Subtleties in asymmetric catalyst structure: the resolution of a 6-phospha-2,4,8-trioxa-adamantane and its applications in asymmetric hydrogenation catalysis

Abstract

An efficient, classical resolution of the versatile P-ligand intermediate 6-phospha-2,4,8-trioxa-adamantane (CgPH) is described and the rhodium complex of the optically pure secondary phosphine β-CgPH is an active and moderately selective asymmetric hydrogenation catalyst.

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The racemic phospha-adamantane cage (denoted CgPH) was first reported in 1961¹ as the product of the high-yielding hydrophosphination–condensation reaction shown in eqn (1). CgPH is readily available in 100 g quantities and is an atypical secondary phosphine in that it is air stable.² The unusual stereoelectronic environment that the cage confers on the P atom in CgP-containing ligands has led to a surge of interest in this class of ligands in recent years.^2–11

The compound CgPH has been shown to be a useful intermediate for tertiary monophosphines and diphosphines featuring the CgP group.^2–5 CgP-containing ligands have found applications in many catalyses, notably alkene carbonylation⁶ and hydroformylation,^7,8 C–C coupling,^3,5,9 C–N coupling¹⁰ and hydrogenation.¹¹ CgPH has C₁-symmetry and thus exists in enantiomeric forms; the α- and β-enantiomers are structurally related to each other by interchanging the two O atoms, which are coloured red in Fig. 1, with the two CH₂ groups.

Fig. 1 Enantiomeric forms of the CgP unit.

In view of the rigid, diamondoid shape of the CgP unit and the similarity in size of the O and CH₂ groups, it was concluded that any enantiodiscrimination by CgP-containing species would have to be subtle. Nevertheless, we show here that classical resolution of CgPH is readily achieved and moreover that optically pure CgPH and ligands derived from it perform surprisingly well in asymmetric hydrogenation catalysis.

The resolution of CgPH was achieved via its phosphinic acid by the route shown in Scheme 1.¹² The ³¹P NMR spectrum of the mixture of diastereomeric quininium salts [CgPO₂][QH] in CD₂Cl₂ showed two, clearly resolved singlets, presumably because of ion-pairing in solution. After seven, high-recovery crystallisations from toluene, there was only one diastereoisomer of the salt detected by ³¹P NMR spectroscopy. The optical purity of the resolved CgPH was determined as follows. Treatment of [PdCl₂(NCPh)₂] with racemic CgPH gave a 1 : 1 mixture of the previously reported² diastereomeric complexes, rac-1 and meso-1 which gave two, well-separated ³¹P NMR signals at δ 3.53 and 3.20 ppm. With the resolved CgPH, only one signal (at δ 3.53) was observed and the er was calculated to be over 100 : 1. The overall yield of optically pure CgPH after the five-step procedure (Scheme 1) was ca. 10% and its [α]²⁹⁵_D in CHCl₃ was +42.2.¹³

Scheme 1 Reagents and conditions (yields): (i) H₂O₂ in MeOH (97%); (ii) quinine in boiling toluene (98%); (iii) 7× recrystallisations from boiling toluene (81% total recovery); (iv) extraction of CH₂Cl₂ solution with 2 M aqueous NaOH and then acidification with 12 M HCl (72%); (v) LiAlH₄ in Et₂O (17%).

Crystal structures for the resolved phosphinic acid and secondary phosphine were obtained (Fig. 2) which showed that the β-enantiomer had been separated.

Fig. 2 Thermal ellipsoid (50% probability) plots of structures of (a) β-CgPOOH and (b) β-CgPH, omitting all carbon-bound hydrogen atoms. Selected geometrical data: bond lengths [Å] and angles [°] for (a) P1–C2 1.8263(16), P1–C9 1.8201(15), P1–O4 1.4942(11), P1–O5 1.5483(11), C2–P1–C9 97.74(7), O4–P1–O5 114.83(6). (b) P1–C2 1.871(4), P1–C9 1.877(4), P1–H21 1.32(3), C2–P1–C9 98.5(16).

Secondary phosphines are rarely used as ligands for catalysis,¹⁴ understandably because the P–H bond is normally reactive and their complexes are susceptible to formation of μ-PR₂ oligomers. Addition of 2 equiv. of β-CgPH to [Rh(cod)₂]BF₄ gave [Rh(cod)(β-CgPH)₂]BF₄ (2) which was tested for the asymmetric hydrogenation of methyl acetamidocinnamate (MAC) and methyl acetamidoacrylate (MAA) and the results are given in Table 1, entry 1. The observed enantiomeric excesses appear modest especially when compared to recently reported monodentate P-ligands¹⁵ but we would argue from the following reasoning that the enantioselectivities obtained with the β-CgPH–Rh catalyst are still impressive.

Table 1 Asymmetric hydrogenation catalysis results^a

Entry	Ligand	MAA	MAC
a Reactions carried out in CH2Cl2 with Rh : olefin = 1 : 100 at 5 bar H2 and 20 °C for 1 h. All conversions were 100%. Enantioselectivities were determined by chiral GC analysis.
1	2	54 (S)	60 (S)
2	3a	90 (R)	58 (R)
3	3b	84 (S)	90 (S)

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Rationalising the enantioselectivity of an asymmetric hydrogenation catalyst has been a challenge ever since Knowles’ original discovery.¹⁶ Enantioselectivity is known to be influenced¹⁷ by electronic effects but discussions of catalytic asymmetric induction normally centre on the chiral shape of the metal–ligand moiety leading to discrimination between the diastereomeric intermediates. Using steric models, the sense of asymmetric induction can be reliably predicted¹⁸ and the success of ligands such as BINAP and DuPhos has been ascribed to the chiral array of P-substituents blocking diagonal quadrants.¹⁹ However, as the space filling model given in Fig. 3(a) shows, the diamondoid structure of CgPH would be expected to make the chiral space created by the enantiomers of CgPH ligands very similar. Fig 3(b) shows a schematic of a CgPH–Rh fragment and while the Me groups on the carbons α to the P (marked in blue) are sterically demanding, they are almost identically so on both sides of the P atom. The main asymmetry lies in the groups β to the P being O or CH₂ which are normally regarded as isosteric.²⁰ Therefore a rationale of the enantioselectivity of β-CgPH–Rh catalysts based on steric arguments has to be very delicate.

Fig. 3 (a) Space filling model of β-CgPH (from the crystal structure shown in Fig. 2a); (b) β-CgPH coordinated to Rh.

To explore the influence the β-CgP group may have on a diphosphine, the diastereomeric ligands L_a and L_b, featuring R,R- and S,S-3,5-dimethylphospholane moieties, respectively, were prepared by the routes shown in Scheme 2. The ³¹P NMR data for L_a and L_b are distinctive and the spectra obtained are consistent with the optical purity of the β-CgPH being over 100 : 1 er. Treatment of [Rh(cod)₂]BF₄ (cod = 1,5-cyclooctadiene) with L_a and L_b gave the corresponding chelates [Rh(L_a)(cod)]BF₄ (3a) and [Rh(L_b)(cod)]BF₄ (3b) which have been fully characterised. The crystal structure of 3b (Fig. 4) confirms the absolute stereochemistry of the CgP and phospholane units and also shows the presence of the third chiral element: the λ-conformation of the five-membered chelate ring.²¹

Scheme 2 Reagents and conditions: (i) vinyl diethyl phosphonate; (ii) LiAlH₄; (iii) 2 equiv. ⁿBuLi followed by the cyclic sulfate of 2R,5R-2,5-pentanediol; (iv) 2 equiv. ⁿBuLi followed by the cyclic sulfate of 2S,5S-2,5-pentanediol.

Fig. 4 Thermal ellipsoid (50% probability) plot of the [Rh(L_b)(cod)]⁺ cation in 3b, omitting hydrogen atoms and the BF₄⁻ counter-anion. Selected geometrical data: bond lengths [Å] Rh1–P1 2.2989(11), Rh1–P2 2.2705(13), P1–C2 1.882(5), P1–C9 1.876(4), P1–C11 1.839(5), P2–C12 1.823(5), P2–C14 1.873(5), P2–C17 1.854(5), C11–C12 1.530(7); angles [°] P1–Rh1–P2 83.01(4), C2–P1–C9 93.9(2), C14–P2–C17 95.1(2); torsion angle [°] P1–C11–C12–P2 −47.9(4).

The enantioselectivities obtained with 3a and 3b (entries 2 and 3, Table 1) show, as expected, the effects of matching and mismatching of the chiral elements, with the matched isomer yielding 90% ee. The absolute stereochemistry of the hydrogenated products is controlled by the phospholane moiety.²² Strikingly, the matched catalyst diastereomer is different for MAA and MAC which implies that the substrate influences the intimate structure of the catalyst. In other words, there is a matching of the substrates with the diastereoisomeric catalysts. Recently an interesting example of substrate–diastereoisomer matching was reported for a palladium–carbene catalysed asymmetric arylation.²³

The substrate might exert its influence on the catalyst by influencing the ratio of the geometric isomers of the Rh–diphos intermediates (as exemplified in eqn (2) for MAA binding to Rh(I)) or the substrate may dictate the shape of the catalyst, i.e. an allosteric effect. It has been shown²⁴ that the λ/δ conformation adopted by the five-membered ring in [Rh(chiraphos)(diene)]BF₄ in the solid state depends on the ligated diene. Moreover we have previously reported evidence supporting the notion that MAC and MAA influence the λ/δ conformational ratio.²⁵ Computational studies are in progress to determine the source and generality of this substrate effect in asymmetric hydrogenation catalysis.

In conclusion, the enantiomers of 6-phospha-2,4,8-trioxa-adamantane (CgPH), which are ostensibly closely similar, have been readily resolved and give catalysts which yield surprisingly good enantioselectivities in asymmetric hydrogenation. This opens up the opportunity for the application of ligands derived from optically pure CgPH in asymmetric versions of the many catalyses in which monodentate and bidentate CgP-containing ligands excel.^6–10 An example of substrate-matching with diastereomeric catalysts has been uncovered which illustrates the subtleties in asymmetric catalyst design.

We thank the EPSRC, the Royal Society, COST action CM0802 “PhoSciNet” and the CCDC for supporting this work and Johnson-Matthey for a loan of precious metal compounds.

Notes and references

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Footnotes

† This article is part of a ChemComm ‘Catalysis in Organic Synthesis’ web-theme issue showcasing high quality research in organic chemistry. Please see our website (http://www.rsc.org/chemcomm/organicwebtheme 2009) to access the other papers in this issue.

‡ Electronic supplementary information (ESI) available: Full experimental details for the synthesis and characterisation of the ligands and complexes, conditions used for the catalysis and X-ray structural data. CCDC 743916–743918. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/b916359j

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