cis-4-Pyrrolidin-1-yl-l-Proline: A Highly Stereoselective Organocatalyst for the Direct Aldol Reaction

Abstract

Modification of the pyrrolidinyl backbone of proline has not been quite successful for improving the catalytic efficiency and enantioselectivity. In this study, cis substitutions on the C4 position of proline with nitrogen-containing groups were found to have significant impacts on both the reactivity and selectivity of the catalyst for the direct aldol reaction of aromatic aldehydes with cyclohexanone. cis-4-Pyrrolidin-1-yl-l-proline exhibited dramatically improved reactivity, diastereo- and enantioselectivity compared with the parent l-proline, affording high isolated yields (up to 99%), excellent diastereoselectivities (>99:1 dr) and enantioselectivities (>99% ee). The presence of trifluoroacetic acid was found to be critical for the outstanding performance of this catalyst.

Key words

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

References and Notes

• 1a Kim BM. Williams SF. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Heathcock CH. Pergamon; Oxford: 1991.  p.229-275  
• 1b Modern Aldol Reactions   Vol. 1-2:  Mahrwarld R. Wiley-VCH; Weinheim: 2004. 
• 2a Trost BM. Science  1991,  254:  1471 
• 2b Trost BM. Angew. Chem. Int. Ed.  1995,  34:  259 
• 3 See review: Machajewski TD. Wong C.-H. Angew. Chem. Int. Ed.  2000,  39:  1352 
• 4a Yamada YMA. Yoshikawa N. Sasai H. Shibasaki M. Angew. Chem. Int. Ed.  1997,  36:  1871 
• 4b Yoshikawa N. Yamada YMA. Das J. Sasai H. Shibasaki M. J. Am. Chem. Soc.  1999,  121:  4168 
• 4c Trost BM. Ito H. J. Am. Chem. Soc.  2000,  122:  12003 
• 5a List B. Lerner RA. Barbas CF. J. Am. Chem. Soc.  2000,  122:  2395 
• 5b Sakthivel K. Notz W. Bui T. Barbas CF. J. Am. Chem. Soc.  2001,  123:  5260 
• 5c Notz W. List B. J. Am. Chem. Soc.  2000,  122:  7386 
• For reviews, see:
• 6a List B. Acc. Chem. Res.  2004,  37:  548 
• 6b Saito S. Yamamoto H. Acc. Chem. Res.  2004,  37:  570 
• 6c Notz W. Tanaka F. Barbas CF. Acc. Chem. Res.  2004,  37:  580 
• 6d List B. Tetrahedron  2002,  58:  5573 
• 6e Alcaide B. Almendros P. Angew. Chem. Int. Ed.  2003,  42:  858 
• 6f Kazmaier U. Angew. Chem. Int. Ed.  2005,  44:  2186 
• For proline catalysis in the asymmetric intermolecular direct aldol reactions, see the other leading references:
• 7a Northrup AB. MacMillan DWC. Science  2004,  305:  1752 
• 7b Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  6798 
• 7c Cordova A. Notz W. Barbas CF. J. Org. Chem.  2002,  67:  301 
• 7d Bøgevig A. Kumaragurubaran N. Jørgensen KA. Chem. Commun.  2002,  620 
• 7e Casas J. Engqvist M. Ibrahem I. Kaynak B. Cordova A. Angew. Chem. Int. Ed.  2005,  44:  1343 
• 7f Enders D. Grondal C. Angew. Chem. Int. Ed.  2005,  44:  1210 
• For selected examples, see:
• 8a Tang Z. Jiang F. Yu LT. Cui X. Gong LZ. Mi AQ. Jiang YZ. Wu Y.-D. J. Am. Chem. Soc.  2003,  125:  5262 
• 8b Tang Z. Yang ZH. Cun LF. Gong LZ. Mi AQ. Jiang YZ. Org. Lett.  2004,  6:  2285 
• 8c Mase N. Tanaka F. Barbas CF. Angew. Chem. Int. Ed.  2004,  43:  2420 
• 8d Torii H. Nakadai M. Ishihara K. Saito S. Yamamoto H. Angew. Chem. Int. Ed.  2004,  43:  1983 
• 8e Halland N. Braunton A. Bachmann S. Marigo M. Jørgensen KA. J. Am. Chem. Soc.  2004,  126:  4790 
• 8f Berkessel A. Koch B. Lex J. Adv. Synth. Catal.  2004,  346:  1141 
• 8g Tang Z. Yang ZH. Chen XH. Cun LF. Mi AQ. Jiang YZ. Gong LZ. J. Am. Chem. Soc.  2005,  127:  9285 
• 8h Krattiger P. Kovasy R. Revell JD. Ivan S. Wennemers H. Org. Lett.  2005,  7:  1101 
• 8i Chen J. Lu H. Li X. Cheng L. Wan J. Xiao W. Org. Lett.  2005,  7:  4543 
• 8j Samanta S. Liu J. Dodda R. Zhao C. Org. Lett.  2005,  7:  5321 
• 8k Wang W. Li H. Wang J. Tetrahedron Lett.  2005,  46:  5077 
• 8l Cobb AJA. Shaw DM. Longbottom DA. Gold JB. Ley SV. Org. Biomol. Chem.  2005,  3:  84 
• 8m Gryko D. Lipinski R. Adv. Synth. Catal.  2005,  347:  1948 
• 8n Tang Z. Cun LF. Cui X. Mi AQ. Jiang YZ. Gong LZ. Org. Lett.  2006,  8:  1263 
• 8o Mase N. Nakai Y. Ohara N. Yoda H. Takabe K. Tanaka F. Barbas CF. J. Am. Chem. Soc.  2006,  128:  734 
• For the work done in this lab, see:
• 9a Cheng C. Sun J. Wang C. Zhang Y. Wei S. Jiang F. Wu Y.-D. Chem. Commun.  2006,  215 
• 9b Cheng C. Wei S. Sun J. Synlett  2006,  2419 
• 10a Benaglia M. Celentano G. Cozzi F. Adv. Synth. Catal.  2001,  343:  171 
• 10b Benaglia M. Cinquini M. Cozzi F. Puglisi A. Celentano G. Adv. Synth. Catal.  2002,  344:  533 
• 10c Calderon F. Fernandez R. Sanchez F. Fernandez-Mayoralas A. Adv. Synth. Catal.  2005,  347:  1395 
• 10d Bellis E. Kokotos G. J. Mol. Catal. A: Chem.  2005,  241:  166 
• 11a Hayashi Y. Yamaguchi J. Hibino K. Sumiya T. Urushima T. Shoji M. Hashizume D. Koshino H. Adv. Synth. Catal.  2004,  346:  1435 
• 11b Bellis E. Kokotos G. Tetrahedron  2005,  61:  8669 
• 11c Hayashi Y. Sumiya T. Takahashi J. Gotoh H. Urushima T. Shoji M. Angew. Chem. Int. Ed.  2006,  45:  958 
• 11d Itagaki N. Kimura M. Sugahara T. Iwabuchi Y. Org. Lett.  2005,  7:  4185 
• 12 Abraham DJ. Mokotoff M. Sheh L. Simmons JE. J. Med. Chem.  1983,  26:  549 
• 13 Significant beneficial effects of strong acid on the enantioselectivity of proline for the same reaction has been previously observed when water was used as the co-solvent, in which case, however, no obvious improvements of the moderate reactivity and diastereoselectivity were achieved, see: Wu Y.-S. Chen Y. Deng D.-S. Cai J. Synlett  2005,  1627 
• See references 8i, 8o, 9b, and 11c. See also:
• 17a Cordova A. Zhou W. Ibrahem I. Reyes E. Engqvist M. Liao W. Chem. Commun.  2005,  3586 
• 17b Zhou W. Ibrahem I. Dziedic P. Sunden H. Cordova A. Chem. Commun.  2005,  4946 

14

Water has recently been demonstrated to be an excellent additive or solvent for the organocatalytic asymmetric aldol reactions, see refs. 8b, 8o and 11c.

15

Procedure for the Preparation of (2 S ,4 S )-4-Pyrrolidin-1-ylproline ( 5): To a solution of Et₃N (11.2 mL, 80.5 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-aminoproline methyl ester (7; 4.9 g, 20 mmol) in DMF (200 mL) was added 1,4-dibromobutane (4.8 mL, 40.5 mmol). The mixture was stirred at 60 °C for 4 h, and then cooled to 0 °C. Sat. aq solution of NaHCO₃ was added, followed by addition of EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine and dried over anhyd Na₂SO₄. After evaporation of the solvents under reduced pressure, the residual yellow oil was purified by flash chromatography on silica gel (eluent: hexane-EtOAc, 3:1) to give pure (2S,4S)-1-(tert-butoxycarbonyl)-4-pyrrolidin-1-ylproline methyl ester (3.5 g, 59%).
To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-pyrrolidin-1-ylproline methyl ester (2.0 g, 6.7 mmol) in THF-H₂O (1:1, 20 mL) was added LiOH·H₂O (0.85 g, 20 mmol). The mixture was stirred at r.t. for 4 h and then concentrated under reduced pressure. The resulting mixture was treated with a mixture of TFA-CH₂Cl₂ (1:2, 20 mL). After stirring for 4 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 recrystallization from MeOH to give the final product (0.65 g, 52% yield).
Compound 5: White solid; mp 232-236 °C; [α]_D ²⁵ -56.0 (c = 0.1, H₂O). ¹H NMR (600 MHz, D₂O): δ = 1.75 (m, 5 H), 2.50 (m, 1 H), 2.78 (br s, 4 H), 3.02 (dd, J = 7.1, 10.6 Hz, 1 H), 3.27-3.32 (m, 2 H), 3.80 (t, J = 8.6 Hz, 1 H). ¹³C NMR (150 MHz, D₂O): δ = 22.8, 33.9, 48.3, 52.8, 60.5, 63.7, 176.6. HRMS (ESI): m/z [M + Na⁺] calcd for C₉H₁₆N₂O₂: 207.1104; found: 207.1091.

16

General Procedure for the Aldol Reaction of Aldehydes with Cyclohexanone: To a mixture of cyclohexanone
(0.2 mL) in DMF (0.2 mL) was added catalyst (0.04 mmol, 20 mol%) and TFA (0.04 mmol, 20 mol%). After stirring at 0 °C for 1 h, aldehyde (0.2 mmol) was introduced. The reaction mixture was stirred at the same temperature for 1-72 h and was quenched with sat. aq 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: hexane-EtOAc, 3:1) to yield the corresponding aldol products for further analysis.

18

It should be noted that when acetone was used as the donor for the aldol reaction of aromatic aldehydes, catalyst 5 showed no obvious advantage over the parent l-proline in terms of either the enantioselectivity or the reactivity.