Macrocyclic amides consisting of helical chiral 1,12- dimethylbenzo[c]phenanthrene-5,8-dicarboxylate

Article abstract of DOI:10.1021/jo981720f

Helical chiral 1,12-dimethylbenzo[c]phenanthrene-5,8-dicarboxylic acid was synthesized and resolved in multigram quantities. The absolute configuration was determined by X-ray analysis of the bis(camphorsultamamide) derivative. A series of optically activ

Full text of DOI:10.1021/jo981720f

9500
J . Org. Chem. 1998, 63, 9500-9509
Ma cr ocyclic Am id es Con sistin g of Helica l Ch ir a l
1,12-Dim eth ylben zo[c]p h en a n th r en e-5,8-d ica r boxyla te
Hitoshi Okubo, Masahiko Yamaguchi,* and Chizuko Kabuto†
Faculty of Pharmaceutical Sciences, Tohoku University Aoba, Sendai 980-8578, J apan
Received August 24, 1998
Helical chiral 1,12-dimethylbenzo[c]phenanthrene-5,8-dicarboxylic acid was synthesized and
resolved in multigram quantities. The absolute configuration was determined by X-ray analysis
of the bis(camphorsultamamide) derivative. A series of optically active macrocyclic amides consisting
of the chiral unit and a dianiline spacer were synthesized by one-pot procedures, and their structures
were compared by spectroscopy and X-ray crystallography. One of the cycloamides exhibited
catalytic activity in the asymmetric addition of diethylzinc to aromatic aldehydes. N-Alkylated
derivatives were also synthesized, which possessed folded structures distinct from those of the
parent cyclic amides.
Sch em e 1
The chirality of helicenes has long been known in the
field of organic chemistry.1 Although the chirality due
to the helical π-electron system is expected to exhibit
interesting properties, its behavior is not well-understood
compared to tetrahedral chirality and axis chirality.2,3
This is largely due to the unavailability of such com-
pounds. Although a variety of optically active helicenes
have been synthesized, generally the methods were not
suitable for large scale preparation. An exception is the
work of Katz, who developed the Diels-Alder method for
the synthesis of helicenes.4 1,12-Dimethylbenzo[c]phenan-
threne, first synthesized and resolved by Newman,5 is a
configurationally stable helicene with a minimal number
of benzene rings. We developed a preparative method
for optically pure 1,12-dimethylbenzo[c]phenanthrene-
5,8-dicarboxylic acid (1) in multigram quantities.6,7 The
synthesis, structure, and properties of a series of mac-
rocyclic amides containing the C2-symmetric chiral unit
is described here.
Synthesis of racemic 1,12-dimethylbenzo[c]phenan-
threne-5,8-dicarboxylic acid (()-1 started from a known
diketone (()-2 prepared by Newman (Scheme 1).5 Com-
pound 2 itself possessed molecular chirality as indicated
by chiral HPLC analysis: The enantiomers were sepa-
rable by Daicel Chiralcel OD. Although we previously
assigned cis stereochemistry to 2 based on the results of
molecular modeling,6 recently a trans configuration was
determined by X-ray analysis.8 The diketone (()-2 was
converted to 1,12-dimethylbenzo[c]phenanthrene-5,8-
dinitrile, (()-3, by cyanation9 and dehydration with
concomitant dehydrogenation. Then, (()-3 was hydro-
lyzed to dicarboxylic acid (()-1 in 58% yield from (()-2.
Optical resolution was examined by forming diastereo-
meric salts with 2 equiv of amines such as cinchonidine,
cinchonine, brucine, and quinine. It was found that
recrystallization of the quinine salt from chloroform-
methanol gave one diastereomer, which was converted
to (+)-1 on acidification. The mother liquid was concen-
trated, and the residue was washed with hot methanol.
Acidification gave the antipode (-)-1. The optical puri-
† Instrumental Analysis Center for Chemistry, Graduate School of
Science, Tohoku University Aoba, Sendai 980-8578, J apan.
(1) Reviews: Martin, R. H. Angew. Chem., Int. Ed. Engl. 1974, 13,
649. Osuga, H.; Suzuki, H. J . Synth. Org. Chem., J pn. 1994, 52, 1020.
For some recent examples: Nakazaki, M.; Yamamoto, K.; Maeda, M.
J . Org. Chem. 1981, 46, 1985. Sudhakar, A.; Katz, T. J . J . Am. Chem.
Soc. 1986, 108, 179. Pereira, D. E.; Neelima, Leonard, N. J . Tetra-
hedron 1990, 46, 5895. Osuga, H.; Suzuki, H.; Tanaka, K. Bull. Chem.
Soc. J pn. 1997, 70, 891. Also see references therein.
(2) Nakazaki, M.; Yamamoto, K.; Ikeda, T.; Kitsuki, T.; Okamoto,
Y. J . Chem. Soc., Chem. Commun. 1983, 787. Yamamoto, K.; Ikeda,
T.; Kitsuki, T.; Okamoto, Y.; Chikamatsu, H.; Nakazaki, M. J . Chem.
Soc., Perkin Trans I 1990, 271.
(3) Hassine, B. B.; Gorsane, M.; Pecher, J .; Martin, R. H. Bull. Soc.
Chim. Belg. 1985, 94, 597. Hassine, B. B.; Gorsane, M.; Geerts-Evrard,
F.; Pecher, J .; Martin, R. H.; Castelet, D. Bull. Soc. Chim. Belg. 1986,
95, 557.
(4) Dai, Y.; Katz, T. J .; Nichols, D. A. Angew. Chem., Int. Ed. Engl.
1996, 35, 2109. Lovinger, A. J .; Nuckolls, C.; Katsz, T. J . J . Am. Chem.
Soc. 1998, 120, 264. Katz, T. J .; Liu, L.; Willmore, N. D.; Fox, J . M.;
Rheingold, A. L.; Shi, S.; Nuckolls, C.; Rickman, B. H. J . Am. Chem.
Soc. 1997, 119, 10054. Also see references therein.
(5) Newman, M. S.; Wolf, M. J . Am. Chem. Soc. 1952, 74, 3225.
Newman, M. S.; Wise, R. M. J . Am. Chem. Soc. 1956, 78, 450.
(6) Preliminary results. Yamaguchi, M.; Okubo, H.; Hirama, M. J .
Chem. Soc., Chem. Commun. 1996, 1771.
(7) Chemistry of optically active hexahelicene-7, 7′-dicarboxylate.
Balan, A.; Gottlieb, H. E. J . Chem. Soc., Perkin Trans. I 1981, 350.
Kim, Y. H.; Balan, A.; Tishbee, A.; Gil-Av, E. J . Chem. Soc., Chem.
Commun. 1982, 1336.
(8) Cheung, J .; Field, L. D.; Hambley, T. W.; Sternhell, S. J . Org.
Chem. 1997, 62, 62.
(9) Oda, M.; Yamamuro, A.; Watabe, T. Chem. Lett. 1979, 1427.
10.1021/jo981720f CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/14/1998

Macrocyclic Amides
J . Org. Chem., Vol. 63, No. 25, 1998 9501
Sch em e 2
ties of 1 were determined to be more than 98% by chiral
HPLC (Daicel Chiralcel OD) analysis of the dimethyl
esters. These procedures provided (-)-1 and (+)-1 in
multigram quantities.
To determine the absolute configuration, (()-1 was
treated with d-(-)-camphorsultam10 giving 4 and 5
(Scheme 2), which were separated by silica gel chroma-
tography. X-ray crystallographic analysis of 4, a chro-
matographically polar diastereomer, revealed (P)-config-
uration at the helicene moiety (Figure 1). The helical
structure of the benzo[c]phenanthrene moiety is indicated
by the dihedral angles between the condensed benzene
rings: 161°, 163°, and 168° for the AB (angle C(1)-
C(12c)-C(4a)-C(5)), BC (angle C(12c)-C(12b)-C(6a)-
C(7)), and CD rings (angle C(12b)-C(12a)-C(8a)-C(9)),
respectively. The chiral auxiliary of (P)-4 was removed
by reduction with lithium aluminum hydride giving diol
(P)-6, to which (+)-1 was correlated by borane reduction.
Here, the absolute configuration, (+)-(P)-1 and (-)-(M)-
1, was determined unambiguously. The circular dichro-
ism (CD) and UV spectra of the dimethyl ester of (P)-1
are shown in Figure 2. It was recently found that the
helical chirality of 1 could be recognized by polysaccha-
rides such as cyclodextrins in water.11
F igu r e 1. ORTEP drawings of (P)-4 (a) and the partial
structure of the benzo[c]phenanthrene moiety (b).
The diacid 1 can be envisaged as a chiral derivative of
1,3-benzenedicarboxylate or 2,7-naphthalenedicarboxy-
late (Figure 3). Since such partial structures are included
in many organic compounds, we investigated the substi-
tution of the aromatic moiety with 1, which converts
achiral aromatic compounds to chiral compounds. Hunter
and Vo¨gtle prepared cyclic amides containing catenanes
by the condensation of 1,3-benzenedicarboxylic acid with
dianiline spacer 7.12 Substitution of the dicarboxylate
(10) Harada, N.; Soutome, T.; Nehira, T.; Uda, H.; Oi, S.; Okamura,
A.; Miyano, S. J . Am. Chem. Soc. 1993, 115, 7547. Harada, N.;
Soutome, T.; Murai, S.; Uda, H. Tetrahedron: Asymmetry 1993, 4,
1755.
(11) Kano, K.; Negi, S.; Takaoka, R.; Kamo, H.; Kitae, T.; Yamagu-
chi, M.; Okubo, H.; Hirama, M. Chem. Lett. 1997, 715. Kano, K.; Negi,
S.; Kamo, H.; Kitae, T.; Yamaguchi, M.; Okubo, H.; Hirama, M. Chem.
Lett. 1998, 151.
(12) Hunter, C. A. J . Am. Chem. Soc. 1992, 114, 5303. Adams, H.;
Carver, F. J .; Hunter, C. A. J . Chem. Soc., Chem. Commun. 1995, 809.
Vo¨gtle, F.; Meier, S.; Hoss, R. Angew. Chem., Int. Ed. Engl. 1992, 31,
1619. Ottens-Hildebrandt, S.; Nieger, M.; Rissannen, K.; Rouvinen,
J .; Meier, S.; Harder, G.; Vo¨gtle, F. J . Chem. Soc., Chem. Commun.
1995, 777. J a¨ger, R.; Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1997,
36, 930.
F igu r e 2. CD and UV spectra of (P)-1 dimethyl ester in CHCl3
at the concentration of 3.3 × 10-2 mM.
moiety with 1 was expected to give optically active
versions of the compounds. The synthesis and spectro-

9502 J . Org. Chem., Vol. 63, No. 25, 1998
Okubo et al.
matography (GPC) to give [2+2]cycloamide (M,M)-9,
[3+3]cycloamide (M,M,M)-10, and [4+4]cycloamide
(M,M,M,M)-11 in 24%, 23%, and 19% yields, respectively.
Using (P)-1 in place of (M)-1, the enantiomeric macro-
cyclic amides (P,P)-9, (P,P,P)-10, and (P,P,P,P)-11 were
synthesized. Here, we define, for example, [3+3]cyclo-
amide as a macrocyclic amide consisting of three mol-
ecules of 1 and three molecules of 7. The GPC method
was effective for the separation of these compounds. This
method has the additional advantage of allowing the
molecular size to be estimated from the retention time.
The combined yield of the three macrocyclic amides
exceeded 60%. However, no catenane could be isolated.
As Hunter and Vo¨gtle pointed out, hydrogen bonding
between the 1,3-benzenedicarbamoyl moiety and carbonyl
oxygen of the acid chloride might be essential for cat-
enane formation.12 In the present case, the two carbonyl
groups of 1 were separated by two benzene rings, which
might have prevented such interactions.
F igu r e 3. 1,12-Dimethylbenzo[c]phenanthrene as chiral m-
phenylene and 2,7-naphthylene unit.
Sch em e 3
In regard to the base, use of 1% pyridine in methylene
chloride was essential for effective cyclization. Et3N gave
an intractable mixture. Hindered base i-Pr2NEt gave
better results than Et3N, although the yield was still
lower than with pyridine. The concentration of the base
was also critical, and no reaction took place in 10%
pyridine or in pyridine solvent. Since addition of metha-
nol to these mixtures gave the methyl ester of (M)-1 in
quantitative yields, it was concluded that excess pyridine
inhibited amide formation. In the presence of pyridine
and not Et3N or i-Pr2NEt, 1H NMR absorption of the
amide proton of (M,M,M)-10 shifted downfield in CDCl3.
Such interactions might be the origin of the above
pyridine effect. Notably, 4,4′-bipyridine considerably
changed the chemical shifts of (M,M,M)-10 in CDCl3. The
complexation phenomena, however, appeared to be rather
complex, and the association constant could not be
obtained by assuming a 1:1 complex.
The cyclic structures of the three macrocyclic amides
9, 10, and 11 were confirmed from the simple NMR
spectra. All the three compounds exhibited four benzo-
[c]phenanthrene aromatic protons and one aniline aro-
matic proton. The molecular compositions of the cycloa-
mides were determined by FAB-MS and/or by vapor
pressure osmometry (VPO) at 5 mM, where the aggrega-
tion was not significant (vide infra). 1H NMR (CDCl3)
chemical shifts of the amide protons of (M,M,M)-10 and
(M,M,M,M)-11 occurred downfield as the concentration
increased (Figure 4). In contrast, 4-H and 6-H of benzo-
[c]phenanthrene shifted upfield. Since no concentration
dependence was observed in DMSO-d6, aggregation via
hydrogen bonding probably took place in the nonpolar
solvent. Binding constants of approximately 30 and 10
were obtained for (M,M,M)-10 and (M,M,M,M)-11, re-
1
spectively.13 In contrast, the H NMR (CDCl3) spectra
of (M,M)-9 showed very slight concentration dependence.
The same trends were observed by IR spectroscopy.14
While (M,M,M)-10 and (M,M,M,M)-11 exhibited hydro-
gen bonded NH at approximately 3300 cm-1 at the
concentration of ca. 10 mM, this absorption was very
weak with (M,M)-9. The UV spectra of the three cyclo-
amides (P,P)-9, (P,P,P)-10, and (P,P,P,P)-11 were very
similar except for the level of absorbance (Figure 5). The
scopic properties of the optically active macrocyclic
amides are described below.
(M)-1 was converted to diacid chloride by treatment
with refluxing thionyl chloride, which was then reacted
with an equimolar amount of 7 in 1% pyridine-methyl-
ene chloride at room temperature for 1 day under highly
diluted conditions (3 mM) (Scheme 3). Oligomers were
separated by preparative recycling gel permeation chro-
(13) Horman, I.; Dreux, B. Helv. Chim. Acta 1984, 67, 754.
(14) Bellamy, L. J . The Infra-red Spectra of Complex Molecules;
Chapman and Hall: London, 1975; Chapter 12, p 231.

Macrocyclic Amides
J . Org. Chem., Vol. 63, No. 25, 1998 9503
F igu r e 4. Concentration dependence of amide proton chemi-
1
cal shifts by H NMR in CDCl3.
F igu r e 6. ORTEP drawings of (P,P)-9.
concentration dependence in 1H NMR (Figure 4).
A
binding constant of approximately 10 was obtained.13 The
1H NMR spectra of (M)-8 differed considerably from those
of other cycloamides: two sets of aromatic protons (δ 6.02
and 6.51) and methyl protons (δ 1.92 and 2.06) appeared
at aniline moiety and did not coalesce up to 80 °C.
Rotation of the aniline ring was restricted, and the
activation energy was estimated to be more than 17 kcal/
mol. The amide carbonyl appeared at 1651 cm-1 on IR
(CHCl3), while higher homologues absorbed at ca. 1670
cm-1
.
The absorption of free N-H at 3374 cm-1 also
differed from the absorption of higher cycloamides at ca.
3414 cm-1. These observations may be ascribed to the
s-cis structure of the secondary amide moiety. The CD
spectra of 8 also differed considerably from those of other
cycloamides (Figure 5).
Racemates (()-8, (()-9, (()-10, and (()-11 were pre-
pared by mixing equal amounts of the enantiomers. 1H
NMR (CDCl3) spectra of the optically active and racemic
macrocyclic amides were identical at the same concentra-
tions. This suggested the presence of certain chiral
recognition in the aggregation of cycloamides: for ex-
ample, the self-aggregation of (P)-8 probably is stronger
than the aggregation between (P)-8 and (M)-8.
The structure of (P,P)-9 was confirmed by X-ray
analysis. It contained 10 ethanol molecules per (P,P)-9
molecule (Figure 6). (P,P)-9 displays a highly sym-
metrical “planar and open” structure which is consistent
F igu r e 5. CD and UV spectra of (P)-8, (P,P)-9, (P,P,P)-10,
and (P,P,P,P)-11 in CHCl3 at the concentration of 1.4 × 10-2
,
1.1 × 10-2, 8.5 × 10-3, and 4.5 × 10-3 mM.
1
with the simple H NMR spectra. The diameter of the
positive Cotton effect of the cycloamides observed by CD
at 280 and 360 nm was ascribed to the helicene structure
(cf. Figure 2). The Cotton effect at 310 nm was charac-
teristic of (P,P)-9 and decreased as the ring size in-
creased.
When (M)-1 was reacted with 7 in refluxing ClCH2-
CH2Cl (1 mM) in the presence of Et3N, [1+1]cycloamide
(M)-(+)-8 and (M,M)-(-)-9 were obtained in 29% and 16%
yield, respectively (Scheme 3). A higher reaction tem-
perature gave macrocyclic amides of smaller ring sizes.
The amide (M)-8 also aggregated as indicated by the
cavity was estimated to be 0.6 nm. The entire amide
moiety possesses an s-trans structure, and the aniline
ring stands perpendicular to the amide plane. It may
be reasonably assumed that 10 and 11 possess related
planar structures with larger cavities.
N-Alkyl derivatives of macrocyclic amides were syn-
thesized (Scheme 4). (P)-Cycloamides were treated with
sodium hydride in THF followed by treatment with excess
methyl iodide or benzyl bromide at room temperature,
and N-methylated or N-benzylated products were ob-

9504 J . Org. Chem., Vol. 63, No. 25, 1998
Okubo et al.
F igu r e 7. ORTEP drawings of (P)-N,N′-dimethyl[1+1]cyclo-
amide. Protons were omitted for clarity.
Sch em e 4
F igu r e 8. 1H NMR (CDCl3) spectra of (P,P)-[2+2]cycloamide
(a), (P,P)-N,N′,N′′,N′′′-tetrabenzyl[2+2]cycloamide (b), and
(P,P)-N,N′,N′′,N′′′-tetramethyl[2+2]cycloamide (c) at 6 mM.
Aniline protons are shown by * and cyclohexyl protons by #.
presence of four aniline methyl proton peaks, two benzo-
[c]phenanthrene methyl proton peaks, and four aniline
ring proton peaks (indicated by *) of tetrabenzyl[2+2]-
cycloamide demonstrated the reduced symmetry of the
structure in solution, where the molecular motions may
be restricted. Notably, considerable proportion of cyclo-
hexyl protons were shifted upfield, to δ -2. Since such
a shift was also observed in the N-methyl derivative
(Figure 8c), it is thought to be due to the shielding effect
of benzo[c]phenanthrene and not of the benzyl group.
tained in good yields. As many as eight reaction sites of
(P,P,P,P)-11 were effectively methylated by this method.
The 1H NMR spectrum of (P)-N,N′-dimethyl[1+1]-
cycloamide was similar to that of (P)-8 except for the
presence of N-methyl protons in the former, indicative
of the similar conformation of the both compounds. X-ray
analysis of (P)-N,N′-dimethyl[1+1]cycloamide was con-
ducted (Figure 7). The crystal contained two chloroform
molecules per cycloamide molecule. Both amides were
fixed in a s-cis conformation. Restricted rotation of the
aniline ring was apparent from the structure.
1
The H NMR assignments of (P,P)-N,N′,N′′,N′′′-tetra-
benzyl[2+2]cycloamide are shown in Figure 9, which
were obtained by NMR spectroscopy using NOE. While
NOE was observed between the methyl A at δ 1.92 and
benzo[c]phenanthrene 1,12-methyl protons, methyl B at
δ 1.74 showed NOE with 6,7-aromatic protons. The
amide moiety existing between these arenes probably
possess an s-cis configuration. The preference of N-
The 1H NMR (CDCl3) spectra of (P,P)-N,N′,N′′,N′′′-
tetrabenzyl[2+2]cycloamide (Figure 8b) was considerably
complicated compared to those of (P,P)-9 (Figure 8a). The

Macrocyclic Amides
J . Org. Chem., Vol. 63, No. 25, 1998 9505
F igu r e 10. Structure of (P,P)-N,N′,N′′,N′′′-tetramethyl[2+2]-
cycloamide obtained by Amber calculations (stereoview).
crystal suitable for X-ray analysis was not obtained, a
calculation method was employed to clarify the structure.
The structure of N,N′,N′′,N′′′-tetramethyl[2+2]cycloamide
determined by Amber16 (Figure 10) is consistent with that
determined by NMR studies (Figure 9), and the Amber
method was demonstrated to be reliable in the present
system. The N-alkylated cycloamides appear to possess
“folded” rather than “open” structures. N-Alkylation
dramatically changed the structures of the cyclic amides.
The most stable conformations of N,N′,N′′,N′′′,N′′′′,N′′′′′-
hexamethyl[3+3]cycloamide and N,N′,N′′,N′′′,N′′′′,N′′′′′,-
N′′′′′′,N′′′′′′′-octamethyl[4+4]cycloamide were predicted by
the calculations, which showed rather complex folded
structures (Figure 11). The former possessed six s-cis
amides, and the latter six s-cis and two s-trans amides.
Various applications of these optically active cyclic
amides are conceivable. Their use in asymmetric cataly-
sis was briefly examined as an example. The asymmetric
addition reaction of diethylzinc to aldehydes was cata-
lyzed by compounds such as amino alcohols, binaphthols,
sulfoneamides, etc.17 The cycloamide (P,P)-9 also cata-
lyzed the asymmetric reaction (Table 1). Lithiation of
the cyclic amide with butyllithium and use of THF
solvent were essential for the asymmetric induction.
Other derivatives, for example, (P)-8, (P,P,P)-10, and
(P,P,P,P)-11, gave racemic alcohols in the reaction of
benzaldehyde. All the adducts derived from aromatic
aldehydes possessed an (R)-configuration, and as high
as 50% ee was attained in the reaction with â-naphthal-
dehyde. Although the asymmetric induction is modest,
asymmetric catalysis by the novel cyclic amide may be
interesting.
F igu r e 9. 1H NMR assignments of (P,P)-N,N′,N′′,N′′′-tetra-
benzyl[2+2]cycloamide (a). Selected NOEs are shown (b and
c).
methylbenzanilide to possess an s-cis structure is known.15
The aniline methyl C at δ 1.40 showed NOE with 4-H of
the benzo[c]phenanthrene, while the methyl D at δ 2.54
showed NOE with 6-H. A s-trans configuration is likely
for this amide moiety. NOEs were observed between
several cyclohexyl protons and benzo[c]phenanthrene
protons.
1
The H NMR spectra of the N-methyl derivative were
more complicated, and many other broad peaks appeared
in addition to those observed for the N-benzyl derivative.
Apparently, the N-methyl derivative was a mixture of
conformers. By silica gel chromatography, (P,P)-N,N′,-
N′′,N′′′-tetramethyl[2+2]cycloamide was separable into
two parts. They were stable at 0 °C in solution, although
equilibrated at room temperature. The 1H NMR spectra
of the polar fraction was similar to the N-benzyl deriva-
tive (Figure 8c), while the less polar fraction appeared
to be a mixture of several conformers. 1H NMR spectra
of the N-alkylated derivatives of [3+3]cycloamides and
[4+4]cycloamides, which could also be mixtures of con-
formers, were extremely complex.
A helical chiral dicarboxylic acid, 1,12-dimethylbenzo-
[c]phenanthrenedicarboxylic acid, was prepared in mul-
tigram quantities, and optically active macrocyclic amides
containing the chiral unit were synthesized. While the
secondary amides possessed an open structure with a
cavity, the N-alkylated derivatives possessed a folded
structure. Studies on the properties of the cycloamides
(16) The calculation was conducted using Amber* (McDonald, D.
Q.; Still, W. C. Tetrahedron Lett. 1992, 33, 7743) contained in the
MacroModel Ver 6.0. Mohamadi, F.; Richards, N. G. J .; Guida, W. C.;
Liskamp, R.; Lipton, M.; Caulsfield, C.; Chang, G.; Hendrickson, T.;
Still, W. C. J . Comput. Chem. 1990, 11, 440.
(17) For reviews: Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 49. Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
The structures of N-alkylated derivatives differed
considerably from those of N-H compounds. Since a
(15) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.;
Shudo, K. Tetrahedron Lett. 1989, 30, 6177. Itai, A.; Toriumi, Y.; Saito,
S.; Kagechika, H.; Shudo, K. J . Am. Chem. Soc. 1992, 114, 10649.

9506 J . Org. Chem., Vol. 63, No. 25, 1998
Okubo et al.
with methylene chloride. The organic layer was washed with
water and brine and dried over MgSO4. The solvents were
evaporated under a reduced pressure, and crude (()-3 (9.40
g) thus obtained was used in the next reaction without further
purification. An analytical sample was obtained by recrystal-
lizing 3 times from benzene: mp >300 °C (benzene). Elemen-
tal analysis. Calcd for C22H14N2: C, 86.25; H, 4.61; N, 9.14%.
Found: C, 86.00; H, 4.69; N, 9.16%. MS (EI, 70 eV) m/z 307
(M+ + H, 27%), 306 (M+, 100), 291 (M+ - Me, 95), 276 (M+
-
2Me, 34). HRMS (EI, 70 eV) calcd for C22H14N2: 306.1157.
Found: 306.1149. UV-vis (CH2Cl2) λmax (ꢀ) 308 nm (5.4 × 104).
IR (KBr) 2220 cm-1 1H NMR (200 MHz, CDCl3) δ 1.92 (6 H,
.
s), 7.59 (2 H, d, J ) 7.2 Hz), 7.83 (2 H, dd, J ) 7.2, 7.5 Hz),
8.29 (2 H, s), 8.34 (2 H, d, J ) 7.5 Hz). 13C NMR (50 MHz,
CDCl3) δ 23.0, 110.6, 117.3, 123.0, 128.8, 129.2, 130.2, 130.7,
131.1, 131.2, 132.0, 137.8.
(()-1,12-Dim eth ylben zo[c]p h en a n th r en e-5,8-d ica r box-
ylic a cid , (()-1. Dinitrile (()-3 (9.40 g, 30.7 mmol) and
sodium hydroxide (4.30 g, 10.8 mmol) were suspended in
ethylene glycol (43 mL), and the mixture was stirred at 185-
195 °C for 21 h. Ammonia evolved vigorously upon heating.
After cooled, the reaction mixture was poured into water and
extracted with ether-benzene. The alkaline aqueous solution
was acidified with 2 M hydrochloric acid and filtered to give
crude (()-1 (6.73 g). Recrystallization from benzene-methanol
gave yellow powder of (()-1 (5.12 g, 58% from (()-2): mp >
300 °C (benzene-methanol). MS (EI, 70 eV) m/z 344 (M+,
100%), 311 (M+ - Me - OH2, 13), 239 (M+ - 2COOH - Me,
20). HRMS (EI, 70 eV) calcd for C22H16O4: 344.1049. Found:
344.1046. Calcd for C22H16O4: C, 76.73; H, 4.68%. Found: C,
76.68; H, 4.79%. UV-vis (MeOH) λmax (ꢀ) 341 (9.8 × 103), 312
nm (2.3 × 104). IR (KBr) 3650-3100, 1684 cm-1
.
1H NMR
(600 MHz, CD3OD) δ 1.85 (6 H, s), 7.39 (2 H, d, J ) 7.0 Hz),
7.71 (2 H, dd, J ) 7.1, 8.4 Hz), 8.58 (2 H, s), 8.87 (2 H, d, J )
8.2 Hz). 13C NMR (150 MHz, CD3OD) δ 24.0, 124.6, 128.7,
129.1, 130.0, 130.3, 131.2, 132.0, 132.2, 132.5, 137.7, 170.8.
Bis(d -ca m p h or su lta m )a m id e of 1, (P )-4 a n d (M)-5.
Under an argon atmosphere, sodium hydride (60% oil suspen-
sion, 1.10 g, 27.5 mmol) was added to a dry benzene (20 mL)
solution of d-(-)-camphorsultam (4.40 g, 20.5 mmol) in flask
A. The mixture was stirred for 2 h at room temperature. In
flask B, a mixture of (()-1 (2.96 g, 8.61 mmol) and thionyl
chloride (20 mL) were refluxed for 4 h. After the mixture was
cooled, excess thionyl chloride was removed under a reduced
pressure. The crude diacid chloride in flask B was diluted with
dry benzene (40 mL) and was added to the flask A. After
stirring for 37 h at room temperature water was added, and
organic materials were extracted with ethyl acetate. The
extracts were washed with water and brine and dried over
MgSO4. After removing the solvents, silica gel chromato-
graphic separation (ethyl acetate:dichloromethane:hexane )
1:4:4) gave polar isomer (P)-4 (0.66 g, 10%) and less polar
isomer (M)-5 (1.28 g, 20%). Analytical samples were obtained
by recrystallization from ethyl acetate. (P)-4: mp >300 °C
F igu r e 11. Structures of (P,P,P)-N,N′,N′′,N′′′,N,′′′′N′′′′′-
hexamethyl[3+3]cycloamide (a) and (P,P,P,P)-N,N′,N′′,N′′′,-
N,′′′′′,N′′′′′,N′′′′′′,N′′′′′′′-octamethyl[4+4]cycloamide (b) obtained
by Amber calculations (stereoview).
Ta ble 1. Asym m etr ic Ad d ition of Dieth ylzin c to
Ar om a tic Ald eh yd es Ca ta lyzed by (P ,P )-9
R
yield/%
ee/%
configuration
Ph
76
66
88
73
81
51
59
33
31
27
28
31
40
50
R
Sa
R
R
R
R
R
p-MeOC6H4
p-MeC6H4
p-ClC6H4
R-naphthyl
â-naphthyl
(ethyl acetate). [R]25 -69.1 (c 1.05, CHCl3). HRMS (EI, 70
D
a
eV) calcd for C42H46N2O6S2: 738.2798. Found: 738.2793.
Calcd for C42H46N2O6S2: C, 68.27; H, 6.27; N, 3.79; S, 8.68%.
Found: C, 67.68; H, 6.31; N, 3.85; S, 8.76%. UV-vis (CHCl3)
λmax (ꢀ) 341 (9.4 × 103), 313 nm (2.3 × 104). IR (KBr) 1680
(M,M)-9 was used.
are now underway. For example, some of the cyclo-
amides were found to form LB films.18
cm-1 1H NMR (500 MHz, CDCl3) δ 1.00 (6 H, s), 1.30-1.37
.
(2 H, m), 1.38 (6 H, s), 1.43-1.48 (2 H, m), 1.85-1.90 (6 H,
m), 1.91 (6 H, s), 1.92-1.99 (2 H, m), 2.18-2.27 (2 H, m), 3.40
(2 H, d, J ) 14.0 Hz), 3.46 (2 H, d, J ) 13.5 Hz), 4.15-4.20 (2
H, m), 7.44 (2 H, d, J ) 7.0 Hz), 7.63 (2 H, dd, J ) 7.0, 8.0
Hz), 8.00 (2 H, s), 8.14 (2 H, d, J ) 8.0 Hz). 13C NMR (125
MHz, CDCl3) δ 19.9, 21.4, 23.5, 26.4, 33.2, 38.5, 45.1, 47.9,
48.4, 53.2, 65.8, 122.6, 127.3, 127.6, 128.5, 128.9, 129.4, 130.3,
130.9 (overlapped), 137.2, 168.5. (M)-5: mp >300 °C (ethyl
acetate). [R]25D -209 (c 0.906, CHCl3). HRMS (EI, 70 eV) calcd
Exp er im en ta l Section
(()-1,12-Dim e t h y lb e n zo[c]p h e n a n t h r e n e -5,8-d in i-
tr ile, (()-3. Under an argon atmosphere, trimethylsilylnitrile
(9.00 mL, 64.1 mmol) was added to a solution of diketone (()-
25 (7.45 g, 25.7 mmol) and zinc iodide (0.2 g) in dry benzene
(10 mL). After stirring for 27 h at room temperature, pyridine
(40 mL) and phosphoryl chloride (12.0 mL, 130 mmol) were
added, and the reaction mixture was heated at reflux for 17
h. After cooling, the contents were poured into ice-cold 2 M
hydrochloric acid, and the organic materials were extracted
for
C42H46N2O6S2: 738.2798. Found: 738.2800. UV-vis
(CHCl3) λmax (ꢀ) 341 (1.1 × 104), 314 nm (2.3 × 104). IR (KBr)
1680 cm-1 1H NMR (500 MHz, CDCl3) δ 0.88 (6 H, s), 1.26-
.
1.34 (2 H, m), 1.39 (6 H, s), 1.40-1.46 (2 H, m), 1.82-1.96 (8
H, m), 1.92 (6 H, s), 2.06-2.15 (2 H, m), 3.44 (2 H, d, J ) 13.5
Hz), 3.51 (2 H, d, J ) 13.5 Hz), 4.21-4.26 (2 H, m), 7.43 (2 H,
(18) Feng, F.; Miyashita, T.; Okubo, H.; Yamaguchi, M. J . Am.
Chem. Soc., 1998, 120, 10166.

Macrocyclic Amides
J . Org. Chem., Vol. 63, No. 25, 1998 9507
d, J ) 7.0 Hz), 7.62 (2 H, dd, J ) 7.0, 8.0 Hz), 8.04 (2 H, d, J
) 8.0 Hz), 8.09 (2 H, s). 13C NMR (125 MHz, CDCl3) δ 19.9,
21.3, 23.3, 26.4, 33.1, 38.4, 45.0, 47.8, 48.4, 53.2, 65.6, 122.5,
127.5, 127.9, 128.3, 129.4, 129.9, 130.1, 131.0, 131.0, 137.0,
169.1.
Op tica l r esolu tion of 1. Methanol solution of (()-1 (70
g, 0.2 mol) and methanol solution of (-)-quinine (130 g, 0.4
mol) were mixed at room temperature, and the solvent was
pressure, and (P)-6 (18 mg, 81%) was obtained by silica gel
chromatography.
Cycloa m id es, (M,M)-9, (M,M,M)-10, a n d (M,M,M,M)-11.
Under an argon atmosphere, (M)-1 (200 mg, 0.58 mmol) in
thionyl chloride (6 mL) was heated at reflux for 2 h. After
removing excess thionyl chloride under a reduced pressure, a
trace amount of thionyl chloride was removed by repeated
addition of dry dichloromethane and evaporation in vacuo. The
diacid chloride was then diluted with dry dichloromethane (300
mL) and pyridine (1 mL), to which 712 (187 mg, 0.58 mmol) in
dichloromethane (5 mL) was added at room temperature over
2 h. The mixture was stirred at the temperature for 48 h.
After removing insoluble materials by filtration, the filtrate
was washed with aqueous saturated potassium hydrogen
sulfate, water, and brine and dried over MgSO4. The solvents
were evaporated under a reduced pressure, and the residue
was chromatographed by recycling GPC giving (M,M)-9 (90
mg, 24%), (M,M,M)-10 (86 mg, 23%), and (M,M,M,M)-11 (69
mg, 19%). (M,M)-9: mp >300 °C (CH2Cl2-MeOH-acetone).
evaporated under
a reduced pressure. The residue was
recrystallized from chloroform-methanol. The crystals ob-
tained were heated in refluxing chloroform-methanol (1:1,
300-400 mL) for 30 min and filtered while hot. The washing
was repeated three times. To the resulted salt was added 4
M hydrochloric acid (300-400 mL), and the suspension was
sonicated for 10 min. Then the powder was filtered and dried.
These neutralizing procedures were repeated 3 times, and the
product was finally dried at 80 °C overnight giving (P)-1 (21
g, 30%, >99% ee). [R]23 +313 (c 0.690, MeOH). The mother
D
liquid obtained by the recrystallization was concentrated, and
the crystals were treated three times with hot methanol as
mentioned above. Neutralization with 4 M hydrochloric acid
as above gave (M)-1 (20 g, 29%, 99% ee). [R]23D -332 (c 0.120,
MeOH). The optical purities were determined by chiral HPLC
analysis (Daicel, Chiral OD) of dimethyl esters, which were
obtained by diazomethane treatment in ether at 0 °C. Di-
methyl ester of (P)-1: mp 242-243 °C (ethyl acetate-hexane).
[R]26D -179 (c 0.332 CHCl3). MS (FAB, NBA) m/z 1261 (M+
+
1). UV-vis (CHCl3) λmax (ꢀ) 303 nm (9.9 × 104). IR (KBr) 3286,
1671 cm-1. IR (CHCl3, 57.1 mM) 3416, 3308, 1673 cm-1 1H
.
NMR (600 MHz, CDCl3-CD3OD, 24 mM) δ 1.52-1.78 (12 H,
m), 1.98 (12 H, s), 2.18-2.35 (8 H, m), 2.36 (24 H, s), 7.06 (8
H, s), 7.47 (4 H, s), 7.53 (4 H, d, J ) 7.0 Hz), 7.73 (4 H, dd, J
) 7.0, 7.7 Hz), 8.13 (4 H, s), 8.61 (4 H, d, J ) 7.7 Hz). 13C
NMR (150 MHz, CDCl3-CD3OD, 24 mM) δ 18.5, 22.8, 22.8,
26.1, 36.3, 45.5, 122.8, 125.6, 127.0, 127.3, 128.9, 129.0, 129.1,
130.2, 131.1, 131.3, 133.1, 134.5, 136.8, 148.2, 168.2. (M,M,M)-
[R]23 +313 (c 0.133 CHCl3). MS (EI, 70 eV) m/z 372 (M+,
D
100%), 341 (M+ - OMe, 11), 239 (M+ - Me - 2COOMe, 8).
HRMS (EI, 70 eV) calcd for C22H20O4: 372.1362. Found
372.1369. UV-vis (CHCl3) λmax (ꢀ) 314 nm (3.2 × 104). IR
10: mp >300 °C (CH2Cl2-MeOH-hexane). [R]27 -147 (c
D
0.230 CHCl3). UV-vis (CHCl3) λmax (ꢀ) 302 nm (1.5 × 105). IR
(KBr) 3244, 1661 cm-1. IR (CHCl3, 17.2 mM) 3412, 3296, 1667
cm-1. MS (FAB, NBA) m/e 1892 (M+ + 2). VPO (CHCl3, 35
°C, 5.3 mM) 1840 ( 100 g mol-1 (benzil as standard). 1H NMR
(600 MHz, CDCl3-CD3OD, 9.5 mM) δ 1.47-1.68 (18 H, m),
1.95 (18 H, s), 2.24-2.42 (12 H, m), 2.43 (36 H, s), 7.14 (12 H,
s), 7.44 (6 H, s), 7.50 (6 H, d, J ) 7.2 Hz), 7.68 (6 H, dd, J )
7.2, 8.0 Hz), 8.10 (6 H, s), 8.45 (6 H, d, J ) 8.0 Hz). 1H NMR
(200 MHz, CDCl3, 0.3 mM) δ 7.40 (1 H, s, NH), 8.13 (1 H, s,
benzo[c]phenanthrene H-6). 1H NMR (200 MHz, CDCl3, 26
mM) δ 7.64 (1 H, s, NH), 7.96 (1 H, s, benzo[c]phenanthrene
H-6). 13C NMR (150 MHz, CDCl3-CD3OD, 9.5 mM) δ 18.8,
22.7, 23.0, 26.1, 36.7, 45.2, 122.6, 124.0, 126.8, 127.2, 128.2,
129.1, 129.3, 129.8, 130.9, 131.1, 133.9, 135.0, 136.8, 147.7,
(KBr) ν 1717 cm-1 1H NMR (600 MHz, CDCl3) δ 1.88 (6 H,
.
s), 4.07 (6 H, s), 7.44 (2 H, d, J ) 6.9 Hz), 7.68 (2 H, dd, J )
6.9, 8.3 Hz), 8.51 (2 H, s), 8.84 (2 H, d, J ) 8.3 Hz). 13C NMR
(150 MHz, CDCl3) δ 23.4, 52.4, 123.1, 127.0, 127.8, 128.8,
129.1, 129.8, 130.6, 131.3, 131.3, 136.8, 167.7. Dimethyl ester
23
of (M)-1: [R]D -310 (c 0.668 CHCl3).
(P )-1,12-Dim eth ylben zo[c]p h en a n th r en e-5,8-d im eth a -
n ol, (P )-6, fr om (P )-4. Under an argon atmosphere, to a
solution of (P)-4 (397 mg, 0.537 mmol) in dry tetrahydrofuran
(3 mL) was added lithium aluminum hydride (69 mg, 1.83
mmol). The mixture was stirred for 10 h at room temperature.
Then, ethanol, water, and 2 M hydrochloric acid were added
successively, and organic materials were extracted with ethyl
acetate. The organic layer was washed with water and brine
and dried over MgSO4. After removing the solvents under a
reduced pressure, silica gel chromatography gave (P)-6 (160
168.7. (M,M,M,M)-11: mp >300 °C (CHCl3-hexane). [R]26
D
-178 (c 0.220, CHCl3). MS (FAB, NBA) m/e 2523 (M+ + 3).
VPO (CHCl3, 35 °C, 4 mM) 2440 ( 120 g mol-1 (benzil as
standard). UV-vis (CHCl3) λmax (ꢀ) 303 nm (2.4 × 105). IR
(KBr) 3278, 1655 cm-1. IR (CHCl3, 4.17 mM) 3414, 2938, 1667
27
mg, 90%): mp 261-264 °C (CHCl3-MeOH). [R]D -186 (c
0.190 CHCl3-MeOH). Calcd for C22H20O2: C, 83.52; H, 6.37%.
Found: C, 83.23; H, 6.51%. MS (EI, 70 eV) m/z 316 (M+,
cm-1 1H NMR (600 MHz, CDCl3-CD3OD, 3.9 mM) δ 1.63-
.
100%), 299 (M+ - OH, 3), 285 (M+ - CH2OH, 2), 239 (M+
-
1.83 (24 H, m), 2.08 (24 H, s), 2.44-2.55 (16 H, m), 2.60 (48
H, s), 7.30 (16 H, s), 7.65 (8 H, d, J ) 7.1 Hz), 7.84 (8 H, dd,
J ) 7.1, 8.8 Hz), 8.34 (8 H, s), 8.56 (8 H, d, J ) 8.1 Hz). 13C
NMR (150 MHz, CDCl3-CD3OD, 3.9 mM) δ 18.5, 22.5, 22.8,
26.0, 36.5, 44.9, 122.4, 124.0, 126.7, 127.0, 128.0, 129.0, 129.3,
129.7, 130.8, 131.0, 133.8, 134.9, 136.7, 147.5, 169.0. Similar
treatment of (P)-1 gave (P,P)-9, (P,P,P)-10, and (P,P,P,P)-11.
Me - 2CH2OH, 9). HRMS (EI, 70 eV) calcd for C22H20O2:
316.1463. Found: 316.1465. UV-vis (MeOH) λmax (ꢀ) 333 (8.4
× 103), 303 nm (1.4 × 104). IR (KBr) 3286 cm-1
.
1H NMR
(600 MHz, CDCl3-CD3OD) δ 1.66 (6 H, s), 4.32 (2 H, s), 4.96
(2 H, d, J ) 13.3 Hz), 5.03 (2 H, d, J ) 13.2 Hz), 7.14 (2 H, d,
J ) 7.0 Hz), 7.33 (2 H, dd, J ) 7.0, 8.0 Hz), 7.61 (2 H, s), 7.84
(2 H, d, J ) 8.1 Hz). 13C NMR (150 MHz, CDCl3-CD3OD) δ
22.7, 62.0, 120.2, 123.6, 124.7, 125.3, 127.6, 129.9, 131.2, 131.2,
135.2, 136.2. Similar procedures converted (M)-5 to (M)-6
(P,P)-9: mp >300 °C (CH2Cl2-MeOH-acetone). [R]27 +179
D
(c 0.698, CHCl3). (P,P,P)-10: mp >300 °C (CH2Cl2-MeOH-
acetone). [R]27D +131 (c 0.206 CHCl3). (P,P,P,P)-11: mp >300
26
(88%). [R]D +182 (c 0.098, CHCl3-MeOH).
°C (CHCl3-hexane). [R]21 +187 (c 0.114, CHCl3).
D
(P )-6 fr om (+)-1. Under an argon atmosphere, to a solution
of (+)-1 (24 mg, 0.069 mmol) in dry tetrahydrofuran (1 mL)
was added 1 M borane tetrahydrofuran solution (0.18 mL, 0.18
mmol). After the mixture was stirred at room temperature
for 15 h aqueous saturated ammonium chloride was added,
and the mixture was stirred vigorously for 30 min. Organic
materials were then extracted with ethyl acetate. The organic
layer was washed with water and brine and was dried over
(M)-[1+1]Cycloa m id e, (M)-8. A mixture of (M)-1 (74 mg,
0.22 mmol) and thionyl chloride (2 mL) was refluxed for 3 h.
After the mixture was cooled to room temperature, thionyl
chloride was removed as above. Under an argon atmosphere
the residue was dissolved in dry 1,2-dichloroethane (200 mL)
and triethylamine (1 mL). Then a solution of 7 (67 mg, 0.21
mmol) in 1,2-dichloroethane (10 mL) was added dropwise at
reflux over 1 h. After refluxing for 13 h, the reaction mixture
was cooled and filtered. The solution was washed with 2 M
hydrochloric acid, water, and brine. After the mixture was
dried over MgSO4, the solvents were evaporated. Separation
by GPC gave (M)-8 (38 mg, 29%), which was accompanied by
MgSO4. The solvents were evaporated under
a reduced
(19) Pickard, R. H.; Kenyon, J . J . Chem. Soc. 1914, 1115.
(20) Capillon, J .; Gue´tte´, J .-P. Tetrahedron. 1979, 35, 1817.
(21) Niwa, S.; Soai, K. J . Chem. Soc., Perkin. Trans. I 1991, 2717.
(22) Oguni, N.; Omi, T.; Yamamoto, Y.; Nakamura, A. Chem. Lett.
(M,M)-9 (21 mg, 16%). Mp >300 °C (benzene-MeOH). [R]27
D
1983, 841.
+35.3 (c 0.774, CHCl3). UV-vis (CHCl3) λmax (ꢀ) 296 nm (3.4

9508 J . Org. Chem., Vol. 63, No. 25, 1998
Okubo et al.
× 104). IR (KBr) 3234, 1655 cm-1. IR (CHCl3, 34.7 mM) 3374,
mmHg for 1 day. MS (FAB, NBA) m/z 2634 (M+ + 2). UV-
vis (CHCl3) λmax (ꢀ) 306 nm (1.1 × 105). IR (KBr) 2930, 2860,
3186, 1651 cm-1
. HRMS (EI, 70 eV) calcd for C22H20O2:
630.3247. Found: 630.3246. 1H NMR (600 MHz, CDCl3, 32
mM) δ 1.45-1.63 (6 H, m), 1.80 (6 H, s), 1.91 (6 H, s), 2.06 (6
H, s), 2.24-2.39 (4 H, m), 6.37 (2 H, s), 6.78 (2 H, s), 6.98 (2
H, s), 7.41 (2 H, d, J ) 7.0 Hz), 7.64 (2 H, dd, J ) 7.0, 8.2 Hz),
7.73 (2 H, s), 8.51 (2 H, d, J ) 8.2 Hz). 13C NMR (150 MHz,
CDCl3, 32 mM) δ 18.6, 19.1, 22.8, 23.3, 26.3, 33.0, 45.1, 123.5,
124.6, 124.9, 125.9, 126.9, 127.3, 127.6, 128.6, 128.9, 129.9,
131.0, 132.5, 134.4, 136.8, 170.0. A similar treatment of (P)-1
gave (P)-8 (30%), which was accompanied by (P,P)-9 (14%).
Mp >300 °C (benzene-MeOH). [R]D26 -32.2 (c 0.534, CHCl3).
1647 cm-1
.
(P )-N,N′-Diben zyl[1+1]cycloa m id e. Under an argon at-
mosphere, to an ice cooled solution of (P)-8 (7.5 mg, 0.012
mmol) in THF (2 mL) were added NaH (60% oil suspension,
1.5 mg, 0.038 mmol) and benzyl bromide (5.7 µL, 0.048 mmol)
successively. The mixture was vigorously stirred for 23 h at
room temperature and was added to 2 M hydrochloric acid.
The organic materials were extracted with chloroform, and the
extracts were washed with water and brine. After the solution
was dried over MgSO4, the solvents were removed in vacuo,
and the crude product was purified by silica gel chromatog-
raphy (n-hexane-ethyl acetate) giving the product (9.7 mg,
(P )-N,N′-Dim eth yl[1+1]cycloa m id e. Under an argon
atmosphere, to an ice cooled solution of (P)-8 (7.5 mg, 0.012
mmol) in tetrahydrofuran (2 mL) was added NaH (60% oil
suspension, 1.5 mg, 0.038 mmol) and methyl iodide (3.0 µL,
0.048 mmol) successively. The mixture was vigorously stirred
for 23 h at room temperature and was added to 2 M hydro-
chloric acid. The organic materials were extracted with
chloroform, and the extracts were washed with water and
brine. After the solution was dried over MgSO4, the solvents
were removed in vacuo, and the crude product was purified
by silica gel chromatography (n-hexane-ethyl acetate) giving
the product (7.8 mg, 100%). Mp >300 °C (ethyl acetate-n-
100%). Mp 201-204 °C (ethyl acetate-n-hexane). [R]27
D
-22.9 (c 0.610 CHCl3). MS (FAB, NBA) m/z 811 (M+ + 1).
UV-vis (CHCl3) λmax (ꢀ) 290 nm (3.2 × 104), 303 nm (3.6 ×
104). IR (KBr) 2932, 2864, 1642 cm-1
.
1H NMR (600 MHz,
CDCl3) δ 1.50-1.65 (6 H, m), 1.59 (12 H, br s), 1.66 (6 H, s),
2.17-2.33 (4 H, m), 4.90-5.40 (4 H, br s), 6.27 (2 H, s), 6.75
(2 H, br s), 6.90 (2 H, br s), 7.28 (2 H, d, J ) 7.1 Hz), 7.28-
7.34 (8 H, m), 7.49 (2 H, dd, J ) 7.0, 8.2 Hz), 7.49-7.52 (4 H,
m), 8.14 (2 H, d, J ) 8.2 Hz). 13C NMR (150 MHz, CDCl3) δ
18.6, 18.8, 22.8, 23.2, 26.3, 29.7, 33.3, 44.8, 52.5, 123.3, 123.5,
125.4, 125.8, 126.2, 126.2, 127.7, 127.7, 128.1, 128.4, 130.1,
130.1, 130.8, 131.0, 135.5, 135.8, 136.5, 137.4, 137.5, 148.9,
168.5.
hexane). [R]27 -16.4 (c 0.675 CHCl3). MS (EI, 70 eV) m/z
D
658 (M+, 100%), 643 (M+ - Me, 2). UV-vis (CHCl3) λmax (ꢀ)
290 nm (2.2 × 104), 303 nm (2.6 × 104). IR (KBr) 2926, 2860,
1642 cm-1 1H NMR (600 MHz, CDCl3) δ 1.53-1.60 (6 H, m),
.
(P ,P )-N,N′,N′′,N′′′-Tet r a b en zyl[2+2]cycloa m id e. Mp
>300 °C (ethyl acetate-n-hexane). [R]27 +71.0 (c 0.420
1.74 (6 H, s), 1.95 (6 H, s), 2.00 (6 H, s), 2.20-2.35 (4 H, m),
3.52 (6 H, s), 6.32 (2 H, s), 6.83 (2 H, s), 6.96 (2 H, s), 7.35 (2
H, d, J ) 7.0 Hz), 7.57 (2 H, dd, J ) 7.1, 8.3 Hz), 8.30 (2 H, d,
J ) 8.2 Hz). 13C NMR (150 MHz, CDCl3) δ 18.4, 18.7, 22.8,
23.3, 26.3, 29.7, 33.4, 36.2, 44.8, 123.7, 123.8, 125.3, 126.0,
126.3, 127.7, 128.2, 130.0, 130.9, 131.0, 135.1, 135.3, 136.6,
138.6, 148.8, 168.8.
D
CHCl3). MS (FAB, NBA) m/z 1622 (M+ + 2). UV-vis (CHCl3)
λmax (ꢀ) 309 nm (8.5 × 104). IR (KBr) 2934, 1638 cm-1
.
1H
NMR (600 MHz, CDCl3, 40 °C) δ -1.86 to -1.70 (2 H, m),
-0.47 to -0.36 (2 H, m), 0.02-0.08 (2 H, m), 0.44-0.57 (4 H,
m), 0.90-0.99 (2 H, m), 1.00-1.11 (4 H, m), 1.40 (6 H, s), 1.38-
1.47 (2 H, m), 1.60-1.75 (2 H, m), 1.66 (6 H, s), 1.72 (6 H, s),
1.81 (6 H, s), 1.92 (6 H, s), 2.54 (6 H, s), 4.28 (2 H, d, J ) 13.5
Hz), 4.93 (2 H, d, J ) 13.5 Hz), 5.44 (2 H, d, J ) 13.5 Hz), 5.52
(2 H, d, J ) 13.5 Hz), 6.02 (2 H, s), 6.03 (2 H, s), 6.51 (2 H, s),
6.74 (2 H, s), 7.12 (4 H, d, J ) 7.1 Hz), 7.28 (4 H, t, J ) 7.3
Hz), 7.32 (2 H, t, J ) 7.3 Hz), 7.35 (4 H, d, J ) 7.3 Hz), 7.43
(4 H, t, J ) 7.7 Hz), 7.44 (2 H, d, J ) 6.2 Hz), 7.50 (2 H, s),
7.48-7.55 (5 H, m), 7.63 (2 H, dd, J ) 6.2, 8.2 Hz), 7.73 (2 H,
s), 7.75 (2 H, t, J ) 7.9 Hz), 8.22 (2 H, d, J ) 8.2 Hz), 8.29 (2
H, d, J ) 8.2 Hz). 13C NMR (150 MHz, CDCl3) δ 18.5, 18.6,
19.0, 19.1, 19.6, 22.1, 22.5, 23.0, 24.7, 35.4, 38.8, 46.0, 51.0,
52.7, 122.7, 122.9, 123.6, 123.7, 125.5, 125.8, 125.9, 126.4,
127.0, 127.5, 127.6, 127.8, 128.0, 128.2, 128.3, 128.4, 128.5,
129.5, 129.8, 129.8, 130.3, 130.9, 131.9, 132.8, 133.6, 135.4,
135.6, 135.8, 136.0, 136.1, 136.3, 136.4, 136.7, 137.8, 142.3,
144.0, 149.8, 169.4, 169.4.
(P ,P )-N,N′,N′′,N′′′-Tet r a m et h yl[2+2]cycloa m id e. Mp
>300 °C (ethyl acetate-hexane). [R]27D +80.7 (c 0.205 CHCl3).
MS (FAB, NBA) m/e 1316 (M+ + 2). UV-vis (CHCl3) λmax (ꢀ)
308 nm (5.0 × 104). IR (KBr) 2936,1647 cm-1. The conformers
were separated by silica gel column chromatography (n-
hexane-ethyl acetate) below -10 °C and one major conformer
was isolated. 1H NMR (600 MHz, CDCl3, -30 °C) δ -2.05 to
-1.95 (2 H, m), -0.60 to -0.50 (2 H, m), -0.20 to -0.10 (2 H,
m), 0.25-0.45 (4 H, m), 0.85-1.00 (4 H, m), 1.30-1.40 (2 H,
m), 1.45-1.55 (2 H, m), 1.63 (6 H, s), 1.60-1.70 (2 H, m), 1.75
(6 H, s), 1.97 (6 H, brs), 2.03 (6 H, s), 2.17 (6 H, s), 2.45 (6 H,
s), 3.23 (6 H, s), 3.60 (6 H, brs), 6.12 (2 H, brs), 6.16 (2 H, brs),
6.52 (2 H, s), 6.83 (2 H, s), 7.29 (2 H, s), 7.31 (2 H, d, J ) 7.5
Hz), 7.32 (2 H, s), 7.33 (2 H, d, J ) 7.5 Hz), 7.54 (2 H, dd, J )
7.5, 8.3 Hz), 7.58 (2 H, dd, J ) 7.5, 8.0 Hz), 8.22 (brd, J ) 8.0
Hz), 8.32 (2 H, d, J ) 8.3 Hz). 13C NMR (150 MHz, CDCl3,
-30 °C) δ 17.9, 18.6, 18.7, 19.6, 22.7 (two carbons), 23.1, 24.0,
25.0, 36.0 (two carbons), 37.3, 39.7, 46.0, 122.4, 122.6, 123.5,
124.4, 126.1 (two carbons), 126.3, 126.6, 127.2, 127.5, 128.2,
128.5, 128.5, 128.6 (two carbons), 129.9, 130.1, 131.2, 131.3,
131.9, 133.6, 134.8, 134.9, 135.4, 136.0, 137.1, 138.4, 140.4,
170.8, 170.9. Two aniline carbons at N-C were not detected.
(P ,P )-[2+2]Cycloa m id e Ca ta lyzed Ad d ition of Dieth -
ylzin c to Ar om a tic Ald eh yd e (Gen er a l P r oced u r es).
Under an argon atmosphere, to a mixture of (P,P)-9 (12 mg,
0.01 mmol) and tetrahydrofuran (3 mL) was added 1.6 M
n-butyllithium (0.048 mmol) in hexane (0.03 mL) at 0 °C. The
mixture was stirred for 30 min, and an aldehyde (0.20 mmol)
was added. After the mixture was warmed to room temper-
ature, 1 M diethylzinc (0.60 mmol) in hexane (0.6 mL) was
added. The mixture was vigorously stirred for 1 day at room
temperature, when 2 M hydrochloric acid was added. Organic
materials were extracted with chloroform, and the organic
layer was successively washed with water and brine. After
the solution was dried over MgSO4, the solvents were evapo-
rated in vacuo, and the crude product was purified by silica
gel chromatography (n-hexane-ethyl acetate), giving an opti-
cally active secondary alcohol. The (P,P)-9 was recovered
(>70%). Spectral data of the secondary alcohols were in
accordance with the reported data. The optical purity was
determined by HPLC analysis using Daicel Chiralcel OB-H
(10% 2-propanol in n-hexane). The absolute configuration was
determined according to the literature.
(P ,P ,P )-N ,N ′,N ′′,N ′′′,N ′′′′,N ′′′′′-H e x a m e t h y l[3+3]-
cycloa m id e. Mp >300 °C (ethyl acetate-n-hexane). [R]27
D
+74.9 (c 1.58, CHCl3). Calcd for C138H138O6N6‚8H2O: C, 78.16;
H, 7.32; N, 3.96%. Found: C, 78.32; H, 7.22; N, 3.86%.
Found: C, 77.37; H, 6.97; N, 3.72%. Found: C, 77.79; H, 6.97;
N, 3.95%. Found: C, 78.11; H, 7.26; N, 4.18%. The analytical
sample was prepared by precipitating from ethyl acetate by
adding hexane and dried at 80 °C/1 mmHg for 1 day. MS
(FAB, NBA) m/z 1977 (M+ + 3). UV-vis (CHCl3) λmax (ꢀ) 303
nm (7.8 × 104). IR (KBr) 2928, 1651 cm-1
.
(P ,P ,P ,P )-N,N′,N′′,N′′′,N′′′′,N′′′′′,N′′′′′′,N′′′′′′′-Octa m eth yl-
[4+4]cycloa m id e. Mp >300 °C (ethyl acetate-n-hexane).
[R]27D +69 (c 0.21, CHCl3). Calcd for C184H184O8N8‚13H2O: C,
77.01; H, 7.38; N, 3.90%. Found: C, 76.49; H, 7.12; N, 3.69%.
Found: C, 76.91; H, 7.17; N, 3.64%. Found: C, 77.44; H, 7.19;
N, 4.04%. The analytical sample was prepared by precipitat-
ing from ethyl acetate by adding hexane and dried at 80 °C/1
(R)-1-P h en yl-1-p r op a n ol. [R]25 +16 (c 0.97, CHCl3).
D
Literature19 [R]D -45.45 (c 5.2, CHCl3), (S)-configuration.
(R)-1-(p-Meth oxyp h en yl)-1-eth a n ol. [R]22 +11 (c 1.9,
D

Macrocyclic Amides
compound
J . Org. Chem., Vol. 63, No. 25, 1998 9509
Ta ble 2. Su m m a r y of Cr ysta l Da ta , Da ta Collection , a n d Refin em en t Deta ils
(P)-4
(P,P)-9
(P)-N,N′-dimethyl[1+1]cycloamide
formula
Mr
C
42H46O6N2S2
C108H144O14N4
1722.34
0.3 × 0.3 × 0.5
C2/c (No. 15)
monoclinic
150
24.038(2)
12.335(2)
35.392(2)
102.29(3)
10253(1)
4
1.116
0.73
Mo KR
0.71069
3728
C48H48O2N2Cl6
897.64
0.1 × 0.2 × 0.4
P212121 (No. 19)
orthorhombic
283
18.982(2)
21.336(2)
11.394(3)
738.96
0.2 × 0.3 × 0.4
P21 (No. 4)
monoclinic
283
10.900(2)
14.974(2)
12.060(2)
112.04(1)
1824.5(5)
2
1.345
17.00
Cu KR
1.54178
784
crystal size, mm
space group
crystal system
temp, K
a, Å
b, Å
c, Å
â, deg
V, Å3
4614.4(10)
4
Z
D
calcd, g/cm3
1.292
18.53
Cu KR
1.54178
1872
µ, cm-1
radiation
λ, Å
F(000)
no. of unique measd data
no. of unique obsd data
3042
2966
9320
4037
4137
3170
[Io > 3σ(Io)]
468
[Io > 3σ(Io)]
574
[Io > 4σ(Io)]
523
no. of variables
R
Rw
0.039
0.052
0.24
0.085
0.087
0.57
0.076
0.074
0.48
(∆F)max, e/Å3
CHCl3). Literature20 [R]22 -17.2 (c 5, benzene, 51% ee), (S)-
package (Crystal Structure Analysis Package, Molecular Struc-
ture Corporation).
D
configuration.
(R)-1-(p-Meth ylp h en yl)-1-eth a n ol. [R]22 +8.7 (c 0.64,
D
CHCl3). Literature20 [R]22 -20.4 (benzene, 52% ee), (S)-
D
Ack n ow led gm en t. We thank Professor M. Hirama
(Tohoku University, Graduate School of Science) for
encouragement during these works. We also thank
Professor N. Harada (Tohoku University, Institute for
Chemical Reaction Science) for providing d-(-)-cam-
phorsultam. Elemental analyses were conducted by Ms.
A. Sato (Tohoku University, Faculty of Pharmaceutical
Sciences). A fellowship to H. O. from the J apan Society
of Promotion of Science for young J apanese scientists
is gratefully acknowledged. This work was supported
by the J apan Society of Promotion of Science (RFTF
97P00302), Grant-in-Aid for Scientific Research in
Priority Areas of “New Polymers and Their nano-
Organized Systems” from the Ministry of Education,
Science, Sports and Culture, J apan. Supports by the
Nissan Science Foundation, the Toray Science Founda-
tion, and the Fujisawa Foundation are also gratefully
acknowledged.
configuation.
(R)-1-(p-Ch lor op h en yl)-1-eth a n ol. [R]22 +8.7 (c 1.2,
D
CHCl3). Literature20 [R]22 -10.4 (c 5, benzene, 43% ee), (S)-
D
configuration.
(R)-1-(1-Na p h th yl)-1-eth a n ol. [R]24 +23 (c 1.0, CHCl3).
D
The enantiomeric excess of the adduct was determined by the
optical rotation. Literature21 [R]D -37.1 (c 4.17 CHCl3, 63%
ee), (S)-configuration.
(R)-1-(2-Na p h th yl)-1-eth a n ol. [R]24 +19 (c 1.0, CHCl3).
D
Literature22 [R]20D -18.8 (benzene, 44.7% ee), (S)-configuration.
X-r a y Cr ysta llogr a p h y. Details of crystal data, data
collection, and refinement for the three compounds are con-
cisely summarized in Table 2. The cell and intensity data were
collected by using a Rigaku four circle diffractometer (AFC5R).
The compound of (P,P)-9 is mildly air-sensitive, so that the
data were measured at low temperature (150 K) by coating
with epoxy-resins. The structures were solved by direct
method (SIR92) and refined by using a full-matrix least-
squares method. Although most hydrogen atoms were found
in D-map, the other atoms were calculated geometrically. The
crystal of (P)-4 does not include a solvent molecule. The crystal
of (P,P)-9 is restricted by a crystallographic 2-fold axis sym-
metry. A total of 10 ethanol solvents per each (P,P)-9 molecule
are included, in which the four solvents are included in the
cavity of the host molecule and the others are included into
the host line channel. The crystal of (P)-N,N-dimethyl[1+1]-
cycloamide contained two chloroform molecules per cycloamide
and the solvents are included in the crystal lattice. All
calculations were carried out by using a teXsan software
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
8-11, N,N′′-dimethyl-8, N,N′′-dibenzyl-8, and N,N′′,N′′′,N′′′′-
tetrabenzyl-9 (8 pages). The material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O981720F