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Synlett 2012(5): 727-730  
DOI: 10.1055/s-0031-1290597
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solvent-Free Stereoselective Organocatalyzed Aldol Reaction of 2-Hydroxycyclobutanone

David J. Aitkena, Francesca Capittaa,b, Angelo Frongia*a,b, Jean Ollivier*a, Pier Paolo Pirasb, Francesco Seccib
a Laboratoire de Synthèse Organique et Méthodologie, Institut de Chimie Moléculaire et des Matériaux d’Orsay, UMR 8182, Université Paris-Sud, 91405 Orsay, France
e-Mail: jean.ollivier@u-psud.fr;
b Dipartimento di Scienze Chimiche, Università di Cagliari, Complesso Universitario di Monserrato, S.S 554, Bivio per Sestu, 09042, Monserrato, Italy
Fax: +39(0706)754388; e-Mail: afrongia@unica.it;
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Publication History

Received 29 November 2011
Publication Date:
28 February 2012 (online)

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Abstract

The stereoselective solvent-free organocatalyzed aldol reaction of 2-hydroxycyclobutanone with a selection of aromatic aldehydes has been investigated. Using l-threonine (20 mol%), deracemized aldol adducts featuring a chiral quaternary center were obtained in yields up to 72%, with syn selectivity up to 85:15 and ee up to 84%. The title compound has markedly superior reactivity to other α-hydroxy ketones.

Key words

cyclobutanone - l-threonine - organocatalysis - aldol ­reaction - stereoselective reaction

    References and Notes

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13

A mixture of aldehyde (0.25 mmol), α-hydroxy ketone (1.25 mmol), and l-threonine (0.075 mmol) was stirred at 0-5 ˚C for the requisite time. The mixture was diluted with EtOAc and washed with half-sat. NH4Cl solution. The water phase was further extracted with EtOAc. The organic layers were combined, dried over Na2SO4, concentrated, and purified by column chromatography (PE-Et2O = 1:1) to afford the desired aldol product as an inseparable syn/anti mixture. The dr was determined by GC analysis. For ee determination, chiral HPLC analysis was used. When indicated, the aldol was first converted into the corresponding acetylated products¹4 in effectively quantitative yield, to facilitated signal separation.
2-Hydroxy-2-[hydroxy(4-nitrophenyl)methyl]-cyclobutanone (3a)
This product was described previously.5
2-[(4-Fluorophenyl)(hydroxy)methyl]-2-hydroxycyclo-butanone (3b)
Data obtained for a syn/anti mixture (85:15); white solid.
IR (nujol): 3455, 1701 cm-¹. ¹H NMR (250 MHz, DMSO-d 6): δ = 1.40-1.80 (m, 1 H, syn), 2.11-2.32 (dd, 1 H, J = 9.7, 10.7 Hz, anti), 2.31-2.51 (m, 3 H, syn + anti), 3.55-2.75 (m, 3 H, syn + anti), 4.57 (d, 1 H, J = 3.75 Hz, syn), 4.72 (br s, 1 H, anti), 5.72 (s, 1 H, syn), 5.94 (m, 1 H, anti), 6.40-6.51 (m, 2 H, syn + anti), 7.00-7.09 (m, 2 H, syn + anti), 7.25-7.38 (m, 2 H, syn + anti). ¹³C NMR (62 MHz, DMSO-d 6): δ = 23.3 (anti), 25.7 (syn), 38.7 (syn), 41.4 (anti), 72.5 (anti), 74.8 (syn), 94.5 (syn), 95.1 (anti), 114.8 (syn), 115.1 (anti), 129.9 (syn), 130.1 (anti), 130.3 (syn), 130.4 (anti), 138.3 (anti), 138.6 (syn), 212.3 (syn), 214.7 (anti). EI-MS: m/z (%) = 192 (66) [M+ - 18], 149 (15), 136 (69), 122 (100), 97 (50), 94 (54), 77 (22), 58 (28). After acetylation, the ee was determined using a Daicel Chiralcel OJ column (hexane-
i-PrOH = 93:7, flow rate 1.1 mL/min, λ = 254 nm): t R (syn) = 15.3 min (major), t R (syn) = 17.4 min (minor).
2-{[4-(Trifluoromethyl)phenyl](hydroxy)methyl}-2-hydroxycyclobutanone (3c)
Data obtained for a syn/anti mixture (84:16); white solid. IR (nujol): 3470, 1703 cm-¹. ¹H NMR (250 MHz, DMSO-d 6):
δ = 1.41-1.58 (m, 1 H, syn), 1.58-1.79 (m, 1 H, anti), 2.08-2.42 (m, 4 H, syn + anti), 2.50-2.80 (m, 2 H, syn + anti), 4.63 (d, 2 H, J = 4.75 Hz, syn + anti), 5.87 (d, 2 H, J = 4.75 Hz, syn + anti), 6.02 (s, 1 H, anti), 6.08 (s, 1 H, syn), 7.28-7.62 (m, 8 H, syn + anti). ¹³C NMR (62 MHz, DMSO-d 6): δ = 23.4 (anti), 26.2 (syn), 38.7 (anti), 42.2 (syn), 72.7 (syn), 75.2 (anti), 94.4 (syn), 94.8 (anti), 123.3 (anti), 125.1 (syn), 125.3 (anti), 127.6 (anti), 128.4 (syn), 129.0 (syn + anti), 129.4 (syn), 147.2 (syn + anti), 212.1 (syn), 214.3 (anti). EI-MS: m/z (%): 242 (47) [M+ - 18], 186 (63), 173 (61), 172 (100), 145 (80), 127 (59), 58 (30). After acetylation, the
ee was determined using a Daicel Chiralcel OJ column (hexane-i-PrOH = 98:2, flow rate 1 mL/min, λ = 254 nm): t R (major) = 28 min (syn), t R (minor) = 38 min (syn); t R (minor) = 26 min (anti), t R (major) = 49.7 min (anti).
2-[(2,4-Dichlorophenyl)(hydroxy)methyl]-2-hydroxycyclobutanone (3d) Spectral data worked out from the syn/anti mixture (70:30); white solid. IR (KBr): 3479, 1723 cm-¹. ¹H NMR (250 MHz, DMSO-d 6): δ = 1.69 (q, 1 H, J = 10. 5 Hz, syn), 1.82 (q, 1 H, J = 10. 4 Hz, anti), 2.30 (dq, 1 H, J = 5.0, 11.3 Hz, anti), 2.51 (q, 1 H, J = 11.3 Hz, syn), 2.66-2.80 (m, 4 H, syn + anti), 5.02 (d, 1 H, J = 4.00 Hz, syn), 5.05 (d, 1 H, J = 3.3 Hz, anti), 5.87 (d, 1 H, J = 4.75 Hz, syn), 6.02 (s, 3 H, syn + anti), 7.34-7.61 (m, 6 H, syn + anti). ¹³C NMR (62 MHz, DMSO-d 6): δ = 23.7 (anti), 25.4 (syn), 40.3 (syn), 40.8 (anti), 68.2 (anti), 70.1 (syn), 94.1 (anti), 94.2 (syn), 126.7 (syn + anti), 127.8 (syn), 127.9 (anti), 131.0(anti), 131.2 (syn), 132.3 (syn + anti), 133.2 (anti), 133.4 (syn), 138.2 (syn), 138.3 (anti), 210.8 (syn), 211.4 (anti). EI-MS: m/z (%) = 242 (36) [M+ - 18], 186 (59), 174 (80), 172 (100), 111 (49), 75 (27). After acetylation, the ee was determined using a Daicel Chiralpak AD-H column (hexane-i-PrOH = 98:2, flow rate 1 mL/min, λ = 254 nm): t R (major) = 8.9 min (syn), t R (minor) = 11.6 min (syn). 4-[Hydroxy-(1-hydroxy-2-oxo-cyclobutyl)-methyl]benzonitrile (3e)
Data obtained for a syn/anti mixture (78:22); colorless oil. IR (neat): 3388, 2236, 1941, 1785 cm-¹. ¹H NMR (500 MHz, CDCl3): δ = 1.76-1.84 (m, 1 H, anti), 1.92 (q, 1 H, J = 11.0 Hz, syn), 1.98-2.07 (m, 1 H, syn), 2.08-2.17 (m, 1 H, anti), 2.27 (dt, 1 H, J = 5.0, 12.0 Hz, syn), 2.35 (dt, 1 H, J = 5.0, 12.5 Hz, anti), 2.38-2.84 (m, 4 H, syn + anti), 4.20-4.80 (m, 2 H, syn + anti), 4.90 (s, 2 H, syn + anti), 7.49-7.62 (m, 8 H, syn + anti). ¹³C NMR (124 MHz, CDCl3): δ = 21.3 (anti), 23.2 (syn), 41.2 (syn), 41.7 (anti), 73.9 (syn), 81.6 (anti), 93.4 (syn + anti), 111.8 (syn + anti), 118.4 (syn + anti), 127.8 (anti), 128.0(syn), 132.0(anti), 132.1 (syn), 143.4 (syn), 144.2 (anti), 210.4 (syn), 211.4 (anti). EI-MS: m/z (%) = 199 (27) [M+ - 18], 143 (37), 130 (48), 129 (56), 115 (21), 102 (29), 77 (14), 40 (100). The ee was determined using a Daicel Chiralpak AD-H column (hexane-i-PrOH = 90:10, flow rate 1 mL/min, λ = 254 nm): t R(major) = 39.9 min (syn), t R (minor) = 25.9 min (syn); t R (minor) = 27.8 min (anti), tR (major) = 32.8 min (anti).
2-Hydroxy-2-[hydroxy(4-nitrophenyl)methyl]-cyclopentanone (5) Data obtained for a syn/anti mixture (69:31), obtained using the modified conditions stated in Table  [¹] (footnote f); orange oil. IR (neat): 3422, 1750 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 1.24-2.43 (m, 12 H), 4.87 (s, 1 H), 4.93 (s, 1 H), 7.53-7.57 (m, 4 H), 8.19-8.22 (m, 4 H). ¹³C NMR (75 MHz, CDCl3): δ = 22.1, 29.6, 30.8, 32.1, 36.1, 37.2, 74.7, 74.8, 79.1, 79.7, 104.1, 104.8, 123.1, 123.3, 128.0, 145.0, 147.0, 216.4, 217.1. EI-MS: m/z (%) = 234 (1) [M+ - 17], 165 (10), 150 (10), 100 (100), 77 (30), 55 (16), 43 (16). The ee was determined using a Daicel Chiralpak AD-H column (hexane-i-PrOH = 92:8, flow rate 0.8 mL/min, λ = 254 nm): t R (major) = 24.1 min (syn), t R (minor) = 25.0 min (syn);
t R (major) = 21.8 min (anti), t R (minor) = 36.7 min (anti).