Aldol Reactions in Water Using a β-Cyclodextrin-Binding Proline Derivative

Abstract

The aldol reaction of various aromatic aldehydes with cyclohexanone is catalyzed by the inclusion complex of a proline derivative and β-cyclodextrin in water, yielding hydroxyketones with anti/syn ratio of up to 99:1 and ee values well above 90%.

adamantane - aldol reaction - β-cyclodextrin - proline - ­organocatalysis

References and Notes

<A NAME="RG18807ST-1A">1a</A> Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2004,  43:  5138 

<A NAME="RG18807ST-1B">1b</A> Berkessel A. Gröger H. Asymmetric Organocatalysis   1st ed.:  Wiley-VCH; Weinheim: 2005. 

<A NAME="RG18807ST-2">2</A> Palomo C. Oiarbide M. Garcia JM. Chem. Soc. Rev.  2004,  33:  65 

<A NAME="RG18807ST-3A">3a</A> List B. Acc. Chem. Res.  2004,  37:  548 

<A NAME="RG18807ST-3B">3b</A> List B. Hoang L. Martin HJ. Proc. Natl. Acad. Sci. U. S. A.  2004,  101:  5839 

<A NAME="RG18807ST-3C">3c</A> Notz W. Tanaka F. Barbas CF. Acc. Chem. Res.  2004,  37:  580 

<A NAME="RG18807ST-3D">3d</A> Steiner DD. Mase N. Barbas CF. Angew. Chem. Int. Ed.  2005,  44:  3706 

<A NAME="RG18807ST-3E">3e</A> Northrup AB. MacMillan DWC. Science  2004,  305:  1752 

<A NAME="RG18807ST-3F">3f</A> Ouellet SG. Tuttle JB. MacMillan DWC. J. Am. Chem. Soc.  2005,  127:  32 

<A NAME="RG18807ST-3G">3g</A> Marigo M. Fielenbach D. Braunton A. Kjoersgaard A. Jørgensen KA. Angew. Chem. Int. Ed.  2005,  44:  3703 

<A NAME="RG18807ST-3H">3h</A> Marigo M. Wabnitz TC. Fielenbach D. Jørgensen KA. Angew. Chem. Int. Ed.  2005,  44:  794 

<A NAME="RG18807ST-3I">3i</A> Tang Z. Jiang F. Yu LT. Cui X. Gong LZ. Mi AQ. Jiang YZ. Wu YD. J. Am. Chem. Soc.  2003,  125:  5262 

<A NAME="RG18807ST-3J">3j</A> Tang Z. Jiang F. Cui X. Gong LZ. Mi AQ. Jiang YZ. Wu YD. Proc. Natl. Acad. Sci. U. S. A.  2004,  101:  5755 

<A NAME="RG18807ST-3K">3k</A> Tang Z. Yang ZH. Chen XH. Cun LF. Mi AQ. Jiang YZ. Gong LZ. J. Am. Chem. Soc.  2005,  127:  9285 

<A NAME="RG18807ST-3L">3l</A> Torii H. Nakadai M. Ishihara K. Saito S. Yamamoto H. Angew. Chem. Int. Ed.  2004,  43:  1983 

<A NAME="RG18807ST-3M">3m</A> Saito S. Yamamoto H. Acc. Chem. Res.  2004,  37:  570 

<A NAME="RG18807ST-4A">4a</A> Heine A. DeSantis G. Luz JG. Mitchell M. Wong CH. Wilson IA. Science  2001,  294:  369 

<A NAME="RG18807ST-4B">4b</A> Zhu X. Tanaka F. Hu Y. Heine A. Fuller R. Zhong G. Olson AJ. Lerner RA. Barbas CF. Wilson IA. J. Mol. Biol.  2004,  343:  1269 

<A NAME="RG18807ST-5A">5a</A> Machajewski TD. Wong CH. Angew. Chem. Int. Ed.  2000,  39:  1352 

<A NAME="RG18807ST-5B">5b</A> Wymer N. Toone EJ. Curr. Opin. Chem. Biol.  2000,  4:  110 

<A NAME="RG18807ST-5C">5c</A> Zhong G. Lerner RA. Barbas CF. Angew. Chem. Int. Ed.  1999,  38:  3738 

<A NAME="RG18807ST-6A">6a</A> Mase N. Nakai Y. Ohara N. Yoda H. Takabe K. Tanaka F. Barbas CF. J. Am. Chem. Soc.  2006,  128:  734 

<A NAME="RG18807ST-6B">6b</A> Mase N. Watanabe K. Yoda H. Takabe K. Tanaka F. Barbas CF. J. Am. Chem. Soc.  2006,  128:  4966 

<A NAME="RG18807ST-6C">6c</A> Hayashi Y. Sumiya T. Takahashi J. Gotoh H. Urushima T. Shoji M. Angew. Chem. Int. Ed.  2006,  45:  958 

<A NAME="RG18807ST-6D">6d</A> Wu YY. Zhang YZ. Yu ML. Zhao G. Wang SW. Org. Lett.  2006,  8:  4417 

<A NAME="RG18807ST-6E">6e</A> Font D. Jimeno C. Pericàs MA. Org. Lett.  2006,  8:  4653 

<A NAME="RG18807ST-6F">6f</A> Maya V. Raj M. Singh VK. Org. Lett.  2007,  9:  2593 

<A NAME="RG18807ST-6G">6g</A> Wu X. Jiang Z. Shen HM. Lu X. Adv. Synth. Catal.  2007,  349:  812 

<A NAME="RG18807ST-7A">7a</A> Brogan AP. Dickerson TJ. Janda KD. Angew. Chem. Int. Ed.  2006,  45:  8100 

<A NAME="RG18807ST-7B">7b</A> Hayashi Y. Angew. Chem. Int. Ed.  2006,  45:  8103 

<A NAME="RG18807ST-7C">7c</A> Blackmond DG. Armstrong A. Coombe V. Wells A. Angew. Chem. Int. Ed.  2007,  46:  2 

<A NAME="RG18807ST-8">8</A> Calderón F. Ferández R. Sánchez F. Fernández-Mayoralas A. Adv. Synth. Catal.  2005,  347:  1395 

<A NAME="RG18807ST-9">9</A>

Synthesis of 6 To a solution of 5 (70.8 mg, 0.2 mmol) in CH₂Cl₂ (1 mL) was added solid 1-adamantane carboxylic acid chloride 4 (44 mg, 0.22 mmol) at 0 °C, followed by addition of DIPEA (52 mg, 0.4 mmol). The reaction mixture was stirred for 4 h at r.t. and finally diluted with CH₂Cl₂ (5 mL). The organic phase was washed consecutively with 1 N HCl, H₂O, brine and dried over Na₂SO₄.The solvent was removed under reduced pressure. Purification of the residue by flash chromatog-raphy using hexane-EtOAc (2:1) affords 6 as an oil (96 mg, 93%); [α]_D ²⁵ -32.1 (c 0.88, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.23-7.37 (m, 10 H), 6.65 (d, 1 H, J = 9.2 Hz), 4.95-5.34 (m, 4 H), 4.69 (m, 1 H), 4.41-4.50 (m, 1 H), 3.51-3.71 (m, 2 H), 2.41-2.50 (m, 1 H), 2.00 (m, 3 H), 1.91 (m, 1 H), 1.63-1.73 (m, 12 H). ¹³C NMR (100 MHz, CDCl₃): δ = 177.86, 177.78, 174.45, 155.16, 154.52, 136.65, 136.57, 135.68, 135.44, 129.06, 128.98, 128.94, 128.89, 128.57, 128.52, 128.44, 128.38, 128.23, 67.82, 67.73, 58.66, 58.20, 54.41, 54.12, 48.70, 47.72, 40.87, 40.86, 39.27, 39.26, 37.39, 36.87, 36.32, 28.47. ESI-MS: m/z = 539.2 [M + Na]⁺, 555.1 [M + K]⁺. Anal. Calcd (%) for C₃₁H₃₆N₂O₅: C, 72.07; H, 7.02; N, 5.42. Found: C, 71.27; H, 7.09; N, 5.20.

<A NAME="RG18807ST-10">10</A>

Synthesis of 1 To a solution of compound 6 (96 mg, 0.186 mmol) in MeOH (2 mL) was added 10% Pd/C (30 mg). The reaction mixture was stirred for 5 h under hydrogen, subsequently filtered through Celite and the catalyst was washed with MeOH three times. The combined organic solutions were concentrated under reduced pressure to afford the proline derivative 1 as a colorless solid (54 mg, 100%); mp 230-232 °C; [α]_D ²⁵ -32.9 (c 0.5, MeOH). ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.60 (d, 1 H, J = 6.8 Hz), 4.34 (m, 1 H), 4.15 (t, 1 H, J = 8.4 Hz), 3.28 (dd, 1 H, J = 11.2, 7.2 Hz), 3.10 (dd, 1 H, J = 11.2, 6.0 Hz), 2.46 (m, 1 H), 1.91 (m, 4 H), 1.58-1.72 (m, 12 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 177.93, 170.99, 58.99, 49.98, 48.50, 39.30, 36.94, 34.67, 28.43. ESI-MS: m/z = 293.4 [M + 1]⁺. Anal. Calcd (%) for C₁₆H₂₄N₂O₃: C, 65.73; H, 8.27; N, 9.58. Found: C, 65.66; H, 8.18; N, 9.44.

<A NAME="RG18807ST-11">11</A>

Spectroscopic Data of Inclusion Complex 3
¹H NMR (600 MHz, D₂O): δ = 5.04 (d, 7 H, H-1′), 4.55 (m, 1 H, H-γ), 4.22 (dd, 1 H, H-α), 3.89 (m, 7 H, H-6′′), 3.87 (m, 7 H, H-3′), 3.84 (m, 7 H, H-6′), 3.75 (m, 7 H, H-5′), 3.64 (dd, 7 H, H-2′), 3.60 (dd, 1 H, H-δ cis), 3.56 (dd, 7 H, H-4′), 3.46 (dd, 1 H, H-δ trans), 2.66 (m, 1 H, H-β cis), 2.20 (m, 1 H, H-β trans to Hα), 2.18 (s, 3 H, H-3), 1.91 (s, 6 H, H-2), 1.78 (s, 6 H, H-4). ¹H NMR (600 MHz, H₂O): δ = 7.37 (d, 1 H, NHC=O). ¹³C NMR (151 MHz, D₂O): δ = 180.7 (NHC=O), 174.3 (COOH), 102.7 (C-1′), 81.9 (C-4′), 73.5 (C-3′), 72.4 (C-2′), 72.3 (C-5′), 60.6 (C-α), 60.5 (C-6′), 50.4 (C-δ), 49.2 (C-γ), 40.9 (C-1), 38.9 (C-2), 36.8 (C-4), 34.8 (C-β), 27.8 (C-3).

<A NAME="RG18807ST-12">12</A> Hwang TL. Shaka AJ. J. Magn. Reson., Ser. A  1995,  112:  275 

<A NAME="RG18807ST-13">13</A>

The NOESY spectrum was acquired on an equimolar mixture of 1 and 2 in D₂O using a mixing time of 500 ms and 512 (142 ms) and 2048 (285 ms) points (acquisition times) in the F1 and the F2 dimension. Assignment of the resonances of this complex was accomplished using standard COSY, HMQC, and HMBC pulse sequences. NMR data were processed using Bruker XWINNMR software.

<A NAME="RG18807ST-14">14</A>

General Procedure for the Aldol Reaction Catalyzed by the Inclusion Complex of 1 and β-Cyclodextrin 2 To a suspension of the proline derivative 1 (5.84 mg, 0.02 mmol) in H₂O (0.2 mL) was added β-cyclodextrin 2 (22.7 mg, 0.02 mmol) and stirred for 10 min at r.t. until a clear solution was obtained; then cyclohexanone (80 µL, 0.8 mmol) was added. The reaction mixture was stirred at r.t. for further 10 min and subsequently aldehyde 7 (0.2 mol) was added. The reaction mixture was stirred for 3-96 h (TLC monitoring the consumption of aldehyde). The reaction was quenched with aq NH₄Cl and extracted with EtOAc. The combined organic layers were washed with H₂O and brine, dried over Na₂SO₄. Purification by flash chromatography (silica gel, hexane-EtOAc, 2:1) gave the pure aldol products for further analysis.
For Recycle Case
After the completion of reaction, the reaction mixture was directly extracted with CH₂Cl₂ for three times. The aqueous-phase-containing catalyst was reused again for next time after removing a little amount of CH₂Cl₂ under reduced pressure.

<A NAME="RG18807ST-15">15</A>

Absolute configuration of the aldol products anti-9 were determined by optical rotation in comparison to reported values⁶ except compound 9h.
The following are the analytical data of 2-hydroxy-methylene-(2′,6′-dichlorophenyl) cyclohexanone (9h): anti-9h: ¹H NMR (400 MHz, CDCl₃): δ = 7.29 (m, 2 H), 7.13 (m, 1 H), 5.82 (dd, 1 H, J = 9.6, 4.4 Hz), 3.67 (d, 1 H, J = 4.4 Hz), 3.46-3.49 (m, 1 H), 2.35-2.52 (m, 2 H), 2.05-2.09 (m, 1 H), 1.78-1.82 (m, 1 H), 1.62-1.69 (m, 2 H), 1.49-1.53 (m, 1 H), 1.34-1.41 (m, 1 H).
¹³C NMR (100 MHz, CDCl₃): δ = 214.85, 136.08, 135.10, 129.92, 70.97, 54.04, 42.85, 30.26, 28.04, 25.10. ESI-MS: m/z (%) = 295.3 (100) [M + Na]⁺. The ee of anti-9h (97%) was determined by HPLC with a Chiralpak AD-H column (heptane-2-PrOH, 90:10), 20 °C, 210 nm, 0.5 mL/min; major enantiomer t _R = 24.2 min, minor enantiomer t _R = 30.9 min.
syn-9h: ¹H NMR(400 MHz, CDCl₃): δ = 7.08-7.31 (m, 3 H), 5.73 (t, 1 H, J = 7.6 Hz), 3.27-3.33 (m, 1 H), 2.84 (d, 1 H, J = 7.6 Hz), 1.17-2.40 (m, 8 H). The ee was determined by HPLC with a Chiralpak AD-H column (heptane-2-PrOH, 90:10), 20 °C, 210 nm, 0.5 mL/min, one enantiomer t _R = 20.2 min, another enantiomer t _R = 22.1 min.