In(III)-pybox complex catalyzed enantioselective Mukaiyama aldol reactions between polymeric or hydrated glyoxylates and enolsilanes derived from aryl ketones

Abstract

A highly efficient In(III)-pybox complex catalyzed enantio-selective Mukaiyama aldol reaction between polymeric or hydrated glyoxylates and enolsilanes derived from aryl ketones is described. Excellent enantioselectivities, diastereoselectivities and yields were obtained with a broad substrate scope. The mild reaction conditions and simple operation make this methodology very practical.

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The aldol reaction offers one of the most efficient access to the versatile β-hydroxyl carbonyl compounds, which are important building blocks for biologically active molecules.¹ It is not surprising that the asymmetric aldol reaction has attracted much attention in recent years. Among the strategies elaborated in the asymmetric aldol reactions, chiral Lewis-acid catalyzed asymmetric Mukaiyama aldol reaction has been developed into a useful tool for organic chemists.² Although asymmetric direct aldol reactions³ have developed very rapidly in the past decades, the asymmetric Mukaiyama aldol still plays an important role in organic synthesis. For example, the organocatalyzed asymmetric direct aldol reaction of poorly reactive aryl ketones represents a challenging topic⁴ albeit exciting results having been achieved in metal complexes such as dinuclear Zn catalysts⁵ and (S,S)-Zn–Zn-linked-BINOL complex⁶ catalyzed asymmetric direct aldol reaction. However, the chiral Lewis acids catalyzed asymmetric Mukaiyama aldol of aryl ketones, in which preformed aryl enol silanes were used as aldol donors, can avoid the disadvantage caused by the low reactivity of aryl ketone.⁷

On the other hand, the enantioselective Mukaiyama aldol reaction of 1,2-dicarbonyl compounds has emerged as an efficient strategy to construct enantiomerically enriched β-hydroxy ketones and esters, which are frequently observed in numerous biologically active molecules.⁸ A number of chiral catalysts have been developed for the asymmetric Mukaiyama aldol reaction of α-keto esters⁹ and glyoxylates.¹⁰ To our surprise, despite the large number of chiral catalyst capable of mediating the asymmetric aldol reaction of glyoxylates and aryl ketones, individually, none of them are effective for the asymmetric aldol reaction between aryl ketones and glyoxylates except for Evans' Sc(III)-pybox complex.¹¹ Unfortunately, Evans' catalyst system only worked for substituted steric bulky aryl ketones¹² and strictly anhydrous reaction conditions were required. Therefore, the asymmetric aldol reaction between glyoxylates and aryl ketones, which can generate the carbonyl precursor of (R)-ethyl 2-hydroxy-4-phenylbutyrate (HPB ester),¹³ a key intermediate of a series of commercially available Angiotensin-Converting Enzyme (ACE) inhibitors,¹⁴ still remained as a formidable challenge. Currently enantioselective synthesis of this compound relies upon asymmetric aza-ene type reaction of enecarbamate,¹⁵ in which the synthesis of enecarbamate is very tedious. Herein, we report a highly efficient asymmetric In(III)-pybox complex catalyzed Mukaiyama aldol reaction between polymeric or hydrated glyoxylate and enolsilanes derived from aryl ketones to give enantioenriched β-hydroxy ketones in excellent yields and enantioselectivities under mild reaction conditions.

In the course of our effort to develop the application of chiral indium complex¹⁶ in asymmetric synthesis, we demonstrated that In(III)-pybox complexes, formed in situ from commercially available In(III) salts and pybox ligands, are efficient catalysts for asymmetric carbonyl-ene reaction of polymeric glyoxylates and trifluoropyruvates.¹⁷ This may be attributed to glyoxylate and trifluoropyruvate, both being bidentate substrates, coordinating to the cationic In(III) centre to form a facially discriminated complex, which is crucial for inducing high enantioselectivity. We hypothesized that this strategy could also be applied to the challenging asymmetric Mukaiyama aldol reaction beween glyoxylate and aryl enol silanes, which are similar to α-methylstyrene.

Initially, we chose polymeric ethyl glyoxylate (50% in toluene) and acetophenone-derived enolsilane as the model substrates to optimize reaction conditions (for details of screening of different Lewis acids and condition optimization, see ESI†). It is notable that among the evaluated Lewis acids, only In(III) based Lewis acids are effective for this reaction. The solvent, ligand, temperature, additive, catalyst loading and counterion effect were all examined. Polar solvents such as CH₃CN and THF proved to be better than non-polar solvents. Pybox (+)-1 is the best choice of ligand and box ligands are ineffective for this transformation. With decreasing temperature, the enantioselectivity was found to increase. In addition, due to the significant counter-ion effect of In(III)-pybox complex observed in the asymmetric carbonyl-ene reactions, the counter-ion effect also had been evaluated in the current study as shown in Table 1. Based on the optimization studies, we found that the combination of 5 mol% of InBr₃, 5 mol% of AgSbF₆ and 6 mol% of pybox (+)-1 with CH₃CN as the solvent in the presence of 4 Å molecular sieves¹⁸ was the best catalytic system.‡

Table 1 Evaluation of counter-ion effect of In(III)-pybox complex^a

Entry	AgX (5 mol %)	T/°C	t/h	Yield^b (%)	ee^c (%) (R)
a The reactions were carried out on a 0.50 mmol scale of enolsilane with 2 equiv of ethyl glyoxylate (1 mmol) in acetonitrile (CH3CN). b Isolated yield. c ee Values were determined by chiral stationary phase HPLC analysis. The absolute configuration of the major products is R, assigned by comparing the optical rotation with the literature.^13
1	AgSbF6	r.t	2	97	77
2	AgPF6	r.t	4	95	77
3	AgBF4	r.t	2	96	72
4	AgClO4	r.t	4	95	73
5	AgOAc	r.t	24	—	nd
6	AgSbF6	−20	19	89	87
7	AgSbF 6	−40	72	91	89

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In our preliminary studies, consistent with Evans' results, we also observed that this reaction is sensitive to the steric effect of reactants. Increasing steric bulk of the substrate is favorable for attaining higher enantioselectivity (unpublished results). These factors promoted us to investigate the steric effect of glyoxylate esters, as well as enolsilanes systematically, with the hope of getting better enantioselectivity, and the results are listed in Table 2. Firstly, acetophenone derived enolsilanes with different size of silane groups were evaluated at room temperature. It is clear that the enantioselectivity increased steadily from 69 to 77% when the silane group changed from small TMS (trimethylsilyl) to bulky TIPS (triisopropylsilyl) (Table 2, entries 1–4). Next, a series of glyoxylate esters with different ester groups were prepared according to the reported method¹⁹ and used as their hydrated form without further distillation. Keeping TIPS as the silane group, similar increasing trend in enantioselectivity was observed with increasing size of glyoxylate ester group (Table 2, entries 4–7). The highest ee (89%) could be achieved when isopropyl glyoxylate ester and TIPS enolsilane derived from acetophenone, both of which contain the bulkiest isopropyl group, were reacted under the standard conditions at room temperature (Table 2, entry 7). The results summarized in Table 2 supported our hypothesis that increasing steric bulk of both enolsilanes and glyoxylate esters will lead to increase in the enantioselectivity. Further improvement of enantioselectivity was observed when the reaction was carried out at low temperature (Table 2, entries 8–10). The optimal temperature to afford the best results in terms of yield and enantioselectivity is −20 °C (Table 2, entry 9), while too low a temperature has a detrimental effect on the reaction efficiency (Table 2, entry 10). Interestingly, unlike Evans' strict anhydrous conditions, under which acidic treatment is necessary to transfer the silane ether product to alcohol, the enantioenriched alcohol could be obtained directly from Mukaiyama aldol reaction in our case. This result demonstrated that a small amount of water in this system plays a role in this process.

Table 2 Investigation of steric effect of reactants^a

Entry	R^1	SiR^23	T/°C	t/h	Yield^b (%)	ee^c (%)
a The reactions were carried out on a 0.50 mmol scale of 3 with 2 equiv of 2 (1 mmol) in acetonitrile (CH3CN). b Isolated yield. c ee Values were determined by chiral-phase HPLC analysis. The absolute configurations of 4a, 4c and 4d were assigned by analogy to that of 4b. d This reaction is not completed after stirring for 3 days.
1	Et	SiMe3	r.t	2	80	69
2	Et	SiEt3	r.t	2	85	72
3	Et	SiMe2^tBu	r.t	2	87	66
4	Et	Si^iPr3	r.t	2	97	77
5	Me	Si^iPr3	r.t	2	62	43
6	Bu	Si^iPr3	r.t	2	92	73
7	^i Pr	Si^iPr3	r.t	2	93	89
8	^i Pr	Si^iPr3	0	12	96	92
9	^i Pr	Si ^i Pr 3	−20	19	91	96
10^d	^i Pr	Si^iPr3	−40	72	28	97

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With the optimal conditions in hand, TIPS enolsilanes derived from various aryl ketones were prepared to investigate the substrate scope of this reaction and the results are summarized in Table 3. Arylenolsilanes containing both electron-withdrawing and donating groups on the aromatic ring proceeded smoothly to give the aldol adducts in good to excellent yields and with excellent enantioselectivities, albeit longer reaction times were required for electron-deficient substrates (Table 3, entries 6–10). Interestingly, although the steric hindrance is favorable for the enantioselectivies, too severe steric hindrance in the transition state has a negative effect on the reaction efficiency. For example, the presence of a substituent at the ortho position of enolsilane prolonged the reaction time (up to 3 days) and required higher reaction temperature (0 °C), regardless whether the substituents are electron-neutral (Table 3, entries 2 and 5) or withdrawing (Table 3, entry 6). The disadvantage caused by steric hindrance of orthomethyl or methoxy group may be compensated by the electron-rich nature of the substrates 3n, 3r and 3s (Table 3, entries 11, 15 and 16). These observations demonstrated that both the electronic effect and steric effect play a role in the reaction. It is noteworthy that enolsilanes derived from heterocyclic aryl ketones also worked well to give enantioenriched alcohols which could be elaborated to other useful chemicals (Table 3, entries 15 and 16).

Table 3 Indium(III) complex-catalyzed asymmetric Mukaiyama aldol reactions between hydrated isopropyl glyoxylate and enolsilanes derived from aryl ketones^a

Entry	Product (4d–x)	T/°C	t/h	Yield^b (%)	ee^c (%)
a The reactions were carried out on a 0.50 mmol scale of 3 with 2 equiv of 2 (1 mmol) in acetonitrile (CH3CN). b Isolated yield. c Ee values were determined by chiral-phase HPLC analysis.
1		−20	19	91	96
2		0	70	81	94
3		−20	22	88	94
4		−20	22	94	96
5		0	70	80	95
6		0	68	60	93
7		0	68	85	93
8		−20	72	71	94
9		−20	64	82	97
10		−20	64	85	97
11		−20	68	83	92
12		−20	48	85	95
13		−20	48	88	96
14		−20	64	89	98
15		−20	68	76	90
16		−20	68	92	96

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To further probe the stereoselectivity of this reaction, α-substituted aryl ketone-derived enolsilane 5, which will lead to two chiral centres in the aldol product 6, was reacted under the standard reaction conditions and excellent diastereoselectivity (dr = 97 : 3) as well as enantioselectivity (98% ee) could be obtained, with the syn diastereomer as the major product (Scheme 1).

Scheme 1

In summary, we have successfully developed the In(III)-pybox complex catalyzed highly enantioselective Mukaiyama aldol reactions between polymeric or hydrated glyoxylate esters and enolsilanes derived from aryl ketones. The enantioenriched β-hydroxy ketones bearing an additional ester group could be obtained in excellent yields and with excellent enantioselectivities under mild conditions. This work not only complements the well-developed Mukaiyama aldol reactions of α-ketone esters but also demonstrates the advantage of In(III)-pybox complexes over other chiral Lewis acids. In addition, solvent and the polymeric or hydrated glyoxylates were used without distillation and the reaction could be carried out in open air, both of which offer great synthetic advantages.

Acknowledgements

We gratefully acknowledge the Nanyang Technological University and Biomedical Research Council (A*STAR Grant No 05/1/22/19/408) for the funding support of this research.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Detailed experimental procedures. See DOI: 10.1039/c0sc00454e

‡ General procedure for the In(III)-pybox complex catalyzed asymmetric Mukaiyama Aldol reactions between polymeric or hydrated glyoxylate esters and aryl ketone-derived enolsilanes: In a 5 mL round-bottom flask containing CH₃CN (1.5 ml) with a stirring bar, InBr₃ (8.9 mg, 0.025 mmol), pybox (+)-1 (11.8 mg, 0.03 mmol) and 4 Å molecular sieves (150.0 mg) were added and stirred at room temperature for 30 min. To the above mixture, silver hexafluoroantimonate (AgSbF₆) (8.6 mg, 0.025 mmol) was added in one portion and stirred for another 30 min. To the pre-prepared catalyst in CH₃CN, the polymeric or hydrated glyoxylate ester (1.0 mmol, 2 eq.) was added using a syringe sequentially. The resulting mixture was cooled to −20 °C before enolsilane (0.5 mmol, 1 eq.) was added using syringe under N₂ atmosphere. It was stirred until the enolsilane had undergone complete reaction using TLC to monitor its progress. The reaction was quenched by saturated NaHCO₃ solution (5 mL). The above mixture was extracted by ethyl acetate three times. The combined organic layer was washed with brine and dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was loaded directly onto a silica gel column and purified by flash column chromatography to obtain the enantio-enriched β-hydroxy ketones.

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