Reactions of Azidoacetate Enolates with Aromatic Aldehydes: Preparation of N-BOC 3-Arylserines

Abstract

Azidoacetates undergo aldol-like reaction with aromaticaldehydes in the presence of sub-stoichiometric amounts of NaOEt. Theproduct azido alcohols (2a)-(2q) may be directly converted to N-BOC phenyl serine analogues Keywords: aminoacids, arylserines As part of a program of research concerning incorporation of non-proteinogenic aminoacids into polypeptides, we required a new entry to a range of 2-amino-3-hydroxyesters. 1 We thought that such compounds would be available from the corresponding azidoalcohols, and that if such compounds could be prepared via an aldol-like reaction, this would represent a useful addition to the armoury of synthetic chemistry. We here report the preliminary results wehave obtained from study of such reactions. Scheme 1The reaction of aryl aldehydes with ethylazidoacetate is well-known to give good yields of 2-azidocinnamates (1), through the intermediacy of hydroxyazide (2) (Scheme 1), the reaction forming the basis of the Hemetsberger-Knittelsynthesis of indoles. 2 Very littlework has been reported concerning the interception of the reaction to allow isolation of these hydroxyazides, 3 and our synthetic studies commenced here. Thus, reaction of benzaldehyde with ethylazidoacetate in the presence of one equivalent of sodium ethoxide in ethanol at room temperature overnight gave, as expected, a good yield of azidocinnamate (1a). We then repeated the reaction at low temperature, this time using a hindered base (LDA) and an aprotic solvent (THF): we isolated only starting materials from the reaction. Using a variety of strong bases, a similar lack of success was observed. When the original, protic reaction was repeated using a sub-stoichiometric amountof base (0.1eq.), rather than a full equivalent, no azidocinnamate was observed and hydroxyazide (2a) was isolated as the only product of the reaction, in 46% yield (Scheme2). This observation is at odds with that previously described, which concluded that azidoalcohols could only be obtained from such reactions when reaction temperatures were considerably lower than ambient (ca. -40°C). 3 Thus, (2a) was obtained as a 2:1 mixture of diastereoisomers, in favour of the syn-isomer (as judged from analysis of 1 H nmr data); 4 the isomers were not separable using standard column chromatography.When (2a) was resubjected to the dipolar, aprotic reaction conditions previously examined, (LHMDS base, THF solvent,-78°C), retro-aldol reaction occurred and only ethyl azidoacetate andbenzaldehyde were isolated from the re- Table 1 Preparation of 2-Azido-3-Hydroxyesters via Azidoaldol reaction Downloaded by: UC Santa Barbara. Copyrighted material.

Highly Stereocontrolled and Regiocontrolled Syntheses of 2,3,4-Trisubstituted Alkanoates and Lactones

“…Microwave experiments were run using a Biotage Initiator system with an external contact temperature probe. 1 H NMR and 13 C NMR spectra were recorded at 400 and 100 MHz or at 300 and 75 MHz, respectively, using the residual solvent peak as the internal standard. High-resolution mass spectrum fast atom bombardment (HRMS-FAB) and electron impact (HRMS-EI) mass spectra were obtained using a VG70SE double-focusing magnetic sector mass spectrometer equipped with a Cs þ ion gun (28 kV @ 2 μA), an off-axis multiplier, and an MSS data system.…”

“…TLC: one spot, R f = 0.50 (40% ethyl acetate in hexanes). 1 AlCl in hexanes (0.028 mL, 1.0 equiv) was added, and the reaction mixture was stirred for 30 min, after which the cooling bath was removed and the reaction was stirred for an additional 1 h. At this time, a 1 M solution of Et 2 AlCl (0.014 mL, 0.5 equiv) was added and the reaction mixture stirred at room temperature for 1 h, after which an additional 1 M solution of Et 2 AlCl (0.014 mL, 0.5 equiv) was added and the reaction stirred for an additional 1 h. At this time, TLC analysis indicated complete consumption of the starting trichloroacetimidate (()-11. The reaction mixture was quenched with H 2 O and extracted with EtOAc (4Â).…”

“…TLC: one spot, R f = 0.57 (40% ethyl acetate in hexanes). 1 Azido Diol (()-21. In a dried 0.5À2.0 mL conical microwave vial, fitted with a magnetic stirrer, were added (()-10 (10 mg, 0.04 mmol), dimethylformamide (0.5 mL), ammonium chloride (6 mg, 0.12 mmol), and sodium azide (7 mg, 0.12 mmol).…”

“…TLC: one spot, R f = 0.44 (40% ethyl acetate in hexanes). 1 H NMR (400 MHz, CDCl 3 ): δ 7.31À7.27 (m, 2H), 7.22À7.17 (m, 3H), 4.06À4.04 (d, 1H, J = 6.4 Hz), 3.75À3.72 (m, 2H), 3.17À3.15 (d, 1H, J = 6.4 Hz), 2.84À2.77 (AX of ABX, 1H), 2.74À2.66 (BX of ABX, 1H), 2.17À2.15 (br d, 1H, J = 5.6 Hz), 2.02À1.93 (A 0 X of A 0 B 0 X, 1H), 1.85À1.76 (B 0 X of A 0 B 0 X, 1H), 1.49 (s, 9H). 13 Dihydroxy Lactone (()-26.…”

“…TLC: one spot, R f = 0.28 (40% ethyl acetate in hexanes). 1 H NMR (400 MHz, CDCl 3 ): δ 7.33À7.29 (m, 2H), 7.24À7.21 (m, 3H), 4.66À4.65 (d, 1H, J = 4.0 Hz), 4.38À4.34 (m, 2H), 2.91À2.84 (AX of ABX, 1H), 2.82À2.75 (BX of ABX, 1H), 2.38À2.29 (A 0 X of A 0 B 0 X including br s at 2.32, 2H), 2.16À2.07 (B 0 X of A 0 B 0 X, 1H), 1.56 (br s, 1H). 13 ' ASSOCIATED CONTENT b S Supporting Information.…”