Iridium catalyzed enantioselective hydrogenation of α-alkoxy and β-alkoxy vinyl ethers

Abstract

Iridium catalyzed, enantioselective hydrogenations of functionalized, acid-sensitive vinyl ethers are reported. These reactions are mediated by the chiral N-carbene–oxazoline complex 1 that, unlike similar N,P-ligated catalysts (6 and 7), gives hydrogenation products (with enantioselectivities up to 96%) without significant acid-mediated degradation. In general, higher enantioselectivities were observed for the allylic alcohol derivatives (2) than the α-methoxycinnamate-based compounds (4).

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Introduction

Asymmetric hydrogenations of vinyl ethers give the same outcome as enantioselective reductions of ketones.^1–4 Unlike ketone reductions, however, they provide chiral ethers directly, and this can be advantageous in access to building blocks for the pharmaceutical and agrochemical industries.^5–9 On the other hand, homogeneous hydrogenation reactions tend to produce protons¹⁰ and, since vinyl ethers are sensitive to acid, this limits application of the vinyl ether approach.

Another limitation on hydrogenations of vinyl ethers relates to the fact that many of the most desirable substrates are hindered trisubstituted alkenes. Hindered alkenes without a proximal coordinating functional group (CFG) are not amenable to hydrogenations with catalysts we broadly refer to as Wilkinson's catalyst analogs (M(phosphine)₂ catalysts where, for instance, M = Rh, Ir). Consequently, for vinyl ethers more complexes are likely to hydrogenate substrates A–C^11–28 than for the functionalized, but not coordinatively functionalized, substrates D and E. Indeed, there are relatively few reports of asymmetric hydrogenation substrates in classes D and E, and the enantioselectivities observed have not reached levels that are practical for applications in organic syntheses (alkylated enol ethers,^29–31 silylated enol ethers,³² furans^31,33).

Crabtree's catalyst³⁴ is the best known of an extremely small group of complexes that will mediate hydrogenation of hindered alkenes that do not contain coordinating functional groups (CFGs).³⁵ Thus it would appear that chiral derivatives of Crabtree's catalyst might be ideal for asymmetric hydrogenations of substrates like D and E. Many chiral derivatives of Crabtree's catalyst with N,P-ligands are, in fact, not suitable because, as we have shown, protons are generated in these reactions and they tend to decompose the substrates before they can be hydrogenated. This assertion is consistent with work from the groups of Andersson³⁶ and of Pfaltz³⁷ for which they reported Ir–N,P catalysts are unsuitable for the more acid-sensitive substrates. Results from our laboratories^10,38 indicated the carbene–oxazoline complex 1^39,40 is the most effective homogenous catalyst for asymmetric hydrogenations of substrates D–E reported to date. We have demonstrated that this is because 1 is less inclined to generate protons than similar N,P-ligated complexes,¹⁰ and it provides a stereoelectronic environment conducive to high enantioselectivities.⁴¹

Studies for this paper were performed to elucidate the scope of catalyst 1 for asymmetric hydrogenations of other enol ethers without strongly coordinating functional groups, specifically the α,ω-functionalized chirons F and the α-oxygenated systems G. An attribute of building blocks F is that they can be homologated from either terminus. Attempted syntheses of chirons G provide opportunities to test how catalyst 1 would process a molecular alkene skeleton that is different to the β-oxygenated systems tested to date.

Results and discussion

It would not be worthwhile to undertake the project outlined above unless there were convenient access to the enol ether substrates. Fortunately, there are good literature procedures for preparing β-alkoxy vinyl ethers 2d,e⁴²via trimethylphosphine mediated conjugate additions of alcohols to electron-deficient alkynes (Scheme 1a). We developed these protocols using a deprotection/Weinreb amide⁴³ formation/protection sequence to generate a broader range of substrates, 2a–c,f,g. Scheme 1b shows an aldol condensation route to substrates 4a–e.⁴⁴ All these alkenes could be prepared with excellent E/Z selectivities (>19 : 1.0) for the crude materials, and subsequent flash chromatographic purification afforded essentially pure E-vinyl ethers 2 and pure Z-vinyl ethers 4.

Scheme 1 Syntheses of α-alkoxy and β-alkoxy vinyl ethers.

Hydrogenations of β-alkoxy vinyl ethers 2a–i were run using the same optimized conditions developed in our previous work (Table 1).³⁸ High conversions could be achieved for all the vinyl ethers except for the sterically hindered alkene 2f, which cannot be hydrogenated at all under the same reaction conditions. The alkene 2a was highly labile to acid, and was converted to a cyclic vinyl ether completely during the hydrogenation. This is unsurprising since even our N,carbene–Ir catalyst generates protons during the hydrogenation (though less than the corresponding N,P-complexes).¹⁰ After 48 h, the cyclic unsaturated vinyl ether 3a′ was isolated as the major product and also crude ¹H NMR identified about 30% hydrogenated product, saturated lactone 3a′′. Lactone 3a′′ presumably arose from the direct hydrogenation; we know this because the unsaturated lactone was not reduced under the same reaction conditions. Protection of the free side-chain hydroxy group in alkenes 2b and 2c circumvented the lactonization issue so the hydrogenation proceeded as expected. Use of a bulky protecting group afforded higher enantioselectivity in these reactions (cf2b (Ac), 74% ee; 2c (TBDPS), 94% ee). Size reduction of the carbonyl-substituent decreased the enantioselectivities (2c, 94% ee; 2d, 82% ee; 2e, 75% ee), but the highest enantioselectivity was obtained when the functional group was an alcohol, (2h, 96% ee). Only 64% ee was observed when that alcohol was converted to an acetate (alkene 2i), so a free-OH appears to be important for the high stereoselectivity. Hydrogenation of the β-benzyloxy vinyl ether 2g proceeded with high efficiency and enantioselectivity (>99% conv., 90% ee) providing a synthesis of the corresponding oxygenated chiral alcohol with an O-protecting group that we would expect to be removable via hydrogenolysis.

All the hydrogenation reactions reported in this paper went cleanly to product; even crude ¹H NMR spectra were acceptable. In general, the crude products were passed through a silica plug (EtOAc/hexanes = 3 : 7) to get rid of catalyst, and then concentrated; the residue was concentrated to give essentially pure products. Consequently, the yields are in close agreement with the conversions observed.

Table 1 Asymmetric hydrogenation of vinyl ethers for chiron F

2	Conv. (%)^a	ee (%)^b	3 ^c
a Determined by ^1H NMR. b Determined via analysis on a chiral GC column or chiral HPLC column. c Stereochemical assignments via comparison with authentic samples. d Assignment of the absolute configuration of the product was not made. e 1.0 equivalent of K2CO3 was added, the reaction time is 12 h. f The reaction time is 12 h.
	>99	na
	>99	74
	>99	94
	>99	82
	>99	75
	na	na	na
	>99	90^d
	>99	96^e
	>99	64^f

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Our previous studies¹⁰ indicated N,P–Ir catalysts cannot hydrogenate the acid-sensitive enol ethers because they promote acid-mediated degradation. Here a simple experiment was performed to check the relative acidities of reaction solutions from the three different catalysts 1, 6 and 7. Proton NMR spectra of the crude hydrogenation products from these reactions show the N,carbene–Ir catalyst 1 gave almost exclusively the desired product 3c whereas the N,P–Ir catalyst 7 only gave a complex mixture (Fig. 1). The N,P-catalyst 6 gave a level of degradation that was between these extremes.

Fig. 1 ¹H NMR spectra of the crude materials from the hydrogenation of 2c show no degradation with the N,carbene complex 1, more when the N,PCy₂-system 6 was used, and the most degradation for the N,PPh₂-catalyst 7.

Optically enriched chiral α-alkoxy carboxylic acid derivatives are generally useful chirons.⁴⁵ In 2010, Zhou's group reported their chiral spiro-N,P–iridium catalyst 8 mediates hydrogenation of α-methoxy cinnamic acid affording the corresponding chiral acid with 99% ee, but strong base was required (reaction 1).²⁵ Others have used chiral diphosphine–Rh complexes at high temperature to obtain similarly good conversions and enantioselectivities.⁴⁶ Zhou demonstrated that the corresponding ester, methyl α-methoxycinnamate was not hydrogenated under the same reaction conditions (reaction 2),²⁵ so presumably the carboxylate was important in this reaction. Consequently, we decided to attempt to hydrogenate this same ester and others (4a–f) with catalyst 1. Table 2, shows that excellent conversions were achieved for all six alkenes, but the enantioselectivities were moderate, up to 61% (the allylic alcohol 4d).

Table 2 Asymmetric hydrogenation of α-methoxy α,β-unsaturated acid derivatives

4	ee (%)^a	5
a Determined via analysis on a chiral GC or HPLC column.
	5
	9
	23
	61
	52
	26

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Conclusion

Chiral N,carbene–Ir catalyst 1 is effective for enantioselective hydrogenation of both α-alkoxy and β-alkoxy vinyl ethers. Hydrogenation of substrates 2 provides an easy access to α,γ-bifunctionalized chirons F, whereas similar N,P–Ir catalysts gave significant or even predominant degradation. The highest enantioselectivity in the series 2 compounds was for the alcohol 2h; our previous studies have indicated allylic alcohols tend not to be directly coordinating (whereas homoallylic alcohols are) so we prefer to describe the OH in this position as a FG rather than a CFG.⁴¹ Catalyst 1 also gives high conversions for α-methoxycinnamate substrates, but there is something about the shape of these substrates that is not conducive to high facial stereoselectivities.

Experimental

General methods

NMR spectra were recorded in CDCl₃. Flash chromatography was performed using silica gel (230–600 mesh) or basic Al₂O₃. Thin layer chromatography was performed using glass plates coated with silica gel 60 F254. All substrates were prepared under an atmosphere of nitrogen in oven-dried glassware with magnetic stirring. Air sensitive reagents and solutions were transferred via syringe and were introduced to the apparatus through rubber septa.

General procedure for synthesis of vinyl ethers 2a–i

According to the method of Paintner and co-workers,⁴² a variety of alcohols was added to butynoate, using trimethylphosphine as a nucleophilic catalyst to give corresponding vinyl ether esters. Then a series of derivatives were made via regular methods.

A solution of butynoate (5.0 mmol) in CH₂Cl₂ (20 mL) was added dropwise to a solution of methanol (15 mmol) and PMe₃ (0.5 mL, 1.0 M in THF, 0.5 mmol) in CH₂Cl₂ (20 mL) at 0 °C by means of a syringe. Then the reaction mixture was allowed to warm to r.t. and stirred overnight. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography.

(E)-Methyl 4-((tert-butyldiphenylsilyl)oxy)-3-methoxybut-2-enoate (2e). A solution of methyl 4-((tert-butyldiphenylsilyl)oxy)but-2-ynoate (1.76 g, 5.0 mmol) in CH₂Cl₂ (20 mL) was added dropwise to a solution of methanol (0.48 g, 15 mmol) and PMe₃ (0.5 mL, 1.0 M in THF, 0.5 mmol) in CH₂Cl₂ (20 mL) at 0 °C by means of a syringe. The reaction mixture was warmed to 23 °C and stirred overnight. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography (5 mol% EtOAc/hexanes) to give pure 2e as a colorless oil (1.31 g, 68%). ¹H NMR (300 MHz, CDCl₃) δ 7.74–7.70 (4H, m), 7.43–7.40 (6H, m), 4.96 (1H, s), 4.91 (2H, s), 3.63 (3H, s), 3.62 (3H, s), 1.10 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 172.8, 167.5, 135.9, 133.8, 129.8, 127.8, 91.0, 61.6, 55.8, 51.1, 27.1, 19.6. HRMS (ESI): calcd for C₂₂H₂₉O₄Si [M + H]⁺ 385.1835. Found 385.1830.

(E)-iso-Propyl 4-((tert-butyldiphenylsilyl)oxy)-3-methoxybut-2-enoate (2d). Starting from iso-propyl 4-((tert-butyldiphenylsilyl)oxy)but-2-ynoate and 2d was isolated as a colorless oil in 60% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.75–7.72 (4H, m), 7.47–7.37 (6H, m), 5.02–4.90 (1H, m), 4.94 (1H, s), 4.93 (2H, s), 3.62 (3H, s), 1.22 (6H, d, J = 6.3 Hz), 1.12 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 172.2, 166.5, 135.9, 133.8, 129.8, 127.7, 91.9, 66.8, 61.5, 55.7, 27.1, 22.2, 19.6. HRMS (ESI): calcd for C₂₄H₃₃O₄Si [M + H]⁺ 413.2148. Found 413.2140.

(E)-4-Hydroxy-N,3-dimethoxy-N-methylbut-2-enamide (2a). To a solution of compound 2e (1.46 g, 3.8 mmol) in THF (20 mL) was added TBAF (1.0 M in THF 4.6 mL, 4.6 mmol) via a syringe. After 1 h, the reaction was quenched with NH₄Cl(s) (20 mL). The layers were separated and the aqueous layer was extracted with Et₂O (3 × 20 mL). Combined organic layers were dried (Na₂SO₄) and concentrated in vacuo. Purification by flash column chromatography, eluting with EtOAc/hexanes (30 : 70) gave the unsaturated lactone (0.43 g, 99%) as a white solid. The lactone was dissolved in CH₂Cl₂ (20 mL) and Me(OMe)NH·HCl (1.83 g, 18.8 mmol) was added in one portion followed by dropwise addition of AlMe₃ solution (2 M in hexanes, 9.4 mL, 18.8 mmol). The resulting mixture was stirred at r.t. for 12 h. The reaction was then cooled to 0 °C, diluted with CH₂Cl₂ (20 mL) and H₂O (5 mL) was carefully added. Saturated potassium sodium tartrate aqueous solution (20 mL) was then added. The resulting mixture was vigorously stirred for 1 h and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic extracts were dried (K₂CO₃) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with EtOAc/hexanes (50 : 50) gave the corresponding vinyl ether 2a (0.32 g, 49%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 5.68 (1H, s), 5.34 (1H, br), 4.31 (2H, s), 3.74 (3H, s), 3.69 (3H, s), 3.26 (3H, s); ¹³C NMR (75 MHz, CDCl₃) δ 175.4, 169.1, 89.7, 63.5, 61.6, 55.9, 32.6. HRMS (ESI): calcd for C₇H₁₄NO₄ [M + H]⁺ 176.0923. Found 176.0918.

(E)-2-Methoxy-4-(methoxy(methyl)amino)-4-oxobut-2-en-1-yl acetate (2b). To a cooled solution of compound 2a (0.42 g, 2.4 mmol) and DMAP (29 mg, 0.24 mmol) in CH₂Cl₂ (10 mL) was added Ac₂O (0.45 mL, 4.8 mmol) and Et₃N (0.67 mL, 4.8 mmol) sequentially. The reaction mixture was stirred at 25 °C for 30 min, then the reaction was quenched by addition of saturated NH₄Cl aqueous solution (10 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL). The combined organic extracts were washed by water, saturated brine and then dried by Na₂SO₄ and concentrated in vacuo. Purification by flash chromatography on basic Al₂O₃ eluting with EtOAc/hexanes (5 : 95) gave the desired product 2b (0.52 g, 100%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 5.71 (1H, s), 5.26 (2H, s), 3.72 (3H, s), 3.71 (3H, s), 3.23 (3H, s), 2.11 (3H, s); ¹³C NMR (75 MHz, CDCl₃) δ 170.8, 167.5, 167.1, 91.5, 61.6, 56.0 (2 peaks), 32.6, 21.0. HRMS (ESI): calcd for C₉H₁₆NO₅ [M + H]⁺ 218.1028. Found 218.1028.

(E)-4-((tert-Butyldiphenylsilyl)oxy)-N,3-dimethoxy-N-methylbut-2-enamide (2c). 2a (0.23 g, 1.3 mmol) was dissolved in CH₂Cl₂ (10 mL) and imidazole (0.12 g, 1.7 mmol) was added in one portion followed by dropwise addition of TBDPSCl (0.43 g, 1.6 mmol). The mixture was stirred at 25 °C for 1 h, then the reaction was quenched by addition of saturated NaHCO₃ aqueous solution (10 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with EtOAc/hexanes (5 : 95) gave the corresponding vinyl ether 2c (0.47 g, 88%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.72–7.69 (4H, m), 7.49–7.34 (6H, m), 5.47 (1H, s), 4.96 (2H, s), 3.64 (3H, s), 3.63 (3H, s), 3.15 (3H, s), 1.08 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 168.1, 135.9, 134.0, 129.7, 127.7, 89.2, 61.9, 61.5, 55.5, 32.6, 27.1, 19.7. HRMS (ESI): calcd for C₂₃H₃₂NO₄Si [M + H]⁺ 414.2101. Found 414.2112.

(E)-4-((tert-Butyldiphenylsilyl)oxy)-3-isopropoxy-N-methoxy-N-methylbut-2-enamide (2f). 2f was isolated as a colorless oil in 87% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.78–7.70 (4H, m), 7.44–7.33 (6H, m), 5.50 (1H, s), 4.95 (2H, s), 4.38–4.50 (1H, m), 3.65 (3H, s), 3.16 (3H, s), 1.32 (6H, d, J = 6.0 Hz), 1.09 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 169.6, 168.8, 136.0, 134.2, 129.7, 127.7, 89.9, 70.3, 62.0, 61.5, 32.5, 27.1, 21.6, 19.6. HRMS (ESI): exact mass calcd for C₂₅H₃₆NO₄Si [M + H]⁺ 442.2412. Found 442.2419.

(E)-3-(Benzyloxy)-4-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylbut-2-enamide (2g). 2g was isolated as a colorless oil in 70% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.77–7.75 (4H, m), 7.46–7.34 (11H, m), 5.67 (1H, s), 5.07 (2H, s), 4.94 (2H, s), 3.56 (3H, s), 3.19 (3H, s), 1.12 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 169.7, 167.7, 135.9, 135.8, 133.8, 129.6, 128.6, 128.2, 127.8, 127.6, 91.0, 70.1, 61.6, 61.3, 32.5, 27.0, 19.5. HRMS (ESI): calcd for C₂₉H₃₆NO₄Si [M + H]⁺ 490.2414. Found 490.2411.

(E)-4-((tert-Butyldiphenylsilyl)oxy)-3-methoxybut-2-en-1-ol (2h). To a cooled solution (−30 °C) of compound 2e (0.89 g, 2.3 mmol) in THF (10 mL) was added DIBAL-H (1.0 M in hexanes, 6.9 mL, 6.9 mmol) slowly via a syringe pump. The reaction mixture was stirred at −30 °C for 1 h, then the reaction was quenched with MeOH (5 mL). Et₂O (20 mL) was added and saturated potassium sodium tartrate aqueous solution (20 mL) was then added. The resulting mixture was vigorously stirred for 1 h and the layers were separated. The aqueous layer was extracted with Et₂O (3 × 20 mL). The combined organic extracts were dried by K₂CO₃ and concentrated in vacuo. Purification by flash chromatography on basic Al₂O₃ eluting with EtOAc/hexanes (20 : 80) gave the desired product 2h (0.46 g, 76%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.74–7.70 (4H, m), 7.49–7.39 (6H, m), 4.85 (1H, t, J = 7.8 Hz), 4.26 (2H, s), 4.10–4.05 (2H, m), 3.53 (3H, s), 1.49 (1H, t, J = 5.7 Hz), 1.07 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 159.6, 135.9, 133.3, 130.0, 127.9, 99.4, 62.0, 58.4, 54.7, 27.0, 19.4. HRMS (ESI): calcd for C₂₁H₂₈KO₃Si [M + K]⁺ 395.1445. Found 395.1437.

(E)-4-((tert-Butyldiphenylsilyl)oxy)-3-methoxybut-2-en-1-yl acetate (2i). To a cooled solution of compound 2h (1.42 g, 4.0 mmol) and DMAP (70 mg, 0.57 mmol) in CH₂Cl₂ (20 mL) was added Ac₂O (1.07 mL, 11.4 mmol) and Et₃N (1.59 mL, 11.4 mmol) sequentially. The reaction mixture was stirred at 25 °C for 30 min, then the reaction was quenched by addition of saturated NH₄Cl aqueous solution (10 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic extracts were dried by K₂CO₃ and concentrated in vacuo. Purification by flash chromatography on basic Al₂O₃ eluting with EtOAc/hexanes (5 : 95) gave the desired product 2i (0.55 g, 33%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.73–7.70 (4H, m), 7.45–7.38 (6H, m), 4.73–4.55 (3H, m), 4.27 (2H, s), 3.52 (3H, s), 2.02 (3H, s), 1.07 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 171.2, 160.7, 135.8, 133.5, 129.9, 127.8, 94.1, 61.6, 60.7, 54.7, 26.9, 21.3, 19.4. HRMS (ESI): calcd for C₂₃H₃₀NaO₄Si [M + Na]⁺ 421.1811. Found 421.1806.

Synthesis of vinyl ethers 4a–f

Vinyl ethers 4c and 4f, are synthesized via the reported procedure.²⁵ Hydrogenation products 5c and 5f, are known compounds. The characterization data for these compounds can be found in the reported literature and our characterization data agree well with those reported.⁴⁷

(Z)-Methyl 2-methoxy-3-phenylacrylate (4a); (Z)-tert-butyl 2-methoxy-3-phenylacrylate (4b). Potassium tert-butoxide (5.95 g, 53 mmol) was dissolved in anhydrous THF (50 mL) and cooled to −40 °C. A solution of benzaldehyde (5.30 g, 50 mmol) and methyl 2-methoxyacetate (5.74 g, 55 mmol) in THF (30 mL) was added to the above solution dropwise. The mixture was stirred for 1 h at −40 °C until the reaction was complete (all benzaldehyde was consumed). Trifluoroacetic anhydride (13.9 ml, 100 mmol) was added dropwise at −40 °C, and then the mixture was warmed to 23 °C slowly. More potassium tert-butoxide (13.5 g, 120 mmol) was added to the resulting brown solution in three portions. The mixture was then heated at 60 °C for 30 min. The solution was cooled to 23 °C and quenched with 1 N HCl. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were dried (Na₂SO₄), concentrated, and purified by flash chromatography (10% EtOAc/hexanes) to give pure 4a (5.0 g, 26 mmol, 52%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.81–7.76 (2H, m), 7.46–7.30 (3H, m), 7.01 (1H, s), 3.88 (3H, s), 3.80 (3H, s); ¹³C NMR (75 MHz, CDCl₃) δ 165.2, 145.7, 133.6, 130.4, 129.3, 128.9, 124.4, 59.5, 52.5. HRMS (ESI): exact mass calcd for C₁₁H₁₃O₃ [M + H]⁺ 193.0865. Found 193.0866. 4b (4.8 g, 20.6 mmol, 41%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.77–7.70 (2H, m), 7.43–7.30 (3H, m), 6.90 (1H, s), 3.79 (3H, s), 1.60 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 163.8, 147.1, 133.9, 130.3, 128.9, 128.8, 123.1, 82.0, 59.3, 28.5. HRMS (ESI): exact mass calcd for C₁₄H₁₉O₃ [M + H]⁺ 235.1334. Found 235.1330.

(Z)-2-Methoxy-3-phenylprop-2-en-1-ol (4d). To a cooled solution (0 °C) of compound 4a (0.83 g, 4.3 mmol) in THF (10 mL) was added DIBAL-H (1.0 M in hexanes, 13 mL, 13.0 mmol) slowly via a syringe pump. The reaction mixture was stirred at 25 °C for 1 h, then the reaction was quenched with MeOH (5 mL). Et₂O (20 mL) was added and saturated potassium sodium tartrate aqueous solution (20 mL) was then added. The resulting mixture was vigorously stirred for 1 h and the layers were separated. The aqueous layer was extracted with Et₂O (3 × 20 mL). The combined organic extracts were dried by K₂CO₃ and concentrated in vacuo. Purification by flash chromatography on basic Al₂O₃ eluting with EtOAc/hexanes (20 : 80) gave the desired product 4d (0.68 g, 95%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.63–7.58 (2H, m), 7.36–7.28 (2H, m), 7.23–7.17 (1H, m), 5.64 (1H, s), 4.32 (2H, s), 3.85 (3H, s), 1.81 (1H, br); ¹³C NMR (75 MHz, CDCl₃) δ 155.1, 135.8, 128.8, 128.5, 126.6, 109.6, 63.1, 56.3. HRMS (ESI): exact mass calcd for C₁₀H₁₃O₂ [M + H]⁺ 165.0916. Found 165.0911.

(Z)-tert-Butyl((2-methoxy-3-phenylallyl)oxy)diphenylsilane (4e). 4d (0.34 g, 2.0 mmol) was dissolved in CH₂Cl₂ (10 mL) and imidazole (0.17 g, 2.5 mmol) was added in one portion followed by dropwise addition of TBDPSCl (0.63 g, 2.3 mmol). The mixture was stirred at 25 °C for 1 h, then the reaction was quenched by addition of saturated NaHCO₃ aqueous solution (10 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel, eluting with EtOAc/hexanes (5 : 95) gave the corresponding vinyl ether 4e (0.79 g, 98%) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.82–7.16 (15H, m), 5.52 (1H, s), 4.34 (2H, s), 3.85 (3H, s), 1.11 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 154.8, 136.2, 135.9, 133.5, 130.1, 128.7, 128.4, 128.0, 126.2, 108.7, 63.8, 56.5, 27.0, 19.5. HRMS (ESI): exact mass calcd for C₂₆H₃₁O₂Si [M + H]⁺ 403.2093. Found 403.2090.

General catalytic hydrogenation conditions

The corresponding alkenes (0.1 mmol) were dissolved in CH₂Cl₂ (0.5 M) and (S)-1 (1 mol%) was then added. The resulting solution was degassed by three cycles of freeze–pump–thaw and then transferred to a Parr Bomb. The bomb was flushed with hydrogen for 1 min without stirring. The mixture was then stirred at 700 rpm under 50 bar H₂. After 48 h (for esters and its derivatives) or 12 h (for alcohols and its derivatives), the bomb was vented and the solvent evaporated. The crude product was passed through a silica plug (EtOAc/hexanes = 3 : 7). The enantiomeric ratio of the crude material was then measured through chiral capillary GC analysis using a β- or γ-CD column⁴⁸ (carrier gas: helium; column pressure: 18.21 psi; gas flow rate: 1.6 mL min⁻¹; temperature: 135 °C) or through chiral HPLC analysis, which is performed with a 254 nm UV detector and a chiral column (Chiralcel OD).

(R)-2-Methoxy-4-(methoxy(methyl)amino)-4-oxobutyl acetate (3b). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 4.26 (1H, dd, J = 3.9, 11.7 Hz), 4.14 (1H, dd, J = 4.8, 11.7 Hz), 4.03–3.94 (1H, m), 3.71 (3H, s), 3.44 (3H, s), 3.21 (3H, s), 2.83 (1H, dd, J = 7.2, 15.9 Hz), 2.54 (1H, dd, J = 5.4, 15.9 Hz), 2.10 (3H, s); ¹³C NMR (75 MHz, CDCl₃) δ 171.7, 171.1, 75.6, 65.1, 61.5, 58.2, 34.4, 32.3, 21.1. HRMS (ESI): calcd for C₉H₁₈NO₅ [M + H]⁺ 220.1185. Found 220.1180.

(R)-4-((tert-Butyldiphenylsilyl)oxy)-N,3-dimethoxy-N-methylbutanamide (3c). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.73–7.70 (4H, m), 7.43–7.38 (6H, m), 3.93–3.85 (1H, m), 3.74–3.65 (2H, m), 3.70 (3H, s), 3.38 (3H, s), 3.22 (3H, s), 2.80 (1H, dd, J = 8.4, 16.2 Hz), 2.62 (1H, dd, J = 4.2, 15.9 Hz), 1.08 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 172.6, 135.9, 135.8, 133.7 (2 peaks), 129.9, 127.9, 78.4, 65.1, 61.5, 58.4, 34.8, 32.3, 27.0, 19.5. HRMS (ESI): calcd for C₂₃H₃₄NO₄Si [M + H]⁺ 416.2257. Found 416.2250.

(R)-iso-Propyl 4-((tert-butyldiphenylsilyl)oxy)-3-methoxybutanoate (3d). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.76–7.68 (4H, m), 7.51–7.39 (6H, m), 5.11–5.02 (1H, m), 3.85–3.62 (3H, m), 3.38 (3H, s), 2.65 (1H, dd, J = 4.5, 15.6 Hz), 2.50(1H, dd, J = 8.1, 15.6 Hz), 1.26 (6H, d, J = 6.3 Hz), 1.08 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 171.5, 135.8, 133.5, 129.9, 127.9, 78.7, 68.0, 65.0, 58.4, 37.9, 27.0, 22.1, 19.5. HRMS (ESI): calcd for C₂₄H₃₅O₄Si [M + H]⁺ 415.2305. Found 415.2300.

(R)-Methyl 4-((tert-butyldiphenylsilyl)oxy)-3-methoxybutanoate (3e). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.72–7.68 (4H, m), 7.49–7.38 (6H, m), 3.83–3.61 (3H, m), 3.71 (3H, s), 3.37 (3H, s), 2.68 (1H, dd, J = 4.5, 15.9 Hz), 2.55 (1H, dd, J = 8.1, 15.9 Hz), 1.08 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 172.4, 135.8 (2 peaks), 133.5 (2 peaks), 130.0, 127.9, 78.6, 64.8, 58.3, 51.9, 37.4, 27.0, 19.5. HRMS (ESI): calcd for C₂₂H₃₁O₄Si [M + H]⁺ 387.1992. Found 387.1987.

3-(Benzyloxy)-4-((tert-butyldiphenylsilyl)oxy)-N-methoxy-N-methylbutanamide (3g). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.70–7.67 (4H, m), 7.46–7.20 (11H, m), 4.63 (1H, d, J = 11.4 Hz), 4.57 (1H, d, J = 11.4 Hz), 4.18–4.11 (1H, m), 3.81–3.71 (2H, m), 3.63 (3H, s), 3.18 (3H, s), 2.85 (1H, dd, J = 8.4, 15.0 Hz), 2.66 (1H, dd, J = 4.5, 15.6 Hz), 1.06 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 172.6, 139.0, 135.8, 133.6 (2 peaks), 129.9, 128.4, 128.0, 127.9, 127.6, 77.1, 73.0, 65.9, 61.5, 35.0, 32.3, 27.0, 19.5. HRMS (ESI): calcd for C₂₉H₃₈NO₄Si [M + H]⁺ 492.2570. Found 492.2566.

(R)-4-((tert-Butyldiphenylsilyl)oxy)-3-methoxybutan-1-ol (3h). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.74–7.70 (4H, m), 7.50–7.39 (6H, m), 3.81–3.57 (4H, m), 3.52–3.48 (1H, m), 3.40 (3H, s), 2.57 (1H, s), 1.90–1.78 (2H, m), 1.10 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 135.8 (2 peaks), 133.5, 133.4, 130.0, 127.9, 81.6, 65.4, 60.9, 58.1, 34.2, 27.0, 19.4. HRMS (ESI): calcd for C₂₁H₃₀LiO₃Si [M + Li]⁺ 365.2124. Found 365.2118.

(R)-4-((tert-Butyldiphenylsilyl)oxy)-3-methoxybutyl acetate (3i). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.72–7.68 (4H, m), 7.46–7.39 (6H, m), 4.21–4.17 (2H, m), 3.74–3.63 (2H, m), 3.37 (3H, s), 3.37–3.35 (1H, m), 2.06 (3H, s), 1.98–1.75 (2H, m), 1.08 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 171.3, 135.8 (2 peaks), 133.7, 133.6, 129.9, 127.9, 78.9, 65.5, 61.7, 58.3, 31.1, 27.1, 21.3, 19.5. HRMS (ESI): calcd for C₂₃H₃₂LiO₄Si [M + Li]⁺ 407.2230. Found 407.2223.

Methyl 2-methoxy-3-phenylpropanoate (5a). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.33–7.18 (5H, m), 3.99 (1H, dd, J = 5.4, 7.8 Hz), 3.73 (3H, s), 3.36 (3H, s), 3.10–2.95 (2H, m); ¹³C NMR (75 MHz, CDCl₃) δ 172.8, 137.2, 129.6, 128.6, 127.0, 82.0, 58.6, 52.1, 39.4. HRMS (ESI): exact mass calcd for C₁₁H₁₅O₃[M + H]⁺ 195.1021. Found 195.1025.

tert-Butyl 2-methoxy-3-phenylpropanoate (5b). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.32–7.28 (5H, m), 3.87 (1H, t, J = 6.0 Hz), 3.67 (3H, s), 3.00 (2H, d, J = 6.6 Hz), 1.43 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 171.5, 137.4, 129.7, 128.5, 126.8, 82.3, 81.8, 58.2, 39.4, 28.2. HRMS (ESI): exact mass calcd for C₁₄H₂₁O₃ [M + H]⁺ 237.1491. Found 237.1497.

2-Methoxy-3-phenylpropan-1-ol (5d). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.38–7.20 (5H, m), 3.72–3.62 (1H, m), 3.57–3.46 (2H, m), 3.44 (3H, s), 3.00–2.75 (2H, m), 2.24 (1H, br); ¹³C NMR (75 MHz, CDCl₃) δ 138.3, 129.6, 128.7, 126.6, 83.1, 63.5, 57.7, 37.1. HRMS (ESI): exact mass calcd for C₁₀H₁₅O₂ [M + H]⁺ 167.1072. Found 167.1077.

tert-Butyl(2-methoxy-3-phenylpropoxy)diphenylsilane (5e). Colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 7.76–7.70 (4H, m), 7.52–7.40 (6H, m), 7.36–7.20 (5H, m), 3.74–3.70 (2H, m), 3.58–3.46 (1H, m), 3.35 (3H, s), 3.04–2.78 (2H, m), 1.15 (9H, s); ¹³C NMR (75 MHz, CDCl₃) δ 139.3, 135.9 (2 peaks) 133.9, 133.8, 130.0, 129.7, 128.5, 128.0, 126.3, 83.4, 64.8, 58.3, 38.1, 27.2, 19.6. HRMS (ESI): exact mass calcd for C₂₆H₃₃O₂Si [M + H]⁺ 405.2250. Found 405.2257.

Acknowledgements

Financial support for this work was provided by the National Science Foundation (CHE-0750193) and the Robert A. Welch Foundation (A1121).

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data for the compounds 4a–f and 5a–f are reported. ¹H and ¹³C NMR spectra of compounds. See DOI: 10.1039/c2ra01350a

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