Short Communication
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Aust. J. Chem. 2005, 58, 63–65
Cyclic α-Amino Acids via Enantioselective Metal-Catalyzed Cascade Reactions of Dienamides in Supercritical Carbon Dioxide Euneace Teoh,A W. Roy Jackson,A and Andrea J. RobinsonA,B A
Centre for Green Chemistry and School of Chemistry, Monash University, Melbourne VIC 3800, Australia. author. Email:
[email protected]
B Corresponding
Highly enantioselective conversion of dienamides into cyclic α-amino acids can be achieved by a single-pot, tandem hydrogenation–hydroformylation–cyclization–elimination sequence using a single catalyst and supercritical carbon dioxide (scCO2 ) as the reaction solvent at total pressures significantly lower than those previously reported for related hydrogenation and hydroformylation reactions. Manuscript received: 22 September 2004. Final version: 2 December 2004.
Supercritical carbon dioxide (scCO2 ) has been shown to be a desirable solvent for a range of homogenous metalcatalyzed transformations,[1–3] including hydrogenation[4] and hydroformylation reactions.[5] Some years ago, Burk and his colleagues showed that it was possible to carry out asymmetric catalytic hydrogenation reactions in scCO2 with very high enantioselectivity, even higher than in conventional solvents.[4] There is also continued interest in atom-efficient metal-catalyzed hydroformylation reactions[6] and the incorporation of such reactions in tandem sequences, leading to the efficient synthesis of key synthetic intermediates.[7] We recently reported a highly enantioselective synthesis of cyclic α-amino acids using a tandem hydrogenation–hydroformylation– cyclization–elimination sequence, in which all of the reactions were carried out in a single pot.[8] The initial
enantioselective hydrogenation of prochiral dienamide esters made use of the DuPHOS ligands[9,10] and was conducted in benzene as a solvent. After surveying many reaction solvents, we found that benzene facilitated the highest enantioselection (>96% e.e.). In this paper we report our attempts to replace this undesirable solvent with environmentally benign scCO2 . Enantioselective hydrogenation of the prochiral dienamides 1 was first carried out to establish appropriate conditions for reactions in scCO2 (Scheme 1). Hydrogenation of 1a using the [(COD)Rh-((2S,5S)-Et-DuPHOS)]OTf catalyst with 0.34 MPa of H2 , i.e. a pressure comparable to that used previously by us for reactions in benzene,[8] gave incomplete conversion and a significant amount of over-reduced material 3a. The desired enamide 2a accounted for only 40% of the total product (entry 1, Table 1).
R
R H2
O Me
N H
OMe O
R
O
scCO2
Me
Rh(I)-Et-DuPHOS
1a R ⫽ H 1b R ⫽ Me
N H
O
⫹
OMe
Me
O
2 Rh(I)-Et-DuPHOS
R
OMe
N H
O
3 H2/CO scCO2
R OMe OMe
N O
Me
O
4
Scheme 1.
N O O
Me
5
Tandem reaction sequence of dienamide esters. © CSIRO 2005
10.1071/CH04219
0004-9425/05/010063
64
E. Teoh, W. R. Jackson and A. J. Robinson
Table 1. Hydrogenation of prochiral dienamides 1 Reaction conditions: 50 : 1 substrate (0.3 mmol)/Rh-Et-DuPHOS in 8.27 MPa of CO2 at 40◦ C. The product ratio was determined by 1 H NMR spectroscopy Entry
1 2 3 4
R
H H H Me
H2 pressure [MPa] 0.34 1.72 1.39 2.07
Time [h] 3 18 18 18
Product ratio 1
2
3
43 7 12 20
40 63 72 80
17 30 16 –
99%. The pyrrolidine 5b could not be separated from 2b, but once again the enantioselectivity (99% e.e.) was accurately measured by chiral HPLC. The exclusive use of syn gas (H2 /CO) in these tandem reactions was also investigated but resulted in complex reaction mixtures. We have previously reported that Rh–DuPHOS is capable of acting as both a hydrogenation and hydroformylation catalyst.[8] The Rhcatalyzed hydrogenation step is regioselective; however, the Rh–DuPHOS-catalyzed hydroformylation is not, and both olefinic bonds are susceptible to hydroformylation. Conclusions
Increasing the H2 pressure to 1.72 MPa gave a high conversion into 2a (63%), but also resulted in an increase in over-reduced product 3a (30%; entry 2). An intermediate H2 pressure of 1.39 MPa gave less over-reduction and 72% conversion into the desired compound 2a (entry 3). The homologous substrate 1b, containing a trans-disubstituted alkene, proved to be much less susceptible to over-hydrogenation, and a reaction using 2.07 MPa of H2 gave an 80% conversion into 2b with no over-reduction (entry 4). It should be noted that these reactions were carried out with a CO2 pressure of 8.27 MPa. This CO2 pressure is considerably lower than that which has been used in previous hydrogenations (total H2 /CO2 pressures: 10.3 MPa in our experiments versus 27.2 MPa).[4] Burk showed that the higher enantioselectivity obtained in the hydrogenation of β-disubstituted enamides when scCO2 was used as the solvent was not associated with the use of high pressures but was due to enamide–scCO2 interactions. Our result appears to show that similar beneficial interactions may occur at much lower total H2 /CO2 pressures with comparable enantioselectivity, as the final cyclized products 4 and 5 had enantiomeric excesses of 98% compared with 95% for reactions in benzene.[8] These optimum reaction conditions were then used in a one-pot tandem reaction sequence in which H2 and CO2 were removed after the first step and replaced with scCO2 and synthesis (syn) gas (1 : 1 CO/H2 ). Reaction of 1a for 18 h under 1.39 MPa of H2 , followed by reaction with 2.76 MPa of CO/H2 for 48 h at 60◦ C, gave 30% of over-reduced product 3a and 70% of a mixture of the cyclic products 4a and 5a in a 3 : 1 ratio. The long hydroformylation time was chosen because exploratory experiments showed little evidence for reaction when shorter times of ≤24 h were used. This result contrasts with those reported for the hydroformylation of alkylacrylates (albeit at 20 MPa versus 10 MPa) which were shown to be faster in scCO2 than in conventional solvents.[5] The cyclic products 4a and 5a were separated and a pure sample of 4a was obtained in 24% yield. Although the pyrrolidine 5a could not be separated from 3a, the determination of enantioselectivity was not compromised and each heterocycle 4a and 5a was determined to have 98% e.e., a value comparable to the stereoselectivity obtained in benzene. Hydrogenation of the higher homologue 1b at 2.07 MPa for 16 h followed by reaction with 2.76 MPa of CO/H2 for 72 h gave non-hydroformylated material 2b (20%) and a mixture of the cyclic products 4b and 5b in a 2 : 1 ratio. Chromatographic separation gave a pure sample of 4b with an e.e. of
This manuscript details the preparation of biologically important chiral five- and six-membered cyclic amino acids with excellent enantioselectivity (>98% e.e.) using a tandem Rh–phosphine-catalyzed asymmetric hydrogenation– hydroformylation–cyclization–dehydration sequence. A single pot and catalyst are used to achieve each of these transformations eliminating the need for isolation of intermediates, multiple reagents, and complicated reaction set-ups. scCO2 provides an excellent replacement solvent for benzene (formerly the optimum solvent for this sequence), and its application at considerably lower vessel pressure further increases its potential for general use. Unfortunately, in this study, the minor five-membered cyclic amino acids are difficult to separate from over-reduced or unreacted intermediate material that arises because of the slower hydroformylation rate in the scCO2 medium. Experimental General experimental details have been previously reported.[8] Optical purity (% e.e.) was assessed by HPLC and was performed on a Varian LC 5000 instrument with a Waters 480 detector using a chiral column (Chiracel OJ, 0.46 cm ID by 25 cm with a particle size of 10 µm). Retention times (tR ) are an average of two runs. [(COD)Rh-((2S,5S)-Et-DuPHOS)]OTf refers to (+)-1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene(cycloocta-1,5diene)rhodium(i) trifluoromethane sulfonate[9] and was used as supplied by Strem Chemicals. H2 , CO2 , and CO/H2 (1 : 1) were obtained from BOC gases. Stainless steel Parr autoclave reaction vessels (100 mL), each fitted with Teflon-coated pressure gauge heads, a glass liner, a stirrer bead, a thermocouple, and a heating block were employed. A high-pressure syringe pump (ISCO, 260D) was used to charge reaction vessels to high pressures (>8.27 MPa). Rhodium-Catalyzed Reaction of (2Z)-Methyl 2-Acetamidopenta-2,4-dienoate 1a (2Z)-Methyl 2-acetamidopenta-2,4-dienoate 1a (50 mg, 0.30 mmol) and [(COD)Rh(S,S)-Et-DuPHOS]OTf (substrate-to-catalyst ratio 50 : 1) were added to a 100 mL Parr autoclave in a dry box. The vessel was charged with hydrogen (1.38 MPa) and liquid CO2 (8.27 MPa) and heated to 40◦ C. After 18 h, the autoclave was cooled to 0◦ C and the gases were slowly vented. The autoclave was then pressurized with CO/H2 (1 : 1 molar ratio; 2.76 MPa) and liquid CO2 (8.27 MPa) and heated to 60◦ C for 48 h before being vented to afford a brown oil (58 mg) whose 1 H NMR spectrum showed the presence of three compounds: (2S)-methyl N-acetyl-5,6-didehydropipecolate 4a, (2S)methyl N-acetyl-4-methyl-4,5-didehydroprolinate 5a, and the fully saturated compound (2S)-methyl 2-acetamidopentanoate 3a in a 52 : 18 : 30 ratio.[8] Column chromatography (3 : 1 ethyl acetate/light petroleum) first afforded (2S)-methyl N-acetyl-5,6-didehydropipecolate 4a (13 mg, 24%; RF 0.5) as a colourless oil. Further elution then gave a 1 : 1.2 mixture (11 mg) of (2S)-methyl N-acetyl-4-methyl-4,5-didehydroprolinate
Cyclic α-Amino Acids via Metal-Catalyzed Cascade Reactions in scCO2
5a and (2S)-methyl 2-acetamidopentanoate 3a (RF 0.3). HPLC analysis of 4a (1.0 mL min−1 , 10% isopropyl alcohol/90% hexane) revealed two peaks: (S) t1 9.9 min and (R) t2 29.29 min with peak areas representing an enantiomeric excess of 97.7%. HPLC analysis of 5a in the mixture containing 3a showed two peaks: (S) t1 13.0 min and (R) t2 30.3 min with peak areas representing an enantiomeric excess of 98.2%. Rhodium-Catalyzed Reaction of (2Z,4E)-Methyl 2-Acetamidohexa-2,4-dienoate 1b (2Z,4E)-Methyl 2-acetamidohexa-2,4-dienoate 1b (50 mg, 0.27 mmol) and [(COD)Rh(S,S)-Et-DuPHOS]OTf (substrate-to-catalyst ratio 50 : 1) were loaded into a 100 mL Parr autoclave in a dry box. The vessel was charged with hydrogen (2.07 MPa) and liquid CO2 (8.27 MPa) and then heated to 40◦ C. After 18 h, the autoclave was cooled to 0◦ C and the gases were vented. The autoclave was then repressurized with CO/H2 (1 : 1 molar ratio; 2.76 MPa) and liquid CO2 (8.27 MPa) and heated at 60◦ C for 72 h before being vented to give a brown oil (58 mg). The 1 H NMR spectrum of the crude oil showed the presence of three compounds: (2S)-methyl N-acetyl-5methyl-5,6-didehydropipecolate 4b, (2S)-methyl N-acetyl-4-ethyl-4,5didehydroprolinate 5b, and the non-hydroformylated material (2S,4E)methyl 2-acetamidohex-4-enoate 2b in a 54 : 26 : 20 ratio.[8] Column chromatography (3 : 1 ethyl acetate/light petroleum) first afforded (2S)methyl N-acetyl-5-methyl-5,6-didehydropipecolate 4b (22 mg, 41%; RF 0.51) as a colourless oil. Further elution then gave a 1.6 : 1 mixture of (2S)-methyl N-acetyl-4-ethyl-4,5-didehydroprolinate 5b and (2S,4E)methyl 2-acetamidohex-4-enoate 2b (24 mg; RF 0.34). HPLC analysis of purified 4b (1.0 mL min−1 , 10% isopropyl alcohol/90% hexane) showed two peaks: (S) t1 8.3 min and (R) t2 11.4 min with peak areas representing an enantiomeric excess of 99.1%. HPLC analysis of 5b in the mixture containing 2b showed two peaks: (S) t1 11.6 min and (R) t2 22.1 min with peak areas representing an enantiomeric excess of 99.2%.
65
Acknowledgments We thank Monash University and the Centre for Green Chemistry for provision of a postgraduate award (to E.T.), the Australian Research Council for its financial support of our research, Johnson Matthey Pty Ltd for a loan of rhodium, and Dr Ulf Kreher, Associate Professor Andrew Smallridge, and Miss Kylie Blake for assistance with scCO2 reactions. References [1] P. G. Jessop, T. Ikariya, R. Noyori, Science 1995, 269, 1065. [2] P. G. Jessop, T. Ikariya, R. Noyori, Chem. Rev. 1999, 99, 475. doi:10.1021/CR970037A [3] N. Shezad, A. A. Clifford, C. M. Rayner, Green Chem. 2002, 4, 64. doi:10.1039/B109894M [4] M. J. Burk, S. Feng, M. J. Gross, W. Tumas, J. Am. Chem. Soc. 1995, 117, 8277. [5] Y. Hu, W. Chen, A. M. Banet Osuna, A. M. Stuart, E. G. Hope, J. Xiao, Chem. Commun. 2001, 725. doi:10.1039/B101043N [6] B. Breit, W. Seiche, Synthesis 2001, 1, 1. doi:10.1055/S-20019739 [7] P. Eilbracht, L. Barfacker, C. Buss, C. Hollmann, B. E. KitsosRzychon, C. L. Kranemann, T. Rische, R. Roggenbuck, A. Schmidt, Chem. Rev. 1999, 99, 3329. doi:10.1021/CR970413R [8] E. Teoh, E. M. Campi, W. R. Jackson, A. J. Robinson, New J. Chem. 2003, 27, 387. doi:10.1039/B209087M [9] M. J. Burk, J. E. Feaster, W. A. Nugent, R. L. Harlow, J. Am. Chem. Soc. 1993, 115, 10125. [10] W. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029. doi:10.1021/ CR020049I
