pubs.acs.org/joc
Enantiopure trans-3-Arylaziridine-2-carboxamides: Preparation by Bacterial Hydrolysis and Ring-Openings toward Enantiopure, Unnatural D-r-Amino Acids† Roberto Mor an-Ramallal, Ram on Liz, and Vicente Gotor* Departamento de Quı´mica Org anica e Inorg anica and Instituto Universitario de Biotecnologı´a de Asturias, Universidad de Oviedo, E-33071 Oviedo, Spain
[email protected] Received July 13, 2010
Several racemic trans-3-arylaziridine-2-carboxamides were prepared and then resolved by Rhodococcus rhodochrous IFO 15564-catalyzed hydrolysis. The resulting enantiopure (2R,3S)-3-arylaziridine-2-carboxamides are adequate substrates to undergo fully stereoselective nucleophilic ring-openings at the C-3 ring position to finally yield enantiopure, unnatural D-R-aminocarboxylic acids. Experimental evidence is provided that suggests the fate of the (2S,3R)-3-arylaziridine-2-carboxylic acids concomitantly formed during the resolution processes. In this context, the similar bacterial resolution of racemic 1-arylaziridine2-carboxamides and -carbonitriles, previously investigated by our research group, has been partially re-examined.
Introduction The current interest in aziridine chemistry is reflected in a series of reviews published during the past 16 years, ranging from those dealing with synthesis and/or reactivity1 to other, more recent and specialized reviews covering areas such as nitrogen transfer reactions,2 parallel- and solid-phase synthesis,3 and C-heteroatom-substituted aziridines4 (including the C-lithiated varieties5). Several aziridine compounds exhibit antibiotic, †
Dedicated to the memory of the late Professor Jose Manuel Concell on. (1) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599–619. (b) Osborn, H. M. I.; Sweeney, J. Tetrahedron: Asymmetry 1997, 8, 1693– 1715. (c) Stamm, H. J. Prakt. Chem. 1999, 341, 319–331. (d) McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365. (e) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247–258. (f) M€ uller, P.; Fruit, C. Chem. Rev. 2003, 103, 2905–2919. (g) Hu, X. E. Tetrahedron 2004, 60, 2701–2743. (h) Zhang, Y.; Lu, Z.; Wulff, W. D. Synlett 2009, 2715–2739. (i) Sweeney, J. Eur. J. Org. Chem. 2009, 4911–4919. (j) Lu, P. Tetrahedron 2010, 66, 2549–2560. (2) Watson, I. D. G.; Lily, Y; Yudin, A. K. Acc. Chem. Res. 2006, 39, 194–206. (3) Olsen, C. A.; Franzyk, H.; Jaroszewski, J. W. Eur. J. Org. Chem. 2007, 1717–1724. (4) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Chem. Rev. 2007, 107, 2080–2131.
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antitumor, or other biological activities.1b,e Moreover, enantiopure or enantioenriched aziridines have recently received a great deal of attention as precursors of bioactive nitrogen-containing molecules, mainly through their varied regio- and stereoselective ring-opening reactions,1a,b,d,6 some of which meet most of the stringent criteria for a process to earn click chemistry status.7 As to their ring-opening processes, aziridines are usually classified as activated (those bearing an electron-withdrawing N-substituent such as acyl, sulfonyl, and phosphoryl) or unactivated (mainly the NH-, N-alkyl-, and N-arylaziridines). Ring-opening reactions of activated aziridines are easier and hence much more widely investigated than those of their unactivated counterparts, but suffer the drawback of requiring a further deprotection step of the amide or carbamate moiety present in their open products. Among recent examples of (5) Hodgson, D. M.; Bray, C. D.; Humphreys, P. G. Synlett 2006, 1–22. (6) (a) Cardillo, G.; Gentilucci, G.; Tolomelli, A. Aldrich. Acta 2003, 36, 39–50. (b) Lee, W. K.; Ha, H.-J. Aldrich. Acta 2003, 36, 57–63. (c) Pineschi, M. Eur. J. Org. Chem. 2006, 4979–4988. (7) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021.
Published on Web 09/02/2010
DOI: 10.1021/jo101377j r 2010 American Chemical Society
Moran-Ramallal et al.
enantiopure unactivated aziridine’s ring-openings, those of the following substrates are worth noting: a sizable number of N-[(R or S)-(1-phenylethyl)]-2-substituted aziridines, frequently converted into bioactive products by Ha, Lee, and co-workers;6b,8 several (10 S,2S)-N-alkyl-2-[1-(dibenzylamino)alkyl]aziridines opened with a set of heteronucleophiles by Concell on and co-workers;9 a 2-(2-pyridyl)aziridine derived from (S)-valinol also opened with a number of heteronucleophiles;10 and two 2-arylaziridines that underwent formal [3þ2] cycloaddition processes.11 Several groups have also investigated intramolecular ring-openings that are in fact aziridine expansion processes.6a,12 Our interest in this chemistry has recently been demonstrated by the preparation of a number of enantiopure N-alkyl- and N-arylaziridine-2-carboxamides by bacterial resolution and their further ring-openings, as well as those of some of their derivatives, with external13 and internal14 nucleophiles. Two weeks after our first paper, M.-X. Wang and coworkers also reported similar bacterial resolution of N-arylaziridine-2-carbonitriles and subsequent ring-openings of the resulting N-arylaziridine-2-carboxamides;15 while about eight months later they extended their work mainly to trans-3-arylN-methylaziridine-2-carbonitriles and -carboxamides.16 After comparing our work, carried out using the commercial bacterium Rhodococcus rhodochrous IFO 15564,17 and that of Wang et al., who use the commercially unavailable strain Rhodococcus erythropolis AJ270,18 several coincidences emerge, but also an important discrepancy (see first paragraph in the Results and Discussion section). In this paper we shall extend our work to trans-3-arylaziridine-2-carboxamides, which, besides having similar sizes to our first substrates, lack the N-substituent, which would lend greater versatility to the possible enantiopure products resulting from their resolutions and further ring-openings. Moreover, with the aim of clarifying the cited discrepancy, some of our first substrates13 will be again resolved and then worked up in an almost identical way to that of Wang et al.16 Results and Discussion Bacterial Resolution of 1-Alkyl- and 1-Arylaziridine-2carboxamides 1 and -carbonitriles 2. Scheme 1 shows our (8) (a) Yoon, H. J.; Kim, Y.-W.; Lee, B. K.; Lee, W. K.; Kim, Y.; Ha, H.-J. Chem. Commun. 2007, 79–81. (b) Kim, Y.; Ha, H.-J.; Yun, S. Y.; Lee, W. K. Chem. Commun. 2008, 4363–4365. (9) Concell on, J. M.; Bernad, P. L.; Suarez, J. R.; Garcı´ a-Granda, S.; Dı´ az, M. R. J. Org. Chem. 2005, 70, 9411–9416, and their own references therein. (10) Savoia, D.; Alvaro, G.; Di Fabio, R.; Gualandi, A. J. Org. Chem. 2007, 72, 3859–3862. (11) Zhu, W.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 5545–5548. (12) (a) Hori, K.; Nishiguchi, T.; Nabeya, A. J. Org. Chem. 1997, 62, 3081–3088. (b) Ferraris, D.; Drury, W. J., III; Cox, C.; Lectka, T. J. Org. Chem. 1998, 63, 4568–4569. (c) Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1, 2153–2156. (d) Lu, Z.; Zhang, Y.; Wulff, W. D. J. Am. Chem. Soc. 2007, 129, 7185–7194. (13) Mor an-Ramallal, R.; Liz, R.; Gotor, V. Org. Lett. 2007, 9, 521–524. (14) Mor an-Ramallal, R.; Liz, R.; Gotor, V. Org. Lett. 2008, 10, 1935– 1938. (15) Wang, J.-Y.; Wang, D.-X.; Zheng, Q.-Y.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2007, 72, 2040–2045. (16) Wang, J.-Y.; Wang, D.-X.; Pan, J.; Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 2007, 72, 9391–9394. The trans stereodescriptor refers to the substituents at the C-2 and C-3 positions. (17) Available from: (a) Institute for Fermentation, Osaka, Japan, IFO 15564 strain; (b) Colecci on Espa~ nola de Cultivos Tipo, Universidad de Valencia, Burjassot, Spain, CECT 5949 strain. (18) Both strains show nitrile hydratase and amidase activities.
JOC Article SCHEME 1. Our Previous Results in the Bacterial Resolution of Aziridines 1 and 2
previous results.13,14 The kinetic resolution of the amides 1 and the nitriles 2 by hydrolysis in the presence of R. rhodochrous IFO 15564 affords very good yields of the enantiopure amides 1, although the corresponding aziridine-2-carboxylic acids, 3, were never observed or isolated, in agreement with several prior observations.19 However, besides the enantiopure or almost enantiopure amides 1, Wang et al. claimed to obtain, in their R. erythropolis AJ270-mediated hydrolysis of a number of 1-arylaziridine-2-carbonitriles 2,20 very good yields of optically active (85 to >99.5% ee) methyl 1-arylaziridine2-carboxylates, which proceed from the in situ treatment of the corresponding acids 3 with diazomethane.15 As our experimental method and that of Wang and coworkers are not identical, we detected the following differences that might perhaps explain the previously mentioned divergent results: (1) Our substrate:whole cells wet weight ratio was approximately 2 mmol/1 g, whereas that of Wang et al. was 1 mmol/1 g. (2) In the isolation of the enantiopure amides 1, we continuously extracted the supernatant liquids resulting from the biotransformations (CH2Cl2, 40 °C, 6 h), whereas Wang et al. extracted them manually (AcOEt, rt). (3) For access to the amino acids 3, Wang et al. freeze-dried the remaining aqueous phases, whereas we concentrated them in vacuo with slight heating (99.5%. IR (CH2Cl2): 3450, 3367, 1665 cm-1. 1 H NMR (CD3OD, 400.13 MHz): 7.36 (d, Hc þ He, 3J = 8.5 Hz), 7.31 (d, Hb þ Hf, 3J = 8.5 Hz), 3.19 (br s, H3), 2.63 (br s, H2). 13 C NMR (CD3OD, 100.63 MHz): 173.5 (CO), 138.5 (Cd), 134.4 (Ca), 129.5, 128.9 (Cb þ Cf, Cc þ Ce), 40.8 (C2), 39.5 (C3). ESI-MS (m/z, %): 197.0 [(M þ H)þ, 100]. EI-HRMS: calcd for C9H9ClN2O, 196.0403; found, 196.0403. Ring-Opening of (2R,3S)-8a with MeOH-BF3 3 Et2O. BF3 3 Et2O (0.34 mmol, 43 μL) was added under nitrogen atmosphere at 0 °C to a stirred solution of (2R,3S)-8a (0.31 mmol, 50 mg) in anhydrous MeOH (2.0 mL). The mixture was heated at 55 °C for 8 h and then cooled in an ice bath. Aqueous 3 M NaOH was added until basic, and the mixture was extracted with AcOEt (3 10 mL). The combined organic layers were dried and the solvents removed under reduced pressure to quantitatively obtain (3R)-β-methoxy-D-phenylalaninamide [(2R,3R)-2-amino-3-methoxy3-phenylpropanamide], (2R,3R)-17 (60 mg). (3R)-β-Methoxy-D-phenylalaninamide [(2R,3R)-17]: white solid; mp 97.0-98.5 °C. [R]20D = -71.2 (c 1.0, MeOH). IR (CH2Cl2): 3405, 3300, 1676 cm-1. 1H NMR (CD3OD, 400.13 MHz): 7.507.30 (m, Ph), 4.42 (d, H3, 3J = 6.6 Hz), 3.68 (br s, H2), 3.26 (s, OCH3). 13C NMR (CD3OD, 100.63 MHz): 177.0 (CO), 138.7 (Cipso), 129.5, 128.9 (2Cortho, 2Cmeta, Cpara), 86.2 (C3), 60.6 (C2), 57.2 (OCH3). ESI-MS (m/z, %): 389.1 [(2M þ H)þ, 60], 357.1 [(2M þ H MeOH), 20], 195.1 [(M þ H)þ, 100]. Ring-Opening of (2R,3S)-8a with H2O-p-TsOH and Subsequent N-tert-Butoxycarbonylation. A mixture of (2R,3S)-8a (0.31 mmol, 50 mg), p-TsOH 3 H2O (0.34 mmol, 65 mg), and 7:1 MeCN-H2O (1.7 mL) was reacted at 55 °C for 8 h. After
Moran-Ramallal et al. removal of MeCN under reduced pressure, aqueous 3 M NaOH was added until basic, subsequently extracting the mixture with AcOEt (3 10 mL). The combined organic layers were dried and concentrated in vacuo, and the obtained residue was then treated overnight at room temperature with Boc2O (0.32 mmol, 70 mg) in MeOH (4.0 mL). After removal of MeOH under reduced pressure, the resulting crude material was purified by flash column chromatography [eluent, hexane-AcOEt: (1) 3:1; (2) 1:3] to yield (3R)-N2-Boc-β-hydroxy-D-phenylalaninamide {tert-butyl N-[(1R,2R)-1-carbamoyl-2-hydroxyethyl]carbamate}, (2R,3R)-20 (60 mg, 70% overall yield). (3R)-N2-Boc-β-Hydroxy-D-phenylalaninamide [(2R,3R)-20]: white solid; mp 183.6-184.9 °C. [R]20D = -29.5 (c 1.0, MeOH). ee > 99.5%. IR (CH2Cl2): 3503, 3393, 3346, 1685, 1663 cm-1. 1 H NMR (CD3OD, 300.13 MHz): 7.49-7.28 (m, Ph), 4.89 (superimposed d, H3), 4.35 (d, H2, 3J = 7.7 Hz), 1.34 [s, (CH3)3C]. 13 C NMR (CD3OD, 75.48 MHz): 175.9 (CONH2), 157.2 (NHCOOBut), 142.2 (Cipso), 129.1, 128.8, 128.2 (2Cortho, 2Cmeta, Cpara), 80.6 (OCMe3), 75.2 (C3), 60.6 (C2), 28.6 [C(CH3)3]. ESI-MS (m/z, %): 303.1 [(M þ Na)þ, 100], 203.1 [(M þ Na - C4H8 CO2)þ, 50]. Ring-Opening of (2R,3S)-8a with NaN3-BF3 3 Et2O. BF3 3 Et2O (0.34 mmol, 43 μL) was added under nitrogen atmosphere at 0 °C to a solution of (2R,3S)-8a (0.31 mmol, 50 mg) in anhydrous MeCN (1.5 mL), and the mixture was stirred at 0 °C during 10 min. A solution of NaN3 (0.93 mmol, 60 mg) in the smallest amount of water was then added, and the mixture was heated to 55 °C for 12 h. After cooling (ice bath), aqueous 3 M NaOH was added until basic, and the mixture was extracted with AcOEt (3 10 mL). The combined organic layers were dried and concentrated in vacuo to obtain (3R)-β-azido-D-phenylalaninamide [(2R,3R)-2-amino3-azido-3-phenylpropanamide], (2R,3R)-22 (58 mg, 92%). (3R)-β-Azido-D-phenylalaninamide [(2R,3R)-22]: white solid; mp 127.0-128.0 °C. [R]20D = -172.5 (c 1.0, MeOH). IR (CH2Cl2): 3377, 3055, 1689 cm-1. 1H NMR (CD3OD, 400.13 MHz): 7.527.30 (m, Ph), 4.86 (partially superimposed d, H3, 3J = 7.0 Hz), 3.66 (d, H2, 3J = 7.0 Hz). 13C NMR (CD3OD, 100.63 MHz): 176.7 (CO), 137.1 (Cipso), 129.9, 129.2 (2Cortho, 2Cmeta, Cpara), 69.7 (C3), 60.0 (C2). ESI-MS (m/z, %): 206.1 [(M þ H)þ, 100], 163.1 [(M þ H CONH2)þ, 23]. Ring-Opening of (2R,3S)-8a by Catalytic Hydrogenolysis. (2R,3S)-8a (0.31 mmol, 50 mg) and 10% Pd/C (48 mg) were placed in a 50 mL round-bottomed flask. The flask was stoppered with a rubber septum and evacuated (rotary pump). A hydrogen-filled balloon was then connected via a needle, and MeOH (6.0 mL) was added via a syringe. The mixture was stirred at room temperature for 2.5 h and then filtered through a pad of diatomaceous earth. After washing the pad with MeOH, the combined methanol solutions were concentrated in vacuo to yield a crude material, which was finally purified by flash column chromatography (MeOH as eluent) to obtain D-phenylalaninamide [(R)-2-amino-3-phenylpropanamide], (R)-31a (46 mg, 90%). The aziridineamide (R)-8g (0.284 mmol, 50 mg) was hydrogenolyzed in a similar way, except that no chromatographic purification was required, to yield almost quantitatively β-(p-tolyl)D-alaninamide [(R)-2-amino-3-(4-methylphenyl)propanamide], (R)-31g. D-Phenylalaninamide [(R)-31a]: white solid; mp 131.0-132.5 °C (lit.:59 135-137 °C). [R]20D = -12.5 (c 1.0, MeOH) [lit.: -9.0 (c 1.0, MeOH), ee 77%]. IR (CH 2 Cl 2 ): 3295, 3200, 3054, 1681 cm-1. 1H NMR (CD3OD, 400.13 MHz): 7.37-7.20 (m, Ph), 3.60 (dd, H2, 3J = 7.6, 3J = 6.0 Hz), 3.06 [dd, C(3)HH, 2J = 13.4, 3 J = 6.0 Hz], 2.83 [dd, C(3)HH, 2J = 13.4, 3J = 7.6 Hz]. 13C NMR (CD3OD, 100.63 MHz): 179.5 (CO), 138.9 (Cipso), 130.4 (2Cortho), 129.5 (2Cmeta), 127.7 (Cpara), 57.4 (C2), 42.5 (C3). ESI-MS (m/z, %): 329.1 [(2M þ H)þ, 15], 165.0 [(M þ H)þ, 100]. (59) Wang, M.-X.; Lin, S.-J. J. Org. Chem. 2002, 67, 6542–6545.
JOC Article General Procedure for N-tert-Butoxycarbonylation of r-Aminoamides (2R,3R)-17, (2R,3R)-22, and (R)-31a,g. Each R-aminoamide (0.31 mmol) was treated overnight at room temperature with Boc2O (0.39 mmol, 84 mg) in MeOH (5.0 mL). After removal of MeOH under reduced pressure, the resulting crude material was purified by flash column chromatography [eluent, hexane-AcOEt: (1) 3:1; (2) 1:1], yielding the following tert-butyl carbamates: (3R)-N2-Boc-β-methoxy-D-phenylalaninamide [(2R,3R)-18]: yield 83%; white solid; mp 200.2-201.4 °C. [R]20D = -61.9 (c 0.8, MeOH). ee > 99.5%. IR (CH2Cl2): 3391, 3354, 1685, 1660 cm-1. 1H NMR (DMSO, 300.13 MHz): 7.41 (br s, CONHH), 7.35-7.21 (m, Ph), 7.01 (br s, CONHH), 6.57 (d, NHBoc, 3J = 9.4 Hz), 4.27 (d, H3, 3J = 9.0 Hz), 4.13 (t, H2, J = 9.2 Hz), 3.06 (s, OCH3), 1.19 [s, (CH3)3C]. 13C NMR (DMSO, 75.48 MHz): 172.3 (CONH2), 154.7 (NHCOOBut), 138.6 (Cipso), 128.0, 127.9 (2Cortho, 2Cmeta, Cpara), 82.9 (C3), 78.1 (OCMe3), 58.5 (C2), 56.6 (OCH3), 28.2 [C(CH3)3]. ESI-MS (m/z, %): 489.2 [(2MþH-C4H8 -CO2)þ, 60], 295.1 [(MþH)þ, 18], 195.1 [(M þ H - C4H8 - CO2)þ, 100]. ESI-TOF-HRMS: calcd for C15H22N2O4, 295.1652; found, 295.1644. (3R)-β-Azido-N2-Boc-D-phenylalaninamide [(2R,3R)-23]: yield 85%; white solid; mp 183.3-184.7 °C. [R]20D = -126.3 (c 1.0, MeOH). ee > 99.5%. IR (CH2Cl2): 3388, 3346, 1686, 1660 cm-1. 1 H NMR (DMSO, 300.13 MHz): 7.63 (br s, CONHH), 7.42-7.25 (m, Ph), 7.23 (br s, CONHH), 6.87 (d, NHBoc, 3J = 9.3 Hz), 4.77 (d, H3, 3J = 9.3 Hz), 4.30 (t, H2, 3J = 9.3 Hz), 1.20 [s, (CH3)3C]. 13C NMR (DMSO, 75.48 MHz): 171.5 (CONH2), 154.7 (NHCOOBut), 136.4 (Cipso), 128.6, 128.5, 128.3 (2Cortho, 2Cmeta, Cpara), 78.4 (OCMe3), 65.5 (C3), 57.0 (C2), 28.1 [C(CH3)3]. ESI-MS (m/z, %): 511.2 [(2M þ H - C4H8 - CO2)þ, 100], 427.1 (85), 306.1 [(M þ H)þ, 10], 279.0 [(M þ H - CHN)þ, 38], 206.0 [(M þ H - C4H8 - CO2)þ, 70]. N2-Boc-D-Phenylalaninamide [(R)-34a]: yield 85%; white solid; mp 153.1-154.3 °C (lit.:60 141-143 °C). [R]20D = -12.8 (c 1.0, MeOH) [lit.: -14.5 (c 1.0, EtOH)]. ee > 99.5%. IR (CH2Cl2): 3392, 3346, 1678, 1657 cm-1. 1H NMR (CDCl3, 400.13 MHz): 7.35-7.17 (m, Ph), 6.24 (br s, CONHH), 6.03 (br s, CONHH), 5.31 (br s, NHBoc), 4.44 (br s, H2), 3.04 [br s, C(3)H2], 1.38 [s, (CH3)3C]. 13C NMR (CDCl3, 100.63 MHz): 174.0 (CONH2), 155.4 (NHCOOBut), 136.6 (Cipso), 129.2, 128.5 (2Cortho, 2Cmeta), 126.8 (Cpara), 80.0 (OCMe3), 55.2 (C2), 38.5 (C3), 28.2 [C(CH3)3]. ESI-MS (m/z, %): 429.2 [(2M þ H - C4H8 - CO2)þ, 100], 165.0 [(M þ H - C4H8 - CO2)þ, 37]. EI-HRMS: calcd for C14H20N2O3, 220.1338 (M - CONH2)þ; found, 220.1339. In a similar way N2Boc-β-(p-tolyl)-D-alaninamide [(R)-34g] (83% yield) was prepared. Hydrolysis of the Carbamoylcarbamates (2R,3R)-18, (2R,3R)-20, and (R)-34a,g. A suspension of the corresponding carbamoylcarbamate (0.14 mmol) in 6 M HCl (2.6 mL) was refluxed for 3 h and then cooled at room temperature. After concentrating to nearly dryness under reduced pressure, the obtained residue was washed with AcOEt (2 7.5 mL), with in vacuo removal of the solvent after each washing. The resulting solid was dried in vacuo over P2O5 (10 h, room temperature) to yield the corresponding D-R-amino acid hydrochloride. The D-R-amino acid hydrochloride (0.13 mmol, 30 mg) proceeding from (2R,3R)-18 was further transformed (for identification purposes) into the free amino acid by treatment with propylene oxide (31 mmol, 2.2 mL) in EtOH (10 mL) at 90 °C for 1 h.61 Finally, the solvent and volatile compounds were removed under reduced pressure to yield (3R)-β-methoxy-D-phenylalanine [(2R,3R)-19]. (3R)-β-Methoxy-D-phenylalanine [(2R,3R)-19]: yield 90%; white solid; mp 190.0-192.0 °C. [R]20D = -37.3 (c 0.6, H2O) [lit.:46 þ34.5 (c 0.6, H2O) for (2S,3S)-19]. IR (Nujol): 3131, 3048, 1614 cm-1. 1H NMR (D2O, 300.13 MHz): 7.40-7.17 (m, Ph), 4.79 (d, H3, 3J = 3.5 Hz), 4.05 (d, H2, 3J = 3.5 Hz), 3.26 (s, OCH3). 13C (60) Pozdnev, V. F. Tetrahedron Lett. 1995, 36, 7115–7118. (61) Jefford, C. W.; McNulty, J. Helv. Chim. Acta 1994, 77, 2142–2146.
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JOC Article NMR (D2O, 100.63 MHz): 174.3 (CO), 135.5 (Cipso), 128.8, 128.7, 127.2 (2Cortho, 2Cmeta, Cpara), 82.4 (C3), 59.5 (C2), 56.6 (OCH3). ESI-MS (m/z, %): 196.1 (Mþ, 100). (3R)-β-Hydroxy-D-phenylalanine hydrochloride [(2R,3R)-21]: yield 95%, white solid; mp 171.5-172.6 °C (dec) [lit.:49 174 °C (dec)]. [R]20D = -59.3 (c 1.0, 6 M HCl) [lit.: -63.2 (c 0.65, 6 M HCl)]. IR (Nujol): 3424, 3315, 3123, 3032, 1735 cm-1. 1H NMR (D2O, 400.13 MHz): 7.42-7.27 (m, Ph), 5.29 (d, H3, 3J = 3.8 Hz), 4.29 (d, H2, 3J = 3.8 Hz). 13C NMR (D2O, 100.63 MHz): 169.4 (CO), 136.9 (Cipso), 129.0, 128.9 (2Cortho or 2Cmeta, Cpara), 126.1 (2Cmeta or 2Cortho), 70.8 (C3), 58.9 (C2). ESI-MS (m/z, %): 182.1 (Mþ, 100). β-(p-Tolyl)-D-alanine hydrochloride [(R)-35g]: yield 95%; white solid; mp 264.0-265.1 °C. [R]20D = þ10.0 (c 1.0, H2O) [lit.:57 -6.5 (c 0.1, 0.5 M HCl) for (S)-35g]. IR (Nujol): 3399, 3142, 2923, 1738 cm-1. 1H NMR (D2O, 300.13 MHz): 7.16 (d, 2Hortho or 2Hmeta, 3J = 8.1 Hz), 7.11 (d, 2Hmeta or 2Hortho, 3J = 8.1 Hz), 4.18 (dd, H2, 3J = 7.6, 3J = 5.5 Hz), 3.19 [dd, C(3)HH, 2 J = 14.5, 3J = 5.5 Hz], 3.07 [dd, C(3)HH, 2J = 14.5, 3J = 7.6 Hz], 2.22 (s, CH3). 13C NMR (D2O, 75.48 MHz): 172.1 (CO), 138.4, 131.1 (Cipso, Cpara), 130.0, 129.6 (2Cortho, 2Cmeta), 54.7 (C2), 35.5 (C3), 20.4 (CH3). ESI-MS (m/z, %): 180.0 (Mþ, 100). In a similar way D-phenylalanine hydrochloride [(R)-35a] (95% yield) was prepared. Hydrogenolysis of the Azido Group in the Azido(carbamoyl)carbamate (2R,3R)-23. (2R,3R)-23 (0.115 mmol, 35 mg) and 10% Pd/C (18 mg) were placed in a 50 mL round-bottomed flask. The flask was stoppered with a rubber septum and evacuated (rotary pump). A hydrogen-filled balloon was then connected via a needle, and MeOH (2.2 mL) was added via a
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Mor an-Ramallal et al. syringe. The mixture was stirred at room temperature for 12 h and then filtered through a pad of diatomaceous earth. After washing the pad with MeOH, the combined methanol solutions were concentrated in vacuo to quantitatively obtain (3R)-β-aminoN2-Boc-D-phenylalaninamide {tert-butyl N-[(2R,3R)-2-amino1-carbamoyl-2-phenylethyl]carbamate}, (2R,3R)-24 (32 mg). (3R)-β-Amino-N2-Boc-D-phenylalaninamide [(2R,3R)-24]: colorless oil. [R]20D = -13.8 (c 1.0, MeOH). IR (film): 3400, 3362, 1680, 1656 cm-1. 1H NMR (CD3OD, 400.13 MHz): 7.45-7.22 (m, Ph), 4.35 (poorly resolved d, H2, 3J = 6.4 Hz), 4.20 (poorly resolved d, H3), 1.36 [s, (CH3)3C]. 13C NMR (CD3OD, 100.63 MHz): 175.8 (CONH2), 157.4 (NHCOOBut), 142.4 (Cipso), 129.4, 128.6, 128.5 (2Cortho, 2Cmeta, Cpara), 80.6 (OCMe3), 60.9 (C3 or C2), 58.5 (C2 or C3), 28.6 [C(CH3)3]. ESI-MS (m/z, %): 280.1 [(M þ H)þ, 100], 180.1 [(M þ H - C4H8 - CO2)þ, 5].
Acknowledgment. The authors gratefully thank Dr. Francisca Rebolledo, University of Oviedo, for prior scientific criticism of the manuscript. R.M.-R. wishes to thank the Ministry of Education and Science of Spain (MEC) for a predoctoral fellowship. This work was supported by the MEC (Project CTQ2007-61126). Supporting Information Available: Experimental procedures, characterization data, assignment of absolute configurations, and copies of 1H, 13C, and HMBC NMR spectra. This material is available free of charge via the Internet at http:// pubs.acs.org.
