CHIRALITY 411C115 (1992)

Unusual Amino Acids I: Asymmetric Synthesis of Furylalanine Derivatives H.W. KRAUSE, F.W. WILCKE, H.-J. KREUZFELD AND CH. WBLER Central Institute of Organic Chemistry,Division of Complex Catalysis, Rostock, Germany

ABSTRACT Nonproteinogenic amino acids are valuable active compounds from their pharmacological and biochemical effects and also as novel building blocks for peptides. The preparation of furylalanine derivatives by asymmetric hydrogenation is described. Aminophosphine-phosphiniterhodiumcomplexescatalyzed the hydrogenation of the prochiral dehydroamino acid precursors in high rate and with enantioselectivitiesof 7&90% ee. Substrate catalyst ratios up to 2,000 can be used depending on the catalyst applied. The procedure turns out to be suitable for larger scale preparations. KEY WORDS: furyldehydroamino acid, enantioselectivity, hydrogenation, chiral rhodium complexes, amino-phosphine-phosphinite,ligands enantiomers, (R)- and @)-. isomers INTRODUCTION

Nonproteinogenicamino acids 1-3 have received much interest recently because of their anticipated pharmacological and biochemical properties and their incorporation in synthetic peptides. Among unnatural amino acids those bearing heterocyclic rings have attracted considerable attention but only a few reports have been published on their preparation via asymmetric hydrogenation of the appropriate prochiral precursors. For the preparation of the precursors excellent reviews have been published showing that the classical Erlenmeyer synthesis is often used to obtain the N-acyldehydro amino acids.%" The condensation of aldehydes with alkyl acetamidomalonates 12J3 has also been applied successfully. The asymmetric hydrogenation of (2)-heterocyclic N-acylpropenoic acids by neutral or cationic Rh-DIOP complexes furnishes optical yields strongly dependent on the heterocyclic moiety and the catalyst The reason may lie in differentmodes of coordination of the Rh complexesdue to the participation of the heteroatoms in the transition state. The low rate and enantiomeric excess in case of the pyridyl derivatives may be due to competition by the nitrogen lone pair for coordination sites on rhodium. Differences in the donating power and the position of the heteroatom are therefore reasonable explanations of the observed stereoselectivities. This fact, coupled with moderate optical yields, prompted us to investigate the neutral and cationic aminophosphine-phosphinite-Rhcomplexes designed by us and which had proved to be rather selective catalysts in the hydrogenation of conventional dehydroamino acid derivatives. 18,19

EXPERIMENTAL Materials and Methods [Rh(COD)C1I2,21 [Rh(CODh]BF4,22 [Propraphos-Rh(COD)]BF4,l9 (R)- and (S)-Propraphos,l9 ( + )- and ( - )-O,N,bis (diphenylphosphino)-2-exo-hydroxy, 3-endo-methylaminonorbornane, l8 were prepared by known procedures. The substrates were prepared according to either Crawford and Littlez or Cativiela et al.9 with some modifications. ( - )-DIOP and (S,S)-BPPMwere purchased from E. Merck, Darmstadt. Melting points were determined on a Boetius melting point apparatus and are uncorrected. Optical rotations were measured with a Polamat A polarimeter (Carl Zeiss,Jena). NMR spectra were recorded with a Tesla (CSFR) BS 487 C (80 MHz) spectrometer, internal standard HMDS. Hydrogenation was performed as described. l2 The enantiomeric excess was determined directly by GLC using a Hewlett-Packard 5880 A chromatograph fitted with fused silica capillary columns of 0.27 mm i.d. coated with XE-60 L-valine-tert-butylamide.Oven temperature 16&172"C, injection temperature 220"C, detection temperature 25O"C, 1 ml argon per min, FID, split 1:60, or by HPLC, Knauer, CHIRALPAK WH (Baker),25 x 0.46 cm 0.5 mmol CuS04.5H20, 1 ml per min, detector UV, 254 nm. 4-[2-Furfurylidene]-2-phenyl-4H-oxazol-5-one. Hippuric acid (89.5 g, 0.5 mol), fused sodium acetate (41 g, 0.5 mol), freshly distilled 2-furaldehyde(41.5 ml, 0.5 mol), and acetic anhydride (140 ml, 1.5 mol) were heated with stirring at 95°C for 1h. After cooling with ice the product was filtered off, washed first with a small amount of cold EtOH and then with EtOH/H20 (50/50 v/v), and dried. Recrystallization from toluene afforded 91.7 g (76.7%) of fine yellow needles, mp 171°C (lit. 171"C15), 'H-

Abbreviations: DIOP, 1,4bis(diphenylphasphino)-l,4-dideoxy-2,3-Oisopropylidene-L-threite; BPPM, (2S,4S)-N-tert-butoxycarbonyl-4diphenylphasphin~ 2-diphenylphosphinomethylpyrrolidine; COD, (cis,cis)-cycloocta-l,5-diene; Received for publication July 27, 1991;accepted September 25,1991. Address reprint requests to H.W.Krause, Central Instituteof Organic ChemisF'ropraphos, 2,50,N-bi diphenylphosphino)-l-(a-~phthoxy)-Z-hydroxy-3isopropylaminopropane;Kp phenyl-4,6-O-(R)-knzylidene-2,3-O-bis(diphenyl-try, Division of Complex Catalysis,Buchbinderstrasse5-6.02500Rostock,Germany. phasphino)-~-~-glucopyranoside-rh~i~-~cl~~l,5dien~te~afluoro~~te.

%.

0

1992 Wiley-Liss,Inc.

111

UNUSUAL AMINO ACIDS BY ASYMMETRIC HYDROGENATION

NMR,(CDCI,): CH 7.18 (S); CHphenyl8.16 (m, 2H), 7.51 (m, 3H); (Z)-2-Benzamido-3-[2-(5-nitrofuryl)]-propenoic acid 4. A mixoxazol-5-one (1.14 g, ture of 2-phenyl-4-(5-nitrofurfurylidene-2) CH, 7.68 (d); CHb,, 6.67 (m, 2H). (Z)-2-Benzamido-3-(2-furyl)-propenoic acid 1.In a round bot- 4 mmol), 30 ml water, and 30 ml dioxane containing sodium tom flask, fitted with stirrer the oxazolone (12 g, 0.05 mol) was carbonate (0.86 g, 8 mmol) was heated for 1 h at 85°C on a heated for 45 min in 0.5 MNaOH (100 ml) at 80°C.After cooling water bath. After cooling with ice water the solution was acidiwith ice water, the filtered solution was acidified carefully with HCl and the gray precipitate washed with water. After drying the acid was recrystallized from EtOH/H20 (90/10 v/v) using charcoal. Needles (light brown) mp 217°C (lit. 237"C9) yield 85%. 'H-NMR, (CDC13):CH 7.34 (S); NH 9.71 (s); cHphenyl8.09 (m, 2H); 7.52 (m, 3H); CH, 7.71 (d); CHb 6.56 (9); CH, 6.82 (d). (Z)-Methyl-2-benzamido-3-(2-furyl)-propenoate 2.In a round bottom flask fitted with a stirrer containing abs. MeOH (360 ml) sodium (0.1 g) was added followed by the addition of the oxazolone (48g, 0.2 mol). The mixture was heated with stirring on the water bath at 60°C for 15 min. A clear solution was formed, from which the ester crystallized on cooling. After 2 h the product was filtered off, washed with cold MeOH and MeOH/H20 (50/50 v/v). Recrystallization from MeOH gave 51.3 g (94%)of colorless crystals, mp 139"C, C15H1304N,271.26. % calcd., C 66.40, H 4.83, N 5.16 Yo found, C 66.59, H 4.81, N 5.14. 'H-NMR, (CDCl,): CH30 3.78 (S);NH 3.86 (S); CHphenyl 7.96 (m, 2 H); 7.51 (m, 3H); CH 7.08 (s);CH, covered; CHb 6.44 (9); CH, 6.58. 2-Phenyl-4-(5-nitrofurfurylidene-2)~-oxaml-5-one. Freshly distilled 5-nitro-2-furaldehyde (4.2 g, 0.03 mol) and 2phenyloxazold-one (9.6 g, 0.06 mol) were heated on a water bath at 80°C for 5 min giving a clear solution from which a red-brown product solidified rapidly on cooling. The solid was reduced to small pieces under ice water, filtered, washed with EtOH/H20 (70/30, v/v), dried, and recrystallized from toluene or acetone/water to give yellow-brown crystals. mp 178°C (lit.lo 178°Cdioxane).Yield: 5.3 g, (73%). Cl4H8O5N2,284.2. % calcd., C 59.16, H 2.83, N 9.86 % found, C 59.22, H 3.08, N 9.88. MS 284 (M +), 268 (M+a), 105 (C~HSCO), 77,51,39 (C6H5), 30 (NO). (Z)-Ethyl-2-benzamido-3-[2-(5-nitrofuryl)]-propenoate 3. To EtOH (100 ml) sodium (0.1 g) was added followed by 4-(5nitrofurfurylidene-2)-2-phenyl-oxazol-5-one (3 g, 0.01 mol) and the mixture was heated for 1 h at 80°C with stirring. The precipitate formed was filtered, washed with EtOH/H20 (50/ 50, v/v), dried, and recrystallized from abs. EtOH. Yellow needles, mp 182°C. Lit. 181"C, yield 2.3 g (67%). C16H1406N2, 330.29. Yo calcd., C 58.18, H 4.27, N 8.48. Yo found, C 57.79, H 4.30, N 8.45. 'H-NMR, (DMSo-De): CH 7.14 (s); NH 10.11 (s); cHphenyl8.13 (m, 2 H); 7.58 (m, 3 H);CH, 7.12 (d); CHb 7.63 (d); CH2 4.28 (q); CH3 1.29 (t). MS 330 (M+),284 (M+46), 105 (C6H5CO),29 (C2H5).

-1

Scheme 1.

fied by diluted HCl yielding the acid which was recrystallized twice from 90% EtOH. Yellow-brown crystals, yield 580 mg (48%). C14H1006N2, 302.24, powder, mp 120°C. % calcd., C 55.63, H 3.34, N 9.27. % found, C 55.51, H 3.50, N 9.40. 'H-NMR, (DMSO-Dc):CH 7.23 (S); NH 10.03 (S); CHpheny,8.13 (m, 2H); 7.59 (m, 3H) CH, 7.08 (d); CHb 7.66 (d) MS 302 @I+), 284 (M +-H20), 258 (M +-c02),105 (C~Hsco),77,51, 39 (c6H5), 44 GO,), 30 WO), 18 0420). ( + )-O,N-Bis(diphenylphosphino)-2-exo-hydroxy,3-endo-met hylamino-norbomane-copper chloride A. To the norbomane derivative18 (1.1 g, 2.15 mmol), [ u ] , +6.5" ~ (c = 1, CHC13) was added CuCl (0.194 g, 1.96 mmol) in methylene chloride (6 ml) at room temperature under argon. On stirring a clear solution was formed from which the solvent was evaporated in vacuo leaving an oil which crystallized on addition of a h . ether. Colorless crystals, mp 141-150°C, yield 854 mg (72%). [ o L ] ,-61.2" ~~ (~=0.3,CHC13). C32HBNOP2 CUCl, 608.6. Yo calcd., C 63.16, H 5.46, N 2.30, P 10.18. YOfound, C 62.40, H 5.48, N 2.32, P 10.50. (Z)-2-Benzamido-3-[2-(5-methylfuryl)]-propenoic acid 5. 2Phenyl-4-(5-methylflidene-2)-~-oxaml-5-one (5 g, 19.7 mmol) was added to a mixture .of MeOH (99.0 ml) and 1M NaOH (49.5 ml, 49.5 mmol) and stirred for approximately 1 h. From the clear solution the MeOH was removed under low pressure and the residue acidified affording a colorless product which was recrystallized from EtOH yielding 2.8 g of the acid. A second crop was isolated from the mother liquor (1.6g, &I%), mp 191-93°C. C15H13N04,271.26. % calcd., C 66.41, H 4.83, N 5.16. YOfound, C 65.67, H 5.24, N 5.05. 13C-NMR,@MSO-D6): C(Me) 13.6, C5 154.8, C4 109.2, C3 117.2, C2 148.2, Cp 121.4, C, 123.0, COOH 165.8, COW 166.4, phenyl C1 134.2, C2 127.8, C3 128.6, C, 131.8.MS 271 (M+), 253 (M +-H20), 227 (M+ 4 0 2 ) , 121 (M +-C~H~CONHZ), 105 (C&jCO) 77.51, 39 (C6H5).

O-CH2-CH

I

0 I

- CH2

PPh2

Me A

0

C

D

X=R=H

Scheme 2.

1

N-Pri

1

PPh2

112

KRAUSE ET AL.

&

&

OTh2,Cl ,Rh\ Coo NPPh2

OPch2,Cl

/Cu,

+

' I 2[Rh (COO)Cl],

NPPh2

+ CuCl

I

I

Me

Me Equation 1.

( + )-(R)-N-Benzoyl-3-(2-furyl)-alanine 6.(2)-2-Benzamido-3(2fury1)-propenoic acid (2.6 g, 10 mmol) was hydrogenated at 25"C, 0.1 MPa H2 pressure using precatalyst C (9.26 mg, 0.01 mmol) in 30 ml methanol. The half life was 38.8 min and the hydrogen uptake ceased after 120 min with 100% conversion. The product was filtered and removal of the solvent gave 2.25 g (87.5%) of the crude acid. Recrystallizationtwice from HzO/ EtOH (80/20 v/v) or toluene yielded colorlesscrystals, 1.8g, mp 129-32°C. C14H1204N,259.25. Yo calcd., C 64.86, H 5.05, N 5.40. '30found, C 64.72, H 5.23, N 6.00. [al, + 27.7" (c= 1, MeOH). 'H-NMR, @MSO-D6,Aceton-D6):CH 4.74 (d,t); NH 8.71 (d), CHmm 7.88 (m, 2H), 7.48 (m, 4H covering CH,), CHb 6.32 (dd, 241 (Mf-H20); 214 lH), CH, 6.19 (d,lH). MS 259 @If); (M'XOOH), 138 (M'XGH~CONH), 105 (C~Hsco),81 (c!j&O), 77,51, 39 (CsH5). ( + )-(R)-Methyl-N-benzoyl-3-(2-furyl)-alaninate 7.(2)-Methyl2-benzamido-3-(2-f-propenoate (2.71 g, 10 mmol) was hydrogenated in methanol (15 ml) following the procedure above (half life 70 rnin and a total hydrogenation time of 300 min) to give 87.2% ee, at 100% conversion. The crude product was recrystallized from ethanol/H20 (40/60v/v) yielding 2.3 g (83%)colorless crystals, mp 86439°C. C15H1504N,273.3. % calcd., C 65.92, H 5.53, N 5.13. % found, C 65.91, H 5.54, N 5.21. [ah 2o + 36.7" (c = 1, MeOH). 'H-NMR, (CDCl,): CH 4.98 (d,t), OCH, 3.68 (s),CH2 3.23 (d), NH 6.98 (d), CH,,, 7.72 (m, 2H), 7.33 (m, 3H), CH, 7.39 (lH), CHb 6.21 (dd,lH),CH, 6.03 (d,lH). M S 273 (M'), 241 (M+4H30H), 114 ( M + 4 W H 3 ) , 152 (M +-H~N-COCGH~), 121 (H~N-COCGH~), 105 (C6H5CO). 2-Phenyl-4-(5-methylfurfurylidene-2)-4H - oxazol - 5 - one. Freshly distilled 5-methylfuraldehyde(10 g, 90.8 mmol), hippuric acid (16.2 g, 90.4 mmol), sodium acetate (7.44 g, 90.6 mmol), and acetic anhydride (25.4 ml) were stirred and heated on a water bath at 80°Cwhereby the yellow solid became liquid and soon solidified. Stirring was continued for 10 rnin and the product then poured into crushed ice, filtered, and washed with water. After drying, the crude product (18g) was recrystallized from EtOH yielding 11.4 g (49.6%) of the yellow oxazolone, mp 152-55°C. CpjHllNO3,253,3. % calcd., C 71.13, H 4.38, N 5.53. % found, C 70.83, H 4.29, N 5.63. 13C-NMR,(acetoneD6): W e ) 13.9, C5 158.8, C4 118.8, C3 118.3, C2 150.1, Cp 128.8, C, 128.1, COOH 167.3, CON 163.0, phenyl C1 133.4, C2' 129.9, C3' 128.7, c4' 133.9 MS 253 (M +), 105 (C~HSCO), 77,51,39 (c6H5). (S)-3-[2-(5-Nitrofuryl)-alanine8. Q-2-Benzamido-3-[2-(5-nitrofury1)-propenoic acid 4 (0.30 g) was hydrogenated as described for 6, half life 12 min, to yield 88.8% ee (S). After the usual workup, the product was isolated as yellow-orange crystals by chromatography on silica gel 60 (Merck).MS 286 (M +), 261 (M +402), 121 (benzamide), 105 (benzoyl). ( - )-(R)-N-I3emyl-3-[2-(5-methylfuryl)]-al 9. (Z)-2-Benzamido-3-[2-(5-methylfuryl)]-propenoic acid 5 (0.85 g) was hydrogenated as described for 6 with a half life = 49 min and

1-5

Equation 2.

with enantiomeric excess of 76.7% (R) for the crude product after the usual workup. Yield 0.80 g. Recrystallization from toluene yielded 0.6 g. CI5Hl5NO4,273.28. % calcd., C 65.93, H 5.53, N 5.13. YO found, C 65.98, H 5.06, N 5.10. 13C-NMR, DMSO-D,): W e ) 13.5, C5 150.3, C4 107.6, C3 106.3, C2 149.9, Cp 29.4, C, 51.8, COOH 172.7, CONH 166.4, phenyl C1' 134.0, C2' 127.6, C3' 128.4, C4' 131.6. MS 273 (M'), 95(CGH70), 105(C&CO), 121(C&5CONH2), 152W '-121). The product is contaminated with the unsaturated compound (approximately 50% as estimated from NMR data). RESULTS AND DISCUSSION The dehydroamino acids (Scheme 1)and their esters were prepared according to the Erlenmeyer synthesis. Starting with phenyl-furfurylideneoxazolone which was obtained in 76% yield, 1 and 2 were obtained in 85 and 95% yield, respectively. From 5-nitrofuraldehydediacetate,the oxazolone was obtained in 73% yield and was converted to 3 in 67% and 4 in 48% yield, respectively." Finally 5 could be prepared in 84% yield from 5-methylfuraldehydvia the oxazolone (yield 56%). The asymmetric hydrogenation of the substrates 1-5 was carried out using the aminophosphine-phosphinite ligands (Scheme 2) A and B and diphosphine ligand D for comparison. From B the crystallized Rh complex C, Propraphos-Rh , is availableas an air-stablecomplex which can be used instead of the in situ system B and [Rh(COD)2JE3F4.A, the crystalline copper complex easily prepared from the ligand and CuCl, gave by addition of [Ph(COD)Cl], or [Rh(COD),JE3F, the neutral Rh complex immediately according to Eq. (1). In case of [Rh(COD)2JE3F4the neutral complex is also fomed. These rhodium complexes have been shown to catalyze the asymmetric hydrogenation of normal dehydroamino acids as, e.g., benzamidocinnamic acid or the ester, respectively,18,19 with high rate, typical of seven-membered ring chelate and an enantiomeric excess between 70 and 90%. Of the prochiral substrates, only 1 has been hydrogenated by neutral and cationic Rh-DIOPcomplexes giving rise to 13% +

UNUSUAL AMINO ACIDS BY ASYMMETRIC HYDROGENATION

113

TABLE 1. Catalytic asymmetric hydrogenationof fury1 dehydroamino acid derivatives catalyzed by neutral Rh aminophosphine-phosphinitecomplexesa Experiment

Substrate

1 2 3 4 5 6 7 8 9 10 11 12

Catalyst*

1 1 1 1 1 2 2 2 2 2 2 1

t/2 (min)

ee (Yo)(

Configuration

7.0 6.4 7.8 8.3 9.0 85.0 73.0 10.0 12.0 9.7 10.0 12.8

73.8 f 1.9 71.1f 0.3 74.1f 0.7 65.5f0.6 67.5 f 0.8 78.6 f 0.4 77.7 f 1.3 74.4 f 1.0 75.0 f 0.1 73.5 f 0.4 74.7 f 0.4 74.1

R R R R S S R R R R S

Remarks

R* Reproduction 1 Reproduction 1 Reproduction 4 Rh depos. Reproduction 6 Reproduction 8 Reproduction 10

"Methanol 15 ml, 25'C, 0.1 MPa H,, substrate-Rh = 100, conversion 100%, [Rh] 0.01 mmol/l5 ml methanol. *Recatalyst prepared in situ, presumably giving the neutral species with [Rh(COD),PF,, too. CDeterminedby GLC of the methyl ester. Acids were directly converted into the methyl esters with diazomethane. y+)-Ligand A gives (-)-copper complex which results in the (R)-configuration of the amino acid. The absolute configuration of the complex is unknown but presumably refers to the (S)-configurationof the ligand.

TABLE 2. Catalytic asymmetric hydrogenation of furyldehydroamino acid derivatives catalyzed by cationic Rh aminophosphine-phosphinitecomplexesD Experiment

Substrate

S/Rh

+ [Rh(COD)$F4

100

11.3

81.6

S

81.3

S

86.1 f 0.3 86.9 f0.3 86.6 f0.3 89.1 f0.8 90.0 f0.5 89.3 f0.2 86.4 90.1 85.4 f 0.8 87.2 f 0.7 42.1 42.1 72.6 f 0.2 87.5 88.0 f 0.3 87.3 76.7 f 0.1 73.7 f 0.4 88.8

S S R RJ R R R R R R R R R R R RJ R R Sh

t/2 (min)

1

1

2

1

100

7.7

3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

2 2 2 2 1 1 1 1 2 2 1 1 2 1 2 1 5 5

100 100 100 100 100 100 looo" lo00 lo00 lo00 100 100 100 2 w 2ooo"

17.4 17.7 15.4 5.4 3.2 3.6 35.0 38.8 83.0 69.0 1.0 1.0 7.4 125.0 180.0 125.0 47.0

850

-

4

100

12.0

B

ee (Yo)