Synthesis of chiral pentacyclo-undecane ligands and their use in the enantioselective alkylation of benzaldehyde with diethylzinc

Article abstract of DOI:10.1016/j.tetasy.2004.07.038

The synthesis of a new class chiral cage annulated bidentate ligands is reported. The ability of the chiral amino alcohols to catalyse the enantioselective addition of diethyl zinc to benzaldehyde was investigated. The cage annulated amino alcohols have C₁ symmetry and showed poor to good enantioselectivity with high chemical yields. The system could be utilised as a versatile probe into the reaction mechanism. The synthesis of a new class of chiral pentacycloundecane cage annulated bidentate ligands is reported. This class of ligands can be used in many reactions that are catalysed by amino alcohol ligands. The ability of the chiral ligands to asymmetrically catalyse the reaction between diethylzinc and benzaldehyde was investigated. The cage annulated bidentate ligands have C₁ symmetry and showed poor to good enantioselectivity with high yields compared to previous systems reported using other amino alcohol ligands. An important conclusion from the results is that both ligands should be involved in the mechanism as the bidentate ligands gives much improved enantioselectivity when compared with a single chiral source molecule. This system could be utilised as a versatile probe for examining the reaction mechanism.

Full text of DOI:10.1016/j.tetasy.2004.07.038

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2661–2666
Synthesis of chiral pentacyclo-undecane ligands and their use in the
enantioselective alkylation of benzaldehyde with diethylzinc
Grant A. Boyle, Thavendran Govender, Hendrik G. Kruger* and Glenn E. M. Maguire
School of Pure and Applied Chemistry, University of KwaZulu-Natal, Durban 4041, South Africa
Received 22 June 2004; accepted 27 July 2004
Abstract—The synthesis of a new class of chiral pentacycloundecane cage annulated bidentate ligands is reported. This class of lig-
ands can be used in many reactions that are catalysed by amino alcohol ligands. The ability of the chiral ligands to asymmetrically
catalyse the reaction between diethylzinc and benzaldehyde was investigated. The cage annulated bidentate ligands have C1 symme-
try and showed poor to good enantioselectivity with high yields compared to previous systems reported using other amino alcohol
ligands. An important conclusion from the results is that both ligands should be involved in the mechanism as the bidentate ligands
gives much improved enantioselectivity when compared with a single chiral source molecule. This system could be utilised as a ver-
satile probe for examining the reaction mechanism.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
N
O
N
O
R
R
Zn(R)2
Zn
Zn
The search for new chiral ligands to be used in asymmet-
ric catalysis is of great interest in the field of synthetic
chemistry.1,2 Carbon–carbon bond forming reactions
remain an active area of research.3 A popular reaction
is that of dialkylzinc with pro-chiral aldehydes3–5 since
the chiral secondary alcohols that are formed are impor-
tant substrates for drug synthesis. Amino alcohols are
impressive ligands for this reaction as shown by Noyori
and Kitamura1,6 The accepted mechanism for the chiral
induced dialkylzinc additions to carbonyl compounds
involves a dinuclear zinc chiral amino alkoxide interme-
diate 3 (see Fig. 1). This intermediate 3, acts as a Lewis
acid to activate the carbonyl substrate, and enhances the
nucleophilicity of the alkyl group on the neighbouring
zinc reagent.
Zn
R
R
1
2
R1CHO
N
O
HO
R
R
H
Zn
O
H
R1
Zn
R1
R
R
4
3
Figure 1. Proposed mechanism for chiral induced dialkylzinc
reactions.6
Chiral pentacyclo-undecane (PCU) cage moieties were
previously used as hosts for chiral ammonium ions,7,8
but the application of a PCU-moiety in chiral ligands
for asymmetric synthesis has not yet been reported.
The results herein form part of a programme to inves-
tigate chiral applications of the pentacyclo-
[5.4.0.02,6.03,10.05,9]undecane framework attached to
amino alcohols. There are a number of reasons why this
programme is likely to enhance our understanding
about the mechanism of the reaction: (a) the proposed
PCU-ligands (see Fig. 3) are the first bidendate ligands
reported with C1 symmetry; it also offers a central ether
type oxygen, which could potentially participate in the
reaction, (b) the alkyl arms of the PCU-moiety can eas-
ily be varied,9 enabling versatility to probe the mecha-
nism of the reaction, (c) the PCU moiety enhances the
lypophilicity of the ligand, which could lead to more
effective recycling of the ligand and (d) the source of
chirality is inexpensive amino acids.
*
Corresponding author. Tel.: +27 312602181; fax: +27 312603091;
e-mail: kruger@ukzn.ac.za
0957-4166/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.038

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G. A. Boyle et al. / Tetrahedron: Asymmetry 15 (2004) 2661–2666
The dione was converted to the 3,5-diallyl-4-oxahexa-
cyclo[5.4.1.02,6.03,10.05.9.08,11]dodecane 14 as described
previously.8,16 Ozonolysis of 14 followed by a reductive
workup using NaBH4 afforded the 3,5-(20,200-bis-(hydroxy-
ethyl))-4-oxahexacyclo[5.4.1.02,6.03,10.05.9.08,11] dodecane
15 (90%). The diol 15 has been previously synthesised
and characterised by Marchand et al. via a different
method.17 The diol 15 was treated with p-toluene sulfo-
nyl chloride and solid KOH in THF to yield the PCU-
ditosylate 16 (62%).18
N
R1
R2
N
N
R1
R2
R1
R2
N
N
R1
R2
H3C
Ph
N
OH
HO
OH
HO
OH
7
5
6
Figure 2. Examples of bidentate ligands with C2 symmetry.10–12
The N-methyl amino alcohols were synthesised from
their respective amino acids (Scheme 2) by treating the
amino acids 17–20 with formic acid and acetic anhy-
dride to give the formamides 21–24, respectively.19–21
The formamides were reduced to the corresponding
N-methyl amino alcohols 25–28 via LiAlH4 at ambient
temperature.20,21
O
O
n=0,1,2
OH
n=0,1,2
R
HO
N
N
N
N
R
OH
HO
(S,S)-12
(R,R)-8 = CH2CH3
(S,S)-9 = CH(CH3)2
(S,S)-10 = CH2CH(CH3)2
(S,S)-11 = Ph
R
O
R
R
O
Ac2O
LiAlH4
THF
*
*
*
HCO2H
H2N
OH
HN
CH3
(R)-25 = CH2CH3
(S)-26 = CH(CH3)2
(S)-27 = CH2CH(CH3)2
(S)-28 = C6H5
OH
HN
OH
Figure 3. Possible chiral PCU ligands.
O
CH
(R)-17 = CH2CH3
(S)-18 = CH(CH3)2
(S)-19= CH2CH(CH3)2
(S)-20 = C6H5
(R)-21 = CH2CH3
(S)-22 = CH(CH3)2
(S)-23 = CH2CH(CH3)2
(S)-24 = C6H5
Very little attention has been given to the use of biden-
tate type ligands in chiral dialkylzinc reactions. Ligands
such as 5 and 6 have C2 symmetry and were found10–12
to exhibit much higher enantioselectivity (up to 90%)
than the corresponding single source of chirality (36%
ee for ligand 7)13 indicating that both arms should be in-
volved in the dialkylzinc addition reaction (Fig. 2).
N
N
OH
OH
LiAlH4
THF
*
*
O
(S)-29
(S)-30
It was also demonstrated12 that the nitrogen of the pyr-
idine ring is involved in the mechanism as ligands of the
type 6 gave opposite enantioselectivity than ligands 5. In
most cases pyridine based ligands 6 also gave higher
enantioselectivity when compared to benzene based lig-
ands 5.
Scheme 2. Synthesis of the amino alcohols.
The reduction of (S)-(+)-proline 29 to (S)-(+)-prolinol
30 does not require the additional formamide formation
step. Ligands 8–12 were formed by reacting the PCU-
ditosylate 16 with the corresponding amino alcohols
25–28 and 30 (Scheme 3).
In light of the discussion above it is clear that the pro-
posed PCU bidentate ligands are likely to enhance our
understanding about this important organic reaction.
13, Na2CO3
25-28, 30
8-12
CH3CN, reflux
2. Results and discussion
Scheme 3. Synthesis of PCU-ligands.
The synthesis of ligands 8–12 (Scheme 1) was accom-
plished in respectable yields starting from the pentacy-
clo[5.4.0.02,6.03,10.05,9]-undecane-8,11-dione 13 (PCU-
dione)14,15 with commercially available amino acids as
the source of chirality.
The catalytic activity of these ligands was investigated
using the standard reaction of diethylzinc and benzalde-
hyde. Reactions were carried out in dry toluene at ambi-
ent temperature in the presence of 10mol% chiral ligand
Ts-Cl
1) O3, dry MeOH
2) NaBH4
KOH, THF
O
O
O
O
O
OTs
OH
TsO
16
HO
15
13
Scheme 1. Synthesis of PCU-ditosylate 16.
14

G. A. Boyle et al. / Tetrahedron: Asymmetry 15 (2004) 2661–2666
2663
and monitored by chiral gas chromatography.3 When
3. Conclusion
complete conversion of the aldehyde was detected
(approximately 5h) the reaction was stirred for a further
48h. Previous reports4,5 indicate that the reaction
should be quenched when there is no more aldehyde pre-
sent, but with the PCU-ligands, this early workup
resulted in lower yields of the desired product and the
formation of benzyl alcohol5,22 as the major by-product.
After the desired reaction time, the reaction was
quenched with 10% HCl and extracted with diethyl
ether. The organic phase was dried, the solvent evapo-
rated and the product purified via preparative thin layer
chromatography (TLC). All reactions were repeated
three times and an average of the yields are reported.
The reaction was also carried out at 0ꢁC and this re-
quired reaction times in excess of 90h with no apprecia-
ble increase in the % ee observed.
A new class of chiral bidentate ligands has been synthe-
sised. They exhibit high yields as catalysts, but with poor
to good enantioselectivity. It is clear that incorporation
of the PCU cage into such ligands warrants further
investigation as it significantly enhances the enantiose-
lectivity of simple chiral amino alcohols such as leucinol.
The bidentate cage system will be utilised in future as a
flexible mechanistic probe since the dentate arm lengths
can be conveniently modified.9 Interestingly it is difficult
to envisage a Noyori6,24 type transition state for biden-
tate ligands especially if the central oxygen (or nitrogen)
atom of the linker between the ligands is also participat-
ing in the reaction. As predicted, the PCU-moiety en-
hances the lypophilicity of the ligand and effective
recycling of the ligand is possible (see Section 4).
The results in Table 1 show that in the presence of the
ligands 8–12, diethylzinc reacts cleanly with benzalde-
hyde providing 1-phenyl-1-propanol in high yields. Only
ligand 10 gave good results with respect to % ee results
(Scheme 4).
4. Experimental
Melting points are uncorrected. Optical rotations were
taken on a Perkin–Elmer 341 polarimeter. All mass
spectrometric analyses were carried out on a VG70-
70E mass spectrometer. FAB mass spectra were
obtained by bombardment of samples with xenon atoms
(1mA at 8keV). m-Nitrobenzyl alcohol was used as the
matrix. NMR spectra were recorded on a Varian Unity
Inova-300MHz spectrometer. Elemental microanalyses
were obtained at the University of KwaZulu-Natal
using a LECO CHNS-932 for carbon, hydrogen and
nitrogen, and LECO VTF-900 for oxygen. The enantio-
meric excess of the products were determined by GC
(SGE Cydex-B chiral column, 25m · 0.22mm, inlet
pressure 12psi, injection volume 0.1lL, isothermal
110ꢁC, T1 = 25.4, T2 = 26.2). Toluene was freshly dis-
tilled on sodium benzophenone ketyl under a nitrogen
atmosphere prior to its use. Commercially available
amino acids and diethylzinc (1.0M solutions in hexane)
was directly used.
Table 1. Results from the addition of diethylzinc to benzaldehyde
catalyseda by ligands 8–12
Ligand
Time (h)b
Yieldc %
% eed
Configuratione
8
30
30
30
30
30
92
90
—
15
—
S
9
10
11
12
8490
60
S
10
—
S
92
—
a Ratio of 0.125mmol ligand: 0.5 benzaldehyde: 0.125 diethylzinc.
b Quenching the reaction as soon as benzaldehyde is no longer
detectable, results in benzylalcohol as a major by-product.
c Product was isolated by preparative TLC.
d Determined by chiral GC as described in Section 4.
e Determined by optical rotation.
O
HO
H
HO
H
4.1. 3,5-(20,200-Bis(hydroxyethyl))-4-oxahexacyclo-
[5.4.1.02,6.03,10.05.9.08,11]dodecane 15
chiral cat.
toluene
H
Et
+
ZnEt2
+
A solution of the diene 14 (5.0g, 20.3mmol) in dry
methanol (150mL) was cooled to À78ꢁC via application
of an external dry ice-acetone bath and then was purged
with argon for 20min. Ozone was bubbled into the mix-
ture until a blue-purple colour persisted, thereby indicat-
ing the presence of excess ozone and completion of
reaction. Excess ozone was flushed from the reaction
vessel with a stream of argon, and the reaction mixture
was transferred to a 2L flask. Sodium borohydride (3g,
81.0mmol) was added over 1h to a stirred, ice bath
cooled mixture of the ozonide. The resulting mixture
was stirred at ambient temperature for 12h. The reac-
tion mixture was concentrated in vacuo, excess sodium
borohydride was quenched with 10% HCl (200mL)
and extracted with ethyl acetate to give pure 1517
(4.4g, 89%) obtained as a colourless microcrystalline
solid: mp 153–153.5ꢁC; IR (KBr): mmax 3320 (m), 2980
33
32
31
benzyl alcohol
1-phenyl-1-propanol
desired product
undesired product
Scheme 4. Chiral addition of diethylzinc to benzaldehyde.
The source of chirality in 10 is leucinol; leucinol on its
own, catalyses this reaction with an ee of 48% (96%
chemical yield);23 this indicates that the cage moiety
has a positive effect on the enantioselectivity of the reac-
tion and that both arms should be involved in the reac-
tion mechanism rather than each arm performing a
separate catalytic conversion. The results for ligand 10
suggest that the intrinsically chiral PCU-unit serves to
position two leucinol units in a favourable chiral orien-
tation. These results complement previous data,11,12
which found that bidentate ligands such as 5 and 6 exhi-
bit much higher enantioselectivity compared to a single
chiral source molecule.
(s)cmÀ1
;
1H NMR [CDCl3, 300MHz]: dH 1.52 (d,
J = 10.3Hz, 1H), 1.70–2.05 (m, 4H), 2.28–2.69 (m,

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G. A. Boyle et al. / Tetrahedron: Asymmetry 15 (2004) 2661–2666
9H), 3.50–3.86 (m, 6H); 13C NMR [CDCl3, 75MHz]: dC
34.3 (t), 41.4 (d), 43.5 (t), 44.1 (d), 47.7 (d), 58.2 (d), 60.0
(t), and 92.4(s).
THF at 0ꢁC. The solution was allowed to gradually
warm to ambient temperature overnight and stirred
for a further 12h at ambient temperature. The reaction
mixture was again cooled to 0ꢁC and an equal volume
of diethyl ether was added. The reaction was quenched
with saturated Na2SO4 aqueous solution. The solution
was filtered and the solvent removed in vacuo.
4.2. Synthesis of PCU ditosylate 1618
To a solution of 15 (5.0g, 20.1mmol) and p-toluene sul-
fonyl chloride (11.5g, 60.3mmol) in THF (200mL) was
added finely powdered KOH (17.0g, 300mmol). This
mixture was stirred under nitrogen and monitored via
TLC (50 hexane:50 ethyl acetate). When no more diol
(Rf = 0.5) and no more mono-tosylated product
(Rf = 0.2) is detected by TLC, water (100mL) is added
to the reaction vessel and the layers are separated. The
aqueous layers were extracted with ethyl acetate and
the combined organic layers were dried over anhydrous
MgSO4. The product was concentrated in vacuo and
purified via column chromatography (20 ethyl ace-
tate:80 hexane) to give the product 16 as a colourless
(R)-(À)-2-Methylamino-butan-1-ol 25:27 75%, 1H NMR
(CDCl3, 300MHz) dH 0.82 (t, J = 7.7Hz, 3H), 1.25–1.52
(m, 2H), 2.32 (s, 3H), 3.20–3.32 (m, 1H), 3.55 (d,
J = 3.9Hz, 1H), 3.51 (d, J = 3.9, 1H).
(S)-(+)-3-Methyl-2-methylamino-butan-1-o1 26:28,29 yield
96%, 1H NMR (CDCl3, 300MHz) dH 0.95 (d, J =
7Hz, 6H), 1.9 (m, 1H), 2.45 (s, 3H), 3.35 (s, 2H), 3.4–
3.8 (m, 3H).
(S)-(+)-4-Methyl-2-methylamino-pentan-1-o1 27:20 yield
1
1
microcrystalline solid; H NMR [CDCl3, 300MHz]: dH
96%, H NMR (CDCl3, 300MHz) dH 0.9 (d, J = 7Hz,
6H), 1.25 (t, J = 7Hz, 2H), 1.5–1.9 (m, 1H), 2.4(s,
3H), 3.3–3.7 (m, 3H), 3.8 (s, 2H).
1.43 (AB, JAB = 10.5Hz, 1H), 1.77 (AB, JAB = 10.5Hz,
1H), 2.03 (t, J = 7.0Hz, 4H), 2.29–2.50 (m, 8H), 2.69
(s, 6H), 4.04 (t, J = 7.0Hz, 4H), 7.29 (AB, JAB = 8.1Hz,
4H), 7.72 (AB, JAB = 8.4Hz, 4H).
(S)-(+)-2-Methylamino-2-phenyl-ethanol 28:21 yield 90%,
1H NMR (CDCl3, 300MHz) dH 2.32 (s, 2H), 2.68 (br s,
2H), 3.51–3.78 (m, 3H), 7.21–7.42 (m, 5H).
4.3. General procedure for preparing N-formyl amino
acids 21–2419–21
(S)-(+)-2-Pyrrolydinemethanol 30:30 yield 92%, 1H NMR
(CDCl3, 300MHz) dH 1.3–1.5 (m, 1H), 1.6–1.9 (m, 4H),
2.8–3.0 (m, 2H), 3.2–3.3 (m, 1H), 3.3–3.4(m, 1H), 3.4–
3.8 (m, 2H).
Acetic anhydride (30equiv) was added dropwise to a
stirred solution of the amino acid (1equiv) dissolved in
formic acid (approx. 50mL/g amino acid) at 0ꢁC. After
addition of the acetic anhydride, the solution was stirred
at room temperature overnight. The solution was treat-
ed with water (half volume of solution). The solvent was
removed under reduced pressure to yield a white residue.
This residue was recrystallised from water to yield the
pure product.
4.5. General procedure for preparing ligands 8–12
A mixture of the N-methyl amino alcohol (2.2equiv),
PCU ditosylate (1equiv) and Na2CO3 in CH3CN was
refluxed for four days under argon. The reaction mix-
ture was cooled, filtered and concentrated in vacuo.
The residue was purified via column chromatography
on silica gel (Merck 7734).
(R)-(À)-2-N-Formylamino-butyric acid 21:25 yield 63%,
1
mp 153–155ꢁC; H NMR (DMSO, 300MHz) dH 0.87
(t, J = 8.1Hz, 3H, 1.50–1.85 (m, 2H), 4.22 (m, 1H),
8.02 (s, 1H, CHO), 8.34(d, J = 7.1Hz, 1H).
4.5.1. Ligand 8. Ligand 8 was prepared as described
above. The crude product was purified by chromatogra-
phy on silica gel using 88 CHCl3:10 MeOH:2 NH4OH as
(S)-(+)-N-Formyl valine 22:19 yield 72%, 1H NMR
(DMSO, 300MHz) dH 1.0 (d, J = 6Hz, 6H), 1.6 (m,
1H), 4.8 (m, 1H), 5.9 (d, J = 8Hz, 1H, NH), 8.2 (s,
1H, CHO).
eluents to give the product 8 as a clear oil (52%).
20
D
½aŠ ¼ À7:8 (c = 5, CHCl3); IR (KBr): mmax 3405
(br, s), 2961 (vs), 1220 (m), 798 (m) cmÀ1; FAB+ MS
1
(m-nitrobenzyl alcohol): m/z 419 [M + H]+; H NMR
(S)-(+)-N-Formyl leucine 23:26 yield 85%, 1H NMR
(DMSO, 300MHz) dH 0.97 (d, J = 6.2Hz, 6H), 1.70–
1.92 (m, 3H), 4.10 (m, 1H), 5.95 (d, J = 8Hz, 1H,
NH), 8.23 (s, 1H, CHO).
[CDCl3, 300MHz]: dH 0.2 (t, 6H), 0.98–1.15 (m, 2H),
1.40–1.60 (m, 3H), 1.75–1.98 (m, 5H), 2.15 (s, 6H),
2.25–2.70 (m, 12H), 3.15 (t, 2H), 3.55 (d, J = 4.4Hz,
2H), 3.90 (d, J = 4.4Hz, 2H); 13C NMR [CDCl3,
75MHz]: dC 11.62 (q), 17.74(t), 17.79 (t), 31.32 (t),
35.59 (q), 35.65 (q), 41.52 (d), 41.59 (d), 43.44 (t),
44.26 (d), 47.76 (d), 47.85 (d), 50.22 (t), 50.28 (t),
58.51 (d), 58.63 (d), 60.47 (t), 66.07 (d), 66.14 (d),
95.03 (s), 95.08 (s). Anal. Calcd for C25H42N2O3 C,
71.73; H, 10.11; N, 6.69; O, 11.47. Found C, 71.65; H,
10.21; N, 6.72; O, 11.53.
(S)-(+)-N-Formyl phenylglycine 24:21 yield 80%,
1H NMR (DMSO, 300MHz) dH 5.37 (d, 1H, J = 8
Hz), 7.27–7.43 (m, 5H), 8.07 (s, 1H), 9.01 (d, 1H,
J = 9 Hz).
4.4. General procedure for the synthesis of N-methyl
amino alcohols 25–28
4.5.2. Ligand 9. Ligand 9 was prepared as described
above. The crude product was purified by chromato-
graphy on silica gel using 93 CHCl3:5 MeOH:2 NH4OH
N-Formyl-amino acid (1equiv) was added to a stirred
solution of lithium aluminium hydride (4equiv) in dry

G. A. Boyle et al. / Tetrahedron: Asymmetry 15 (2004) 2661–2666
2665
as eluents to give the product 9 as a clear oil (64%).
FAB+ MS (m-nitrobenzyl alcohol): m/z 415 [M + H]+;
1H NMR [CDCl3, 300MHz]: dH 1.49 (AB,
JAB = 10.5Hz, 1H), 1.60–2.10 (m, 13H), 2.15–2.62 (m,
16H), 2.74–2.84(m, 2H), 3.08–3.64(m, 6H, 2H are deu-
terium exchangeable); 13C NMR [CDCl3, 75MHz]: dC
23.55 (t), 27.51 (t), 31.38 (t), 41.56 (d), 43.44 (t), 44.22
(d), 44.27 (d), 47.74 (d), 48.09 (d), 50.90 (t), 50.94 (t),
54.24 (t), 54.27 (t), 58.54 (d), 58.87 (d), 62.24 (t), 65.17
(d), 65.21 (d), 95.00 (s), 95.09 (s). Anal. Calcd for
C25H38N2O3 C, 72.43; H, 9.24; N, 6.76; O, 11.58. Found
C, 72, 35; H, 9.17; N, 6.70; O, 11.49.
20
½aŠ ¼ À9:0 (c = 2.3, CHCl3); IR (KBr): cmax 3343 (br
D
s), 2952 (vs), 1454 (m), 1056 (m) cmÀ1; FAB+ MS (m-
nitrobenzyl alcohol): m/z 446 [M + H]+; 1H NMR
[CDCl3, 300MHz]: dH 0.70 (d, J = 6.6Hz, 6H), 0.85
(d, J = 6.6Hz, 6H), 1.48 (AB, JAB = 10.5Hz, 1H),
1.62–1.93 (m, 5H), 2.1–2.9 (m, 22H), 3.0–3.12 (m, 2H),
3.46–3.50 (m, 2H), 4.1 (br s, 2H, deuterium exchange-
able); 13C NMR [CDCl3, 75MHz]: dC 19.83 (q), 22.20
(q), 27.87 (q), 31.06 (t), 34.91 (q), 35.07 (q), 41.28 (d),
41.45 (d), 43.39 (t), 44.02 (d), 44.11 (d), 46.83 (d),
48.32 (d), 52.49 (t), 52.63 (t), 57.45 (d), 58.87 (d),
59.31 (t), 71.22 (d), 71.29 (d), 95.08 (s), 95.18 (s).
Anal. Calcd for C27H46N2O3C, 72.60; H, 10.38; N,
6.27; O, 10.75. Found C, 72, 31; H, 10.35; N, 6.35; O,
10.69.
4.6. General procedure for the enantioselective addition of
diethylzinc to benzaldehyde promoted by enantiopure
ligands 8–124,5
To a solution of the ligand (0.125mmol) in dry toluene
(5mL) under a nitrogen atmosphere at ambient temper-
ature, was added a solution of ZnEt2 in hexane (1.0M,
1.25mL, 1.25mmol). The mixture was stirred for
30min, and then benzaldehyde (60mg, 0.5mmol) was
added. The mixture was monitored by GC analysis until
no more benzaldehyde was present and stirred for a fur-
ther 48h. The reaction was quenched by adding 10%
HCl and extracted with Et2O and the organic phase
was washed with brine and dried over anhydrous
Na2SO4. After evaporation of the solvent, the crude
oil was purified via preparative TLC (hexane/ethyl acet-
ate) and its enantiomeric excess determined by chiral
GC. An average % ee of three experiments was taken.
4.5.3. Ligand 10. Ligand 10 was prepared as described
above. The crude product was purified by chromatogra-
phy on silica gel using 93 CHCl3:5 MeOH:2 NH4OH as
eluents to give the product 10 as a clear oil (62%).
20
D
½aŠ ¼ þ23:2 (c = 5, CHCl3); IR (KBr): cmax 3411 (br
À1
s), 2954(vs), 1644(m), 1057 (m), 1032 (m)cm
;
FAB+ MS (m-nitrobenzyl alcohol): m/z 475 [M + H]+;
1H NMR [CDCl3, 300MHz]: dH 0.85 (t, 12H), 0.91–
1.05 (m, 2H), 1.19–1.32 (m, 2H), 1.48–1.52 (m, 3H),
1.79–1.98 (m, 5H), 2.15 (s, 6H), 2.25–2.80 (m, 16H),
3.10–3.21 (m, 2H), 3.35–3.45 (m, 2H); 13C NMR
[CDCl3, 75MHz]: dC 22.15 (q), 23.74(q), 25.30 (d),
25.35 (d), 31.31 (t), 33.73 (t), 33.78 (t), 35.64(q), 35.72
(q), 41.52 (d), 41.58 (d), 43.46 (t), 44.25 (d), 47.88 (d),
49.83 (t), 58.55 (d), 58.59 (d), 61.11 (t), 62.05 (d),
62.09 (d), 95.03 (s), 95.08 (s). Anal. Calcd for
C29H50N2O3C, 73.37; H, 10.62; N, 5.90; O, 10.11.
Found C, 73.25; H, 10.56; N, 6.00; O, 10.15.
The PCU-ligand can be effectively recovered (>90%)
from the acidic aqueous phase by adjusting the pH to
approximately 7.5, followed by extraction.
4.5.4. Ligand 11. Ligand 11 was prepared as described
above. The crude product was purified by chromatogra-
phy on silica gel using 93 CHCl3:5 MeOH:2 NH4OH as
Acknowledgements
This work was supported by Grants from the National
Research Foundation Gun 2046819 (South Africa) and
the University of KwaZulu-Natal. Dr. Louis Fourie,
University of Potchefstroom, is acknowledged for the
MS analysis and Mrs. Anita Naidoo, University of
KwaZulu-Natal for the elemental microanalysis.
eluents to give the product 11 as a waxy solid (59%).
20
½aŠ þ28:6 (c = 7, CHCl3); IR (KBr): cmax 3393 (br s),
D
2961 (vs), 1458 (m), 1026 (m), 706 (m)cmÀ1; FAB+
MS (m-nitrobenzyl alcohol): m/z 515 [M + H]+; 1H
NMR [CDCl3, 300MHz]: dH 1.49 (AB, JAB = 10.5Hz,
1H), 1.85 (AB, JAB = 10.5Hz, 1H), 1.89–2.05 (m, 4H),
2.15 (s, 6H), 2.25–2.70 (m, 12H), 3.05 (br s, 2H, deute-
rium exchangeable), 3.55–3.65 (m, 2H), 3.70–3.82 (m,
2H); 3.86–4.00 (m, 2H), 7.10–7.40 (m, 10H); [CDCl3,
75MHz]: dC 30.28 (t), 36.95 (q), 37.17 (q), 41.53 (d),
41.59 (t), 43.48 (t), 44.25 (d), 44.30 (d), 47.90
(d), 47.99 (d), 50.06 (t), 50.21 (t), 58.53 (d), 58.68 (d),
60.75 (t), 68.77 (d), 68.83 (d), 95.16 (s), 95.20 (s),
127.80 (d), 128.20 (d), 128.96 (d), 135.69 (s), 135.79
(s). Anal. Calcd for C33H42N2O3. C, 77.01; H, 8.22;
N, 5.44; O, 9.33. Found C, 76.90; H, 8.18; N, 5.57, O,
9.27.
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