Synthesis of some new chiral bifunctional o-hydroxyarylphosphonodiamides and their application as ligands in Ti(IV) complex catalyzed asymmetric silylcyanation of aromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2004.08.082

Some new chiral bifunctional o-hydroxyarylphosphonodiamides were synthesized starting from (+)-cis-1,2,2-trimethylcyclopentane-1,3-diamine and the absolute configuration of the phosphorus atom was determined by X-ray diffraction analysis. Excellent enantioselectivity (up to 98% ee) was achieved in asymmetric silylcyanation of aromatic aldehydes using a chiral titanium complex formed in situ from Ti(OⁱPr)₄ and o-hydroxyarylphosphonodiamide as the catalyst. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.08.082

Tetrahedron 60 (2004) 10505–10513
Synthesis of some new chiral bifunctional
o-hydroxyarylphosphonodiamides and their application as ligands
in Ti(IV) complex catalyzed asymmetric silylcyanation of
aromatic aldehydes
*
Ke He, Zhenghong Zhou, Lixin Wang, Kangying Li, Guofeng Zhao, Qilin Zhou
and Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Received 24 June 2004; revised 6 August 2004; accepted 23 August 2004
Available online 16 September 2004
Abstract—Some new chiral bifunctional o-hydroxyarylphosphonodiamides were synthesized starting from (C)-cis-1,2,2-trimethylcyclo-
pentane-1,3-diamine and the absolute configuration of the phosphorus atom was determined by X-ray diffraction analysis. Excellent
enantioselectivity (up to 98% ee) was achieved in asymmetric silylcyanation of aromatic aldehydes using a chiral titanium complex formed
in situ from Ti(OiPr)4 and o-hydroxyarylphosphonodiamide as the catalyst.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
exists at an appropriate position in the ligand molecule, the
unshared electron pair on the oxygen atom should act as a
Lewis base (LB) which will activate the nucleophile
trimethylsilyl cyanide. If the catalyst, contains both a
Lewis acid center and a Lewis base center, namely, LALB
catalyst, it is a new type of chiral bifunctional catalyst.4a,b,5e,11
Based on these findings, recently, a new chiral bifunctional
cyclic o-hydroxynaphthylphosphonodiamide 1 was syn-
thesized starting from (K)-a-phenylethylamine and
employed in the asymmetric silylcyanation of aromatic
aldehydes in the presence of Ti(OiPr)4 by our research
group. The corresponding cyanohydrins were obtained in
high chemical yields with good to excellent enantiomeric
excesses up to 90%.5a In order to further improve the
enantioselectivity of this type of bifunctional cyclo-
phosphonodiamde, in this paper, we will report the synthesis
of two new cyclic o-hydroxyarylphosphonodiamides 2 and
3 containing a phosphorus stereocenter starting from (C)-
cis-1,2,2-trimethylcyclopentane-1,3-diamine 4 and their
application in asymmetric silylcyanation of aromatic
aldehydes.
Optically active cyanohydrins are important intermediates
in organic synthesis for the synthesis of a variety of valuable
classes of chiral compounds, such as a-amino acids,
a-hydroxy carboxylic acids, b-amino alcohols, vicinal diols,
a-hydroxyketones, etc. Many efficient approaches have
been reported for obtaining them by biochemical and
chemical methods.1 In the latter, the most important one is
the asymmetric silylcyanation of aldehydes with trimethyl-
silylcyanide catalyzed by a Lewis acid, such as Ti(OiPr)4,
TiCl4, AlCl3, SmCl3 etc. in the presence of a chiral ligand.
In this reaction, a wide range of chiral ligands have been
elaborated, such as bis-Schiff bases (salen),2 Schiff bases,3
dihydroxy compounds,4 phosphorus compounds,5 bis-oxa-
zolines,6 diamides,7 ferrocenes,8 sulfur9 and boron com-
pounds,10 etc. As shown in the literature, most of the
effective chiral ligands have a free hydroxyl group or an
amino group bearing at least a N–H bond which is favorable
to coordinate conveniently with the metal atom in the Lewis
acid. Thus the moiety of the coordinated metal atom should
work as a Lewis acid center (LA) which will activate the
substrate aldehyde. Moreover, if a phosphoryl group (P]O)
Keywords: Chiral cyclophosphonodiamide; Asymmetric silylcyanation;
Catalysis; Enantioselectivity; Aromatic aldehyde.
* Corresponding author. Tel./fax: C86-22-23503438;
e-mail: z.h.zhou@nankai.edu.cn
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.082

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K. He et al. / Tetrahedron 60 (2004) 10505–10513
Scheme 1.
2. Results and discussion
nucleophilic attack of carbanion formed at the a-position of
the naphthalene ring in (K)-(R)-7 occurs at the phosphorus
opposite the N0 atom in the 1,3-diazaphosphorine, which
results in the formation of the TBP-1 intermediate in which
the b-carbon of naphthalene and the N0 atom are both placed
at apical positions. The P–O–C in the oxaphosphetane has
better apicophilicity than the N0 atom, and at the same time
it is also a good leaving group. Therefore, ligand
reorganization through Berry pseudorotation (BPR) of the
initially formed TBP-1 to form the TBP-2 intermediate is
possible.17 Then the leaving group, naphthoxy, departs from
2.1. Synthesis of ligands (C)-2, (C)-3 and determination
of their stereochemistry
Condensation of 2 equiv of benzaldehyde with (C)-cis-
trimethylcyclopentane-1,3-diamine 412,13 derived from
D-camphor led to N,N0-dibenzylidene-1,2,2-trimethylcyclo-
pentane-1,3-diamine 5. The reduction of the latter with
sodium borohydride gave N,N0-dibenzyl-1,2,2-trimethyl-
cyclopentane-1,3-diamine 6. Then cyclization of compound
6 with O-aryl phosphorodichloridate afforded cyclic
phosphorodiamidate 7 (ArZ1-naphthyl) or 8 (ArZphenyl).
A pair of diastereomers of 7 and 8 was obtained and
separated via column chromatography. A subsequent P–O
to P–C rearrangement upon treatment of (K)-7 and (K)-8
with n-BuLi resulted in the formation of (C)-cyclo-
phosphonodiamides 2 and 3. The rearrangement of (C)-7
and (C)-8 was carried out under the same condition,
unfortunately, a complicated mixture rather than the desired
corresponding rearrangement product was obtained
(Scheme 1).
The absolute configuration of the phosphorus atom in (C)-7
was determined as S via X-ray diffraction analysis (shown in
Fig. 1).14 Thus the absolute configuration of the phosphorus
atom in (K)-7 should be R. At the same time, a
crystallographic study showed that the absolute configur-
ation of the phosphorus atom in (C)-2 was S (shown in
Fig. 2).15 Therefore, the rearrangement from (K)-(R)-7 to
(C)-(S)-2 proceeded with retention of configuration at the
phosphorus atom.
The trigonal bipyrimidal (TBP) concept and Berry’s
pseudorotation theory16 could be used to explain the
mechanism of this type of rearrangement. Firstly, the
Figure 1. Molecular structure of (C)-(S)-7.

K. He et al. / Tetrahedron 60 (2004) 10505–10513
10507
contrast, for some other substrates, such as p-methoxy-
benzaldehyde, m-methoxybenzaldehyde and a-naphthyl
aldehyde, this change led to an obvious decrease in
enantioselectivity (entries 12 and 13, 14 and 15, 18 and
19). Further reducing the amount of (C)-(S)-2 to 10 mol%
resulted in a remarkable decrease both in yield and
enantioselectivity (entry 8). These results showed that the
change from the ligand 1 to (C)-(S)-2 led to a significant
improvement in the enantioselectivity. Under the same
conditions, the use of 40 mol% of ligand 1 led to only 90%
ee for the substrate o-methoxybenzaldehyde.5a Although a
slightly high ligand loading (20–40 mol%) was required for
the silylcyanation, it is gratifying that ligand (C)-(S)-2 was
very stable and could be readily recovered and reused
without loss of its catalytic activity and asymmetric
induction ability. It was found that a 4:1 molar ratio of
ligand to Ti(OiPr)4 resulted in better enantioselectivity,
whereas the use of 1 equiv of ligand (C)-(S)-2 per Ti(OiPr)4
led to higher chemical yield (entries 1 and 5 and 6 and 9).
Buono reported that the introduction of i-PrOH as an
additive has a dramatic influence on the enantioselectivity in
asymmetric silylcyanation.5f However, only a small
increase in selectivity was observed in our research (entries
1 and 4 and 6 and 11). The reaction temperature was also
found to be an essential factor to the reaction. The reaction
at 20 8C generally led to better results than that carried out at
0 8C. An increase in reaction temperature resulted in a
detrimental effect to the reaction due to the instability of the
adduct silyl ether. The nature of the substrate aromatic
aldehyde has a dramatic influence on the catalytic effect.
Generally, the enantioselectivity of aldehydes substituted
with electron donating groups (methyl and methoxy) on the
benzene ring was better than that of electron withdrawing
group (chloro and nitro) substituted ones. Moreover, the
enantioselectivity was also affected by the position of the
substituent on the benzene ring. When methoxy substituted
benaldehyde was employed as the substrate, it was found
that the enantioselectivity falls in the order: oOmOp
(entries 6, 14 and 12). This finding indicates that not only
the electronic effect but also the position of the subtituent
(or steric effect) had a decisive role on the enantioselectivity
of the reaction.
Figure 2. Molecular structure of (C)-(S)-2.
the apical position and the rearranged product with retention
of configuration is obtained (Scheme 2).
2.2. (C)-(S)-2/Ti(OiPr)4 catalyzed asymmetric
silylcyanation of aldehydes
The catalytic effect of the titanium complex formed in situ
from (C)-(S)-2 and Ti(OiPr)4 in the asymmetric silyl-
cyanation of aromatic aldehydes was investigated. The
experimental results are listed in Table 1.
Usually, the silylcyanation reaction was best conducted in
methylene chloride. We first examined the influence of the
amount of ligand used on the enantioselectivity of the
reaction. It was found that a decrease in yield and
enantiomeric excesses value was observed, depending on
the substrate employed, with a reduction of the amount of
(C)-(S)-2 from 40 to 20 mol%. As to the substrate,
o-methoxybenzaldehyde the ee value for which was 98 and
97%, respectively, only a very slight change in yield and
enantioselectivity was observed (entries 6 and 7). In
2.3. (C)-(S)-3/Ti(OiPr)4 catalyzed asymmetric
silylcyanation of aldehydes
The catalytic effect of the titanium complex formed in situ
Scheme 2.

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K. He et al. / Tetrahedron 60 (2004) 10505–10513
Table 1. Asymmetric silylcyanation of aromatic aldehydes catalyzed by (C)-(S)-2/Ti(OiPr)4
Entry
Ar
(C)-(S)-2
(mol%)
Ti(OiPr)4
(mol%)
i-PrOH
(mol%)
React. tem-
perature (8C)
Yielda (%)
[a]D (c 1,
CHCl3)
eeb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
40
20
40
40
40
40
20
10
40
40
40
40
20
40
20
40
20
40
20
40
40
40
10
5
20
10
20
/
20
20
10
5
20
20
0
20
20
20
20
20
20
0
20
20
20
20
20
20
20
20
20
20
20
20
84
74
90
90
96
87
78
69
91
78
86
64
50
78
73
75
74
66
55
81
71
73
C23.8
53 (54.2)c
44
34
28
47
98 (98.3)c
97
53
90
92
91
54
32
84
26
78
C19.6
C15.1
C12.5
C22.2
C26.8
C26.4
C14.4
C24.5
C25.0
C24.8
C25.5
C15.4
C34.6
C10.6
C32.5
C30.5
C55.0
C37.3
C40.0
C22.5
C5.5
10
10
40
10
5
2.5
40
10
10
10
5
10
5
10
5
10
5
10
10
10
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3-MeOC6H4
3-MeOC6H4
2-MeC6H4
9
20
20
/
10
11
12
13
14
15
16
17
18
19
20
21
22
20
10
20
10
20
10
20
10
20
20
20
2-MeC6H4
72 (70.0)c
84
57
78
55
35
a-Naphthyl
a-Naphthyl
4-MeC6H4
4-ClC6H4
4-NO2C6H4
a
Isolated yield.
b
Determined by comparison of specific rotation values: ArZPh, [a]2D0ZC45 (c 1, CHCl3) in Ref. 1c; ArZ2-MeOC6H4, [a]D20ZK21.0 (c 1.25, CHCl3)
with 77% ee in Ref. 1c; ArZ4-MeOC6H4, [a]2D0ZC45.5 (c 1, CHCl3) with 95% ee in Ref. 1c; ArZ3-MeOC6H4, [a]D20ZK40.8 (c 1.25, CHCl3) with 99%
ee in Ref. 1c; ArZ2-MeC6H4, [a]2D0ZC21.3 (c 1.03, CHCl3) with 99% ee in Ref. 18; ArZa-Naphthyl, [a]D20ZC48.0 (c 1.325, CHCl3) with 73% ee in
Ref. 18; ArZ4-MeC6H4, [a]2D0ZC47.4 (c 1.822, CHCl3) with 92% ee in Ref. 18; ArZ4-ClC6H4, [a]D20ZC27.2 (c 1.487, CHCl3) with 66% ee in Ref. 18;
ArZ4-NO2C6H4, [a]2D0ZC4.6 (c 1.417, CHCl3) with 29% ee in Ref. 18.
c
Determined by HPLC analysis of the silyl ether on a chiralcel OD column.
from (C)-(S)-3 and Ti(OiPr)4 in the asymmetric silyl-
cyanation of aromatic aldehydes was also examined. The
experimental results are listed in Table 2.
73% (Table 2, entry 8) and 92% (Table 1, entry 10),
respectively. This difference was more obvious when the
reaction was run at 20 8C, 57% ee (Table 2, entry 6) and
98% ee (Table 1, entry 6), respectively, was obtained. These
findings show that the nature of the ligand has a dramatic
influence on the enantioselectivity of the reaction. The
introduction of a bulky naphthyl group into the ligand
molecule has a great advantage over a phenyl group, which
reveals that the steric effect of the naphthyl group plays a
decisive role on the enantioselectivity of the reaction.
As shown in Table 2, the observed enantioselectivity of
(C)-(S)-3/Ti(OiPr)4 catalyzed asymmetric silylcyanation of
aromatic aldehydes was obviously lower than that of the
(C)-(S)-2/Ti(OiPr)4 catalyzed process. For example, when
o-methoxybenzaldehyde was employed as substrate, the
enantioselectivity of (C)-(S)-3 and (C)-(S)-2 at 0 8C was
Table 2. Asymmetric silylcyanation of aromatic aldehydes catalyzed by (C)-(S)-3/Ti(OiPr)4
Entry
Ar
(C)-(S)-3
(mol%)
Ti(OiPr)4
(mol%)
i-PrOH
(mol%)
React. tem-
perature (8C)
Yielda (%)
[a]D (c 1,
CHCl3)
eeb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
40
40
40
20
40
40
40
40
10
1
20
/
20
20
0
20
20
20
20
0
84
90
84
73
96
64
82
73
C19.6
44
12
34
53
47
57
41
C5.5
C15.1
C23.8
C21.2
C15.5
C11.2
C19.8
10
10
40
10
10
10
20
20
20
20
/
2-MeOC6H4
2-MeOC6H4
2-MeOC6H4
20
73 (70.0)c
a
Isolated yield.
b
Determined by comparison of specific rotation values: ArZPh, [a]2D0ZC45 (c 1, CHCl3) in Ref. 1c; ArZ2-MeOC6H4, [a]D20ZK21.0 (c 1.25, CHCl3)
with 77% ee in Ref. 18.
Determined by HPLC analysis of the silyl ether on a chiralcel OD column.
c

K. He et al. / Tetrahedron 60 (2004) 10505–10513
10509
interaction between the electropositive silicon and the
oxygen of phosphoryl group, which leads to the activation
and control of the orientation of nucleophile trimethylsilyl
cyanide by the Lewis base phosphoryl group. Then the
cyanide anion attacks the carbonyl of the aldehyde from its
si-face to afford the adduct mandelonitrile silyl ether.
Finally, the oxygen of the phosphoryl group is again
coordinated to the central titanium atom to release the
product cyanohydrin silyl ether and regenerate the inter-
mediate complex A.
3. Conclusions
In conclusion, a new type of chiral bifunctional cyclic
o-hydroxyarylphosphonodiamide was synthesized and the
absolute configuration of the phosphorus atom was
determined by X-ray diffraction analysis. Excellent results
(up to 98% ee) were achieved in the asymmetric
silylcyanation of aromatic aldehydes using these
bifunctional phosphorus reagents as the catalyst ligand in
the presence of Ti(OiPr)4. Investigations on further extend-
ing the range of substrates and application of this kind of
bifunctional LALB catalyst for other asymmetric reaction
are continuing in our laboratory.
Figure 3. 31P NMR spectrum of a 4:1 mixture of (C)-(S)-3 and Ti(OiPr)4.
2.4. Mechanism of the silylcyanation
A 4:1 and 2:1 (molar ratio) mixture of (C)-(S)-3 and
Ti(OiPr)4 was stirred at room temperature for 1 h and
analyzed by 31P nucleus magnetic resonance spectroscopy,
respectively (Figs. 3 and 4). As shown in Figure 3, a new
doublet peak (d 34.21 and 33.23 ppm, respectively)
corresponding to the chemical shift of the Ti(IV) complex
formed in situ from (C)-(S)-3 and Ti(OiPr)4 appeared at
higher field than the single signal (d 39.03 ppm) of (C)-(S)-
3. The integral value of the signal of (C)-(S)-3 and that of
the Ti(IV) complex had a ratio of 1:1. Moreover, in Figure 4,
the integral value of the signal of (C)-(S)-3 and that of the
Ti(IV) complex had a ratio of 1:10.4, which indicated that
almost all of (C)-(S)-3 had coordinated with the titanium
atom to form the Ti(IV) complex. These results showed that
it was favored to form a Ti(IV) complex with a molar ratio
of 2:1 when mixing (C)-(S)-3 and Ti(OiPr)4 together. Based
on this finding and the LALB concept a possible mechanism
for this type of asymmetric silylcyanation is shown in
Scheme 3.
4. Experimental
4.1. General methods
1H and 31P NMR spectra were recorded in CDCl3 on a
Bruker AC-P300 instrument using TMS as an internal
standard for 1H NMR and 85% H3PO4 as an external
standard for 31P NMR. Specific rotations were measured on
a Perkin–Elmer 341MC polarimeter. Elemental analyses
were conducted on a Yanaco CHN Corder MT-3 automatic
analyzer. Melting points were determined on a T-3 melting
point apparatus. All temperatures and pressures were
uncorrected. All solvents were dried and used after fresh
distillation. Ti(OiPr)4 was purchased from Fluka.
First, intermediate complex A is formed from a 2:1 molar
ratio of (C)-(S)-3 and Ti(OiPr)4. With the addition of aryl
aldehyde the central titanium metal acts as a Lewis acid to
activate and control the orientation of the substrate aldehyde
through the formation of a new complex B in which the
oxygen of the carbonyl group is coordinated to the central
titanium atom. The introduction of trimethylsilyl cyanide
results in the formation of intermediate complex C via the
4.1.1. Trimethylsilyl cyanide.19 Trimethylsilyl cyanide
was prepared through the reaction of silver cyanide and
trimethylsilyl chloride in a 68% yield, bp 116–118 8C, nD20
1.3911 (literature:19 bp 114–117 8C).
4.1.2. O-Phenyl phosphorodichloridate.20 Reaction of
phenol and phosphorus trichloride in the presence of sodium
chloride afforded O-phenyl phosphorodichloridate in 80%
yield, bp 138–140 8C/2.80 kPa, n2D0 1.5264 (literature:20a bp
106–107.5 8C/0.92 kPa).
4.1.3. O-Naphthyl phosphorodichloridate.20 The reaction
between 1-naphthol and phosphorus trichloride in the
presence of sodium chloride resulted in the formation of
O-1-naphthyl phosphorodichloridate in 78% yield, bp 224–
226 8C/2.80 kPa, n2D0 1.6012 (literature:20b bp 199–201 8C/
2.67 kPa, n2D2 1.5960).
4.1.4. (C)-cis-1,2,2-Trimethylcyclopentane-1,3-diamine
4. Diamine 4 was prepared from the reaction of (1R,3S)-
(C)-camphoric acid with sodium azide in the presence of
Figure 4. 31P NMR spectrum of a 2:1 mixture of (C)-(S)-3 and Ti(OiPr)4.

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K. He et al. / Tetrahedron 60 (2004) 10505–10513
Scheme 3. Proposed mechanism for silylcyanation of aromatic aldehydes.
concentrated sulfuric acid in 91% yield and used directly
without further purification.
column chromatography on silica gel (200–300 mesh,
gradient eluted with petroleum ether/ethyl acetate) to afford
1
6 (2.20 g) as a pale yellow oil. Yield: 68%; H NMR (d,
4.1.5. (C)-cis-N,N0-Dibenzylidene-1,2,2-trimethylcyclo-
pentane-1,3-diamine 5. To a stirring mixture of (C)-4
(7.11 g, 0.05 mol), p-toluenesulfonic acid (0.5 g) and
toluene (100 mL) was added dropwise a solution of
benzaldehyde (10.6 g, 0.1 mol) in toluene (40 mL) at
room temperature. The resulting mixture was stirred at
80 8C for 8 h. After removal of solvent 5 (14.2 g) was
obtained as a pale yellow solid. Yield: 89%; mp 77–78 8C;
1H NMR (d, CDCl3): 0.91 (s, 3H, CH3), 0.96 (s, 3H, CH3),
1.22 (s, 3H, CH3), 1.66–2.40 (m, 4H, 2CH2), 3.57 (t, 1H, JZ
8.3 Hz, CH), 7.38–7.76 (m, 10Harom), 8.26 (s, 2H, 2CH).
CDCl3): 1.00 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.16 (s, 3H,
CH3), 1.39–2.18 (m, 6H, 2CH2 and 2NH), 2.88 (t, 1H, JZ
7.1 Hz), 3.66–3.92 (m, 4H, 2CH2), 7.28–7.36 (m,
10Harom).
4.1.7. O-1-Naphthyl cyclophosphorodiamidate 7. To a
stirring mixture of 6 (3.22 g, 0.01 mmol), triethylamine
(2.40 g, 0.024 mol) and methylene chloride (40 mL) was
added dropwise O-1-naphthyl phosphorodichloridate
(3.13 g, 0.012 mol) at 0 8C. The resulting mixture was
warmed to room temperature and stirred for 24 h, then
washed successively with distilled water and brine. The
organic layer was separated and dried over anhydrous
magnesium sulfate. After removal of solvent the residue
was purified by column chromatography on silica gel (200–
300 mesh, gradient eluted with petroleum ether/ethyl
acetate) to afford a pair of diastereomers of 7.
4.1.6. (C)-cis-N,N0-Dibenzyl-1,2,2-trimethylcyclopen-
tane-1,3-diamine 6. To a solution of 5 (3.18 g, 0.01 mol)
in chloroform (40 mL) was added sodium borohydride
(1.14 g, 0.03 mol) at intervals at room temperature. After
stirring for an additional 10 min, the reaction mixture was
warmed to reflux (60–65 8C) for 10 h. The resulting mixture
was cooled to room temperature and adjusted to pH 1–2
with 2 M hydrochloric acid. The organic layer was
separated and washed with distilled water, the combined
water phase was adjusted to pH O12 with 10% aqueous
sodium hydroxide solution and extracted with chloroform.
After drying over anhydrous magnesium sulfate and
removal of solvent, the crude product was purified by
Compound (C)-(S)-7. White solid, 1.25 g. Yield: 25%; mp
20
578
1
140–142 8C, [a] ZC39.9 (cZ1, CHCl3); H NMR (d,
CDCl3): 0.78 (s, 3H, CH3), 0.97 (s, 3H, CH3), 1.24 (s, 3H,
Z
3
CH3), 1.87–2.76 (m, 4H, CH2CH2), 2.94 (dd, 1H, JP–H
34.0 Hz, JH–HZ8.0 Hz, CH), 4.15–4.69 (m, 4H, 2CH2Ph),
7.14–8.24 (m, 17Harom); 31P NMR (d, CDCl3): 12.17.

K. He et al. / Tetrahedron 60 (2004) 10505–10513
10511
20
recovered). Yield: 63%; mp 174–175 8C, [a] ZC5.2
578
Anal. Calcd for C32H35N2O2P: C, 75.29; H, 6.86; N, 5.49.
Found: C, 75.23; H, 6.85; N, 5.59.
(cZ1, CHCl3); 1H NMR (d, CDCl3): 0.79 (s, 3H, CH3), 0.92
(s, 3H, CH3), 1.41 (s, 3H, CH3), 1.79–2.75 (m, 4H,
3
Compound (K)-(R)-7. Pale yellow viscous liquid, 3.14 g.
CH2CH2), 2.99 (dd, 1H, JP–HZ25.2 Hz, JH–HZ5.4 Hz,
20
578
1
Yield: 62%; [a] ZK21.5 (cZ1, CHCl3); H NMR (d,
CH), 3.84–4.49 (m, 4H, 2CH2Ph), 6.80–8.00 (m, 14Harom),
11.96 (s, 1H, OH); 31P NMR (d, CDCl3): 39.06. Anal. Calcd
for C28H33N2O2P: C, 73.06; H, 7.17; N, 6.08. Found: C,
72.94; H, 7.19; N, 6.05.
CDCl3): 0.84 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.59 (s, 3H,
Z
3
CH3), 1.70–2.43 (m, 4H, CH2CH2), 2.98 (dd, 1H, JP–H
27.6 Hz, JH–HZ5.2 Hz, CH), 3.98–4.92 (m, 4H, 2CH2Ph),
7.11–8.30 (m, 17Harom); 31P NMR (d, CDCl3): 12.21.
Anal. Calcd for C32H35N2O2P: C, 75.29; H, 6.86; N, 5.49.
Found: C, 75.26; H, 6.70; N, 5.70.
4.2. (C)-2 or (C)-3/Ti(OiPr)4 Catalyzed silylcyanation
of aromatic aldehyde (general preceedure)
4.1.8. O-1-Phenyl cyclophosphorodiamidate 8. A pair of
diastereomers of 8 was obtained from 6 (3.22 g, 0.01 mol),
triethylamine (2.40 g, 0024 mol) and O-phenyl phosphoro-
dichloridate (2.53 g, 0.012 mol) following the same
procedure for the preparation of 7 (Section 4.1.7).
To a solution of ligand (C)-(S)-2 (or (C)-(S)-3)
(0.54 mmol) in methylene chloride (5 mL) was added
Ti(OiPr)4 (37.2 mL, 0.13 mmol) under a nitrogen atmo-
sphere at room temperature and the resulting mixture was
stirred for 1 h. Then iso-propanol (15.6 mL, 0.26 mmol),
methylene chloride (2 mL), aldehyde (1.34 mmol) and
trimethylsilyl cyanide (200 mL, 1.6 mmol) were added and
the reaction stirred for 24 h at the same temperature.
Different work-up was carried out according to the methods
used for determination of the enantiomeric excess.
Compound (C)-(S)-8. White solid, 1.16 g. Yield: 25%; mp
20
578
1
125–126 8C, [a] ZC53.3 (cZ1, CHCl3); H NMR (d,
CDCl3): 0.74 (s, 3H, CH3), 0.92 (s, 3H, CH3), 1.17 (s, 3H,
Z
3
CH3), 1.76–2.75 (m, 4H, CH2CH2), 2.88 (dd, 1H, JP–H
26.0 Hz, JH–HZ6.0 Hz, CH), 4.07–4.70 (m, 4H, 2CH2Ph),
7.19–7.37 (m, 15Harom); 31P NMR (d, CDCl3): 12.17.
Anal. Calcd for C28H33N2O2P: C, 73.06; H, 7.17; N, 6.08.
Found: C, 72.70; H, 7.23; N, 6.24.
(1) After removal of solvent, the residue was purified by
column chromatography on silica gel (200–300 mesh,
gradient eluted with petroleum ether/ethyl acetate) to
afford the silyl ether of the corresponding cyanohydrin
which was used for determination of the ee by chiral
HPLC analysis.
(2) The reaction mixture was poured into a mixture of 1 M
hydrochloric acid (30 mL) and ethyl acetate (40 mL)
and stirred vigorously for 6 h at room temperature. The
organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2!20 mL). The combined
organic phase was washed with brine and dried over
anhydrous magnesium sulfate. After removal of solvent
the residue was purified by column chromatography on
silica gel (200–300 mesh, gradient eluted with
petroleum ether/ethyl acetate) to give the corresponding
cyanohydrin. The ee value was determined by com-
parison of specific rotation values of the cyanohydrin or
by chiral HPLC analysis of the corresponding acetated
cyanohydrin.
Compound (K)-(R)-8. Pale yellow viscous liquid, 2.53 g.
20
578
1
Yield: 55%; [a] ZK3.2 (cZ1.5, CHCl3); H NMR (d,
CDCl3): 0.78 (s, 3H, CH3), 0.97 (s, 3H, CH3), 1.40 (s, 3H,
Z
3
CH3), 1.70–2.45 (m, 4H, CH2CH2), 2.88 (dd, 1H, JP–H
27.2 Hz, JH–HZ5.3 Hz, CH), 3.90–4.89 (m, 4H, 2CH2Ph),
7.06–7.49 (m, 15Harom); 31P NMR (d, CDCl3): 14.77.
Anal. Calcd for C32H35N2O2P: C, 73.06; H, 7.17; N, 6.08.
Found: C, 72.93; H, 7.25; N, 5.90.
4.1.9. (C)-(S)-1-Hydroxy-2-naphthyl cyclophosphono-
diamidate 2. To a stirring solution of (K)-7 (4.74 g,
8.1 mmol) in dry THF (30 mL) was added dropwise a
solution of n-BuLi (12.7 mL, 1.8 M in n-hexane) at K78 8C
under a nitrogen atmosphere. After 15 min the cold bath was
removed and the reaction mixture was poured into saturated
aqueous NH4Cl (50 mL). The resulting mixture was
extracted with ethyl acetate (3!30 mL). The combined
organic layer was dried over anhydrous magnesium sulfate.
After removal of solvent the crude product was purified by
column chromatography on silica gel (200–300 mesh,
gradient eluted with petroleum ether/ethyl acetate) to
recover (K)-7 (3.20 g, conversion: 23%) and give com-
Recovery of ligand (C)-2. (C)-2 was recovered in 86%
yield as pale yellow solid during the process of purification
of the cyanohydrin by column chromatography on silica gel
(200–300 mesh, gradient eluted with petroleum ether/ethyl
20
acetate). Mp 205–207 8C, [a] ZC7.1 (cZ1, CHCl3).
578
pound (C)-2 (0.51 g) as a white solid. Yield: 54%; mp 206–
20
207 8C, [a] ZC7.2 (cZ1, CHCl3); 1H NMR (d, CDCl3):
578
0.80 (s, 3H, CH3), 0.92 (s, 3H, CH3), 1.47 (s, 3H, CH3),
1.82–2.75 (m, 4H, CH2CH2), 2.99 (dd, 1H, 3JP–HZ25.5 Hz,
JH–HZ5.0 Hz, CH), 3.84–4.52 (m, 4H, 2CH2Ph), 7.04–8.32
(m, 16Harom), 12.00 (s, 1H, OH); 31P NMR (d, CDCl3):
40.59. Anal. Calcd for C32H35N2O2P: C, 75.29; H, 6.86; N,
5.49. Found: C, 75.29; H, 6.77; N, 5.54.
4.2.1. (G)-o-Methoxymandelonitrile silyl ether.1c To a
stirring solution of Ti(OiPr)4 (37.2 mL, 0.13 mmol) and iso-
propanol (15.6 mL, 0.26 mmol) in methylene chloride
(5 mL) was added successively o-methoxybenzaldehyde
(0.183 g, 1.34 mmol) and trimethylsilyl cyanide (200 mL,
1.6 mmol) at room temperature under a nitrogen atmo-
sphere. The resulting mixture was stirred for 24 h. After
removal of solvent the crude product was purified by
column chromatography on silica gel (200–300 mesh,
gradient eluted with petroleum ether/ethyl acetate) to yield
racemic o-methoxymandelonitrile silyl ether for compari-
son in chiral HPLC analysis.
4.1.10. (C)-(S)-1-Hydroxyphenyl cyclophosphonodiami-
date 3. In the same manner described in Section 4.1.10,
(C)-3 (0.69 g) was obtained as a white solid through the
rearrangement of (K)-8 (3.60 g, 7.8 mmol) upon treatment
with n-BuLi. Conversion: 31% (2.50 g of (K)-8 was

10512
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4.2.2. o-Methoxymandelonitrile acetate. To a stirring
mixture of o-methoxymandelonitrile (164 mg, 1 mmol),
acetic anhydride (204 mg, 2 mmol) and methylene chloride
(5 mL) was added pyridine (80 mg) at room temperature,
and the reaction was stirred at the same temperature for
12 h. The mixture was washed sequentially with 5% H2SO4,
distilled water and saturated aqueous NaHCO3, and dried
over anhydrous magnesium sulfate. After removal of
solvent the crude product was purified by column
chromatography on silica gel (200–300 mesh, 5:1 petroleum
ether/ethyl acetate as eluent) to give the acetylated
cyanohydrin which was analyzed by HPLC with a chiral
column to determine the ee.
Acknowledgements
We are grateful to the National Natural Science Foundation
of China and the Ph.D. Programs and Key Science and
Technology projects of Ministry of Education of China for
generous financial support for our programs.
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