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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).
