4212 J . Org. Chem., Vol. 61, No. 13, 1996
Andre´s et al.
1
CHCl3); IR (film) 3420 cm-1; H NMR δ 0.93 (t, 3H, J ) 7.3
Hz), 1.00 (d, 3H, J ) 6.7 Hz), 1.14 (m, 1H), 1.54 (m, 1H), 2.55
(dq, 1H, J 1 ) 6.7 Hz, J 2 ) 2.7 Hz), 3.30 (d, 2H, J ) 13.6 Hz),
3.41 (m, 1H); 3.82 (d, 2H, J ) 13.6 Hz), 7.20-7.40 (m, 10H);
13C NMR δ 7.9, 9.9, 26.4, 53.1, 57.9, 71.8, 127.1,128.4, 128.9,
138.8.
(2S,3R)-2-(N,N-Dib en zyla m in o)-3-p en t a n ol (a n ti-5a ):
hexane/EtOAc 10/1; 11% yield; colorless oil; [R]23 ) +48.2 (c
D
1, CHCl3); IR (film) 3320 cm-1; 1H NMR δ 0.87 (t, 3H, J ) 7.4
Hz), 1.11 (d, 3H, J ) 6.8 Hz), 1.30 (m, 1H); 1.77 (m, 2H), 2.71
(m, 1H), 3.47 (d, 2H, J ) 13.8 Hz), 3.52 (m, 1H), 3.76 (d, 2H,
J ) 13.8 Hz), 7.15-7.40 (m, 10H); 13C NMR δ 8.5, 10.2, 27.1,
54.6, 56.9, 75.0, 126.8, 128.1, 128.6, 140.0.
F igu r e 1.
ing the cis relationship of these substituents and thus
the trans relative stereochemistry for 4-H and 5-H.
Finally, the identity of the minor diastereomers anti-
5a and anti-5c obtained by us was established by
comparison of their physical and spectroscopic properties
with those obtained as major components in the reactions
of 4a and 4c with ethylmagnesium bromide as described
by Reetz.2
This unprecedent syn selectivity for the addition to
dibenzylamino aldehydes can be explained by ethylation
from the less hindered si face of the carbonyl group in a
Cram chelate complex (Figure 1). Moreover, the efficient
alkylation observed for the compounds described here is
in contrast with the low reactivity of diethylzinc with
aldehydes and can be attributed to the well-known
“ligand acceleration” promoted by the amino group13
present in R-(dibenzylamino) aldehydes. Nevertheless,
the nature of the reaction intermediate probably was
rather complex, and the ethylzinc alkoxide formed in the
reaction is likely to be involved in the reactive species.
In summary, diethylzinc shows a very high syn selec-
tivity in reactions with chiral R-(dibenzylamino) alde-
hydes, and the reactions described here are complemen-
tary and constitute an alternative to the use of other
organometallics described in the literature.
(3S ,4S )-4-(N ,N -Dib e n zyla m in o)-5-m e t h yl-3-h e xa n ol
(syn -5b): hexane/EtOAc 15/1; 64% yield; colorless oil; [R]23
D
) +12.5 (c 1, CHCl3); IR (film) 3380 cm-1; H NMR δ 0.93 (t,
1
3H, J ) 7.3 Hz), 1.03 (d, 3H, J ) 7.0 Hz), 1.06 (d, 3H, J ) 7.0
Hz), 1.11 (m, 1H), 1.58 (m, 1H), 2.25 (m, 1H), 2.33 (dd, 1H, J 1
) 9.3 Hz, J 2 ) 2.1 Hz), 3.43 (d, 2H, J ) 13.0 Hz), 3.67 (m,
1H), 3.92 (d, 2H, J ) 13.0 Hz), 4.50 (br s, 1H), 7.20-7.40 (m,
10H); 13C NMR δ 10.1, 19.1, 23.9, 24.6, 27.9, 53.8, 65.3, 68.2,
127.1, 128.3, 129.1, 138.9 .
(3S,4S)-4-(N,N-Dib en zyla m in o)-6-m et h yl-3-h ep t a n ol
(syn -5c): hexane/EtOAc 15/1; 57% yield; colorless oil; [R]23
)
D
+34.3 (c 1, CHCl3); IR (film) 3440 cm-1 1H NMR δ 0.92 (t,
;
3H, J ) 7.3 Hz), 0.94 (d, 6H, J ) 6.4 Hz), 1.18 (m, 2H), 1.57
(m, 2H), 1.70 (m, 1H), 2.48 (m, 1H), 3.38 (m, 1H), 3.41 (d, 2H,
J ) 13.4 Hz), 3.85 (d, 2H, J ) 13.4 Hz), 4.55 (br s, 1H), 7.20-
7.40 (m, 10H); 13C NMR δ 10.2, 22.9, 23.4, 26.6, 35.6, 53.7,
60.4, 72.3, 127.1, 128.4, 128.9, 139.1.
(3R,4S)-4-(N,N-Dib en zyla m in o)-6-m et h yl-3-h ep t a n ol
(a n ti-5c): hexane/EtOAc 15/1; 5% yield; colorless oil; [R]23
)
D
+15.7 (c 1, CHCl3); IR (film) 3420 cm-1; H NMR δ: 0.72 (d,
3H, J ) 6.5 Hz), 0.91 (d, 3H, J ) 6.6 Hz), 0.94 (t, 3H, J ) 7.3
Hz), 1.15-1.65 (m, 4H), 1.76 (m, 1H), 2.10 (br s, 1H), 2.72 (dt,
1H, J 1 ) 7.0 Hz, J 2 ) 3.6 Hz), 3.63 (d, 2H, J ) 13.6 Hz), 3.65
(m, 1H), 3.68 (d, 2H, J ) 13.6 Hz), 7.20-7.40 (m, 10H); 13C
NMR δ 11.1, 22.7, 23.1, 24.7, 27.6, 34.4, 55.0, 58.1, 72.2, 126.9,
128.2, 129.0, 140.2.
1
(2S,3S)-2-(N,N-Dib en zyla m in o)-1-p h en yl-3-p en t a n ol
(syn -5d ): hexane/EtOAc 8/1; 63%; colorless oil; [R]23D ) +25.0
Exp er im en ta l Section
1
(c 1, CHCl3); IR (film) 3400 cm-1; H NMR δ 0.81 (t, 3H, J )
7.3 Hz), 1.06 (m, 1H), 1.46 (m, 1H), 2.65 (dd, 1H, J 1 ) 14.3
Hz, J 2 ) 6.0 Hz), 2.88 (m, 1H), 3.07 (dd, 1H, J 1 ) 14.3 Hz, J 2
) 6.5 Hz), 3.35 (d, 2H, J ) 13.2 Hz), 3.52 (m, 1H), 3.89 (d, 2H,
J ) 13.2 Hz), 4.47 (s, 1H), 7.10-7.40 (m, 15H); 13C NMR δ
9.7, 26.8, 32.2, 53.7, 63.3, 71.3, 126.1, 127.1, 128.3, 128.4, 128.9,
129.0, 138.7, 140.4.
Gen er a l P r oced u r es. Optical rotations were measured on
a digital polarimeter in a 1-dm cell. 1H-NMR and 13C-NMR
were taken at 300 and 75 MHz, respectively, in CDCl3, and
chemical shifts are given in ppm relative to TMS as internal
standard. Only the most significant IR signals are given, and
microanalyses have been done at the Department of Inorganic
Chemistry. Chromatographic separations was done by flash
chromatography using 240-400 mesh silica gel.
The starting R-(dibenzylamino) aldehydes were prepared by
a modified described method.2 Diethylzinc (1 M solution in
hexanes) is commercially available. All the reactions were
carried out in oven-dried glassware under argon atmosphere.
Solvents were distilled prior to use: toluene and THF from
benzophenone ketyl, CH2Cl2 from CaH2, and methanol from
magnesium turnings.
Alk yla tion of Am in o Ald eh yd es 4 w ith Et2Zn . Gen er a l
Meth od . A 50 mL oven-dried flask equipped with a septum
and a magnetic stirrer and purged with argon was charged
with the corresponding N,N-dibenzylamino aldehyde (2 mmol)
in 8 mL of anhydrous toluene. The solution was cooled to 0
°C (ice bath), and 4 mL of a 1 M solution of diethylzinc in
hexane (4 mmol, 2 equiv) was injected through the septum.
The mixture was stirred at that temperature until the reaction
was finished (TLC) and then quenched with 40 mL of an
aqueous saturated solution of ammonium chloride. The
organic layer was separated, and the aqueous phase was
extracted with diethyl ether (3 × 20 mL). The combined
organic layers were washed with brine and dried over anhy-
drous Na2SO4. The solvents were eliminated on a Rotavapor,
and the residue was purified by flash chromatography (silica
gel, hexane/ethyl acetate).
(2S,3R)-2-(N,N-Dib en zyla m in o)-1-p h en yl-3-p en t a n ol
(a n ti-5d ): hexane/EtOAc 8/1; 7% yield; colorless oil; [R]23
)
D
+20.1 (c 1, CHCl3); IR (film) 3420 cm-1 1H NMR δ 0.88 (t,
;
3H, J ) 7.3 Hz), 1.37 (m, 1H), 1.68 (m, 1H), 1.90 (br s, 1H),
2.80 (dd, 1H, J 1 ) 12.7 Hz, J 2 ) 5.8 Hz), 3.05 (m, 2H), 3.60
(m, 1H), 3.65 (d, 2H, J ) 13.8 Hz), 3.77 (d, 2H, J ) 13.8 Hz),
7.10-7.40 (m, 15H); 13C NMR δ 10.9, 27.6, 31.9, 55.0, 63.0,
73.2, 125.9, 126.9, 128.2, 128.3, 128.7, 129.3, 139.7, 140.6.
(1S,2S)-1-(N,N-Diben zylam in o)-1-ph en yl-2-bu tan ol (syn -
5e): hexane/EtOAc 15/1; 65% yield; colorless solid; mp 85-86
°C (from hexane); [R]23 ) +151.5 (c 1, CHCl3); IR (KBr) 3420
D
cm-1; H NMR δ 0.86 (t, 3H, J )7.3 Hz), 1.04 (m, 1H), 1.26
1
(m, 1H), 3.02 (d, 2H, J ) 13.3 Hz), 3.49 (d, J ) 10.3 Hz), 3.96
(d, 2H, J ) 13.3 Hz), 4.15 (m, 1H), 4.50 (br s, 1H), 7.15 (m
15H); 13C NMR δ 10.0, 26.7, 53.5, 67.1, 69.0, 127.2, 127.8,
128.2, 128.5, 129.0, 129.9, 134.1, 138.6. Anal. Calcd for
C24H27NO: C, 83.44; H, 7.88; N, 4.05. Found: C, 83.20; H,
7.74; N, 4.21.
(1R,2R)-1-(N,N-Diben zylam in o)-1-ph en yl-2-bu tan ol (syn -
en t-5e): 68% yield; white solid; mp 85-86 °C (from hexane);
[R]23 ) -151.3 (c 1, CHCl3).
D
(2S,3S)-2-(N,N-Diben zyla m in o)-1-[(2-m eth oxyeth oxy)-
m eth oxy]-3-p en ta n ol (syn -5f): hexane/EtOAc 5/1; 67% yield;
colorless oil; [R]23 ) +58.3 (c 1, CHCl3); IR (film) 3420 cm-1
;
D
1H NMR δ 0.90 (t, 3H, J ) 7.4 Hz), 1.20 (m, 1H), 1.57 (m, 1H),
2.69 (m, 1H), 3.43 (s, 3H), 3.56 (d, 2H, J ) 13.2 Hz), 3.60 (m,
3H), 3.77 (m, 4H), 3.96 (d, 2H, J ) 13.2 Hz), 4.25 (br s, 1H),
(2S,3S)-2-(N,N-Diben zylam in o)-3-pen tan ol (syn -5a): hex-
ane/EtOAc 10/1; 84% yield; colorless oil; [R]23 ) +70.5 (c 1,
D