Bifunctional bis(oxazolines) as potential ligands in catalytic asymmetric reactions

Article abstract of DOI:10.1139/v03-198

C₂-symmetrical bis(oxazoline) ligands bearing pendant alkylthio ether groups were synthesized, and the structures of Cu complexes were determined by single crystal X-ray diffraction. The potential utility in catalysis was shown in the asymmetric addition of methyllithium to an aromatic aldimine, which resulted in a mixture of products with an enantiomeric excess of 68%.

Full text of DOI:10.1139/v03-198

306
Bifunctional bis(oxazolines) as potential ligands in
catalytic asymmetric reactions1
Stephen Hanessian, Eric Jnoff, Noemy Bernstein, and Michel Simard
Abstract: C2-symmetrical bis(oxazoline) ligands bearing pendant alkylthio ether groups were synthesized, and the
structures of Cu complexes were determined by single crystal X-ray diffraction. The potential utility in catalysis was
shown in the asymmetric addition of methyllithium to an aromatic aldimine, which resulted in a mixture of products
with an enantiomeric excess of 68%.
Key words: two-center catalysis, bis(oxazoline), aldimine, imine alkylation.
Résumé : On a effectué la synthèse de ligands bis(oxazoline) à symétrie C2 portant des groupes alkylthioéthers pen-
dants et on a déterminé les structures de complexes de cuivre par diffraction des rayons X de cristaux uniques. Leur
utilité potentielle en catalyse a été mise en évidence par l’addition asymétrique du méthyllithium sur une aldimine aro-
matique qui a conduit à la formation d’un mélange de produits avec un excès énantiomérique de 68%.
Mots clés : catalyse à deux centres, bis(oxazoline), aldimine, alkylation d’imine.
[Traduit par la Rédaction] Hanessian et al. 313
Introduction
X-ray crystal structures of several novel C2-symmetrical
bis(oxazolino)methanes 2–5 and related structures with pen-
dant ether and thioether appendages (Fig. 1). These ligands
could have potentially interesting applications in catalysis.
In this regard, we show an example of a catalytic asymmet-
ric addition of MeLi to an aromatic aldimine (8).
Catalytic asymmetric reactions have assumed great impor-
tance in the realm of organic synthesis (1). In practice, a
ligand possessing one or more elements of chirality is used
in sub-stoichiometric amounts, with or without the presence
of a metal (2). Among the more popular and synthetically
useful ligands are the so-called C2-symmetric bis(oxazolines)
(3), which are easily prepared from naturally available amino
acids by well-precedented chemical transformations (4).
Fig. 1 depicts the structure of a typical 2,2′-bis(oxa-
zolino)methane with appropriate stereodifferentiating ap-
pendages (t-Bu Box, 1) (4). This ligand has been extensively
used in conjunction with divalent metals as chiral Lewis ac-
ids in a number of catalytic reactions (3).
The use of bis(oxazoline) ligands that possess additional
coordination sites leading to bifunctional catalysis has been
less studied (5). Aggarwal et al. (6) prepared C2-symmetric
bis(oxazoline) ligands from cysteine and methionine and
studied a catalytic version of an asymmetric sulfur ylide
epoxidation of aldehydes mediated by Cu(II).
Synthesis
The synthesis of bis(oxazoline) ligands 2–5 is shown in
Scheme 1 and follows an established protocol for other
alkyl-substituted analogues (4). Thus, the amino acids L-
cysteine, D-penicillamine, and D-methionine were individu-
ally reduced to the corresponding amino alcohols, S-methyl-
ated in the case of L-cysteine and D-penicillamine, and then
reacted with 2,2-dimethylmalonyl dichloride to afford the
corresponding bis-amides. Treatment with TsCl and Et3N ef-
fected cyclization to the respective ligands 2–4. The L-serine
analogue 5 was similarly prepared from the O-TBDPS ether.
Another set of ligands representing a constrained scaffold
(9) was prepared from 1,2-trans-cyclohexane dicarboxylic
acid using the same protocol. Thus, treatment of the racemic
diacid with S-methyl L-cysteine-ol, D-methionine-ol, L-valinol,
O-TBDPS L-serinol, and L-tert-butylglycinol afforded mix-
tures of diastereomeric diamides that could be separated by
chromatography. These were individually cyclized to the
diastereomeric bis-(oxazoline) derivatives 6–10. The identity
of the major diastereomer was ascertained from the X-ray
structure of the tert-butylglycinol product 7, prepared from
the resolved diacid as the quinine salt and inferred in the
others.
Recently, we described the catalytic asymmetric reduction
of ketones by borane in the presence of thiazolidines derived
from penicillamine (7). We report herein the synthesis and
Received 19 September 2003. Published on the NRC
Research Press Web site at http://canjchem.nrc.ca on
6 February 2004.
Dedicated to Professor Ed Piers, wishing him the best in
chemistry and in life.
S. Hanessian,2 E. Jnoff, N. Bernstein, and M. Simard.
Department of Chemistry, Université de Montréal, Montréal,
QC H3C 3J7, Canada.
X-ray structures of ligands and Cu(II)
complexes
1This article is part of a Special Issue dedicated to Professor
Ed Piers.
The ORTEP diagrams of selected ligands and their Cu(II)
complexes are shown in Fig. 2, with corresponding bond
2Corresponding author (e-mail: stephen.hanessian@umontreal.ca).
Can. J. Chem. 82: 306–313 (2004)
doi: 10.1139/V03-198
© 2004 NRC Canada

Hanessian et al.
307
Fig. 1. Structures of bis(oxazoline) ligands.
Scheme 1.
Table 1. Bond lengths and bond angles
for ligand 3 and Cu(II) complex 3a.
Bond lengths (Å)
Cu(1)—N(11)
Cu(1)—N(12)
Cu(1)—O(13)
Cu(1)—S(11)
Cu(1)—S(12)
1.942(7)
1.934(6)
2.282(6)
2.337(2)
2.371(2)
Bond angles (°)
N(11)-Cu(1)-N(12)
N(11)-Cu(1)-S(11)
N(12)-Cu(1)-S(12)
N(11)-Cu(1)-N(12)
S(11)-Cu(1)-S(12)
N(12)-Cu(1)-S(11)
87.5
85.21(19)
85.3(2)
143.2(2)
104.66(8)
170.0(2)
dral geometry was observed in which the two methionine
sulfur atoms were engaged as equatorial coordination sites
in two seven-membered rings. In contrast to complex 3a,
both axial sites were occupied by triflates. A strong Jahn–
Teller effect was observed in this neutral complex, as evi-
denced by the shorter C4—N and Cu—S distances com-
pared with Cu—OTf. The Cu atom was moved out of plane,
by 0.2 Å, toward O31.
Ligand 7 crystallized with a molecule of water that was
internally hydrogen-bonded in a bidentate fashion with the
two oxazoline nitrogens (Fig. 4A, Table 4). The correspond-
ing Cu(II) dichloride complex 7a afforded monoclinic crys-
tals with quasi-equidistant coordination sites, forming a
distorted seven-membered ring (Fig. 4B).
lengths and angles shown in Table 1.3 Bis-(oxazoline)ditri-
flate 3a formed monoclinic crystals in which Cu was penta-
coordinated with the oxazoline nitrogens and the
penicillamine methylthio groups, forming
a
trigonal
bipyramid with N12 and S11 in the axial positions (164°–
171°) (Fig. 2B). It is of interest that the two S-methyl groups
occupy an anti-relationship in the complex. Only one triflate
group was coordinated to copper.
Complex 4a formed orthorhombic crystals with an un-
usual coordination around Cu (Fig. 3A, Table 2). The two
oxazoline nitrogens and only one of the methionine sulfur
atoms were coordinated to Cu in an axial orientation (N1-
Cu-S2 angle = 172.3°), and two chlorines were in equatorial
positions, forming a trigonal bipyramidal geometry. Curi-
ously, the S-methyl group of the other methionine side-chain
remained uncoordinated, thus adding an element of struc-
tural dissymmetry.
Catalytic asymmetric addition to an aldimine
The addition of organometallic reagents to aldimines is a
method of synthesis of secondary amines (8). Although there
are examples for the asymmetric synthesis of amines using
stoichiometric amounts of external ligands (8, 10), by com-
parison there are fewer catalytic versions (11).
Ligand 4 also gave a crystalline complex 4b with
Cu(II)bis-triflate (Fig. 3B, Table 3). In this case an octahe-
3 Supplementary data may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Research Council Can-
ada, Ottawa, ON K1A 0S2, Canada (http://www.nrc.ca/cisti/irm/unpub_e.shtml for information on ordering electronically). CCDC 229278–
229283 contain the supplementary data for this paper. These data can be obtained, free of charge, via www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, U.K.; fax +44 1223 336033; or de-
posit@ccdc.cam.ac.uk).
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Can. J. Chem. Vol. 82, 2004
Fig. 2. ORTEP diagram for (A) ligand 3 and (B) Cu(II) complex 3a.
The groups of Tomioka and co-workers (12) and Denmark
et al. (13) have reported on catalytic additions of alkyl-
lithium reagents to N-arylaldimines in the presence of exter-
nal ligands such as β-amino ethers, chiral amino alcohols,
(–)-sparteine, and bis(oxazolines). The most promising lig-
ands were (–)-sparteine and bis(oxazolines), giving ee values
as high as 80% in some instances (13).
Initially, Denmark et al. (13) reported that N-arylaldi-
mines were practically unreactive to MeLi at low tempera-
ture, unless ligands such as (–)-sparteine or t-Bu Box (1)
were present in stoichiometric amounts. Catalytic versions
with aryl N-p-methoxyphenylaldimines and arylalkyl ana-
logues (possessing an enolizable α-hydrogen) with MeLi
were reported with 0.1–0.2 equiv. of (–)-sparteine or t-Bu
© 2004 NRC Canada

Hanessian et al.
309
Fig. 3. ORTEP diagram for Cu(II) complexes (A) 4a and (B) 4b.
Table 2. Bond lengths and bond angles
for Cu(II) complex 4a.
Table 3. Bond lengths and bond angles
for Cu(II) complex 4b.
Bond lengths (Å)
Bond lengths (Å)
Cu—N(1)
Cu—N(2)
Cu—S(2)
Cu—Cl(1)
Cu—Cl(2)
Bond angles (°)
Ni(1)-Cu-N(2)
N(1)-Cu-S(2)
N(2)-Cu-S(2)
N(2)-Cu-Cl(1)
N(2)-Cu-Cl(2)
N(1)-Cu-Cl(2)
N(2)-Cu-Cl(2)
C1(1)-CuCl(2)
S(2)-Cu-Cl(2)
2.016(2)
2.023(3)
2.354(9)
2.278(8)
2.450(9)
Cu—N(1)
Cu—N(2)
CU—S(1)
Cu—S(2)
Cu—O(41)
1.961(3)
1.965(3)
2.363(13)
2.363(13)
2.564(4)
2.578(4)
Cu—O(31)
87.66(8)
172.32(6)
92.40(6)
90.97(6)
148.37(7)
102.96(6)
97.62(6)
113.43(4)
84.65(3)
Bond angles (°)
N(1)-Cu-N(2)
N(1)-Cu-S(2)
N(2)-Cu-S(2)
N(1)-Cu-S(1)
N(2)-Cu-S(1)
S(2)-Cu-S(1)
N(1)-Cu-O(41)
N(2)-Cu-O(41)
S(1)-Cu-O(41)
S(2)-Cu-O(41)
N(1)-Cu-O(31)
N(2)-Cu-O(31)
S(1)-Cu-O(31)
S(2)-Cu-O(31)
O(31)-Cu-O(41)
89.80(13)
169.08(11)
89.41(10)
89.46(9)
166.43(10)
93.84(5)
104.28(14)
80.88(13)
86.18(9)
86.34(9)
Box 1, affording the corresponding secondary amines
(Scheme 2) in excellent yields and enantiomeric excesses of
82% (for BuLi) and 68% (for MeLi), respectively. Denmark
and Stiff (14) also studied the effect of ligand structure of
the bis-(oxazoline) in the reaction of aryl N-p-
methoxyphenyl aldimines with MeLi. They concluded that
the ligand bite angle φ played a minor role and that the na-
ture of the stereodifferentiating oxazoline substituents (e.g.
t-Bu) had a dramatic effect on selectivity.
The catalytic asymmetric alkylation of N-p-methoxy-
phenyl benzaldehyde imine with MeLi was tried with lig-
ands 2–4, using the t-Bu Box catalyst 1 as a control
(Scheme 2). The best ligand proved to be the one derived
from D-penicillamine 3, which gave an ee equal to 1. In the
83.89(13)
100.71(14)
92.69(10)
85.56(8)
171.73(1)
presence of Cu(OTf)2 or Yb(OTf)3 in toluene, the ees for 1
and 4 were 48% and 33%, respectively, with either additive.
Structurally, the thioether appendage in ligand 3 is very
similar to a tert-butyl group, except for the replacement of a
C-methyl by an S-methyl group. While it can be assumed
that the Li cation may be coordinated by the oxazoline nitro-
gens, there is no direct evidence that the thioether groups are
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Can. J. Chem. Vol. 82, 2004
Table 4. Bond lengths and bond angles
for ligand 7 monohydrate and Cu(II)
complex 7a.
Fig. 4. ORTEP diagram for (A) ligand 7 monohydrate and
(B) Cu(II) complex 7a.
Bond lengths (Å)
Cu—N(1)
Cu—N(2)
Cu—Cl(1)
1.993(3)
2.003(3)
2.221(13)
2.240(14)
Cu—Cl(2)
Bond angles (°)
N(1)-Cu-N(2)
N(1)-Cu-Cl(1)
N(2)-Cu-Cl(1)
N(1)-Cu-Cl(2)
N(2)-Cu-Cl(2)
Cl(1)-Cu-Cl(2)
90.24(13)
95.48(11)
147.86(10)
134.88(11)
97.27(10)
100.78(6)
Thus, treatment of styrene with ethyl diazoacetate in the
presence of 4 and CuOTf gave the corresponding cyclo-
propane in 40% ee for the trans-isomer (cis:trans, 1:2 by
NMR) (15). Addition of methylmagnesium bromide to p-
methoxybenzaldehyde in the presence of ligand 3 (10 mol%)
gave the secondary alcohol in 10% ee. Using stoichiometric
ligand raised the ee to 55% (HPLC). Applications to asym-
metric reduction with BH3·THF of acetophenone, allylation
of benzaldehyde with allyltributylstannane, Michael addition
to cyclohexenone, and Diels–Alder reaction with cyclopenta-
diene and N-acryloyloxazolidinone gave racemic products.
Future work will focus on exploiting other ligands with
bidentate character in catalytic asymmetric reactions.
Experimental
General procedure
Flash chromatography was carried out using 230–400
mesh silica gel. Mixtures of ethyl acetate – hexanes were
used as the eluents, unless otherwise specified. Analytical
thin layer chromatography (TLC) was performed on glass
plates coated with a 0.02 mm layer of silica gel 60 F-254.
Melting points were uncorrected. IR spectra were recorded
1
as films. H and 13C NMR spectra were recorded at 300 and
75 MHz, respectively, and the chemical shifts are reported in
parts per million on the δ scale, with CDCl3 as reference, un-
less otherwise specified. MS and HR-MS spectra were re-
corded using electron ionization or by the FAB technique.
Optical rotations were measured in CHCl3 at 23 °C. All re-
actions were carried out under nitrogen or argon unless oth-
erwise specified. The –78 °C temperature is approximate, as
achieved by a dry ice – acetone bath. The term “normal
workup” means the addition of saturated aqueous NH4Cl so-
lution to the reaction mixture, followed by extraction with
ethyl acetate, drying over Na2SO4, filtration, and evaporation
of the filtrate in vacuo to afford the crude product.
also involved in a bidentate manner. Thus, it is not surpris-
ing that in the absence of such a tetracoordination (as ob-
served for the Cu complexes), the extent of asymmetric
induction was equal to the t-Bu Box ligand 1 (13).
The lower enantioselectivities shown in the case of 2 and
4 may be because of the smaller size of the thioether ap-
pendage compared with 3 and 1, as observed by Denmark
and Stiff for bis-(oxazolines) with different side-chains (14).
In spite of the interesting structural data available from
the X-ray structures of the Cu complexes, especially 4a with
a tricoordinated geometry, we were not able to effectively
utilize them as catalysts in a variety of representative model
reactions.
Representative procedure for the bis-amide formation
To a solution of D-penicillaminol (0.20 g, 1.40 mmol) in
dry CH2Cl2 (3 mL) was added Et3N (0.5 mL, 3.6 mmol) at
room temperature (r.t.), followed by dropwise addition of
dimethylmalonyl chloride (0.10 g, 0.59 mmol) in dry
CH2Cl2 (0.5 mL). A white precipitate began to form, and the
mixture was stirred overnight, then concentrated in vacuo al-
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Hanessian et al.
311
Scheme 2.
most to dryness (without a warming bath), and the crude res-
idue was dissolved in CH2Cl2, and several drops of MeOH
were added. Chromatography, using 3% MeOH–CH2Cl2,
yielded the desired bis-amide as a white solid (172 mg, 74%
24.12, 15.91. HR-MS calcd. for C13H23O2N2S2: 303.1201;
found: 303.1197.
Ligand 4
1
Viscous oil (145 mg, 52%). [α]D +140.5 (c 0.76, CHCl3).
1H NMR (400 MHz) (CDCl3): 4.31 (2H, dd, J = 9.5, 8.15,
2 × OCHHCHN), 4.20 (2H, m, 2 × NCH), 3.91 (2H, dd, J =
8.1, 7.0, 2 × OCHHCHN), 2.56–2.52 (4H, m, 2 × CH2SMe),
2.08 (6H, s, 2 × SCH3), 1.87 (2H, m, CHHCH2SMe), 1.76
(2H, m, 2 × CHHCH2SMe), 1.48 (6H, s, C(CH3)2. 13C NMR
(100 MHz) (CDCl3): 169.03, 72.43, 64.95, 38.43, 34.97,
30.09, 24.19, 15.38. HR-MS calcd. for C15H27O2N2S2:
331.1514; found: 331.1508.
total). H NMR (300 MHz) (CDCl3): 6.92 (2H, d, J = 9.07,
2 × NH), 4.15 (2H, m, 2 × NHCH), 4.01 (2H, dd, J = 11.54,
3.57 2 × CHHOH), 3.73 (2H, dd, J = 11.54, 7.97, 2 ×
CHHOH), 2.14 (6H, s, 2 × SCH3), 1.61 (6H, s, C(CH3)2),
1.41 and 1.37 (each 6H, s, C(CH3)2SMe). 13C NMR
(75 MHz) (CDCl3): 174.81, 62.93, 58.96, 50.58, 46.67,
26.55, 26.19, 23.91, 11.68. HR-MS calcd. for
C17H34O4N2S2: 394.1960; found: 394.1979.
In the case of racemic 1,2-cyclohexanedicarboxylic acid,
the diastereomeric bis-amides were separated and individu-
ally cyclized.
Ligand 5
1
Viscous oil (115 mg, 87%). [α]D –61 (c 0.57, CHCl3). H
NMR (400 MHz) (CDCl3): 7.70–7.65 (8H, m, ArH), 7.45–
7.35 (12H, m, ArH), 4.40–4.29 (4H, m, 2 × OCH2CHN),
4.27 (2H, m, 2 × NCH), 1.53 (6H, s, C(CH3)2), 1.06 (18H, s,
2 × Si(Ph)2C(CH3)3. 13C NMR (100 MHz) (CDCl3): 170.26,
135.50, 135.46, 133.29, 133.18, 129.62, 129.54, 127.60,
127.56, 70.08, 67.35, 64.91, 38.56, 26.69, 24.39, 19.17. HR-
MS calcd. for C43H55O4N2Si2: 719.3701; found: 719.3723.
Representative procedure for bis-(oxazoline) formation
Ligand 3
To a solution of penicillaminol bis-amide (0.172 g,
0.436 mmol) in dry CH2Cl2 (4 mL) was added a catalytic
amount of DMAP (spatula tip), followed by Et3N (0.31 mL,
2.2 mmol) and tosyl chloride (0.30 g, 1.05 mmol) in one
portion. The solution was stirred overnight at r.t., then the
mixture was concentrated in vacuo (without a warming bath)
and chromatographed on silica gel using 35% ethyl acetate –
hexanes as eluant to give 3, a viscous oil, which partly solid-
Ligand 6
Diastereomer A
Viscous oil (78 mg, 65%). [α]D –23.4 (c 0.52, CHCl3). H
1
NMR (400 MHz) (CDCl3): 4.11 (2H, dd, J = 8.85, 7.55,
NCH), 3.85–3.75 (4H, m, 2 × OCH2CHN), 2.60 (2H, m,
CH2CHCHCH2), 1.93 (2H, br, CHHCH2CH2CHH), 1.72–
1.62 (4H, m, CHHCH2CH2CHH and 2 × CH(Me)2), 1.48–
1.42 and 1.32–1.21 (each 2H, m, CH2CH2CH2CH2), 0.89
and 0.80 (each 6H, d, J = 6.8, CH(CH3)2. 13C NMR
(100 MHz) (CDCl3): 168.65, 71.75, 69.51, 39.75, 32.35,
29.89, 24.90, 18.79, 17.81. HR-MS calcd. for C18H31O2N2:
307.2386; found: 307.2377.
1
ified (139 mg, 89%). [α]D +46.2 (c 0.525, CHCl3). H NMR
(400 MHz) (CDCl3): 4.32 (2H, dd, J = 8.1, 6.7, 2 × NCH),
4.25–4.15 (4H, m, 2 × OCH2CH), 2.03 (6H, s, 2 × SCH3),
1.50 (6H, s, C(CH3)2), 1.38 and 1.10 (each 6H, s, 2 ×
C(CH3)2SMe). 13C NMR (100 MHz) (CDCl3): 169.65,
73.60, 69.65, 46.32, 38.77, 25.83, 24.13, 21.86, 10.65. HR-
MS calcd. for C17H31O2N2S2: 359.1827; found: 359.1833.
Ligand 2
Diasteromer B
Viscous oil (124 mg, 56%). [α]D –37.8 (c 0.72, CHCl3).
1H NMR (400 MHz) (CDCl3): 4.35–4.29 (4H, m, 2 ×
OCH2CHN), 4.13 (2H, m, 2 × NCH), 2.81 (2H, dd, J = 13.5,
4.4, 2 × CHHSMe), 2.49 (2H, m, 2 × CHHSMe), 2.12
(6H, s, 2 × SCH3), 1.49 (6H, s, C(CH3)2). 13C NMR
(100 MHz) (CDCl3): 169.89, 72.22, 65.54, 38.78, 38.56,
1
(90 mg, 70%). [α]D –136.0 (c 0.55, CHCl3). H NMR
(400 MHz) (CDCl3): 4.12 (2H, dd,
OCHHCHN), 3.89–3.77 (4H, m, 2 × OCHHCHN & NCH),
2.62 (2H, m, CH2CHCHCH2), 1.98–1.94 & 1.72–1.62 (each
2H, m, CH2CH2CH2CH2), 1.68 (2H, m, 2 × CH(Me)2),
J = 9.4, 8.1,
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Can. J. Chem. Vol. 82, 2004
1.48–1.40 and 1.35–1.26 (each 2H, m, CH2CH2CH2CH2),
0.90 and 0.82 (each 6H, d, J = 6.8, CH(CH3)2). 13C NMR
(100 MHz) (CDCl3): 168.80, 71.62, 69.51, 39.84, 32.39,
30.07, 25.00, 18.67, 17.80. HR-MS calcd. for C18H31O2N2:
307.2386; found: 307.2377.
OCHHCHN), 4.09 (2H, m, 2 × NCH), 3.77 (2H, t, J = 7.9,
2 × OCHHCHN), 2.59–2.47 (6H, m, 2 × CH2SMe and
CH2CHCHCH2), 2.06 and 2.0595 (each 3H, s, SCH3), 1.93
(2H, m, CHCHH(CH2)2CHHCH), 1.83–1.65 (6H, m,
CHCHH(CH2)2CHHCH and 2 × CH2CH2SMe), 1.47–1.41
and 1.28–1.23 (each 2H, m, CH2CH2CH2CH2). 13C NMR
(100 MHz) (CDCl3): 169.05, 71.87, 64.87, 39.80, 35.30,
30.42, 29.61, 24.84, 15.39. HR-MS calcd. for
C18H31O2N2S2: 371.1827; found: 371.1821.
Ligand 7
Diastereomer B
White solid (53 mg, 69%). H NMR (400 MHz) (CDCl3):
1
4.07 (2H, dd, J = 9.9, 8.8, 2 × OCHHCH), 3.94 (2H, t, J =
8.3, 2 × NCH), 3.76 (2H, dd, J = 10.1, 8.1, 2 × OCHHCH),
2.66 (2H, m, CH2CHCHCH2), 1.99 and 1.73 (each 2H, m,
CH2(CH2)2CH2), 1.53–1.44 and 1.37–1.25 (each 2H, m,
CH2CH2CH2CH2), 0.86 (18H, s, 2 × C(CH3)3). 13C NMR
(100 MHz) (CDCl3): 168.86, 75.31, 68.22, 39.51, 33.36,
30.29, 25.71, 24.97. HR-MS calcd. for C20H35O2N2:
335.2699; found: 335.2713.
Ligand 10
Diastereomers
cyclization (59% total).
A
and
B
could be separated after
Diastereomer A
1
White solid (26 mg). [α]D –58 (c 1.33, CHCl3). H NMR
(400 MHz) (CDCl3): 7.67–7.62 (8H, m, ArH), 7.43–7.31
(12H, m, ArH), 4.21–4.07 (6H, m, 2 × OCH2CHN), 3.79
(2H, dd, J = 10.07, 3.51, 2 × CHHOTBDPS), 3.51 (2H, dd,
J = 10.03, 6.68, 2 × CHHOTBDPS), 2.59 (2H, m,
CH(CH2)4CH), 1.91, 1.73, 1.49 & 1.27 (each 2H, m,
CH2CH2CH2CH2), 1.04 (18H, s, 2 × C(CH3)3). 13C NMR
(100 MHz) (CDCl3): 170.16, 135.44, 133.27, 129.60,
129.55, 127.59, 69.97, 67.20, 65.58, 40.08, 29.29, 26.73,
24.79, 19.15. LR-MS: ([M + 1]) 740.
Ligand 8
Diastereomer A
Viscous oil (95 mg, 69%). [α]D +23.8 (c 1.0, CHCl3). H
NMR (400 MHz) (CDCl3): 4.26–4.15 (4H, m, 2 ×
1
OCH2CHN), 3.99 (2H, m, 2 × NCHCH2), 2.75 (2H, dd, J =
13.3, 4.2,
2 × CHCHHSMe), 2.55 (2H, m, 2 ×
CH2CHCHCH2), 2.41 (2H, dd, J = 13.3, 8.1, 2 ×
CHCHHSMe), 2.09 (6H, s, 2 × SCH3), 1.94 and 1.72 (each
2H, m, CH2CH2CH2CH2), 1.48–1.39 and 1.31–1.20 (each
2H, m, CH2CH2CH2CH2). 13C NMR (100 MHz) (CDCl3):
170.11, 71.53, 65.43, 39.68, 39.05, 29.66, 24.80, 15.84. HR-
MS calcd. for C16H27O2N2S2: 343.1514; found: 343.1520.
Diastereomer B
White solid (30 mg). [α]D –21.9 (c 1.65, CHCl3). 1H
NMR (400 MHz) (CDCl3): 7.67–7.62 (8H, m, ArH), 7.44–
7.35 (12H, m, ArH), 4.20–4.12 (6H, m, 2 × OCH2CHN),
3.80–3.77 (2H, m, 2 × CHHOTBDPS), 3.56–3.52 (2H, m,
2 × CHHOTBDPS), 2.53 (2H, m, CH(CH2)4CH), 1.97, 1.72,
1.48 & 1.26 (each 2H, m, CH2CH2CH2CH2), 1.04 (18H, s,
2 × C(CH3)3). 13C NMR (100 MHz) (CDCl3): 170.62,
135.47, 133.27, 129.60, 129.54, 127.59, 127.55, 69.77,
67.29, 65.53, 39.82, 29.75, 26.69, 24.85, 19.14.
Diastereomer B
Viscous oil (70 mg, 70%). [α]D –49 (c 0.51, CHCl3). H
NMR (400 MHz) (CDCl3): 4.26–4.16 (4H, m, 2 ×
1
OCH2CHN), 4.00 (2H, m, 2 × NCHCH2), 2.75 (2H, dd, J =
13.2, 4.3,
2 × CHCHHSMe), 2.54 (2H, m, 2 ×
CH2CHCHCH2), 2.37 (2H, dd, J = 13.3, 8.5, 2 ×
CHCHHSMe), 2.09 (6H, s, 2 × SCH3), 1.94 and 1.74 (each
2H, m, CH2CH2CH2CH2), 1.43–1.38 and 1.31–1.21 (each
2H, m, CH2CH2CH2CH2). 13C NMR (100 MHz) (CDCl3):
170.26, 71.62, 65.38, 39.90, 39.04, 29.68, 24.89, 15.75. HR-
MS calcd. for C16H27O2N2S2: 343.1514; found: 343.1520.
General procedure for ligand–Cu complexes
To a solution of the ligand (0.067 mmol) in anhydrous
CH2Cl2 was added the copper salt (0.06 mmol). The mixture
was stirred until it became homogeneous. Hexanes (0.3–
0.5 mL) were added, and the solution was allowed to stand
2 days at room temperature and several days at 0 °C to af-
ford the crystalline complexes.
Ligand 9
Diastereomer A
Viscous oil (7 mg, 71%). [α]D +95.6 (c 1.5, CHCl3). H
1
Catalytic asymmetric addition of MeLi to an aldimine
(13)
NMR (400 MHz) (CDCl3): 4.23 (2H, dd, J = 9.4, 8.3, 2 ×
OCHHCHN), 4.10 (2H, m, 2 × NCH), 3.79 (2H, t, J = 7.6, 2
× OCHHCHN), 2.60–2.48 (6H, m, 2 × CH2SMe and
CH2CHCHCH2), 2.07 (6H, s, 2 × SCH3), 1.95 (2H, m,
A solution of MeLi (2 equiv., 1.6 mol L–1 Et2O) and
ligand (0.1 equiv.) in toluene was stirred for 30 min at
−41 °C. A solution of N-p-methoxyphenyl benzaldehyde
imine in toluene was added over 10 min. After 60 min stir-
ring at −41 °C, the mixture was quenched with 2 mL metha-
nol. After dilution with water, the organic phase was
extracted with ether and dried over Na2SO4. The product
was purified by flash chromatography (hexanes:EtOAc
85:15). The enantiomeric excesses were measured by chiral
HPLC analysis; OD, l: 210 nm; flow: 0.5 mL min–1; hex-
anes:isopropanol 95:5; with elution times of 18.70 and
20.59 min for a racemic mixture.
CHCHH(CH2)2CHHCH),
1.82–1.65
(6H,
m,
CHCHH(CH2)2CHHCH and 2 × CH2CH2SMe), 1.44–1.37
and 1.30–1.25 (each 2H, m, CH2CH2CH2CH2). 13C NMR
(100 MHz) (CDCl3): 169.37, 71.86, 64.88, 39.92, 35.36,
30.43, 29.87, 24.97, 15.39. HR-MS calcd. for
C18H31O2N2S2: 371.1827; found: 371.1821.
Diastereomer B
Viscous oil (140 mg, 54%). [α]D +53° (c 0.5 CHCl3). H
NMR (400 MHz) (CDCl3): 4.21 (2H, dd, J = 9.5, 8.5, 2 ×
1
© 2004 NRC Canada

Hanessian et al.
313
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Acknowledgments
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) for generous financial assis-
tance through the Medicinal Chemistry Chair Program and
the University of Louvain (fellowship to E.J.).
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© 2004 NRC Canada