Advanced
Diastereoselective Reduction of 2,3-Dioxo-4-carboxy-5-substituted Pyrrolidines Using NaBH<sub>4</sub>/AcOH and Heterogenous Hydrogenation Reactions
Diastereoselective Reduction of 2,3-Dioxo-4-carboxy-5-substituted Pyrrolidines Using NaBH4/AcOH and Heterogenous Hydrogenation Reactions
Journal of the Korean Chemical Society. 2015. Feb, 59(1): 31-35
Copyright © 2015, Korean Chemical Society
  • Received : November 19, 2014
  • Accepted : December 11, 2014
  • Published : February 20, 2015
Download
PDF
e-PUB
PubReader
PPT
Export by style
Article
Author
Metrics
Cited by
TagCloud
About the Authors
Mohd Fazli Mohammat
Nurul Shulehaf Mansor
Department of Chemistry, Universiti Teknologi MARA, 40450 Shah Alam, Selangor, Malaysia.
Zurina Shaameri
Ahmad Sazali Hamzah

Abstract
Diastereoselective reduction of 2,3-dioxo-4-carboxy-5-(substituted)pyrrolidine 1 by NaBH 4 /AcOH and heterogenous hydrogenation were reported. Stereochemical assignment and diastereomeric ratios of the products were determined using 1 H NMR and single crystal X-ray analyses. The steric factors of the C-5 substituents of the pyrrolidinone was shown to have an interesting influence on both the yield and diastereoselectivity of the reduced product.
Keywords
INTRODUCTION
2,3-Dioxo-4-carboxy-5-substituted pyrrolidines are of great medicinal interest as they are substructures in a variety of bioactive compounds. 1 These include natural compounds such as (−)-codonopsinine, radicamine, rigidiusculamide, plakoridine and salinosporamide which display interesting biological activities. 24 Consequently, many types of natural or unnatural dioxopyrrolidinone and its modification have been successfully reported. Several experimental protocol have been successfully demonstrated on the preparation and exploration of 2,3-dioxo-4-carboxy- 5-substituted-pyrrolidines. Some examples include decarboxylation reaction, bipiridines synthesis, oxidative cleavage for β-lactone synthesis and conversion of the 2,3-dioxopyrrolidine to enamine using amino-dehydroxylating agent of potassium cyanate. 5,6 Deprotonation of the hydroxyl group to give the enol ether and acetyl compound were also succesfully reported. 7 Interestingly, this class of 2,3-dioxopyrrolidines type of compounds has known existed predominantly in enolic tautomer which gave positive ferric chloride test. 8
In conjunction towards the total synthesis of polyhydroxy alkaloids, we have successfully synthesized library of 2,3-dioxo-5-substituted pyrrolidines type of compounds. 9 From 1 H NMR analysis, the preference of the enolic tautomer structure of the 2,3-dioxo-4-carboxy-5-substituted pyrrolidines, were observed for all synthesized compounds either in deuterated CDCl 3 or DMSO. Remarkably, several attempts towards reduction of the 2,3-dioxo-4-carboxy-5-substituted pyrrolidines using NaBH 4 /MeOH only led to negative results, even in the present of complexating agent of CaCl 2 . 10 It concurred that inability of the hydride to reduce the ene of the enol tautomer led to these negative results. To our knowledge, only one successful example on direct ene-reduction of the enolic 2,3-dioxo-4-carboxy-5-substituted pyrrolidines tautomer are documented in literature. Upon treating enol 2,3-dioxo-4-carboxy-5-substituted pyrrolidines 1 with Zn dust in acidic conditions, Dehaen et al. successfully furnished the corresponding alcohols. 11
PPT Slide
Lager Image
Reduction of 1.
For further understanding of this enolic reduction, we have further explored and reported herein, a different systems of heterogenous hydrogenation and borohydride reduction, as simpler and more general approach for reduction enolic 2,3-dioxo-4-carboxy-5-substituted-pyrrolidines.
EXPERIMENTAL
- Experimental Protocols
IR spectra were recorded on Varian Excalibur 3100 in the spectral range of 4000 to 400 cm −1 . 1 H NMR spectra were recorded using Varian NMR Spectrometer instrument operating at 300 MHz.
- Synthesis
NaBH4/AcOH, Method A: To a stirred solution of 1 (1 mmol) in CH 2 Cl 2 (50 mL) was added acetic acid (1 mmol) then NaBH 4 (1.1 mmol) at 0 ℃. The resulting mixture was stirred for a further 1 h, then at room temperature for an additional 8 h and the solvent was then removed in vacuo . The residue was partitioned between EtOAc, washed with saturated NaHCO 3 solution. The organic phase was dried with MgSO 4 and concentrated in vacuo . The crude product was purified by column chromatography to give the hydroxy ester product.
H2/Pd, Method B: To a stirred solution of 1 (1 mmol) in ethanol (37 ml) and Pd-C (10% wt) (1 mmol) was added. The reaction was stirred vigorously under hydrogen atmosphere for 3 h and then filtered through Celite. After removal of the solvent, the crude product was purified by column chromatography to give the hydroxy ester product.
- Ethyl-4-hydroxy-1-methyl-5-oxopyrrolidine-3-carboxylate, (all cisXa) and (all transZa)
IR (KBr): 1729, 1693 cm −1 ; all cis (Xa): 1 H NMR (300 MHz, CDCl 3 ): δ 1.24−1.28 (t, J =7.0 Hz, 3H, CH 3 ), 2.88 (s, 3H, NCH 3 ), 3.34−3.39 (p, J =3.6 Hz, 1H, CH 2 ), 3.38−3.46 (dd, J =7.5 Hz, 1H, CH CO 2 Et), 3.67−3.71 (dd, J =4 Hz, 1H, CH 2 ), 4.16−4.23 (q, J =7.2 Hz, 2H, OCH 2 ), 4.50−4.52 (d, J =7.5 Hz, 1H, CH OH); 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 29.9, 42.8, 48.5, 61.3, 70.1, 170.2, 172.5. all trans ( Za ): 1 H NMR (300 MHz, CDCl 3 ): δ 1.24−1.29 (t, J =7.2 Hz, 3H, CH 3 ), 2.85 (s, 3H, NCH 3 ), 3.10−3.18 (q, J =8.4 Hz, 1H, CHCO 2 Et), 3.42−3.48 (t, J =9.3 Hz, 1H, CH 2 ), 3.48−3.55 (t, J =9.6 Hz, 1H, CH 2 ), 4.16−4.23 (q, J =7.2 Hz, 2H, OCH 2 ), 4.53−4.56 (d, J =8.7 Hz, 1H, CH OH); 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 29.9, 45.1, 47.7, 61.5, 72.1, 171.6, 173.0.
- Ethyl-4-hydroxy-1,2-dimethyl-5-oxopyrrolidine-3-carboxylate, (all cisXb) and (all transZb)
IR (KBr): 1721, 1677 cm −1 ; all cis Xb 1 H NMR (300 MHz, CDCl 3 ): δ 1.20−1.25 (t, J =7.2 Hz, 3H, CH 3 ), 1.26−1.28 (d, J =6.6 Hz, 3H, CH 3 ), 2.79 (s, 3H, NCH 3 ), 3.33−3.37 (t, J =6.7 Hz, 1H, CH CO 2 Et), 3.66−3.75 (p, J =6.6 Hz, 1H, CH 3 C H NCH 3 ), 3.80−3.81 (d, J =3.0 Hz, 1H, O H ), 4.12−4.20 (q, J =7.2 Hz, 2H, OCH 2 ), 4.42−4.43 (d, J =3.9 Hz, 1H, CH OH; 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 15.0, 27.1, 49.1, 52.8, 60.9, 70.6, 169.4, 172.8. all trans Zb: IR (KBr): 1738, 1684 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.25−1.30 (t, J =7.0 Hz, 3H, CH 3 ), 1.34−1.36 (d, J =6.3 Hz, 3H, CH 3 ), 2.63−2.68 (t, J =8.4 Hz, 1H, C H CO 2 Et), 2.79 (s, 3H, N C H 3 ), 3.55−3.64 (p, J =6.8 Hz, 1H, CH 3 C H NCH 3 ), 4.17−4.24 (q, J =7.1 Hz, 2H, O C H 2 ), 4.54−4.58 (dd, J =8.5 Hz, 1H, C H OH), 4.81−4.82 (d, J =3.3 Hz, 1H, O H ); 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 19.1, 27.3, 54.3, 54.3, 61.5, 72.1, 171.5, 173.0.
- Ethyl-4-hydroxy-1-methyl-5-oxo-2-propylpyrrolidine-3-carboxylate, (all cisXc) (all transZc) and (cis transYc)
IR (KBr): 1738, 1703 cm −1 ; all cis Xc 1 H NMR (300 MHz, CDCl 3 ): δ 0.91−0.96 (t, J =7.2 Hz, 3H, CH 3 ), 1.21−1.26 (t, J =7.0 Hz, 3H, CH 3 ), 1.28−1.38 (m, 1H, CH 2 ), 1.39−1.53 (m, 2H, CH 2 ), 1.77−1.86 (m, 1H, CH 2 ), 2.71 (br s, 1H, OH), 2.82 (s, 3H, NCH 3 ), 3.44−3.48 (t, J =7.0 Hz, 1H, C H CO 2 Et), 3.52−3.59 (p, J =5.0 Hz, 1H, CH (CH 2 ) 2 CH 3 ), 4.11−4.23 (m, 2H, OCH 2 ), 4.42−4.44 (d, J =7.8 Hz, 1H, C H OH); 13 C NMR (75 MHz, CDCl 3 ): δ 14.0, 14.1, 18.8, 27.5, 31.1, 48.6, 57.1, 60.8, 70.8, 169.3, 173.2 all trans Zc: IR (KBr): 1718, 1687 cm −1 , 1 H NMR (300 MHz, CDCl 3 ): δ 0.90−0.95 (t, J =7.2 Hz, 3H, CH 3 ), 1.22−1.36 (m, 2H, CH 2 ), 1.25−1.29 (t, J =7.0 Hz, 3H, CH 3 ), 1.45−1.57 (m, 1H, CH 2 ), 1.73−1.84 (m, 1H, CH 2 ), 2.73−2.78 (t, J =7.6 Hz, 1H, C H CO 2 Et), 2.80 (s, 3H, NCH 3 ), 3.61−3.67 (dt, J =7.5 Hz, 1H, C H (CH 2 ) 2 CH 3 ), 4.14−4.25 (m, 2H, OCH 2 ), 4.49−4.52 (d, J =7.8 Hz, 1H, C H OH); 13 C NMR (75 MHz, CDCl 3 ): δ 13.9, 14.1, 16.9, 27.8, 34.5, 51.6, 58.6, 61.5, 72.8, 172.2, 173.0. cis trans Yc: 1 H NMR (300 MHz, CDCl 3 ): δ 0.90−0.95 (t, J =7.2 Hz, 3H, CH 3 ), 1.22−1.36 (m, 2H, CH 2 ), 1.25−1.29 (t, J =7.0 Hz, 3H, CH 3 ), 1.45−1.57 (m, 1H, CH 2 ), 1.73−1.84 (m, 1H, CH 2 ), 2.83 (s, 3H, NCH 3 ), 3.06-3.10 (dd, J =8.55 Hz, 1H, C H CO 2 Et), 3.76−3.81(dq, J =3.9 Hz, 1H, C H (CH 2 ) 2 CH 3 ), 4.14−4.25 (m, 2H, OCH 2 ), 4.53−4.56 (d, J =8.4 Hz, 1H, C H OH); 13 C NMR (75 MHz, CDCl 3 ): δ 13.9, 14.1, 17.9, 28.2, 34.3, 48.4, 59.9, 61.2, 69.6, 170.3,172.6.
- Ethyl-2-heptyl-4-hydroxy-1-methyl-5-oxopyrrolidine-3-carboxylate, (all cisXd) (all transZd) and (cis transYd)
IR (KBr): 1738, 1706 cm −1 ; all cis Xd 1 H NMR (300 MHz, CDCl 3 ): δ 0.84−0.88 (t, J =6.7 Hz, 3H, CH 3 ), 1.21−1.26 (t, J =7.2 Hz, 3H, CH 3 ), 1.21−1.35 (m, 9H, CH 2 ), 1.39−1.50 (m, 2H, CH 2 ), 1.78−1.87 (m, 1H, CH 2 ), 2.82 (s, 3H, N C H 3 ), 3.44−3.48 (t, J =6.6 Hz, 1H, C H CO 2 Et), 3.50−3.57 (p, J =5.1 Hz, 1H, C H (CH 2 ) 6 CH 3 ), 4.13−4.21 (dq, J =7.2 Hz, 2H, OCH 2 ), 4.42−4.44 (d, J =7.5 Hz, 1H, C H OH); 13 C NMR (75 MHz, CDCl 3 ): δ 14.0, 14.1, 22.5, 25.4, 27.5, 29.0, 29.5, 31.6, 48.6, 57.3, 60.8, 70.8, 169.3, 173.2. all trans Zd: 1 H NMR (300 MHz, CDCl 3 ): δ 0.82−0.87 (t, J =6.7 Hz, 3H, CH 3 ), 1.22−1.29 (m, 10H, CH 2 ), 1.24−1.29 (t, J =7.2 Hz, 3H, CH 3 ), 1.48−1.57 (m, 1H, CH 2 ), 1.76−1.85 (m, 1H, CH 2 ), 2.73−2.78 (t, J =7.8 Hz, 1H, C H CO 2 Et), 2.79 (s, 3H, NCH 3 ), 3.60−3.66 (dt, J =7.6 Hz, 1H, C H (CH 2 ) 6 CH 3 ), 4.14−4.26 (m, 2H, OCH 2 ), 4.49−4.52 (d, J =7.8 Hz, 1H, CHOH); 13 C NMR (75 MHz, CDCl 3 ): 14.0, 14.1, 22.5, 23.5, 27.8, 29.0, 29.4, 31.6, 32.2, 51.6, 58.7, 61.5, 72.8, 172.3, 173.0. cis trans Yd: 1 H NMR (300 MHz, CDCl 3 ): δ 0.82−0.87 (t, J =6.7 Hz, 3H, CH 3 ), 1.22−1.29 (m, 10H, CH 2 ), 1.24−1.29 (t, J =7.2 Hz, 3H, CH 3 ), 1.48−1.57 (m, 1H, CH 2 ), 1.76−1.85 (m, 1H, CH 2 ), 2.83 (s, 3H, NCH 3 ), 3.06−3.10 (dd, J =8.7 Hz, 1H, C H CO 2 Et), 3.74−3.81 (s, J =3.9 Hz, 1H, C H (CH 2 ) 6 CH 3 ), 4.14−4.26 (m, 2H, OCH 2 ), 4.53−4.56 (d, J =8.4 Hz, 1H, C H OH); 13 C NMR (75 MHz, CDCl 3 ): δ 14.0, 14.1, 22.5, 24.5, 28.7, 29.0, 29.4, 31.6, 32.1, 48.4, 60.1, 61.2, 69.6, 170.3, 172.6.
Ethyl-4-hydroxy-1-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate, ( all cis Xe) ( all trans Ze) and ( cis trans Ye)
IR (KBr): 1732, 1676 cm −1 ; all cis Xe 1 H NMR (300 MHz, CDCl 3 ): δ 0.82−0.87 (t, J =7.0 Hz, 3H, CH 3 ), 2.75 (s, 3H, NCH 3 ), 3.61−3.65 (t, J =7.3 Hz, 1H, C H CO 2 Et), 3.62−3.73 (m, 1H, OCH 2 ), 3.75−3.86 (m, 1H, OCH 2 ), 4.55−4.57 (d, J =7.5 Hz, 1H, C H OH), 4.73−4.76 (d, J =7.2 Hz, 1H, ArC H NCH 3 ), 7.24−7.26 (m, 2H, ArC H ), 7.27−7.36 (m, 3H, ArC H ); 13 C NMR (75 MHz, CDCl 3 ): 13.5, 28.9, 49.1, 61.0, 63.1,70.4, 127.8, 128.6, 128.7, 134.9, 169.4, 173.3. all trans Ze: IR (KBr): 1732, 1689 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.18−1.23 (t, J =7.0 Hz, 3H, CH3), 2.64 (s, 3H, NCH 3 ), 3.02−3.07 (t, J =8.2 Hz, 1H, C H CO 2 Et), 3.62 (s br, 1H, OH), 4.13−4.21 (2H, dq, J =7.2 Hz, OCH 2 ), 4.60−4.63 (d, J =7.8 Hz, 1H, ArC H NCH 3 ), 4.66−4.68 (d, J =8.1 Hz, 1H, C H OH), 7.25−7.28 (dd, J =7.6 Hz, 2H, ArC H ), 7.35−7.39 (m, 3H, ArC H ); 13 C NMR (75 MHz, CDCl 3 ): 14.1, 28.4, 55.9, 61.5, 63.2, 72.4, 127.3, 128.6, 128.9, 137.7, 171.2, 173.3. cis trans Ye: 1 H NMR (300 MHz, CDCl 3 ): δ 1.23−1.28 (t, J =7.2 Hz, 3H, CH 3 ), 2.73 (s, 3H, NCH 3 ), 3.19−3.23 (dt, J =6.6 Hz, 1H, C H CO 2 Et), 4.12−4.22 (m, 2H, OCH 2 ), 4.69−4.72 (d, J =7.8 Hz, 1H, C H OH), 4.96−4.98 (d, J =5.7 Hz, 1H, ArC H NCH 3 ), 7.25−7.28 (d, J =7.2 Hz, 1H, ArC H ), 7.32−7.41 (m, 4H, ArC H ); 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 28.5, 52.9, 61.3, 64.1, 69.7, 126.7, 129.1, 129.2,138.1, 169.2, 173.2.
- Ethyl-4-hydroxy-1-methyl-2-(4-methylphenyl)-5-oxo-2-pyrrolidine-3-carboxylate, (all cisXf) (all transZf) and (cis transYf)
IR (KBr): 1739, 1673 cm −1 ; all cis Xf 1 H NMR (300 MHz, CDCl 3 ): δ 0.86−0.90 (t, J =7.2 Hz, 3H, CH 3 ), 2.32 (s, 3H, CH 3 ), 2.74 (s, 3H, NCH 3 ), 3.58−3.62 (t, J =7.3 Hz, 1H, C H CO 2 Et), 3.68−3.74 (m, 1H, OCH 2 ), 3.81−3.86 (m, 1H, OCH 2 ), 4.53−4.55 (d, J =7.2 Hz, 1H, C H OH), 4.70−4.73 (d, J =7.5 Hz, 1H, ArC H NCH 3 ), 7.14 (s, 4H, Ar C H); 13 C NMR (75 MHz, CDCl 3 ): δ 13.5, 21.0, 28.8, 49.1, 61.0, 62.9, 70.4, 127.7, 129.2,131.8,138.6, 169.5, 173.2. all trans Zf: IR (KBr): 1739, 1689 cm −1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 1.18−1.23 (t, J =7.2 Hz, 3H, CH 3 ), 2.35 (s, 3H, CH 3 ), 2.62 (s, 3H, NCH 3 ), 3.0−3.06 ( J =8.2 Hz, 1H, C H CO 2 Et), 3.10 (br s, 1H, O H ), 4.12−4.20 (dq, J =7.08 Hz, 2H, OCH 2 ), 4.56−4.58 (d, J =7.8 Hz, 1H, ArC H NCH 3 ), 4.63−4.66 (d, J =8.7 Hz, 1H, C H OH), 7.13−7.16 (d, J =8.4 Hz, 2H, ArC H ), 7.18−7.20 (d, J =8.1 Hz, 2H, ArC H ); 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 21.1, 28.3, 56.0, 61.5, 63.0, 72.4, 127.3, 129.8, 134.6,138.7, 171.3, 173.1. cis trans Yf: 1 H NMR (300 MHz, CDCl 3 ): δ 1.23−1.28 (t, J =7.0 Hz, 3H, CH 3 ), 2.34 (s, 3H, CH 3 ), 2.72 (s, 3H, NCH 3 ), 3.17−3.22 (dt, J =6.6 Hz, 1H, C H CO 2 Et), 4.12−4.20 (dq, J =7.0 Hz, 2H, OCH 2 ), 4.69−4.71 (d, J =7.8 Hz, 1H, C H OH), 4.92−4.94 (d, J =5.1 Hz, 1H, ArC H NCH 3 ), 7.07−7.09 (d, J =7.8 Hz, 2H, ArC H ), 7.13−7.16 (d, J =8.4 Hz, 2H, ArC H ); 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 21.1, 28.4, 52.9, 61.3, 63.9, 69.8, 126.6, 129.8, 135.1, 138.4,169.3, 173.1.
- Ethyl-4-hydroxy-2-(4-methoxyphenyl)-1-methyl-5-oxopyrrolidine-3-carboxylate, (all cisXg) (all transZg) and (cis transYg)
IR (KBr): 1733, 1677 cm −1 ; all cis Xg 1 H NMR (300 MHz, CDCl 3 ): δ 0.84−0.89 (t, J =7.0 Hz, 3H, CH 3 ), 2.68 (s, 3H, NCH 3 ), 3.55−3.60 (t, J =7.3 Hz, 1H, C H CO 2 Et), 3.65−3.83 (m, 2H, OCH 2 ), 3.742 (s, 3H, OCH 3 ), 4.27 (s br, 1H, O H ), 4.52−4.54 (d, J =7.2 Hz, 1H, C H OH), 4.69−4.67 (d, J =7.5 Hz, 1H, ArC H NCH 3 ), 6.80−6.83 (d, J =8.7 Hz, 2H, ArC H ), 7.14−7.17 ( J =8.7 Hz, 2H, ArC H ); 13 C NMR (75 MHz, CDCl 3 ): δ 13.6, 28.7, 49.2, 55.2, 60.9, 62.6, 70.3, 113.8, 126.8, 129.1, 159.8, 169.5, 173.4. all trans Zg: IR (KBr): 1735, 1687; 1 H NMR (300 MHz, CDCl 3 ): δ 1.16−1.21 (t, J =7.0 Hz, 3H, CH 3 ), 2.59 (s, 3H, NCH 3 ), 2.99−3.05 (t, J =8.1 Hz, 1H, C H CO 2 Et), 3.78 (s, 3H, OCH 3 ), 4.10−4.19 (m, 2H, OCH 2 ), 4.53−4.55 (d, J =8.1 Hz, 1H, ArC H NCH 3 ), 4.63−4.66 (d, J =8.4 Hz, 1H, C H OH), 5.19 (br s, 1H, O H ), 6.87−6.89 (d, J =8.1 Hz, 2H, ArC H ), 7.16−7.19 (d, J =7.8 Hz, 2H, ArC H ); 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 28.3, 55.2, 56.0, 61.4, 62.8, 72.4, 114.4, 128.6, 129.5, 159.9, 171.4, 173.4. cis trans Yg: 1 H NMR (300 MHz, CDCl 3 ): δ 1.21−1.25 (t, J =6.7 Hz, 3H, CH 3 ), 2.67 (s, 3H, NCH 3 ), 3.14−3.18 (t, J =6.7 Hz, 1H, C H CO 2 Et), 3.78 (s, 3H, OCH 3 ), 4.10−4.19 (m, 2H, OCH 2 ), 4.69−4.71 (d, J =7.8 Hz, 1H, C H OH), 4.93−4.95 (d, J =5.7 Hz, 1H, ArC H NCH 3 ), 5.19 (br s, 1H, O H ), 6.87−6.89 (d, J =8.1 Hz, 2H, ArC H ), 7.10−7.13 (d, J =8.4 Hz, 2H, ArC H ); 13 C NMR (75 MHz, CDCl 3 ): δ 14.1, 28.3, 53.1, 55.2, 61.2, 63.6, 69.8, 114.5, 128.1, 129.9, 159.7,169.2, 173.3.
RESULTS AND DISCUSSION
As shown in 1 , the reduction of the 2,3-dioxo-4-carboxy-pyrrolidines 1 using NaBH 4 /AcOH gave moderate to good yields (57−89%). Nevertheless it gave superior diastereoselectivity, leading majority of the product to the all trans alcohol Z . During the reaction, it was anticipated that conversion of the enol tautomers to more stable keto form occurred in the aqueous acidic solution, 12 unlike in previous neutral borohydride reduction. In term of diastereoselection, the steric effect imposed by bulky C-5 substituent were markedly effecting in this reduction system to give the more thermodynamic trans products Z . For compound 1a , which free of C-5 substituent, less diastereoselectivity were observed ( d.e =24:0:76, entry 1). The key diastereoselectivity in this borohydride acid mediated reduction was alleged to occur from coordination of the NaBH 4 with both carbonyl functionalities. 9(b) Then, the incoming hydride of NaBH 4 was delivered from the less hindered side of (i), forcing the carbonyl ester away from the C-5 substituent to be in stable trans -position state. Consequently, the oxyborohydride group attaching to the new C-2 chiral center will adopt the similar thermodynamic advantages concertedly, as depicted in 2 .
Stereoselective reduction of1using NaBH4/AcOH (Method A) and H2/Pd (Method B)
PPT Slide
Lager Image
aYield was based on the mixture of diastereomeric compound obtained after purification by column chromatography. bDiastereomeric ratio was based on the isolated yield after column chromatrography. cDiastereomeric ratio was determined by 1H NMR spectroscopic analysis of crude reaction mixtures. dDiasteromeric ratio was determined by 1H NMR spectroscopic analysis and isolated yield.
PPT Slide
Lager Image
Proposed mechanistic reduction of 1.
Conversely, reduction of the enolic tautomers 1 via syn -hydrogenation in neutral conditions gave excellent yields of the cis hydroxy ester product (71−99%) ( 1 ). Excellent diastereoselectivity can be seen with compound 1a , which produced the all cis Xa as the sole hydroxyl ester product ( d.e =100:0:0) ( 1 , entry 1). However, diastereoselection becoming less significant as the substituents at C-5 sterically increased (entries 2−7), which gave rise to mixture of all the diastereomers. Nevertheless, this syn -hydrogenation reaction showed that the ratio of all cis X always succeed than the other diastereomers. Oppositely, the mechanism of the syn -hydrogenation to enolate (iii) happened from the less hindered face leading to the trans reduced product Z ( 2 ). The unlikely trans diastereomers was also reported by Bessen et al during hydrogenation of exocyclic pyrolidine β-enamino esters. 13 Bulkier substituent of aromatics also contributed to lower yields, which attributed by blocking off the complexation Pd/ene site (entries 5−7). It was reported that during the hydrogenation process, the C=C double bond and the OH group are involved in the reactant-Pd interaction. 13
Noted that, the enolic hydroxyl ester 1 has three prochiral centers which are located at C-3, C-4 and C-5 positions and could produce eight possible diastereoisomers. Regardless the absolute configuration, only three main diastereomers of all cis X , all trans Z and cis trans Y were consider to present in the racemic mixture. Confirmation of all the diastereoisomers were assigned by 1 H NMR and 2D NMR experiments. Generally, all proton of Ha and Hb of trans reduced products display higher shift values as compared to cis reduced product ( 1 , 2 ) which is in agreement with previous report. 11 This was due to deshielding effect imposed by the ethoxyester onto the Ha protons of the all trans product. Hence, this also contributes to higher coupling constant values. Resulted consistency of Ha coupling constant values of the all trans product indicate that Ha are indeed in close proximity to the ester functionality.
1H NMR assignment for Ha and Hb for alltrans/cisproduct 1a−g
PPT Slide
Lager Image
1H NMR assignment for Ha and Hb for all trans/cis product 1a−g
Furthermore, the structure of some of the trans/cis reduced product was confirmed by X-ray investigation as shown in 1 . 14
PPT Slide
Lager Image
Single X-ray structure for all cis 1e and all trans 1b.
CONCLUSION
In summary, we have described a general and simple method for the diastereoselective reduction of the enolic 2,3-dioxo-4-carboxyl-5-substituted pyrrolidines in mild conditions. Excellent yields with high diastereoselectivity were observed in both strategies. Currently the synthesized hydroxyl pyrrolidine are further functionalized in our laboratory towards the synthesis of other interesting biologically active compounds.
Acknowledgements
We thank to UiTM and Malaysian Goverment (MOSTI) for the financial support (FRGS fund {600-RMI/ST/FRGS 5/3/Fst (11/2008).
References
Royles B. J. L. 1995 Chem. Rev. 95 1981 - 2001
Li J. , Liu S. , Niu S. , Zhuang W. , Che Y. 2009 J. Nat. Prod. 72 2184 - 2187
Endo A. , Danishefsky S. J. 2005 J. Am. Chem. Soc. 127 8298 - 8299
Bender D. R. , Bjeldanes L. F. , Knapp D. R. , Rapoport H. 1975 J. Org. Chem. 40 1264 - 1269
Dasse O. A. , Evans J. L. , Zhai H. , Zou X. D. , Kintigh J. T. 2007 Lett. Drug. Des. Discov. 4 263 - 271
Southwick P. L. , Previc E. P. , Casanova J. , Carlson E.H. 1956 J. Org. Chem. 21 1087 - 1095
Frage C. A. M. , Barreiro E. J. 1995 Synth. Commun. 25 1133 -
Metten B. , Kostermans M. , Van Baelen G. , Smet M. , Dehaen W. 2006 Tetrahedron 62 6018 - 6028
Iglesias M. 2003 J. Org. Chem. 68 2680 - 2688
Besson M. , Pinel C. 2003 Top. Catal. 25 43 - 61
Mansor N. S. , Mohammat M. F. , Shaameri Z. , Khaledi H. 2013 Acta. Cryst. E. E69 293 - 294