Syntheses of chiral homoazacalix[4]arenes incorporating amino acid residues: Molecular recognition for racemic quaternary ammonium ions

Article abstract of DOI:10.1021/jo020300u

Chiral calixarene analogues incorporating amino acid residues into the macrocyclic rings were prepared from the cyclization reactions of bis(chloromethyl)phenol-formaldehyde tetramer with amino acid methyl ester in moderate yields. The macrocycles form a chiral concavity, which is induced by the chiral transmission from the point chirality of the amino acid residues to the phenol-formaldehyde tetramer unit. The macrocycles have the cavity π-basic enough to include the quaternary ammonium ion due to the cation-π interaction and can serve as a shift reagent for racemic ammonium ions during ¹H NMR analysis.

Full text of DOI:10.1021/jo020300u

great extent. It occurred to us to make the chiral
calixarene analogue, which was constructed by changing
from the methylene moiety to a chiral unit. Introduction
of a chiral unit into the cyclic array confers chirality on
the entire macrocycle, thus providing the possibility for
enantiomeric selectivity toward chiral guests. The chiral
unit employed in the instance is an amino acid moiety,
and the chiral guests are quaternary ammonium ions.
Macrocycles 1 were synthesized from the cyclization
reactions of bis(chloromethyl)phenol-formaldehyde tet-
ramers 4 with amino acid methyl esters in 17-67% yields
(Scheme 1). The bis(hydroxymethyl)phenol-formalde-
hyde tetramers 3 were prepared by hydroxymethylation
of the corresponding tetramers 2 with 35% formalin in
the presence of base at 60 °C in 41% (3a ) and 39% (3b)
yields, respectively. Then, 3 was treated with thionyl
chloride in dry benzene at room temperature to give 4a
and 4b in 91 and 92% yields, respectively. They were
identified on the basis of IR, mass, 1D and 2D NMR
spectral data, and elemental analysis.
Syn th eses of Ch ir a l Hom oa za ca lix[4]a r en es
In cor p or a tin g Am in o Acid Resid u es:
Molecu la r Recogn ition for Ra cem ic
Qu a ter n a r y Am m on iu m Ion s
Kazuaki Ito,* Motoyoshi Noike, Atsushi Kida, and
Yoshihiro Ohba
Department of Chemistry and Chemical Engineering,
Faculty of Engineering, Yamagata University,
Yonezawa 992-8510, J apan
itokazu@yz.yamagata-u.ac.jp
Received April 29, 2002
Abstr a ct: Chiral calixarene analogues incorporating amino
acid residues into the macrocyclic rings were prepared from
the cyclization reactions of bis(chloromethyl)phenol-form-
aldehyde tetramer with amino acid methyl ester in moderate
yields. The macrocycles form a chiral concavity, which is
induced by the chiral transmission from the point chirality
of the amino acid residues to the phenol-formaldehyde
tetramer unit. The macrocycles have the cavity π-basic
enough to include the quaternary ammonium ion due to the
cation-π interaction and can serve as a shift reagent for
1
The OH phenolic protons of 1 in the H NMR spectra
were observed at δ 10.0-10.4 ppm as broad singlets. In
the IR spectra in chloroform, the OH stretching vibration
absorption was observed in the region of 3180-3240 cm-1
as broad bands (Table 13). Based on the findings, the
intramolecular hydrogen bonding of 1 is compatible with
that of calix[4]arene (νOH 3138 cm-1 in CCl4, δOH 10.2 ppm
in CDCl3).1a
The conformation of the macrocycles was determined
using NMR spectroscopy. The ArCH2Ar methylene pro-
tons of 1 appeared as three pairs of doublets due to the
geminal coupling between Hexo and Hendo even at 20 °C
and did not coalesce in CDCl3 up to 55 °C. The differences
between the chemical shifts of the doublets (∆δ) of 1 are
in the range of 0.67-0.76 ppm, indicating that the
adjacent aryl rings adopt a syn orientation (Table 23).1a
The chemical shifts of the ArCH2Ar carbon atoms of 1 (δ
31.6-32.7 ppm) provided further support for the all-syn
orientation (Table 13).4 These observations indicate that
these calixarene analogues adopt a cone form as the
preferred conformation in a solution.
The absence of symmetry in compounds 1a -j is
reflected in their very complex 1H and 13C NMR spectra.
This chiral character is also manifested in their CD
spectra which, interestingly, are more intense in hexane
than in methanol, the difference probably being the result
of the disruption of the intramolecular hydrogen bonding
by the more polar methanol (Figure 1 and Table 33). Since
it is known that calixarenes can bind quaternary am-
monium ions,5 we chose R-methylbenzyl trimethylam-
mnoium iodide (5a ) as a putative guest, measuring the
complexation by means of 1H NMR spectroscopy in CDCl3
1
racemic ammonium ions during H NMR analysis.
Modifying calixarenes to provide various properties
into the molecules is a field that has great promise. Many
studies of the modification of calixarenes have so far been
made at the small (lower) and large (upper) rims of the
calixarene skeleton.1 Although some groups have made
calixarene analogues,2 we noticed that the modification
of the methylene bridges has not been exploited to any
* To whom correspondence should be addressed. Tel: +81-0238-
26-3097. Fax: +81-0238-26-3413.
(1) (a) Gutsche, C. D. Calixarenes; Royal Society of Chemistry:
London, 1989. (b) Gutsche, C. D. Calixarene Revisited; Royal Society
of Chemistry: London, 1998. (c) Ikeda, A.; Nagasaki, T.; Shinkai, S.
J . Phys. Org. Chem. 1992, 5, 699. (d) Iwamoto, K.; Shimizu, H.; Araki,
K.; Shinkai, S. J . Am. Chem. Soc. 1993, 115, 3997. (e) Nagasaki, T.;
Tajiro, Y.; Shinkai, S. Recl. Trav. Chim. Pays-Bas 1993, 112, 407. (f)
Nagasaki, T.; Fujishima, H.; Shinkai, S. Chem. Lett. 1994, 989. (g)
Casnati, A.; Fabbi, M.; Pelizzi, N.; Pochini, A.; Sansone, F.; Modugno,
E.; Tarzia, G. Bioorg. Med. Chem. Lett. 1996, 2699. (h) Dondoni, A.;
Kleban, M.; Marra, A. Tetrahedron Lett. 1997, 38, 7801. (i) Dondoni,
A.; Marra, A.; Scherrmann, M.-C.; Casnati, A.; Sansone, F.; Ungaro,
R. Chem. Eur. J . 1997, 3, 1774. (j) Sansone, F.; Barboso, S.; Casnati,
A.; Fabbi, M.; Pochini, A.; Ugozzoli, F.; Ungaro, E. Eur. J . Org. Chem.
1975, 40, 4741. (k) Sansone, F.; Barboso, S.; Casnati, A.; Sciotto, D.;
Ungaro, E. Tetrahedron Lett. 1999, 40, 4741. (l) Castello, R. K.;
Nuckolls, C.; Rebeck, J ., J r. J . Am. Chem. Soc. 1999, 121, 11156. (m)
Nomura, E.; Takagi, M.; Nakaika, C.; Uchida, M.; Taniguchi, H. J .
Org. Chem. 1999, 64, 3151.
(2) (a) Gruttner, C.; Bo¨hmer, V.; Vogt, W.; Thondorf, I.; Biali, S. E.;
Grynszpan, F. Tetrahedron Lett. 1994, 35, 6267. (b) Takemura, H.;
Shinmyozu, T.; Miura, H.; Khan, I. U.; Inazu, T. J . Inclusion Phenom.
1994, 19, 193. (c) Araki, K.; Inada, K. Shinkai, S. Angew. Chem., Int.
Ed. Engl. 1996, 35, 72. (d) Ito, K.; Izawa, S.; Ohba, T.; Ohba, Y.; Sone,
T. Tetrahderon Lett. 1996, 37, 5959. (e) Sone, T.; Ohba, Y.; Moriya,
K.; Kumada, H.; Ito, K. Tetrahedron 1997, 53, 10689. (f) Yamato, T.;
Saruwatari, Y.; Yasumatsu, M. J . Chem. Soc., Perkin Trans. 1 1997,
1731. (g) Chirakul, P.; Hampton, P. D.; Duesler, E. N. Tetrahedron
Lett. 1998, 39, 5473.
(3) Tables 1-4 and Figure 3 are given in the Supporting Informa-
tion.
(4) (a) J aime, C.; de Mendoza, J .; Prados, P.; Nieto, P. M.; Sanchez,
C. J . Org. Chem. 1991, 56, 3372. (b) Stewart, D. R.; Krawise, M.;
Kashyap, R. P.; Watson, W. H.; Gutsche, C. D. J . Am. Chem. Soc. 1995,
117, 586.
10.1021/jo020300u CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/17/2002
J . Org. Chem. 2002, 67, 7519-7522
7519

SCHEME 1
F IGURE 2. Partial 1H NMR spectra of racemic ammonium
iodide 5a in CDCl3: (a) [5a ] ) 1.0 × 10-2 M; (b) [5a ] ) [1a ] )
1.0 × 10-2 M.
was split into two peaks (δN-CH 3.240 and 3.256 ppm)
3
with 1:1 intensity ratio. The 1H NMR spectrum of 1a with
the R- or S-ammonium ion 5a showed a single peak
(δN-CH 3.240 ppm for the R-form, δN-CH 3.256 ppm for
3
3
F IGURE 1. CD Spectra of 1a and 1f.
the S-form). The same phenomena were also observed
in the complexes of the racemic 5a with 1d (δN-CH 3.240
3
ppm for the R-form, δN-CH 3.234 ppm for the S-form).6
solution. In the presence of 1a , all protons of the
ammonium salt moved to high field due to the ring
current effect of the π-cavity of 1a during the formation
3
Contrary to this, the similar experiment using the achiral
macrocycle 1e shifted to high field (δN-CH 3.310 ppm) but
3
of the complex ([1a ] ) [5a ] ) 10 mM, ∆δ ) δobs - δfree
,
did not split. In the same experiment using 1j, the
∆δN-CH3 ) -0.137 and -0.153 ppm, ∆δCH ) -0.084
ppm, ∆δCH3 ) -0.023 ppm). The higher chemical shifts
of the N-CH3 protons suggest that the N-CH3 group is
included in the cavity of 1a .
chemical shift of the methyl group (δN-CH 3.385 ppm) of
3
5a scarcely changed due to the steric repulsion of the tert-
butyl group on the phenol ring during the formation of
the complex (Table 43). The 1:1 stoichiometry of the
complexes (1-5) was confirmed using J ob’s method.7 The
association constants (Ka) of 1d to 5a were determined
Figure 2 shows the trimethyl signal (δN-CH 3.393 ppm)
3
of the racemic 5a in the 1H NMR spectra. In the presence
of 1a , the trimethyl signal of the racemic ammonium ion
(6) (a) Kabuto, K.; Sasaki, Y. J . Chem. Soc., Chem. Commun. 1987,
670. (b) Yanagihara, R.; Tominaga, M.; Aoyama, Y. J . Org. Chem. 1994,
59, 6865. (c) Kitae, T.; Nakayama, T.; Kano, K. J . Chem. Soc., Perkin
Trans. 2 1998, 207.
(5) (a) Araki, K.; Shimizu, H.; Shinkai, S. Chem. Lett. 1993, 205.
(b) Morozumi, T.; Shinkai, S. J . Chem. Soc., Chem. Commun. 1994,
1219. (c) Konishi, H.; Tamura, T.; Ohkubo, H.; Kobayashi, K.;
Morikawa, O. Chem. Lett. 1996, 685.
(7) J ob, A. Ann. Chim. 1928, 2, 113.
7520 J . Org. Chem., Vol. 67, No. 21, 2002

128.6, 144.1, 144.4, 147.1, 149.2. Anal. Calcd for C45H58Cl2O4:
C, 73.65; H, 7.97. Found: C, 73.92; H, 7.66.
by a nonlinear least-squares fitting method of a binding
1
curve obtained from the H NMR titrations8 (Ka ) 22 (
Gen er a l P r oced u r e of th e P r ep a r a tion of Dih om oa za -
ca lix[4]a r en e Der iva tives (1). To a solution of bis(chloro-
methyl)phenol-formaldehyde tetramer (4) (1.0 mmol) in dry
DMF (24 mL) in the presence of sodium carbonate (0.42 g, 4.0
mmol) was slowly added a solution of amino acid methyl ester
monohydrochloride (1.0 mmol) in dry DMF (14 mL) over 1 h.
After the addition was completed, the mixture was allowed to
react at 30 °C for 2 h. Removal of DMF under reduced pressure
a gave yellow oil containing a white powder, which was dissolved
in chloroform. The solution was filtered, and evaporation of the
solvent gave a yellow oily residue, which was subjected to column
chromatography on silica gel using hexane/ethyl acetate 9:1 as
an eluent to give macrocyclic compound (1) as crystals. Recrys-
tallization from dichloromethane-hexane gave pure 1 as crys-
tals.
2 for 1d -(R)-5a complex, Ka ) 20 ( 2 for 1d -(S)-5a ).
These results indicate that 1 form the diastereomeric
complexes with the racemic ammonium ion 5 through the
cation-π interaction.9
The synthesis of chiral calixarenes via the insertion of
amino acid moieties into the cyclic array has been
demonstrated. The ability of these chiral macrocyclic
compounds to act as chiral hosts has been measured
using quaternary ammonium salts, which are thought
to reside in the cavity of the host as the results of
π-cation attractions. These chiral calixarenes may serve
as chiral shift reagents for racemic quaternary am-
1
monium ions in H NMR analyses.9
1a : mp 183-186 °C; [R]20 ) +58 (c ) 0.1, CHCl3); FAB-
D
MS m/z 624 [M + 1]+; H NMR (CDCl3) δ 0.88 (d, J ) 6.5 Hz,
1
Exp er im en ta l Section
3H), 1.35 (br s, 6H), 2.17 (s, 3H), 2.18 (s, 9H), 2.41 (m, 1H), 3.03
(d, J ) 14.5 Hz, 1H), 3.07 (d, J ) 10.5 Hz, 1H), 3.39 (d, J ) 13.5
Hz, 1H), 3.42 (d, J ) 13.5 Hz, 1H), 3.43 (d, J ) 13.5 Hz, 1H),
3.44 (d, J ) 12.2 Hz, 1H), 3.75 (s, 3H), 3.97 (d, J ) 14.5 Hz,
1H), 4.06 (d, J ) 13.5 Hz, 1H), 4.17 (d, J ) 13.5 Hz, 1H), 4.18
(d, J ) 13.5 Hz, 1H), 4.39 (d, J ) 12.2 Hz, 1H), 6.52 (d, J ) 2.0
Hz, 1H), 6.72 (d, J ) 2.0 Hz, 1H), 6.85 (d, J ) 2.0 Hz, 1H), 6.91
(d, J ) 2.0 Hz, 1H), 6.94 (d, J ) 2.0 Hz, 1H), 6.96 (d, J ) 2.0 Hz,
1H), 6.97 (d, J ) 2.0 Hz, 1H), 7.02 (d, J ) 2.0 Hz, 1H), 10.32 (br
s, 4H); 13C NMR (CDCl3) δ 19.3, 20.2, 20.5, 27.5, 31.6, 32.1, 50.0,
50.8, 54.1, 69.0, 120.6, 122.4, 126.8, 127.2, 127.8, 128.1, 128.3,
128.8, 129.1, 129.1, 129.2, 129.2, 129.4, 129.6, 129.8, 130.5, 131.1,
131.5, 132.2, 146.9, 147.4, 150.1, 151.3, 171.4. Anal. Calcd for
All chemicals were reagent grade and were used without
further purification. Compounds 2a (lit.10 mp 173 °C), 2b (lit.11
mp 208-209 °C), and 3b (lit.12 mp 139-140 °C) were prepared
according to the methods reported in the literature.
Syn t h esis of Bis(h yd r oxym et h yl)p h en ol-F or m a ld e-
h yd e Tetr a m er (3). To a mixture of 2a (4.75 g, 10.2 mmol),
20% potassium hydroxide aqueous solution (20 mL), and 1,4-
dioxane (10 mL) was added 35% formalin (80 mL) over 2 h at 0
°C. After the addition was complete, the mixture was heated at
60 °C for 5.5 h under a nitrogen atmosphere. The reaction
mixture was cooled to room temperature and acidified by 10%
hydrochloride aqueous solution. White precipitates were col-
lected by filtration and dissolved with chloroform. The solution
was washed with 10% hydrochloride aqueous solution and dried
over anhydrous sodium sulfate. Removal of solvent gave a pale
yellow solid, which was subjected to column chromatography on
silica gel to give 3a as colorless crystals.
C
39H45NO6: C, 75.09; H, 7.27; N, 2.25. Found: C, 75.11; H, 7.31;
N, 2.12.
1b: mp 232-236 °C; [R]20 ) +37 (c ) 0.1, CHCl3); FAB-
D
MS m/z 672 [M+ 1]+; 1H NMR (CDCl3 at -60 °C) δ 2.20 (s, 3H),
2.23 (s, 3H), 2.24 (s, 3H), 2.28 (s, 3H), 3.11 (d, 1H), 3.29 (dd, J
) 5.5, 13.8 Hz, 1H), 3.39 (d, J ) 13.5 Hz, 1H), 3.41 (d, J ) 13.5
Hz, 1H), 3.47 (d, J ) 13.5 Hz, 1H), 3.49 (d, J ) 13.5 Hz, 1H),
3.70 (dd, J ) 5.5, 8.0 Hz, 1H), 3.77 (s, 3H), 3.88 (d, J ) 13.5 Hz,
1H), 3.91 (d, J ) 13.5 Hz, 1H), 3.93 (dd, J ) 8.0, 13.8 Hz, 1H),
4.20 (d, J ) 13.5 Hz, 2H), 4.58 (d, J ) 12.0 Hz, 1H), 6.57 (br s,
1H), 6.79 (br s, 1H), 6.89 (br s, 1H), 6.97 (br s, 2H), 7.01 (br s,
1H), 7.05 (br s, 1H), 7.09 (br s, 1H), 7.30-7.50 (m, 5H), 8.98 (br
s, 1H), 9.88 (br s, 1H), 10.05 (br s, 1H), 11.95 (br s, 1H); 13C
NMR (CDCl3) δ 20.3, 20.4, 20.5, 31.5, 32.0, 34.8, 51.4, 53.5, 63.5,
120.7, 122.2, 126.7, 127.1, 127.5, 127.6, 127.7, 128.1, 128.3, 128.6,
128.7, 128.9, 129.2, 129.2, 129.3, 129.4, 129.5, 130.2, 130.6, 131.0,
131.2, 131.4, 138.1, 146.9, 147.4, 150.5, 151.2, 170.8. Anal. Calcd
for C43H45NO6: C, 76.88; H, 6.75; N, 2.08. Found: C, 76.84; H,
6.94; N, 1.96.
3a : mp 143-145 °C (CH2Cl2-hexane); FAB-MS m/z 511 [M
1
- OH]+; IR (KBr) 3381, 3014, 2918, 2852, 1483 cm-1; H NMR
(CDCl3) δ 2.21 (s, 12H), 3.79 (s, 6H), 4.68 (s, 4H), 6.75 (d, J )
2.0 Hz, 2H), 6.92 (s, 4H), 7.00 (d, J ) 2.0 Hz, 2H), 9.18 (bs, 4H);
13C NMR (CDCl3) δ 20.3, 20.4, 30.9, 31.5, 63.6, 125.6, 127.1,
127.2, 127.3, 127.4, 129.5, 129.6, 129.9, 130.5, 130.6, 147.4, 149.7.
Anal. Calcd for C33H36O6: C, 74.98; H, 6.06. Found: C, 75.12;
H, 5.92.
Syn th esis of Bis(ch lor om eth yl)p h en ol-F or m a ld eh yd e
Tetr a m er (4). To a solution of 3 (1.44 mmol) in dry benzene
(20 mL) was added a solution of thionyl chloride (1.10 g, 9.1
mmol) in dry benzene (5 mL) over 1 h. After the addition was
completed, the mixture was allowed to stir at rt for 5 h. Removal
of benzene gave white crystals that were recrystallized from
benzene to give 4 as crystals.
1c: mp 172-177 °C; [R]20D ) +54 (c ) 0.1, CHCl3); FAB-MS
m/z 688 [M + 1]+; 1H NMR (CDCl3 at -60 °C) δ 2.16 (s, 3H),
2.17 (s, 3H), 2.18 (s, 3H), 2.20 (s, 3H), 3.19 (br s, 1H), 3.26 (br s,
1H), 3.29 (br s, 1H), 3.36 (d, J ) 13.5 Hz, 1H), 3.43 (d, J ) 13.5
Hz, 1H), 3.45 (d, J ) 12.5 Hz, 1H), 3.52 (d, J ) 13.5 Hz, 1H),
3.64 (br s, 1H), 3.70 (br s, 3H), 3.83 (d, J ) 12.5 Hz, 1H), 3.91
(d, J ) 13.5 Hz, 1H), 4.14 (br s, 2H), 4.39 (br s, 1H), 6.57 (d, J
) 2.0 Hz, 1H), 6.71 (d, J ) 2.0 Hz, 1H), 6.78 (m, 2H), 6.82 (d, J
) 2.0 Hz, 1H), 6.90 (d, J ) 2.0 Hz, 1H), 6.91 (br s, 2H), 6.95 (d,
J ) 2.0 Hz, 1H), 7.02 (d, J ) 2.0 Hz, 1H), 7.08 (m, 2H), 10.03
(br s, 4H); 13C NMR (CDCl3) δ 20.3, 20.5, 31.6, 32.0, 33.9, 51.2,
51.4, 53.5, 63.7, 115.4, 120.5, 122.0, 127.1, 127.5, 127.7, 127.8,
128.1, 128.6, 128.8, 128.9, 129.1, 129.3, 129.5, 129.8, 130.2, 130.6,
131.0, 131.3, 131.4, 147.0, 147.4, 150.5, 151.5, 154.5, 171.0. Anal.
Calcd for C43H45NO7 E1/2(H2O): C, 74.12; H, 6.65; N, 2.01.
Found: C, 74.09; H, 6.59; N, 1.93.
4a : mp 200-205 °C (benzene); FAB-MS m/z 565 [M + 1]+;
IR (KBr) 3329, 3012, 2922, 2860, 1483 cm-1; 1H NMR (CDCl3) δ
2.22 (s, 6H), 2.24 (s, 6H), 3.80 (s, 2H), 3.83 (s, 4H), 4.65 (s, 4H),
6.93 (m, 6H), 7.07 (d, 2H, J ) 2.0 Hz), 8.51 (bs, 4H); 13C NMR
(CDCl3) δ 20.4, 20.5, 31.0, 31.2, 31.6, 43.3, 124.0, 127.0, 127.4,
128.1, 129.2, 129.6, 129.7, 130.6, 131.0, 132.1, 147.2, 149.3. Anal.
Calcd for C33H34Cl2O4: C, 70.07; H, 6.06. Found: C, 69.96; H,
6.15.
4b: mp 180-185 °C (benzene); FAB-MS m/z 733 [M + 1]+;
IR (KBr) 3356, 2960, 2904, 2868, 1487 cm-1; 1H NMR (CDCl3) δ
1.25 (s, 18H), 1.27 (s, 18H), 3.87 (s, 2H), 3.90 (s, 4H), 4.68 (s,
4H), 7.11 (d, 2H, J ) 2.0 Hz), 7.16 (s, 4H), 7.31 (d, 2H, J ) 2.0
Hz), 8.70 (bs, 4H); 13C NMR (CDCl3) δ 31.4, 31.5, 31.7, 32.2, 34.0,
34.1, 43.8, 123.5, 125.5, 125.9, 126.0, 126.0, 126.9, 127.2, 128.0,
1d : mp 216-220 °C; [R]20 ) +60 (c ) 0.1, CHCl3); FAB-
D
MS m/z 711 [M + 1]+; H NMR (CDCl3) δ 2.14 (s, 3H), 2.19 (s,
1
(8) Hirose, K. J . Inclusion Phenom. Macrocycl. Chem. 2001, 39, 193.
(9) Dougherty, D. A.; Stauffer, D. A. Science 1990, 250, 1558.
(10) Imoto, M.; Ijichi, I.; Tanaka, C.; Kinoshita, M. Makromol. Chem.
1968, 113, 117.
(11) Casiragi, G.; Comia, M.; Ricci, R.; Balduzzi, G.; Casnati, G.
Makromol. Chem. 1983, 184, 1363.
3H), 2.21 (s, 3H), 2.22 (s, 3H), 3.31 (d, J ) 13.5 Hz, 2H), 3.44 (d,
J ) 13.5 Hz, 1H), 3.46 (d, J ) 13.5 Hz, 1H), 3.47 (dd, J ) 5.2,
12.5 Hz, 1H), 3.54 (d, J ) 14.0 Hz, 1H), 3.61 (dd, J ) 8.1, 12.5
Hz, 1H), 3.70 (s, 3H), 3.77 (d, J ) 13.5 Hz, 1H), 3.87 (dd, J )
5.2, 8.1 Hz, 1H), 3.90 (d, J ) 14.0 Hz, 1H), 4.18 (d, J ) 13.5 Hz,
(12) Dhawan, B.; Gutsche, C. D. J . Org. Chem. 1983, 46, 1536.
J . Org. Chem, Vol. 67, No. 21, 2002 7521

2H), 4.52 (d, J ) 11.5 Hz, 1H), 6.55 (d, J ) 2.0 Hz, 1H), 6.75 (d,
J ) 2.0 Hz, 1H), 6.85 (d, J ) 2.0 Hz, 1H), 6.89 (d, J ) 2.0 Hz,
1H), 6.94 (d, J ) 2.0 Hz, 1H), 6.96 (d, J ) 2.0 Hz, 1H), 6.98 (d,
J ) 2.0 Hz, 1H), 7.02 (dd, J ) 7.0, 8.0 Hz, 1H), 7.04 (d, J ) 2.0
Hz, 1H), 7.15 (br s, 1H), 7.16 (dd, J ) 7.0, 8.0 Hz, 1H), 7.36 (d,
J ) 8.0 Hz, 1H), 7.45 (d, J ) 2.0 Hz, 1H), 7.15 (br s, 1H), 7.16
(dd, J ) 7.0, 8.0 Hz,1H), 7.36 (d, J ) 8.0 Hz, 1H), 7.45 (d, J )
8.0 Hz, 1H), 8.00 (br s, 1H), 10.27 (br s, 4H); 13C NMR (CDCl3)
δ 20.3, 20.4, 20.5, 24.9, 31.3, 31.6, 32.1, 51.0, 51.3, 53.5, 61.7,
111.1, 111.3, 118.5, 119.1, 120.6, 121.8, 122.3, 123.6, 127.2, 127.3,
127.5, 127.7, 127.8, 128.1, 128.5, 128.8, 128.9, 129.2, 129.2, 129.3,
129.5, 130.0, 130.6, 131.0, 131.4, 131.4, 136.2, 147.0, 147.4, 150.5,
151.1, 171.0. Anal. Calcd for C45H46N2O6: C, 76.03; H, 6.52; N,
3.93. Found: C, 76.01; H, 6.79; N, 3.71.
1i: mp 169-171 °C; [R]20 ) +30 (c ) 0.1, CHCl3); EI-MS
D
(70 eV) 839 M+; H NMR (CDCl3) δ 1.16 (s, 27H), 1.17 (s, 9H),
1
3.21 (dd, J ) 5.4, 11.9 Hz, 1H), 3.33 (dd, J ) 7.3, 11.9 Hz, 1H),
3.47 (d, J ) 14.0 Hz, 1H), 3.49 (d, J ) 14.0 Hz, 2H), 3.55 (d, J
) 12.0 Hz, 1H), 3.57 (s, 3H), 3.61 (d, J ) 14.0 Hz, 1H), 3.68 (dd,
J ) 5.4, 7.3 Hz, 1H), 3.81 (d, J ) 12.0 Hz, 1H), 3.99 (d, J ) 14.0
Hz, 1H), 4.13 (d, J ) 14.0 Hz, 2H), 4.28 (d, J ) 14.0 Hz, 1H),
6.69 (d, J ) 2.0 Hz, 1H), 6.81 (d, J ) 2.0 Hz, 1H), 7.01-7.23 (m,
12H), 10.44 (br s, 4H); 13C NMR (CDCl3) δ 31.4, 31.5, 32.1, 32.8,
33.9, 34.0, 51.3, 53.7, 63.8, 120.3, 121.6, 12.5,1 125.4, 125.5,
125.7, 126.7, 127.2, 127.3, 127.6, 127.7, 127.9, 128.4, 128.6, 129.5,
138.3, 142.7, 144.1, 144.4, 147.1, 150.6, 151.1, 171.0. Anal. Calcd
for C55H69NO6‚1/2(C6H12): C, 78.96; H, 8.57; N, 1.59. Found: C,
78.75; H, 8.87; N, 1.54.
1e: mp 237-241 °C; FAB-MS m/z 582 [M + 1]+; 1H NMR
(CDCl3) δ 2.19 (s, 12H), 3.10-4.10 (m, 12H), 6.66 (d, J ) 2.4
Hz, 2H), 6.90 (d, J ) 2.4 Hz, 2H), 6.93 (d, J ) 2.4 Hz, 2H), 7.00
(d, J ) 2.4 Hz, 2H), 10.28 (br s, 4H); 13C NMR (CDCl3) δ 20.3,
20.5, 31.6, 32.1, 51.2, 55.3, 121.6, 127.5, 127.9, 128.1, 129.0,
129.4, 129.5, 129.6, 130.8, 130.9, 147.3, 151.2, 170.0. Anal. Calcd
for C45H46N2O6: C, 76.03; H, 6.52; N, 3.94. Found: C, 76.01; H,
6.79; N, 3.71.
1j: mp 188-190 °C; [R]20 ) +22 (c ) 0.1, CHCl3); EI-MS
D
(70 eV) 878 M+; 1H NMR (CDCl3) δ 1.14 (s, 9H), 1.19 (s, 9H),
1.22 (s, 9H), 1.24 (s, 9H), 2.94 (d, J ) 14.0 Hz, 1H), 3.31 (d, J )
14.0 Hz, 1H), 3.46 (d, J ) 14.0 Hz, 1H), 3.52 (d, J ) 14.0 Hz,
1H), 3.55 (dd, J ) 12.2, 13.0 Hz, 1H), 3.74 (dd, J ) 1.0, 13.0 Hz,
1H), 3.86 (d, J ) 14.0 Hz, 1H), 4.07 (d, J ) 14.0 Hz, 1H), 4.33
(d, J ) 11.5 Hz, 1H), 4.35 (dd, J ) 1.0, 12.2 Hz, 2H), 4.46 (d, J
) 14.0 Hz, 1H), 4.70 (d, J ) 14.0 Hz, 1H), 5.02 (d, J ) 11.5 Hz,
1H), 6.64 (d, J ) 2.0 Hz, 1H), 6.76 (d, J ) 2.0 Hz, 1H), 6.91 (dd,
J ) 7.3, 7.6 Hz, 1H), 6.96 (d, J ) 2.0 Hz, 1H), 7.01 (d, J ) 2.0
Hz, 1H), 7.06 (d, J ) 7.8 Hz, 1H), 7.10 (d, J ) 2.0 Hz, 1H), 7.13
(d, J ) 2.0 Hz, 1H), 7.15 (d, J ) 2.0 Hz, 1H), 7.21 (dd, J ) 7.3,
7.8 Hz, 1H), 7.37 (d, J ) 2.0 Hz, 1H), 7.72 (s, 1H), 7.85 (d, J )
8.4 Hz, 1H); 13C NMR (CDCl3) δ 31.4, 31.5, 31.9, 32.0, 32.7, 33.8,
34.0, 51.4, 53.7, 62.0, 110.9, 111.3, 118.5, 119.2, 119.8, 121.2,
121.9, 123.8, 124.7, 125.3, 125.5, 125.6, 125.7, 126.6, 127.1, 127.3,
127.4, 127.5, 127.6, 127.9, 128.0, 128.8, 136.6, 142.6, 142.8, 144.0,
144.4, 147.0, 147.2, 150.4, 151.0, 170.9. Anal. Calcd for
C57H70N2O6‚H2O: C, 76.31; H, 8.09; N, 3.12. Found: C, 76.29;
H, 8.22; N, 3.06.
1f: mp 176-180 °C; [R]20 ) -60 (c ) 0.1, CHCl3); FAB-MS
D
m/z 624 [M + 1]+. Anal. Calcd for C39H45NO6: C, 75.09; H, 7.27;
N, 2.25. Found: C, 74.98; H, 7.31; N, 2.40.
1g: mp 160-165 °C; EI-MS (70 eV) 749 M+; 1H NMR (CDCl3)
δ 1.23 (s, 12H), 3.00-4.30 (m, H), 6.84 (d, J ) 2.4 Hz, 2H), 7.13
(s, 4H), 7.23 (d, J ) 2.4 Hz, 2H), 10.44 (br s, 4H); 13C NMR
(CDCl3) δ 31.4, 31.5, 32.1, 32.7, 33.8, 34.0, 51.4, 53.4, 55.2, 120.9,
125.5, 125.7, 125.8, 127.2, 127.4, 127.7, 127.8, 142.6, 144.1, 147.2,
151.1, 170.3. Anal. Calcd for C48H63NO6: C, 76.87; H, 8.47; N,
1.87. Found: C, 76.60; H, 8.72; N, 1.80.
1h : mp 232-235 °C; [R]20 ) +57 (c ) 0.1, CHCl3); FAB-
D
MS m/z 792 [M + 1]+; H NMR (CDCl3) δ 0.90 (d, J ) 5.5 Hz,
1
3H), 1.23 (s, 27H), 1.24 (s, 9H), 1.40 (d, J ) 5.5 Hz, 3H), 2.43
(m, 1H), 3.03 (d, J ) 14.5 Hz, 1H), 3.11 (d, J ) 10.5 Hz, 1H),
3.44 (d, J ) 13.6 Hz, 2H), 3.47 (d, J ) 13.6 Hz, 1H), 3.50 (d, J
) 12.2 Hz, 1H), 3.72 (s, 3H), 4.00 (d, J ) 14.5 Hz, 1H), 4.14 (d,
J ) 13.6 Hz, 1H), 4.19 (d, J ) 13.6 Hz, 1H), 4.21 (d, J ) 13.6
Hz, 1H), 4.42 (d, J ) 12.2 Hz, 1H), 6.65 (d, J ) 2.0 Hz, 1H), 6.83
(d, J ) 2.0 Hz, 1H), 7.00 (d, J ) 2.0 Hz, 1H), 7.01 (d, J ) 2.0 Hz,
1H), 7.11 (d, J ) 2.0 Hz, 1H), 7.13 (d, J ) 2.0 Hz, 1H), 7.14 (d,
J ) 2.0 Hz, 1H), 7.16 (d, J ) 2.0 Hz, 1H), 10.33 (br s, 4H); 13C
NMR (CDCl3) δ 19.3, 20.2, 27.5, 31.4, 31.5, 31.9, 32.1, 32.7, 33.8,
33.9, 34.0, 50.1, 50.7, 54.3, 68.9, 120.1, 121.8, 128.4, 129.2, 142.4,
142.9, 143.9, 144.4, 146.9, 147.3, 150.0, 151.1, 171.8. Anal. Calcd
for C51H69NO6: C, 77.33; H, 8.78; N, 1.77. Found: C, 77.39; H,
9.01; N, 1.67.
Ack n ow led gm en t. We are indebted to Emeritus
Professor Tyo Sone (Yamagata University) for his useful
suggestions.
Su p p or tin g In for m a tion Ava ila ble: Tables 1-4 and
Figure 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O020300U
7522 J . Org. Chem., Vol. 67, No. 21, 2002