Highly enantioselective hydrogenation of α-aryl-β-substituted acrylic acids catalyzed by Ir-SpinPHOX

Abstract

The enantioselective hydrogenation of a series of challenging substrates, α-aryl-β-substituted acrylic acids, was realized with high efficiency and enantioselectivity (up to 96%) under the catalysis of Ir(I) complex of Spiro-based P,N ligand, SpinPHOX.

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Enantiopure α-arylpropanic acid and their derivatives are key intermediates for the synthesis of various biologically important compounds.¹ The development of a straightforward approach to their direct access represents one of the most challenging issues in terms of synthetic chemistry, in which asymmetric hydrogenation of the corresponding prochiral α-arylacrylic acid derivatives has proven to be the most promising.² In the past decades, transition metal catalyzed asymmetric hydrogenation of α,β-unsaturated carbonyl compounds has been very successful.^3–5 However, asymmetric hydrogenation of α-aryl-β-substituted acrylic acids with high efficiency remains unsatisfactory. On the other hand, the asymmetric hydrogenation of unsaturated carboxylic acids using chiral Ir catalysts has recently received significant attention. For example, the Ir–PHOX or Ir–SIPHOX complexes (Scheme 1) have been employed in the asymmetric hydrogenation of a variety of α,β-unsaturated acids including 2-phenylacrylic acid⁶ or α-alkyl-β-aryl/alkyl acrylic acids,⁷ respectively, affording the corresponding optically active acids in good yields with moderate to excellent ees. Despite of the facts mentioned above, the catalytic asymmetric hydrogenation of α-aryl-β-substituted acrylic acids 1, the most direct approach to a key chiral intermediate for the synthesis of potential antidiabetic drug PSN-GK1 (in phase I clinic),⁸ still remains a challenging theme (Scheme 1). In the present communication, we report our preliminary results on the use of Ir(I) complexes of a novel class of spiro[4,4]-1,6-nonadiene-based phosphine–oxazoline ligands (SpinPHOX, 2)⁹ in the catalytic asymmetric hydrogenation of a variety of α-aryl-β-substitued acrylic acids (1), leading to the production of a series of biologically interesting carboxylic acids with excellent yields and up to 96% enantioselectivity.

Scheme 1 Representative P,N chiral ligands for Ir(I)-catalyzed hydrogenation of α,β-unsaturated carboxylic acids.

The trisubstituted α,β-unsaturated carboxylic acid, (E)-2-phenyl-3-(tetrahydro-2H-pyran-4-yl) acrylic acid (1a), was initially taken as the model substrate in order to optimize the hydrogenation reaction conditions. The iridium complexes of (R,S)-2a and (S,S)-2a were employed as the catalyst (1 mol%).¹⁰ After screening of various reaction conditions (see Table S1 in electronic supplementary information, ESI‡) including the effects of solvent, temperature, and hydrogen pressure, the hydrogenation of 1a in methanol at 50 °C under 30 atm of H₂ turned out to be optimal. Considering the poor solubility of the substrate in the reaction medium and the potential impact of a carboxylate group on the catalysis, we then examined the effect of base additives on the reaction rate and enantioselectivity of the catalysis. Notably, the addition of 1 equiv. of NEt₃^7,11 (see Table S2 in ESI‡) gave the best result in terms of both conversion of the substrate and enantiomeric excess of the product. In the presence of 1 mol% of Ir(I)/(R,S)-2a, the hydrogenation of 1a proceeded smoothly with 92% conversion in 20 h, affording (–)-2-phenyl-3-(tetrahydro-2H-pyran-4-yl) propanoic acid (3a) with 93% ee (Table 1, entry 1). In order for comparison, Pfaltz’s Ir/PHOX (Ar = Ph, R = iPr) catalyst was also employed in the hydrogenation of 1a, 31% conv. of substrate and 32% ee of the product were obtained. It should be noted in the hydrogenation of the (Z)-isomer of 1a in the presence of (R,S)-2h under identical reaction conditions, the conversion of substrate is negligible.

Table 1 Substituent effect of ligands (2a–h) on Ir-catalyzed asymmetric hydrogenation of (E)-2-phenyl-3-(tetrahydro-2H-pyran-4-yl) acrylic acid (1a)^a

Entry	Ligand	Conv. (%)^b	Ee (%)^c
a Reaction conditions: 0.1 mmol scale of 1a with [1a] = 0.1 mol L^−1 in MeOH, PH2 = 30 atm, s/c = 100, T = 50 °C. b Determined by ^1H NMR. c Determined by HPLC analysis on a Chiralcel AD-H column after esterification with diazomethane.
1	(R,S)-2a	92	93 (–)
2	(S,S)-2a	> 99	69 (+)
3	(R,S)-2b	56	84 (–)
4	(R,S)-2c	59	58 (–)
5	(R,S)-2d	85	92 (–)
6	(R,S)-2e	75	92 (–)
7	(R,S)-2f	> 99	94 (–)
8	(R,S)-2g	76	83 (–)
9	(R,S)-2h	> 99	96 (–)

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The chirality at the spiro backbone of ligand 2 was found to have a significant impact on the asymmetric induction of the reaction. The combination of a R configuration in the spiro backbone and an S configuration in the oxazoline component was disclosed to be a matched case as in Ir(I)/(R,S)-2a, whereas the Ir(I) complex of the corresponding diastereomeric ligand (S,S)-2a gave lower enantioselectivity with opposite asymmetric induction, although a complete conversion of 1a was observed in the latter (entry 2 vs. 1 in Table 1). Therefore, the sign of asymmetric induction in the hydrogenation is predominately determined by the chirality of the spiro backbone. The examination of the substituent effect of the oxazoline moiety in ligand (R,S)-2a–e revealed that (R,S)-2a bearing a phenyl group was the best in terms of both reactivity and enantioselectivity (entry 1 vs. entries 3–6 in Table 1). To further improve the catalytic performance of the reaction, three new ligands (R,S)-2f–h bearing different aryl groups at the P atom were synthesized and employed in the hydrogenation of 1a (entries 7–9). Gratifyingly, the catalyst composed of ligand (R,S)-2h with two o-tolyl groups at P-atom showed remarkable reactivity (>99% conv.) and enhanced enantioselectivity (96% ee) (Table 1, entry 9).

With the optimized catalyst Ir(I)/(R,S)-2h in hand, we then investigated its applicability in the catalysis of trisubstituted α,β-unsaturated carboxylic acids 1a–l. The substrates were well-chosen considering the possibility for the use of the hydrogenation products as the key intermediates for the synthesis of analogous compounds of PSN-GK1.⁸ Accordingly, a variety of α-aryl acrylic acids with various β-substituents (variation at R¹) (1a–e) were prepared and subsequently hydrogenated in methanol using Ir(I)/(R,S)-2h (1 mol%) as the catalyst under 30 atm of H₂ at 50 °C. The corresponding hydrogenated carboxylic acids were obtained quantitatively with good to excellent enantioselectivities (88–96% ee; Table 2, entries 1–8). It is of note that the reaction of β-alkyl or phenyl substituted acrylic acids (1a, 1c–e) generally affords excellent enantioselectivity (94–96%) while the parent α-phenyl acrylic acid (1b) provides a somewhat inferior result (88% ee), implying that the present catalyst system is particularly suitable for the sterically more demanding substrate at the β-position of acrylic acids. On the other hand, the electronic properties of substituent (R²) at para-position of α-phenyl ring has less impact on the enantioselectivity of the reaction (entry 1 vs. entries 6–8, Table 2).

Table 2 Synthesis of optically active carboxylic acids (3a–l) with biological importance via asymmetric hydrogenation of acrylic acid derivatives 1a–l under the catalysis of Ir(I)/(R,S)-2h^a

Entry	R^1	R^2	Ee (%)^b
a For the reaction conditions and analysis of reaction system, see footnotes a,b in Table 1. The complete conversion of substrates was observed for all entries. b Determined on a Chiralcel column after esterification with diazomethane. The absolute configuration was determined by comparison of the optical rotation with that reported in the literature.^12 c Determined on a Chiralcel AD-H column after being transformed to dehalogenated methyl ester. d s/c = 50. e Determined on a Chiralcel OD-H column after being transformed to their corresponding sulfone derivatives.
1	Tetrahydro-2H-pyran-4-yl (1a)	H	96 (–)
2	H (1b)	H	88 (R)
3	Me (1c)	H	94 (R)
4	Ph (1d)	H	94 (R)
5	Cyclopentyl (1e)	H	95 (–)
6	Tetrahydro-2H-pyran-4-yl (1f)	MeO	95 (–)
7	Tetrahydro-2H-pyran-4-yl (1g)	F	95 (–)
8	Tetrahydro-2H-pyran-4-yl (1h)	I	91^c (–)
9	Tetrahydro-2H-pyran-4-yl (1i)	MeSO2	91 (R)
10	Tetrahydro-2H-pyran-4-yl (1j)	c-PrSO2	89 (R)
11	Tetrahydro-2H-pyran-4-yl (1k)	MeS	94^d^,^e (R)
12	Tetrahydro-2H-pyran-4-yl (1l)	c-PrS	95^e (R)

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Both the β-tetrahydro-2H-pyran-4-yl moiety and the sulfonyl unit at the para-position of the α-aryl group of the carboxylic acid have proven to be critically important in the chiral antidiabetic drug PSN-GK1 and analogous molecules. Therefore, the development of the catalyst system for the direct access of these key intermediates is highly desirable. Accordingly, the ideal catalyst must tolerate the presence of both sulfonyl and tetrahydro-2H-pyran-4-yl moieties in the acid substrates or related precursors. As described above, our catalyst system is particularly effective for the hydrogenation of substrate 1a containing β-tetrahydro-2H-pyran-4-yl moiety. The further introduction of an alkylthio- or alkylsulfonyl group to the para-position of the α-phenyl of acrylic acid 1a afforded substrates 1i–l, which were subsequently hydrogenated under the optimized conditions in the presence of Ir(I)/(R,S)-2h. It was good to find that the hydrogenation of all these four substrates gave the corresponding carboxylic acids 3i–l in almost quantitative yields with 89–95% ee (entries 9–12, Table 2). These facts indicate that the present catalyst system not only has the advantage of high enantioselective control in the reaction but also possesses excellent substrate functional group tolerance if one considers the strong coordination tendency of sulfide or sulfone with a transition metal catalyst. Fortunately, the hydrogenation of 1l afforded the corresponding carboxylic acid 3l with 95% ee which can be directly oxidized by mCPBA to give 3j in >99% yield without any racemization. Simple condensation of 3j with 5-fluoro-2-aminothiazole gave the antidiabetic drug PSN-GK1 conveniently in good yield with the same enantiomeric excess. In order to demonstrate the practicality of the catalysis, a hydrogenation with 4 mmol (1.2 g) scale of substrate 1l was carried out in the presence of 1 mol% of (R,S)-2h under 30 atm of H₂ at 50 °C, complete conversion of 1l and 95% ee of 3l were obtained. It should be noted that the chirality of the stereocenter in the PSN-GK1 molecule is critically important for its bioactivity, in which the R-enantiomer has the desired clinical actions in vivo while the S-enantiomer is completely inactive, although both R- and S-congeners act equi-potently in vitro.¹³ Therefore, the present work has not only furnished a facile method for rapid synthesis of the related chiral drug in a large scale for clinical study, but has also provided an excellent opportunity for generating a small library of both enantiomers of analogous compounds with the variation at the α- or β-position of the carboxylic moiety for further structure–activity-relationship (SAR) study to identify more potent leading compounds.

This work is partially supported by NSFC (nos. 20632060, 20821002, 20620140429, 30772625), the Chinese Academy of Sciences, the Major Basic Research Development Program of China (grant no. 2010CB833300), the Science and Technology Commission of Shanghai Municipality, and Merck Research Laboratories.

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/organicwebtheme2009) to access the other papers in this issue.

‡ Electronic supplementary information (ESI) available: Experimental details and characterization data for all new compounds. See DOI: 10.1039/b919902k

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