Chiral C2-symmetric 2,3-disubstituted aziridine and 2,6-disubstituted piperidine as chiral ligands in the addition reaction of diethylzinc with arylaldehydes

Article abstract of DOI:10.1016/S0957-4166(00)00479-1

Chiral C₂-symmetric 2,3-disubstituted aziridines and 2,6-disubstituted piperidines having a β-amino alcohol moiety have been successfully synthesized and their catalytic chiral induction properties have been examined in the asymmetric addition reactions of diethylzinc with arylaldehydes in hexane. When N-(2,2-diphenyl-2-hydroxyethyl)-(S,S)-2,3-bis(methoxymethyl)aziridine 11 was used as a catalytic chiral ligand, sec-alcohols having (S)-configuration formed in high yields of 86-92% but low enantiomeric excesses (ee's) of 11-13%. However, when N-(2,2-diphenyl-2-hydroxyethyl)-(R,R)-2,6-disubstituted piperidine derivatives 16 and 20 were used as the chiral ligands under the same reaction conditions, the ee's of the corresponding sec-alcohols were 20-30 and 5-6%, respectively, along with the inversion of absolute configuration. A plausible mechanism for this inversion is proposed.

Full text of DOI:10.1016/S0957-4166(00)00479-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4923–4933
Chiral C2-symmetric 2,3-disubstituted aziridine and
2,6-disubstituted piperidine as chiral ligands in the addition
reaction of diethylzinc with arylaldehydes
Min Shi,* Jian-Kang Jiang and Yan-Shu Feng
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Received 26 October 2000; accepted 27 November 2000
Abstract
Chiral C2-symmetric 2,3-disubstituted aziridines and 2,6-disubstituted piperidines having a b-amino
alcohol moiety have been successfully synthesized and their catalytic chiral induction properties have been
examined in the asymmetric addition reactions of diethylzinc with arylaldehydes in hexane. When
N-(2,2-diphenyl-2-hydroxyethyl)-(S,S)-2,3-bis(methoxymethyl)aziridine 11 was used as a catalytic chiral
ligand, sec-alcohols having (S)-configuration formed in high yields of 86–92% but low enantiomeric
excesses (ee’s) of 11–13%. However, when N-(2,2-diphenyl-2-hydroxyethyl)-(R,R)-2,6-disubstituted piperi-
dine derivatives 16 and 20 were used as the chiral ligands under the same reaction conditions, the ee’s of
the corresponding sec-alcohols were 20–30 and 5–6%, respectively, along with the inversion of absolute
configuration. A plausible mechanism for this inversion is proposed. © 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
The high efficiencies of C2-symmetric chiral reagents, including auxiliaries and catalyst
ligands, in asymmetric induction has attracted much attention in asymmetric synthesis.1 Previ-
ously, we reported chiral C2-symmetric 2,4-disubstituted azetidine and 2,5-disubstituted pyrroli-
dine derivatives as chiral catalyst ligands in the reaction of diethylzinc with aldehydes.2 Very
high yields and very high enantioselectivities have been achieved in this asymmetric addition
reaction.2,3 The relatively rigid C2-symmetric four- and five-membered ring structures are
considered to be the determining factor for the effectiveness of these ligands in such asymmetric
catalytic reactions. Although the backbone structures of chiral scaffolds are important to chiral
induction, little is known about the real influence of chiral C2-symmetric cyclic amines of
* Corresponding author.
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00479-1

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M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
different ring sizes on chiral induction. As such, our aim is to design and synthesize novel chiral
ligands with C2-symmetric three- and six-membered ring structures to enable us to observe the
effect of ring structure variations of the catalyst on chiral induction. This systematic investiga-
tion will give us useful information for the future design and synthesis of these ligands. Herein,
we present the synthesis of some novel chiral C2-symmetric aziridine and piperidine derivatives
bearing a b-amino alcohol moiety and their use as asymmetric catalysts in the reaction between
diethylzinc and arylaldehydes.
2. Results and discussion
The key intermediate of C2-symmetric aziridine 7 was prepared from the chiral pool -tartaric
L
acid according to the literature4 (Scheme 1). But when compound 7 was treated with ethyl
a-bromoacetate, we found that a ring opened compound 9 was obtained as the major product
rather than N-(ethoxycarbonylmethyl)-(S,S)-2,3-bis(methoxymethyl) 8. We examined this reac-
tion under various conditions and eventually we confirmed that 8 could not be obtained from
the reaction of 7 with ethyl a-bromoacetate. Somfai also reported in 1994 that attempts to
benzylate aziridine using triethylamine and benzyl bromide in THF gave, somewhat surprisingly,
only a low yield of N-benzylated aziridine along with considerable amounts of N,N-dibenzylated
amines.5 They gave the plausible mechanism to explain why the ring opened amine could be
Scheme 1. Conditions: (a) Me2C(OMe)2, TsOH, MeOH, reflux; 83%. (b) LiAlH4, THF, reflux, 3 h; 85%. (c) MeI,
NaH, THF, rt–reflux; 89%. (d) 9% H2SO4 in MeOH, 0°C–rt, 2 h; 90%. (e) SOCl2, NaIO4, RuCl3·3H2O, THF, reflux;
90%. (f) LiN3, THF, reflux, 8 h then LiAlH4, THF, reflux, 30 h; 40%. (g) BrCH2CO2Et, K2CO3, MeCN, 0°C–rt, 24
h; 50%

M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
4925
formed. Meanwhile, they found an improved procedure for achieving the N-alkylation of
aziridine using K2CO3/18-crown-6 in THF.5 But in the reaction of 7 with ethyl a-bromoacetate
or ethyl a-chloroacetate, only the ring opened amine formed even when Somfai’s improved
reaction procedure was employed. We believe that this is due to the highly strained aziridine ring
which can be easily opened by nucleophilic attack of bromide or chloride ion. In an alternative
approach we also tried to utilize 7 to directly react with 1,1-diphenylethylene oxide in the
presence of Lewis acids such as Cu(OTf)2, Yb(OTf)3 or Ti(OPri)4 to synthesize the desired
ligand. But we found that no reactions occurred (Scheme 2). Thus, we finally utilized the
Mukaiyama condensation reagent (2-bromo-1-ethylpyridinium tetrafluoroborate: BEP)6 to suc-
cessfully prepare the desired chiral b-amino alcohol 11, in a low 26% yield (Scheme 2).
Scheme 2. Conditions: (a) CH2Cl2, DIPEA, 2 days, −20°C–rt; 41%. (b) LiAlH4, THF, 0°C, 24 h; 26%
The optically active C2-symmetric 2,6-disubstituted piperidine derivatives could be synthesized
by the method reported for the preparation of chiral C2-symmetric azetidine 2,4-dicarboxylic
acid esters and pyrrolidine 2,5-dicarboxylic acid esters.4,7 Optical resolution was achieved by
silica gel column chromatographic separation (eluent: methanol/dichloromethane=1/100) to
afford the (2R,6R)-diol 128 (Scheme 3). We could readily introduce protecting methoxy groups
on the 2,6-position of the ring to obtain compound 13 (Scheme 3). The 2-phenethyl chiral
auxiliary was then removed by catalytic hydrogenation over Pd(OH)2/C (20%) to give the
corresponding chiral C2-symmetric 2,6-disubstituted piperidine 14 which was subsequently
treated with ethyl a-bromoacetate and then phenylmagnesium bromide in a Grignard reaction
to afford the desired b-amino alcohol 16. All of the synthetic steps are very similar to those used
in the synthesis of the corresponding 2,4-disubstituted azetidine and 2,5-disubstituted pyrrolidine
derivatives2,3 (Scheme 3). It should be emphasized here that the separation of the diol 12 was
very difficult because of its high polarity and additionally the three diastereomers have very
similar Rf in TLC. Only the (2R,6R)-diastereomer could be isolated in pure form, and we
obtained only 120 mg of pure compound 12 from 6 g of diastereomeric mixture. The optical
purity of 12 was checked by comparison of the specific rotation of 14 {[h]2D0 −7.8 (c 0.6, CHCl3)}
with that of an authentic sample {[h]2D0 −7.9 (c 0.6, CHCl3)}.8

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M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
Scheme 3. Conditions: (a) MeI, NaH, THF, rt–reflux, 89%. (b) H2, Pd(OH)2, MeOH; 80%. (c) BrCH2CO2Et, K2CO3,
MeCN, 0°C–rt, 24 h; 50%. (d) PhMgBr, THF, 0°C, 12 h; 75%
Moreover, we found that the (2S,6S)-diastereomer 17 could be isolated in pure form if TBS
(tert-butyldimethylsilyl) groups were introduced on the 2,6-positions of the six-membered ring
(Scheme 4). Compound 17 (100 mg) was obtained from 2.24 g of diastereomeric mixture using
silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1). After removal
of the 2-phenethyl chiral auxiliary by catalytic hydrogenation over Pd(OH)2/C (20%), the optical
purity was checked by comparison of the specific rotation of 18 {[h]2D0 +18.2 (c 0.44, CHCl3)}
with that of an authentic sample {[h]D20 +18.9 (c 0.9, CHCl3)}.8 The novel chiral C2-symmetric
b-amino alcohol 20 was then prepared by treating 18 with ethyl a-bromoacetate and then
phenylmagnesium bromide (Scheme 4). Thus, the (2S,6S)-diastereomer with a six-membered
ring could be isolated in pure form by changing the alcohol protecting group.
Scheme 4. Conditions: (a) TBDMSCl, imidazole, CH2Cl2, rt, 30 h; 76%, then silica gel column chromatography
(eluent: petroleum ether/ethyl acetate=100/1). (b) H2, Pd(OH)2, MeOH; 90%. (c) BrCH2CO2Et, K2CO3, MeCN,
0°C–rt, 24 h; 90%. (d) PhMgBr, THF, 0°C, 12 h; 70%

M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
4927
It is well known that the reaction of aldehydes with diethylzinc to give the corresponding
sec-alcohols takes place in the presence of a catalytic amount of b-amino alcohol.9 Excellent
chiral inductions including asymmetric amplifications by use of chiral b-amino alcohols in this
reaction have been reported.10
In order to clarify the chiral induction properties of these C2-symmetric aziridine, pyrrolidine
and piperidine functionalised b-amino alcohols and the difference on chiral induction between
the three-, five- and six-membered ring, we examined the asymmetric addition reaction of
diethylzinc with arylaldehydes in the presence of a catalytic amount (5 mol%) of chiral b-amino
alcohols 11, 16 and 20. The results are summarized in Tables 1 and 2.
The enantiomeric excesses (ee’s) of the products were determined by HPLC analysis using
chiral stationary-phase column (Chiralcel OD and OJ), and the absolute configuration of the
major enantiomer was assigned according to the sign of their specific rotations.11,12 As shown in
Table 1, very high yields (86–92%) but low enantiomeric excesses (11–13%) were achieved by
Table 1
Asymmetric addition reaction of diethylzinc with aldehydes in the presence of 5 mol% chiral C2-symmetric
2,3-disubstituted aziridine 11
R
Cat.
Yield (%)a
Ee (%)b
Absolute configuration
Ph
11
11
11
91
92
86
11
13
12
S
S
S
p-ClPh
Ph-CHꢀCH
a Isolated yields.
b Determined by chiral HPLC.
Table 2
Asymmetric addition reaction of diethylzinc with aldehydes in the presence of 5 mol% chiral C2-symmetric
2,6-disubstituted piperidines 16 and 20
R
Cat.
Yield (%)a
Ee (%)b
Absolute configuration
Ph
16
16
16
16
20
20
20
20
88
83
84
90
76
80
86
82
24
20
22
21
5
4
5
5
S
S
S
S
R
R
R
R
p-MePh
p-ClPh
Ph-CHꢀCH
Ph
p-MePh
p-ClPh
p-MeOPh
a Isolated yields.
b Determined by chiral HPLC.

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M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
using 5 mol% of the chiral C2-symmetric b-amino alcohol 11. However, we previously reported
that, using the azetidine or pyrrolidine b-amino alcohol, the ee can reach 90% for the same
reaction under the same conditions.2 We were very surprised to find that the most rigid
three-membered aziridine ring gave the lowest ee’s. Comparing the space-filling models of
C2-symmetric aziridine, azetidine and pyrrolidine, we found that for C2-symmetric aziridine 11
the two substituents are further away from the nitrogen atom than in an azetidine or pyrrolidine
complex. The methoxy group on the side chain of aziridine 11 cannot therefore provide
additional coordination to the b-amino alcohol-chelated zinc atom.13 This is not the case in the
azetidine or pyrrolidine complexes (Fig. 1).2,3 Thus, 11 cannot affect the stereoselectivity of the
addition reaction.
Figure 1.
On the other hand, when the chiral C2-symmetric (2R,6R)-disubstituted piperidine 16 was
used as the catalytic ligand in the same addition reaction, the ee’s of the corresponding
sec-alcohols increased to 20% with (S)-configuration (Table 2). Meanwhile, chiral C2-symmetric
(2S,6S)-disubstituted piperidine derivative 20 having bulky substituents on the 2,6-position was
also used as the chiral ligand under the same reaction conditions; the ee’s of the corresponding
sec-alcohols decreased to 5% with the (R)-configuration preferred. A similar effect has been
observed in the same addition reaction using chiral C2-symmetric 2,4-disubstituted azetidine and
2,5-disubstituted pyrrolidine derivatives as the chiral ligands.2
As can be seen from Fig. 2, (2R,6R)-disubstituted piperidine should give sec-alcohols with
(R)-configuration. But we surprisingly found that b-amino alcohol 16 gave the opposite absolute
configuration as b-amino alcohol ligands having three-, four- or five-membered rings (Fig. 2).2,3
This may be due to the fact that the six-membered rings do not have the same degree of rigidity
as four- or five-membered rings, therefore, the sec-alcohol products were formed via sterically
different transition states to those of complexes with ligands containing four- or five-membered
rings.
Figure 2.

M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
4929
Thus, C2-symmetric chiral ligands 16 or 20 having flexible ring structure can give the product
with opposite absolute configuration to that formed when a catalyst with relatively rigid ring
substituents is used, although a detailed mechanism for this interesting inversion phenomenon is
presently unclear.
In conclusion, we found that, in the preparation of C2-symmetric chiral ligands from the
chiral scaffold of cyclic amines, the four- and five-membered rings, azetidine and pyrrolidine, are
excellent candidates. The three-membered aziridine ring would be problematic during synthetic
processes because its backbone structure is too unstable to nucleophilic attack and can be easily
opened by even a very poor nucleophile such as a chloride ion. The six-membered piperidine
ring has given an unusual result and very low enantioselectivity owing to its flexible backbone
structure, for example, C2-symmetric b-amino alcohol 16 having a six-membered ring backbone
structure gave the opposite absolute configuration of the sec-alcohol compared to those of
C2-symmetric b-amino alcohols having a three-, four- or five-membered ring for catalytic
asymmetric addition reactions of diethylzinc to aldehydes.
We are now planning to synthesize more ligands based upon C2-symmetric cyclic amines of
different ring size to assess them as novel chiral catalysts for other asymmetric reactions in order
to gain more information on this mode of chiral induction. Undoubtedly these results give us
helpful information on the design and synthesis of new catalysts. Further work in this direction
is currently in progress.
3. Experimental
Mps were obtained with a Yanagimoto micro melting point apparatus and are uncorrected.
Optical rotations were determined in a solution of CHCl3 and methanol at 20°C by using a
1
Perkin–Elmer 241 MC digital polarimeter; [h]D values are given in units of 10−1 deg cm2 g−1. H
NMR spectra were determined for solutions in CDCl3 with tetramethylsilane (TMS) as internal
standard on a Bruker AMX-300 spectrometer; J values are in Hz. IR spectra were determined
by a Perkin–Elmer 983 spectrometer. Mass spectra were recorded with a HP-5989 instrument.
High mass spectra were recorded on a Finnigan MA+ instrument. Compounds 1–7, 12 and 13
were prepared according to the literature.4,5 Their spectral data have been checked with those
reported in previous papers.4,5 Benzilic acid was purchased from Aldrich Co.
3.1. Preparation of ring opened compound 9
To a solution of (S,S)-2,3-bis(methoxymethyl)aziridine 7 (175 mg, 1.34 mmol) and potassium
carbonate (257 mg, 1.88 mmol) in acetonitrile (10 mL) was added ethyl a-bromoacetate (266 mg,
1.60 mmol) and the reaction mixture was stirred at 0°C for 18 h. The solvent was removed under
reduced pressure and the residue was washed with brine and extracted with ethyl acetate (20
mL). The organic layer was dried over anhydrous Na2SO4 and then evaporated under reduced
pressure. The residue was purified by silica gel column chromatography to give compound 9
(266 mg, 52%) as a colorless oil (eluent: ethyl acetate/petroleum ether=1/4). [h]D −15.7 (c 0.98,
1
CHCl3); IR (neat) w 1730 cm−1 (CꢀO); H NMR (CDCl3, 300 MHz) l 1.23 (6H, t, J=7.2 Hz),
3.19 (1H, ddd, J=9.4, 4.4, 2.1 Hz), 3.29 (3H, s, OMe), 3.40 (3H, s, OMe), 3.56 (2H, d, J=7.8
Hz), 3.77 (2H, d, J=7.8 Hz), 3.82 (2H, dd, J=6.0, 3.2 Hz), 3.85 (2H, dd, J=5.4, 2.7 Hz), 4.18
(4H, q, J=7.2 Hz), 4.30–4.43 (1H, m); HRMS (EI) m/z 383.0930 (M+), C14H26BrNO6 requires
383.0944.

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M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
3.2. Preparation of N-(2,2-diphenyl-2-hydroxyacetyl)-(S,S)-2,3-bis(methoxymethyl)aziridine 10
To a solution of (S,S)-2,3-bis(methoxymethyl)aziridine 7 (60 mg, 0.46 mmol) and benzilic acid
(105 mg, 0.46 mmol) in dichloromethane (4 mL) was added 2-bromo-1-methylpyridinium
tetrafluoroborate (BEP) (138 mg, 0.51 mmol) at room temperature. The reaction mixture was
cooled to −20°C and diisopropylethylamine (DIPEA) (198 mg, 0.25 mL, 1.37 mmol) was added
dropwise in 30 min at −20°C. The reaction solution was stirred for 24 h at room temperature.
The reaction mixture was directly subject to flash chromatography to give 10 as a colorless oil
(eluent: ethyl acetate/petroleum ether=1/4). Yield: 64 mg, 41%; [h]D +18.7 (c 1.6, CHCl3); IR
(neat) w 1740 cm−1 (CꢀO); 1H NMR (CDCl3, 300 MHz) l 2.31 (1H, t, J=4.3 Hz, CH), 2.71 (1H,
t, J=4.4 Hz, CH), 2.94 (1H, br. s, OH), 3.20 (1H, dd, J=10.7, 3.2 Hz, CH), 3.12–3.20 (2H, m,
CH2), 3.25 (6H, s, OMe), 3.78 (1H, dd, J=10.7, 3.2 Hz, CH2), 7.20–7.60 (10H, m, Ar); [HRMS
(EI) m/z 325.1670 (M+), C20H23NO3 requires 325.1678].
3.3. Preparation of N-(2,2-diphenyl-2-hydroxyethyl)-(S,S)-2,3-bis(methoxymethyl)aziridine 11
To a solution of 10 (68 mg, 0.20 mmol) in THF (5 mL) was added LiAlH4 (22.8 mg, 0.60
mmol) at 0°C and the reaction mixture was stirred overnight at 0°C. The reaction was quenched
with 10% NaOH aqueous solution (0.5 mL) and the mixture was filtered. The filtrate was
extracted with dichloromethane (3×5 mL). The organic layer was washed with brine and dried
over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by
flash chromatography to give 11 as a colorless oil (eluent: ethyl acetate/petroleum ether=1/4).
1
Yield: 17 mg, 26%; [h]D +10.4 (c 0.65, CHCl3); IR (neat) w 3380 cm−1 (O–H); H NMR (CDCl3,
300 MHz) l 2.35 (2H, t, J=5.3 Hz, CH), 3.01 (2H, dd, J=10.0, 6.8 Hz, CH2), 3.17 (2H, dd,
J=10.0, 5.7 Hz, CH2), 3.23 (6H, s, OMe), 3.47 (1H, br. s, OH), 4.2 (1H, d, J=10.6 Hz, CH),
4.33 (1H, d, J=10.6 Hz, CH), 7.10–7.60 (10H, m, Ar); [HRMS (EI) found: (MH+) 328.1930.
C20H26NO3 requires 328.1913].
3.4. Preparation of (R,R)-2,6-bis(methoxymethyl)piperidine 14
To a solution of 13 (110 mg, 0.40 mmol) in methanol (15 mL) was added Pd(OH)2/C (20%,
75 mg) and the reaction mixture was stirred at room temperature for 24 h under a hydrogen
atmosphere. The solvent was removed under reduced pressure and the residue was used for the
next reaction without purification. Yield: 52 mg, 76%; [h]2D0 −7.8 (c 0.6, CHCl3);7 IR (neat) w
1
3320 cm−1 (N–H); H NMR (CDCl3, 300 MHz) l 1.29–1.71 (6H, m, CH2), 2.49 (1H, br. s, NH),
3.0–3.15 (2H, m, CH), 3.36 (6H, s, OMe), 3.30–3.48 (4H, m, CH2); [HRMS (EI) found: 173.1412
(M+). C9H19NO2 requires 173.1416].
3.5. Preparation of N-(ethoxycarbonylmethyl)-(R,R)-2,6-bis(methoxymethyl)piperidine 15
To a solution of 14 (48 mg, 0.28 mmol) and potassium carbonate (57 mg, 0.41 mmol) in
acetonitrile (20 mL) was added ethyl a-bromoacetate (56 mg, 37 mL, 0.33 mmol) and the
reaction mixture was stirred at room temperature for 18 h. The solvent was removed under
reduced pressure and the residue was extracted with ether (3×10 mL). The organic layer was
washed with water, brine and dried over NaSO4. The solvent was removed under reduced
pressure and the residue was purified by flash chromatography to give 15 as a colorless oil

M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
4931
(eluent: ethyl acetate/petroleum ether=1/4). Yield: 42 mg, 58%; [h]D +12.8 (c 0.31, CHCl3); IR
(neat) w 1740 cm−1 (CꢀO); 1H NMR (CDCl3, 300 MHz) l 1.27 (3H, t, J=7.1 Hz, Me), 1.50–1.80
(6H, m, CH2), 3.10–3.30 (2H, m, CH2), 3.28 (6H, s, OMe), 3.40 (2H, dd, J=9.8, 4.4 Hz), 3.51
(2H, dd, J=4.4, 4.3 Hz), 3.54 (1H, d, J=18.0 Hz), 3.67 (1H, d, J=18.0 Hz), 4.16 (2H, q, J=7.1
Hz); [HRMS (EI) found: 260.1863 (MH+). C13H26NO4 requires 260.1862].
3.6. Preparation of N-(2,2-diphenyl-2-hydroxyethyl)-(R,R)-2,6-bis(methoxymethyl)piperidine 16
To a solution of phenylmagnesium bromide prepared from the reaction of bromobenzene (242
mg, 1.5 mmol) and magnesium (44 mg, 1.85 mmol) in THF (10 mL) was added 15 (40 mg, 0.15
mmol) at 0°C and the reaction mixture was stirred for 24 h. The reaction was quenched with
saturated NH4Cl aqueous solution and extracted with ether (3×15 mL). The organic layer was
washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and
the residue was purified by flash chromatography to give 16 as a colorless oil (eluent: ethyl
acetate/petroleum ether=1/3). Yield: 41 mg, 72%; [h]D +31.5 (c 0.13, CHCl3); IR (neat) w 3406
1
cm−1 (O–H); H NMR (CDCl3, 300 MHz) l 1.22–1.42 (2H, m, CH2), 1.50–1.72 (4H, m, CH2),
2.60–2.73 (2H, m, CH2), 3.16 (6H, s, OMe), 3.23 (4H, dd, J=10.2, 1.0 Hz), 3.37 (1H, d, J=13.9
Hz), 3.52 (1H, d, J=13.9 Hz), 5.60 (1H, br. s, OH), 7.10–7.40 (6H, m, Ar), 7.40–7.60 (4H, m,
Ar); [HRMS (EI) found: 370.2386 (MH+). C23H32NO3 requires 370.2382].
3.7. Preparation of (S,S)-2,6-bis[(tert-butyldimethylsiloxy)methyl]-N-[(S)-1-phenylethyl]-
piperidine 17
To a solution of 12 (1.50 g, 6.02 mmol) and imidazole (1.07 g, 15.66 mmol) in
dichloromethane (50 mL) was added tert-butyldimethylsilyl chloride (2.23 g, 14.48 mmol) and
the reaction mixture was stirred for 36 h at room temperature. The mixture was washed with
brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue
(2.24 g) was purified by flash chromatography to give 17 as a colorless oil (eluent: ethyl
acetate/petroleum ether=1/100). Yield: 100 mg, 4.5%; [h]D −26.7 (c 0.4, CHCl3); IR (neat) w
1598 cm−1 (CꢀC); 1H NMR (CDCl3, 300 MHz) l −0.13 (6H, s, SiMe), −0.088 (6H, s, SiMe), 0.82
(18H, s, Me3C), 1.47 (3H, d, J 6.8, Me), 1.40–1.63 (6H, m, CH2), 2.90–3.12 (2H, m), 3.40 (2H,
dd, J=10.2, 5.3 Hz), 3.56 (2H, dd, J=10.2, 10.1 Hz), 4.28 (1H, q, J=6.2 Hz), 7.10–7.50 (5H,
m, Ar); [HRMS (EI) found: 477.3451 (M+). C27H51NO2Si2 requires 477.3458].
3.8. Preparation of (S,S)-2,6-bis[(tert-butyldimethylsiloxy)methyl]piperidine 18
To a solution of 17 (100 mg, 0.14 mmol) in methanol (5 mL) was added Pd(OH)2/C (20%, 50
mg) and the reaction mixture was stirred at room temperature for 24 h under a hydrogen
atmosphere. The solvent was removed under reduced pressure and the residue was used for the
next reaction without purification. Yield: 69 mg, 89%; [h]D +18.2 (c 0.44, CHCl3); IR (neat) w
1
3332 cm−1 (N–H); H NMR (CDCl3, 300 MHz) l 0.07 (12H, s, SiMe), 0.92 (18H, s, Me3C),
1.30–1.60 (4H, m, CH2), 1.62–1.84 (2H, m, CH2), 2.34 (1H, br. s, NH), 3.0–3.13 (2H, m, CH2),
3.48 (2H, dd, J=9.8, 4.3 Hz), 3.67 (2H, dd, J=9.8, 9.8 Hz); [HRMS (EI) found: 373.2836 (M+).
C19H39NO2Si2 requires 373.2832].

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M. Shi et al. / Tetrahedron: Asymmetry 11 (2000) 4923–4933
3.9. Preparation of N-(ethoxycarbonylmethyl)-(S,S)-2,6-bis[(tert-butyldimethylsiloxy)methyl]-
piperidine 19
To a solution of 18 (45 mg, 0.12 mmol) and potassium carbonate (25 mg, 0.18 mmol) in
acetonitrile (4 mL) was added ethyl a-bromoacetate (24 mg, 0.14 mmol) and the reaction
mixture was stirred at room temperature for 24 h. The solvent was removed under reduced
pressure and the residue was extracted with ethyl acetate. The organic layer was washed with
water, brine and dried over MgSO4. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography to give 19 as a colorless oil (eluent: ethyl
acetate/petroleum ether=1/10). Yield: 48 mg, 87%; [h]D −11.1 (c 0.94, CHCl3); IR (neat) w 1740
1
(CꢀO) cm−1; H NMR (CDCl3, 300 MHz) l 0.08 (6H, s, SiMe), 0.10 (6H, s, SiMe), 0.89 (18H,
s, Me3C), 1.26 (3H, t, J=7.2 Hz, Me), 1.40–1.90 (6H, m, CH2), 2.85–3.0 (2H, m, CH2),
3.50–3.90 (6H, m, CH2), 4.15 (2H, q, J=7.1 Hz); [HRMS (EI) found: 460.3291 (MH+).
C23H50NO4Si2 requires 460.3278].
3.10. Preparation of N-(2,2-diphenyl-2-hydroxyethyl)-(S,S)-2,6-bis[(tert-butyldimethylsiloxy)-
methyl]piperidine 20
This compound was prepared in the same manner as that described above. Yield: 49 mg, 86%;
1
[h]D −3.8 (c 0.24, CHCl3); IR (neat) w 3384 cm−1 (O–H); H NMR (CDCl3, 300 MHz) l 0.08
(12H, s, SiMe3), 0.96 (18H, s, Me3C), 1.10 (2H, m, CH2), 1.40–1.53 (4H, m, CH2), 2.50–2.62
(2H, m), 3.30–3.56 (6H, m, CH2), 5.40 (1H, br. s, OH), 7.0–7.25 (6H, m, Ar), 7.40–7.52 (4H, m,
Ar); [HRMS (EI) found: 570.3796 (MH+). C33H56NO3Si2 requires 570.3799].
Typical reaction procedure: To a suspension of b-amino alcohol 16 (8.5 mg, 0.025 mmol) in
hexane (1.0 mL), diethylzinc (1.1 mmol, 1.1 mL of 1.0 M hexane solution) was added at 0°C.
After stirring for 0.5 h, benzaldehyde (53 mg, 0.5 mmol) was added and the reaction mixture
was stirred for 24 h at 0°C. The reaction was quenched by the addition of a 3% HCl aqueous
solution and the organic product was extracted with ethyl acetate. The extract was dried over
MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by
silica gel TLC to give the optically active 1-phenylpropanol (60 mg, 88%).
Acknowledgements
We thank the Inoue Photochirogenesis Project for chemical reagents and the State Key
Project of Basic Research (Project 973) (No. G2000048007) for financial support.
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