Synthetic studies for novel structure of alpha;-nitrogenously functionalized alpha;-fluorocarboxylic acids. Part 1. The first synthesis and reactions ofN-protected alpha;-fluoroglycines

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1991 Synthetic Studies for Novel Structure of a-Nitrogenously Functionalized a-Fluorocarboxylic Acids. Part I. The First Synthesis and Reactions of N-Protected a-Fluoroglycines Yoshio Takeuchi," Manabu Nabetani, Kumiko Takagi, Toru Hagi and Toru Koizumi Faculty of Pharmaceutical Sciences, Toyama Medical amp; Pharmaceutical University, Sugitani 2630, Toyama 930-01,Japan The first synthesis of the N-protected a-fluoro-or-amino acid esters 12, 13, 21 and 22, and the corresponding acids 16 and 24, is described. Reaction of ethyl and t-butyl bromofluoroacetates 4 and 9 with di-t-butyl and dibenzyl iminodicarboxylate potassium salts IOc and 20b gave the fluoroglycine derivatives 12, 13, 21 and 22, respectively. Hydrolysis of the ethyl ester 12 and the t-butyl ester 22 successfully afforded the key compounds N,N-di(t-butoxycarbonyl) -a-fluoroglycine 16 and N,N-di( benzyloxycarbonyl) -a-fluoroglycine 24.Conversion into the novel structure of a-fluoroglycine itself (1; R = H) by acidic N-deprotection of compound 16 or hydrogenative debenzylation of compound 24, however, failed to produce any decomposition products associated with de h yd rof Iuori nat ion. Following recent rapid progress in studies on the synthesis and reactions of organofluorine compounds, many attempts have been made to introduce a fluorine atom into biologically significant molecules such as sugars and steroids.' There have also been quite a few attempts at chemical2 and enzymatic3 syntheses and biological activity examination of fluorine- containing a-amino acids in anticipation of the inherent chemical properties and activities caused by the introduction of a fluorine atom.However, no compounds have been reported where fluorine (or any other halogen atom) is introduced into the a-position (k,on the chiral centre) of any a-amino acid. The reason for this seems to be the inherent instability of the geminally halogenated amine moiety, which easily dehydro- halogenates to form another unstable structure -an imine. The a-amino-a-halogeno acids are therefore significant not only as modified bioactive compounds but also from a structural chemistry viewpoint, although they are small molecules. F IR -C-C02-I+ N"3 1 We thought the a-fluoro-a-amino acid structure 1 might be capable of existing under certain controlled conditions because of the general strength of the C-F bond, as evidenced by the meagre leaving ability of fluoride ion compared with the other halide ions.There had been, however, no published syntheses of any a-nitrogenously functionalized a-fluorocarboxylic acid derivatives before we first reported our preliminary work.6 We here describe a full account of the synthetic details of the preparation of this new class of fluorine compounds and our attempted construction of the novel a-fluoro-a-amino acid structure 1. Results and Discussion Since both selective monofluorination7 at the a carbon of protected amino acid derivatives and electrophilic amination t of 2-fluoro esters seemed very difficult, we attempted nucleo- philic introduction of the amino functionality into 2-fluoro esters.Ammonolysis of 2-bromo-2-fluorocarboxylic acids 2a or esters 2b,prepared from the corresponding a-amino esters," produced mixtures of undesired dehydrohalogenated products 3a or 3b. In order to avoid the problem of elimination, we next examined the simplest structure of the clan, namely ethyl bromofluoroacetate 4. Reaction of compound 4 with ammonia 5a or the protected amine derivatives 5M l1 in the presence of an appropriate base, however, did not give the desired compounds 8, yielding instead mainly bromofluoroacetamide (6) l2 from substrates 5a-and defluorination product 7from 5d, respectively, probably due to the instability of the metal amide nucleophiles or the high reactivity of the products (Scheme 1).F = PhIRi-C-C02R2 (R' = Me,CH2Ph) -I (" )H C02R2 X=F*BrIBr 2a; R~=H b; R2= Et F IH-C-CO2Et + RNH2 ii I Br 4 5a;R=H b; R=COCF3 C; R = C02CHzPh d; R=COCH2Ph 3a; R~ = H b; R2 = Et BrFCHCONH2 6 F * I I NHR H-C-CO2Et OH I H-C-CO2Et a I N HCOC H2P h 7 Scheme 1 Reagents: i, NH,, EtOH; ii, NaH, KH, KOBu', or LDA, THF or EtOH Our next attempt at the introduction of nitrogenous functionality onto the fluorine-bearing carbon focused on Gabriel's method.' Reaction of bromo ester 4 with potassium phthalimide 10a in heated N,N-dimethylformamide (DMF) successfully produced the first a-fluorinated a-amino acid derivative, N-phthaloyl-a-fluoroglycine ethyl ester 11.6 How-ever, application of the rather vigorous conditions required for removal of the phthaloyl group l4 and also for cleavage of the t Electrophilic amination using various reagents * was unsuccessful presumably due to the difficulty of generating a-fluorocarbanion~.~ 50 ester linkage 15,16 to product 11 damaged the C-F bond.In the course of considering much more gentle deprotective conditions adaptable to later stages of our synthetic strategy, we chose di-t- butyl iminodicarboxylate 10b as an amino functionality, which was prepared easily from t-butyl oxamate according to the method l7 of Jones. Condensation of the potassium salt 1Oc with the ethyl ester 4 and the corresponding t-butyl ester 9 ' in DMF gave the fluoroglycine derivatives 12 and 13, respectively, in gaod yield (Scheme 2).F I H-C-CO2R' + MN(COR2)2I Br 4 R' = Et 10 a; M = K, R2-$ = 9 R'= But b; M = H, R2= OBu' C; M = K,R~= OBU' Ii t F I H-C-CO2R' I N(COR2), 12 R' = Et, R2 = OBU' 13 R' = But, R2 = OBu' Scheme 2 Reagents and conditions: i, DMF, 9amp;120 "C (72-89 yield) The key compounds 12 and 13 now being to hand, we started to investigate their possible construction into the novel m-fluoro amino acid structure (1; R = H). The well known C-F bond stability was also a matter of interest in our case.19 Acidic cleavage of the amino protective group of compound 12 with CF,CO,D resulted in the formation of defluorinated products 15, presumably via the oxazolone intermediate 14.Therefore, cleavage of the ester moiety prior to deprotection of the amino group seemed indispensable to maintain the fluorine atom. Saponification of the ethyl ester 12 with 5 NaOH was accomplished smoothly, happily without the anticipated defluorination, to afford the N-protected a-fluoroglycine 16 in excellent yield. The final process was attempted by treatment of compound 16 with a catalytic amount of CF3C02D or HF in CDC1, as monitored by 'H and 19FNMR spectroscopy. One of the two carboxylates protecting the amino group was cleaved easily to form the unstable N-t-butoxycarbonyl-a-fluoroglycine 17.*However, prolonged exposure of compound 17 to an excess of acidic media (HF in CDCI,), in expectation of complete deprotection, seemed unsatisfactory.Decomposition of com- pound 17 under acidic media via the N-carboxyimine structure 18 could be the possible reason.? Similar acid-treatment of * As the signals of 16 decreased in intensity, new signals which originated from compound 17 S, 1.51 (9 H, s, But) and 6.27 (1 H, d, J 47.9 Hz); 6, -157.06 (d, J47.8 Hz) and Bu'F S, 1.38 (9 H, d, J21.2 Hz, Bu'); SF -131.11 (10-plet, J21.4 Hz) appeared as monitored by NMR spectroscopy.7 Finally, a t-butyl signal S, 1.28 (s) which seemed to correspond to structure 18 was observed, and after removal of all volatile material no fluorine-containing compounds were found in the residue as checked by the NMR spectra.$ The yield of 20a was sometimes meagre both because of its instability and the difficulty of separating it from the reaction admixture. 5 When the saponification of ester 21 was carried out with aq. NaOH- THF, N-benzyloxycarbonyl-cc-hydroxyglycinewas obtained. J. CHEM. SOC. PERKIN TRANS. 1 1991 t-butyl ester 13 resulted in the formation of the partially deprotected t-butyl ester 19 as evidenced by NMR spectroscopy, which upon application of the stronger acidic conditions produced the same compound 18 (Scheme 3). ii IH-C-CO~H iii 12 -F - H-C-CO,H I N(CO2BU32 iHC0,Bd I 16 17 li -1iL OBu' 1 // 14 F I l5 / -"H-C-COZHII .---*decomposition NHCO~BU' NC02But products 19 18 Scheme 3 Reagents and conditions: i, CF,CO,D, CDCl,; ii, 5 NaOH, EtOH (92 yield); iii, catalytic amount of CF,CO,D or HF, CDCl,; iv, excess of HF, CDCl, From these results, application of acidic conditions for the removal of the N-protective group at the final step seemed unfavourable because we anticipated that protonation on the fluorine atom would accelerate dehydrofluorination. Free amine generation and concomitant zwitterion formation (as depicted by structure 1) should be necessary at the final stage since carboxylate ion formation would suppress deprotonation of the amino group which could be the initial stage of dehydrofluorination.In considering these results, we decided that neutral conditions for N-deprotection such as hydro-genative deprotection at the final stage would probably be the only way in which we might accomplish our synthesis.Neutral conditions would also be helpful in the work-up procedure so that the target compound could be isolated without tedious manipulation. It was now necessary to obtain the benzyl analogue 20a, which Jones reported as being so difficult to prepare. After several attempts, including the unsuccessful application of a modified published procedure,20 we finally found a simple reaction to obtain compound 20a. Reaction of benzyl carbamate with benzyl chloroformate in the presence of an equimolar amount of potassium hydride produced target compound 20a in 64 yield.$ The dibenzyl iminodicarboxylate 20a was treated with aqueous KOH to afford the potassium salt 20b.Introduction of the new amino functionality 20b into bromo esters 4 and 9 was achieved satisfactorily, under conditions similar to the preparation of compounds 12 and 13, to produce the protected fluoroglycine esters 21 and 22, respectively. In contrast to the case of the t-butyl carbamate derivative 12, attempted hydrolysis of the benzyl carbamate ethyl ester 21 produced unwanted products. Thus, saponification of com- pound 21 with aq. NaOH-EtOH gave the fluorination product 23,s presumably via the same mechanism as the formation of compound 15. More gentle saponification conditions using LiOH or Ba(OH), afforded the carbamate 20a. Application of trimethylsilyl iodide (TMSI) or other non-saponificative conditions to compound 21 was also unsuccessful, yielding J.CHEM. SOC. PERKIN TRANS. 1 1991 F 4or11 I H2NC02CH2Ph + CIC02CH2Ph MN(C02CH2Ph)2 iii H-C-CO2RN(C02CH2Ph)2I 5c 20a; M=H-J~~ 21 R=Et b; M=K 22 R = Bu' OEt iv I- 21 H-C-CO2H 1 NHC02CHZPh 22 20a viiPhCH21 F F I I H-C-C02--+H-C-C02H decomposition I+ I NH3 N(C02CH2Ph)2 1; R=H 24 25 Scheme 4 Reagents and conditions:i, KH, THF (64yield); ii, aq. KOH, EtOH (100 yield); iii, DMF, 90-120 "C, 2-5 h (38-52'/; yield); iv, 5 NaOH, EtOH; v, LiOH or Ba(OH),, aq. THF; vi, TMSI, CDCI,; vii, CF,CO,D, CDC1, (49 yield); viii, H,/Pd-C, EtOH mainly PhCH,I rather than EtI and the decomposed counterpart. We finally tried the t-butyl ester 22,treatment of which with CF3C0,D in CDCl, successfully produced the desired carboxylic acid 24 in 49 yield. Compound 24 was submitted to Pd/C-catalysed hydrogenation.We hoped that, after completion of the reaction, removal of the catalyst and evaporation of any volatile material would yield the target compound (1; R = H) in an almost pure state. Hydrogenolysis of an ethanolic solution of compound 24 in the presence of 5 Pd/C, however, to our extreme disappointment, produced again unidentified defluorination products, as verified by 'H and "F NMR spectroscopy.* The use of TMSI for carbamate cleavage ,' of compound 24 was also attempted, but afforded initially the oxazolone 25, which decomposed slowly, accompanied by defluorination as had already been observed (Scheme 4).To sum up, we have developed the new amino functionality 20b and have succeeded for the first time in the preparation of several novel a-fluorinated a-amino acid derivatives, viz. 12,13, 16,21,22and 24.Although interconversion of protected amino acid 16 or 24 into the a-fluoro-a-amino acid itself was unsuccessful, we are currently examining the possible construction of the structural moiety of peptides containing an a-fluoro amino acid as a constituent. Experimental M.p.s were determined on a Yanagimoto apparatus and are uncorrected. B.p.s for micro-scale distillation indicate bath temperature. IR spectra were recorded on a JASCO A-102 or a Perkin-Elmer 1600 spectrometer. 'H NMR spectra were measured in CDCl, with Meamp; as internal standard and were recorded on a JEOL PMX-60 (60 MHz) or a JEOL GX-270 (270 MHz) spectrometer. 19F NMR spectra were measured in CDCl, with CFC13 as internal standard and were taken with a JEOL GX-270 (254 MHz) spectrometer.Upfield shifts are quoted as negative. Electron-impact (EI) mass spectra were taken with a JEOL JMS-300 spectrometer. Column chromatography was performed using Kieselgel60 (Merck, Art. 9385). * After substrate 24 had disappeared as monitored by TLC (ca. 30 h hydrogenation), the catalyst and the volatile materials were removed to give a semi-solid. Although debenzylation proceeded completely NMR spectra (in CD,COCD,), the characteristic signals S, 4.92 (d, J 116.0 Hz); 6, -150.81 (s) and -150.52(d, J 115.8 Hz) were difficult to assign to the target structure (1; R = H).General Procedure for Preparation of Bromojluoroacetamide 6.',-To a stirred, ice-cooled solution of trifluoroacetamide 5b or benzyl carbamate 5c (2 mmol) and an appropriate base (2 mmol) in tetrahydrofuran (THF) (10 cm3) was added a solution of ethyl bromofluoroacetate 4 (370 mg, 2 mmol) in THF (2 cm3). Precipitates formed immediately. The reaction mixture was stirred at 0-20 "C for 3.5-12 h. Evaporation of the solvent gave a semi-solid, which was chromatographed on silica gel with PhH-AcOEt (2: 1) as eluent to afford the title compound 6 as crystals in 35-8 1 yield; m.p. 40.5-41.0 "C; v,,,(KBr)/cm-' 3400 (NH) and 1685 (CO); amp;(60 MHz) 6.65 (1 H, d, J 51.2 Hz, CHF) and 6.80 (2 H, br, NH,); m/z 157,155 (M') and 113,111 (M+ -CONHI).Reaction of bromo ester 4 with ethanolic ammonia also produced the amide 6.' Ethyl 2-Hydro,uy-2-(phenylacetamido)acetate7.-A mixture of phenylacetamide 5d (203 mg, 1.5 mmol), bromo ester 4 (279 mg, 1.5 mmol) and Et3N (152 mg, 1.5 mmol) in THF (6 cm3) was heated at reflux for 2 days. The solvent was evaporated off under reduced pressure and the residue was chromatographed on silica gel with AcOEt-hexane (3:2) as eluent to afford the title compound 7 as crystals (180 mg, 50.6). Recrystallization from AcOEt gave prisms, m.p. 122.0-122.5 "C (Found: C, 60.5; H, 6.2; N, 6.0. CI2Hl5NO4 requires C, 60.8; H, 6.4; N, 5.9); v,,,(KBr)/cm-' 3410 (OH), 3320 (NH), 1725 (CO,), 1640 (CONH) and 1595 (Ph); 6,(60 MHz) 1.26 (3 H, t, J 7.2 Hz, Me), 1.63 (1 H, br s, OH), 3.72 (2 H, s, CH,CO), 4.27 (2 H, q, J 7.2 Hz, CH,O), 5.92 (1 H, d, J8.8 Hz, CH), 6.86 (1 H, br d, J8.8 Hz, NH) and 7.40 (5 H, s, Ph); m/z 237 (M'), 219 (Mf -H,O) and 164(Mf -C0,Et).General Procedure for the Preparation of Protected Amino Esters 11-13.-A suspension of potassium salt 10a or 1Oc (4 mmol) in dry DMF (30 cm3) was heated at 80 "C for 30 min. To the mixture was added dropwise a solution of bromo ester 4 or 9 (2mmol) in dry DMF (10 cm3) and the resultant solution was stirred at 90-120 "C for 2-5 h. The solvent was evaporated off under reduced pressure. Water (10 cm3) was added to the residue and the whole was extracted with AcOEt (10 cm3 x 3).The organic layer was washed with brine and dried over MgS04. Evaporation of the solvent gave a yellow oil, which was chromatographed on silica gel with PhH-AcOEt (3 : 1) or hexane-AcOEt (5: 1) as eluent to afford the title compounds 11,6 12 and 13. N,N-Bis(t-butoxycarbony1)-a-fluoroglycineethyl ester 12. Obtained as needles (928 mg, 72.3); m.p. 53.0 "C (Found: C, 52 52.3; H, 7.7; N, 4.6. C1,H,,FNO6 requires C, 52.3; H, 7.5; N, 4.4); v,,,(KBr)/cm-' 2990 (CH) and 1780, 1763 and 1727 (CO); SH(270 MHz) 1.36 (3 H, t, J7.1 Hz, CH,Me), 1.55 (18 H, s, But x 2),4.36(2H,q,J7.1Hz,CH2)and6.47(1H,d,J48.6Hz, +CH); 8, -156.78 (d, J 47.7 Hz); m/z 322 (M + l), 266 (M '-CH,=CMe, + 1) and 57 (t-Bu'). N,N-Bis(t-butoxycarbony1)-a-Juoroglycinet-butyl ester 13.Obtained as an oil (1.05 g, 75.4); b.p. 12G125 "C/4 x lo-, mmHg (Found: c, 55.1; euro;3, 8.2; N, 4.25. C16H,,FN06 requires C, 55.0; H, 8.1; N, 4.0); v,,,(film)/cm-' 3050 (CH) and 1785, 1760 and 1725 (CO); 6,(270 MHz) 1.51 (9 H, s, CFCO,Bu'), 1.53(18 H, s, NC0,Bu' x 2) and 6.27 (1 H, d, J47.9 Hz, CH); 6, -157.04 (d, J 47.8 Hz); m/z 350 (M' + l), 294 (M' -CH,=CMe, + 1) and 57 (t-Bu'). Also prepared was: N-(t-Butoxycarbony1)-cr-ethoxyglycineethyi ester 15. Ob-tained as prisms; m.p. 176.5-177.0 "C; v,,,(KBr)/cm-' 3380 and 3330(NH), 2960 (CH), 1742 (CHCO,) and 1687 (NHCO,); 6,(60 MHz) 1.21 (3 H, t, J7.1 Hz, CHOCH,Me), 1.24 (3 H, t, J 7.1 Hz, C02CH2Me), 1.48 (9 H, s, But), 3.72 (2 H, q, J 7.1 Hz, CHOCHJ, 4.27 (2 H, 9, J7.1 Hz, CO,CH,), 5.32 (1 H, d, J 11.4 Hz, CH) and 5.70 (br d, J 11.4 Hz, NH); m/z 248 (M + l), 202 + (Mf -OEt) and 102 (C0,Bu').N,N-Bis( t-butoxycarbony1)-a-Juoroglycine16.-A mixture of the ester 12 (102 mg, 0.32 mmol) in 5 NaOH (0.5 cm3)-EtOH (0.5 cm3) was stirred at room temperature for six hours. The mixture was evaporated and diethyl ether (5 cm3) was added to the residue. The mixture was extracted with 10 Na,CO, (5 cm3 x 3). The aq. layer was acidified with 5 HCl and extracted with CHC1, (5 cm3 x 3). The extract was washed with brine and dried over MgS0,. Evaporation of the solvent gave the title compound 16 as a viscous oil (86 mg, 92.4) Found: m/z 222.039. C7H9FNO6 (M' -CH,=CMe, -Me) requires m/z 222.041. Found: m/z 193.075. C7H12FN04 (M -+ CH,=CMe, -CO,) requires m/z 193.075.Found: m/z 174.077. C7Hl,NO4 (M' -CH,=CMe, -CO, -F) re-quires m/z 174.0771; v,,,(film)/cm-l 3380 (OH) and 1705 (CO); 6,(270 MHz) 1.53 (18 H, s, Bu' x 2), 5.45 (1 H, br s, OH) and 6.47 (1 H, d, J 47.6 Hz, CHF); ZF -156.31 (d, J 47.8 Hz); m/z 222 (M+ -CH,=CMe, -Me), 193 (M+ -CH,-CMe, -CO,), 174 (M' -CH,=CMe, -CO, -F) and 57 (t-Bu'). Dibenzyl Iminodicarboxylate 20a.-To a solution of benzyl carbamate 5c (1.76 g, 11.6 mmol) in dry THF (30 cm3) at 0 "C was added potassium hydride (24.6 suspension in mineral oil; 2.10 g, 12.9 mmol) and the mixture was stirred for 30 min. A solution of benzyl chloroformate (2.39 g, 13.9 mmol) in dry THF (3 cm3) was added and the mixture was stirred at room temperature for 20 min.The mixture was evaporated and water (10 cm3) was added to the residue. The aq. solution was acidified with 10 HCl and then extracted with AcOEt (30 cm3 x 3). The extract was washed with brine and dried over MgS0,. Evaporation of the solvent gave an oil, which was dissolved in diethyl ether (40 cm'). Sodium hydride (60 dispersion in mineral oil) was added in portions to the solution until no more gas generation was observed. After storage at room temperature for 1 h, crystals (sodium salt) were collected on a filter. The crystals were dissolved in water (20 cm3), the solution was acidified with 10 HCl and extracted with AcOEt (20 cm3 x 3), and the extract was washed with brine and dried over MgS04. Evaporation of the solvent gave a residual oil, which was dissolved in CCl,.The resultant solution was partially concentrated to give the title compound 20a as crystals (2.1 1 g, 63.8). An analytical sample was obtained by recrystallization from CCl, as needles, m.p. 110.5-1 11.0 "C (Found: C, 67.6; H, 5.25; N, 5.1. C16H15NO4 requires C, 67.35; H, 5.3; N, 4.9); J. CHEM. SOC. PERKIN TRANS. I 1991 v,,,(KBr)/cm-' 3200 (NH) and 1770 (CO); 6,(270 MHz) 1.62 (1 H, br s, NH), 5.22 (4 H, s, CH, x 2) and 7.35 (10 H, s, Ph x 2); mlz285 (Mf), 194(M+ -CH,Ph), 177 (M+ -OCH,Ph)and 91 (PhCHc). Dibenzyl Iminodicarboxylate Potassium Salt 2Ob.To a solution of dibenzyl iminodicarboxylate 20a (1.56 g, 5.5 mmol) in EtOH (6 cm3) was added slowly a solution of KOH (377 mg, 6.7 mmol) in water (2 cm3).The solvent was evaporated off and residual crystals were dried over P,O, under reduced pressure for two days. The title compound 20b was obtained as crystals in quantitative yield (1.75 g); m.p. 270 "C; v,,,(KBr)/cm-' 1695 (CO) and 1610 (Ph). General Procedure for Preparution of Triesters 21 and 22.-Compounds 21 and 22 were prepared by reaction of bromo esters 4 and 9 with the salt 20b in hot DMF by a procedure similar to that of the preparation of triesters 12 and 13. N,N-Bis(henzylo-~~~carbon~l)-a-Jluorogl.vcineethyl ester 21. Obtained as an oil in 51.5 yield; b.p. 175-185 "C/4 x mmHg Found: C, 61.7; H, 5.05; N, 3.7; m/z 298.066. C20H20FN06 requires C, 61.7; H, 5.2; N, 3.6; C,3H1,FNO6 +(M -CH,Ph) requires m/z 298.0661; v,,,(film)/cm-' 3000 (CH) and 1775, 1755 and 1720 (CO); 6,(270 MHz) 1.15 (3 H, t, J 7.2 Hz, Me), 4.06 (2 H, q, J 7.2 Hz, CH,Me), 5.28 (4 H, AB-type q, A6 0.04 ppm, J 12.0 Hz, CH2Ph x 2), 6.53 (1 H, d, J47.4 Hz, CH) and 7.34 (10 H, s, Ph x 2); 6, -157.59 (d, J 46.0 Hz); m/z 390 (M+ + l), 298 (M' -CH,Ph) and 91 (PhCHc).N,N-Bis(benzyloxycarbony~)-a-Jluoroglyc~net-butyl ester 22. Obtained as an oil in 37.6 yield; b.p. 19Cb195 "C/6 x lo-, mmHg Found: C, 63.7; H, 5.6; N, 3.2; m/z 361.098. C2,H2,FNO6 requires c, 63.3; H, 5.8; N, 3.4; C18H16FN06 (M -CH,=CMe,) requires m/z 361.0961; v,,,(film)/cm-' 3000+ (CH) and 1770,1740 and 1725 (CO); 6,(270 MHz) 1.39 (9 H, s, But), 5.27 (4 H, AB-type q, AS 0.05 ppm, J 12.2 Hz, CH, x 2), 6.41 (1 H, d, J47.4 Hz, CH) and 7.33 (10 H, s, Ph x 2); ;SF -157.29 (d, J47.8 Hz); m/z 417 (M'), 361 (M+ -CH,=CMe,) and 91 (PhCH?).Also prepared was N-(benzyloxycarbony1)-;r-ethoxyglycine 23. Obtained as prisms; m.p. 183.0-184.5 "C; v,,,(KBr)/cm-l 3350 (NH) and 1760 and 1660 (CO,); tjH(6O MHz) 1.25 (3 H, t, J 7.1 Hz, Me), 3.70 (2 H, q, J 7.1 Hz, CH,Me), 5.17 (2 H, s, CH2Ph),5.41 (1 H, d, J 9.4 Hz, CH), 6.07 (1 H, br d, J 9.4 Hz, NH), 7.35 (5 H, s, Ph) and 8.77 (1 H, br s, OH); m/z 254 (M' + l), 208 (M+ -OEt) and 164 (M' -OEt -CO,). N,N-Bis( benzylo"~}?carbonyl)-a-Jluoroglycine 24.-To a solution of compound 22 (120 mg, 0.289 mmol) in CDC13 (0.5 cm3) was added dropwise CF3C02D until the starting material had disappeared as monitored by 'H NMR spectroscopy.Evaporation of the solvent gave an oil, which was dissolved in diethyl ether (5 cm3). The ethereal solution was extracted with 10 Na,C03 (2 cm3 x 3). The aq. layer was carefully acidified with 5"/; HCI and extracted with CHCl, (5 cm3 x 3) and the extract was dried over MgSO,. Evaporation of the solvent gave the title compound 24 as a viscous oil (51 mg, 48.9) Found: m/z 360.088. CI8Hl5FNO6 (M+ -H) requires m/z 360.0881; v,,,(film)/cm-' 3380 (OH) and 1710 (CO); 6,(270 MHz) 5.27 (4 H,s,CH, x 2), 5.70(1 H, br,OH), 6.56(1 H,d, J47.1 Hz,CHF) and 7.32 (10 H, s, Ph x 2); SF -157.41 (d, J45.8 Hz); m/z 360 (M' -l), 91 (PhCH;) and 20 (HF). Acknowledgements We owe a great deal to Dr. M. Kimura, Mr. T. Yamaba and Mrs.R. Masanoto who worked on the preliminary projects. J. 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H. Stammer, J. Chem. SOC.,Chem. Commun., 1979,495. Paper 0/029141 Received 28th June 1990 Accepted 20th August 1990