Enantioselective diethylzinc addition to aromatic and aliphatic aldehydes using (3R,5R)-dihydroxypiperidine derivatives catalyst

Article abstract of DOI:10.1016/j.tet.2005.11.070

A series of chiral (3R,5R)-dihydroxypiperidine derivatives 3a-f were conveniently prepared from trans-4-hydroxy-l-proline and applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal. Among them, 3d was found to show

Full text of DOI:10.1016/j.tet.2005.11.070

Tetrahedron 62 (2006) 2388–2394
Enantioselective diethylzinc addition to aromatic and aliphatic
aldehydes using (3R,5R)-dihydroxypiperidine derivatives catalyst
*
´
Remi Roudeau, Domingo Gomez Pardo and Janine Cossy
´ ´
Laboratoire de Chimie Organique associe au CNRS, Ecole Superieure de Physique et de Chimie Industrielles de la Ville
de Paris (ESPCI), 10 rue Vauquelin, 75231-Paris Cedex 05, France
Received 27 September 2005; revised 21 November 2005; accepted 28 November 2005
Available online 20 December 2005
Abstract—A series of chiral (3R,5R)-dihydroxypiperidine derivatives 3a–f were conveniently prepared from trans-4-hydroxy-L-proline and
applied to the catalytic enantioselective addition of diethylzinc to benzaldehyde and heptanal. Among them, 3d was found to show the best
asymmetric induction in promoting the addition of Et2Zn to various aldehydes, providing (R)-secondary alcohols in up to 98% ee.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Ligands 3a–f were prepared from the commercially
available trans-4-hydroxy-L-proline by utilizing a ring
expansion7,8 that we have devised previously to synthesize
(3R,5R)-dihydroxypiperidine derivatives.
Among asymmetric catalysis of C–C bond formation, the
enantioselective addition of diorganozinc reagents to
aldehydes in the presence of a catalytic amount of a chiral
ligand is a convenient method for the preparation of
optically active secondary alcohols.1 Among the numerous
chiral catalysts developed for asymmetric organozinc
additions, b-amino alcohols hold a prominent position.1e,2
The use of these catalysts for the addition of diethylzinc
to aromatic aldehydes produces 1-aryl-1-ethanols in
both excellent chemical yield and enantioselectivity3,4
(Scheme 1). In contrast, the enantioselectivity for aliphatic
aldehydes is usually considerably lower.5
Compounds 3a,7g 3b, and 3c were prepared from the
corresponding prolinols 2 by treatment with trifluoroacetic
anhydride followed by the addition of triethylamine
and then by treatment with sodium hydroxide.7g The
(3R,5R)-dihydroxypiperidine derivatives 3a, 3b, and 3c
were obtained in 82, 64, and 47% yield, respectively,
(Scheme 2). Compound 3a was then transformed into 3d–f.
OH
*
O
chiral amino alcohol
(5–20 mol%)
+
Et2Zn
R
R
H
Scheme 1. Enantioselective addition of diethylzinc to aldehydes catalyzed
by chiral amino alcohols.
2. Results
In the course of our studies on the synthesis and applications
of optically active 3,5-dihydroxy-piperidines,6 we would
like to report here the use of (3R,5R)-dihydroxypiperidine
derivatives on the enantioselective addition of diethylzinc to
aryl aldehydes as well as to aliphatic aldehydes.
Keywords: Enantioselective addition; Aliphatic aldehydes; Chiral ligands.
*
Corresponding author. Tel.: C33 140794429; fax: C33 140794660;
e-mail: janine.cossy@espci.fr
Scheme 2.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.070

R. Roudeau et al. / Tetrahedron 62 (2006) 2388–2394
2389
Scheme 3.
For obtaining 3d, the hydroxypiperidine 3a was treated with
triphenylmethane chloride (CH2Cl2, Et3N, 0 8C) and the
resulting piperidine 4 was mono-deprotected with n-Bu4NF
(THF, rt) to produce 3d with an overall yield of 60%. The
3,5-dihydroxypiperidine 3e7g was obtained in 75% yield by
deprotection of 3a using HCl (1.2 N) (Scheme 3).
entry 2). By decreasing the number of equivalents of Et2Zn,
from 2.2 to 1.5 or 1.2 equiv, the yield in 9 was increased in
the range of 93–99% and the ee was similar and
reproducible 87–92%.
We have to point out that the use of (R)-N-benzyl-3-
hydroxypiperidine7g led to 9 in 85% yield but the ee was
only 65%, which means that 3,5-dihydroxypiperidines were
promising (Scheme 4).
The synthesis of N-t-butyl-3,5-dihydoxypiperidine 3f was
achieved from 3a in four steps. After protection of the
hydroxyl group (TBDMSCl, DMAP, Et3N) and depro-
tection of the nitrogen (H2, Pd/C), the amine 6 was treated
with acetone cyanohydrin followed by the addition of
methylmagnesium bromide9 and, after addition of n-Bu4NF
to the resulting N-t-butylpiperidine 7 (THF, rt), compound
3f was isolated with an overall yield of 26% (Scheme 3). It
is worth noting that by using this synthetic pathway, a
library of chiral ligands should be easily prepared. The
novel chiral ligands 3a–f were then evaluated in the
asymmetric induction efficiency of diethylzinc addition to
aryl aldehydes and aliphatic aldehydes.
Scheme 4.
Due to these results, ligands 3a–e were then evaluated to
check their asymmetric induction in the addition of
diethylzinc to benzaldehyde 8.
The first test was performed on benzaldehyde using ligand
3e under standard conditions. The reaction was carried out
in dry toluene in the presence of 10 mol% of the chiral
ligand 3e and 2.2 equiv of Et2Zn at rt for 24 h. The reaction
was quenched with HCl (1.2 N) and after extraction and
purification by chromatography over silica gel 1-phenyl-
propan-1-ol 94l was isolated in 84% yield and 89% ee with
the (R) configuration (Table 1, entry 1). When the
temperature was lowered to 0 8C, the yield in 9 was
decreased to 73% and the ee remained similar (Table 1,
N-Benzyl monoprotected 3,5-dihydroxypiperidine 3a–d
were tested as well as the N-t-butyl non-protected
dihydroxypiperidine 3f. As reported in Table 2, 3d shows
the best asymmetric induction as 1-phenylpropanol 9 was
obtained with 98% ee using 2 mol% of 3d as catalyst
Table 2. Enantioselective addition of diethylzinc to benzaldehyde
catalyzed by ligands 3a–d and 3f
Table 1. Enantioselective addition of diethylzinc to benzaldehyde
catalyzed by ligand 3e
Entry
Ligand
mol%
Yield (%)
ee (%)
(conf.)a
Entry
Et2Zn (equiv) T (8C)
Yield
(%)
ee (%)a
Conf.b
1
2
3
4
5
3a
3b
3c
3d
3f
10
2
10
2
76
94
85
74
77
80 (R)
89 (R)
88 (R)
98 (R)
91 (R)
1
2
3
4
2.2
2.2
1.5
1.2
rt
0
rt
rt
84
73
93
99
89
87
87
92
R
R
R
R
2
a Determined by using a Chiralcel OD-H column and eluting with hexane–
iPrOH (99/1) at the flow rate of 1 mL/min.
a Determined by using a Chiralcel OD-H column and eluting with hexane–
iPrOH (99/1) at the flow rate of 1 mL/min; the absolute configuration was
determined by comparison with the absolute optical rotation given in the
literature.
b Determined by comparison with the absolute optical rotation reported in
the literature.

2390
R. Roudeau et al. / Tetrahedron 62 (2006) 2388–2394
(Table 2, entry 4). Obviously, the presence of a bulky trityl
substituent at C3 is crucial to obtain the best asymmetric
induction. It is interesting to note that the N-t-butyl
substituent in 3f also plays an important role in the
enantioselectivity (Table 2, entry 5) as 9 was obtained
with an ee of 91%.
3f were tested (Table 3). The best ligand for aliphatic
aldehydes seems to be the N-t-butyl-3,5-dihydroxypiperi-
dine 3f as 17 was obtained with an overall yield of 57% and
with an ee of 81% (Table 3, entry 6).
In conclusion, a series of new chiral ligands 3a–f for the
addition of dialkylzinc to aldehydes have been prepared
from trans-4-hydroxy-L-proline. Compound 3d was
found to be highly efficient for the enantioselective
addition of diethylzinc to aromatic aldehydes and good for
the enantioselective addition of diethylzinc to aliphatic
aldehydes. In the case of aliphatic aldehydes a better ee
was obtained with 3f.
By using 3d as the catalyst, ethyl alcohol 1310 (88% ee),
1411 (90% ee) and 153e,12 (76% ee) were obtained with good
ee and in good yield from aldehydes 10, 11, and 12,
respectively, (Scheme 5).
The chiral ligands described in this study might be used in
other asymmetric catalytic transformations. Such as for
example, the enantioselective Henry reaction of nitro-
methane with aldehydes.14
3. Experimental
3.1. General
All reactions were carried out under argon atmosphere.
Commercially available reagents and solvents were used as
received. Anhydrous solvents were distilled: tetra-
hydrofuran and diethyl ether were purified by distillation
from sodium and benzophenone, methylene chloride, and
toluene were dried by distillation from CaH2. Flash column
chromatography was performed on silica gel (Merck-
Kieselgel 60, 230–400 mesh).
Scheme 5.
1
Melting points (mp) were not corrected. H and 13C NMR
spectra were, respectively, recorded on a Bruker AC 300 at
300 and 75 MHz. Spectra were recorder in CDCl3 as
solvent, and chemical shifts (d) were expressed in ppm
Chiral ligand 3d was then examined for the asymmetric
addition of diethylzinc to the aliphatic aldehyde 16. In order
to facilitate the ee determination by chiral HPLC, the
alcohol obtained after the addition of Et2Zn was benzoylated
to produce 17. The benzoate 1713 was obtained with an
overall yield of 57% with an ee of 69% (Table 3, entry 4). In
the aim of increasing the ee, the chiral ligands 3a–c, 3e, and
1
relative to residual CHCl3 at dZ7.27 ppm for H and to
1
CDCl3 at dZ77.1 ppm for 13C. H NMR J values given in
Hz. IR spectra were recorded as neat films (NaCl cell) and
KBr pellets for solids on a Perkin-Elmer 298. Mass spectra
were obtained by GC/MS with electron impact (EI)
ionization by using a 5971 Hewlett Packard instrument at
70 eV: only selected ions are reported. HRMS were
performed at the Laboratoire de Spectrochimie de l’Ecole
Table 3. Enantioselective addition of diethylzinc to heptanal catalyzed by
ligand 3a–f
´
Normale Superieure in Paris. Optical rotations were
measured on a Perkin-Elmer 343 polarimeter in a 10 cm
cell. Analytical HPLC was carried out using a Waters 515
solvent-delivery system and a Waters 2487 variable-
wavelength absorbance detector operating at 254 nm. The
ee of the products were determined using a Chiralcel OD-H
column and eluting with hexane–iPrOH (99/1) at the flow
rate of 1 mL/min. Elemental analysis were performed by the
Entry
Ligand
mol%
Yield (%)a
ee (%)
(conf.)b
´
Centre Regional de Microanalyses (Universite Pierre
et Marie Curie, Paris VI).
´
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
10
10
10
2
10
2
34
39
42
57
25
57
35 (R)
59 (R)
62 (R)
69 (R)
60 (R)
81 (R)
3.1.1. (2S,4R)-1-Benzyl-4-[(tert-butyldimethylsilyl)oxy]-
2-methoxycarbonylpyrrolidine (1a);15 typical procedure
To a stirred suspension of (2R,4R)-4-hydroxy-2-methoxy-
carbonylpyrrolidine (5.0 g, 38.1 mmol, 1.0 equiv) in MeOH
(150 mL) at 0 8C thionyl chloride (3.4 mL, 45.7 mmol,
1.2 equiv) was added dropwise. After 72 h at rt, the organic
solvent was removed in vacuo to afford a white solid.
a Overall yield for addition and benzoylation.
b Determined by using a Chiralcel OD-H column and eluting with hexane–
iPrOH (99/1) at the flow rate of 1 mL/min; the absolute configuration was
determined by comparison with the absolute optical rotation given in the
literature.

R. Roudeau et al. / Tetrahedron 62 (2006) 2388–2394
2391
To a stirred suspension of the resulting white solid in CH2Cl2
(40 mL) at rt was added Et3N (21.4 mL, 152.4 mmol,
4 equiv), followed by BnBr (5.5 mL, 45.7 mmol,
1.2 equiv). After 10 min at rt, the reaction mixture was
heated at reflux for 5 h and cooled to rt. DMAP (0.5 g,
3.8 mmol, 0.1 equiv) and TBDMSCl (6.9 g, 45.7 mmol,
1.2 equiv) were added. After 12 h at rt, the reaction mixture
was quenched with a saturated aqueous Na2CO3 solution
until pHw10. The aqueous layer was extracted with CH2Cl2
and EtOAc and the combined organic phases were dried over
MgSO4 and filtered. The solvent was removed in vacuo to
afford an oil, which was purified by flash column
chromatography on silica gel (EtOAc/cyclohexane 30:70)
to give 1a (9.0 g, 25.8 mmol, 68% yield) as a colorless oil;
[a]2D0 K49.6 (c 3.65, CHCl3); IR (neat): 1740, 1375, 780,
After stirring at 0 8C for 10 min, the reaction mixture was
heated at reflux for 2 h and then cooled to 0 8C. Water
(0.09 mL), an aqueous 3.75 M NaOH solution (0.89 mL),
and water (2.7 mL) were successively added. The obtained
precipitate was collected on a Celite pad and washed with
THF. The organic solvent was removed in vacuo to give 2a
(3.4 g, 10.6 mmol, 92% yield) as a colorless oil; [a]2D0K43.4
(c 1.00, CHCl3), IR (neat): 3400, 1375, 780, 700 cmK1; 1H
NMR (CDCl3) d: 7.37–7.27 (5H), 4.27 (m, 1H), 3.97 (d, JZ
13.2 Hz, 1H), 3.67 (dd, JZ11.0, 3.3 Hz, 1H), 3.47 (d, JZ
13.2 Hz, 1H), 3.39 (d, JZ11.0 Hz, 1H), 3.14 (dd, JZ9.9,
5.5 Hz, 1H), 3.07 (m, 1H), 2.65 (s, 1H), 2.37 (dd, JZ9.9,
5.7 Hz, 1H), 2.09 (ddd, JZ12.9, 7.4, 7.4 Hz, 1H), 1.84 (ddd,
JZ13.0, 8.6, 4.6 Hz, 1H), 0.8 (s, 9H), 0.03 (s, 3H), 0.02 (s,
3H); 13C NMR (CDCl3) d: 139.0 (s), 128.5 (d), 128.3 (d),
126.9 (d), 70.6 (d), 63.3 (d), 62.1 (t), 60.9 (t), 58.6 (t), 37.7
(t), 25.7 (q), 17.9 (s), K4.9 (q); EI MS m/z (relative
intensity) 306 (MC%KCH3, 3), 292 (7), 291 (24), 290 (100),
158 (14), 91 (61), 75 (7).
700 cmK1 1H NMR (CDCl3) d: 7.35–7.21 (5H), 4.41
;
(m, 1H), 3.91 (d, JZ12.5 Hz, 1H), 3.65 (s, 3H), 3.60 (d, JZ
12.5 Hz, 1H), 3.53 (t, JZ8.1 Hz, 1H), 3.27 (dd, JZ9.6,
5.7 Hz, 1H), 2.37 (dd, JZ9.6, 5.2 Hz, 1H), 2.19 (ddd, JZ
13.1, 7.5, 7.3 Hz, 1H), 2.03 (ddd, JZ12.8, 8.5, 4.0 Hz, 1H),
0.8 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C NMR (CDCl3) d:
174.1 (s), 138.0 (s), 129.0 (d), 128.1 (d), 127.0 (d), 70.3 (d),
64.2 (d), 61.5 (t), 59.3 (t), 51.7 (q), 39.4 (t), 25.6 (q), 17.8 (s),
K5.0 (q); EI MS m/z (relative intensity) 349 (MC%, 1),
292 (10), 291 (27), 290 (100), 158 (14), 91 (41).
3.1.5. (2S,4R)-2-{1-Benzyl-4-[(tert-butyldiphenylsilyl)-
oxy]-pyrrolidinyl}methanol (2b). Yield: 90% from 1b;
colorless oil; [a]2D0 K1.2 (c 2.40, CHCl3); IR (neat): 3350,
1425, 1375, 735, 700 cmK1; 1H NMR (CDCl3) d: 7.73–7.63
(4H), 7.53–7.23 (11H), 4.34 (m, 1H), 3.99 (d, JZ12.9 Hz,
1H), 3.63 (dd, JZ11.0, 3.7 Hz, 1H), 3.54 (d, JZ13.2 Hz,
1H), 3.36 (dd, JZ11.0, 1.8 Hz, 1H), 3.14 (tdd, JZ8.1, 3.3,
1.8 Hz, 1H), 3.06 (dd, JZ10.3, 5.5 Hz, 1H), 2.52 (dd, JZ
10.1, 4.9 Hz, 1H), 2.48 (br s, 1H), 1.90–1.98 (2H), 1.09 (s,
9H); 13C NMR (CDCl3) d: 139.0 (s), 135.5 (d), 134.4 (s),
129.6 (d), 129.5 (d), 128.5 (d), 128.2 (d), 127.5 (d), 127.4
(d), 126.9 (d), 71.7 (d), 63.4 (d), 62.1 (t), 60.8 (t), 58.7 (t),
37.5 (t), 26.8 (q), 18.9 (s); EI MS m/z (relative intensity) 445
(MC%, 1), 414 (100), 199 (14), 183 (5), 158 (12), 91 (49);
HRMS (CI) calcd for C28H36O2NSi (MCHC) 446.2515,
found 446.2508.
3.1.2. (2S,4R)-1-Benzyl-4-[(tert-butyldiphenylsilyl)oxy]-
2-methoxycarbonylpyrrolidine (1b). Yield: 93% from
(2R,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine; color-
less oil; [a]2D0 K20.8 (c 3.65, CHCl3); IR (neat): 1740,
1375, 740, 710, 700 cmK1; 1H NMR (CDCl3) d: 7.78–7.73
(1H), 7.68–7.60 (4H), 7.48–7.23 (10H), 4.46 (m, 1H), 3.92
(d, JZ12.9 Hz, 1H), 3.66 (d, JZ12.9 Hz, 1H), 3.62 (s, 3H),
3.61 (dd, JZ8.1, 8.1 Hz, 1H), 3.19 (dd, JZ9.9, 5.9 Hz, 1H),
2.53 (dd, JZ9.9, 4.8 Hz, 1H), 2.13 (m, 1H), 2.04 (m, 1H),
1.09 (s, 9H); 13C NMR (CDCl3) d: 174.0 (s), 138.0 (s), 135.5
(d), 134.7 (d), 133.7 (s), 133.6 (s), 129.7 (d), 129.6 (d),
129.0 (d), 128.1 (d), 127.6 (d), 127.5 (d), 127.0 (d), 71.4 (d),
64.3 (d), 61.5 (t), 59.1 (t), 51.6 (q), 39.4 (t), 26.8 (q), 18.9
(s); EI MS m/z (relative intensity) 473 (MC%, 1), 458 (1),
414 (100) 199 (11), 183 (6), 158 (11), 135 (5), 91 (49).
3.1.6. (2S,4R)-2-{1-Benzyl-4-[(triisopropylsilyl)oxy]-pyr-
rolidinyl}methanol (2c). Yield: 96% from 1c; colorless oil;
[a]2D0 K9.9 (c 1.06, CHCl3); IR (neat): 3390, 1460, 1380,
1
735, 680 cmK1; H NMR (CDCl3) d: 7.38–7.24 (5H), 4.37
(m, 1H), 3.97 (d, JZ12.9 Hz, 1H), 3.65 (dd, JZ10.8,
3.3 Hz, 1H), 3.51 (d, JZ13.2 Hz, 1H), 3.40 (d, JZ10.7 Hz,
1H), 3.19 (dd, JZ8.1, 5.5 Hz, 1H), 3.11 (tdd, JZ8.1, 3.3,
1.8 Hz, 1H), 2.91 (br s, 1H), 2.43 (dd, JZ9.9, 5.1 Hz, 1H),
2.11 (dt, JZ12.9, 7.4 Hz, 1H), 1.88 (ddd, JZ12.8, 8.3,
4.1 Hz, 1H), 1.07–1.05 (21H); 13C NMR (CDCl3) d: 139.0
(s), 128.5 (d), 128.3 (d), 126.9 (d), 70.8 (d), 63.3 (d), 62.6
(t), 60.1 (t), 58.7 (t), 38.0 (t), 17.8 (q), 17.6 (q), 12.2 (d), 11.9
(d); EI MS m/z (relative intensity) 332 (MC%KCH2OH,
100), 207 (19), 158 (15), 91 (60), 75 (8), 61 (5); HRMS (CI)
calcd for C21H38O2NSi (MCHC) 364.2672, found
364.2665.
3.1.3. (2S,4R)-1-Benzyl-4-[(triisopropylsilyl)oxy]-2-
methoxycarbonylpyrrolidine (1c). Yield: 65% from
(2R,4R)-4-hydroxy-2-methoxycarbonylpyrrolidine; colorless
oil; [a]2D0 K17.3 (c 1.54, CHCl3); 1H NMR (CDCl3)
d: 7.36–7.22 (5H), 4.51 (m, 1H), 3.91 (d, JZ12.9 Hz, 1H),
3.64 (s, 3H), 3.62 (d, JZ12.9 Hz, 1H), 3.55 (dd, JZ8.1,
8.1 Hz, 1H), 3.33 (dd, JZ9.7, 5.7 Hz, 1H), 2.43 (dd, JZ9.7,
5.0 Hz, 1H), 2.23 (ddd, JZ12.9, 8.1, 7.0 Hz, 1H), 2.09 (ddd,
JZ12.7, 8.7, 4.1 Hz, 1H), 1.06–1.03 (21H); 13C NMR
(CDCl3) d: 174.0 (s), 138.0 (s), 129.0 (d), 128.1 (d), 127.0
(d), 70.5 (d), 64.3 (d), 62.0 (t), 59.1 (t), 51.7 (q), 39.9 (t),
17.8 (q), 17.6 (q), 12.1 (d), 11.8 (d); EI MS m/z (relative
intensity) 387 (13), 344 (11), 332 (MC%KCOOMe, 100),
316 (5), 288 (5), 215 (6), 183 (4), 158 (11), 131 (7), 103 (6),
91 (77), 75 (11), 61 (5).
3.1.7. (3R,5R)-1-Benzyl-5-[(tert-butyldimethylsilyl)oxy]-
piperidin-3-ol (3a);6 typical procedure Trifluoroacetic
anhydride (1.1 mL, 7.5 mmol, 1.2 equiv) was added
dropwise to a solution of pyrrolidine 2a (2.0 g, 6.2 mmol,
1.0 equiv) in THF (60 mL), cooled to 0 8C. After 1 h, Et3N
(3.5 mL, 24.8 mmol, 4.0 equiv) was added dropwise. The
reaction mixture was stirred for 20 min at 0 8C and then
heated at reflux for 72 h. After addition of an aqueous 2.5 M
NaOH solution (15 mL), the mixture was stirred for 2 h at rt
3.1.4. (2S,4R)-2-{1-Benzyl-4-[(tert-butyldimethylsilyl)-
oxy]-pyrrolidinyl}methanol (2a);16 typical procedure
To a suspension of LiAlH4 (0.87 g; 23.0 mmol, 2.0 equiv)
in THF (15 mL) at 0 8C, a solution of pyrrolidine 1a (4.0 g,
11.5 mmol, 1.0 equiv) in THF (15 mL) was added dropwise.

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R. Roudeau et al. / Tetrahedron 62 (2006) 2388–2394
and then extracted with EtOAc, dried with MgSO4, and
evaporated to dryness in vacuo. The residue was purified by
flash column chromatography on silica gel (EtOAc/
cyclohexane 30:70) to give 3a (1.65 g, 5.1 mmol, 82%
yield) as an oil; [a]2D0 C25.3 (c 1.75, EtOH); IR (neat):
3450, 1460, 1250, 1150, 1090, 840, 775, 740, 700 cmK1; 1H
NMR (CDCl3) d: 7.37–7.24 (5H), 4.05 (h, JZ4.8 Hz, 1H),
3.96 (s, 1H), 3.63 (d, JZ13.2 Hz, 1H), 3.53 (d, JZ13.2 Hz,
1H), 2.90 (m, 1H), 2.75 (m, 1H), 2.50 (br s, 1H), 2.19 (dd,
JZ11.4, 1.84 Hz, 1H), 2.09 (m, 1H), 1.97 (t, JZ10.1 Hz,
1H), 1.38 (ddd, JZ13.0, 10.3, 2.6 Hz, 1H), 0.88 (s, 9H),
0.06 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3) d: 137.7 (s),
128.8 (d), 128.1 (d), 127.0 (d), 65.8 (d), 65.2 (d), 62.1
(t), 61.0 (t), 58.5 (t), 40.8 (t), 25.7 (q), 18.0 (s), K4.8 (q),
K4.9 (q); EI MS m/z (relative intensity) 321 (MC%, 5), 304
(2), 264 (39), 246 (7), 134 (23), 120 (10), 101 (10), 91 (100),
73 (11).
1H), 2.65 (dd, JZ10.6, 3.3 Hz, 1H), 2.17 (dd, JZ11.6,
5.5 Hz, 1H), 2.12 (dd, JZ10.8, 3.3 Hz, 1H), 1.86 (dd, JZ
11.4, 2.6 Hz, 1H), 1.42 (m, 1H), 1.19 (m, 1H), 0.85 (s, 9H),
0.00 (s, 3H), K0.01 (s, 3H); 13C NMR (CDCl3) d: 146.8 (s),
145.1 (s), 138.7 (s), 128.9 (d), 128.8 (d), 128.7 (d), 127.9
(d), 127.8 (d), 127.5 (d), 127.1 (d), 126.7 (d), 126.6 (d), 86.7
(s), 67.7 (d), 66.2 (d), 62.1 (t), 60.2 (t), 57.7 (t), 40.0 (t), 25.8
(q), 18.0 (s), K4.8 (q), K4.9 (q); EI MS m/z (relative
intensity) 548 (MC%KCH3, 1), 320 (100), 243 (17), 165
(21), 91 (59), 73 (7).
3.1.11. (3R,5R)-1-Benzyl-5-trityloxypiperidin-3-ol (3d).
To a stirred solution of piperidine 4 (0.38 g, 0.68 mmol,
1.0 equiv) in THF (1 mL) at rt was added a solution of
tetrabutylammonium fluoride 1 M in THF (2.7 mL,
2.7 mmol, 4.0 equiv). After stirring at rt for 72 h, the
reaction was quenched with water (6 mL). After extraction
with EtOAc, the combined organic layers were dried with
MgSO4 and filtered. The solvent was removed in vacuo to
afford a yellow gum, which was purified by flash column
chromatography on silica gel (EtOAc/cyclohexane 30:70) to
give 3d (0.22 g, 0.49 mmol, 72% yield) as a white solid. Mp
76 8C; [a]2D0 C28.7 (c 1.23, CHCl3); IR (KBr): 3300, 1440,
1150, 1020, 740, 700 cmK1; 1H NMR (CDCl3) d: 7.52–7.44
(15H), 7.33–7.09 (5H), 3.95–3.82 (2H), 3.37 (d, JZ
12.9 Hz, 1H), 3.27 (d, JZ13.2 Hz, 1H), 2.64 (m, 1H),
2.24–1.94 (4H), 1.84–1.69 (2H); 13C NMR (CDCl3) d:
144.8 (s), 137.6 (s), 128.8 (d), 128.7 (d), 128.0 (d), 127.6
(d), 126.9 (d), 126.8 (d), 86.8 (s), 66.9 (d), 65.9 (d), 62.1 (t),
59.0 (t), 58.9 (t), 38.9 (t). Anal. Calcd for C31H31NO2: C,
82.82; H, 6.95; N, 3.12. Found C, 82.68; H, 7.14; N, 3.13.
3.1.8. (3R,5R)-1-Benzyl-5-[(tert-butyldiphenylsilyl)oxy]-
piperidin-3-ol (3b). Yield: 64% from 2b; oil; [a]D20
C46.8 (c 1.57, EtOH); IR (neat): 3350, 1420, 1100, 900,
1
820, 740, 700 cmK1; H NMR (CDCl3) d: 7.69–7.61 (4H),
7.48–7.18 (11H), 4.08 (m, 1H), 3.95 (s, 1H), 3.49 (s, 2H),
2.80–2.59 (2H), 2.33–2.23 (2H), 2.10–1.98 (2H), 1.55 (ddd,
JZ12.9, 9.9, 2.9 Hz, 1H), 1.07 (s, 9H); 13C NMR (CDCl3)
d: 137.7 (s), 135.6 (d), 135.5 (d), 134.2 (s), 133.9 (s), 129.5
(d), 129.4 (d), 128.7 (d), 128.1 (d), 127.5 (d), 127.4 (d),
127.0 (d), 66.2 (d), 65.8 (d), 62.0 (t), 60.4 (t), 58.9 (t), 53.3
(t), 40.7 (t), 26.8 (q), 19.0 (s); EI MS m/z (relative intensity)
445 (MC%, 2), 388 (45), 310 (43), 199 (18), 183 (15), 134
(10), 91 (100); HRMS (CI) calcd for C28H36O2NSi (MC
HC) 446.2515, found 446.2514.
3.1.12. (3R,5R)-1-Benzylpiperidin-3,5-diol (3e).7g To a
stirred solution of piperidine 3a (0.52 g, 1.6 mmol,
1.0 equiv) in EtOAc (0.5 mL) at rt was added an aqueous
1.2 M solution of HCl (10.0 mL, 27.4 mmol, 17.1 equiv).
After stirring at rt for 8 h, the reaction was quenched with an
aqueous 3.75 M NaOH solution until pHw11. After
extraction with EtOAc, the combined organic layers were
dried with MgSO4 and filtered. The solvent was removed in
vacuo to afford a colorless oil, which was purified by flash
column chromatography on silica gel (EtOAc/MeOH 95:5)
to give 3e (0.25 g, 1.21 mmol, 75% yield) as a white solid.
Mp 109 8C; [a]2D0 C15.2 (c 0.99, EtOH); IR (KBr): 3440,
3.1.9. (3R,5R)-1-Benzyl-5-[(triisopropylsilyl)oxy]-piperi-
din-3-ol (3c). Yield: 47% from 2c; oil; [a]2D0 C17.9 (c 2.00,
EtOH); IR (neat): 3460, 1450, 1150, 1100, 910, 880, 800,
1
735, 680 cmK1; H NMR (CDCl3) d: 7.36–7.23 (5H), 4.10
(m, 1H), 3.97 (s, 1H), 3.60 (d, JZ13.2 Hz, 1H), 3.55 (d, JZ
13.2 Hz, 1H), 2.96 (m, 1H), 2.77 (m, 1H), 2.53 (br s, 1H),
2.25–2.11 (2H), 1.95 (dd, JZ10.3, 9.6 Hz, 1H), 1.40 (ddd,
JZ13.1, 10.3, 2.6 Hz, 1H), 1.05–1.00 (21H); 13C NMR
(CDCl3) d: 137.8 (s), 128.8 (d), 128.1 (d), 127.0 (d), 66.0
(d), 65.2 (d), 62.1 (t), 61.1 (t), 58.8 (t), 41.0 (t), 17.8 (q), 12.1
(d); EI MS m/z (relative intensity) 363 (MC%, 6), 320 (28),
190 (9), 172 (7), 134 (14), 120 (10), 91 (100). Anal. Calcd
for C21H37NO2Si: C, 69.37; H, 10.26; N, 3.85. Found C,
69.23; H, 10.42; N, 3.82.
1
1200, 1140, 1100, 1050, 1000, 960, 760 cmK1; H NMR
(CD3OD) d: 7.60–7.40 (5H), 4.19 (m, 2H), 3.65 (s, 2H), 2.73
(dd, JZ10.9, 1.7 Hz, 2H), 2.50 (dd, JZ10.9, 6.8 Hz, 2H),
1.38 (t, JZ5.5 Hz, 2H); 13C NMR (CD3OD) d: 139.0 (s),
130.8 (d), 129.5 (d), 128.5 (d), 66.1 (t), 64.0 (t), 60.9 (t),
41.1 (t); EI MS m/z (relative intensity) 207 (MC%,14), 189
(2), 134 (12), 130 (10), 120 (14), 116 (27), 91 (100), 65 (8).
3.1.10. (3R,5R)-1-Benzyl-5-[(tert-butyldimethylsilyl)-
oxy]-5-trityloxypiperidine (4). To a stirred solution of
piperidine 3a (0.30 g, 0.93 mmol, 1.0 equiv) in CH2Cl2
(4 mL) at rt was added triphenylmethyl chloride (0.29 g,
1.0 mmol, 1.1 equiv), followed by the addition of Et3N
(0.26 mL, 1.9 mmol, 2.0 equiv). After stirring at rt for 48 h,
the reaction was quenched with an aqueous 3.75 M NaOH
solution (6 mL). After extraction with EtOAc, the combined
organic layers were dried with MgSO4 and filtered. The
solvent was removed in vacuo to afford a yellow oil, which
was purified by flash column chromatography on silica gel
(EtOAc/petroleum ether 20:80) to give 4 (0.44 g,
0.78 mmol, 83% yield) as a amorphous solid. 1H NMR
(CDCl3) d: 7.54–7.47 (5H), 7.34–7.16 (15H), 4.16 (m, 1H),
3.89 (m, 1H), 3.53 (d, JZ13.6 Hz, 1H), 3.33 (d, JZ13.6 Hz,
3.1.13. (3R,5R)-1-Benzyl-3,5-di[(tert-butyldimethylsilyl)-
oxy]-piperidine (5).6 To a stirred solution of piperidine 3a
(1.30 g, 4.0 mmol, 1.0 equiv) in CH2Cl2 (10 mL) at rt were
added TBDMSCl (1.2 g, 8.0 mmol, 2.0 equiv), Et3N
(0.68 mL, 4.8 mmol, 1.2 equiv) and DMAP (0.05 g,
0.4 mmol, 0.1 equiv). After 16 h at rt, the reaction mixture
was quenched with a saturated aqueous Na2CO3 until
pHw10. The aqueous layer was extracted with EtOAc and
the combined organic phases were dried over MgSO4 and
filtered. The solvent was removed in vacuo to afford
a yellow oil, which was purified by flash column

R. Roudeau et al. / Tetrahedron 62 (2006) 2388–2394
2393
chromatography on silica gel (EtOAc/petroleum ether
10:90) to give 5 (1.50 g, 3.45 mmol, 86% yield) as a
colorless oil. 1H NMR (CDCl3) d: 7.39–7.21 (5H), 4.11 (m,
2H), 3.73 (d, JZ13.6 Hz, 1H), 3.45 (d, JZ13.6 Hz, 1H),
2.47 (dd, JZ11.0, 3.0 Hz, 2H), 2.33 (dd, JZ11.0, 6.3 Hz,
2H), 1.66 (t, JZ5.1 Hz, 2H), 0.91 (s, 18H), 0.06 (s, 6H),
0.04 (s, 6H); 13C NMR (CDCl3) d: 138.6 (s), 128.7 (d),
128.0 (d), 126.7 (d), 66.1 (d), 62.2 (t), 59.9 (t), 42.0 (t), 25.8
(q), 18.1 (s), K4.8 (q), K4.9 (q); EI MS m/z (relative
intensity) 435 (MC%, 9), 420 (10), 378 (61), 344 (11), 315
(11), 303 (17), 263 (13), 246 (20), 212 (21), 159 (17), 134
(48), 101 (25), 91 (100), 75 (10), 59 (8).
Mp 112 8C; [a]2D0 C21.3 (c 0.94, CH3OH); IR (KBr): 3300,
1
1320, 1200, 1060, 960, 830 cmK1; H NMR (CD3OD) d:
4.14 (m, 2H), 2.88 (dd, JZ11.0, 2.9 Hz, 2H), 2.63 (dd, JZ
11.0, 6.6 Hz, 2H), 1.88 (t, JZ5.5 Hz, 2H), 1.29 (s, 9H); 13C
NMR (CD3OD) d: 66.7 (t), 55.0 (s), 54.3 (t), 41.4 (t), 26.6
(q); HRMS (CI) calcd for C9H20O2N (MCHC) 174.1494,
found 174.1490.
3.2. Asymmetric addition of diethylzinc to aldehydes;
general procedure
Diethylzinc (1.1 M in toluene, 1.2 equiv) was added to
ligand 3 in toluene under argon at 0 8C and the mixture was
stirred for 0.5 h at 0 8C. After the addition of aldehyde
(1.0 equiv) at 0 8C, the mixture was stirred at rt and after
24 h an aqueous 1.2 M solution of HCl was added. After
usual work-up, pure alcohols were obtained by flash column
chromatography. The ee and the absolute configuration of
the resulting alcohol were determined by using HPLC.
3.1.14. (3R,5R)-3,5-Di[(tert-butyldimethylsilyl)oxy]-
piperidine (6)6 To a solution of piperidine 5 (1.5 g,
3.45 mmol, 1.0 equiv) in absolute EtOH (10 mL) was
added Pd/C (367 mg, 10%, 0.36 mmol, 0.1 equiv). The
mixture was stirred under 4 atm of hydrogen at rt for 18 h
and was filtered through silica gel. The filtrate was
concentrated under reduced pressure to give 6 (1.16 g,
3.36 mmol, 97% yield) as a colorless gum. 1H NMR
(CDCl3) d: 3.95 (m, 2H), 2.97 (br s, 1H), 2.83 (dd, JZ14.1,
3.1 Hz, 2H), 2.57 (dd, JZ13.4, 6.4 Hz, 2H), 1.73 (t, JZ
5.3 Hz, 2H), 0.89 (s, 18H), 0.07 (s, 6H), 0.06 (s, 6H); 13C
NMR (CDCl3) d: 66.3 (d), 52.4 (t), 41.6 (t), 25.7 (q), 18.0
(s), 5.0 (q); EI MS m/z (relative intensity) 345 (MC%, 1), 330
(6), 301 (23), 288 (100), 156 (34), 116 (10), 101 (10), 82
(40), 75 (15), 73 (32), 59 (7).
3.3. Asymmetric addition of diethylzinc to aldehydes
and benzoylation; general procedure
Diethylzinc (1.1 M in toluene, 1.2 equiv) was added to
ligand 3 in toluene under argon at 0 8C and the mixture was
stirred for 0.5 h at 0 8C. After addition of heptanal
(1.0 equiv) at 0 8C, the mixture was stirred at rt and after
24 h an aqueous 1.2 M solution of HCl was added. After
extraction with EtOAc, the combined organic layers were
dried with MgSO4 and filtered. The solvent was removed in
vacuo to afford the crude nonan-3-ol, which was dissolved
in CH2Cl2. Benzoyl chloride (1.5 equiv), followed by Et3N
(2 equiv) and DMAP (1 equiv) were added to the previously
prepared alcohol solution. After stirring at rt for 18 h, the
reaction was quenched with an aqueous 1.2 M solution of
HCl. After usual work-up, the pure esters were obtained
by flash column chromatography. The ee and the absolute
configuration of the resulting ester were determined by
using HPLC.
3.1.15. (3R,5R)-1-tert-Butyl-3,5-di[(tert-butyldimethyl-
silyl)oxy]-piperidine (7). To a stirred solution of piperidine
6 (0.40 g, 1.2 mmol, 1.0 equiv) in acetone (3 mL) at rt was
added acetone cyanohydrin (0.11 mL, 1.2 mmol, 1.0 equiv).
After stirring at rt for 16 h, the solvent was removed in
vacuo to afford a colorless gum, which was dissolved in
ether (2 mL). A 3 M solution of MeMgBr in ether (3.5 mL,
10.5 mmol, 8.75 equiv) was added dropwise to the
previously prepared a-aminonitrile solution at 0 8C. After
stirring at rt for 20 h, the reaction was quenched with ice.
After extraction with EtOAc, the combined organic layers
were dried with MgSO4 and filtered. The solvent was
removed in vacuo to afford a yellow oil, which was purified
by flash column chromatography on silica gel (CH2Cl2/
petroleum ether/Et3N 50:50:1) to give 7 (0.32 g, 0.8 mmol,
67% yield) as a colorless oil. 1H NMR (CDCl3) d: 4.02 (m,
2H), 2.59 (dd, JZ11.0, 2.9 Hz, 2H), 2.34 (dd, JZ10.7,
6.3 Hz, 2H), 1.61 (t, JZ5.5 Hz, 2H), 1.04 (s, 9H), 0.90 (s,
18H), 0.07 (s, 12H); 13C NMR (CDCl3) d: 66.9 (d), 53.1 (t),
53.0 (s), 42.1 (t), 26.0 (q), 25.8 (q), 18.0 (s), K4.9 (q), K4.8
(q); EI MS m/z (relative intensity) 401 (MC%, 1), 386 (100),
82 (4), 73 (13), 57 (4).
References and notes
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