trans-4-Hydroxy-l-proline Hydrazide-Trifluoroacetic Acid as Highly Stereoselective Organocatalyst for the Asymmetric Direct Aldol Reaction of Cyclohexanone

Abstract

Protonated N′-benzyl-N′-l-prolyl-trans-4-hydroxy-l-proline hydrazide has been found to be superior to the l-proline hydrazide counterpart as the catalyst for the asymmetric aldol reaction of cyclohexanone and aromatic aldehydes, resulting in excellent ­diastereoselectivities (up to >99:1 dr) and enantioselectivities (up to >99% ee).

proline hydrazide - enantioselectivity - diastereoselectivity - cyclohexanone - asymmetric direct aldol reaction

References and Notes

1a Modern Aldol Reactions   Vol. 1:  Mahrwarld R. Wiley-VCH; Weinheim: 2004. 

1b Modern Aldol Reactions   Vol. 2:  Mahrwarld R. Wiley-VCH; Weinheim: 2004. 

For recent reviews, see:

2a Palomo C. Oiarbide M. Garcia JM. Chem. Soc. Rev.  2004,  33:  65 

2b Saito S. Yamamoto H. Acc. Chem. Res.  2004,  37:  570 

3a List B. Lerner RA. Barbas CF. J. Am. Chem. Soc.  2000,  122:  2395 

3b Sakthivel K. Notz W. Bui T. Barbas CF. J. Am. Chem. Soc.  2001,  123:  5260 

3c Notz W. List B. J. Am. Chem. Soc.  2000,  122:  7386 

For selected examples, see:

4a Tang Z. Jiang F. Yu LT. Cui X. Gong LZ. Mi AQ. Jiang YZ. Wu Y.-D. J. Am. Chem. Soc.  2003,  125:  5262 

4b Tang Z. Yang ZH. Cun LF. Gong LZ. Mi AQ. Jiang YZ. Org. Lett.  2004,  6:  2285 

4c Mase N. Tanaka F. Barbas CF. Angew. Chem. Int. Ed.  2004,  43:  2420 

4d Torii H. Nakadai M. Ishihara K. Saito S. Yamamoto H. Angew. Chem. Int. Ed.  2004,  43:  1983 

4e Halland N. Braunton A. Bachmann S. Marigo M. Jørgensen KA. J. Am. Chem. Soc.  2004,  126:  4790 

4f Berkessel A. Koch B. Lex J. Adv. Synth. Catal.  2004,  346:  1141 

4g Tang Z. Yang ZH. Chen XH. Cun LF. Mi AQ. Jiang YZ. Gong LZ. J. Am. Chem. Soc.  2005,  127:  9285 

4h Krattiger P. Kovasy R. Revell JD. Ivan S. Wennemers H. Org. Lett.  2005,  7:  1101 

4i Chen J. Lu H. Li X. Cheng L. Wan J. Xiao W. Org. Lett.  2005,  7:  4543 

4j Samanta S. Liu J. Dodda R. Zhao C. Org. Lett.  2005,  7:  5321 

4k Wang W. Li H. Wang J. Tetrahedron Lett.  2005,  46:  5077 

4l Cobb AJA. Shaw DM. Longbottom DA. Gold JB. Ley SV. Org. Biomol. Chem.  2005,  3:  84 

4m Tang Z. Cun LF. Cui X. Mi AQ. Jiang YZ. Gong LZ. Org. Lett.  2006,  8:  1263 

4n Hayashi Y. Sumiya T. Takahashi J. Gotoh H. Urushima T. Shoji M. Angew. Chem. Int. Ed.  2005,  44:  958 

4o Mase N. Nakai Y. Ohara N. Yoda H. Takabe K. Tanaka F. Barbas CF. J. Am. Chem. Soc.  2006,  128:  734 

5 Cheng C. Sun J. Wang C. Zhang Y. Wei S. Jiang F. Wu Y.-D. Chem. Commun.  2006,  215 

For the currently available highly diastereoselective and enantioselective organocatalysts for the same reactions, see references 4i, 4n, 4o. See also:

6a Cordova A. Zhou W. Ibrahem I. Reyes E. Engqvist M. Liao W. Chem. Commun.  2005,  3586 

6b Zhou W. Ibrahem I. Dziedic P. Sunden H. Cordova A. Chem. Commun.  2005,  4946 

6c Wu Y. Chen Y. Deng D. Cai J. Synlett  2005,  1627 

7a Hayashi Y. Yamaguchi J. Hibino K. Sumiya T. Urushima T. Shoji M. Hashizume D. Koshino H. Adv. Synth. Catal.  2004,  346:  1435 

7b Bellis E. Kokotos G. Tetrahedron  2005,  61:  8669 

7c Casas J. Engqvist M. Ibrahem I. Kaynak B. Cordova A. Angew. Chem. Int. Ed.  2005,  44:  1343 

8

General Procedure for the Preparation of Catalysts 2-4:
To a solution of Boc-l-Pro-NHNH₂ (for 2) or trans-4-(tert-butyldimethylsilyloxy)-Boc-l-Pro-NHNH₂ (for 3 and 4; 8.0 mmol) in toluene (20 mL) was added benzaldehyde (935 mg, 8.8 mmol). The reaction mixture was stirred at r.t. for 24 h, and then concentrated under reduced pressure. The residue was dissolved in MeOH (80 mL), and 5% Pd/C (0.2 g) was added. After stirring under hydrogen (1 atm) for 1 h, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified through column chromatography on silica gel (eluent: PE-EtOAc, 3:1) to give N′-benzyl-Boc-l-proline hydrazide or N′-benzyl-trans-4-(tert-butyldimethylsilyloxy)-Boc-l-proline hydrazide.
To a solution of N′-benzyl-Boc-l-proline hydrazide or N′-benzyl-trans-4-(tert-butyldimethylsilyloxy)-Boc-l-proline hydrazide (2.0 mmol) in DMF (20 mL) were added Boc-l-Pro (for 4) or trans-4-hydroxy-Boc-l-Pro (for 2 and 3; 2.4 mmol), N,N-diisopropylethylamine (DIPEA, 700 µL) and HATU (922 mg, 2.4 mmol) at 0 °C. The reaction mixture was stirred at r.t. for 24 h, and then concentrated under reduced pressure. The residue was dissolved in EtOAc. The organic phase was then washed with sat. aq NaHCO₃ and brine and dried over anhyd Na₂SO₄. After removal of solvent under reduced pressure, the residue was purified through column chromatography on silica gel (eluent: PE-EtOAc, 2:1) to give a white solid, which was then treated with a mixture of TFA-CH₂Cl₂ (1:2, 20 mL). After stirring at r.t. for 1 h, the reaction mixture was concentrated under reduced pressure. The residue was subjected to chromatography on a H⁺ ion-exchange resin column with NH₃·H₂O (3.0 M) as eluent to give a crude product, which was further purified through column chromatography on silica gel (eluent: CH₂Cl₂ saturated with NH₃ gas-MeOH, 10:1) to give the final product.

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The following are the analytic data of catalyst 4: [α]_D ²⁵ -43.2 (c = 0.206, MeOH); mp 59-62 °C. ¹H NMR (600 MHz, CD₃OD): δ = 1.57-1.72 (m, 4 H), 1.88-1.95 (m, 2 H), 2.66-2.71 (m, 2 H), 2.84-2.86 (dd, J = 3.90, 11.94 Hz, 1 H), 3.01-3.05 (m, 1 H), 3.71 (q, J = 8.46 Hz, 2 H), 4.21 (s, 1 H), 4.54 (br s, 1 H), 4.75 (br s, 1 H), 7.17-7.25 (m, 5 H). ¹³C NMR (150 MHz, CD₃OD): δ = 25.6, 30.0, 39.4, 46.5, 50.5, 54.7, 57.5, 58.0, 71.8, 127.6, 128.3, 128.8, 135.4, 174.2, 175.6. HRMS (ESI): m/z [M +H]⁺ calcd for C₁₇H₂₅N₄O₃: 333.1921; found: 333.1915.

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Typical Procedure for the Aldol Reaction of Aldehydes with Cyclohexanone:
To a solution of 4 (12.6 mg, 0.04 mmol) in toluene (0.2 mL) were added cyclohexanone (210 µL) and TFA (3.1 µL, 0.04 mmol). After stirring at 0 °C for 15 min, aldehyde (0.2 mmoL) was introduced. The reaction was stirred at the same temperature until completion, and was then quenched with sat. aq solution of NH₄Cl. EtOAc was added to dilute the mixture. The organic layer was separated, washed with brine, dried over anhyd MgSO₄ and concentrated under reduced pressure. The residue was purified through column chromatography on silica gel (eluent: PE-EtOAc, 3:1) to yield the corresponding aldol products for further analysis.

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Further investigations, including computational studies, are needed to fully understand why catalyst 4 is superior to 1. A plausible explanation is that the existence of the trans-4-hydroxyl group in 4, which had no obvious effect on the solubility of the catalyst, favors the catalytic conformation that led to the major diastereomer and enantiomer.