Novel Catalytic Synthetic Route to Protected α-Methyl Threonine and the First Asymmetric Acetyl Migration in a Steglich Rearrangement Reaction

Abstract

A short synthetic route to protected a-methyl threonine 5 as a representative example for (protected) a-methylated a-amino-b-hydroxy acids bearing a stereogenic quaternary carbon center in a-position was developed. This multistep synthesis is based on the use of an easily accessible prochiral starting material in the presence of an organocatalyst, and allows the access to all four types of stereoisomers. In addition, the first enantioselective acetyl migration in a Steglich rearrangement reaction as a key step in this multistep synthesis of 5 was achieved. The heterocycle 12, which was used in Steglich rearrangement reaction for the first time, turned out to be an efficient organocatalyst leading to an enantioselectivity of up to 63% ee.

acylation - amino acids - asymmetric catalysis - rearrangements - stereoselective synthesis

References and Notes

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Diastereoselective multistep syntheses with stoichiometric amount of chiral auxiliaries:

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6 Kuroda S, Nozaki H, Watanabe K, Yokozeki K, and Imabayashi Y. inventors; WO  2006123745. Enzymatic production of l-serine derivative by using microbial 2-methylserine hydroxymethyltransferases:

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9

Preparation of rac -4-Acetyl-4-methyl-2-phenyloxazol-5-one ( rac -7)In analogy to a protocol described in ref. 8, 5-acetyloxy-4-methyl-2-phenyloxazole (8, 2.0 g, 9.3 mmol) and DMAP (10, 90 mg, 0.7 mmol) were dissolved in CH₂Cl₂ (50 mL) at r.t. After 3 h of stirring, the solvent was removed to give 7 (2.05 g, 9.4 mmol, purity >95%) as yellow oil. ¹H NMR (400 MHz, CDCl₃): d = 1.69 (3 H, s), 2.27 (3 H, s), 7.45-7.60 (3 H, m), 8.00-8.02 (2 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): d = 20.95, 25.84, 77.96, 125.20,128.10, 128.87, 133.28, 162.61, 174.42, 198.39 ppm. MS-FAB: m/z = 218, 176.

10

Preparation of rac -2-Benzoylamino-2-methyl-3-oxobutyric Acid Isopropyl Ester ( rac -6)4-Acetyl-4-methyl-2-phenyloxazol-5-one (rac- 7, 1.5 g, 6.9 mmol) and DMAP (10, 90 mg, 0.7 mmol) were dissolved in i-PrOH (40 mL). The reaction mixture was stirred for 16 h and the excess of i-PrOH was removed in vacuo. The resulting crude product was purified by column chromatography [SiO₂ 60 Å, cyclohexane-EtOAc (3:1)] to give rac-6 (1.62 g, 5.8 mmol, 84% yield). ¹H NMR (400 MHz, CDCl₃): d = 1.18 (3 H, d, J = 6.3 Hz), 1.21 (3 H, d, J = 6.3 Hz), 1.79 (3 H, s), 2.21 (3 H, s), 5.08 (1 H, sept, J = 6.3 Hz), 7.40-7.44 (2 H, m), 7.48-7.52 (1 H, m), 7.71 (1 H, br s), 7.78-7.81 (2 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): d = 19.97, 21.36, 21.39, 23.97, 68.62, 70.51, 127.02, 128.58, 131.84, 133.51, 165.85, 168.56, 200.23 ppm. MS (EI): m/z = 278, 234. IR: 3412, 3327, 2984, 1722, 1664 cm^-1. Anal. Calcd (%) for C₁₅H₁₉NO₄: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.61; H, 6.88; N, 4.89.

11

Preparation of Diastereomers of rac -2-Benzoylamino-3-hydroxy-2-methylbutyric Acid Isopropyl Ester ( rac - l -5, rac - u -5)2-Benzoylamino-2-methyl-3-oxobutyric acid isopropyl ester (rac-6, 200 mg, 0.72 mmol) was dissolved in i-PrOH (20 mL) and cooled in an ice bath. After adding NaBH₄ (13.6 mg, 0.36 mmol) the mixture was stirred at ice-bath temperature for 2 h, and further 2 h at r.t. Subsequently, dilute HCl was added until no further hydrogen was evolved. After addition of H₂O the reaction mixture was extracted 5 times with MTBE. Removal of the solvent furnished a crude product of the resulting racemic diastereomers l-5 and u-5 (dr = 60:40), which were separated by column chroma-tography [SiO₂ 60 Å, cyclohexane-EtOAc (3:1)] to give rac-l- 5 (36 mg, 0.13 mmol, 18%) and rac-u- 5 (37 mg, 0.13 mmol, 18%).Compound rac-l-5: R _f = 0.16. ¹H NMR (400 MHz, CDCl₃): d = 1.07 (3 H, d, J = 6.5 Hz), 1.25-1.29 (6 H, m), 1.69 (3 H, s), 4.14-4.22 (1 H, m), 5.05-5.14 (1 H, m), 5.49 (1 H, d, J = 10.1 Hz), 7.41-7.45 (2 H, m), 7.48-7.53 (1 H, m), 7.61 (1 H, br s), 7.79-7.81 (2 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): d = 18.67, 18.85, 21.49, 65.90, 70.53, 71.19, 127.09, 128.67, 131.99, 133.82, 167.89, 173.42 ppm. MS-FAB: m/z = 280. IR: 3516, 3242, 2984, 1706, 1633 cm^-1. Anal. Calcd (%) for C₁₅H₂₁NO₄: C, 64.50; H, 7.58; N, 5.01. Found: C, 62.82; H, 7.51; N, 4.75.Compound rac-u-5: R _f = 0.06. ¹H NMR (400 MHz, CDCl₃): d = 1.20-1.26 (9 H, m), 1.58 (3 H, s), 3.71 (1 H, br s), 4.13-4.20 (1 H, m), 5.04-5.13 (1 H, m), 6.86 (1 H, br s), 7.38-7.42 (2 H, m), 7.46-7.50 (1 H, m), 7.74-7.77 (2 H, m) ppm. ¹³C NMR (100 MHz, CDCl₃): d = 17.85, 18.60, 21.63, 21.69, 64.60, 69.57, 71.29, 127.00, 128.56, 131.67, 134.39, 167.83, 172.09 ppm. MS-FAB: m/z = 280. IR: 3412, 3331, 2976, 1733, 1640 cm^-1. Anal. Calcd (%) for C₁₅H₂₁NO₄: C, 64.50; H, 7.58; N, 5.01. Found: C, 64.13; H, 7.61; N, 4.87.

12a Ruble JC. Fu GC. J. Am. Chem. Soc.  1998,  120:  11532 

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13b For an excellent review about development and application of these type of catalysts, see: Fu GC. Acc. Chem. Res.  2004,  37:  542 

14 For an overview about organocatalytic methodologies in general, see: Berkessel A. Gröger H. Asymmetric Organocatalysis   Wiley-VCH; Weinheim: 2005. 

15

Experimental Procedure (Exemplified for Reaction in Table 1, Entry 1)5-Acetyloxy-4-methyl-2-phenyloxazole (8, 500 mg, 2.3 mmol) and 4-dimethylaminopyridinyl-(pentaphenyl-cyclopentadienyl)iron [(S)-11, 40 mg, 0.06 mmol] were dissolved in CH₂Cl₂ (20 mL) and stirred at r.t. for 3 h. Subsequently the solvent was removed to give 4-acetyl-4-methyl-2-phenyloxazol-5-one 7 (537 mg) as an oily crude product. The conversion (84%) and enantioselectivity (25% ee) were determined by ¹H NMR spectroscopy and chiral HPLC chromatography [after derivatization to 6, Daicel Chiralcel OD column, hexane/2-PrOH (97:3)], respectively. The spectroscopic properties are in accordance with those for the racemic product rac-7. The other reactions with catalyst (S)-11 (Table [1] , entries 2-4) as well as the reaction with (-)-tetramisole [(S)-12] as a catalyst in CH₂Cl₂ (Table [1] , entry 6) were carried out on a 2 mL scale using 100 mg of substrate 8. The reaction with (S)-12 as a catalyst (Table [1] , entry 5) was carried out on a 1 mL scale, and the conversion was directly determined from the reaction mixture by ¹H NMR spectroscopy in this experiment.

16a Birman VB. Li X. Org. Lett.  2006,  8:  1351 

16b

The Birman group also reported that benzotetramisole turned out to be an improved and very efficient organocatalyst in resolution processes compared with (-)-tetramisole [(S)-12]. Thus, this catalyst might also give improved enantioselectivities in the synthesis of 7, which is planned to be studied next.