CSIRO PUBLISHING Short Communication

www.publish.csiro.au/journals/ajc Aust. J. Chem. 2005, 58, 63–65

Cyclic α-Amino Acids via Enantioselective Metal-Catalyzed CascadeReactions 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.B Corresponding author. Email: Andrea.Robinson@sci.monash.edu.au

Highly enantioselective conversion of dienamides into cyclic α-amino acids can be achieved by a single-pot, tandemhydrogenation–hydroformylation–cyclization–elimination sequence using a single catalyst and supercritical carbondioxide (scCO2) as the reaction solvent at total pressures significantly lower than those previously reported for relatedhydrogenation and hydroformylation reactions.

Manuscript received: 22 September 2004.Final version: 2 December 2004.

Supercritical carbon dioxide (scCO2) has been shown tobe a desirable solvent for a range of homogenous metal-catalyzed transformations,[1–3] including hydrogenation[4]and hydroformylation reactions.[5] Some years ago, Burkand his colleagues showed that it was possible to carryout asymmetric catalytic hydrogenation reactions in scCO2

with very high enantioselectivity, even higher than inconventional solvents.[4] There is also continued inter-est in atom-efficient metal-catalyzed hydroformylationreactions[6] and the incorporation of such reactions intandem sequences, leading to the efficient synthesisof key synthetic intermediates.[7] We recently reporteda highly enantioselective synthesis of cyclic α-aminoacids using a tandem hydrogenation–hydroformylation–cyclization–elimination sequence, in which all of thereactions were carried out in a single pot.[8] The initial

Me NH

OMe

O

O

R

1a R � H1b R � Me

H2

scCO2

Rh(I)-Et-DuPHOSMe N

H

OMe

O

O

R

2

�

Me NH

OMe

O

O

R

3

Rh(I)-Et-DuPHOSH2/COscCO2

N

MeO

OMe

O

R

4 5

N

R

OMe

O

MeO

Scheme 1. Tandem reaction sequence of dienamide esters.

enantioselective hydrogenation of prochiral dienamide estersmade use of the DuPHOS ligands[9,10] and was conductedin benzene as a solvent. After surveying many reaction sol-vents, we found that benzene facilitated the highest enantio-selection (>96% e.e.). In this paper we report our attemptsto replace this undesirable solvent with environmentallybenign scCO2.

Enantioselective hydrogenation of the prochiral dien-amides 1 was first carried out to establish appropriate condi-tions for reactions in scCO2 (Scheme 1). Hydrogenation of1a using the [(COD)Rh-((2S,5S)-Et-DuPHOS)]OTf catalystwith 0.34 MPa of H2, i.e. a pressure comparable to that usedpreviously by us for reactions in benzene,[8] gave incompleteconversion and a significant amount of over-reduced material3a. The desired enamide 2a accounted for only 40% of thetotal product (entry 1, Table 1).

© 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 1Reaction conditions: 50 : 1 substrate (0.3 mmol)/Rh-Et-DuPHOS in

8.27 MPa of CO2 at 40◦C. The product ratio was determined by1H NMR spectroscopy

Entry R H2 pressure Time Product ratio[MPa] [h]

1 2 3

1 H 0.34 3 43 40 172 H 1.72 18 7 63 303 H 1.39 18 12 72 164 Me 2.07 18 20 80 –

Increasing the H2 pressure to 1.72 MPa gave a high con-version into 2a (63%), but also resulted in an increase inover-reduced product 3a (30%; entry 2). An intermediate H2

pressure of 1.39 MPa gave less over-reduction and 72% con-version into the desired compound 2a (entry 3). The homol-ogous 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% conver-sion into 2b with no over-reduction (entry 4). It should benoted that these reactions were carried out with a CO2 pres-sure of 8.27 MPa. This CO2 pressure is considerably lowerthan that which has been used in previous hydrogenations(total H2/CO2 pressures: 10.3 MPa in our experiments versus27.2 MPa).[4] Burk showed that the higher enantioselectivityobtained in the hydrogenation of β-disubstituted enamideswhen scCO2 was used as the solvent was not associated withthe use of high pressures but was due to enamide–scCO2

interactions. Our result appears to show that similar beneficialinteractions may occur at much lower total H2/CO2 pressureswith comparable enantioselectivity, as the final cyclized prod-ucts 4 and 5 had enantiomeric excesses of 98% compared with95% for reactions in benzene.[8]

These optimum reaction conditions were then used in aone-pot tandem reaction sequence in which H2 and CO2 wereremoved after the first step and replaced with scCO2 andsynthesis (syn) gas (1 : 1 CO/H2). Reaction of 1a for 18 hunder 1.39 MPa of H2, followed by reaction with 2.76 MPaof CO/H2 for 48 h at 60◦C, gave 30% of over-reduced product3a and 70% of a mixture of the cyclic products 4a and 5ain a 3 : 1 ratio. The long hydroformylation time was chosenbecause exploratory experiments showed little evidence forreaction when shorter times of ≤24 h were used. This resultcontrasts with those reported for the hydroformylation ofalkylacrylates (albeit at 20 MPa versus 10 MPa) which wereshown to be faster in scCO2 than in conventional solvents.[5]The cyclic products 4a and 5a were separated and a pure sam-ple of 4a was obtained in 24% yield.Although the pyrrolidine5a could not be separated from 3a, the determination of enan-tioselectivity was not compromised and each heterocycle 4aand 5a was determined to have 98% e.e., a value comparableto the stereoselectivity obtained in benzene.

Hydrogenation of the higher homologue 1b at 2.07 MPafor 16 h followed by reaction with 2.76 MPa of CO/H2 for 72 hgave non-hydroformylated material 2b (20%) and a mixtureof the cyclic products 4b and 5b in a 2 : 1 ratio. Chromato-graphic separation gave a pure sample of 4b with an e.e. of

99%. The pyrrolidine 5b could not be separated from 2b,but once again the enantioselectivity (99% e.e.) was accu-rately measured by chiral HPLC. The exclusive use of syngas (H2/CO) in these tandem reactions was also investigatedbut resulted in complex reaction mixtures. We have previ-ously reported that Rh–DuPHOS is capable of acting as botha hydrogenation and hydroformylation catalyst.[8] The Rh-catalyzed hydrogenation step is regioselective; however, theRh–DuPHOS-catalyzed hydroformylation is not, and botholefinic bonds are susceptible to hydroformylation.

Conclusions

This manuscript details the preparation of biologically impor-tant chiral five- and six-membered cyclic amino acidswith excellent enantioselectivity (>98% e.e.) using a tan-dem Rh–phosphine-catalyzed asymmetric hydrogenation–hydroformylation–cyclization–dehydration sequence. A sin-gle pot and catalyst are used to achieve each of thesetransformations eliminating the need for isolation of interme-diates, multiple reagents, and complicated reaction set-ups.scCO2 provides an excellent replacement solvent for ben-zene (formerly the optimum solvent for this sequence), andits application at considerably lower vessel pressure furtherincreases its potential for general use. Unfortunately, in thisstudy, the minor five-membered cyclic amino acids are diffi-cult to separate from over-reduced or unreacted intermediatematerial that arises because of the slower hydroformylationrate in the scCO2 medium.

Experimental

General experimental details have been previously reported.[8] Opti-cal purity (% e.e.) was assessed by HPLC and was performedon a Varian LC 5000 instrument with a Waters 480 detec-tor using a chiral column (Chiracel OJ, 0.46 cm ID by 25 cmwith a particle size of 10 µm). Retention times (tR) are anaverage of two runs. [(COD)Rh-((2S,5S)-Et-DuPHOS)]OTf refersto (+)-1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene(cycloocta-1,5-diene)rhodium(i) trifluoromethane sulfonate[9] and was used as suppliedby Strem Chemicals. H2, CO2, and CO/H2 (1 : 1) were obtained fromBOC gases. Stainless steel Parr autoclave reaction vessels (100 mL),each fitted with Teflon-coated pressure gauge heads, a glass liner, astirrer bead, a thermocouple, and a heating block were employed. Ahigh-pressure syringe pump (ISCO, 260D) was used to charge reactionvessels to high pressures (>8.27 MPa).

Rhodium-Catalyzed Reaction of (2Z)-Methyl2-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 vesselwas 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 andthe gases were slowly vented. The autoclave was then pressurizedwith 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 brownoil (58 mg) whose 1H NMR spectrum showed the presence of threecompounds: (2S)-methyl N-acetyl-5,6-didehydropipecolate 4a, (2S)-methyl N-acetyl-4-methyl-4,5-didehydroprolinate 5a, and the fully satu-rated compound (2S)-methyl 2-acetamidopentanoate 3a in a 52 : 18 : 30ratio.[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 mix-ture (11 mg) of (2S)-methyl N-acetyl-4-methyl-4,5-didehydroprolinate

Cyclic α-Amino Acids via Metal-Catalyzed Cascade Reactions in scCO2 65

5a and (2S)-methyl 2-acetamidopentanoate 3a (RF 0.3). HPLC analysisof 4a (1.0 mL min−1, 10% isopropyl alcohol/90% hexane) revealed twopeaks: (S) t1 9.9 min and (R) t2 29.29 min with peak areas representingan enantiomeric excess of 97.7%. HPLC analysis of 5a in the mixturecontaining 3a showed two peaks: (S) t1 13.0 min and (R) t2 30.3 minwith peak areas representing an enantiomeric excess of 98.2%.

Rhodium-Catalyzed Reaction of (2Z,4E)-Methyl2-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 vesselwas 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 to0◦C and the gases were vented. The autoclave was then repres-surized 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 togive a brown oil (58 mg). The 1H NMR spectrum of the crude oilshowed the presence of three compounds: (2S)-methyl N-acetyl-5-methyl-5,6-didehydropipecolate 4b, (2S)-methyl N-acetyl-4-ethyl-4,5-didehydroprolinate 5b, and the non-hydroformylated material (2S,4E)-methyl 2-acetamidohex-4-enoate 2b in a 54 : 26 : 20 ratio.[8] Columnchromatography (3 : 1 ethyl acetate/light petroleum) first afforded (2S)-methyl N-acetyl-5-methyl-5,6-didehydropipecolate 4b (22 mg, 41%; RF0.51) 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 ofpurified 4b (1.0 mL min−1, 10% isopropyl alcohol/90% hexane) showedtwo peaks: (S) t1 8.3 min and (R) t2 11.4 min with peak areas representingan enantiomeric excess of 99.1%. HPLC analysis of 5b in the mixturecontaining 2b showed two peaks: (S) t1 11.6 min and (R) t2 22.1 minwith peak areas representing an enantiomeric excess of 99.2%.

Acknowledgments

We thank Monash University and the Centre for Green Chem-istry for provision of a postgraduate award (to E.T.), theAustralian Research Council for its financial support of ourresearch, Johnson Matthey Pty Ltd for a loan of rhodium, andDr Ulf Kreher, Associate Professor Andrew Smallridge, andMiss Kylie Blake for assistance with scCO2 reactions.

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