Synthesis of Ethyl (S)-3-(1-Methyl-2-Oxo-Cyclohexyl)-2-Oxopropanoate Through Stereoselective Michael Addition

Abstract

A practical four-step sequence for the synthesis of α,δ-dioxoesters with high enantiomeric excess was developed. It makes use of a regio- and stereoselective Michael addition of a chiral ketimine to ethyl 2-(phenylthio)-2-propenoate as a key transformation. The synthetic elaboration of the Michael adduct provides the new ethyl 3-(1-methyl-2-oxo-cyclohexyl)-2-oxopropanoate, bearing a quaternary stereocenter with 95% ee and high yield.

1. Introduction

α-keto acid derivatives play an important role in organic chemistry due to their synthetic applications [1,2], among which various addition reactions to give tertiary alcohols are particularly studied [3]. They are also synthetic precursors of many biologically active natural compounds, such as 2-keto-3-deoxygluconate, 3-deoxy-D-manno-2-octulosonic acid, 3-deoxy-D-glycero-D-galacto-2-nonulosonic acid [4], and N-acetylneuraminic acid [5]. The interest in these compounds also extends to the pharmacological field as they have been successfully incorporated into peptide molecules to generate inhibitors of proteolytic enzymes such as serine and cysteine proteinase [6,7]. The α-keto amide moiety has been shown to be a privileged structure in medicinal chemistry due to interactions with target receptors [8].

The aim of this work was to carry out a stereoselective Michael reaction in order to obtain the deracemization of 2-methylcyclohexanone, at the same time installing a new quaternary stereocenter bearing the pyruvic acid residue, to give the hitherto unknown ethyl 3-(1-methyl-2-oxo-cyclohexyl)-2-oxopropanoate (10).

Despite the extraordinary development of methods to generate all-carbon chiral quaternary stereocenters in the last decades [9], even through biocatalytic routes [10], the need to design simple and practical methods remains highly desirable.

2. Results and Discussion

The chiral ketimine 3, derived from racemic 2-methylcyclohexanone (1) upon reaction with enantiopure (R)-1-phenylethyl amine (2), was reacted with ethyl 2-(phenylthio)-2-propenoate (4), used as an electrophilic partner (Figure 1).

Since 1985, the year of its discovery, this methodology has played a fundamental synthetic role for the stereoselective formation of quaternary carbon atoms. In addition to the relevant regio- and stereoselectivity, this reaction offers the advantage of employing a simple experimental protocol and mild operating conditions [11]. Moreover, cheap (R)-1-phenylethyl amine (2) could be used as a chiral auxiliary that can be easily recovered in quantitative yield.

The crude imine 3 was reacted with ethyl 2-(phenylthio)-2-propenoate (4) under neutral conditions at room temperature to generate the desired adduct 5 in a 75% overall yield after acidic hydrolysis, followed by chromatographic purification, allowing us to separate the minor undesired regioisomer 5′ (1.5% yield) (Figure 1). The starting amine (R)-2 was recovered in almost quantitative yield without loss of optical purity upon neutralization of the aqueous phase.

The reaction proceeds in a highly regio- and stereoselective fashion through the Michael-type addition to the electrophilic alkene 4 by the nucleophilic substituted secondary enamine 3′ in tautomeric equilibrium with the imine 3 [12]. The absolute stereochemistry of the newly formed quaternary stereocenter has been tentatively assigned in accordance with a cyclic-like transition state, as previously described [13,14]. Moreover, a computational study enabled us to corroborate the origin of stereoselectivity [15].

The subsequent elaboration of the thiophenyl moiety of the Michael adduct 5 allowed us to generate the title compound through the protection of the keto group, followed by a sulfenylation reaction, leading to the dithioketal 9.

Thus, compound 5 was first converted to the ketal 7 in quantitative yield by using 1,3-bis(trimethylsilyloxy)ethane (6) in the presence of a catalytic amount of trimethylsilyl trifloromethansulfonate (TMSTfO). Then, the ester enolate generated through lithium diisopropylamide (LDA) deprotonation of 7 was trapped with S-phenylbenzene sulfonothioate (8) to give the dithioketal 9 in a 94% yield.

The unmasking of both carbonyl functionalities was carried out in a single step by reacting a dichloromethane solution of compound 9 with iron trichloride hexahydrate at 25 °C [16]. The title compound, ethyl (S)-3-(1-methyl-2-oxo-cyclohexyl)-2-oxopropanoate (10), could be obtained in an 85% yield. In addition to standard analysis (see below in the Materials and Methods Section), the structure of the desired compound 10 was confirmed through ¹H-¹³C NMR heteronuclear single-quantum correlation spectroscopy (HSQC), providing the list of directly bound ¹H-¹³C pairs.

The enantiomeric excess was determined to be 95% by gas chromatography using a chiral (β-cyclodextrin) column. The racemic compound (±)-10 taken as a reference for GC analysis was prepared with the same synthetic scheme, starting with the racemic 1-phenylethyl amine.

3. Materials and Methods

3.1. General

The solvents used in the syntheses were of technical grade and freshly distilled prior to use. All commercially available compounds were purchased from Merck Life Science S.r.l., Via Monte Rosa, Milano, Italy, or TCI Europe, Boereveldseweg 6-Haven 1063, Zwijndrecht, Belgium. Melting points were determined with a BÜCHI 535 (BÜCHI Labortechnik AG Meierseggstrasse 40, Postfach, Flawil, Switzerland) and were corrected. NMR spectra were recorded with a Bruker AC 300 (Bruker, Billerica, MA, USA) operating at 300.13 MHz for ¹H NMR and 75.3 MHz for ¹³C NMR. Chemical shifts were reported by using CHCl₃ (7.24 ppm for ¹H NMR and 77.0 for ¹³C NMR) as external standards. APT experiments were used in the assignment of carbon spectra. Column chromatography on silica gel (230–400 mesh) was performed by the flash technique. For thin-layer chromatography (TLC), silica gel plates Merck 60 F254 (Merck KGaA, Darmstadt, Germany) were used, and compounds were visualized by irradiation with UV light.

Gas chromatographic analysis was carried out using a GC HP 6890 (Agilent Technologies). Optical activity was measured with a polarimeter Jasco P-1030.

Mass spectra were recorded with an Expression model mass spectrometer (CMS) (Advion 61 Brown Road, Suite 100, Ithaca, NY, USA). Spectra were acquired in APCI positive mode, with a capillary voltage of 100 V, with an APCI corona discharge of 5.0 μA.

IR spectra were recorded with an FT/IR-4600 spectrometer (Jasco UK Limited Unit 10F Ponderosa Business Park, Smithies Lane, Heckmondwike W. Yorkshire WF16 0PR).

HPLC analysis was carried out with an Agilent 1100 HPLC instrument (Agilent Technologies Italia S.p.A., Via P. Gobetti 2/C, 20063 Cernusco sul Naviglio MI, Italy).

3.2. Synthesis of Michael Adduct 5

In a round-bottom flask under nitrogen, (R)-1-phenylethylamine (2) (15 mmol; 1.82 g) was added to a stirred solution of 2-methylcyclohexanone (1) (1.68 g; 15 mmol) in dry toluene (2 mL) in the presence of 5 Å molecular sieves (3 g). The mixture was stirred under reflux for 24 h, cooled to room temperature, filtered, and evaporated to dryness under reduced pressure. The pure compound 3 (12.5 mmol; 2.7 g; 82% yield) was obtained by distillation (bp 140 °C; 3 mmHg). The latter was dissolved in dry THF (36 mL) and reacted with ethyl 2-(phenylthio)-2-propenoate (4) [17] (12.5 mmol; 2.61 g). After 24 h of stirring at room temperature, the reaction mixture was treated with 20% aqueous acetic acid (20 mL) and stirred for 2 h. The crude reaction mixture was extracted with ethyl acetate (3 × 10 mL), and the resulting collected organic phases were washed with a saturated NaHCO₃ solution, dried, and evaporated to dryness at reduced pressure. The crude mixture was purified with column chromatography (AcOEt/PE 1:9) to give 60 mg of the minor diastereoisomer and 3.01 g of the desired α-thiophenyl-δ-keto ester 5 in a 75% yield. The starting amine (R)-2 was recovered in almost quantitative yield upon neutralization of the aqueous phase.

¹H NMR (CDCl₃, δ): 1.10–1.18 (m, 6H), 1.69–1.91 (m, 6H), 2.54–2.62 (m, 4H), 3.73 (dd, 1H, J = 3.2 and 10.1 Hz), 4.02–4.07 (m, 2H), 7.30–7.35 (m, 3H), and 7.49–7.52 (m, 2H).

¹³C NMR (CDCl₃, δ): 13.8 (CH₃), 20.9 (CH₂), 22.5 (CH₃), 27.3 (CH₂), 38.5 (CH₂), 40.0 (CH₂), 40.2 (CH₂), 46.9 (CH), 48.6 (Cquat), 61.1 (CH₂), 128.2 (CH), 128.9 (CH), 133.3 (CH), 172.2 (Cquat), and 214.4 (Cquat).

¹H NMR (CDCl₃, δ) of 5′: 1.07 (d, 3H, J = 10.4), 1.16 (t, 3H, J = 10.7), 2.00–1.60 (m, 8H), 2.50–2.30 (m, 2.70–2.60 (m, 1H)), 2.90–2.80 (m, 1H), 3.71–3.67 (m, 1H), 4.09 (q, 2H, J = 10.7 Hz), 7.26–7.30 (m, 3H), and 7.41–7.46 (m, 2H).

3.3. Synthesis of (S)-Ethyl 3-(1-Methyl-2-Oxo-Cyclohexyl)-2-Oxopropanoate (10)

To a stirred solution of trimethylsilyl trifloromethansulfonate (0.18 mmol; 0.033 mL) in dry CH₂Cl₂ (5 mL) kept at −78 °C, ketone 5 (9 mmol; 2.88 g), followed by 1,2-bis(trimethylsiloxy)ethane (6) (9 mmol; 1.86 g), were added. After 3 h at −78 °C, the mixture was quenched with dry pyridine (0.4 mL) and poured into a saturated NaHCO₃ aqueous solution (20 mL). The two resulting phases were separated, the aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL), and the collected organic phase was dried and evaporated to dryness to give 3.12 g of ethyl 3-(6-methyl-1,4-dioxa-spiro [4,5]dec-6-yl)-2-phenylsulfanyl-propanoate (7) in a 95% yield.

¹H NMR (CDCl₃, δ): 0.92 (s, 3H), 1.09 (t, 3H, J = 7.1 Hz), 1.39–1.52 (m, 8H), 1.86 (dd, 1H, J = 2.8 and 14.6 Hz), 2.33 (dd, 1H, J = 9.5 and 14.6 Hz), 3.86–3.92 (m, 5H), 3.99–4.03 (m, 2H), 7.25–7.33 (m, 3H), and 7.48–7.51 (m, 2H).

¹³C NMR (CDCl₃, δ): 13.8 (CH₃), 19.8 (CH₃), 20.6 (CH₂), 23.3 (CH₂), 30.1 (CH₂), 35.3 (CH₂), 37.6 (CH₂), 41.7 (C_quat), 47.1 (CH), 60.7 (CH₂), 64.6 (CH₂), 64.7 (CH₂), 112.3 (C_quat), 127.6 (CH), 128.5 (CH), 133.1 (CH), 133.7 (C_quat), and 173.0 (C_quat).

The protected ketone 7 (8.20 mmol; 2.99 g) was dissolved in dry THF (28 mL) and added dropwise to a stirred solution of lithium diisopropylamide (1M in THF/hexane (8.20 mL)) at −78 °C under nitrogen. After 10 min at −78 °C and 10 min at 0 °C, the resulting enolate solution was transferred to a stirred solution of S-phenyl benzenesulfonothioate (8) (8.20 mmol; 2.05 g) [18] dissolved in dry THF (8 mL). After 30 min, the crude reaction mixture was poured into a separatory funnel containing 1 N aqueous hydrochloric acid. The resulting mixture was extracted with AcOEt (2 × 20 mL), and the organic layers were combined, washed with aqueous sodium bicarbonate, dried, and evaporated to dryness to give 3.64 g of the expected product 9 (94%), which was used in the next reaction.

The latter was dissolved in CH₂Cl₂ (30 mL) and treated with FeCl₃^.6 H₂O (53 mmol; 14.30 g). The suspension thus obtained was stirred for 1 h at room temperature. Saturated aqueous NaHCO₃ (30 mL) was added, the two resulting phases were separated, the aqueous phase was extracted with CH₂Cl₂ (3 × 15 mL), and the collected organic phase was dried over Na₂SO₄ and evaporated to dryness. The crude was purified with column chromatography (AcOEt/PE 1:9) to give the title compound 10 (oil; 1.48 g; 85% yield).

¹H NMR (CDCl₃, δ): 1.35 (s, 3H), 1.44 (t, 3H, J = 7.1 Hz), 1.78–1.85 (m, 4H), 1.98–2.08 (m, 2H), 2.37–2.56 (m, 2H), 2.94 (dd, 2H, J = 16.3, 20.4 Hz), and 4.36 (q, 2H, J = 7.1 Hz).

¹³C NMR (CDCl₃, δ): 14.0 (CH₃), 21.1 (CH₂), 23.7 (CH₃), 26.7 (CH₂), 38.1 (CH₂), 38.8 (CH₂), 45.9 (CH₂), 50.1 (C), 62.4 (CH₂),161.4 (C), 192.7 (C), and 214.0 (C). GC (HP chiral 20% permethylated β-cyclodextrin; 30 m × 0.25 mm × 0.25 μm): 150 °C for 90 min and then 5 °C/min until 220 °C. t_R = 73.8 (minor); 75.3 (major) ee = 95%. [α]_D = 37.1 (c = 0.01 g/cm³; CHCl₃).

APCI-MS (m/z) 227 (MH⁺). HPLC (Zorbax SB-C18 column (5 μm; 4.6 × 250 mm)) (CH₃CN-H₂O 65-35): a flow of 1 mL/min, and a t_R of 4.32 min (95% purity).

C₁₂H₁₈O₄ (226.1): calcd. C: 63.70 (H: 8.02); found C: 63.82 (H: 7.99).

IR (neat) ν = 2916, 2848, 1726, 1703, 1464, 1270, 1157, 1146, 1127, and 1090 cm⁻¹.

4. Conclusions

In summary, a linear four-step synthetic scheme that promises general applicability for the synthesis of α,δ-dioxoesters with high enantiomeric excess was developed. It makes use of a Michael addition of a chiral ketimine to ethyl 2-(phenylthio)-2-propenoate (4) and subsequent elaboration of the Michael adduct thus obtained. The desired absolute configuration of the quaternary stereocenter can be obtained at will by the judicious choice of the chiral amine.

A weak nucleophile, such as the ketimine used in this work, could be added to ethyl 2-(phenylthio)-2-propenoate (4) under mild reaction conditions, in a neutral environment, at room temperature, and with a stoichiometric ratio.

The following transformation of the thiophenyl functionality into the keto group is simple and provides high chemical yield of the title compound in a 57% overall yield from 2-methylcyclohexanone (1). Ethyl 2-(phenylthio)-2-propenoate (4) can, therefore, be considered an efficient Michael acceptor and a useful electrophilic equivalent of the pyruvate moiety.