Novel chiral tridentate Schiff base ligands of the [2.2]paracyclophane series: Synthesis and application

Article abstract of DOI:10.1016/S0957-4166(03)00326-4

The first example of the efficient application of chiral tridentate N,O-[2.2]paracyclophane ligands of the imino type for enantioselective diethylzinc addition to aliphatic and aromatic aldehydes is presented. The enantiomeric excess of the resulted secondary alcohols is up to 93% e.e.

Full text of DOI:10.1016/S0957-4166(03)00326-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2013–2019
Novel chiral tridentate Schiff base ligands of the
[2.2]paracyclophane series: synthesis and application
Tatyana I. Danilova,a Valeria I. Rozenberg,a,* Elena V. Sergeeva,a Zoya A. Starikovaa and
Stefan Bra¨seb,*
aA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Science, Vavilova 28, 119991 Moscow, Russia
bKekule´-Institut fu¨r Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms-Universita¨t Bonn,
Gerhard-Domagk Straße 1, D-53121 Bonn, Germany
Received 1 April 2003; accepted 10 April 2003
Abstract—The first example of the efficient application of chiral tridentate N,O-[2.2]paracyclophane ligands of the imino type for
enantioselective diethylzinc addition to aliphatic and aromatic aldehydes is presented. The enantiomeric excess of the resulted
secondary alcohols is up to 93% e.e. © 2003 Elsevier Science Ltd. All rights reserved.
aldehydes and imines.13–16 Tetradentate salen deriva-
tives of FHPC 6 (R1=R2=H) were successfully used in
the stereoselective trimethylsilylcyanation of benzalde-
1. Introduction
For a long while, chiral Schiff bases have traditionally
been used as effective ligands for specific asymmetric
reactions such as cyclopropanation and epoxidation of
alkenes as well as the oxidation of sulfides.1–3 Recently,
the scope of this highly effective ligand system has been
extended for its application to other stereoselective
processes. For example, the synthesis of the chiral
cyanhydrins,4 the stereoselective pinacol coupling of
aldehydes5,6 and diorganozinc addition reactions to
aldehydes7,8 have been found to be effectively catalyzed
by chiral Schiff bases.
The overwhelming majority of the Schiff base ligands
employed for asymmetric catalysis have been con-
structed from chiral diamines or aminoalcohols and
achiral salicylaldehyde derivatives.1–3,5–7 Axially or pla-
nar chiral salicylaldehyde analogues have been used for
the design of such ligands to a lesser extent.8–10 Among
them planar chiral ortho-formyl-111 (FHPC) as well
ortho-acetyl-2, (AHPC) and ortho-benzoylhydroxy-
[2.2]paracyclophanes-312 (BHPC) have become parent
compounds for a family of different Schiff base ligands
4–7 (Fig. 1). Thus, chiral diastereomeric bidentate
imines of type 4 and 512 were found to catalyze
efficiently the asymmetric diorganozinc addition to
* Corresponding authors. Tel.: 007-095-135-9268; fax: 007-095-135-
5085 (V.I.R.); Tel.: +49(0)228-732-653 and 732-671; fax: +49(0)228-
73-9608 (S.B.); e-mail: lera@ineos.ac.ru; braese@uni-bonn.de
Figure 1.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00326-4

2014
T. I. Danilo6a et al. / Tetrahedron: Asymmetry 14 (2003) 2013–2019
hyde.17 The symmetric as well as unsymmetric salens of
type 6 together with tridentate hemisalen type ligands
718 have also recently been shown to exhibit good
efficiency in stereoselective diethylzinc additions to
aldehydes.19
able homochiral starting material for a wide range of
useful N,O-ligands12,18,23,24 because of it’s quite high
overall chemical yield (up to 65% of the resolved mate-
rial) starting from parent commercial [2.2]paracyclo-
phane.
We present here the preparation and application in
asymmetric synthesis of a new series of chiral Schiff
base tridentate ligands derived from aldehyde FHPC 1
and ketone AHPC20 2 with different achiral or chiral
aminoalcohols.
Enantio- and diastereomerically pure iminoalcohols 8–
12 were synthesized by refluxing the corresponding
enantiomers of 125 and 2 with several 2-aminoalcohols
(achiral ethanolamine or centrally chiral (R)-, (S)-vali-
nol and (S)-leucinol) in toluene in the presence of
12
Et2SnCl2 as catalyst (Fig. 3). Although the condensa-
tion of this type sometimes leads to 1,3-oxazolidines
besides imines,26 no such side products were formed in
this case. The crude products were purified by simply
passing the reaction mixture through a pad of silica and
the desired 8–12 were obtained in high chemical yields.
2. Results and discussion
The first key building block, 1 (FHPC), was obtained in
accordance with an improved procedure which includes
Friedel–Crafts oxaloylation of the 4-hydroxy-
[2.2]paracyclophane followed by the reduction of the
a-ketoester obtained and oxidation of the intermediate
triol.21 The resolution into enantiomers was carried out
following the reported procedure.22
For (Rp)-10 (Fig. 4, left) and (Sp,S)-11 (Fig. 4, right)
single crystals suitable for an X-ray diffraction study
were obtained.
Thus, we prepared a number of novel planar chiral
iminophenol ligands bearing additional carbinol moiety
which in most cases were also modified by the presence
of a stereogenic center. To the best of our knowledge,
this type of tridentate N,O-ligand has never been used
in the stereoselective Et2Zn addition to aldehydes. We
believe that such ligands, having an additional O-atom
able to coordination, can provide more rigid monozinc
dialkoxide structures and thus more differentiated
diastereomeric transition states during the reaction pro-
ceeding as proposed for pyridine derived tridentate
ligands.27,28
The other key intermediate of our strategy, 2 (AHPC),
was prepared by ortho-regioselective direct acylation of
rac-4-hydroxy[2.2]paracyclophane.12 The result of the
X-ray diffractional study of rac-2 is shown in Figure 2.
The efficiency of the iminophenols 8–12 in the Et2Zn
addition to aldehydes was therefore tested. The stan-
dard experiment includes the successive addition of 2
equiv. of Et2Zn and 1 equiv. of benzaldehyde to a
solution of the iminophenol catalyst (10 mol%) in tolu-
ene at 0°C and subsequent stirring at room temperature
for 15 h. The excess of Et2Zn was then destroyed by
addition of 1N HCl and after standard work up, the
conversion and enantiomeric excess of the resulted sec-
ondary alcohol were determined by GC and chiral GC
analysis. The results obtained are collected in Table 1.
Figure 2. X-Ray structure of rac-2.
Our recent elaborated resolution technique12 based on
the separation of the diastereomeric ketimines 4 of
AHPC with (S)-a-phenylethylamine by combination of
fractional crystallization and preparative chromato-
graphy was improved in this study. We were fortunate
to find an appropriate eluent (benzene/ethyl acetate/
hexane 10/1/11) allowing almost complete separation of
the diastereomeric 4 on silica gel without additional
labor-consuming crystallizations. Thus, starting from a
1:1 mixture of diastereomers, individual diastereomers
(Rp,S)-4 and (Sp,S)-4 were isolated in chemical yields
of 48 and 47%, respectively, with diastereomeric puri-
All reactions proceeded smoothly with high conversions
of the starting aldehydes to give the corresponding
secondary alcohols 13 and 14. In the reaction with
(Rp,R)-9 as the ligand (Table 1, entry 2) the formation
of the traces of benzyl alcohol (2–5%) due to reduction
of the benzaldehyde by Et2Zn was observed. In the case
of aldimine ligand (Rp)-8 with an achiral ethanolamine
moiety (Table 1, entry 1) essentially no enantioselection
was observed. The introduction of an additional stereo-
genic center in the carbinol moiety does not enhance
the enantioselectivity significantly (Table 1, entry 2). At
the same time the changing of hydrogen (FHPC type)
to methyl (AHPC type) in the carbonyl moiety of the
ligand has an impressive influence and the stereoselec-
tive formation of 1-phenylpropanol [(R)-13, 74% e.e.]
was observed when the iminophenol (Rp)-10 was used
1
ties >99% (by H NMR). Individual enantiomers of 2
were obtained by subsequent quantitative hydrolysis of
the corresponding diastereomerically pure ketimines 4.
Thus, AHPC can now be regarded as a readily avail-

T. I. Danilo6a et al. / Tetrahedron: Asymmetry 14 (2003) 2013–2019
2015
Figure 3.
Figure 4. X-Ray crystal structure of (Rp)-10 and (Sp,S)-11.
(Table 1, entry 3). Thus, the AHPC type ligand is
beneficial for the highly selective generation of the
new stereocenter in the product as demonstrated ear-
lier.14
The combination of the planar chirality of the ketimine
with the central chirality of the aminoalcohol allows the
investigation of the cooperative effect of two chiral
elements. The combination of the (Sp)-ketimine moiety

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T. I. Danilo6a et al. / Tetrahedron: Asymmetry 14 (2003) 2013–2019
Table 1. Enantioselective addition of diethylzinc to alde-
hydes catalyzed by in situ formed zinc-complexes of lig-
ands 8–12 (toluene, 25°C, 10 mol% of chiral ligand)
enantioselectivity (Table 1, entries 8 and 9), but inver-
sion of the configuration of the product 14 was
observed.
The high stability of the iminoalcohols 8–12 to acidic
hydrolysis under work up conditions allows them to be
recovered by preparative chromatography in high
chemical yields and unchanged enantiomeric excess and
reuse for the same reaction.
In summary, a series of novel chiral tridentate Schiff
base N,O-[2.2]paracyclophanyl ligands starting from
easily available FHPC and AHPC and different
aminoalcohols were synthesized. Among them,
ketimines revealed very high levels of enantioselectivity
in diethylzinc addition to aldehydes. Further investiga-
tions of these ligands and their analogues are in pro-
gress in our laboratories.
Entry
Chiral ligand
Aldehyde
Conversion
(%)a
E.e.%b
1
2
3
4
5
6
7
8
9
(Sp)-8
(Rp,R)-9
(Rp)-10
(Sp,S)-11
(Rp,S)-11
(Sp,S)-12
(Rp,S)-12
(Rp)-10
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
Quant.
Quant.
Quant.
Quant.
89
6 (R)
10 (R)
74 (R)
93 (S)
67 (S)
93 (S)
62 (S)
92 (S)
93 (R)
Quant.
68
C6H11CHO Quant.
C6H11CHO Quant.
3. Experimental
(Sp,S)-11
a The conversion was determined by GC of the reaction mixtures
after standard work up.
Toluene was distilled over Na before use. Benzene,
heptane, hexane and ethyl acetate were distilled and
used without further purification. Ethanolamine was
distilled over Na before use. (R)- and (S)-valinol, (S)-
leucinol and Et2Zn (1 M solution on hexane) were
purchased from Fluka and used without purification.
Benzaldehyde and cyclohexanecarbaldehyde were pur-
chased from Aldrich, stored and used under argon
atmosphere without further purification. TLC analyses
were performed on silica gel precoated plates DC-Alu-
folien Kieselgel 60 F254 (Merck). Column chromatogra-
phy was performed on Kieselgel 60 (Merck). NMR:
Bruker AMX-400 (400.13 MHz for 1H), CDCl3 as
solvent, lH (CHCl3)=7.27. MS: KRATOS MS890A
(70 eV). Optical rotations: EPO-1 in thermostated cell
at 22°C. Enantiomerically pure 4-formyl-5-hydroxy-
[2.2]paracyclophane 122 and 4-acetyl-5-hydroxy-
[2.2]paracyclophane 212 were obtained according to a
literature procedures. All reactions of asymmetric addi-
tion of diethylzinc to aldehydes were carried out with
dry glassware under the argon atmosphere. Yields of
iminoalcohols 8–12 are given after column chromatog-
raphy.
b The absolute configurations of alcohols 13 and 14 were determined
by the elution order on chiral GC analysis in comparison with
standard samples.14
with a stereogenic center with the (S)-configuration
gives rise to the ligand (Sp,S)-11, which yields (S)-13
with an enantioselection of 93% e.e. (Table 1, entry 4).
At the same time the application of the ligand (Rp,S)-
11 strongly affects the stereochemical course of the
reaction and results in the formation of the alcohol 13
with the opposite configuration with moderate enan-
tioselectivity (Table 1, entry 5). Similar results were
observed for the pair of diastereomers (Rp,S)-12 and
(Sp,S)-12 constructed from enantiomers AHPC and
(S)-leucinol, which promoted the addition with almost
the same levels of selectivity (Table 1, entries 6 and 7,
correspondingly). The positive cooperative effect of the
(Sp,S)-ligand over the (Rp,S)-ligand has been already
observed in a similar reaction, promoted by para-
cyclophane ketimine ligands having no additional
hydroxy group.13 The configuration of the resulting
alcohol was in this case determined by the planar chiral
moiety of the ligand. It is interesting to note, that in the
case of the tridentate ligands 11 and 12 the configura-
tion of the stereogenic center in the 1-phenylpropanol
was specified by central chirality of the alkylcarbinol
fragment of the imine.
3.1. Preparation of iminophenols 8–12
General methodology: The solution of 0.400 mmol of
enantiomerically pure 1 or 2, 0.400 mmol of aminoalco-
hol and catalytic quantity of Et2SnCl2 in 7 ml of
toluene was refluxed in an apparatus equipped with a
Dean–Stark trap filled with anhydrous MgSO4 for 24 h.
After solvent removal the orange crude product was
purified by column chromatography on SiO2 (eluent
hexane/ethylacetate 5/1 to 1/1) from the small quanti-
ties of unreacted starting material to provide the corre-
sponding Schiff base. Analytically pure samples were
obtained by additional crystallization from toluene/hep-
tane (1/3) or from pure heptane.
The results obtained reveal that the enantioselectivity of
the addition reaction was dependent both on the pres-
ence of the methyl substituent a- to the carbonyl moiety
(CꢀN group) and the stereogenic center of the appro-
priate configuration in the b-position of the carbinol
moiety of the ligand. Therefore, the iminoalcohols
(Rp)-10 and (Sp,S)-11 which demonstrated the best
results in the benzaldehyde series, were also tested as
chiral ligands for the Et2Zn addition to the sterically
more hindered cyclohexanecarbaldehyde. In both cases
the reaction proceeded with the same high level of
(Sp)-8: Yield 85%; mp (orange plates) 215–217°C;
1
[h]2D2=−481.8 (c 0.230, CHCl3); H NMR (CDCl3): l
1.60 (br. s, 1H, -OH), 2.52–2.62 (m, 1H, -CH2-CHH-),

T. I. Danilo6a et al. / Tetrahedron: Asymmetry 14 (2003) 2013–2019
2017
2.72–2.88 (m, 2H, -CHH-CH2-), 2.96–3.05 (m, 1H,
-CHH-CH2-), 3.08–3.22 (m, 2H, -CHH-CH2-), 3.37–
3.48 (m, 2H, -CHH-CH2-), 3.70–3.84 (m, 2H, ꢀNCH2-),
217 (15), 216 (88), 204 (30), 160 (60), 104 (100). Anal.
calcd for C23H29NO2: C, 78.65; H, 8.26; N, 3.99.
Found: C, 78.78; H, 8.40; N, 3.87.
3
3.93–4.00 (t, 2H, -CH2OH), 6.15 (d, 1H, J=7.8 Hz,
H-7 or H-8), 6.28 (dd, 1H, 3J=7.8, 4J=1.8 Hz, H-15 or
(Rp,S)-11: Yield 66%; mp (yellow needles) 149.5–
150°C; [h]2D2=+653.5 (c 0.250, CHCl3); 1H NMR
H-16), 6.40 (dd, 1H, 3J=7.8, 4J=1.8 Hz, H-12 or
3
3
H-13), 6.49 (d, 1H, J=7.8 Hz, H-7 or H-8), 6.59 (dd,
(CDCl3): l 1.10 (d, 3H, J=6.5 Hz, CHCH3), 1.15 (d,
3
4
3
1H, J=7.8, J=1.8 Hz, H-12 or H-13), 6.85 (dd, 1H,
3J=7.8, 4J=1.8 Hz, H-15 or H-16), 8.29 (s, 1H,
-CHNꢀ) 14.00 (br. s, 1H, OH); MS (70 eV): m/z
(%)=295 (22, M+), 191 (78), 160 (87), 118 (27), 104
(100). Anal. calcd for C19H21NO2: C, 77.30; H, 7.11; N,
4.74. Found: C, 77.25; H, 7.28; N, 4.67.
3H, J=6.5 Hz, CHCH3), 1.60 (br. s, 1H, -OH), 2.00–
2.18 (m, 1H, -CH(CH3)2), 2.35 (s, 3H, CH3), 2.44–2.56
(m, 1H, -CHH-CH2-), 2.62–2.73 (m, 1H, -CHH-CH2-),
2.88–3.20 (m, 4H, -CHH-CH2-), 3.25–3.43 (m, 2H,
-CHH-CH2-), 3.69–3.87 (m, 1H, ꢀNCH-, 2H,
3
-CH2OH), 6.17 (d, 1H, J=7.8 Hz, H-7 or H-8), 6.35
3
4
(dd, 1H, J=7.8, J=1.8 Hz, H-15 or H-16), 6.40 (d,
3
3
4
(Rp,R)-9: Yield 72%; mp (orange needles) 162.5–164°C;
1H, J=7.8 Hz, H-7 or H-8), 6.48 (dd, J=7.8, J=1.8
1
[h]2D2=+553.5 (c 0.360, MeOH); H NMR (CDCl3): l
3
4
Hz, H-12 or H-13), 6.62 (dd, 1H, J=7.8, J=1.8 Hz,
3
3
4
0.90 (d, 6H, J=6.5 Hz, CH(CH3)2), 1.60 (br. s, 1H,
H-12 or H-13), 6.94 (dd, 1H, J=7.8, J=1.8 Hz, H-15
or H-16), 15.9 (br. s, 1H, OH); MS (70 eV): m/z
(%)=351 (47, M+), 247 (78), 216 (100), 204 (31), 162
(62), 161 (55), 160 (60), 104 (97). Anal. calcd for
C23H29NO2: C, 78.65; H, 8.26; N, 3.99. Found: C,
78.49; H, 8.39; N, 3.82.
-OH), 1.88–2.01 (m, 1H, -CH(CH3)2), 2.52–2.62 (m,
1H, -CHH-CH2-), 2.72–2.89 (m, 2H, -CHH-CH2-),
2.95–3.21 (m, 4H, -CHH-CH2-), 3.39–3.52 (m, 1H,
ꢀNCH, 1H, -CHH-CH2-), 3.82–3.92 (t, 1H, -CH2OH),
3
3.93–4.02 (m, 1H, -CH2OH), 6.19 (d, 1H, J=7.8 Hz,
H-7 or H-8), 6.41 (d, 1H, H-15 or H-16, 1H, H-12 or
3
H-13), 6.48 (dd, J=7.8 Hz, H-7 or H-8), 6.58 (dd, 1H,
(Sp,S)-12: Yield 72%; mp (yellow floss) 101–102°C;
3J=7.8, 4J=1.8 Hz, H-12 or H-13), 6.85 (dd, 1H,
3J=7.8, 4J=1.8 Hz, H-15 or H-16), 8.29 (s, 1H,
CHNꢀ) 14.0 (br. s, 1H, OH); MS (70 eV): m/z (%)=
337 (10, M+), 233 (30), 147 (20), 117 (16), 104 (100).
Anal. calcd for C22H27NO2: C, 78.35; H, 8.01; N, 4.15.
Found: C, 78.25; H, 8.23; N, 3.93.
1
[h]2D2=−560.8 (c 0.220, CHCl3); H NMR (CDCl3): l
3
3
1.05 (d, 3H, J=6.5 Hz, -CHCH3), 1.07 (d, 3H, J=6.5
Hz, -CHCH3), 1.45–1.57 (m, 1H, -CHH-iPr), 1.59–1.71
(m, 1H, -CHH-iPr), 1.81–1.92 (m, 1H, -CH(CH3)2),
2.25 (br. s, 1H, -OH), 2.35 (s, 3H, CH3), 2.44–2.57 (m,
1H, -CHH-CH2-), 2.58–2.69 (m, 1H, -CHH-CH2-),
2.87–3.20 (m, 4H, -CHH-CH2-), 3.30–3.43 (m, 2H,
-CHH-CH2-), 3.64–3.80 (m, 2H, -CH2OH), 3.94–4.03
(Rp)-10: Yield 89%; mp (orange plates) 155–155.5°C;
1
[h]2D2=+611.7 (c 0.210, CHCl3); H NMR (CDCl3): l
3
(m, 1H, ꢀNCH-), 6.15 (d, 1H, J=7.8 Hz, H-7 or H-8),
2.10 (br. s, 1H, -OH), 2.23 (s, 3H, CH3), 2.47–2.59 (m,
1H, -CH2-CHH-), 2.60–2.72 (m, 1H, -CHH-CH2-),
2.87–3.23 (m, 4H, -CHH-CH2-), 3.32–3.47 (m, 2H,
-CHH-CH2-), 3.62–3.79 (m, 2H, ꢀNCH2-), 4.03–4.14 (t,
3
4
6.27 (dd, 1H, J=7.8, J=1.8 Hz, H-15 or H-16), 6.40
(d, 1H, 3J=7.8 Hz, H-7 or H-8), 6.49 (dd, 3J=7.8,
4J=1.8 Hz, H-12 or H-13), 6.64 (dd, 1H, 3J=7.8,
4J=1.8 Hz, H-12 or H-13), 6.96 (dd, 1H, 3J=7.8,
4J=1.8 Hz, H-15 or H-16), 16.0 (br. s, 1H, OH); MS
(70 eV): m/z (%)=365 (38, M+), 261 (55), 230 (79), 188
(27), 186 (21), 162 (44), 160 (58), 145 (32), 104 (96).
Anal. calcd for C24H31NO2: C, 78.92; H, 8.49; N, 3.83.
Found: C, 79.04; H, 8.67; N, 3.74.
3
2H, -CH2OH), 6.20 (d, 1H, J=7.8 Hz, H-7 or H-8),
3
4
6.34 (dd, 1H, J=7.8, J=1.8 Hz, H-15 or H-16), 6.42
3
3
(d, 1H, J=7.8 Hz, H-7 or H-8), 6.49 (dd, 1H, J=7.8,
4J=1.8 Hz, H-12 or H-13), 6.62 (dd, 1H, 3J=7.8,
4J=1.8 Hz, H-12 or H-13), 6.96 (dd, 1H, 3J=7.8,
4J=1.8 Hz, H-15 or H-16), 15.3 (br. s, 1H, OH); MS
(70 eV): m/z (%)=309 (38, M+), 205 (67), 188 (34), 174
(100), 162 (26), 161 (93), 160 (88), 146 (24), 131 (24),
104 (100). Anal. calcd for C20H23NO2: C, 77.68; H,
7.44; N, 4.53. Found: C, 77.87; H, 7.58; N, 4.40.
(Rp,S)-12: Yield 77%; mp (orange floss) 97–97.5°C;
1
[h]2D2=+646.8 (c 0.240, CHCl3); H NMR (CDCl3): l
3
3
0.85 (d, 3H, J=6.5 Hz, -CHCH3), 0.92 (d, 3H, J=6.5
Hz, -CHCH3), 1.41–1.60 (m, 1H, -CH(CH3)2), 1.60 (br.
s, 1H, -OH), 1.62–1.75 (m, 2H, -CH2-iPr), 2.35 (s, 3H,
CH3), 2.48–2.60 (m, 1H, -CH2-CHH-), 2.62–2.71 (m,
1H, -CHH-CH2-), 2.84–2.94 (m, 1H, -CHH-CH2-),
2.95–3.20 (m, 3H, -CHH-CH2-), 3.35–3.48 (m, 2H,
-CHH-CH2-), 3.75–3.84 (m, 1H, -CH2OH), 3.88–4.02
(Sp,S)-11: Yield 73%; mp (orange needles) 141–142°C;
1
[h]2D2=−603.8 (c 0.270, CHCl3); H NMR (CDCl3): l
3
3
0.98 (d, 3H, J=6.5 Hz, CHCH3), 1.02 (d, 3H, J=6.5
Hz, CHCH3), 1.60 (br. s, 1H, -OH), 1.92–2.10 (m, 1H,
-CH(CH3)2), 2.32 (s, 3H, CH3), 2.44–2.56 (m, 1H,
-CHH-CH2-), 2.57–2.71 (m, 1H, -CHH-CH2-), 2.80–
3.20 (m, 4H, -CHH-CH2-), 3.30–3.46 (m, 2H, -CH2-
CHH-), 3.62–3.72 (m, 1H, ꢀNCH-), 3.80–3.89 (t, 1H,
-CHHOH), 3.95–4.06 (m, 1H, -CHHOH), 6.19 (d, 1H,
3
(m, 1H, -CH2OH, 1H, ꢀNCH-), 6.22 (d, 1H, J=7.8
3
4
Hz, H-7 or H-8), 6.41 (dd, 1H, J=7.8, J=1.8 Hz,
3
H-15 or H-16), 6.43 (d, 1H, J=7.8 Hz, H-7 or H-8),
3
4
6.47 (dd, J=7.8, J=1.8 Hz, H-12 or H-13), 6.62 (dd,
3
4
3
4
3J=7.8 Hz, H-7 or H-8), 6.38 (dd, 1H, J=7.8, J=1.8
1H, J=7.8, J=1.8 Hz, H-12 or H-13), 6.97 (dd, 1H,
4
3J=7.8, J=1.8 Hz, H-15 or H-16), 15.6 (br. s, 1H,
3
Hz, H-15 or H-16), 6.40 (d, 1H, J=7.8 Hz, H-7 or
OH); MS (70 eV): m/z (%)=365 (37, M+), 261 (55), 230
(80), 188 (27), 162 (44), 160 (58), 145 (34), 104 (99).
Anal. calcd for C24H31NO2: C, 78.92; H, 8.49; N, 3.83.
Found: C, 78.92; H, 8.65; N, 3.70.
H-8), 6.45 (dd, 3J=7.8, 4J=1.8 Hz, H-12 or H-13), 6.60
3
4
(dd, 1H, J=7.8, J=1.8 Hz, H-12 or H-13), 6.95 (dd,
1H, J=7.8, J=1.8 Hz, H-15 or H-16), 15.45 (br. s,
1H, OH); MS (70 eV): m/z (%)=351 (37, M+), 247 (73),
3
4

2018
T. I. Danilo6a et al. / Tetrahedron: Asymmetry 14 (2003) 2013–2019
3.2. Enantioselective diethylzinc addition to aldehydes
hydrogen atoms) approximation. All hydrogen atoms
in 2 were located from the difference Fourier syntheses
and refined in isotropic approximation. For structures
10 and 11 all hydrogen atoms (except the hydrogen
atoms in OH groups) were placed in geometrically
calculated positions and included in final the refinement
using the ‘riding’ model with the Uiso(H) parameters
equal to 1.2 Ueq(Ci) or 1.5 Ueq(Cii), where U(Ci) and
U(Cii) are, respectively, the equivalent thermal parame-
ters of the methyne and methylene carbon atoms to
which corresponding H atoms are bonded. All calcula-
tions were performed on an IBM PC/AT using the
SHELXTL software [G. M. Sheldrick, SHELXTL-97,
Version 5.10, Bruker AXS Inc., Madison, WI, 53719,
USA]. Crystallographic data for structures 2, 10 and 11
reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supple-
mentary publications (Ref. Numbers CCDC 206295,
206296, 206297, respectively). Copies of the data can be
obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ UK (Fax: (int.)
+44-1223/336-033; e-mail: deposit @ccdc.cam.ac.uk.
catalyzed by iminophenols 8–12
Typical experimental procedure: To a solution of imino-
alcohol 8–12 (0.007 mmol) in 0.28 ml of toluene, 0.140
ml (0.142 mmol) of Et2Zn (1 M solution in hexane) was
added in one portion at 0°C followed by the aldehyde
(0.071 mmol). The resulting yellow solution was
warmed to rt and allowed to stir for an additional 15 h.
The excess of Et2Zn was hydrolyzed with 0.25 ml of 1N
HCl; the reaction mixture was then diluted with 4 ml of
Et2O and 3 ml of H2O. The organic layer was separated
and the aqueous fraction was additionally extracted
with Et2O (5×4 ml) or CH2Cl2. Combined organic
fractions were washed with brine (2 ml) and dried over
Na2SO4. After solvent removal the oily residue, without
further purification, was subjected to the GC and chiral
GC for the conversion and enantiomeric excess analy-
sis. The conversion was determined by GC (Hewlett–
Packard HP 5890 Series II gas chromatograph) on
HP-1 (12 m×0.25 mm) with N2 as carrier gas. Split
temperature 200°C, detector FID 250°C, temperature
program: 40°C (1 min), flow rate 30°C/min, end tem-
perature 250°C (10 min). Enantiomeric analysis of the
product secondary alcohols was performed by GC
(Hewlett–Packard HP 5890 Series II gas chro-
matograph) on CP-Chirasil-Dex CB (25 m×0.25 mm)
with N2 as carrier gas. Temperature data for 1-phenyl-
propanol: split temperature 200°C, detector FID 250°C,
temperature program: 40°C (1 min), flow rate 5°C/min,
end temperature 190°C (20 min); the retention times
(min) were 26.94 (S) and 27.20 (R). Temperature data
for 1-cyclohexylpropanol: split temperature 200°C,
detector FID 250°C, temperature program: 40°C (10
min), flow rate 20°C/min, end temperature 100°C (35
min), flow rate 20°C/min, end temperature 190°C (5
min); the retention times (min) were 16.70 (S) and 16.98
(R).
Acknowledgements
Financial support of Russian authors by Russian Foun-
dation for Basic Research (Project Nos. 03-03-32957
and 03-03-32214), and Funds provided by the EU
Descartes Prize is gratefully acknowledged. The authors
are grateful to Dr. E. V. Vorontsov (Moscow, Russia)
for NMR spectra analysis and for helpful discussion.
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