Stereoselective Synthesis of Chiral Furan Amino Acid Analogues of d- and l-Serine from d-Sugars

Abstract

The synthesis of chiral furan amino acid analogues of d- and l-serine is reported. The developed methodology starting from d-xylose affords the corresponding amino acid derivative analogue of d-serine enantiomerically pure. Starting from d-arabinose, the corresponding analogue of l-serine was isolated in 92.3% enantiomeric purity. The analogue of d-serine was transformed into a stable Fmoc activated derivative ready to be incorporated into peptides.

Key words

furan amino acids - cyclic sulfites - serine analogues - polyhydroxyalkyl furans - α-furfuryl amines

References and Notes

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  For the same reaction on a similar but unstable cyclic sulfite giving only one diasteroisomer, see ref. 8d.

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17

Selected data for compound 7: [α]_D ²⁰ +99 (c 0.98, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃, 298 K): δ = 7.40-7.28 (m, 5 H, H-arom.), 6.75 (s, 1 H, H-4), 5.29 (s, 2 H, CH₂Ph), 4.56 (d, 1 H, J _{1 ′,2 ′} = 7.3 Hz, H-1′), 4.02 (m, 1 H, H-2′), 3.76 (dd, 1 H, J _{3 ′a,3 ′b} = 11.5 Hz, J _{3 ′a,2 ′}= 3.4 Hz, H-3′a), 3.72 (dd, 1 H, J _{3 ′b,2 ′} = 5.2 Hz, H-3′b), 2.60 (s, 3 H, CH₃) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 298 K): δ = 163.5 (CO), 160.4, 147.5 (C-2, C-5), 135.9, 128.6, 128.3, 128.2 (6 C-arom.), 114.2 (C-3), 110.9 (C-4), 71.9 (C-2′), 66.2 (CH₂Ph), 62.9 (C-3′), 59.9 (C-1′), 14.3 (CH₃) ppm. HRMS (CI): m/z calcd for C₁₆H₁₈N₃O₅ + H⁺: 332.1246; found: 332.1236.

18

Selected data for compound 9: [α]_D ²⁰ +25 (c 2.62, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃, 298 K): δ = 7.42-7.36 (m, 10 H, H-arom.), 6.67 (s, 1 H, H-4), 5.30 (s, 2 H, CH₂Ph), 4.75 (t, 1 H, J _{1 ′,2 ′a} = J _{1 ′,2 ′b} = 6.5 Hz, H-1′), 4.56 (d, 2 H, H-2′a and H-2′b), 3.55 (q, 3 H, J _CH,F = 1.2 Hz, CH₃O), 2.58 (s, 3 H, CH₃) ppm. ¹³C NMR (75.4 MHz, CDCl₃, 298 K): δ = 166.2 (CO), 163.1 (CO), 160.5, 146.0 (C-2, C-5), 131.8-127.2 (12 C, C-arom.), 123.1 (q, 1 C, ¹ J _C,F = 288, CF₃), 114.2 (C-3), 110.5 (C-4), 84.7 [q, 1 C, ² J _C,F = 28.2 Hz, (C(OMe)(CF₃)Ph], 66.2 (CH₂Ph), 65.0 (C-2′), 56.5 (C-1′), 55.5 (OCH₃), 13.9 (CH₃) ppm.

20

Experimental Procedure for the Preparation of Fmoc-Activated Amino Acid Derivative 16 from 1.
To a stirred mixture of 1 (26 mg, 0.138 mmol) in dry pyridine (2 mL) at 0 °C, TMSCl (54 µL, 0.414 mmol) was dropped and the reaction mixture stirred for 45 min at r.t. Then the reaction mixture was cooled to 0 °C, 9-fluorenyl-methoxycarbonyl chloride (46 mg, 0.18 mmol) was added and the mixture stirred for 1.5 h at r.t. Afterwards, H₂O (0.1 mL) was added, the mixture stirred for 1 h at r.t., and then evaporated to give 15 that was used in the next step without any purification. Crude 15 was dissolved in DMF, then DIEA (53 µL, 0.3 mmol) and PyBOP (88 mg, 0.168 mmol) were added. The mixture was stirred for 1 h at r.t., then the solution was evaporated in vacuo. The resulting residue was purified by column chromatography (EtOAc-PE, 1:1) to give 16 (57 mg, 0.108 mmol, 78%) as a white solid. [α]_D ²⁰ +38 (c 0.84, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃, 298 K): δ = 7.57-7.27 (m, 12 H, H-arom.), 6.74 (s, 1 H, H-4), 5.56 (d, 1 H, J _{NH,1 ′} = 7.5 Hz, NHFmoc) 4.90 (br s, 1 H, H-1′), 4.51 (d, 2 H, J = 6.5 Hz, CH₂ of Fmoc), 4.22 (t, 1 H, CH of Fmoc), 3.94 (br m, 2 H, H-2′a and H-2′b), 2.62 (CH₃) ppm.
¹³C NMR (75.4 MHz, CDCl₃, 298 K): δ = 163.4 (CO), 159.5 (C-2), 156.1 (CO of Fmoc), 152.3 (C-5), 143.7, 143.4, 141.4, 128.8, 127.8, 127.1, 124.9, 120.4, 120.0, 107.3 (18 C, C-arom.), 108.8 (C-3), 108.4 (C-4), 67.0 (CH₂ of Fmoc), 63.3 (C-2′), 50.9 (C-1′), 47.2 (CH of Fmoc), 14.2 (CH₃).

21

The OBt esters of protected amino acids are not isolable and must be generated in situ. Only less reactive OPfp esters are commercially available, see: Novabiochem,^® 2004/5 catalogue.