BINOL-based azacrown ether catalyzed enantioselective Michael addition: Asymmetric synthesis of α-aminophosphonates

Article abstract of DOI:10.1016/j.tetasy.2011.02.002

Several novel 1,1′-bi-2-naphthyl-appended azacrown ethers with donor side-arms were synthesized and applied for the first time as chiral catalysts in the asymmetric Michael addition of an N-protected aminomethylenephosphonate onto acrylonitriles, resultin

Full text of DOI:10.1016/j.tetasy.2011.02.002

Tetrahedron: Asymmetry 22 (2011) 480–486
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
BINOL-based azacrown ether catalyzed enantioselective Michael addition:
asymmetric synthesis of a-aminophosphonates
Truong Son Pham a, János B. Czirok a, László Balázs b, Krisztina Pál c, Miklós Kubinyi c, István Bitter a,c
,
Zsuzsa Jászay d,
⇑
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
b Chinoin Ltd, Tó utca 1-5, H-1045 Budapest, Hungary
c Chemical Research Center of Hungarian Academy of Sciences, H-1525 Budapest, Hungary
d Research Group for Organic Chemical Technology, Hungarian Academy of Sciences, H-1521 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Several novel 1,10-bi-2-naphthyl-appended azacrown ethers with donor side-arms were synthesized and
applied for the first time as chiral catalysts in the asymmetric Michael addition of an N-protected amin-
omethylenephosphonate onto acrylonitriles, resulting in high diastereoselectivity and enantioselectivity.
The absolute configuration of the adduct was determined from its experimental and calculated CD
spectra.
Article history:
Received 17 January 2011
Accepted 3 February 2011
Available online 14 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
none of these molecules have been used as chiral catalysts for
asymmetric reactions promoted by alkali bases.
Over the last few decades 1,10-bi-2-naphthyl derivatives have
received constantly growing interest as chiral catalysts, mediators,
and chelators in asymmetric syntheses and chiral recognition pro-
cesses.1 1,10-Bi-2-naphthol (BINOL) has become one of the best
known and utilized atropisomer, possessing an axial chirality due
to its easy availability and versatile chemical modifications on
the aromatic core in addition to the phenolic OH groups1b,1c The
O,O-cyclized derivatives and related macrocycles also represent
an important family of chiral receptors.2 (S,S)-Bis(1,10-bi-2-naph-
tho)-22-crown-6, first reported by Cram et al. in 1973, was dis-
closed to exhibit remarkable chiral discrimination between the
enantiomers of organic ammonium salts.3 So far the choice of bina-
phthocrowns has scarcely been widened, with only modifications
on the crown ether ring size and some combination with
calix[4]arenes were reported.4 Conversely, the number of chiral
crown ethers based on natural chiral sources or constructed by
the incorporation of stereogenic centers into the crown rings has
increased significantly.5 However, some recent publications
revealed that binaphthocrowns with auxiliary binding sites at-
tached to the crown ether ring may have potential in various rec-
ognition processes.6 Interestingly, BINOL-azacrowns have rarely
been reported. Beside the parent 1,10-bi-2-naphtho(17-monoaza-
crown-5)ether,7 only a few N-substituted fluorescent and photo-
chromic derivatives have been described and their optical
responses toward metal ions studied.7b,8 It should be noted that
A series of asymmetric Michael additions, Darzens condensa-
tions, and epoxidations catalyzed by different carbohydrate-based
crown ethers were studied and it was found that lariate monoaza-
15-crown-5 ethers derived from
enantioselectivities.9 Our ongoing work has been focused on the
asymmetric synthesis of -aminophosphonates of biological impor-
D-glucose gave the highest
a
tance. These compounds have found widespread interest as peptide
mimics,10 as well as antibacterial,11 antihypertensive,12 and anti-
HIV agents13 and haptens for catalytic antibodies.14 Various syn-
thetic methods, both catalytic15 and chiral auxiliary mediated,16
providing non-racemic
a-aminophosphonates have been developed
over the last decade.17
Recently we published an alkali base-promoted Michael addi-
tion of N-protected aminomethylenephosphonates onto acrylic
acid derivatives using D-glucose-based monoaza-15-crown-5 lari-
ate ethers as chiral catalysts.15f We found that these macrocycles
catalyzed the addition of aminomethylenephosphonate 3 to a wide
range of Michael acceptors, although the stereoselectivity was only
good in cases where the Michael acceptor possessed cyano group.
We also established that the character of the side arm of the crown
ether is crucial with regards to the selectivity.
2. Results and discussion
2.1. Synthesis of catalysts 1a–I and and aminophosphonates 5a–f
To obtain further examples for the beneficial lariate effect, novel
side-arms were designed and introduced on the N-atom to achieve
⇑
Corresponding author.
E-mail address: zsjaszay@mail.bme.hu (Z. Jászay).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.02.002

T. S. Pham et al. / Tetrahedron: Asymmetry 22 (2011) 480–486
481
We found that the above new crown ethers efficiently catalyzed
the Michael addition of N-protected aminomethylenephosphonate
3 onto acrylic acid derivatives 4a–f. In an initial study, nine BINOL-
azacrown ethers 1a–i were evaluated in the Michael addition of 3
to methacrylonitrile 4a (Scheme 2, Table 1).
The reactions were performed in toluene at ꢀ75 °C in the pres-
ence of NaOtBu (1.5 equiv) and with 10 mol % of catalyst loading.
The results showed that all of the crown ethers catalyzed the reac-
tion, except for those with no side arm 1a and 1b gave poor enan-
O
O
O
O
n
N
R
n
(
OMe
1f; n = 1, R =
1a; n = 1, R = H
tio- and diastereoselectivity (entries
1 and 2). The inferior
enantioselectivity of 1b as compared to 1a can be attributed to
the larger crown ring in 1b, which is capable of less efficient bind-
ing of the Na+ counter ion of the carbanion derived from 3, thereby
forming a less stable chiral environment for enantioselection. The
n-butyl side arm 1c had no beneficial effect on the stereoselectivity
(entry 3). In the case of the crown ether with a hydroxypropyl side
chain 1d the accelerating effect and the diastereoselectivity were
not sufficient, while the enantioselectivity for the anti-isomer
greatly improved (entry 4). For the crown ethers bearing methoxy-
propyl 1e or o-methoxyphenylethyl 1f side arms, the conversion,
diastereoselectivity, and enantioselectivity were improved (entries
5 and 6), while the best results were obtained with those contain-
ing a methoxy group at the meta-1g, para-1h or 3,4-position 1i on
the phenyl ring (entries 7–9). In conclusion, these experiments
showed that the parent BINOL-azacrown ethers 1a,b and the crown
ether bearing n-butyl side arm 1c were unsuited to generate signif-
icant chiral induction in the present Michael addition, while the
presence of an oxygen atom in an appropriate (5–6 atom) distance
in the enfolding podand arm significantly enhanced the stereose-
lectivity, presumably due to the formation of a three dimensional
binding site for the cation. The poor catalytic activity of the
hydroxypropyl derivative 1d could be attributed to its low solubil-
ity in toluene. Solvent effects were also examined with catalyst 1i.
OMe
1b; n = 2, R = H
1c; n = 1, R =
1g n = 1, R =
1h; n = 1, R =
OH
1d; n = 1, R =
1e; n = 1, R =
OMe
OMe
OMe
1i n = 1, R =
OMe
Figure 1. (R)-BINOL-appended azacrown ethers 1a–i.
improved selectivity. As 1,10-binaphthocrowns have not been tried
as catalysts, we planned to synthesize the respective BINOL-aza-
crown analogs 1a–i supplied with a wide range of side arms differ-
ing in length and complex forming ability in order to compare the
catalytic efficiency of the glucose- and the BINOL-crown series
(Fig. 1).
The new azacrowns 1c–i were readily synthesized by Mitsunobu
alkylation of (R)-BINOL with 2-(2-chloroethoxy)ethanol.7a Next, a
ClꢀI exchange was performed by NaI followed by an Na2CO3
promoted ring closure with the respective amines (Scheme 1).
O
RNH2
NaI
O
O
O
O
O
O
X
X
2b
N
R
Na2CO3
MeCN
acetone
O
1c-i
2a (X=Cl)
2b (X=I)
Scheme 1.
O
Ph
Ph
O
Ph
catalyst 1 (10%)
N
P(OEt)2
NaOtBu
N
P(OEt)2
+
*
Ph
toluene, -75°C
CN
*
CN
4a
5a
3
Scheme 2.
R1
R2
O
Ph
Ph
O
catalyst 1i (10%)
NaOtBu
Ph
Ph
N
P(OEt)2
N
P(OEt)2
+
*
toluene, -75°C
R2
X
R1
*
*
X
5
3
4
Scheme 3.

482
T. S. Pham et al. / Tetrahedron: Asymmetry 22 (2011) 480–486
Table 1
Table 3
Catalytic asymmetric Michael reactions of 3 to methacrilonitrile 4a using 10 mol % of
Catalytic asymmetric Michael reactions of 3 to acrylic acid derivatives 4b–f using
catalyst 1a–ia
10 mol % of catalyst 1ia
Entry
Catalyst
Conversionb (%)
Yieldc (%) (anti/syn)d
eed,e(%)
Entry
R1
R2
X
Conv.b (%)
Yieldc (%), (dr)d
eed (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
89
87
81
30
94
96
93
92
94
78 (74/26)
75 (58/42)
72 (55/45)
23 (58/42)
85 (88/12)
87 (83/17)
81 (92/8)
44/22
8/7
1
2
3
4
5
H
H
H
H
H
Me
H
H
H
COOtBu 4b
COOtBu 4c
CONMe2 4d
CN 4e
100
86
100
87
92, 5b
80 (68/32), 5c
93, 5d
75, 5e
91 (89/11), 5f
21 (S)f
33/31
44
32/19
87/17
84/77
86/67
94/35
94/51
96/46
95 (S)e,f
71/38
Ph
CN 4f
100
a
b
c
d
e
f
Catalyst 1 can be recovered by column chromatography, and reused.
Determined by 31P NMR.
Isolated products after chromatography.
81 (93/7)
86 (99.3/0.7)
Determined by chiral HPLC in comparison with authentic racemic materials.
For the absolute configuration, see Figure 4.
a
b
c
Catalyst 1 can be recovered by column chromatography, and reused.
Determined by 31P NMR.
For the absolute configuration see the literature.15e
Isolated products after chromatography.
Determined by chiral HPLC in comparison with authentic racemic materials.
For the absolute configuration, see Figure 4.
d
e
It is noteworthy that the accelerating effect of (R)-BINOL- and
the D-glucose-azacrown ethers is similar on these Michael reac-
tions, while the selectivity of the (R)-BINOL based family 1a–i is
superior to that of the crown ethers with a sugar backbone. The
scope of the catalysts in other asymmetric conjugate addition reac-
tions will be examined in due course.
Table 2
The dependence of yield and ee on the solvent and amount of catalyst 1ia
Entry Solvent
Catalyst
(mol %)
Conversionb Yieldc (%)
eed
(%)
(%)
(anti/syn)d
2.2. Calculations
1
2
3
4
5
6
7
8
Toluene
CH3CN
Xylene
CH2Cl2
THF
10
10
10
10
10
10
5
94
86 (99.3/0.7)
96/
46
38/
16
76/
51
25/
13
21/
25
63/
18
86/
51
81/
32
100
92
97
82
65
84
78
92 (46/54)
82 (87/13)
89 (37/63)
73 (66/34)
58 (79/21)
77 (87/13)
71 (85/15)
In order to obtain information on the absolute configurations,
the UV–vis and CD spectra of 5a and 5e were recorded. The UV–
vis and CD spectra of a derivative with known absolute configura-
tion, (S)-5b,15f were also measured (Fig. 2).
4x104
3x104
2x104
Toluene/
hexane 2:1
Toluene
5a
(S)-5b
5e
Toluene
3
1x104
a
b
c
0
Catalyst 1 can be recovered by column chromatography, and reused.
Determined by 31P NMR.
Isolated products after chromatography.
6
4
d
Determined by chiral HPLC in comparison with authentic racemic materials.
2
0
-2
-4
Toluene proved to be the best solvent both in terms of yield and
200
225
250
275
300
325
350
stereoselectivity (entry 1). In more polar solvents, such as CH3CN,
CH2Cl2, and THF yields were good, but the enantiomeric excess
(ee) values dropped dramatically (entries 2, 4, 5). The reaction
was sluggish in a toluene/hexane 2:1 mixture probably due to
the poor solubility of both the catalyst and the substrate (entry 6).
It can also be seen from Table 2 that applying a lesser amount of
catalyst 1i (5 and 3 mol %) slowed down the reaction slightly and
gave a lower ee.
To obtain more data on the efficacy of the catalysts, additions
onto further acrylic acid derivatives 4b–f were also examined;
the products are relevant for the synthesis of substituted phospho-
glutamic acid derivatives (Scheme 3, Table 3).
In these experiments the most effective catalyst 1i bearing 3,4-
dimethoxyphenylethyl side-arm and toluene as the most suitable
solvent were used. Good yield and low selectivity were obtained in
the cases of the acrylic esters 4b and 4c (entries 1, 2) and the acrylic
amide 4d (entry 3), while good yield and excellent enantioselectivity
were obtained with acrylonitrile 4e in favor of the (S)-enantiomer
(entry 4). The addition was quantitative with trans-cinnamonitrile
4f providing adduct 5f with good diastereoselectivity and moderate
enantioselectivity (entry 5).
wavelength [nm]
Figure 2. UV–vis absorption and circular dichroism spectra of 5a, (solid, black line),
(S)-5b (solid, red line),. and 5e (dashed, black line).
Although the bands in the spectrum of 5e were very weak, the
spectra of the three compounds showed great similarity, they con-
tained two negative bands around 290 and 215 nm and a positive
band around 243 nm. The close similarities of the spectra of 5e and
5b suggest that their only stereocenter has the same (S)-configura-
tion. In case of 5a, the configurations of the two stereocenters
could not be assigned in a similar way, because of the lack of a suit-
able reference compound with a known stereochemistry. The abso-
lute configuration of this derivative has been established by
comparing its experimental CD spectrum to the theoretically cal-
culated CD spectra of the possible stereoisomers. The (1S,3R)-
and (1S,3S)-diastereomers were chosen for the calculations; the
spectra of the (1R,3S)- and (1R,3R)-isomers could then be obtained
as the mirror images of the spectra of their enantiomers. After
a
conformational analysis the geometry of the most stable

T. S. Pham et al. / Tetrahedron: Asymmetry 22 (2011) 480–486
483
conformer of the diastereomers was optimized by a density func-
4. Experimental
4.1. General
tional theory (DFT) method. Next, the absorption and CD spectra
of these conformers were computed by TD-DFT method. The
experimental CD spectrum of 5a and the calculated spectra of
two diastereomers along with the quantum chemical calculations
can be seen in Figure 3.
NMR spectra were recorded on a Bruker Avance-DRX-500 and
300 instruments using tetramethylsilane (1H, 13C) as an internal
standard and 85% H3PO4 (
31P) as an external standard, all in CDCl3
solution. High-resolution MS measurements were carried out on a
Waters LCT Premier XE spectrometer coupled with Acquity UPLC
system [ESI, 2.5 kV spray voltage, 250 °C capillary temperature,
solvent: CH3CN (+0.035 v/v% TFA):H2O (+0.05 v/v% TFA) grad: 5–95%
CH3CN]. The HPLC measurements were carried out on Jasco PU
1580 equipment supplied with a Jasco UV1575 detector. Optical
rotations were measured with Perkin Elmer 241 polarimeter at
room temperature. Circular dichroism spectra were taken on a
Jasco J-810 spectropolarimeter.
(1S,3R) configuration (calculated)
measured
80
6
(1S,3S) configuration
60
(calculated)
4
40
2
20
0
-2
-4
-6
0
-20
-40
-60
-80
4.2. Procedure for the synthesis of catalysts 1c–i
4.2.1. (R)-2,20-Bis[2-(2-Iodoethoxy) ethoxy]-1,10-binaphthyl 2b
Compound 2a (2.19 g, 4.38 mol) and dry NaI (2.63 g, 17.5 mol)
in dry acetone (40 ml) were refluxed under argon excluding light
for 48 h. The reaction was monitored by TLC (CH2Cl2). If necessary,
another portion of NaI (1.57 g, 10.5 mol) was added and the reac-
tion continued for an additional five days. The solvent was then
evaporated and the residue taken up in a mixture of CH2Cl2
(20 ml) and water (20 ml) and separated. After standard work-
up, the crude brown oil was subjected to flash chromatography
(CHCl3 eluent) and if necessary further purified by column chroma-
tography on silica (hexane–EtOAc = 9:1?8:2) to give 2b (2.70 g,
90%). 1H NMR (300 MHz) d 2.69–2.74 (4H, m, ICH2), 3.11–3.17
(4H, m, OCH2), 3.45–3.47 (4H, t, OCH2), 4.03–4.06 (2H, m, OCH2),
4.07–4.13 (2H, m, OCH2), 7.16 (2H, d, J = 8.5 Hz, BINOL-H), 7.22
(2H, t, J = 7.5 Hz, BINOL-H), 7.32 (2H, t, J = 7.5 Hz, BINOL-H), 7.41
(2H, d, J = 9 Hz, BINOL-H), 7.86 (2H, d, J = 8 Hz, BINOL-H), 7.94
(2H, d, J = 9 Hz, BINOL-H) ppm. 13C NMR (125 MHz) d 3.4 (ICH2),
69.3 (OCH2), 69.9 (OCH2), 71.6 (OCH2), 115.6 (BINOL-C), 120.5 (BI-
NOL-C), 123.8 (BINOL-C), 125.4(BINOL-C), 126.4 (BINOL-C), 127.9
200
220
240
260
280
300
320
340
wavelength [nm]
Figure 3. Experimental circular dichroism spectra of 5a (solid, black line), and the
calculated CD spectra of the (1S,3R) (solid, red line) and the (1S,3S) (dotted, red line)
diastereomers.
The good agreement between the calculated CD spectrum of the
(1S,3R)-isomer and the experimental CD spectrum of 5a clearly
indicates that the adduct 5a has also (1S,3R)-absolute configura-
tion (Fig. 4).
(BINOL-C), 129.4 (2 peaks, BINOL-C), 134.0 (BINOL-C), 154.2 (BI-
NOL-C) ppm. ½a 2D0
ꢁ
¼ þ40 (c 1, CHCl3). HRMS: C28H29I2O4 m/z calcd
þ
683.0155, found 683.0135 (diff. ꢀ2.0 mDa, ꢀ2.9 ppm).
4.2.2. General procedure for the synthesis of the lariat crown
ethers 1c–i
Compound 2b (1.40 g, 2.05 mmol) and the appropriate amine
(2.22 mmol) in 30 ml abs MeCN were stirred and refluxed with
an excess of dry Na2CO3 (1.40 g) for 16–24 h under argon. After
completion, the suspension was filtered and the filtrate was con-
centrated. The residue was taken up in 20 ml of chloroform and
washed twice with water (20 ml), dried over Na2SO4 and concen-
trated. The products were pale yellow oils.
Figure 4. Calculated structure of the most stable conformer of (1S,3R)-5a.
4.2.2.1. (R)-13-(3-Butyl)-8,9,12,13,14,15,17,18-octahydro-11H-
dinaphtho[1,2-p:1,2-n] [1,4,10,13,7]tetraoxaazacycloheptade-
cine 1c.
Purification: column chromatography (CHCl3–MeOH =
3. Conclusion
9:1). Yield: 49%. 1H NMR (500 MHz) d 0.90 3Y, t, J = 7.4 Hz, CY3,
1.29 (2H, q, J = 7.4 Hz, NCH2CH2CH2CH3), 1.45 (2H, m, NCH2
CH2CH2CH3), 2.65 (4H, br s, NCH2), 2.78 (2H, br s, NCH2), 3.38–
3.65 (8H, m, OCH2), 3.93–3.96 (2H, m, OCH2), 4.27–4.31 (2H, m,
OCH2), 7.11 (2H, d, J = 8.5 Hz, BINOL-H), 7.20 (2H, td, J = 7.0 Hz,
BINOL-H), 7.30 (2H, td, J = 7.0 Hz, BINOL-H), 7.46 (2H, d,
J = 9.0 Hz, BINOL-H), 7.85 (2H, d, J = 8.1 Hz, BINOL-H), 7.93 (2H, d,
J = 9.0 Hz, BINOL-H) ppm. 13C NMR (75 MHz) d 14.1 (N(CH2)3CH3)
20.7 (NCH2CH2CH2CH3), 28.3 (NCH2CH2CH2CH3), 54.1 (NCH2), 56.2
(NCH2), 68.8 (OCH2), 69.5 (OCH2), 70.3 (OCH2), 116.0 (BINOL-C),
In conclusion, we have developed a series of new (R)-BINOL-
based azacrown ethers 1c–i for the stereoselective phase-transfer
catalytic Michael addition of an N-protected aminomethylenephos-
phonate 3 onto acrylic acid derivatives 4a–f. Adducts 5a and 5e
can be considered as useful precursors of enantiopure substituted
aminophosphonic acid derivatives. Moreover, the absolute configu-
ration of 5a was determined to be (1S,3R) by comparing the experi-
mental CD spectrum with the quantum chemically calculated CD
spectra of the four possible stereoisomers.

484
T. S. Pham et al. / Tetrahedron: Asymmetry 22 (2011) 480–486
120.4 (BINOL-C), 123.8 (BINOL-C), 125.6 (BINOL-C), 126.5 (BINOL-C),
128.0 (BINOL-C), 129.4 (BINOL-C), 129.5 (BINOL-C), 134.3 (BINOL-C),
1H NMR (500 MHz) d 2.58 (2H, br s, NCH2), 2.70 (6H, br s, NCH2
and ArCH2), 3.35 (4H, br s, OCH2), 3.39–3.44 (2H, m, OCH2), 3.60–
3.63 (2H, m, OCH2), 3.77 (3H, s, OCH3), 3.94–3.97 (2H, m, OCH2),
4.24–4.28 (2H, m, OCH2), 6.71–6.75 (3H, m, ArH), 7.12 (2H, d,
J = 8.5 Hz, BINOL-H), 7.16 (1H, t, J = 7.5 Hz, ArH), 7.20 (2H, t,
J = 7.3 Hz, BINOL-H), 7.31 (2H, t, J = 7.3 Hz, BINOL-H), 7.47 (2H, d,
J = 9 Hz, BINOL-H), 7.85 (2H, d, J = 8 Hz, BINOL-H), 7.92 (2H, d,
J = 9 Hz, BINOL-H) ppm.13C NMR (75 MHz) d 33.5 (ArCH2), 54.1
(NCH2), 55.0 (OCH3), 58.2 (NCH2), 69.3 (OCH2), 69.8 (OCH2), 69.9
(OCH2), 111.1 (ArC), 114.5 (ArC), 115.9 (BINOL-C), 120.2 (BINOL-C),
121.0 (ArC), 123.5 (BINOL-C), 125.3 (BINOL-C), 126.1 (BINOL-C),
127.8 (BINOL-C), 129.0 (BINOL-C), 129.2 (BINOL-C), 134.0 (BINOL-C),
154.5 (BINOL-C) ppm,
½
a 2D0
ꢁ
¼ þ127:4 (c 0.95, CHCl3). HRMS:
þ
C32H38NO4 m/z calcd 500.2801, found 500.2796 (diff. ꢀ0.5 mDa,
ꢀ1.0 ppm).
4.2.2.2. (R)-13-(3-Hydroxypropyl)-8,9,12,13,14,15,17,18-octahy-
dro-11H-dinaphtho[1,2-p:1,2-n] [1,4,10,13,7]tetraoxaazacy-
cloheptadrcine 1d.
Purification: column chromatography
(CHCl3–MeOH = 9:1). Yield: 42%. 1H NMR (500 MHz) d 1.29 (1H,
br, OH), 1.65 (2H, m, NCH2CH2CH2OH), 2.65 (2H, m, NCH2), 2.86
(2H, m, NCH2), 2.98 (2H, m, NCH2), 3.38–3.85 (8H, m, OCH2),
3.96–3.99 (2H, m, OCH2), 4.30–4.32 (2H, m, OCH2), 7.12 (2H, d,
J = 8.1 Hz, BINOL-H), 7.22 (2H, td, J = 7.4 Hz, BINOL-H), 7.34 (2H,
td, J = 7.3 Hz, BINOL-H), 7.49 (2H, d, J = 9.0 Hz, BINOL-H), 7.88
(2H, d, J = 8.1 Hz, BINOL-H), 7.97 (2H, d, J = 9.0 Hz, BINOL-H) ppm.
13C NMR (75 MHz) (NCH2CH2CH2O), 54.3 (NCH2), 56.0 (NCH2),
63.0 (CH2OH), 68.5 (OCH2), 69.5 (OCH2), 70.2 (OCH2), 116.1 (BI-
NOL-C), 120.3 (BINOL-C), 123.8 (BINOL-C), 125.5 (BINOL-C), 126.5
(BINOL-C), 128.1 (BINOL-C), 129.4 (BINOL-C), 129.5 (BINOL-C),
141.8 (ArC), 154.4 (BINOL-C), 159.5 (ArC) ppm. ½a D20
¼ þ154
ꢁ
þ
(c 0.94, CHCl3). HRMS: C37H40NO5 m/z calcd 578.2906, found
578.2887 (diff. ꢀ1.9 mDa, ꢀ3,3 ppm).
4.2.2.6. (R)-13-[2-(4-Methoxyphenyl)ethyl]-8,9,12,13,14,15,17,18
octahydro-11H-dinaphtho[1,2-p:1,2-n][1,4,10,13,7]tetraoxaza-
cycloheptadecine 1h.
Purification: as for 1d. Yield: 29%. 1H
NMR (500 MHz) d 2.53–2.60 (2H, m, NCH2), 2.64–2.70 (6H, m,
NCH2 and ArCH2), 3.32–3.38 (4H, m, OCH2), 3.41–3.45 (2H, m,
OCH2), 3.58–3.62 (2H, td, OCH2), 3.74 (3H, s, OCH3), 3.94–3.98 (2H,
td, OCH2), 4.24–4.28 (2H, m, OCH2), 6.77 (2H, d, J = 8.5 Hz, ArH),
7.05 (2H, d, J = 8.5 Hz, ArH), 7.11 (2H, d, J = 8.5 Hz, BINOL-H), 7.20
(2H, t, J = 7.5 Hz, BINOL-H), 7.31 (2H, t, J = 7.5 Hz, BINOL-H), 7.48
(2H, d, J = 9 Hz, BINOL-H), 7.85 (2H, d, J = 8 Hz, BINOL-H), 7.93 (2H,
d, J = 9 Hz, BINOL-H) ppm. 13C NMR (125 MHz) d 29.7 (ArCH2), 54.4
(NCH2), 55.3 (OCH3), 58.9 (NCH2), 69.5 (OCH2), 70.0 (OCH2), 70.2
(OCH2), 113.8 (ArC), 116.2 (BINOL-C), 120.4 (BINOL-C), 123.6 (BI-
NOL-C), 125.4 (BINOL-C), 126.2 (BINOL-C), 127.9 (BINOL-C), 128.8
(ArC), 129.1 (BINOL-C), 129.4 (BINOL-C), 129.7 (ArC), 134.1 (BI-
134.2 (BINOL-C), 154.5 (BINOL-C) ppm. ½a D20
¼ þ171 (c 0.76,
ꢁ
þ
CHCl3). HRMS: C31H36NO5 m/z calcd 502.2602, found 502.2593
(diff. 0.9 mDa, ꢀ1.8 ppm).
4.2.2.3. (R)-13-(3-Methoxypropyl)-8,9,12,13,14,15,17,18-octa-
hydro-11H-dinaphtho[1,2-p:1,2-n] [1,4,10,13,7]tetraoxaaza-
cycloheptadecine 1e.
Purification: column chromatography
(CHCl3–MeOH = 9:1). Yield: 77%. 1H NMR (500 MHz) d 1.67 (2H,
m, NCH2CH2CH2O), 2.51 (4H, br s, NCH2), 2.63 (2H, br s, NCH2),
3.26 (3H, s, OCH3), 3.30–3.46 (8H, m, OCH2), 3.58–3.62 (2H, m,
OCH2), 3.95–3.98 (2H, m, OCH2), 4.24–4.28 (2H, m, OCH2), 7.11
(2H, d, J = 8.5 Hz, BINOL-H), 7.19 (2H, td, J = 7.3 Hz, BINOL-H),
7.30 (2H, td, J = 7.3 Hz, BINOL-H), 7.47 (2H, d, J = 9.5 Hz, BINOL-
H), 7.85 (2H, d, J = 8 Hz, BINOL-H), 7.92 (2H, d, J = 9 Hz, BINOL-H)
ppm. 13C NMR (75 MHz, CDCl3) d 31.4 (NCH2CH2CH2O), 53.1
(NCH2), 54.4 (NCH2), 58.5 (OCH3), 69.4 (OCH2), 69.9 (OCH2), 70.1
(OCH2), 71.0 (OCH2), 116.1 (BINOL-C), 120.4 (BINOL-C), 123.6 (BI-
NOL-C), 125.4 (BINOL-C), 126.2 (BINOL-C), 127.8 (BINOL-C), 129.1
NOL-C), 154.5 (BINOL-C), 157.9 (ArC) ppm, ½a D20
¼ þ100 (c 1.6,
ꢁ
þ
CHCl3). HRMS: C37H40NO5 m/z calcd 578.2906, found 578.2916
(diff. 1.0 mDa, 1.7 ppm).
4.2.2.7. (R)-13-[2-(3,4-Dimethoxyphenyl)ethyl]-8,9,12,13,14,15,
17,18-octahydro-11H-dinaphtho[1,2-p:1,2-n] [1,4,10,13,7]tetra-
oxazacycloheptadecine 1i.
Purification: column chroma-
(BINOL-C), 129.4 (BINOL-C), 134.1 (BINOL-C), 154.5 (BINOL-C)
tography (CHCl3–MeOH = 9:1) or preparative TLC (alumina,
toluene–MeOH = 97:3). Yield: 13%. 1H NMR (500 MHz) d 2.56–
2.60 (2H, m, NCH2), 2.67 (6H, br s, NCH2 and ArCH2), 3.27–3.44
(6H, m, OCH2), 3.58–3.62 (2H, td, OCH2), 3.81 (3H, s, OCH3), 3.84
(3H, s, OCH3), 3.93–3.97 (2H, td, OCH2), 4.24–4.28 (2H, m, OCH2),
6.67–6.73 (3H, m, ArH), 7.11 (2H, d, J = 8.5 Hz, BINOL-H), 7.19
(2H, td, J = 7.5 Hz, BINOL-H), 7.30 (2H, td, J = 7.5 Hz, BINOL-H),
7.47 (2H, d, J = 9 Hz, BINOL-H), 7.84 (2H, d, J = 8.5 Hz, BINOL-H),
7.92 (2H, d, J = 9 Hz, BINOL-H) ppm.13C NMR (75 MHz) d 33.1
(ArCH2), 54.1 (NCH2), 55.8 (OCH3), 55.9 (OCH3), 58.5 (NCH2),
69.4 (OCH2), 69.7 (OCH2), 70.0 (OCH2), 111.2 (ArC), 112.1 (ArC),
116.0 (BINOL-C), 120.3 (BINOL-C), 120.6 (ArC), 123.5 (BINOL-C),
125.3 (BINOL-C), 126.2 (BINOL-C), 127.8 (BINOL-C), 129.1 (BI-
NOL-C), 129.3 (BINOL-C), 132.8 (ArC), 134.0 (BINOL-C), 147.3
ppm. ½a 2D0
ꢁ
¼ þ140 (c 1.5, CHCl3). HRMS: C32H38NO5 m/z calcd
þ
516.2750, found 516.2742 (diff. ꢀ0.8 mDa, ꢀ1.5 ppm).
4.2.2.4. (R)-13-[2-(2-Methoxyphenyl)ethyl]-8,9,12,13,14,15,17,
18-octahydro-11H-dinaphtho[1,2-p:1,2-n] [1,4,10,13,7]tetraox-
azacycloheptadecine 1f.
Purification: preparative TLC (silica,
CHCl3–MeOH = 9:1 or alumina, CH2Cl2). Yield: 33%. 1H NMR
(500 MHz) d 2.56–2.66 (4H, m, NCH2), 2.69–2.74 (4H, m, NCH2 and
ArCH2), 3.31–3.36 (2H, m, OCH2), 3.38–3.45 (4H, m, OCH2), 3.58–
3.61 (2H, td, OCH2), 3.77 (3H, s, OCH3), 3.94–3.97 (2H, td, OCH2),
4.23–4.28 (2H, m, OCH2), 6.81 (1H, d, J = 8.5 Hz, ArH), 6.84 (1H, t,
J = 8 Hz, ArH), 7.08 (1H, d, J = 7 Hz, ArH), 7.12 (2H, d, J = 8.5 Hz, BI-
NOL-H), 7.16 (1H, t, J = 7.5 Hz, ArH), 7.19 (2H, t, J = 8.5 Hz, BINOL-
H), 7.30 (2H, t, J = 7.5 Hz, BINOL-H), 7.47 (2H, d, J = 9 Hz, BINOL-H),
7.84 (2H, d, J = 8 Hz, BINOL-H), 7.91 (2H, d, J = 9 Hz, BINOL-H) ppm.
13C NMR (125 MHz, CDCl3) d 27.7 (ArCH2), 54.0 (NCH2), 55.2
(OCH3), 56.4 (NCH2), 69.4 (OCH2), 69.9 (2 peaks, OCH2), 110.2
(ArC), 116.1 (BINOL-C), 120.4 (BINOL-C), 120.4 (ArC), 123.5 (BI-
NOL-C), 125.4 (BINOL-C), 126.2 (BINOL-C), 127.3 (ArC), 127.8 (BI-
NOL-C), 129.1 (BINOL-C), 129.3 (BINOL-C), 130.3 (ArC), 134.1
(ArC), 148.8 (ArC), 154.4 (BINOL-C) ppm. ½a D20
¼ þ120 (c 1.1,
ꢁ
þ
CHCl3). HRMS: C38H42NO6 m/z calcd 608.3012, found 608.3027
(diff. 1.5 mDa, 2.5 ppm).
4.3. Typical procedure for the synthesis of 5
A stirred mixture of 3 (0.5 g, 1.5 mmol), catalyst 1 (0.15 mmol)
and NaOtBu (0.192 g, 2 mmol) in abs. toluene (7 mL) was cooled to
78 °C under an argon atmosphere. After 10 min., a toluene solution
(3 mL) of the acrylic acid derivative 4 (1.8 mmol) was added. After
stirring for the given time at 78 °C, the reaction was quenched with
saturated aqueous NH4Cl and extracted with toluene. The com-
bined organic extracts were dried over MgSO4, and the toluene
was evaporated under reduced pressure. Product 5 was isolated
(BINOL-C), 154.5 (BINOL-C), 157.5 (ArC) ppm. ½a D20
¼ þ118 (c 2,
ꢁ
þ
CHCl3). HRMS: C37H40NO5 m/z calcd 578.2906, found 578.2907
(diff. 0.1 mDa, 0.2 ppm).
4.2.2.5. (R)-13-[2-(3-Methoxyphenyl)ethyl]-8,9,12,13,14,15,17,
18octahydro-11H-dinaphtho[1,2-p:1,2-n][1,4,10,13,7] tetraox-
azacycloheptadecine 1g.
Purification: as for 1d. Yield: 19%.

T. S. Pham et al. / Tetrahedron: Asymmetry 22 (2011) 480–486
485
by column chromatography on silica using EtOAc–hexane = 7:3
(for 5a, b, c, e, f) and CH2Cl2–MeOH = 9:1 (for 5d) as eluent. Cata-
lyst 1 was also recovered during column chromatography.
9H), 1.80–2.4 (m, 1H), 2.22–2.40 (m, 1H), 2.40–2.51 (m, 1H),
3.90–4.01 (m, 1H), 4.04–4.26 (m, 4H), 7.30–7.83 (m, 10H).). 13C
NMR (60 MHz, CDCl3, TMS): d 16.61, (OCH2CH3), 16.72 (OCH2CH3),
18.92 (CHCH3), 27.97 (C(CH3)3), 35.16 (d, JPC = 4.9 Hz, CH2), 37.74
(d, JPC = 14.4 Hz, CHCH3), 59.52 (d,, JPꢀC = 158 Hz, CHP), 62.30 (d,
JPC = 6.60 Hz, POCH2CH3), 62.60 (OC(CH3)3), 62.65 (d, JPC = 6.60 Hz,
POCH2CH3), 127.99 (Ph), 128.41 (Ph), 128.45 (Ph), 128.57 (Ph),
128.71 (Ph), 128.84 (Ph), 128.86 (Ph), 128.93 (Ph), 130.18 (Ph),
130.28 (Ph), 135.70 (Ph), 135.74 (Ph), 139.53 (Ph), 139.58 (Ph),
170.88 (CN), 175.56 (CO), 31P NMR (121 MHz CDCl3, H3PO4): d
24.3. MS (ESI): m/z 474.24005 [M+H]+, calcd for C26H37NO5P:
474.24039.
4.3.1. [(1S)-(Benzhydrylidene-amino)-(3R)-cyano-3-methyl-
propyl]-phosphonic acid diethyl ester 5a
Colorless oil. ½a D20
¼ þ17:1 (c 0.8, CHCl3). HPLC conditions: Chi-
ꢁ
ralpack ADH (hexane-IPA 95:5, flow rate: 0.8 mL/min, 256 nm,
5 °C) major diastereomer: tmajor = 53.4 min and tminor = 22.5 min;
minor diastereomer: tmajor = 27.7 min and tminor = 69.2 min. Major
diastereomer: 1H NMR (500 MHz): d 1.02 (d, J = 7.0 Hz, 3H), 1.24 (t,
J = 7.0 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.98–2.10 (m, 1H), 2.22–2.70
(m, 2H), 3.88–4.00 (m, 1H), 4.00–4.20 (m, 2H), 7.19–7.62 (m, 10H)
ppm. 13C NMR (60 MHz): d 16.53, (OCH2CH3), 16.60, (OCH2CH3),
18.63 (CH3), 23.02 (d, JPC = 16.2 Hz, CHCH3), 36.34 (d, JPC = 4.3 Hz,
CH2), 59.14 (d, JPC = 157.34 Hz, CHP), 62.78 (d, JPC = 7.89 Hz,
POCH2CH3), 65.40 (d, JPC = 6.54 Hz, POCH2CH3), 122.68 (CHCN),
128.13 (Ph), 128.32 (Ph), 128.46 (Ph), 128.48 (Ph), 128.48 (Ph),
128.56 (Ph), 128.68 (Ph), 128.90 (Ph), 128.91 (Ph), 129.0 (Ph),
129.08 (Ph), 130.1 (Ph), 130.65 (Ph), 132.46 (Ph), 135.06 (Ph),
135.32 (Ph), 139.12 (Ph), 139.25 (Ph), 171.90 (CN) ppm. 31P NMR
(121 MHz): d 22.8 ppm. Minor diastereomer: 1H NMR (500 MHz): d
1.18 (d, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz,
3H), 1.98–2.10 (m, 1H), 2.22–2.70 (m, 2H), 3.88–4.0 (m, 1H), 4.0–
4.2 (m, 2H), 7.19–7.62 (m, 10H) ppm. 13C NMR (60 MHz): d 16.53,
(OCH2CH3), 16.60, (OCH2CH3), 17.70 (CH3), 22.69 (d, JPC = 15.2 Hz,
CHCH3), 35.94 (d, JPC = 4.8 Hz, CH2), 59.20 (d, JPC = 159.09 Hz, CHP),
62.87 (d, JPC = 4.41 Hz, POCH2CH3), 62.97 (d, JPC = 4.0 Hz, POCH2CH3),
122.04 (CHCN), 128.13 (Ph), 128.32 (Ph), 128.46 (Ph), 128.48 (Ph),
128.48 (Ph), 128.56 (Ph), 128.68 (Ph), 128.90 (Ph), 128.91 (Ph),
129.0 (Ph), 129.08 (Ph), 130.1 (Ph), 130.65 (Ph), 132.46 (Ph),
135.06 (Ph), 135.32 (Ph), 139.12 (Ph), 139.25 (Ph), 172.61 (CN)
ppm. 31P NMR (121 MHz): d 22.8. MS (ESI): m/z 399.18296 [M+H]+,
calcd for C22H28N2O3P: 399.18321.
4.3.4. [1-(Benzhydrylidene-amino)-3-dimethylcarbamoyl-
propyl]-phosphonic acid diethyl ester 5d
White solid. HPLC conditions: Kromasil Amycoat (hexane–EtOH
90:10, flow rate: 0.5 ml/min, 256 nm, 20 °C) tmajor = 49.5 min and
tminor = 59.6 min.1H NMR (500 MHz): d 1.29 (3H, t, JHH = 7.1 Hz),
1.33 (3H, t, JHH = 7.1 Hz), 2.20–2.28 (3H, m), 2.34–2.38 (1H, m),
2.86 (3H, s), 2.95 (1H, s), 3.89–3.96 (1H, m), 4.08–4.21 (4H, m),
7.22–7.84 (10H, m) ppm. 13C NMR (60 MHz): d 16.70 (OCH2CH3),
16.78 (OCH2CH3), 27.0 (d, JPC = 4.7 Hz, CHCH2CH2CO), 30.31 (d,
JPC = 12.8 Hz, CHCH2CH2CO), 35.54 (NCH3), 37.39 (NCH3), 60.93
(d, JPC = 159.1 Hz, CHP), 62.67 (d, JPC = 7.1 Hz, OCH2CH3), 62.77 (d,
JPC = 7.1 Hz, OCH2CH3), 128.25 (Ph), 128.29 (Ph), 128.48 (Ph),
128.69 (Ph), 128.91 (Ph), 128.94 (Ph), 128.96 (Ph), 130.26 (Ph),
130.55 (Ph), 132.62 (Ph), 135.91 (d, JPC = 2.5 Hz, CArq), 139.53, (d,
JPC = 3.4 Hz, CArq), 171.15 (d, JPC = 16.7 Hz, Ph2CN), 172.36 (CO)
ppm. 31P NMR: (121.5 MHz): d 24.3 ppm. MS (ESI): m/z 431.2108
[M+H]+, calcd for C23H32N2O4P: 431.2100.
4.3.5. [(1S)-(Benzhydrylidene-amino)-3-cyano-propyl]-
phosphonic acid diethyl ester 5e15e
Oil. HPLC conditions: Chiralpack AD, (hexane-IPA 9:1 flow rate:
0.5 mL/min, 256 nm, 20 °C) tminor = 20.5 min and tmajor = 33.9 min.
1H NMR (300 MHz): d 1.29 (3H, t, JHH = 7.1 Hz), 1.35 (3H, t,
JHH = 7.1 Hz), 2.25–2.45 (4H, m), 3.86–3.95 (1H, m), 4.09–4.20
(4H, m), 7.27–7.82 (10H, m). 13C NMR d (75.5 MHz): 15.9, 16.5,
16.7, 26.2 (d, JPC = 4.2 Hz), 60.1 (d, JPC = 155.9 Hz), 62.4 (d,
JPC = 7.1 Hz), 117.3, 128.4, 128.9, 130.7 131.1, 139.8, 142.9, 170.5.
31P NMR: (121.5 MHz): d 22.6.
4.3.2. (S)-4-(Benzhydrylidene-amino)-4(diethoxy-phosphoryl)-
butyric acid tert-butyl ester 5b15e
Colorless oil. HPLC conditions: Chiralpack ADH (hexane-IPA
95:5, flow rate: 1 ml/min, 256 nm,, 20 °C) tminor = 13.0 min, tmajor
=
26.9 min. 1H NMR (300 MHz, CDCl3): d 1.29 (3H, t, JHH = 7.1 Hz),
1.34 (3H, t, JHH = 7.1 Hz), 1.37, (9H, s), 2.15–2.26 (4H, m), 3.85–
3.89 (1H, m), 4.09–4.19 (4H, m), 7.19–7.58 (10H, m). 13C NMR
(75.5 MHz, CDCl3): d 16.5, 16.6, 26.6 (d, JPC = 4.3 Hz), 28.1, 32.5,
60.8 (d, JPC = 158.3 Hz), 62.6 (d, JPC = 7.1 Hz), 80.3, 128.0, 128.5,
130.3, 132.4, 135.7, 137.6 139.4, 171.1, 172.5. 31P NMR:
(121.5 MHz, CDCl3): d 23.9. FAB-MS m/z 460.5 [M+1]+, calcd 459.52.
4.3.6. [1-(Benzhydrylidene-amino)-3-cyano-2-phenyl-propyl]-
phosphonic acid diethyl ester 5f
Colorless oil. HPLC conditions: Chiralpack ADH (hexane-IPA
95:5, flow rate: 1 ml/min, 256 nm, 5 °C) major diastereomer: tmajor
=
32.7 min and tminor = 62.8 min; minor diastereomer: tmajor = 27.7 min
and tminor = 69.2 min. Major diastereomer: 1H NMR (500 MHz): d
1.24 (t, J = 7.05 Hz, 3H), 1.29 (t, J = 7.03 Hz, 3H), 3.30 (dd,
JHaHb = 17.22 Hz, JHH = 5.59 Hz, 1H), 3.55 (dd, JHaHb = 17.22 Hz,
JHH = 3.98 Hz, 1H), 3.71–3.80 (m, 1H), 3.99–4.16 (m, 5H), 7.04–
7.62 (m, 15Har) ppm. 13C NMR (60 MHz): d 16.7, (d, JPC = 5,71 Hz,
CH3), 16.7, (d, JPC = 5,66 Hz, CH3), 18.7 (d, JPC = 4.03 Hz, CH2), 44.0
(d, JPC = 3.42 Hz, CHPh), 62.9 (d, JPC = 7.0 Hz, OCH2), 63.1 (d,
JPC = 7.21 Hz, OCH2), 65.4 (d, JPC = 155.45 Hz, CHP), 119.6 (CH2CN),
127.8 (Ph), 127.8 (Ph), 127.8 (Ph), 128.2 (Ph), 128.4 (Ph), 128.4
(Ph), 128.6 (Ph), 128.9 (Ph), 129.0 (Ph), 129.00 (Ph), 131.0 (Ph),
135.0 (d, JPC = 2,63 Hz, CArq), 139.1 (d, JPC = 3,73 Hz, CArq), 139.3
(d, JPC = 13.97 Hz, CArqCH), 172.9 (d, JPC = 15,59 Hz, Ph2CN) ppm.
31P NMR (121 MHz): d 21.80 ppm. Minor diastereomer: 1H NMR
(500 MHz): d 1.10 (t, J = 7.03 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H),
4.3.3. 4-(Benzhydrylidene-amino)-4(diethoxy-phosphoryl)-2-
methyl-butyric acid tert-butyl ester 5c15f
Colorless oil. HPLC conditions: Chiralpack ADH (hexane–IPA
95:5, flow rate: 0.8 ml/min, 256 nm, 20 °C) major diastereomer:
tmajor = 6.8 min and tminor = 12.8 min; minor diastereomer: tmajor
=
9.1 min and tminor = 65.1 min. Major diastereomer: 1H NMR
(500 MHz, CDCl3, TMS): d 0.81 (d, J = 8.0 Hz, 3H), 1.28–1.38 (m,
6H), 1.36 (s, 9H), 1.80–2.4 (m, 1H), 2.22–2.40 (m, 1H), 2.40–2.51
(m, 1H), 3.90–4.01 (m, 1H), 4.04–4.26 (m, 4H), 7.30–7.83 (m,
10H). 13C NMR (60 MHz, CDCl3, TMS): d 16.56, (OCH2CH3), 16.63
(OCH2CH3), 18.92 (CHCH3), 28.04 (C(CH3)3), 34.73 (d, JPC = 4.6 Hz,
CH2), 37.40 (d, JPC = 15.0 Hz, CHCH3), 59.52 (d, JPꢀC = 158 Hz,
CHP), 62.37 (d, JPC = 6.60 Hz, POCH2CH3), 62.60 (OC(CH3)3), 62.71
(d, JPC = 6.70 Hz, POCH2CH3), 127.99 (Ph), 128.41 (Ph), 128.45
(Ph), 128.57 (Ph), 128.71 (Ph), 128.84 (Ph), 128.86 (Ph), 128.93
(Ph), 130.18 (Ph), 130.28 (Ph), 135.70 (Ph), 135.74 (Ph), 139.53
(Ph), 139.58 (Ph), 170.88 (CN), 175.56 (CO). 31P NMR (121 MHz
CDCl3, H3PO4): d 24.4. Minor diastereomer: 1H NMR (500 MHz,
CDCl3, TMS): d 1.12 (d, J = 6.8 Hz, 3H), 1.28–1.38 (m, 6H), 1.27 (s,
2.85 (dd, JHaHb = 16.52 Hz, JHH = 9.80 Hz, 1H), 3.10 (dd, JHaHb
=
16.52 Hz, JHH = 4.0 Hz, 1H), 3.51–3.58 (dd, JHaHb = 13.25 Hz,
JHH = 3.98 Hz, 1H), 3.71–3.8 (m, 1H), 3.99–4.16 (m, 5H), 7.04–7.62
(m, 15Har) ppm. 13C NMR (60 MHz): d 16.4, (d, JPC = 6.11 Hz, CH3),
16.4, (d, JPC = 6.12 Hz, CH3), 18.7 (d, JPC = 4.03 Hz, CH2), 50.1 (d,

486
T. S. Pham et al. / Tetrahedron: Asymmetry 22 (2011) 480–486
3. Kyba, E. B.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Cram, D. J. J. Am. Chem. Soc. 1973,
95, 2692–2693.
4. (a) Kubo, Y. Synlett 1999, 161–174; (b) Bitter, I.; Koszegi, É.; Grün, A.; Bakó, P.;
JPC = 16.17 Hz, CHPh), 62.9 (d, JPC = 7 Hz, OCH2), 63.1 (d,
JPC = 7.21 Hz, OCH2), 59.8 (d, JPC = 168.87 Hz, CHP), 127.8 (Ph),
127.8 (Ph), 127.8 (Ph), 128.2 (Ph), 128.4 (Ph), 128.4 (Ph), 128.6
(Ph), 128.9 (Ph), 129.0 (Ph), 129.0 (Ph), 131.0 (Ph) ppm, CH2CN, CArq
and Ph2CN cannot be assigned.31P NMR (121 MHz): d 21.8. MS
(ESI): major diastereomer: m/z 461.1985 [M+H]+, minor diastereo-
mer: m/z 461.2001 [M+H]+, calcd for C27H30N2O3P: 461.1994.
}
Pál, K.; Grofcsik, A.; Kubinyi, M.; Balázs, B.; Tóth, G. Tetrahedron: Asymmetry
2003, 14, 1025–1035.
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3195–3199; (c) Mazaleyrat, J. P.; Wright, K.; Azzini, M.-V.; Gaucher, A.;
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7. (a) Grün, A.; Koszegi, É.; Bitter, I. Tetrahedron 2004, 60, 5041–5048; (b) Kim, K.
4.4. CD spectra and calculations
S.; Jun, E. J.; Kim, S. K.; Choi, H. J.; Joo, J.; Lee, C.-H.; Hyun, M. H.; Yoon, J.
Tetrahedron Lett. 2007, 48, 2481–2484.
}
8. Koszegi, É.; Grün, A.; Bitter, I. Supramol. Chem. 2006, 18, 67–76.
4.4.1. Circular dichroism spectra
Experimental spectra: The UV–vis absorption and CD spectra of
5a, (S)-5b, and 5e were taken in acetonitrile. The spectra are shown
}
}
9. (a) Bakó, P.; Szöllosy, Á.; Bombicz, P.; Toke, L. Synlett 1997, 291–292; (b) Bakó,
}
}
T.; Bakó, P.; Szöllosy, Á.; Czugler, M.; Keglevich, Gy.; Toke, L. Tetrahedron:
Asymmetry 2002, 13, 203–209; (c) Bakó, T.; Bakó, P.; Keglevich, Gy.; Báthori, N.;
Czugler, M.; Tatai, J.; Novák, T.; Parlagh, Gy.; Toke, L. Tetrahedron: Asymmetry
in Figure 2. UV–vis (k [nm],
e
[Mꢀ1 cmꢀ1]): Compound 4a: 252,
}
2003, 14, 1917–1923.
1.20 ꢂ 104. Compound (S)-4b: 251, 1.37 ꢂ 104. Compound 4e:
10. Kafarski, P.; Lejczak, B. Phosphorus Sulfur Silicon Relat. Elem. 1991, 63, 193–215.
11. (a) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassal, C. H.; Holmes, S. W.; Lambert,
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Cortes, C. Biochemistry 2003, 42, 14785–14793.
252, 1.52 ꢂ 104. CD (k [nm],
De
[Mꢀ1 cmꢀ1]): Compound 4a: 290,
ꢀ3.40; 243, +5.81; 219, ꢀ3.68. Compound (S)-4b: 290, ꢀ1.31;
243, +1.86; 215, ꢀ1.77. Compound 4e: 288, ꢀ0.25; 241.5, +0.30;
212.5, ꢀ1.01.
13. Abdel-Meguid, S. S.; Zhao, B.; Murthy, K. H. M.; Winborne, E.; Choi, J. K.;
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Herrera, R. P.; Sgarzani, V.; Ricci, A. J. Org. Chem. 2006, 71, 6269–6272; For C-C
bond formation see: (e) Jászay, Zs. M.; Németh, G.; Truong, S. P.; Petneházy, I.;
4.4.2. Calculations
Conformational analysis, providing only the lowest energy con-
former, was carried out on the (1S,3R)- and (1S,3S)-diastereomers
of 5a with the Conformer Plugin of the program Marvin,18 which
applies the Dreiding force field. For each diastereomer the geome-
try of the most stable conformer was optimized by DFT with stan-
dard B3LYP functional19 and Pople’s 6-31++G(d,p) basis set.20 Then
the energies, oscillatory and rotatory strengths of the first 25 sin-
glet transitions have been determined by TD-DFT calculations
using the same functional and basis set. The quantum chemical cal-
culations were performed using the GAUSSIAN-03 suite of pro-
grams.21 The absorption and CD spectra obtained were plotted
based on these data, approaching the spectral bands with Gaussian
curves having bandwidths of 0.3 eV.22 The calculated CD spectra of
the diastereomers are compared to the experimental spectrum of
5a in Figure S2. The wavelength scale of the calculated CD spectra
was shifted in the figure so that the lowest energy bands in the
experimental and calculated absorption spectra overlap. The sol-
vent effect on the spectra was tested with the help of the PCM
model.23 It was found that the solvent effect does not affect the
sign of the bands in the CD spectrum, it leads only to small shifts,
between (+1) and (ꢀ5) nm, of the spectral bands, thus it does not
influence the determined absolute configuration.
}
}
Grun, A.; Toke, L. Tetrahedron: Asymmetry 2005, 16, 3837–3840; (f) Jászay, Zs.
}
M.; Truong, S. P.; Németh, G.; Bakó, P.; Petneházy, I.; Toke, L. Synlett 2009,
1429–1432.
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Chem. Soc. 1995, 117, 10879–10888; (b) Mikolajczyk, M.; Lyzwa, P.; Drabowicz,
J. Tetrahedron: Asymmetry 1997, 8, 3991–3994; (c) Lefebvre, I. M.; Evans, A. S.,
Jr. J. Org. Chem. 1997, 62, 7532–7533; (d) Davis, F. A.; Lee, S.; Yan, H.; Titus, D. D.
Org. Lett. 2001, 3, 1757–1760; For C–C bond formation see: (e) Schöllkopf, U.;
Schütze, R. Liebigs Ann. Chem. 1987, 45–49; (f) Groth, U.; Richter, L.; Schöllkopf,
U. Liebigs Ann. Chem. 1992, 903–909; (g) Ouazzani, F.; Roumestant, M. L.;
Viallefont, P. Tetrahedron: Asymmetry 1991, 2, 913–917.
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Hudson, H. R., Eds.; John Wiley and Sons: Chichester, 2000; pp 537–558.
Chapter15; (b) Ordonez, M.; Rojas-Cabrera, H.; Cativiela, C. Tetrahedron 2009,
65, 17–49.
18. Marvin 5.2.5.1., 2009, ChemAxon. http://www.chemaxon.com.
19. (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, B37, 785; (b) Becke, A. D. J.
Chem. Phys. 1993, 98, 5648.
20. Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213.
21. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J. .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Gonzalez, C.; Pople, J. A. GAUSSIAN 03, Revision B.01; Gaussian: Pittsburg, PA,
2003.
Acknowledgment
Financial support by the Hungarian Scientific Research Fund
(OTKA No. K 60284 and K 67585 and NF 72194) is gratefully
acknowledged.
References and notes
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2. Izatt, R. M.; Zhu, C. Y.; Huszthy, P.; Bradshaw, J. S. Enantiomeric Recognition in
Macrocycle-Primary Ammonium Cation System In Crown Compounds: Toward
Future Applications; Cooper, S. R., Ed.; VCH: New York, 1992. Chapter 12.
22. McCann, D. M.; Stephens, P. J. J. Org. Chem. 2006, 71, 6074.
23. Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117.