Parallel synthesis of modular chiral Schiff base ligands and evaluation in the titatium(IV) catalyzed asymmetric trimethylsilylcyanation of aldehydes

Article abstract of DOI:10.1016/j.tetasy.2005.11.022

Highly modular tridentate Schiff base ligands arising from enantiopure epoxyalcohols have been prepared and evaluated in catalysis using parallel methods. The key structural motifs and experimental parameters have been identified, allowing enantioselectivities of up to 77% ee in the titatium-catalyzed trimethylsilyl cyanide addition to aldehydes.

Full text of DOI:10.1016/j.tetasy.2005.11.022

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 151–160
Parallel synthesis of modular chiral Schiff base ligands
and evaluation in the titatium(IV) catalyzed asymmetric
trimethylsilylcyanation of aldehydes
a
a
b
a,b,
*
`
´
´
´
Belen Rodrıguez, Mireia Pasto, Ciril Jimeno and Miquel A. Pericas
aInstitute of Chemical Research of Catalonia (ICIQ), Av. Pa¨ısos Catalans, 16, E-43007 Tarragona, Spain
b
`
Parc Cientı´fic de Barcelona, Departament de Quı´mica Organica, Universitat de Barcelona, c/Martı i Franques,
´
`
1-11, E-08028 Barcelona, Spain
Received 10 November 2005; accepted 21 November 2005
Available online 9 January 2006
Abstract—Highly modular tridentate Schiff base ligands arising from enantiopure epoxyalcohols have been prepared and evaluated
in catalysis using parallel methods. The key structural motifs and experimental parameters have been identified, allowing enantio-
selectivities of up to 77% ee in the titatium-catalyzed trimethylsilyl cyanide addition to aldehydes.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
through the analysis of ligand libraries prepared by par-
allel methods,4 we turned our attention to the prepara-
tion of modular Schiff base tridentate ligands arising
from the condensation of salicylaldehydes with enantio-
pure amino alcohols. The amino alcohols would be pre-
pared by regioselective and stereospecific ring-opening
of enantiopure epoxyalcohols 1 with nitrogen nucleo-
philes (Scheme 1). These epoxyalcohols, in turn, are
readily available through the catalytic asymmetric
Sharpless epoxidation.5
Enantiomerically pure cyanohydrins are important
intermediates for the preparation of a variety of bio-
logically active compounds, since they can be easily
converted into different functional groups.1 For this
reason, their preparation using catalytic asymmetric
methods has received great attention and continued
interest.2 In particular, the combination of Schiff base
ligands and Ti(IV) Lewis acids has proven to be among
the most active and efficient catalytic systems available
for the cyanation of aldehydes.3
Amino alcohols such as 2 have previously been prepared
in our group and used as ligands for the enantioselective
reduction of ketones with borane,6 for the asymmetric
Ru catalyzed hydrogen transfer to ketones,7 and as start-
ing materials for the preparation of C2-symmetric
bis(oxazolines) for asymmetric allylic alkylation.8 It is
In the context of our research project devoted to the syn-
thesis of modular ligands for asymmetric catalysis from
synthetic, yet enantiopure epoxides, and taking into
account useful chiral catalysts that have been developed
R''
NH2
O
R
N
R
OR'
R
OH
OH
2
OH
R''
OR'
HO
1
Scheme 1. Modular enantiopure Schiff base ligands from epoxyalcohols. In color, controllable sources of structural diversity.
*
Corresponding author. Tel.: +34 977 920 211; fax: +34 977 920 222; e-mail: mapericas@iciq.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.022

152
B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
noteworthy that there are three sources of structural
diversity present in this type of ligands: (i) the protecting
group of the primary alcohol in the starting epoxyalcohol
(H, methyl, benzyl, benzhydryl, trityl, or SiiPr3), (ii) the
substituents on the aromatic ring in the salicylaldehyde
moiety (typically H or tert-butyl), and (iii) the nature of
the substituent (phenyl or n-propyl) at C-3 in the epoxy-
alcohol hydrocarbon chain. The selected motifs cover a
great range of steric and electronic characteristics.
A family of Schiff base ligands was then constructed by
simple condensation reactions using parallel synthesis
methods: an excess of aldehyde was used to ensure com-
plete reaction of amino alcohols 2, while the remaining
unreacted aldehyde was scavenged with a polyamine
resin HL in ꢀtea bagsꢁ, so that not even solid phase extrac-
tion was necessary to isolate the ligands from the
scavenger polymer. In this way, 3a–3f, 4a–4f, 5c, 5e,
6c, and 6e were isolated in quantitative yields with no
need for any conventional purification step (Scheme 3).
2. Results and discussion
With these ligands in hand, their catalytic activity in the
asymmetric cyanide addition to aldehydes was evaluated
using parallel techniques in this case also. The experi-
mental conditions originally developed by Oguni et al.
were used while optimizing the reaction temperature.12
Thus, 20 mol % of Ti(OiPr)4 and ligand were used to
form in situ the active catalyst, and an excess (2.2 equiv)
of TMSCN was added as a source of cyanide. High
throughput sampling of the crude reaction mixtures
containing benzaldehyde cyanohydrin (TMS-protected)
and subsequent GC analysis with a chiral stationary
phase (b-DEX column), allowed conversions and
enantioselectivities to be determined simultaneously
(Fig. 1). The absolute configuration of the cyanohydrins
was determined to be S by comparison of the specific
rotation using their acetyl derivatives, and comparison
with literature data.12
In order to proceed with the synthesis of the target
ligands, the initial ring opening of (2S,3S)-phenylglycidol
and its O-protected derivatives9 was carried out directly
with aqueous ammonia in a sealed tube10 (Scheme 2A).
It should be noted, though, that the ring opening of
(2S,3S)-3-(propyloxiran-2-yl)methanol under the afore-
mentioned conditions was not successful: low conver-
sions were recorded and the process was not
regioselective. Therefore, the corresponding amino alco-
hols had to be synthesized using a somewhat lengthy
approach through the intermediacy of azido alcohols:
Ti(N3)2(OiPr)2 was the reagent of choice for the stereo-
specific and regioselectively ring opening,11 and the
intermediate azido alcohols were subsequently reduced
with LiAlH4 to afford the desired amino alcohols
(Scheme 2B).
20 mol% Ti(OiPr)4
21 mol% L*
The order of the ring opening and primary alcohol pro-
tection steps was adapted so as to avoid interference
with the functional groups that are already present in
the substrate. Thus, the trityl group (triphenylmethyl)
had to be introduced via selective alkylation of the pri-
mary alcohol in the corresponding azido diol, since no
ring opening took place otherwise. On the other hand,
the benzyl group was best introduced on a (2S,3S)-3-
(propyloxiran-2-yl)methanol to ensure site selectivity.
The corresponding ether was then submitted to ring
opening with Ti(N3)2(OiPr)2. In any case, azide reduc-
tion with LiAlH4 was the final step in the sequence,
which allowed the isolation of the desired amino alco-
hols 2 in excellent overall yield.
TMSO CN
Ph
PhCHO + 2.2 eq. Me3SiCN
H
CH2Cl2, T
(S )
As can be readily appreciated, ligands derived from
(2S,3S)-3-(propyloxiran-2-yl)methanols 5–6 (R = n-prop-
yl) exhibited poor catalytic activity and enantioselectiv-
ity. The best example in this series was ligand 5e, which
induced a modest 58% conversion and 64% ee at
ꢀ80 ꢁC. Ligands derived from (2S,3S)-phenylglycidol
(3–4) seemed better suited for this particular reaction.
Within these series, however, imines bearing an unpro-
tected primary alcohol 3a and 4a or a very bulky SiiPr3
group 3f and 4f were still inefficient.
A) Phenyl series
NH2
Refs. 9 and 10
O
Ph
OH
Ph
OR
OH
B) Propyl series
O
1) Ti(N3)2(OiPr)2, tol, reflux 98%
2) [py-CPh3]BF4, CH3CN, r.t.
NH2
OH
OCPh3
OH
2e
3) LiAlH , 60 C
˚
4
55% (2 steps)
NH2
1) PhCH Br, NaH, -20 C
100%
˚
2
O
OCH2Ph
2) Ti(N3)2(OiPr)2, tol, reflux
96%
88%
OH
OH
3) LiAlH , 60 C
˚
4
2c
Scheme 2. Synthesis of the starting amino alcohols.

B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
153
CHO
OH
R''
R''
R''
1)
R''
MeOH or CH2Cl2
NH2
NH2
R
N
R
OR'
OH
OH
2) Polyamine resin HL
HO
OR'
N
3a-f, 4a-f
5c, 5e, 6c, 6e
2
N
H
NH2
R=Ph, R''=H
3a R'=H
3b R'=Me
3c R'=CH2Ph
3d R'=CHPh2
3e R'=CPh3
3f R'=SiiPr3
R=Ph, R''=tBu R=n-Pr
4a R'=H
5c R'=CH2Ph, R''=H
5e R'=CPh3, R''=H
6c R'=CH2Ph, R''=tBu
6e R'=CPh3, R''=tBu
4b R'=Me
4c R'=CH2Ph
4d R'=CHPh2
4e R'=CPh3
4f R'=SiiPr3
Scheme 3. Synthesis of Schiff base ligands 3a–3e, 4a–4e, 5c, 5e, 6c, and 6e.
Conversion [%]
100
90
80
70
60
50
40
30
20
10
0
-25
C
˚
˚
-40
C
-60
-80
C
C
˚
˚
3a
-25
C
3b
3c
˚
3d
3e
3f
4a
4b
4c
4d
-80
C
4e
4f
˚
5c
5e
6c
6e
ee [%]
80
70
60
50
40
30
20
10
0
-25
-40
-60
-80
C
˚
˚
˚
˚
C
C
C
3a
3b
3c
-80
C
3d
3e
˚
3f
4a
4b
4c
4d
4e
-25
C
4f
˚
5c
5e
6c
6e
Figure 1. High throughput screening of modular Schiff base ligands at different temperatures in the cyanide addition to benzaldehyde. In all cases,
the (S)-enantiomer predominates.

154
B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
The most interesting results were recorded for the O-
protected ligands 3b–3e and 4b–4e. Thus, under the opti-
mal reaction temperature, good enantioselectivities, and
high conversions were achieved. These results were
highly dependent on the steric hindrance of the O-pro-
tecting group. In Figure 2, we have graphically repre-
sented these data.
were recorded for ligands 4b and 4e (87% and 90%,
respectively), whereas enantioselectivities in the range
of 70–75% ee were observed in all cases. In terms of effi-
ciency, ligand 4b must be considered as the most suitable
for this reaction within this series of ligands (87% con-
version, 75% ee) at the optimal reaction temperature
(ꢀ40 ꢁC).
It is clear from Figure 2 that, for the 3b–3e series (con-
taining salicylaldehyde as a building block), both the
conversion and enantioselectivity decrease as the bulki-
ness of the O-protecting group increases from methyl
to trityl. Thus, 3b (R0 = Me) is the best catalyst in the
series, affording 82% conversion and 73% ee in the
asymmetric addition of trimethylsilylcyanide to benz-
aldehyde under optimal conditions (ꢀ60 ꢁC, 3.5 days).
In the case of the 4b–4e series (containing the 3,5-
di-tert-butylsalicylaldehyde moiety), higher conversions
It is worth mentioning that both the best matches for the
catalytic asymmetric cyanation of benzaldehyde (ligands
3b and 4b) present a very similar catalytic behavior
regardless of the completely different steric hindrance
at the salicylaldehyde moiety. This trend indicates that
this part of the ligand does not affect either the catalyst
structure or activity,13 and that the enantioselective step
(the cyanide addition) does not take place through the
spatial region of the Ti(IV)–Schiff base complex occu-
pied by this moiety. Conversely, it was suggested that
the methoxy group in the ligand may play an important
role in the activity of the catalyst. According to the
model proposed by Oguni12b and more recent structural
and mechanistic considerations,14–16 it may be possible
that an oxygen-assisted, intramolecular cyanide delivery
to the coordinated aldehyde takes place.16 In that case,
the neighboring group participation of the methoxy
group would help release the cyanide on the Si face of
the titanium-coordinated aldehyde through hydrogen-
bonding stabilization of the approaching hydrogen cya-
nide molecule (Fig. 3).
Conversion [%]
90
80
70
60
50
40
30
20
10
The aldehyde, in turn, would adopt the necessary anti
coordination mode by steric repulsion minimization
with the phenyl group of the amino alcohol. This model
also justifies the small effect (if any) on the enantioselec-
tivity of the bulky subtituents at the salicylaldehyde
moiety.
4
0
b
3
To test the scope of its applicability, ligand 4b was then
used in the asymmetric cyanide addition to a representa-
tive family of aldehydes. Aromatic aldehydes with diverse
substituents placed at different positions at the aromatic
ring were tested, as well as some aliphatic aldehydes.
Results are summarized in Table 1. Conversions were
high in all cases, with the best enantioselectivities being
recorded for the o-methyl and o-chloro derivatives and
for benzaldehyde (73–77% ee; entries 1, 2, and 6). Good
enantioselectivities (66–68% ee) were also obtained for
the fluorine containing benzaldehydes (entries 8–10).
c
d
e
ee [%]
80
70
60
50
40
30
20
10
0
Ph
H
O
Ph
O
N
X
4
R2
O
N
b
Ti
O
3
c
d
O
e
O
Figure 2. Optimized conversions and ees for ligands 3b–3e and 4b–4e.
Ligands 3b–3e: ꢀ60 ꢁC, 3.5 days. Ligand 4b: ꢀ40 ꢁC, 4 days. Ligands
4c and 4d: ꢀ80 ꢁC, 7 days. Ligand 4e: ꢀ60 ꢁC, 3.5 days. In all cases the
S enantiomer predominates.
Figure 3. Model for the cyanide addition mediated by neighboring
group participation. X = H or Me3Si.

B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
155
Table 1. Catalytic asymmetric addition of TMSCN to a family of aldehydes using ligand 4b
Ph
20 mol% Ti(OiPr)4, 20 mol% 4b
TMSO CN
t-Bu
MeO
N
RCHO
R
H
TMSCN, CH2Cl2, -40 C, 4 days
˚
OH
4b
HO
t-Bu
Entry
1
RCHO
Conv (%)
87
ee (%)
CHO
75
73
CHO
2
3
4
5
6
7
8
9
100
100
96
Me
CHO
52
48
40
77
53
68
66
OMe
CHO
MeO
CHO
98
NC
CHO
98
Cl
CHO
99
Cl
CHO
100
99
F
CHO
F
CHO
10
11
12
100
97
68
67
28
F
Ph
CHO
77
CHO
For the rest of the aromatic aldehydes, enantioselectivi-
ties were in the range of 40–52% ee, while for the two
aliphatic aldehydes tested, a reasonable 67% ee was
recorded in the case of phenylacetaldehyde while
only 28% ee was achieved for pivalaldehyde (entries 11
and 12).
using parallel synthesis methods and high throughput
screening. Enantioselectivities up to 77% have been
achieved in the asymmetric cyanation of aldehydes cat-
alyzed by Ti(OiPr)4. Analysis of the results obtained
with diversely substituted ligands allows the formulation
of a working hypothesis on the mechanism of cyanide
delivery. Research aimed at the synthesis and evaluation
of a second generation of modular imines, characterized
by increased basicity at the primary alcohol site and
modified steric characteristics of the skeletal C-3 substi-
tuent is currently under way in our laboratory and will
be reported in due course.
3. Conclusion
In conclusion, a new family of modular tridentate chiral
Schiff base ligands has been constructed and evaluated

156
B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
4. Experimental
4.2.1.2. Attempted ring-opening of (2S,3S)-2-triphen-
ylmethoxymethyl-3-propyloxirane. (2S,3S)-2-Triphenyl-
methoxiymethyl-3-propyloxirane (100 mg, 0.279 mmol)
in 2 mL of toluene was added via canula to a hot suspen-
sion (75 ꢁC) of 83 mg (0.330 mmol) of Ti(N3)2(OiPr)2 in
3 mL of toluene, prepared in a flame-dried flask under
nitrogen. After 60 min, the reaction was allowed to cool
down to rt, and the solvent removed under vacuum. The
resulting mixture was treated with 10 mL of Et2O and
4 mL of 5% aq H2SO4, and stirred until two clear phases
separated. The aqueous phase was extracted with
3 · 10 mL of Et2O, and the combined organic extracts
dried over MgSO4. The starting material was recovered
in an almost quantitative yield.
4.1. General
Optical rotations were measured at 23 ꢁC (concentration
in g/100 mL). Melting points were determined in open
capillary tubes and are uncorrected. IR spectra were
recorded as film between NaCl plates or by KBr pellet
1
techniques. H and 13C NMR spectra were recorded in
CDCl3 solution. Carbon multiplicities have been
assigned by distortionless enhancement by polarization
transfer (DEPT) experiments. Elemental analyses were
`
carried out by the Servei d’Analisis Elementals del
CSIC de Barcelona. CH2Cl2 was distilled from
CaH2 and stored under N2 prior to use. Toluene was
distilled from Na wire and stored under N2 prior to
use. THF was freshly distilled from Na/benzophenone
under N2. All reagents were purchased from Aldrich
or Acros, and used without purification unless other-
wise stated. Polyamine resin HL was purchased from
Novabiochem.
4.2.2. Synthesis of 2e through a ring-opening plus
protection strategy
4.2.2.1. Preparation of (2R,3R)-3-azido-1-triphenyl-
methoxyhexan-2-ol. (2R,3R)-3-Azidohexan-1,2-diol (330
mg, 2.09 mmol) was dissolved in 4 mL of acetonitrile
(HPLC grade) under a nitrogen atmosphere. A solution
of 1.00 g (2.44 mmol) of N-triphenylmethylpyridinium
tetrafluoroborate in 2 mL of acetonitrile was then added
via canula, and the resulting mixture stirred at rt for
4 days. The reaction was quenched with 10 mL of Et2O
and the precipitates removed by filtration. The solvents
were then removed in vacuo, and the reaction crude puri-
fied by flash chromatography on silica gel (2.5% Et3N by
volume) eluting with mixtures of hexane–ethyl acetate
99:1–93:7. The tritylated azido alcohol was isolated
(800 mg) as a colorless oil, and used in the next step with-
(2S,3S)-Phenylglycidol and (2S,3S)-3-(propyloxiran-2-
yl)methanol are known compounds and were prepared
according to the Sharpless epoxidation procedure.5 Phen-
ylglycidol ethers have been previously describe.9
(2S,3S)-3-(Propyloxiran-2-yl)methanol O-benzyl ether
was prepared according to the literature methods,17 as
well as (2R,3R)-3-azido-hexan-1,2-diol11 and Ti(N3)2-
(OiPr)2.18
1
4.2. Synthesis of amino alcohol 2e
out further purification. H NMR (400 MHz, CDCl3): d
0.88 (t, J = 7.0 Hz, 3H), 1.22–1.55 (m, 4H), 2.65 (br s,
1H), 3.26–3.33 (m, 2H), 3.39 (m, 1H), 3.66 (m, 1H),
7.17–7.28 (m, 15H) ppm. 13C NMR (100 MHz, CDCl3):
d 13.7 (CH3), 19.3 (CH2), 31.8 (CH2), 63.8 (CH), 64.2
(CH2), 72.6 (CH), 87.0 (C), 127.1 (CH), 127.8 (CH),
128.5 (CH), 143.5 (C) ppm.
4.2.1. Attempted synthesis of 2e through a protection plus
ring-opening strategy
4.2.1.1. Preparation of (2S,3S)-2-triphenylmethoxy-
methyl-3-propyloxirane. (2S,3S)-3-Propyl-2,3-epoxypro-
pan-1-ol (0.49 g, 4.22 mmol) was dissolved in 8 mL of
acetonitrile (HPLC grade) under an N2 atmosphere. A
solution of 2.10 g (5.13 mmol) of triphenylmethylpyridi-
nium tetrafluoroborate in 2 mL of acetonitrile was the
added via canula, and the resulting mixture stirred at
room temperature for 72 h. Then, the reaction was
quenched with 15 mL of diethyl ether and precipitates
were removed by vacuum filtration. The crude product
obtained after removal of the solvent was purified by
flash chromatography on silica gel (2.5% Et3N by vol-
ume) eluting with a mixture of hexane–ethyl acetate 98:2.
4.2.2.2. Preparation of (2R,3R)-3-amino-1-triphenyl-
methoxyhexan-2-ol, 2e. LiAlH4 (260 mg, 6.51 mmol)
was suspended in 10 mL of anhydrous THF in a flame-
dried flask, under a nitrogen atmosphere. A solution of
800 mg (0.50 mmol) of (2R,3R)-3-azido-1-triphenylmeth-
oxyhexan-2-ol in 10 mL of anhydrous THF was then
added via canula, and the mixture heated at 65 ꢁC for
4 h. The reaction was quenched and after applying the
same work up and purification than in the previous rec-
ipe, 390 mg (55% yield for two steps-tritylation and
reduction) of product were isolated as a colorless oil.
½aꢁ2D3 = ꢀ18.8 (c 5.6, CHCl3). IR (film, mmax/cmꢀ1):
3370, 2958, 2930, 2872, 1491, 1449, 1477, 1033. 1H
NMR (400 MHz, CDCl3): d 0.84 (t, J = 7.0 Hz, 3H),
1.05–1.45 (m, 4H), 2.85 (m, 1H), 3.16 (dd, J = 9.6 Hz,
J0 = 6.0 Hz, 1H), 3.34 (dd, J = 9.6 Hz, J0 = 4.0 Hz,
1H), 3.59 (m, 1H), 7.47 (m, 5H) ppm. 13C NMR
(100 MHz, CDCl3): d 14.0 (CH3), 19.4 (CH2), 35.2
(CH2), 53.3 (CH), 64.5 (CH2), 73.1 (CH), 86.7 (C),
126.9 (CH), 127.7 (CH), 128.5 (CH), 143.8 (C) ppm.
MS (CI, CH4) m/z: 376 (1.3%, C25H29NO2ÆH+), 243
(100%, CPh3+). HRMS (CI) calculated for C25H29-
NO2ÆH+ (M++1): 376.2277. Found: 376.2293.
The product was isolated as a colorless oil (0.71 g, 61%
23
yield). ½aꢁD = ꢀ3.8 (c 1.0, CHCl3). IR (film, mmax/cmꢀ1):
3058, 3023, 2959, 2930, 2871, 1491, 1448, 1220, 1074,
1032, 902, 763, 747. 1H NMR (400 MHz, CDCl3): d
0.95 (m, 3H), 1.40–1.58 (m, 4H), 2.80 (m, 1H), 2.92 (m,
1H), 3.14 (dd, J = 10.6 Hz, J0 = 5.4 Hz, 1H), 3.25 (dd,
J = 10.6 Hz, J0 = 3.4 Hz, 1H), 7.20–7.32 (m, 9H),
7.44–7.47 (m, 6H) ppm. 13C NMR (100 MHz, CDCl3):
d 13.8 (CH3), 18.9 (CH2), 33.4 (CH2), 55.8 (CH),
56.7 (CH), 64.3 (CH2), 86.3 (C), 126.7 (CH), 127.5
(CH), 128.3 (CH), 143.6 (C) ppm. MS (CI, NH3) m/z:
358 (1%, C25H26O2+), 243 (100%, CPh3+). HRMS (CI)
calculated for C25H26O2 (M+): 358.1933. Found:
358.1928.

B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
157
4.3. Synthesis of amino alcohol 2c using a protection plus
ring-opening strategy
filtered through a pack of Celiteꢂ and the solvent was
removed in vacuo. Excess aldehyde was then removed
by redisolving the crude in 5 mL of CH2Cl2 and scavenging
it with 250 mg of polyamine resin HL (Novabiochemꢂ)
in tea bags. Isolated yields were P95% in all cases.
4.3.1. Preparation of (2R,3R)-3-azido-1-benzyloxyhexan-
2-ol. (2S,3S)-2-Benzyloximethyl-3-propyloxirane (220
mg, 1.10 mmol) in 5.5 mL of toluene was added via can-
ula to a hot suspension (75 ꢁC) of 310 mg (1.20 mmol) of
Ti(N3)2(OiPr)2 in 10 mL of toluene, prepared in a flame-
dried flask under nitrogen. After 60 min, the reaction
was allowed to cool down to rt, and the solvent removed
under vacuum. The resulting mixture was treated with
20 mL of Et2O and 8 mL of 5% aq H2SO4, and stirred
until two clear phases separated. The aqueous phase
was extracted with 3 · 10 mL of Et2O and the combined
organic extracts dried over MgSO4. The product was
isolated after removal of the volatiles in 96% yield
4.4.1. (2R,3R)-3-(N-Salicyliden)-amino-3-phenylpropan-
23
1,2-diol, 3a. ½aꢁD = +111.4 (c 1.0, CHCl3). Mp 88–
91 ꢁC. IR (film, mmax/cmꢀ1): 3400, 3058, 3026, 2926,
2877, 1628, 1581, 1494, 1453, 1277, 1051, 757. 1H
NMR (400 MHz, CDCl3): d 3.50 (dd, J = 11.3 Hz,
J0 = 6.2 Hz, 1H), 3.62 (d, J = 11.1 Hz, 1H), 4.00 (m,
1H), 4.39 (d, J = 6.6 Hz, 1H), 6.82 (dd, J = 7.4 Hz,
J0 = 7.4 Hz, 1H), 6.91 (d, J = 8.3 Hz, 1H), 7.16 (d,
J = 7.6 Hz, 1H), 7.32–7.32 (m, 6H), 8.28 (s, 1H),
12.90–13.80 (br s, 1H) ppm. 13C NMR (100 MHz,
CDCl3): d 62.6 (CH2), 75.0 (CH), 75.1 (CH), 117.0
(CH), 118.5 (C), 118.7 (CH), 127.5 (CH), 127.7 (CH),
128.7 (CH), 131.8 (CH), 132.7 (CH), 139.4 (C), 161.2
(C), 166.2 (CH). MS (CI, CH4) m/z: 272 (100%,
(260 mg), and used in the next step without further puri-
23
fication. ½aꢁD = +3.2 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): d 0.95 (t, J = 7.0 Hz, 3H), 1.67–
1.32 (m, 4H), 2.57 (br s, 1H), 3.44 (m, 1H), 3.57 (dd,
J = 9.6 Hz, J0 = 6.4 Hz, 1H), 3.61 (dd, J = 9.6 Hz,
J0 = 3.6 Hz, 1H), 3.75 (m, 1H), 4.56 (d, J = 11.8 Hz,
1H), 4.60 (d, J = 11.8 Hz, 1H), 7.30–7.40 (m, 5H)
ppm. 13C NMR (100 MHz, CDCl3): d 13.7 (CH3), 19.4
(CH2), 32.3 (CH2), 63.9 (CH), 70.8 (CH2), 72.4 (CH),
73.1 (CH2), 127.75 (CH), 127.82 (CH), 128.4 (CH),
137.5 (C) ppm.
C16H17NO3ÆH+).
HRMS
(CI)
calculated
for
C16H17NO3ÆH+ (M++1): 272.1287. Found: 272.1292.
4.4.2. (1R,2R)-1-(N-Salicyliden)-amino-1-phenyl-3-meth-
23
oxypropan-2-ol, 3b. ½aꢁD = +114.9 (c 1.0, CHCl3). Mp
103–107 ꢁC. IR (film, mmax/cmꢀ1): 3450, 3062, 2929,
2829, 2850, 1629, 1578, 1495, 1457, 1277, 1147, 762.
1H NMR (400 MHz, CDCl3): d 13.60–12.90 (br s, 1H),
8.43 (s, 1H), 7.43–7.25 (m, 7H), 6.98 (d, J = 8.4 Hz,
1H), 6.88 (ddd, J = 7.5 Hz, J0 = 7.5 Hz, J00 = 0.9 Hz,
1H), 4.53 (d, J = 6.4 Hz, 1H), 4.20 (ddd, J = 6.4 Hz,
J0 = 6.3 Hz, J00 = 3.1 Hz, 1H), 3.52 (dd, J = 9.8 Hz,
J0 = 3.1 Hz, 1H), 3.46 (dd, J = 9.8, J0 = 6.3 Hz, 1H),
3.34 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): d
166.3 (CH), 161.0 (C), 139.5 (C), 132.7 (CH), 131.7
(CH), 128.8 (CH), 127.8 (CH), 127.5 (CH), 118.8 (C),
116.9 (CH), 75.4 (CH), 73.9 (CH), 72.6 (CH2), 59.1
(CH3) ppm. MS (CI, NH3) m/z: 286 (100%,
4.3.2. Preparation of (2R,3R)-3-amino-1-benzyloxy-
hexan-2-ol, 2c. LiAlH4 (33 mg, 0.83 mmol) was sus-
pended in 6 mL of anhydrous THF in a flame-dried
flask, under nitrogen atmosphere.
A solution of
124 mg (0.50 mmol) of (2R,3R)-3-azido-1-benzyloxi-
hexan-2-ol in 6 mL of THF was slowly added via
canula, and the reaction was heated to 60 ꢁC for 1 h.
After cooling to rt, 1.5 mL of methanol and 2 mL of
water were successively added dropwise to quench the
reaction. After diluting with more water, the mixture
was extracted with CH2Cl2 (3 · 10 mL), and the com-
bined organic extracts dried over MgSO4, and the sol-
vents removed in vacuo. The crude was purified by
flash chromatography on silica gel (2.5% Et3N by vol-
ume) eluting with mixtures of CH2Cl2–MeOH 97:3 to
C17H19NO3ÆH+).
HRMS
(CI)
calculated
for
C17H19NO3ÆH+ (M++1): 286.1443. Found: 286.1431.
4.4.3. (1R,2R)-1-(N-Salicyliden)-amino-3-benzyloxy-1-
23
phenylpropan-2-ol, 3c. ½aꢁD = +53.3 (c 0.8, CHCl3). IR
(film, mmax/cmꢀ1): 3490, 3062, 3031, 2947, 2865, 1630,
1582, 1495, 1455, 1279, 1117, 756. 1H NMR
(400 MHz, CDCl3): d 3.58 (dd, J = 9.8 Hz, J0 = 5.9 Hz,
1H), 3.63 (dd, J = 9.8, J00 = 3.2 Hz, 1H), 4.36 (m, 1H),
4.51 (m, 3H), 6.88 (ddd, J = 7.5 Hz, J0 = 7.4 Hz,
J00 = 1.0 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 7.22–7.42
(m, 12H), 8.39 (s, 1H), 13.25 (br s, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d 70.4 (CH2), 73.5 (CH2),
73.9 (CH), 75.4 (CH), 116.9 (CH), 118.7 (C), 127.6
(CH), 127.7 (CH), 127.8 (CH), 128.3 (CH), 128.7
(CH), 131.7 (CH), 132.6 (CH), 137.6 (C), 139.5 (C),
160.9 (C), 166.1 (CH) ppm. MS (CI, NH3) m/z: 362
(23%, C23H23NO3ÆH+), 361 (100%, C23H23NO3+).
HRMS (CI) calculated for C23H23NO3ÆH+ (M++1):
362.1756. Found: 362.1751.
afford 98 mg (88% yield) of the desired product.
23
½aꢁD = ꢀ11.5 (c 4.1, CHCl3). IR (film, mmax/cmꢀ1):
3362, 2957, 2929, 2870, 1587, 1496, 1454, 1364, 1101,
738. 1H NMR (400 MHz, CDCl3): d 0.92 (t, J =
6.8 Hz, 3H), 1.20–1.55 (m, 4H), 1.90 (br s, 3H), 2.91
(m, 1H), 3.55–3.65 (m, 2H), 3.68 (m, 1H), 4.55 (s, 2H),
7.29–7.36 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3):
d 14.0 (CH3), 19.4 (CH2), 35.0 (CH2), 53.3 (CH), 71.4
(CH2), 72.8 (CH), 73.3 (CH2), 127.6 (CH), 128.3 (CH),
137.9 (C) ppm. MS (CI, CH4) m/z: 224 (100%,
C13H21NO2ÆH+).
HRMS
(CI)
calculated
for
C13H21NO2ÆH+ (M++1): 224.1651. Found: 224.1652.
4.4. General method for the preparation of chiral Schiff
base ligands
Amino alcohol (1 mmol) and aldehyde (1.1 mmol) were
mixed in 5 mL of MeOH with Na2SO4 and stirred at
reflux for 4–80 h. After cooling to rt, the reaction was
4.4.4.
(1R,2R)-1-(N-Salicyliden)-amino-1-phenyl-3-di-
23
phenylmethoxypropan-2-ol, 3d. ½aꢁD = +29.4 (c 1.0,
CHCl3). IR (film, mmax/cmꢀ1): 3568, 3460, 3061, 3028,

158
B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
2918, 2868, 1629, 1581, 1494, 1453, 1278, 757. 1H NMR
(400 MHz, CDCl3): d 2.35 (br s, 1H), 3.57 (dd,
J = 9.9 Hz, J0 = 5.4 Hz, 1H), 3.63 (dd, J = 9.9 Hz,
J0 = 3.3 Hz, 1H), 4.25 (m, 1H), 4.55 (d, J = 7.1 Hz,
1H), 5.33 (s, 1H), 6.87 (ddd, J = 7.5 Hz, J0 = 7.4 Hz,
J00 = 1.0 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 7.17–7.41
(m, 17H), 8.37 (s, 1H), 13.15 (br s, 1H) ppm. 13C
NMR (75 MHz, CDCl3): d 69.6 (CH2), 74.2 (CH),
75.6 (CH), 84.4 (CH), 116.9 (CH), 118.7 (C),
118.8 (CH), 126.5 (CH), 126.8 (CH), 127.0 (CH), 127.5
(CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 127.40
(CH), 128.41 (CH), 128.5 (CH), 128.7 (CH), 131.7
(CH), 132.6 (CH), 139.6 (C), 141.5 (C), 141.7
(C), 160.9 (C), 166.1 (CH) ppm. MS (CI, NH3) m/z:
438 (100%, C29H27NO3ÆH+). HRMS (CI) calcu-
lated for C29H27NO3ÆH+ (M++1): 438.2069. Found:
438.2067.
9H), 1.48 (s, 9H), 2.36–2.82 (br s, 2H), 3.65 (dd,
J = 11.4, J0 = 5.8 Hz, 1H), 3.78 (dd, J = 11.4,
J0 = 2.6 Hz, 1H), 4.12 (m, 1H), 4.46 (d, J = 7.6 Hz,
1H), 7.10 (d, J = 2.4 Hz, 1H), 7.30 (m, 1H), 7.36–7.44
(m, 5H), 8.44 (s, 1H), 13.50 (br s, 1H). 13C NMR
(100 MHz, CDCl3): d 29.4 (CH3), 31.4 (CH3), 34.1 (C),
35.0 (C), 63.0 (CH2), 75.2 (CH), 75.4 (CH), 117.8 (C),
126.4 (CH), 127.5 (CH), 127.8 (CH), 127.9 (CH), 128.8
(CH), 136.7 (C), 139.7 (C), 140.4 (C), 157.9 (C), 167.6
(CH). MS (CI, CH4) m/z: 384 (100%, C24H33NO3ÆH+),
383 (32%, C24H33NO3+). HRMS (CI) calculated for
C24H33NO3ÆH+ (M++1): 384.2539. Found: 384.2533.
4.4.8. (1R,2R)-1-(N-30,50-Di-tert-butylsalicyliden)-amino-
23
1-phenyl-3-methoxypropan-2-ol, 4b. ½aꢁD = +90.6 (c 0.7,
CHCl3). IR (film,
m
max/cmꢀ1): 3450, 2958, 2900,
2867, 1628, 1600, 1443, 1250, 1147, 758. 1H NMR
(400 MHz, CDCl3): d 1.29 (s, 9H), 1.46(s, 9H), 3.36 (s,
3H), 3.48 (dd, J = 9.8 Hz, J0 = 6.4 Hz, 1H), 3.54 (dd,
J = 9.8, J0 = 3.1 Hz, 1H), 4.23 (ddd, J = 6.6 Hz,
J0 = 6.5 Hz, J00 = 3.1 Hz, 1H), 4.50 (d, J = 6.9 Hz, 1H),
7.09 (d, J = 2.5 Hz, 1H), 7.27–7.45 (m, 6H), 8.43 (s,
1H), 13.50 (br s, 1H) ppm. 13C NMR (75 MHz, CDCl3):
d 29.4 (CH3), 31.4 (CH3), 34.1 (C), 35.0 (C), 59.1 (CH3),
72.8 (CH2), 73.9 (CH), 75.6 (CH), 117.9 (C), 126.4 (CH),
127.4 (CH), 127.66 (CH), 127.73 (CH), 128.7 (CH),
136.7 (C), 139.8 (C), 140.3 (C), 158.0 (C), 167.3 (CH)
ppm. MS (CI, NH3) m/z: 398 (28%, C25H35NO3ÆH+),
397 (100%, C25H35NO3+). HRMS (CI) calculated for
C25H35NO3ÆH+ (M++1): 398.2695. Found: 398.2702.
4.4.5. (1R,2R)-1-(N-Salicyliden)-amino-1-phenyl-3-triiso-
23
propylsilyloxypropan-2-ol, 3f. ½aꢁD = +51.6 (c 1.2,
CHCl3). IR (film, mmax/cmꢀ1): 3500, 2942, 2890, 2866,
1630, 1494, 1462, 1277, 1119, 883, 755. 1H NMR
(400 MHz, CDCl3): d 1.00–1.10 (m, 21H), 2.66 (br s,
1H), 3.77 (dd, J = 10.2 Hz, 6.0 Hz, 1H), 3.83 (dd,
J = 10.2 Hz, 3.6 Hz, 1H), 4.37 (m, 1H), 4.54 (d,
J = 6.8 Hz, 1H), 6.87 (ddd, J = 7.5 Hz, J0 = 7.5 Hz,
J00 = 1.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 7.22–7.43
(m, 7H), 8.43 (s, 1H), 13.25 (br s, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d 11.8 (CH), 17.9 (CH3), 63.6
(CH2), 75.0 (CH), 75.1 (CH), 116.9 (CH), 118.7 (C),
118.8 (CH), 127.6 (CH), 127.7 (CH), 128.7 (CH), 131.7
(CH), 132.6 (CH), 139.7 (C), 161.0 (C), 166.2 (CH)
ppm. MS (CI, CH4) m/z: 428 (47%, C25H37NO3SiÆH+),
427 (35%, C25H37NO3Si+), 384 (37%, [C25H37NO3SiÅ–
(CH(CH3)2)]+). HRMS (CI) calculated for C25H37NO3-
SiÆH+ (M++1): 428.2647. Found: 428.2612.
4.4.9. (1R,2R)-1-(N-30,50-Di-tert-butylsalicyliden)-amino-
23
3-benzyloxy-1-phenylpropan-2-ol, 4c. ½aꢁD = +40.6 (c
1.8, CHCl3). IR (film, mmax/cmꢀ1): 3430, 3031, 2958,
2919, 2869, 1629, 1472, 1452, 1250, 1094, 1065, 735.
1H NMR (400 MHz, CDCl3): d 1.29 (s, 9H), 1.46 (s,
9H), 4.26 (m, 1H), 4.47 (d, J = 11.8 Hz, 1H), 4.51 (d,
J = 6.9 Hz, 1H), 4.56 (d, J = 11.8 Hz, 1H), 7.06 (d,
J = 2.5 Hz, 1H), 7.26–7.43 (m, 11H), 8.40 (s, 1H),
13.45 (br s, 1H) ppm. 13C NMR (75 MHz, CDCl3): d
29.4 (CH3), 31.4 (CH3), 35.0 (C), 70.5 (CH2), 73.4
(CH2), 74.0 (CH), 75.5 (CH), 117.9 (C), 126.3 (CH),
127.3 (CH), 127.68 (CH), 127.74 (CH), 127.8 (CH),
128.4 (CH), 128.7 (CH), 136.6 (C), 137.7 (C), 139.8
(C), 140.2 (C), 157.9 (C), 167.3 (CH) ppm. MS (CI,
NH3) m/z: 475 (34%, C31H39NO3ÆH+), 474 (100%,
4.4.6.
(1R,2R)-1-(N-Salicyliden)-amino-1-phenyl-3-tri-
23
phenylmethoxypropan-2-ol, 3e. ½aꢁD = +27.9 (c 1.0,
CHCl3). IR (film, mmax/cmꢀ1): 3450, 3059, 3031, 2930,
2876, 1629, 1582, 1492, 1449, 1278, 1064, 757. 1H
NMR (400 MHz, CDCl3): d 2.18 (m, 1H), 3.16 (dd,
J = 10.0 Hz, J0 = 4.9 Hz, 1H), 3.40 (dd, J = 10.0 Hz,
J0 = 3.4 Hz, 1H), 4.08 (m, 1H), 4.58 (d, J = 7.3 Hz,
1H), 6.85 (ddd, J = 7.5 Hz, J0 = 7.5, J00 = 1.0 Hz, 1H),
6.91 (d, J = 8.3 Hz, 1H), 7.11–7.40 (m, 22H), 8.32 (s,
1H), 12.98 (br s, 1H) ppm. 13C NMR (100 MHz,
CDCl3): d 63.7 (CH2), 74.4 (CH), 75.6 (CH), 86.8 (C),
116.8 (CH), 118.60 (CH), 118.62 (C), 127.0 (CH),
127.47 (CH), 127.71 (CH), 127.74 (CH), 127.8 (CH),
127.9 (CH), 128.54 (CH), 128.6 (CH), 131.7 (CH),
132.5 (CH), 139.6 (C), 143.6 (C), 160.9 (C), 165.9
(CH) ppm. MS (CI, CH4) m/z: 514 (1%,
C35H31NO3ÆH+), 243 (100%, CPh3+). HRMS (CI) calcu-
lated for C35H31NO3ÆH+ (M++1): 514.2382. Found:
514.2387.
C31H39NO3+).
HRMS
(CI)
calculated
for
C31H39NO3ÆH+ (M++1): 474.3008. Found: 474.3017.
4.4.10. (1R,2R)-1-(N-30,50-Di-tert-butylsalicyliden)-amino-
23
1-phenyl-3-diphenylmethoxypropan-2-ol,
4d. ½aꢁD
=
/
+34.2 (c 1.0, CHCl3). Mp 64–66 ꢁC. IR (film, mmax
cmꢀ1): 3437, 3029, 2958, 2907, 2868, 1627, 1468, 1453,
1
1250, 1089, 1064, 758. H NMR (400 MHz, CDCl3): d
1.29 (s, 9H), 1.44 (s, 9H), 2.33 (br s, 1H), 3.60 (dd,
J = 10.0, J0 = 5.5 Hz, 1H), 3.66 (dd, J = 10.0,
J0 = 3.3 Hz, 1H), 4.28 (m, 1H), 4.52 (d, J = 7.2 Hz,
1H), 5.34 (s, 1H), 7.02 (d, J = 2.0 Hz, 1H), 7.20–7.40
(m, 16H), 8.37 (s, 1H), 13.40 (br s, 1H) ppm. 13C
NMR (100 MHz, CDCl3): d 29.4 (CH3), 31.5 (CH3),
34.1 (C), 35.0 (C), 69.7 (CH2), 74.1 (CH), 75.6 (CH),
84.3 (CH), 117.8 (C), 126.3 (CH), 126.8 (CH), 127.0
(CH), 127.3 (CH), 127.5 (CH), 127.6 (CH), 127.7
4.4.7. (2R,3R)-3-(N-30,50-Di-tert-butylsalicyliden)-amino-
23
3-phenylpropan-1,2-diol, 4a. ½aꢁD = +81.0 (c 1.0,
CHCl3). Mp 75–76 ꢁC. IR (film, mmax/cmꢀ1): 3395,
2959, 2905, 2870, 1627, 1599, 1468, 1441, 1250, 1173,
1053, 759. 1H NMR (400 MHz, CDCl3): d 1.31 (s,

B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
159
(CH), 127.8 (CH), 128.4 (CH), 128.7 (CH), 136.6 (C),
139.9 (C), 140.2 (C), 141.6 (C), 141.8 (C), 157.9 (C),
167.3 (CH) ppm. MS (CI, NH3) m/z: 549 (100%,
C37H43NO3+), 550 (40%, C37H43NO3ÆH+). HRMS (CI)
calculated for C37H43NO3ÆH+ (M++1): 550.3347.
Found: 550.3333.
165.3 (CH) ppm. MS (CI, CH4) m/z: 328 (7%,
C20H25NO3ÆH+), 327 (8%, C20H25NO3), 177 (31%,
C11H14NOÆH+).
HRMS
(CI)
calculated
for
C20H25NO3ÆH+ (M++1): 328.1913. Found: 328.1914.
4.4.14.
(2R,3R)-3-(N-Salicyliden)-amino-1-triphenyl-
23
methoxyhexan-2-ol, 5e. ½aꢁD = ꢀ19.0 (c 1.0, CHCl3).
IR (film, mmax/cmꢀ1): 3455, 3058, 2957, 2930, 2871,
1630, 1582, 1491, 1448, 1278, 1074, 758. 1H NMR
(400 MHz, CDCl3): d 0.88 (t, J = 7.4 Hz, 3H), 1.10–
1.34 (m, 2H), 1.54 (m, 1H), 1.78 (m, 1H), 2.35 (br
s, 1H), 3.11 (dd, J = 10.0 Hz, J0 = 5.6 Hz, 1H), 3.32
(m, 1H), 3.37 (dd, J = 10.0 Hz, J0 = 3.0 Hz, 1H), 3.74
(m, 1H), 6.86 (dd, J = 7.6 Hz, J0 = 7.6 Hz, 1H), 6.90
(d, J = 8.4 Hz, 1H), 7.14–7.89 (m, 17H), 8.19 (s, 1H),
12.95 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3): d
13.8 (CH3), 19.2 (CH2), 34.3 (CH2), 64.2 (CH2), 71.8
(CH), 73.3 (CH), 86.8 (C), 116.9 (CH), 118.4 (CH),
118.5 (C), 127.1 (CH), 127.9 (CH), 128.5 (CH), 131.4
(CH), 132.2 (CH), 143.6 (C), 161.1 (C), 165.1 (CH)
ppm. MS (CI, CH4) m/z: 480 (6%, C32H33NO3ÆH+),
243 (100%, CPh3+). HRMS (CI) calculated for
C32H33NO3ÆH+ (M++1): 480.2539. Found: 480.2532.
4.4.11. (1R,2R)-1-(N-30,50-Di-tert-butylsalicyliden)-amino-
23
1-phenyl-3-triphenylmethoxypropan-2-ol,
4e. ½aꢁD
=
+19.8 (c 1.0, CHCl3). IR (film, mmax/cmꢀ1): 3375, 3060,
3031, 2957, 2870, 1628, 1597, 1468, 1448, 1250, 1064,
1
760. H NMR (400 MHz, CDCl3): d 1.27 (s, 9H), 1.43
(s, 9H), 2.47 (d, J = 4.4 Hz, 1H), 3.16 (dd, J = 10.0,
J0 = 5.4 Hz, 1H), 3.41 (dd, J = 10.0 Hz, J0 = 3.2 Hz,
1H), 4.20–4.33 (m, 1H), 4.54 (d, J = 6.8 Hz, 1H), 6.93
(d, J = 2.8 Hz, 1H), 7.16–7.40 (m, 47H), 8.32 (s, 1H),
13.20 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3): d
29.4 (CH3), 31.4 (CH3), 34.0 (C), 35.0 (C), 64.2 (CH2),
74.5 (CH), 75.6 (CH), 86.8 (C), 117.8 (C), 126.3 (CH),
127.0 (CH), 127.6 (CH), 127.8 (CH), 127.87 (CH),
127.89 (CH), 128.5 (CH), 128.6 (CH), 136.5 (C), 139.9
(C), 140.1 (C), 143.7 (C), 157.9 (C), 167.2 (CH) ppm.
MS (CI, CH4) m/z: 626 (7%, C43H47NO3ÆH+), 625
(7%, C43H47NO3+), 243 (100%, CPh3+). HRMS (CI)
calculated for C43H47NO3 (M+): 625.3556. Found:
4.4.15. (2R,3R)-3-(N-30,50-Di-tert-butylsalicyliden)-amino-
+
23
625.3563.
1-benzyloxyhexan-2-ol, 6c. ½aꢁD = ꢀ37.3 (c 1.0, CHCl3).
IR (film, mmax/cmꢀ1): 3460, 2957, 2910, 2870, 1629, 1596,
1468, 1454, 1441, 1361, 1273, 1250, 733. 1H NMR
(400 MHz, CDCl3): d 0.90 (t, J = 7.3 Hz, 3H), 1.32 (s,
9H), 1.44 (s, 9H), 1.16–1.50 (m, 2H), 1.59–1.86 (m,
2H), 2.44 (d, J = 4.9 Hz, 1H), 3.26 (m, 1H), 3.47 (dd,
J = 9.6 Hz, J0 = 6.8 Hz, 1H), 3.65 (dd, J = 9.6 Hz,
J0 = 3.1 Hz, 1H), 3.92 (m, 1H), 4.47 (d, J = 11.9 Hz,
1H), 4.55 (d, J = 11.7 Hz, 1H), 7.09 (d, J = 2.4 Hz,
1H), 7.26–7.32 (m, 5H), 7.40 (d, J = 2.8 Hz, 1H), 8.28
(s, 1H), 13.50 (br s, 1H) ppm. 13C NMR (100 MHz,
CDCl3): d 13.8 (CH3), 19.3 (CH2), 29.4 (CH3), 31.5
(CH3), 34.1 (C), 34.4 (CH2), 35.0 (C), 71.3 (CH2), 72.0
(CH), 72.8 (CH), 73.4 (CH2), 117.7 (C), 126.1 (CH),
127.1 (CH), 127.8 (CH), 128.4 (CH), 136.7 (C), 137.8
(C), 140.1 (C), 158.1 (C), 166.4 (CH) ppm. MS (CI,
CH4) m/z: 440 (100%, C20H25NO3ÆH+), 439 (97%,
C20H25NO3). HRMS (CI) calculated for C28H41NO3ÆH+
(M++1): 440.3165. Found: 440.3155.
4.4.12. (1R,2R)-1-(N-30,50-Di-tert-butylsalicyliden)-amino-
23
1-phenyl-3-triisopropylsilyloxypropan-2-ol, 4f. ½aꢁD
=
+62.4 (c 1.0, CHCl3). IR (film, mmax/cmꢀ1): 3568,
3464, 3063, 3031, 2958, 2867, 1629, 1466, 1442,
1250, 1116, 881. 1H NMR(400 MHz, CDCl3): d 1.12
(m, 47H), 1.28 (s, 9H), 1.45 (s, 9H), 2.58 (d,
J = 4.0 Hz, 1H), 3.78 (dd, J = 10.1 Hz, J0 = 6.2 Hz,
1H), 3.85 (dd, J = 10.1 Hz, J0 = 3.5 Hz, 1H), 4.12
(m, 1H), 4.50 (d, J = 7.1 Hz, 1H), 7.06 (d, J = 2.4 Hz,
1H), 7.25–7.44 (m, 6H), 8.42 (s, 1H), 13.50 (br s,
1H) ppm. 13C NMR (100 MHz, CDCl3): d 11.9 (CH),
17.9 (CH3), 29.4 (CH3), 31.4 (CH3), 34.1 (C), 35.0 (C),
63.9 (CH2), 75.06 (CH), 75.11 (CH), 117.9 (C), 126.3
(CH), 127.2 (CH), 127.6 (CH), 127.8 (CH), 128.6
(CH), 136.6 (C), 140.0 (C), 140.2 (C), 158.0 (C), 167.2
(CH) ppm. MS (CI, CH4) m/z: 540 (100%, C33H53NO3-
SiÆH+), 539 (41%, C33H53NO3Si+), 496 (37%,
[C33H53NO3SiÅ–(CH(CH3)2)]+). HRMS (CI) calculated
for C33H53NO3SiÆH+ (M++1): 540.3873. Found:
540.3879.
4.4.16. (2R,3R)-3-(N-30,50-Di-tert-butylsalicyliden)-amino-
23
1-triphenylmethoxyhexan-2-ol, 6e. ½aꢁD = ꢀ16.3 (c 1.0,
CHCl3). IR (film, mmax/cmꢀ1): 3450, 3060, 2959, 2871,
1631, 1448, 1391, 1362, 1250, 1076, 762. 1H NMR
(400 MHz, CDCl3): d 0.88 (t, J = 7.4 Hz, 3H), 1.30 (s,
9H), 1.14–1.34 (m, 2H), 1.42 (s, 9H), 1.56 (m, 1H),
1.75 (m, 1H), 3.07 (dd, J = 9.8 Hz, J0 = 6.0 Hz, 1H),
3.26 (m, 1H), 3.40 (dd, J = 9.8 Hz, J0 = 3.2 Hz, 1H),
3.83 (m, 1H), 6.98 (d, J = 2.4 Hz, 1H), 7.17–7.39 (m,
16H), 8.19 (s, 1H) ppm. 13C{1H} NMR (100 MHz,
CDCl3): d 13.9 (CH3), 19.2 (CH2), 29.5 (CH3), 31.5
(CH3), 34.1 (C), 34.3 (CH2), 35.0 (C), 64.6 (CH2), 72.0
(CH), 73.5 (CH), 86.8 (C), 117.6 (C), 126.1 (CH),
126.8 (CH), 127.1 (CH), 127.8 (CH), 128.5 (CH),
136.5 (C), 139.9 (C), 143.7 (C), 158.1 (C), 166.2 (CH)
ppm. EM (CI, CH4) m/z: 592 (25%, C40H49NO3ÆH+),
243 (100%, CPh3+). HRMS (CI) calculated for
C40H49NO3ÆH+ (M++1): 592.3791. Found: 592.3777.
4.4.13. (2R,3R)-3-(N-Salicyliden)-amino-1-benzyloxyh-
23
exan-2-ol, 5c. ½aꢁD = ꢀ48.5 (c 1.0, CHCl3). IR (film,
m
max/cmꢀ1): 3456, 2957, 2929, 2870, 1630, 1581, 1497,
1
1455, 1278, 1091, 756. H NMR (400 MHz, CDCl3): d
0.90 (t, J = 7.3 Hz, 3H), 1.15–1.40 (m, 2H), 1.57–1.85
(m, 2H), 2.55 (br s, 1H), 3.28 (m, 1H), 3.45 (dd,
J = 9.6, J0 = 6.7 Hz, 1H), 3.63 (dd, J = 9.6, J0 = 2.9 Hz,
1H), 4.45 (d, J = 11.7 Hz, 1H), 3.91 (m, 1H), 4.51 (d,
J = 11.7 Hz, 1H), 6.88 (ddd, J = 7.5 Hz, J0 = 7.4 Hz,
J00 = 1.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 7.23–7.33
(m, 7H), 8.27 (s, 1H), 13.25 (br s, 1H) ppm. 13C NMR
(100 MHz, CDCl3): d 13.8 (CH3), 19.3 (CH2), 34.3
(CH2), 71.2 (CH2), 71.9 (CH), 72.7 (CH2), 73.4 (CH),
116.9 (CH), 118.6 (CH), 127.7 (CH), 127.8 (CH), 128.4
(CH), 131.4 (CH), 132.3 (CH), 137.7 (C), 161.1 (C),

160
B. Rodrı´guez et al. / Tetrahedron: Asymmetry 17 (2006) 151–160
Cao, G.; Zheng, Z. Tetrahedron 2004, 60, 10469–10477; (j)
Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67, 2702–2704;
4.4.17. General method for the asymmetric addition of
trimethylsilylcyanide to benzaldehyde. In a flame-dried
flask, 0.033 mmol of the corresponding Schiff base was
weighed, and the system purged with argon. A 0.2 M
solution of Ti(OiPr)4 (150 lL, 0.030 mmol) in CH2Cl2
were added via syringe, and the mixture was stirred at
rt for 1 h. The mixture was then cooled to ꢀ78 ꢁC and
45 lL (0.33 mmol) of TMSCN, and 15 lL of freshly dis-
tilled benzaldehyde successively added. The reaction was
then kept at the desired temperature and time, and even-
tually quenched with water and extracted with CH2Cl2.
The crude product was analyzed by GC: b-DEX chiral
´
(k) Gama, A.; Flores-Lopez, L. Z.; Aguirre, G.; Parra-
Hake, M.; Somanathan, R.; Cole, T. Tetrahedron: Asym-
´
metry 2005, 16, 1167–1174; (l) Gama, A.; Flores-Lopez, L.
Z.; Aguirre, G.; Parra-Hake, M.; Somanathan, R.; Walsh,
P. J. Tetrahedron: Asymmetry 2002, 13, 149–154; (m) Li,
Y.; He, B.; Qin, B.; Feng, X.; Zhang, G. J. Org. Chem.
2004, 69, 7910–7913; (n) Jiang, Y.; Gong, L.; Feng, X.;
Hu, W.; Pan, W.; Li, Z.; Mi, A. Tetrahedron 1997, 53,
14327–14338.
4. Gennari, C.; Piarulli, U. Chem. Rev. 2003, 103, 3071–3100.
5. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780.
column (30 m) [Isocratic 105 ꢁC, P = 15 psi]: tPhCHO
=
17.0 min, tS = 108.5 min, tR = 110.0 min.
`
6. Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Pericas, M.
A.; Riera, A. J. Org. Chem. 1999, 64, 7902–7911.
´
`
7. (a) Pasto, M.; Riera, A.; Pericas, M. A. Eur. J. Org. Chem.
Acknowledgements
´
´
2002, 2337–2341; (b) Ferrer, S.; Pasto, M.; Rodrıguez, B.;
`
Riera, A.; Pericas, M. A. Tetrahedron: Asymmetry 2003,
14, 1747–1752.
We thank DGI-MCYT (Grant No. BQU2002-02459),
`
8. Pericas, M. A.; Puigjaner, C.; Riera, A.; Vidal-Ferran, A.;
´
´
DURSI (Grant No. 2001SGR50), Fundacion Ramon
Areces, and ICIQ Foundation for financial support.
B.R. thanks MCYT, for a predoctoral fellowship.
´
´
Gomez, M.; Jimenez, F.; Muller, G.; Rocamora, M.
Chem. Eur. J. 2002, 8, 4164–4178.
`
9. Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.; Riera, A. J.
Org. Chem. 1997, 62, 4970–4982.
´
´
`
10. Pasto, M.; Rodrıguez, B.; Riera, A.; Pericas, M. A.
References
Tetrahedron Lett. 2003, 44, 8369–8372.
11. Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem.
1988, 53, 5185.
1. (a) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649–3682; (b)
North, M. Tetrahedron: Asymmetry 2003, 14, 147–176.
2. For a recent review, see: Brunel, J.-M.; Holmes, I. P.
Angew. Chem. Int. Ed. 2004, 43, 2752–2778.
12. (a) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J.
Chem. Soc., Chem. Commun. 1991, 1752–1753; (b) Hay-
ashi, M.; Inoue, T.; Miyamoto, Y.; Oguni, N. J. Org.
Chem. 1993, 58, 1515–1522; (c) Hayashi, M.; Miyamoto,
Y.; Inoue, T.; Oguni, N. Tetrahedron 1994, 50, 4385–4398.
13. The tert-butyl groups on the salicylaldehyde are supposed
to prevent the formation of inactive complexes such as
Ti(L*)2. See Refs. 12 and 14.
3. For some recent key references using Ti(IV)–Schiff base
ligands complexes for cyanide addition to aldehydes, see:
(a) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg,
C. J. Am. Chem. Soc. 2005, 127, 11592–11593; (b) Li, Z.-
B.; Rajaram, A. R.; Decharin, N.; Qin, Y.-C.; Pu, L.
Tetrahedron Lett. 2005, 46, 2223–2226; (c) Belokon, Y. N.;
Carta, P.; North, M. Lett. Org. Chem. 2004, 1, 81–83; (d)
Belokon, Y. N.; Blacker, A. J.; Clutterbuck, L. A.; North,
M. Org. Lett. 2003, 5, 4505–4507; (e) Belokon, Y. N.;
Gutnov, A. V.; Moskalenko, M. A.; Yashkina, L. V.;
Lesovoy, D. E.; Ikonnikov, N. S.; Larichev, V. S.; North,
M. Chem. Commun. 2002, 244–245; (f) Belokon, Y. N.;
Carta, P.; Gutnov, A. V.; Maleev, V.; Moskalenko, M. A.;
Yashkina, L. V.; Ikonnikov, N. S.; Voskoboev, N. V.;
Khrustalev, V. N.; North, M. Helv. Chim. Acta 2002, 85,
3301–3311; (g) Noth, M.; Parkins, A. W.; Shariff, A. N.
Tetrahedron Lett. 2004, 45, 7625–7627; (h) Huang, W.;
Song, Y.; Bai, C.; Cao, G.; Zheng, Z. Tetrahedron Lett.
2004, 45, 4763–4767; (i) Huang, W.; Song, Y.; Wang, J.;
´
14. Flores-Lopez, L. Z.; Parra-Hake, M.; Somanathan, R.;
Walsh, P. J. Organometallics 2000, 19, 2153–2160.
15. Belokon, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L.
A.; North, M. Tetrahedron 2004, 60, 10433–10447.
16. Josephsohn, N. S.; Kuntz, K. W.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2001, 123, 11594–
11599.
17. (a) Arbelo, D. O.; Prieto, J. A. Tetrahedron Lett. 2002, 43,
´
4111–4114; (b) Thurner, A.; Faigl, F.; Toke, L.; Mordini,
A.; Valacchi, M.; Reginato, G.; Czira, G. Tetrahedron
2001, 57, 8173–8180; (c) Bonini, C.; Righi, G.; Sotgiu, G.
J. Org. Chem. 1991, 56, 6206.
18. Choukroum, R.; Gervais, D. J. Chem. Soc., Dalton Trans.
1980, 1800.