LETTER
Stereoselective Organocatalyzed Aldol Reaction of 2-Hydroxycyclobutanone
729
2-[(4-Fluorophenyl)(hydroxy)methyl]-2-hydroxycyclo-
butanone (3b)
Acknowledgment
Financial support from the MIUR-Rome, from the University of
Cagliari, and from CINMPIS and FIRB 2008 is acknowledged. A.
F. is grateful for financial support for travel grants from the Regione
Autonoma of Sardinia.
Data obtained for a syn/anti mixture (85:15); white solid.
IR (nujol): 3455, 1701 cm–1. 1H NMR (250 MHz, DMSO-
d6): d = 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-d6): d =
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, l = 254 nm): tR (syn)
= 15.3 min (major), tR (syn) = 17.4 min (minor).
References and Notes
(1) (a) Salaün, J. Science of Synthesis, Vol. 26; Thieme:
Stuttgart, 2004, 557. (b) Bloomfield, J. J.; Nelke, J. M. Org.
Synth. 1977, 57, 1.
(2) Ohno, M.; Oguri, I.; Shoji, E. J. Org. Chem. 1992, 64, 8995.
(3) Saalfrank, R. W.; Hafner, W.; Markmann, J.; Welch, A.;
Peters, K.; Hans, G. Z. Naturforsch., B: J. Chem. Sci. 1994,
49, 389.
(4) Danappe, S.; Pal, A.; Alexandre, C.; Aubertin, A.-M.;
Bourgougnon, N.; Huet, F. Tetrahedron 2005, 61, 5782.
(5) Aitken, D. J.; Capitta, F.; Frongia, A.; Ollivier, J.; Piras,
P. P.; Secci, F. Synlett 2011, 712.
(6) Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH:
Weinheim, 2003.
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-d6):
d = 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-d6): d =
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, l = 254 nm):
tR (major) = 28 min (syn), tR (minor) = 38 min (syn);
tR (minor) = 26 min (anti), tR (major) = 49.7 min (anti).
2-[(2,4-Dichlorophenyl)(hydroxy)methyl]-2-
(7) (a) Guillena, G.; Hita, M. d. C.; Nájera, C.; Viózquez, S. F.
J. Org. Chem. 2008, 73, 5933. (b) Worch, C.; Bolm, C.
Synlett 2009, 2425. (c) Teo, Y.-C.; Lee, P. P.-F. Synth.
Commun. 2009, 39, 3081. (d) Agarwal, J.; Peddinti, R. K.
Tetrahedron: Asymmetry 2010, 21, 1906. (e) Hernández, J.
G.; Juaristi, E. J. Org. Chem. 2011, 76, 1464. (f) Martínez-
Casteñada, M.; Poladura, B.; Rodríguez-Solla, H.;
Concellón, C.; del Amo, V. Org. Lett. 2011, 13, 3032.
(8) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047.
(9) (a) Wu, C.; Fu, X.; Li, S. Eur. J. Org. Chem. 2011, 1291.
(b) Wu, X.; Ma, Z.; Ye, Z.; Qian, S.; Zhao, G. Adv. Synth.
Catal. 2009, 351, 158. (c) Mase, N.; Inoue, A.; Nishio, M.;
Takabe, K. Bioorg. Med. Chem. Lett. 2009, 19, 3955.
(10) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F.
III. J. Am. Chem. Soc. 2007, 129, 288.
(11) (a) Li, W.-D. Z.; Zhang, X.-X. Org. Lett. 2002, 4, 3485.
(b) Crane, S. N.; Burnell, D. J. J. Org. Chem. 1998, 63, 1352.
(12) For recent illustrative examples, see: (a) Pottie, I. R.; Crane,
S. N.; Gosse, A. L.; Miller, D. O.; Burnell, D. J. Can. J.
Chem. 2010, 88, 1118. (b) Kamijo, S.; Hoshikawa, T.;
Inoue, M. Tetrahedron Lett. 2010, 51, 872. (c) Herrera, A.
J.; Rondón, M.; Suárez, E. J. Org. Chem. 2008, 73, 3384.
(d) Biswas, B.; Sarkar, D.; Venkateswaran, R. V.
Tetrahedron 2008, 64, 3212. (e) Maulide, N.; Markó, I. E.
Org. Lett. 2007, 9, 3757. (f) Zhang, X.; Li, W. Z. Synth.
Commun. 2006, 36, 249. (g) Gao, F.; Burnell, D. J. J. Org.
Chem. 2006, 71, 356.
(13) A mixture of aldehyde (0.25 mmol), a-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.
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-d6): d = 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-
d6): d = 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,
l = 254 nm): tR (major) = 8.9 min (syn), tR (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): d = 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,
2-Hydroxy-2-[hydroxy(4-nitrophenyl)methyl]-
cyclobutanone (3a)
This product was described previously.5
© Thieme Stuttgart · New York
Synlett 2012, 23, 727–730