Synchronized stereocontrol of planar chirality by crystallization-induced asymmetric transformation

Article abstract of DOI:10.1016/j.tetlet.2008.11.021

Synchronized stereocontrol of two planar-chiral units was accomplished by using crystallization-induced asymmetric transformation (CIAT) of cyclophane-type bridged bisnicotinate derivatives 5b and 7. After screening various linkers, (S)-2-amino-1-butanol

Full text of DOI:10.1016/j.tetlet.2008.11.021

Tetrahedron Letters 50 (2009) 409–412
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synchronized stereocontrol of planar chirality by crystallization-induced
asymmetric transformation
Nobuhiro Kanomata , Gou Mishima , Jun Onozato b
a,*
b
a
Department of Chemistry and Biochemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku–ku, Tokyo 169-8555, Japan
Department of Applied Chemistry, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Synchronized stereocontrol of two planar-chiral units was accomplished by using crystallization-induced
asymmetric transformation (CIAT) of cyclophane-type bridged bisnicotinate derivatives 5b and 7. After
screening various linkers, (S)-2-amino-1-butanol and (S)-tert-leucinol were found to be the most effective
for CIAT of the corresponding bridged bisnicotinate 5b and 7, respectively, whose diastereomeric ratio
finally reached 97% and 88%, respectively.
Received 19 September 2008
Revised 2 November 2008
Accepted 7 November 2008
Available online 12 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Planar-chiral organic molecules represented by cyclophanes1,2
and other related compounds3 are recently becoming attractive
targets for organic chemists because of their potent and character-
OH
R
OH
R
O
O
O
N
110 °C
N
1) Recrystallization
2) NaOMe
OH
H
H
N
CH2)10
R = Bn
N
N
(
istic functionality as distinctive chiral sources for asymmetric reac-
(MeO) CO
2
4
3) LiOH
tions.
However, research on that area has been still
(
Sp,3'S)-1h: mp, 179 °C
(Sp,3'S)-1h
99% de
(Sp)-2
underdeveloped according to the limited numbers of efficient syn-
thetic routes to access such chiral molecules.5 We had previously
reported new synthetic methods for [n](2,5)cyclophane-3-carbox-
ylates (or bridged benzoates)7 and for [n](2,5)pyridinophane-3-
(Rp,3'S)-1h: oil
,6
R
O
R
NHBoc
NHBoc
O
O
90-100 °C
O
1) Recrystallization
2) LiOH
(
Rp)-2
8
carboxylates (or bridged nicotinates) and also their stereocontrol
N
R = Bn
N
(
CH2)10
p
of planar chirality via crystallization-induced asymmetric transfor-
7
,9
mation (CIAT) and adsorption-induced asymmetric transforma-
(S ,4'S)-3h: oil
(R ,4'S)-3h
98% de
p
1
0
(R ,4'S)-3h: mp, 118 °C
tion (AIAT).
In these transformations, linkers derived from
p
amino alcohols play a key role in forming hydrogen bonds at amide
functionality and neighboring stereochemistry at chiral centers on
the auxiliary transfers to the configuration of planar chirality accu-
p p
Scheme 1. Synthesis of chiral bridged nicotinic acid (S )-2 and (R )-2 via crystal-
lization-induced asymmetric transformation.
0
9
0
11
p p
mulated in (S ,3 S)-1h (R = Bn) or (R ,4 S)-3h (R = Bn) with 99%
or 98% de, respectively (Scheme 1). On the other hand, only a little
is known about asymmetric transformation concerning simulta-
neous stereocontrol of multi chiral centers6 and, therefore, we
turned our attention to seeking stereocontrol of multi planar chi-
rality by using single asymmetric center. For achieving such stereo-
control in pyridinophane systems, we have synthesized bridged
bisnicotinic acid derivatives 5a–h whose two planar-chiral units
are linked together with the chiral amino alcohols (S)-4a–h. We
describe here the first synchronized stereocontrol of planar chiral-
ity via CIAT: a dynamic ‘induced-fit’ of two independent atropiso-
meric units in a crystal field.
mixtures of each stereoisomer due to their similar polarity, we ini-
tially synthesized every single diastereoisomer of 5a–h indepen-
dently for examining their physical states to find out a suitable
candidate for the synchronized stereocontrol. The reaction of ami-
no alcohol (S)-4a–h with 1.5 equiv amount of (S)-methyl
[10](2,5)pyridinophane-3-carboxylate [(S )-2 in Scheme 1] in the
p
presence of EDCꢀHCl salt and a catalytic amount of DMAP resulted
0
0
in the formation of ca. 1/1 mixture of (S ,3 S,S )-5a–h and (S ,3 S)-
p
p
p
1a–h. Similarly, (S)-4a–h reacted with 1.5 equiv amount of (R )-2
p
0
0
afforded (R ,3 S,R )-5a–h and (R ,3 S)-1a–h. After separation of
p
p
p
Syntheses of bisnicotinic acid derivatives 5a–h are described in
Scheme 2. Since the compounds 5a–h are generally inseparable
the mono- and bis-nicotinate derivatives, the latter mono-nicotin-
0
amide derivatives (S ,3 S)-1a–h and (R ,3’S)-1a–h were treated
p
p
with (R
diastereomers, (S
p p
)-2 and (S )-2, respectively, to furnish the rest of the
0
0
p
p p p
,3 S,R )-5a–h and (R ,3 S,S )-5a–h. Melting
*
Corresponding author. N.K. used to be a faculty member of Meiji University
points of these bridged bisnicotinate derivatives were tabulated
in Table 1.
(
1995–2005). Tel.: +81 5286 3193; fax: +81 3 5286 3487.
E-mail address: kanomata@waseda.jp (N. Kanomata).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.021

4
10
N. Kanomata et al. / Tetrahedron Letters 50 (2009) 409–412
A 1/1/1/1 mixture of the four diastereoisomers 5b was simply
N
prepared from dehydrocondensation of (S)-4b with two equivalent
amounts of (±)-2 in 89% yield. Table 2 summarizes the results of
thermal asymmetric transformation of 5b. After heating the mix-
O
R
O
OH
R
(Sp)-2 (1.5eq)
O
O
O
N
H
p
(S ,3'S)-1a-h
+
EDC•HC, DMAP
CH2Cl2, RT
H2N
(S
N
ture without solvent for one day at 90 °C, the relative amount of
0
(R
p
,3 S,R
p
)-5b whose initial ratio was statistical 25% largely in-
)-4a-h
(
S
p
,
3'S,Sp)-5a-h
N
(
R
p)-2
creased to 43% and those of the other three isomers decreased to
O
R
O
57% (entry 1). Further successive heating of the mixture at 100 °C
EDC•HC, DMAP
CH2Cl2, RT
0
slowly but steadily amplified the fraction of (R
p
,3 S,R
p
)-5b in accor-
N
H
dance with acceleration of the rope-skipping isomerization (en-
N
tries 2–4). The ratio eventually reached 97% among all the four
(
S
p
,
3'S,Rp)-5a-h
N
13
stereoisomers, which is worth being 96% ee of (R
It is indeed that the 97% grade of 5b afford (R
9% yield by clean removal of the amino alcohol linker with so-
p
)-2 (entry 5).
O
R
p
)-6 with 97% ee in
O
(
R
p)-2 (1.5eq)
9
N
H
(
S
)-4a-h
p
(R ,3'S)-1a-h
+
14
EDC•HC, DMAP
CH2Cl2, RT
dium methoxide/dimethyl carbonate reagents (Scheme 3).
N
Surprisingly, heating the 1/1/1/1 mixture at 100 °C from the
beginning seems to be inappropriate to complete the asymmetric
transformation: the major isomer reached at most 80% even after
10 days. This indicates that initial temperature control is extremely
important to achieve high stereoselectivity of the synchronized
stereocontrol of 5b.
(
(
R
R
p
,
3'S,Rp)-5a-h
N
(Sp)-2
O
R
O
EDC•HC, DMAP
CH2Cl2, RT
O
N
H
N
p
,
3'S,Sp)-5a-h
Scheme 2. Syntheses of chiral bridged bisnicotinate derivatives 5a–h.
Table 2
a
All the compounds of 5a–h are desired solid molecules except
Synchronized stereocontrol of planar-chiral nicotinate 5b
0
(S
p
,3 S,R
p
)-5a, but the melting points of 5a,d,f–h are not high en-
(
CH2)10
ough (less than 59 °C) to keep a solid state at such temperatures
for CIAT that allow rope-skipping isomerization of the planar-chi-
ral moieties (usually above 80–90 °C). On the other hand, com-
pounds 5b, 5c, and 5e, simply having a series of linear alkyl
groups on the linker, share a similarity in common that there are
only one diastereoisomer each which has significantly higher melt-
N
O
O
O
90–100 °C
N
Et
1
2
H
(Rp,3'S,Rp)-5b
+
Other 5b
N
CH2)10
5 days
(
A mixture of 5b
t db
0
)-5bc (%)
Entry
T (°C)
(R
p
,3 S,R
p
ing point as compared to those of the other three isomers. Among
0
43d
76
90
92.5
97
compounds 5c and 5e, the compounds (S
p
,3 S,R
p
)-5c,e fulfill the
1
2
3
4
5
1
2
3
4
5
90
100
100
100
100
prerequisite for crystal growth by CIAT; however, those com-
pounds incorporate a pair of (R )- and (S )-bridged nicotinate units,
p
p
leading to racemic 2. On the other hand, it is noteworthy that
0
(R
p
,3 S,R
p
)-5b, derived from (S)-(+)-2-amino-1-butanol [(S)-4b],
)-configurations even with a higher
a
Heat isomerization was carried out by using a glass tube oven (Shibata Scien-
tific Technology, Ltd) known as a Kugelrohr apparatus.
incorporates two identical (R
p
melting point by more than 100 °C. Therefore, we chose a diaste-
b
Cumulative reaction time for CIAT.
0
c
reomeric mixture of 5b to explore CIAT to (R
p
,3 S,R
p
)-5b with syn-
The ratio was determined by HPLC. For conditions, see Ref. 13.
d
Determined by using 1H NMR.
chronized stereocontrol of planar chirality.
Table 1
Physical properties of bridged bisnicotinate derivatives 5a–h
Compound
R
Configurationa
Mp (°C)
Compound
R
Configurationa
Mp (°C)
0
0
5a
5b
5c
5d
a
Me
(S
p
,3 S,S
p
)
53.0–54.0
Oil
33.0–33.5
48.1–48.5
5e
Bu
(S
(S
(R
(R
p
,3 S,S
p
)
38.0–39.0
114.0–115.0
34.0–35.0
42.0–43.0
0
0
(
(
(
S
R
R
p
,3 S,R
p
)
)
p
,3 S,R
p
)
)
0
0
p
,3 S,S
p
p
,3 S,S
p
0
0
p
,3 S,R
p
)
p
,3 S,R
p
)
0
0
Et
(S
p
,3 S,S
p
)
44.5–45.1
48.5–49.5
44.0–44.8
5f
i-Bu
t-Bu
Bn
(S
(S
p
,3 S,S
p
)
47.5–48.5
53.5–54.5
48.0–49.0
52.0–53.0
0
0
(
(
(
S
R
R
p
,3 S,R
p
)
)
p
,3 S,R
p
)
)
0
0
p
,3 S,S
p
(R
(R
p
,3 S,S
p
0
0
p
,3 S,R
p
)
143.5–144.0
p
,3 S,R
p
)
0
0
Pr
(S
p
,3 S,S
p
)
43.0–44.0
128.5–129.5
43.0–44.0
5g
5h
(S
(S
p
,3 S,S
p
)
56.0–56.8
55.0–56.0
53.0–54.0
58.0–59.0
0
0
(
(
(
S
R
R
p
,3 S,R
p
)
p
,3 S,R
p
)
0
0
p
,3 S,S
p
)
(R
(R
p
,3 S,S
p
)
0
0
p
,3 S,R
p
)
49.5–50.5
p
,3 S,R
p
)
0
0
i-Pr
(S
p
,3 S,S
p
)
52.5–53.5
41.5–42.5
48.2–49.0
48.5–49.2
(S
(S
p
,3 S,S
p
)
48.7–50.4
47.5–50.0
50.8–52.6
51.3–53.1
0
0
(
(
(
S
R
R
p
,3 S,R
p
)
p
,3 S,R
p
)
0
0
p
,3 S,S
p
)
(R
(R
p
,3 S,S
p
)
0
0
p
,3 S,R
p
)
p
,3 S,R
p
)
Configuration of 5a–h is expediently shown in a bracket from left to right indicating (1) configuration of nicotinamide moiety with subscript ‘p’ standing for planar
chirality, (2) central chirality on linker at 3 position, and (3) configuration of nicotinate moiety.
0

N. Kanomata et al. / Tetrahedron Letters 50 (2009) 409–412
411
O
O
(CH2)10
N
(CH2)10
NaOMe (5eq)
CO(OMe)2 (5eq)
OMe
N
(
R
9
p
,
3'S,Rp)-5b
HN
Et
O
+
O
O
7% grade
N
CH2Cl2, RT, 24 h
O
O
O
N
O
9
9%
(
9
R
p)-6
t-Bu
N
H
N
H
t-Bu
120°C, 7 d
7% ee
(
(
(
Sp,S,S,Sp)-7: mp, 152.1 °C
Sp,S,S,Rp)-7: mp, 118.5 °C
Rp,S,S,Rp)-7: mp, 123.0 °C
N
N
Scheme 3. Synthesis of bridged nicotinate (R
p
)-6 by removal of chiral auxiliary
0
O
O
from (R
p
,3 S,R
p
)-5b.
O
O
O
N
O
t-Bu
N
H
N
H
t-Bu
(Sp,S,S,Sp)-7
88%
(
CH2)10
(
CH2)10
N
N
O
O
O
O
O
O
heat
several days
N
H
N
H
No significant
t-Bu
t-Bu
crystalline growth
N
(
(
(
Sp,S,S,Sp)-8: mp, 133.8 °C
Sp,S,S,Rp)-8: mp, 127.7 °C
Rp,S,S,Rp)-8: mp, 130.6 °C
Scheme 4. Bridged bisnicotinate derivatives
stereocontrol of 7.
7 and 8 and the synchronized
the accumulated planar-chiral units to give bridged nicotinate
)-6 with 87% ee in 90% yield as well as the recovery of the
(S
p
2
6
linker, N ,N -bis((S)-1-hydroxy-3,3-dimethyl-2-butanyl)pyridine-
,6-dicarboxamide, in quantitative yield. On the other hand, each
2
isomer of bispyridinophane 8 did not show any significant differ-
ence in melting points and, thereby, no significant crystal growth
was observed with stereocontrol of planar chirality.
Consequently, we have accomplished synchronized stereocon-
tol of two planar-chiral units by CIAT method accumulating the
same atropisomeric configuration in the crystalline bispyridino-
phane compounds, 5b and 7 as the first examples of multi-stereo-
control of planar chirality.
Figure 1. CD spectra of bridged bisnicotinate derivatives 5b.
Figure 1 depicted CD spectrum of each diastereoisomer of 5b to
demonstrate that its line shape is dependent upon absolute config-
12
uration regarding the planar-chiral moieties (Fig. 1). The com-
0
0
pounds (S
p
,3 S,S
p
)- and (R
p
,3 S,R
p
)-5b comprising the two
) exhibit two
Acknowledgment
identical planar-chiral units (i.e., 2 ꢁ S
p
or 2 ꢁ R
p
strong CD bands at 230 and 283 nm with either two positive or
The authors acknowledge The Asahi Glass Foundation for finan-
cial support to this work.
0
two negative intensities. On the other hand (S
p
,3 S,R
p
)- and
0
(
(
2
R
p
,3 S,S
p
)-5b having a pair of the opposite planar-chiral units
and R ) showed three weaker CD bands at
08, 235–260, and 277–280 nm regions with either positive–nega-
i.e., one each of S
p
p
References and notes
tive–positive or negative–positive–negative intensity. These obser-
vations are in good accordance with usefulness of CD spectra for
structural elucidation of the related chiral cyclophane molecules.
1. (a)For reviews of cyclophanes, see: Modern Cyclophane Chemistry; Gleiter, R.,
Hopf, H., Eds.; Wiley: Chichester, 2004; (b)Cyclophane Chemistry; Vögtle, F., Ed.;
Wiley: Chichester, UK, 1993.
7
,9
2.
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It is of interest to note that those spectra are nearly superimpos-
able on sum spectra of the corresponding nicotinamide 1b
9
15
(
R = Et) and nicotinate 3b (R = Et), indicating that intensities of
D
e
are approximately additive.
2
We have also designed some other candidates such as C -sym-
metric bispyridinophane 716 and 8 having longer linkers derived
3.
For optically active planar-chiral molecules other than cyclophane-type, see:
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chlorides derived from pyridine-2,6-dicaroboxylic and pyridine-
4
9
369; (e) Lee, E. C.; McCauley, K. M.; Fu, G. C. Angew. Chem., Int. Ed. 2007, 46,
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we found that tert-butyl group is the best choice for CIAT since one
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mers and are apparently worth being examined for synchronized
stereocontrol. Indeed, heat isomerization of a 1/2/1 diastereomeric
mixture of 7 initiated a crystal growth of (S
its percentage among all the three isomers reached 88% in a
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1
7
week. The hydrolysis of the final mixture with LiOH liberated

4
12
N. Kanomata et al. / Tetrahedron Letters 50 (2009) 409–412
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ext = 283 (
ꢂ18.4), 261 (ꢂ1.3), 230 (ꢂ40.1), 203.7 (+20.5).
p
13. HPLC analysis showed that the final mixture contained 96.9% of (R )-5b,
3
CN):
2
k
De
0
p
,3 S,R
0 0 0
p p p p p p
1.5% of (S ,3 S,R )-5b, 0.9% of (S ,3 S,S )-5b, and 0.7% of (R ,3 S,S )-5b (column:
7
8
.
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44, 3599–3603; (b) Miao, R.; Zheng, Q.-Y.; Chen, C.-F.; Huang, Z.-T. J. Org. Chem.
2005, 70, 7662–7671.
15. CD spectral data for (S
0
9
.
Kanomata, N.; Ochiai, Y. Tetrahedron Lett. 2001, 42, 1045–1048.
p
, 4 S)-3b: CD (CH
3
CN): kext = 283 (
D
e
+8.4), 261 (+2.2),
ꢂ6.9),
0
1
0. Kanomata, N.; Oikawa, J. Tetrahedron Lett. 2003, 44, 3625–3628.
232 (+23.6), 203 (ꢂ24.5). For (R
p
, 4 S)-3b: CD (CH
3
CN): kext = 283 (De
1
1. (a) Kanomata, N.; Yamaguchi, M.; Mishima, G., unpublished results.; (b)
Kanomata, N. J. Synth. Org. Chem. Jpn. (Yuki Gosei Kagaku Kyokaishi) 2003, 61,
262 (ꢂ1.7), 232 (ꢂ20.3), 205 (+18.7).
16. Selected spectral data for (S ,S,S,S
p
p
)-7: 1H NMR (400 MHz, CDCl
3
) d = ꢂ0.20 (m,
3
52–359.
0
)-5b: 1H NMR (270 MHz, CDCl
p p 3
2. Selected spectral data for (S ,3 S,S ) d = 0.13 (m,
2H), 0.21 (m, 2H), 0.31 (m, 2H), 0.45–0.60 (m, 6H), 0.60–0.75 (m, 4H), 0.75–
1.01 (m, 6H), 1.02–1.25 (m, 4H), 1.13 (s, 18H), 1.34 (m, 2H), 1.54 (m, 2H), 1.72
(m, 2H), 2.49–2.66 (m, 6H), 3.58 (ddd, J = 12.6, 6.9, 4.1 Hz, 2H), 4.36–4.48 (m,
4H), 4.81–4.89 (m, 2H), 7.83 (d, J = 2.4 Hz, 2H), 7.94 (t, J = 7.6 Hz, 1H), 8.09 (d,
J = 10.0 Hz, 2H), 8.26 (d, J = 7.6 Hz, 2H), 8.36 (d, J = 2.4 Hz, 2H); 13C NMR
1
1H), 0.35 (m, 1H), 0.38–0.90 (m, 16H), 0.95–1.29 (m, 8H), 1.31–1.48 (m, 4H),
1.10 (t, J = 7.8 Hz, 3H), 1.49–1.95 (m, 4H), 2.54–2.90 (m, 6H), 3.25 (ddd, J = 12.7,
6.8, 4.4 Hz, 1H), 3.75 (ddd, J = 10.7, 5.8, 4.4 Hz, 1H), 4.35–4.62 (m, 3H), 5.88 (d,
J = 7.4 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 7.97 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 1.9 Hz,
3
(100 MHz, CDCl ) d = 24.4 (2C), 25.0 (2C), 26.1 (2C), 26.3 (2C), 26.7 (6C), 27.5
(2C), 27.6 (2C), 27.8 (2C), 28.1 (2C), 31.7 (2C), 34.3 (2C), 35.6 (2C), 57.4 (2C),
64.0 (2C), 125.1 (4C), 134.5 (2C), 138.8 (2C), 138.9, 148.5 (2C), 152.0 (2C), 161.2
1
3
1
1
3
2
2
H), 8.47 (d, J = 2.4 Hz, 1H); C NMR (68 MHz, CDCl
57.2, 152.1, 150.6, 138.8, 135.5, 134.7, 134.6, 131.8, 124.8, 77.2, 66.3, 50.7,
6.1, 35.1, 31.9, 31.8, 28.3, 28.2, 28.1, 27.82, 27.81, 27.7, 27.6, 27.5, 26.4, 26.38,
3
) d = 168.4, 166.8, 161.5,
(2C), 163.4 (2C), 167.2 (2C); CD (MeCN): kext = 285 (
D
e
+26.5), 262 (+10.1), 231
6.27, 25.24, 25.2, 24.8, 24.6, 24.4, 10.5; CD (CH
3
CN): kext = 283 (
D
e
+ 17.5),
(+51.5). For (S ,S,S,R
p
p
)-7: 1H NMR (400 MHz, CDCl
3
) d = ꢂ0.17 (m, 1H), ꢂ0.05
0
1
60 (+3.1), 230 (+33.3). For (S
p
,3 S,R
p
)-5b: H NMR (270 MHz, CDCl
3
) d = 0.13
(m, 1H), 0.20–0.45 (m, 4H), 0.45–0.65 (m, 10H), 0.80–1.02 (m, 6H), 1.02–1.20
(m, 4H), 1.13 (s, 9H), 1.14 (s, 9H), 1.30–1.35 (m, 2H), 1.51–1.57 (m, 2H), 1.69–
1.75 (m, 2H), 2.49–2.66 (m, 6H), 3.49–3.54 (m, 2H), 4.43–4.45 (m, 4H), 4.84–
4.90 (m, 2H), 7.80 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 8.0,
(
3
m, 1H), 0.35 (m, 1H), 0.38–0.90 (m, 16H), 0.95–1.29 (m, 8H), 1.10 (t, J = 5.3 Hz,
H), 1.31–1.48 (m, 4H), 1.49–1.95 (m, 4H), 2.51–2.92 (m, 6H), 3.25 (ddd,
J = 12.7, 7.8, 4.4 Hz, 1H), 3.75 (ddd, J = 10.2, 6.3, 3.9 Hz, 1H), 4.42–4.59 (m, 3H),
.83 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 8.40 (d,
5
7.6 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 9.6 Hz, 1H), 8.24 (d, J = 8.0 Hz,
1
3
13
J = 2.0 Hz, 1H), 8.46 (d, J = 2.0 Hz, 1H); C NMR (68 MHz, CDCl
3
) d = 168.2,
66.8, 161.2, 157.2, 151.9, 150.4, 138.7, 135.1, 134.5, 134.4, 131.4, 124.8, 77.0,
6.0, 50.5, 35.9, 34.9, 31.7, 31.6, 28.1, 28.0, 27.8, 27.7, 27.65, 27.6, 27.5, 27.4,
6.24, 26.23, 26.1, 25.1, 24.9, 24.6, 24.4, 24.2, 10.3; CD (CH CN): kext = 277
)-5b: H NMR (270 MHz,
) d = 0.13 (m, 1H), 0.35 (m, 1H), 0.38–0.90 (m, 16H), 0.95–1.29 (m, 8H),
1H), 8.25 (d, J = 7.6 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H);
C
1
6
2
NMR (100 MHz, CDCl ) d = 24.2, 24.4, 25.2, 25.5, 26.0, 26.2, 26.5 (2C), 26.7 (3C),
3
26.9 (3C), 27.5, 27.6, 27.8, 27.9, 28.0, 28.1, 28.2 (2C), 31.5, 31.7, 34.1, 34.2, 35.8,
36.1, 57.1, 57.2, 64.0, 64.1, 124.8, 125.0, 129.8, 129.9, 133.0, 133.2, 134.5,
138.7, 138.8, 150.2, 150.5, 152.0, 152.4, 161.5, 161.6, 164.5, 164.9, 167.2,
3
0
p p
,3 S,S
1
(D
e
+ 2.1), 237 (ꢂ3.9), 208 (+11.7). For (R
CDCl
3
p p
167.6; CD (MeCN): kext = 285 (De +8.4), 270 (+4.6), 253 (+7.2). For (R ,S,S,R )-7:
1
1
3
4
1
.08 (t, J = 5.3 Hz, 3H), 1.31–1.48 (m, 4H), 1.49–1.95 (m, 4H), 2.54–2.90 (m, 6H),
.25 (ddd, J = 12.7, 8.8, 4.4 Hz, 1H), 3.75 (ddd, J = 10.2, 6.3, 3.9 Hz, 1H), 4.45–
.62 (m, 3H), 5.87 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 2.5 Hz, 1H), 7.99 (d, J = 1.9 Hz,
H NMR (400 MHz, CDCl
3
) d = ꢂ0.08 (m, 2H), 0.25–0.40 (m, 4H), 0.50–0.60 (m,
6H), 0.67–0.75 (m, 4H), 0.80–0.95 (m, 6H), 1.00–1.20 (m, 4H), 1.12 (s, 18H),
1.20–1.39 (m, 4H), 1.55–1.68 (m, 4H), 2.47–2.58 (m, 4H), 2.64 (m, 2H), 3.51
(ddd, J = 12.6, 6.9, 4.1 Hz, 2H), 4.41–4.48 (m, 4H), 4.92 (m, 2H), 7.80 (d,
J = 2.3 Hz, 2H), 7.93 (t, J = 7.8 Hz, 1H), 8.03 (d, J = 10.0 Hz, 2H), 8.23 (d,
1
3
3
H), 8.42 (d, J = 2.5 Hz, 1H), 8.47 (d, J = 1.9 Hz, 1H); C NMR (68 MHz, CDCl )
d = 168.4, 167.0, 161.5, 157.6, 152.2, 150.6, 138.8, 135.1, 134.7, 134.5, 131.7,
1
2
24.8, 77.2, 66.3, 50.7, 36.2, 35.0, 31.9, 31.8, 28.3, 28.2, 28.0, 27.88, 27.85, 27.7,
7.5, 26.43, 26.4, 26.38, 26.3, 25.24, 25.2, 24.7, 24.6, 24.4, 10.5; CD (CH CN):
)-5b: H NMR (270 MHz,
) d = 0.13 (m, 1H), 0.35 (m, 1H), 0.38–0.90 (m, 16H), 0.95–1.29 (m, 8H),
J = 7.8 Hz, 2H), 8.34 (d, J = 2.3 Hz, 2H); 13C NMR (100 MHz, CDCl
3
) d = 24.4 (2C),
3
25.1 (2C), 26.2 (2C), 26.3 (2C), 26.7 (2C), 27.6 (6C), 27.8 (4C), 28.1 (2C), 31.7
(2C), 34.4 (2C), 35.9 (2C), 57.4 (2C), 63.9 (2C), 125.0 (4C), 134.3 (2C), 138.7 (2C),
138.9, 148.6 (2C), 151.8 (2C), 160.9 (2C), 163.7 (2C), 167.8 (2C); CD (MeCN):
0
p p
,3 S,R
1
kext = 280 (
D
e
ꢂ4.7), 240 (+2.6), 208 (ꢂ21.1). (R
CDCl
3
1
3
4
1
.05 (t, J = 6.9 Hz, 3H), 1.31–1.48 (m, 4H), 1.49–1.95 (m, 4H), 2.54–2.90 (m, 6H),
.25 (ddd, J = 12.7, 7.8, 3.9 Hz, 1H), 3.75 (ddd, J = 10.8, 6.9, 4.0 Hz, 1H), 4.55–
.62 (m, 3H), 5.88 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.0 Hz,
k
ext = 282 (
17. The final mixture after the heat isomerization consists of 87.7% of (S
11.5% of (S ,S,S,R )-7, and 0.8% of (R ,S,S,R )-7. The ratio was determined by
De ꢂ14.8), 259 (+3.9), 233 (ꢂ60.5).
p p
,S,S,S )-7,
p
p
p
p
1
3
H), 8.40 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H); C NMR (68 MHz, CDCl
3
)
HPLC analysis using CHIRALPAK IA, Dicel Chemical Industries, Ltd, with
hexane/ethyl acetate (2/1) as a mobile phase (flow rate: 1.0 mL/min; oven
temperature: 40 °C).
d = 168.5, 167.1, 161.5, 157.5, 152.2, 150.6, 138.9, 135.2, 134.7, 134.5, 131.8,
24.9, 77.2, 66.2, 50.7, 36.2, 35.0, 32.0, 31.9, 29.7, 28.3, 28.1, 27.88, 27.82, 27.7,
1