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

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 S_N2′-S_N2′ ­reaction and water-driven ring-opening cascades in a one-pot procedure, which are salient features of the present investigation.

Morita-Baylis-Hillman reaction - S_N2 reaction - α-amino acids - regio- and diastereoselective - one-pot synthesis

References and Notes

<A NAME="RG03709ST-1A">1a</A> Wang L. Schultz PG. Angew. Chem. Int. Ed.  2005,  44:  34 

<A NAME="RG03709ST-1B">1b</A> Medical Chemistry of Bioactive Natural Products   Liang X.-T. Fang W.-S. Wiley; Hoboken NJ: 2006.  p.35-72  

<A NAME="RG03709ST-1C">1c</A> Kim RM, Kahne DE, and Chapman KT. inventors; PCT Int. Appl. WO  2000069893.  ; Chem. Abstr. 2000, 134, 5162

<A NAME="RG03709ST-1D">1d</A> Shang G. Yang Q. Zhang X. Angew. Chem. Int. Ed.  2006,  45:  6360 

<A NAME="RG03709ST-1E">1e</A> Williams RM. Hendrix JA. Chem. Rev.  1992,  92:  889 

<A NAME="RG03709ST-1F">1f</A> Stammer CH. Tetrahedron  1990,  46:  2231 

<A NAME="RG03709ST-1G">1g</A> Heimgartner H. Angew. Chem., Int. Ed. Engl.  1991,  30:  238 

<A NAME="RG03709ST-2">2</A> Shendage DM. Fröhlich R. Haufe G. Org. Lett.  2004,  6:  3675 

<A NAME="RG03709ST-3A">3a</A> Basavaiah D. Rao AJ. Satyanarayana T. Chem. Rev.  2003,  103:  811 

<A NAME="RG03709ST-3B">3b</A> Yeo JE. Yang X. Kim HJ. Koo S. Chem. Commun.  2004,  236 

<A NAME="RG03709ST-3C">3c</A> Luo S. Wang PG. Cheng J.-P. J. Org. Chem.  2004,  69:  555 

<A NAME="RG03709ST-3D">3d</A> Aggrawal VK. Patin A. Tisserand S. Org. Lett.  2005,  7:  2555 

<A NAME="RG03709ST-3E">3e</A> Lee KY. Gowrisankar S. Kim JN. Tetrahedron Lett.  2005,  46:  5387 

<A NAME="RG03709ST-3F">3f</A> Wasnaire P. Wiaux M. Touillaux R. Markó IE. Tetrahedron Lett.  2006,  47:  985 

<A NAME="RG03709ST-3G">3g</A> Basavaiah D. Rao KV. Reddy R. J. Chem. Soc. Rev.  2007,  36:  1581 

<A NAME="RG03709ST-3H">3h</A> Shi Y.-L. Shi M. Eur. J. Org. Chem.  2007,  2905 

<A NAME="RG03709ST-3I">3i</A> Masson G. Housseman C. Zhu J. Angew. Chem. Int. Ed.  2007,  4614 

<A NAME="RG03709ST-3J">3j</A> Singh V. Yadav GP. Maulik PR. Batra S. Tetrahedron  2008,  64:  2979 

<A NAME="RG03709ST-4A">4a</A> Kundu MK. Sundar N. Kumar SK. Bhat SV. Biswas S. Valecha N. Bioorg. Med. Chem. Lett.  1999,  9:  731 

<A NAME="RG03709ST-4B">4b</A> Basavaiah D. Hyma RS. Kumaragurubaran N. Tetrahedron  2000,  56:  5905 

<A NAME="RG03709ST-4C">4c</A> Kaye PT. Musa MA. Synth. Commun.  2003,  33:  1755 

<A NAME="RG03709ST-4D">4d</A> Patra A. Batra S. Bhaduri AP. Khanna A. Chander R. Dikshit M. Biosci. Med. Chem.  2003,  11:  2269 

<A NAME="RG03709ST-4E">4e</A> de Souza ROMA. Meireles BA. Aguiar CS. Vasconcellos M. Synthesis  2004,  1595 

<A NAME="RG03709ST-4F">4f</A> Vasconcellos M. Silva TMS. Camara CA. Martins RM. Lacerda KM. Lopes HM. Pereira VLP. de Souza ROMA. Crespo LTC. Pest. Manage. Sci.  2006,  62:  288 

<A NAME="RG03709ST-4G">4g</A> de Souza ROMA. Pereira VLP. Muzitano MF. Falcao CAB. Rossi-Bergmann B. Filho EBA. Vasconcellos M. Eur. J. Med. Chem.  2007,  42:  99 

<A NAME="RG03709ST-5A">5a</A> Cho C.-W. Kong J.-R. Krische MJ. Org. Lett.  2004,  6:  1337 

<A NAME="RG03709ST-5B">5b</A> Singh V. Saxena R. Batra S. J. Org. Chem.  2005,  70:  353 

<A NAME="RG03709ST-5C">5c</A> Ma S. Yu S. Peng Z. Guo H. J. Org. Chem.  2006,  71:  9865 

<A NAME="RG03709ST-5D">5d</A> Singh V. Batra S. Eur. J. Org. Chem.  2007,  2970 

<A NAME="RG03709ST-5E">5e</A> Gowrisankar S. Kim SJ. Lee J.-E. Kim JN. Tetrahedron Lett.  2007,  48:  4419 

<A NAME="RG03709ST-5F">5f</A> Lee HS. Kim JM. Kim JN. Tetrahedron Lett.  2007,  48:  4119 

<A NAME="RG03709ST-5G">5g</A> Selvakumar N. Kumar PK. Shekar Reddy KC. Chandra Chary B. Tetrahedron Lett.  2007,  48:  2021 

<A NAME="RG03709ST-6A">6a</A> Yadav LDS. Yadav S. Rai VK. Green Chem.  2006,  8:  455 

<A NAME="RG03709ST-6B">6b</A> Yadav LDS. Rai VK. Synlett  2007,  1227 

<A NAME="RG03709ST-6C">6c</A> Yadav LDS. Rai VK. Tetrahedron Lett.  2008,  49:  5553 

<A NAME="RG03709ST-6D">6d</A> Yadav LDS. Rai VK. Yadav BS. Tetrahedron  2009,  65:  1306 

<A NAME="RG03709ST-7A">7a</A> Yadav LDS. Awasthi C. Rai A. Tetrahedron Lett.  2008,  49:  6360 

<A NAME="RG03709ST-7B">7b</A> Yadav LDS. Patel R. Srivastava VP. Synlett  2008,  1789 

<A NAME="RG03709ST-7C">7c</A> Yadav LDS. Awasthi C. Tetrahedron Lett.  2009,  50:  715 

<A NAME="RG03709ST-8">8</A> Vandenberg GE. Harrison JB. Carter HE. Magerlein BJ. Org. Synth., Coll. Vol. V  1973,  946 

<A NAME="RG03709ST-9">9</A> Moorthy JN. Singhal N. J. Org. Chem.  2005,  70:  1926 

<A NAME="RG03709ST-10A">10a</A> Basavaiah D. Pandiaraju S. Padmaja K. Synlett  1996,  393 

<A NAME="RG03709ST-10B">10b</A> Basavaiah D. Satyanarayana T. Org. Lett.  2001,  3:  3619 

<A NAME="RG03709ST-10C">10c</A> Kabalka GW. Venkataiah B. Dong G. Org. Lett.  2003,  5:  3803 

<A NAME="RG03709ST-10D">10d</A> Yadav JS. Gupta MK. Pandey SK. Reddy BVS. Sarma AVS. Tetrahedron Lett.  2005,  46:  2761 

<A NAME="RG03709ST-10E">10e</A> Nag S. Pathak R. Kumar M. Shukla PK. Batra S. Bioorg. Med. Chem. Lett.  2006,  16:  3824 

<A NAME="RG03709ST-11A">11a</A> Chung YM. Gong JH. Kim TH. Kim JN. Tetrahedron Lett.  2001,  42:  9023 

<A NAME="RG03709ST-11B">11b</A> Du Y. Han X. Lu X. Tetrahedron Lett.  2004,  45:  4967 

<A NAME="RG03709ST-11C">11c</A> Li J. Wang X. Zhang Y. Tetrahedron Lett.  2005,  46:  5233 

<A NAME="RG03709ST-11D">11d</A> Singh V. Yadav GP. Maulik PR. Batra S. Tetrahedron  2006,  62:  8731 

<A NAME="RG03709ST-11E">11e</A> Lee KY. Gowrisankar S. Lee YJ. Kim JN. Tetrahedron  2006,  62:  8798 

<A NAME="RG03709ST-12">12</A> Cho C.-W. Krische MJ. Angew. Chem. Int. Ed.  2004,  43:  6689 

<A NAME="RG03709ST-13A">13a</A> Trost BM. Tsui HC. Toste FD. J. Am. Chem. Soc.  2000,  122:  3534 

<A NAME="RG03709ST-13B">13b</A> Roy O. Riahi A. Henin F. Muzart J. Tetrahedron  2000,  56:  8133 

<A NAME="RG03709ST-13C">13c</A> Kobalaka GW. Dong G. Venkataiah B. Chen C. J. Org. Chem.  2005,  70:  9207 

<A NAME="RG03709ST-13D">13d</A> Nemot T. Fukuyama T. Yamamoto E. Tamura S. Fukuda T. Matsumoto T. Akimoto Y. Hamada Y. Hamada Y. Org. Lett.  2007,  9:  927 

<A NAME="RG03709ST-14">14</A> Shafiq Z. Liu L. Liu Z. Wang D. Chen Y.-J. Org. Lett.  2007,  9:  2525 

<A NAME="RG03709ST-15">15</A> Basavaiah D. Krishnamacharyulu M. Hyma RS. Sarma PKS. Kumaragurubaran N. J. Org. Chem.  1999,  64:  1197 

<A NAME="RG03709ST-16">16</A>

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): ν_max = 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 H_arom). ^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.

<A NAME="RG03709ST-17">17</A>

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): ν_max = 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 H_arom), 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): ν_max = 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 H_arom), 7.71-7.87 (m, 2 H_arom), 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.