Chem. Commun. 2005, 2843. (e) Streiff, S. et al. Chem. Commun. 2005, 2957. (f) Bertozzi, F. et al. Org. Lett. 2000, 2, 933. (g) Hartwig, J. F. et al. J. Am. Chem. Soc. 2002, 124, 15164.
  3. (a) Pena, D. et al. J. Am. Chem. Soc. 2002, 124, 14552. (b) Van den Berg, M. et al. Adv. Synth. Catal. 2003, 345, 308.
  4. Bernsmann, H. et al. J. Org. Chem. 2005, 70, 943.

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