NOBIN-Prolinamide Organocatalyzed Enantioselective Direct Aldol Reaction: Remarkable Activity in Apolar Medium

Abstract

Amides easily obtained from enantiopure (R)- and (S)-NOBIN and l-proline have been shown to promote the enantioselective direct aldol reaction under low catalytic loadings (5 mol%), in apolar hexane as the solvent and using only a slightly higher ­molar excess of the acetone with respect to the aldehyde. Aldol products are isolated in good to high yields and up to 77% ee at room temperature.

aldol reaction - asymmetric organocatalysis - prolin­amides - NOBIN - apolar solvent

References and Notes

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Racemic NOBIN was synthesized according to procedures reported in the following references:

<A NAME="RG34606ST-12A">12a</A> Ding K. Xu Q. Wang Y. Liu J. Yu Z. Du B. Wu Y. Koshima H. Matsuura T. Chem. Commun.  1997,  693 

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<A NAME="RG34606ST-13">13</A> (R)- and (S)-NOBIN were obtained by optical resolution according to the procedure reported in the literature: Ding K. Wang Y. Yun H. Liu J. Wu Y. Terada M. Okubo Y. Mikami K. Chem. Eur. J.  1999,  5:  1734 

<A NAME="RG34606ST-14">14</A>

Procedure for the Synthesis of Catalysts 2 and 3
To a solution of N-carbobenzyloxy l-proline (320 mg, 1.26 mmol) in anyd CH₂Cl₂ (4 mL) and MeCN (4 mL) was added DMAP (80 mg, 1 mmol), EDC·HCl (368 mg, 3 mmol) at 0 °C under argon atmosphere. Stirring was mantained for 1 h, then (R)-or (S)-NOBIN (400 mg, 1.4 mmol) dissoved in anhyd DMF (2 mL) was cannulated in the reaction vessel and stirring was mantained for 3 d at r.t. The solvent was removed, the crude mixture was diluted with HCl solution (0.1 N) and extracted with CHCl₃ (2 × 50 mL). The organic phase was then dried over Na₂SO₄. The crude mixture was purified by flash chromatography eluting with PE-Et₂O (1:1) to PE-EtOAc (2:1) mixtures to give 400 mg (60%) and 380 mg (57%) yield, respectively, as white gummy compounds. To N-carbobenzyloxy-l-prolinamide (R)-NOBIN (400 mg) dissolved in anhyd MeOH (8 mL) was added Pd/C (10% w/w). The reaction mixture was stirred under H₂ (1 atm) at 50 °C for 3 h. After cooling, the mixture was filtered over a pad of Celite^®. The solvent was removed and the crude mixture was purified by flash chromatography eluting with CHCl₃-MeOH (2:1) mixture to give 2 (266 mg, 90%) as a white solid. Compound 3 was obtained with the same yield.
Compound 2: mp 199-201 °C (dec.); [α]_D ²³ -46.7 (c 0.25, EtOH). IR (neat): 3203, 3056, 2870, 1670, 1506, 818, 751 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 9.70 (br s, 1 H), 8.62 (d, 1 H, J = 9.0 Hz), 8.03-7.80 (m, 5 H), 7.41-7.31 (m, 4 H), 7.25-7.21 (m, 1 H), 7.03-6.99 (m, 1 H), 3.55-3.50 (m, 1 H), 2.58-2.53 (m, 1 H), 2.32-2.28 (m, 1 H), 1.90-1.87 (m, 1 H), 1.81-1.76 (m, 1 H), 1.50-1.27 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.0, 152.0, 136.0, 133.3, 133.1, 132.8, 131.1, 130.6, 130.0, 129.3, 128.3, 128.1, 127.1, 127.0, 125.3, 125.2, 124.3, 123.6, 120.4, 117.8, 113.6, 60.5, 46.6, 30.6, 25.6. ESI-MS: m/z 383 [M + H⁺]. Anal. Calcd (%) for C₂₅H₂₂N₂O₂: C, 78.51; H, 5.80; N, 7.32. Found: C, 78.70; H, 5.96; N, 7.18.
Compound 3: mp 215-218 °C (dec.). [α]_D ¹⁸ -25.8 (c 0.20, EtOH). IR (neat): 3232, 3056, 2972, 1661, 1505, 865, 749 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 9.72 (br s, 1 H), 8.75 (d, 1 H, J = 9.0 Hz), 8.07-7.80 (m, 5 H), 7.43-7.31 (m, 4 H), 7.24-7.20 (m, 1 H), 7.03-6.99 (m, 1 H), 3.57-3.52 (m, 1 H), 2.35-2.31 (m, 1 H), 1.84-1.80 (m, 1 H), 1.69-1.62 (m, 1 H), 1.54-1.48 (m, 1 H), 1.30-1.20 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 174.0, 151.9, 136.0, 133.3, 133.1, 132.8, 131.0, 130.6, 130.0, 129.3, 128.3, 128.1, 127.1, 127.0, 125.0, 124.9, 124.2, 123.7, 119.9, 117.8, 113.6, 60.6, 46.1, 30.6, 25.3. ESI-MS: m/z = 383 [MH⁺]. Anal. Calcd (%) for C₂₅H₂₂N₂O₂: C, 78.51; H, 5.80; N, 7.32. Found: C, 78.39; H, 5.62; N, 7.20.

<A NAME="RG34606ST-15A">15a</A> List B. Hoang L. Martin HJ. Proc. Natl. Acad. Sci. U. S. A.  2004,  101:  5839 

<A NAME="RG34606ST-15B">15b</A> List B. Chem. Commun.  2006,  819 

<A NAME="RG34606ST-16">16</A>

Procedure for the Synthesis of Catalyst 6
N-Carbobenzyloxy-d-prolinamide-(R)-NOBIN (180 mg, 0.348 mmol) was stirred with Cs₂CO₃ (566 mg, 1.74 mmol) in MeCN (5 mL) at r.t. for 30 min. Then MeI (870 µL, 14 mmol) was added and the mixture was stirred for 18 h. The solvent was removed, the crude mixture was diluted with HCl solution (0.1 N) and extracted with CHCl₃ (2 × 50 mL). The organic phase was then dried over Na₂SO₄. The crude mixture was purified by flash chromatography eluting with PE-EtOAc (6:4) to give 124 mg (67%) of the methylated product. Deprotection of this compound, carried out as previously reported for compound 2 and 3, furnished 88 mg (95%) of 6 as a white solid.
Compound 6: mp 167-171 °C (dec); [α]_D ²³ +33.9 (c 0.25, EtOH). IR (neat): 3443, 2927, 1658, 1507, 1249, 812, 753 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 9.70 (br s, 1 H), 8.05-7.85 (m, 6 H), 7.56-7.17 (m, 6 H), 3.95 (s, 3 H), 3.50-3.45 (m, 1 H), 3.37-3.32 (m, 2 H), 2.17-1.98 (m, 2 H), 1.33-1.20 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.0, 154.9, 138.2, 133.7, 133.0, 132.8, 131.0, 130.7, 129.5, 129.0, 128.5, 128.3, 127.6, 127.0, 126.0, 125.2, 125.1, 124.7, 124.0, 123.7, 115.5, 58.8, 58.3, 47.6, 29.9, 25.4. ESI-MS: m/z = 403 [M + H⁺]. Anal. Calcd (%) for C₂₆H₂₄N₂O₂: C, 78.76; H, 6.10; N, 7.07. Found: C, 78.92; H, 6.25; N, 7.21.

<A NAME="RG34606ST-17">17</A>

Typical Procedure for the Aldol Reaction
In a capped vial under air catalyst 3 (3.8 mg, 0.01 mmol), aldehyde (0.2 mmol) and hexane (400 µL) were added at r.t. To this stirred mixture, acetone (44 µL, 0.6 mmol) was added. Upon completion of the reaction, monitored by TLC, the reaction mixture was directly purified by flash chromatography (PE-EtOAc 90:10 to 60:40 mixtures) to provide aldol 5. Analytical data of aldols matched those reported in the literature. [5] [6]

<A NAME="RG34606ST-18">18</A>

For the sake of comparison, the optimized Gong’s catalyst at -25 °C in cyclohexanone furnished the aldol product as anti/syn 95:5 ratio in 83% yield. The anti-isomer was isolated in 79% ee. [6c]

Asymmetric organocatalyzed aldol reactions are generally performed using 10-30 mol% of catalyst loading. Few examples reported lower amounts of the promoters, see:

<A NAME="RG34606ST-19A">19a</A> Córdova A. Tetrahedron Lett.  2004,  45:  3949 

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<A NAME="RG34606ST-19C">19c</A> Krattiger P. Kovasy R. Revell JD. Ivan S. Wennemers H. Org. Lett.  2005,  7:  1101 

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<A NAME="RG34606ST-19F">19f</A>

See ref. 6c.

<A NAME="RG34606ST-20">20</A> For the only example of stoichiometric use of the ketone donors in organocatalyzed asymmetric aldol reaction, see: Mase N. Nakai Y. Ohara N. Yoda H. Takabe K. Tanaka F. Barbas CF. J. Am. Chem. Soc.  2006,  128:  734 

<A NAME="RG34606ST-21">21</A>

One way to achieve this goal might be the employment of proper mixtures of hexane and ethereal cosolvents.