Efficient Synthesis of N-Benzyloxycarbonyl- and N-tert-Butoxycarbonyl-(S)-Isoserine and their Derivatives

Abstract

A mild and efficient synthesis of N-protected (S)-iso­serine from (S)-malic acid monoester via an oxazolidin-2-one is described.

Key words

amino acids - asymmetric synthesis - oxazolidin-2-ones - ring opening - protecting groups

References

• 1a Hettinger TP. Craig LC. Biochemistry  1970,  9:  1224 
• 1b Heaney-Kieras J. Kurylo-Borowska Z. J. Antibiot.  1980,  33:  359 
• 2a Sowinski JF. Toogood PL. Tetrahedron Lett.  1995,  68:  67 
• 2b Kobayashi J. Itagaki F. Shigemori I. Takao T. Shimonishi Y. Tetrahedron  1995,  51:  2525 
• 2c Sowinski JF. Toogood PL. Chem. Commun.  1999,  981 
• 2d Uemoto H. Yahiro Y. Shigemori H. Tsuda M. Takao T. Shimonishi Y. Kobayashi J. Tetrahedron  1998,  54:  6719 
• 2e Dohren H. von Kleinkauf H. Biotechnology  1999-2001,  7:  313 
• 3a Schmidt EW. Bewley CA. Faulkner DJ. J. Org. Chem.  1998,  63:  1254 
• 3b Moore BS. Nat. Prod. Rep.  1999,  16:  653 
• 4a Matsunaga S. Fusetani N. J. Org. Chem.  1995,  60:  1177 
• 4b Taylor CM. Tetrahedron  1998,  54:  11317 
• 5 Bewley C. Faulkner DJ. J. Org. Chem.  1994,  59:  4849 
• 6a Wright JJ. Cooper A. Daniels PJL. Nagabhushan TL. Rane D. Turner WN. Weinstein J. J. Antibiot.  1976,  29:  714 
• 6b Haskell TH. Rodebaugh R. Plessas N. Watson D. Westland RD. Carbohydr. Res.  1973,  28:  263 
• 7 Floreancig PE. Swalley SE. Trauger JW. Dervan PB. J. Am. Chem. Soc.  2000,  122:  6342 
• 8 For a review see: Andruszkiewicz R. Pol. J. Chem.  1998,  72:  1 
• 9a Andruszkiewicz R. Walkowiak A. Org. Prep. Proc. Int.  2001,  33:  379 
• 9b

  Czajgucki, Z.; Sowinski, P.; Andruszkiewicz, R. Amino Acids 2002, in press.

• 10a Andruszkiewicz R. Milewski S. Borowski E. J. Enzyme Inhib.  1995,  9:  123 
• 10b Andruszkiewicz R. Je drzejczak R. Zieniawa T. Wojciechowski M. Borowski E. J. Enzyme Inhib.  2000,  15:  429 
• 11 Cammas S. Renard I. Boutault K. Guerin P. Tetrahedron: Asymmetry  1993,  4:  1925 
• 15a

  Representative Experimental Procedure: Compound 5a-5c (5 mmol) was quickly dissolved in dry THF (50 mL) and cooled under argon to -40 °C. Benzyltrimethyl-ammonium hydroxide (5.5 mL of 40% solution in methanol, 10.5 mmol) was added over 20 min to the solution of 5a-5c and stirred for an additional 1 h. HOAc (1.1 mL) and water (2.5 mL) were then added and the reaction mixture was warmed to r.t. and the solvent was evaporated under reduced pressure. The residue was extracted with EtOAc (2 × 50 mL). The extracts were washed, dried over MgSO₄ and evaporated. The solid residue was crystallized from a mixture of EtOAc and hexane to yield 6a (0.77 g, 75%). Mp: 93-94 °C; [α]_D +6.4 (c 2.5, MeOH). Similarily, 6b was also obtained (0.89 g, 75%). Mp: 117-119 °C; [α]_D +3.2 (c 2.5, MeOH). Physical and spectral data for 6a and 6b are in agreement with literature values, see ref. [15b]

• 15b Burger K. Windeisen E. Pires R. J. Org. Chem.  1995,  60:  7641 

12

Typical Procedure for the Preparation of 4a and 4b: The appropriate substrate 2a,b (5 mmol), and DPPA (1.18 mL, 5.5 mmol) were dissolved in t-BuOH (20 mL). The reaction flask was flushed with argon, and Et₃N (0.75 mL, 5.5 mmol) was added. The reaction mixture was refluxed for 4 h and cooled to r.t. The solvent was removed under reduced pressure, the residue dissolved in EtOAc (50 mL). In the case of 4a, the solution was washed with sat. NaHCO₃ solution, water and finally dried over anhyd MgSO₄. After evaporation of the solvent, the solid residue was crystallized from EtOAc and hexane to yield 4a (0.77 g, 70%). Mp: 128-129 °C; [α]_D +10.0 (c 1, EtOAc). ¹H NMR (200 MHz, CDCl₃): δ = 3.66-3,74 (dd, J _4a,4b = 9.5 Hz, J _4a,5a = 5.6 Hz, 1 H CHCH ₂ , 4H_a), 3.85-3.95 (dd, J _4b,4a = 9.5 Hz, 1 H, CHCH ₂ , 4 H_b), 5.05-5.10 (dd, J _5a,4b = 9.5 Hz, J _5a,4a = 5.6 Hz, 1 H, CHCH₂, 5 H_a), 5.28 (s, 2 H, CH ₂ C₆H₅), 5.9 (br s, 1 H, NH), 7.40(s, 5 H, C ₆ H ₅ ). Anal. Calcd for C₁₁H₁₁NO₄: C, 59.73; H, 5.01; N, 6.33. Found: C, 59.58; H, 5.12; N, 6.38. In the case of 4b, after evaporation of the solvent, the product was purified by column chromatography (silica gel, hexane-ethyl acetate 2:3) furnishing 4b (0.58g, 80%) which was crystallized from ethyl acetate and hexane. Mp: 95-97 °C; [α]_D +20.1 (c 1, EtOAc). ¹H NMR (200 MHz, CDCl₃): δ = 3.65-3.75(dd, J _4a,4b = 9.6 Hz, J _4a,5a = 5.5 Hz, 1 H, CHCH ₂ , 4 H_a), 3.85 (s, 3 H, CH ₃ ), 3.86-3.96 (dd, J _4a,4b = 9.6, J _4b,5a = 5.5 Hz, 1 H, CHCH ₂ , 4 H_b), 5.01-5.09 (dd, J _5a,4b = 9.6 Hz, J _5a,4b = 5.5 Hz, 1 H, CHCH₂, 5 H_a), 6.24
(br s, 1 H, NH). Anal. Calcd for C₅H₇NO₄: C, 41.38; H, 4.86; N, 9.65. Found: C, 41.22; H, 4.74; N, 9.60.

13

Typical Procedure, 4a,b to 5a-5c: Compound 4a or 4b (9 mmol), DMAP (25 mg) and Et₃N (1.5 mL, 11 mmol) were dissolved in dry THF (25 mL) and cooled in an ice bath. A solution of (Boc)₂O (2.05 g, 9.4 mmol) in THF (8 mL) was added to a stirred reaction mixture over 20 min. The temperature of the reaction was kept between 5 °C and 10 °C overnight. Then, equimolar amounts of NaHSO₄ (1.32 g, 11 mmol) in water (10 mL) were added. After evaporation of the solvent under reduced pressure, the white suspension was dissolved in EtOAc (50 mL), and the solution was washed with dilute NaHSO₄ solution, water and finally dried (MgSO₄) and evaporated. The solid was crystallized from diethyl ethyl ether and hexane to give 5a (2.5 g, 85%). Mp: 130-131 °C; [α]_D +24.0 (c 1, EtOAc). ¹H NMR (200 MHz, CDCl₃): δ = 1.56 [s, 9 H (CH ₃ )C],. 4.00-4.07 (dd, J _4a,4b = 10.7, J _4a,5a = 5.5 Hz, 1 H, CHCH ₂ , 4 H_a), 4.14-4.24 (dd, J _5a,4b = 9.5 Hz, J _4a,4b = 10.7 Hz, 1 H, CHCH ₂ , 4 H_b), 4.91-4.99 (dd, J _5a,4b = 9.5 Hz, J _5a,4a = 5.5 Hz, 1 H, CHCH₂), 5.29 (s, 2 H, CH ₂ C₆H₅), 7.40 (s, 5 H, C ₆ H ₅ ). Anal. Calcd for C₁₆H₁₉NO₆: C, 59.18; H, 5.96; N, 4.36. Found: C, 59.34; H, 5.92; N, 4.22. In the same manner compound 5c was obtained (1.54 g, 70%). Mp: 76-78 °C; [α]_D +36.8 (c 2.5, MeOH). ¹H NMR (200 MHz, CDCl₃): δ = 1.55 [s, 9 H (CH ₃ )C], 3.87 (s, 3 H, CH₃), 4.00-4.08 (dd, J _4a,4b = 10.7, J _4a,5a = 5.5 Hz, 1 H, CHCH ₂ , 4H_a), 4.14-4.25 (dd, J _5a,4b = 9.5 Hz, J _4a,4b = 10.7 Hz, 1 H, CHCH ₂ , 4 H_b), 4.89-4.97 (dd, J _5a,4b = 9.5 Hz, J _5a,4a = 5.5 Hz, 1 H, CHCH₂). Anal. Calcd for C₁₀H₁₅NO₆: C, 48.98; H, 6.17; N, 5.71. Found: C, 49.17; H, 6.22; N, 5.58.

14

Synthesis of 5b: (5S)-5-Benzyloxycarbonyl-2-oxazol-idinone 4a (1.99 g, 9 mmol) was dissolved in THF (30 mL) and Et₃N (10 mL). The reaction mixture was cooled to
-20 °C. A solution of benzyl chloroformate (2.6 mL, 18 mmol) in THF (3.3 mL) was slowly added over 20 min. The stirred reaction mixture was then kept at -10 °C overnight. The reaction mixture was quickly neutralized with a stoichiometric amount of cold 10% aq solution of NaHSO₄ and extracted with EtOAc (2 × 50 mL). The extracts were washed with water, dried (MgSO₄) and evaporated. The solid residue was dissolved in a small volume of hot EtOAc and diluted with a large volume of diethyl ether. Crystals were collected to give 5b (2.4g, 80%). Mp: 112-114 °C; [α]_D +24.0 (c 2.5, EtOAc). ¹H NMR (200 MHz, CDCl₃):
δ = 4.04-4.12 (dd, J _4a,4b = 10.6, J _4a,5a = 5.5 Hz, 1 H, CHCH ₂ , 4H_a), 4.18-4.28 (dd, J _5a,4b = 9.5 Hz, J _4a,4b = 10.6 Hz, 1 H, CHCH ₂ , 4 H_b), 4.93-5.01 (dd, J _5a,4b = 9.5 Hz, J _5a,4a = 5.5 Hz, 1 H, CHCH₂), 5.27 (s, 2 H, CH ₂ C₆H₅-benzyl ester), 5.31 (s, 2 H, CH ₂ C₆H₅-benzyloxycarbonyl group), 7.35-7.45 (br s, 10 H, 2 × C ₆ H ₅ ). Anal. Calcd for C₁₉H₁₇NO₆: C, 64.22; H, 4.82; N, 3.94. Found: C, 64.34; H, 4.68; N, 3.88.

16

Preparation of 7a: Compound 5a (0.64 g, 2 mmol) was dissolved in a mixture of THF (10 mL) and MeOH (15 mL) and palladium on activated carbon (5%, 50 mg) was added. The reaction flask was flushed with hydrogen and the hydrogenation was performed at atmospheric pressure for 1 h at r.t. The catalyst was filtered off and the solvents were evaporated. The residue was crystallized from a mixture of EtOAc and hexane to give 7a (0.43g, 94%). Mp: 99-100 °C; [α]_D +28.2 (c 1, MeOH). ¹H NMR (500 MHz, CDCl₃): δ = 1.56 [s, 9 H (CH ₃ )C],. 4.08-4.11 (dd, J _4a,4b = 10.7, J _4a,5a = 5.4 Hz, 1 H, CHCH ₂ , 4 H_a), 4.21-4.25 (dd, J _5a,4b = 9.8 Hz, J _4a,4b = 10.7 Hz, 1 H, CHCH ₂ , 4 H_b), 4.95-4.98 (dd, J _5a,4b = 9.8 Hz, J _5a,4a = 5.4 Hz, 1 H, CHCH₂). Anal. Calcd for C₉H₁₃NO₆: C, 46.75; H, 5.67; N, 6.06. Found: C, 46.78; H, 5.52; N, 5.98.