Highly Efficient Privileged Ligands

Introduction

In collaboration with DSM, we are pleased to offer a range of MonoPhos™ ligands to the research market. Feringa and co-workers have invented a diverse array of these 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

Advantages of the MonoPhos™ ligands:

  • Superior enantiocontrol in numerous transformations
  • High activities at low catalyst loadings
  • Hydrogenations under low-pressure conditions
  • Applied in tandem reactions to yield valuable chiral organics
  • First-to-market exclusivity for selected portfolio ligands

Representative Applications:

The reactivity profile of these innovative, chiral ligands is covered below and highlights the impressive breadth of valuable transformations mediated by the various portfolio products. In many documented cases, specific ligands have displayed unprecedented selectivities in reactions that form, for instance, chiral quaternary centers that cannot be readily generated via alternative methodologies.

Asymmetric 1,4-additions of Organometallic Reagents

Feringa and co-workers exploited the high activity of the (S,R,R)-phosphoramidite ligand shown in the figure below 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. The Feringa group then completed a formal annulation process through a palladium-catalyzed Wacker oxidation, followed by an aldol cyclization. The high (96%) enantioselectivity of this methodology is completely retained throughout this synthetic strategy.

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.3a Impressively, the (S)-N-benzyl-N-methyl-MonoPhos™ derivative shown below has been utilized in highly selective hydrogenations of (E)-N-acylated dehydro-β-amino acid esters, affording the corresponding enantiopure β-amino acid derivatives.3 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.

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 below clearly shows the power of this methodology, wherein cinnamyl acetate was converted to the allylic benzyl amine in excellent yield and enantiopurity. 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.

As a complement to the Hartwig chemistry, Helmchen and co-workers have performed highly enantioselective iridium-catalyzed intra- and intermolecular aminations with N-nucleophiles.4a Impressively, dicarbonate 3 reacts smoothly under the reaction conditions to afford the pyrrolidine products in moderate yield but with excellent selectivity.

Asymmetric Hydrovinylation – An Efficient Route to All-Carbon Quaternary Centers

These highly practical enantioselective reactions have been accomplished by the RajanBabu research group at Ohio State University.5 Generation of all-carbon quaternary centers is extremely attractive to drug discovery groups, as evidenced in the example below. Note that the asymmetric hydrovinylation of substituted vinylarenes offers an attractive, general method for creating an asymmetric center. The low ligand loadings, excellent yields, and superb enantioselectivities ensure that this methodology can be utilized in the production of chiral building blocks and directly applied to the synthesis of natural products such as Lyngbyatoxin A.6

Zhang and RajanBabu have also extended this methodology to the asymmetric hydrovinylation of 1,3-dienes. 1,3-dienes were found to be less reactive than the vinylarene derivatives, thus higher temperatures were applied to drive high conversions. Under these conditions, the hydrovinylation of conjugated 1,3-diene 5 with the (S,R,R)-phosphoramidite ligand gave exquisite regio- and enantioselectivities.7

Asymmetric Allylic Substitution Reactions

The (R)-MonoPhos™ ligand has been effectively utilized in the enantioselective, iridium-catalyzed allylic substitution reactions.8 Simply mixing an iridium precatalyst and the ligand in THF in the presence of LiCl creates a highly active catalyst, which generates a chiral C-C bond in good to excellent enantioselectivities. The high product yields and short reaction times further accentuate this methodology for application to the expeditious construction of chiral building blocks.

Loading
1.
Feringa BL. 2000. Phosphoramidites:  Marvellous Ligands in Catalytic Asymmetric Conjugate Addition. Acc. Chem. Res.. 33(6):346-353. http://dx.doi.org/10.1021/ar990084k
2.
Feringa BL, Pineschi M, Arnold LA, Imbos R, de Vries AHM. 1997. Highly Enantioselective Catalytic Conjugate Addition and Tandem Conjugate Addition?Aldol Reactions of Organozinc Reagents. Angew. Chem. Int. Ed. Engl.. 36(23):2620-2623. http://dx.doi.org/10.1002/anie.199726201
3.
Martina SL, Minnaard AJ, Hessen B, Feringa BL. 2005. Highly enantioselective rhodium-catalyzed conjugate addition of arylboronic acids to enones at room temperature. Tetrahedron Letters. 46(42):7159-7163. http://dx.doi.org/10.1016/j.tetlet.2005.08.095
4.
Malda H, van Zijl AW, Arnold LA, Feringa BL. 2001. Enantioselective Copper-Catalyzed Allylic Alkylation with Dialkylzincs Using Phosphoramidite Ligands. Org. Lett.. 3(8):1169-1171. http://dx.doi.org/10.1021/ol0156289
5.
Alexakis A, Albrow V, Biswas K, d'Augustin M, Prieto O, Woodward S. 2005. Highly enantioselective copper(i)-phosphoramidite-catalysed additions of organoaluminium reagents to enones. Chem. Commun..(22):2843. http://dx.doi.org/10.1039/b503074a
6.
Streiff S, Welter C, Schelwies M, Lipowsky G, Miller N, Helmchen G. 2005. Carbocycles via enantioselective inter- and intramolecular iridium-catalysed allylic alkylations. Chem. Commun..(23):2957. http://dx.doi.org/10.1039/b503713a
7.
Bertozzi F, Crotti P, Macchia F, Pineschi M, Arnold A, Feringa BL. 2000. A New Catalytic and Enantioselective Desymmetrization of Symmetrical Methylidene Cycloalkene Oxides. Org. Lett.. 2(7):933-936. http://dx.doi.org/10.1021/ol005584o
8.
Ohmura T, Hartwig JF. 2002. Regio- and Enantioselective Allylic Amination of Achiral Allylic Esters Catalyzed by an Iridium?Phosphoramidite Complex. J. Am. Chem. Soc.. 124(51):15164-15165. http://dx.doi.org/10.1021/ja028614m
9.
Peña D, Minnaard AJ, de Vries JG, Feringa BL. 2002. Highly Enantioselective Rhodium-Catalyzed Hydrogenation of ?-Dehydroamino Acid Derivatives Using Monodentate Phosphoramidites. J. Am. Chem. Soc.. 124(49):14552-14553. http://dx.doi.org/10.1021/ja028235t
10.
Van Den Berg M. 2003. Monodentate Phosphoramidites: A Breakthrough in Rhodium-Catalysed Asymmetric Hydrogenation of Olefins. Advanced Synthesis & Catalysis. 345(12):308-323. http://dx.doi.org/10.1002/adsc.200390026
11.
Weihofen R, Dahnz A, Tverskoy O, Helmchen G. 2005. Highly enantioselective iridium-catalysed allylic aminations with anionic N-nucleophiles. Chem. Commun..(28):3541. http://dx.doi.org/10.1039/b505197e
12.
Streiff S, Welter C, Schelwies M, Lipowsky G, Miller N, Helmchen G. 2005. Carbocycles via enantioselective inter- and intramolecular iridium-catalysed allylic alkylations. Chem. Commun..(23):2957. http://dx.doi.org/10.1039/b503713a
13.
Zhang A, RajanBabu TV. 2006. All-Carbon Quaternary Centers via Catalytic Asymmetric Hydrovinylation. New Approaches to the Exocyclic Side Chain Stereochemistry Problem. J. Am. Chem. Soc.. 128(17):5620-5621. http://dx.doi.org/10.1021/ja060999b
14.
Edwards DJ, Gerwick WH. 2004. Lyngbyatoxin Biosynthesis:  Sequence of Biosynthetic Gene Cluster and Identification of a Novel Aromatic Prenyltransferase. J. Am. Chem. Soc.. 126(37):11432-11433. http://dx.doi.org/10.1021/ja047876g
15.
Zhang A, RajanBabu TV. 2006. Hydrovinylation of 1,3-Dienes:  A New Protocol, an Asymmetric Variation, and a Potential Solution to the Exocyclic Side Chain Stereochemistry Problem. J. Am. Chem. Soc.. 128(1):54-55. http://dx.doi.org/10.1021/ja0561338
16.
Bartels B, Helmchen G. 1999. Ir-catalysed allylic substitution: mechanistic aspects and asymmetric synthesis with phosphorus amidites as ligands. Chem. Commun..(8):741-742. http://dx.doi.org/10.1039/a900864k