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Synlett 2009(9): 1423-1428  
DOI: 10.1055/s-0029-1217164
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Novel One-Pot Stereoselective Synthesis of N-Protected α-Amino Acids from Morita-Baylis-Hillman Acetates

Lal Dhar Singh Yadav*, Vijai Kumar Rai, Santosh Singh
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax: +91(532)2460533; e-Mail: ldsyadav@hotmail.com;
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Publication History

Received 6 February 2009
Publication Date:
13 May 2009 (online)

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Abstract

The first example of an operationally simple direct regio- and diastereoselective introduction of N-protected α-amino acids into Morita-Baylis-Hillman (MBH) acetates is reported. The ­DABCO-catalyzed reaction of MBH acetates with 2-phenyl-1,3-oxazol-5-one affords N-protected α-amino acids regioselectively in excellent yield (81-93%) with high diastereoselectivity (>92%) at ambient temperature. The synthetic protocol involves SN2′-SN2′ ­reaction and water-driven ring-opening cascades in a one-pot procedure, which are salient features of the present investigation.

Key words

Morita-Baylis-Hillman reaction - SN2 reaction - α-amino acids - regio- and diastereoselective - one-pot synthesis

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Isolation of Intermediate 3a and its Conversion into the Corresponding N-Protected α-Amino Acid 4a
To a well-stirred solution of MBH acetate 1 (2 mmol) in THF (10 mL), DABCO (0.4 mmol) was added and stirred for 30 min at r.t. followed by addition of 2-phenyl-1,3-oxazol-5-one 2 (2 mmol) and stirring at r.t. for 5.5 h (Table  [¹] ). After completion of the reaction as indicated by TLC, the solvent was evaporated under reduced pressure, H2O (20 mL) was added, and the product was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (25 mL), dried over MgSO4, filtered, and evaporated to dryness. The crude product thus obtained was purified by column chromatography to afford an analytically pure sample of a single diastereomer 3a (Table  [¹] ). The product 3a (2 mmol) was dissolved in THF (10 mL), then H2O (5 mL) was added, and the reaction mixture was stirred at r.t. for 3 h. After completion of the reaction, H2O (10 mL) was added and the combined organic layer was extracted with CH2Cl2 (3 × 10 mL), concentrated under reduced pressure, and the crude product 4a thus obtained was recrystallized from EtOH to afford an analytically pure sample of 4a quantitatively.
Characterization Data for the Isolated Intermediate 3a
Pale yellow solid; yield 89%; mp 199-201 ˚C. IR (KBr): νmax = 3039, 2217, 1773, 1605, 1579, 1459, 1316 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 4.19 (d, 1 H, J ArCH,NCH = 11.6 Hz, ArCH), 4.41 (d, 1 H, J ArCH,NCH = 11.6 Hz, NCH), 5.80 (s, 1 H, =CH), 5.92 (s, 1 H, =CH), 7.17-7.73 (m, 10 Harom). ¹³C NMR (100 MHz, CDCl3/TMS): δ = 39.1, 63.8, 117.2, 119.8, 126.5, 127.3, 128.1, 129.2, 129.8, 130.6, 131.3, 132.0, 133.1, 165.9, 172.8. MS (EI): m/z = 302 [M+]. Anal. Calcd for C19H14N2O2: C, 75.48; H, 4.67; N, 9.27. Found: C, 75.19; H, 4.31; N, 9.46.

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General Procedure for the One-Pot Synthesis of N-protected α-Amino Acids 4
The MBH acetate 1 (2 mmol) was dissolved in THF (10 mL) DABCO (0.4 mmol) was added, and the reaction mixture was stirred for 30 min at r.t. Thereafter, 2-phenyl-1,3-oxazol-5-one (2, 2 mmol) was added to the reaction mixture, and it was stirred at r.t. for 6-8 h followed by addition of H2O (5 mL) and stirring was continued for the next 1-2 h at r.t. (Table  [²] ). After completion of the reaction as indicated by TLC, the solvent was evaporated under reduced pressure, H2O (10 mL) was added to the reaction mixture and extracted with CH2Cl2 (3 × 10 mL), the combined organic phase concentrated under reduced pressure, and the crude product 4 thus obtained was recrystallized from EtOH to afford a diastereomeric mixture (>92:<8; in the crude products the ratio was >90:<10 as determined by ¹H NMR spectroscopy). The product on second recrystallization from EtOH furnished an analytically pure sample of a single diastereomer 4 (Table  [²] ). On the basis of comparison of J values to literature ones,³j,¹¹e the anti stereochemistry was assigned to 4, as the coupling constant (J NCH,ArCH = 11.6-11.9 Hz) for 4 was greater than that for very minor (<6%) syn diastereomer, J NCH,ArCH = 3.8 Hz. Characterization Data of Representative Compounds 4
Compound 4a: pale yellow solid; yield 90%; mp 143-145  ˚C. IR (KBr): νmax = 3355-2659, 3044, 2218, 1677, 1601, 1588, 1453, 1319 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 4.47 (d, 1 H, J ArCH,NCH = 11.8 Hz, ArCH), 4.91 (d, 1 H, J ArCH,NCH = 11.8 Hz, NCH), 5.79 (s, 1 H, =CH), 5.96 (s, 1 H, =CH), 7.23-7.89 (m, 10 Harom), 8.19 (br s, 1 H, NH, exchangeable with D2O), 11.21 (br s, 1 H, OH, exchangeable with D2O). ¹³C NMR (100 MHz, CDCl3/TMS): δ = 39.5, 60.1, 117.3, 120.3, 125.9, 126.7, 127.9, 129.3, 130.0, 130.8, 131.5, 132.3, 133.5, 171.2, 173.8. MS (EI): m/z = 320 [M+]. Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C, 71.49; H, 4.71; N, 9.12.
Compound 4i: pale yellow solid; yield 86%; mp 172-174 ˚C. IR (KBr): νmax = 3357-2663, 3451, 3055, 2213, 1676, 1599, 1581, 1455, 1321 cm-¹. ¹H NMR (400 MHz, CDCl3/TMS): δ = 4.41 (d, 1 H, J ArCH,NCH = 11.9 Hz, ArCH), 4.95 (d, 1 H, J ArCH,NCH = 11.9 Hz, NCH), 5.75 (s, 1 H, =CH), 5.98 (s, 1 H, =CH), 7.19-7.58 (m, 7 Harom), 7.71-7.87 (m, 2 Harom), 8.22 (br s, 1 H, NH, exchangeable with D2O), 11.20 (br s, 1 H, OH, exchangeable with D2O). ¹³C NMR (100 MHz, CDCl3/TMS): δ = 39.2, 60.3, 117.7, 120.9, 124.8, 125.5, 126.2, 127.0, 128.1, 129.2, 130.3, 131.0, 132.6, 133.7, 142.5, 171.5, 174.1. MS (EI): m/z = 398 [M+]. Anal. Calcd for C19H15BrN2O3: C, 57.16; H, 3.79; N, 7.02. Found: C, 57.54; H, 3.98; N, 6.79.