Stereochemistry of 1,5-benzothiazepin-4-one S-oxide: Insight into the stereogenic elements at the sulfur atom and axis

Article abstract of DOI:10.1021/jo401020y

Oxidation of 1,5-benzothiazepin-4-one (5-A) stereoselectively afforded the S-oxide 8I-A (aS,1S) in preference to the diastereomer 8II-A (aS,1R) affected by the remote stereogenic axis. All the enantiomers (8I-A/8I-B and 8II-A/8II-B) were separated and isolated, and the interconversion between 8I and 8II (equilibrium ratio ≈5:1) was unequivocally verified to be caused by the rotation around the axis.

Full text of DOI:10.1021/jo401020y

Article
pubs.acs.org/joc
Stereochemistry of 1,5-Benzothiazepin-4-one S‑Oxide: Insight into
the Stereogenic Elements at the Sulfur Atom and Axis
Hidetsugu Tabata, Tetsuya Yoneda, Tetsuta Oshitari, Hideyo Takahashi, and Hideaki Natsugari*
Faculty of Pharma Sciences, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan
S
* Supporting Information
ABSTRACT: Oxidation of 1,5-benzothiazepin-4-one (5-A)
stereoselectively afforded the S-oxide 8I-A (aS,1S) in preference
to the diastereomer 8II-A (aS,1R) affected by the remote stereo-
genic axis. All the enantiomers (8I-A/8I-B and 8II-A/8II-B)
were separated and isolated, and the interconversion between 8I
and 8II (equilibrium ratio ≈5:1) was unequivocally verified to
be caused by the rotation around the axis.
INTRODUCTION
The 1,5-benzothiazepin-4-one nucleus (1) has been used as the
core structure of various biologically active molecules (Figure 1).
■
Figure 2. Seven-membered-ring benzolactams (5−7) as potent ACAT
inhibitors, the sulfoxide analogue (8), and atropisomers A and B.
(enantiomers A and B) of 5−7 were separated, and the axial
Figure 1. Seven-membered-ring benzolactams (1−4) and atropisomeric
chirality of type A was revealed to be recognized by the ACAT
structures A and B.
enzyme. Interesting information was also obtained in the 1,5-
benzodiazepin-2-one nucleus (for 7-A/B, X = NCH3), in which
the axial chirality induces a latent chiral center at amine N-5
exhibiting chiroptical properties different from those of 5-A/B
and 6-A/B.
Diltiazem,1 with antihypertensive and antianginal activity, and
thiazesim,2 with antidepressant activity, are the typical thera-
peutic agents developed using the nucleus. The S-oxide deriva-
In this context, we next focused on the S-oxide derivative of
tives (4) have also been shown to display biological activities,
such as growth hormone secretagogue activity3 and the inhi-
bition of angiotensin converting enzyme,4 human leukocyte
elastase,5 and HIV-reverse transcriptase.6 Thus, the stereo-
chemical and physicochemical analyses of these relatively flexible
heterocycles are important and should provide useful informa-
tion for future drug design.
1,5-benzothiazepin-4-one (for 4/8, X = S*O), which possesses a
configurational stereogenic center at the sulfur atom in addition
to the chirality due to the axis at Ar−N(CO). There have been
many reports on S-oxidation of 1,5-benzothiazepin-4-ones with a
substituent(s) (chiral center) in the lactam ring and separation of
the diastereomeric mixtures.3−6,10 However, few reports have
described the exact (relative and absolute) stereochemistry, and
even less attention has been paid to another chirality based on
the axis at Ar−N(CO).11 This is because the axis of the 1,5-
benzothiazepin-4-one S-oxide, without a substituent at the
6-position (i.e., compound 4), is too labile to examine the pro-
perties. In this paper, using the 1,5-benzothiazepin-4-one (5),8b
in which the axis is sterically frozen by a phenyl group at the
As part of our research on atropisomerism in biologically active
molecules,7 we have recently reported the atropisomeric
properties of pharmaceutically important seven-membered-ring
benzolactams [1 (X = S), 2 (X = CH2), and 3 (X = NCH3)]
(Figure 1) due to an sp2−sp2 axis at Ar−N(CO) (a
conformational stereogenic axis)8a by introducing a substituent
at the 6-position9 to freeze the conformation, which led to the
successful discovery of the potent new acyl-CoA cholesterol
acyltransferase (ACAT) inhibitors 5, 6, and 7, having 6-phenyl
and N-CH2CONH−Ar substituents (Figure 2).8b The atropisomers
Received: May 9, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401020y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. S-Oxidation of 1,5-Benzothiazepin-4-one (5) with mCPBA and Separation of the Sulfoxide (8) into the Diastereomers
a
(8I and 8II)
a
The preferred approach of the oxidant from the pseudoequatorial side is shown in brackets.
Figure 3. X-ray crystal structures of the sulfide 5-A,8b the major sulfoxide 8I-A, and sulfone 9-A. The structure of the (aS) atropisomeric form (A) of 8I
and 9 is extracted from the CIF data of the X-ray analysis of the racemate.
a
Table 1. Selected 1H NMR Data of the Sulfide (5), Diastereomeric Sulfoxides (8I and 8II), and Sulfone (9)
compound
X (ps.eq.)
Y (ps.ax.)
H2a (ppm)
3J (Hz) (H2a,H3a) (H2a,H3b)
H2b (ppm)
3J (Hz) (H2b,H3a) (H2b,H3b)
a
5
3.48
2.93
3.47
3.60
5.9
8.9
6.0
6.8
2.9
1.4
2.9
2.2
3.37
4. 14
3.65
3.90
11.1
10.8
10.5
12.2
8.1
7.2
7.4
7.2
8I
8II
9
O
O
O
O
a
For reference, see 8b.
6-position, we elucidate the stereochemistry of the sulfoxide 8 from
the viewpoint of the relation between two stereogenic elements at
the sulfur atom and axis and demonstrate the importance of the axial
chirality in controlling the stereochemistry of the lactam ring.
was performed with meta-chloroperoxybenzoic acid (mCPBA)
(1.05 equiv) at 23 °C for 0.5 h in CH2Cl2 to afford a mixture of
sulfoxide (8) (91%) and sulfone (9) (4%). HPLC analysis of the
sulfoxide (8) using a nonchiral column revealed that 8 is a
mixture of diastereomers (8I and 8II) with a ratio of ≈5:1
(Scheme 1), which was separated by preparative HPLC. The
oxidation at −78 °C gave similar results, affording 8I as the major
RESULTS AND DISCUSSION
■
S-Oxidation of 1,5-Benzothiazepin-4-one (5) with
mCPBA. S-Oxidation of the 1,5-benzothiazepin-4-one (5)8b
B
dx.doi.org/10.1021/jo401020y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
product, although the reaction proceeded slowly and took approxi-
mately 3 h to complete.
H2b are observed, whereas the minor isomer 8II shows a smaller
downfield shift of H2b. Also characteristic are moderate
downfield shifts of both protons (H2a and H2b) for the sulfone
(9). Furthermore, the chemical shifts of the amide-NH are
noteworthy. The NH proton of 8I and 9 was observed at δ 8.29
and 8.95 ppm, respectively, while that of 8II was at a markedly
lower field (δ 10.19 ppm). The relatively lower shift of the NH of
9 at 8.95 ppm may be ascribed to the hydrogen bond,15 which
was supported by the distance between SOax···HN (1.92 Å)
and the Oax···H−N angle (159°) as determined by the X-ray
structure of 9 (Figure 3). In addition, the markedly lower field
shift of the NH of 8II (δ 10.19 ppm) implies that the oxygen at
the S-oxide takes a pseudoaxial orientation to form a very strong
hydrogen bond between the amide-NH.
The stereoselective oxidation of 5 to 8I is of interest. It should
be emphasized that the stereocontrolled S-oxidation was affected
by the remote stereogenic axis at Ar−N(CO), which indicates
that the axial chirality controls the conformation of the entire
lactam ring. From the X-ray crystal analysis of the chiral 1,5-
benzothiazepin-4-one (5-A) (Figure 3),8b the pseudoaxial side of
the S-atom is shown to form a hydrogen bond with the amide-
NH and is covered by the substituent at the lactam nitrogen,
whereas the pseudoequatorial side is open, as illustrated in Scheme 1
(in brackets). Thus, the reagent preferably approaches from the
sterically less-hindered equatorial lone-pair side to form 8I with the
S-oxygen disposed in a pseudoequatorial orientation as the major
product and 8II with a pseudoaxial S-oxygen as the minor product.
Stereochemical Stability of the Sulfoxides (8I and 8II).
During the separation and isolation of the diastereomeric iso-
mers (8I and 8II), we noted that the minor isomer 8II is labile
and easily transformed into the isomer 8I. The transformation
process is of interest because two stereogenic elements are present
in the molecule. Because the chiral center of the S-oxide is relatively
stable against thermal pyramidal inversion (racemization),16 the
isomerization was assumed to be caused by the rotation around the
axis at Ar−N(CO). Thus, the conversion is presumably triggered
by the conformational change in the S-oxide of 8II from the
The major sulfoxide (8I) and sulfone (9) were successfully
analyzed by X-ray crystallography, and both exhibited a similar
boat-like conformation of the seven-membered lactam ring,
which the starting sulfide (5) also adopts in the crystal structure
(Figure 3).8b The sulfoxide 8I was revealed to have a relative
stereochemistry of (aS*,1S*),12 with the S-oxygen in a stable
pseudoequatorial orientation. Attempts to obtain single crystals
1
of the minor sulfoxide (8II) for X-ray analysis failed, but H
NMR analysis (vide infra) implied that 8II also takes a boat-like
conformation of the lactam ring with the pseudoaxial S-oxygen
and hence has the relative stereochemistry of (aS*,1R*).
13
1
The H NMR spectral data of 8I, 8II, and 9 for the
methylene protons of the lactam ring are shown in Table 1, which
revealed that structures similar to those demonstrated by X-ray
crystal analysis exist in solution, as well. For determination of the
stereochemistry of 8I, 8II, and 9, the vicinal coupling (3J)
between H2 and H3 was diagnostic: a smaller 3J value for (H2a,H3b)
(1.4−2.9 Hz) and a larger one for (H2b,H3a) (10.5−12.2 Hz)
correspond well with the values estimated from the torsion angles
obtained from the X-ray crystal structure (vide supra).14 As seen
in Table 1, characteristic shifts of the protons (H2a and H2b) are
found for the sulfoxide diastereomers (8I and 8II) when
compared with the parent sulfide (5). Thus, for the major isomer
8I, a strong upfield shift of H2a and a marked downfield shift of
Figure 4. Interconversion between the diastereomeric sulfoxides
(8I and 8II) in CHCl3.
Figure 5. Separation of the sulfoxide (8I and 8II) and sulfone (9) into the enantiomers (A and B) on a chiral column and the chiral HPLC
chromatogram of the oxidation of 5 with mCPBA at 23 °C for 30 min. The enantiomers of 5 were not separated under those conditions.
C
dx.doi.org/10.1021/jo401020y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
pseudoaxial orientation to the stable pseudoequatorial one,
accompanied by the rotation around the axis to form the isomer
8I. The stereochemical stability of 8I and 8II was examined at
37 °C in CHCl3. The isomerization profile is shown in Figure 4,
which shows that upon heating both isomers reach an equili-
brium state in a ratio of 8I/8II ≈5:1. The activation free-energy
barriers to rotation (ΔG⧧)17 calculated from these data are 100
kJ/mol (from 8II to 8I) and 109 kJ/mol (from 8I to 8II), which
reflects the equilibrium ratio of ≈5:1. These results indicate that
the isomer 8I (with pseudoequatorial oxygen) is preferable to 8II
(vide supra) both kinetically and thermodynamically.
Separation of Sulfoxides (8I and 8II) and Sulfone (9)
into the Enantiomers (A and B). After obtaining general
information on the oxidation products (8I, 8II, and 9) in the
racemic form, the separation into the enantiomers was next attempted
using chiral HPLC. Fortunately, all the oxidative products were suc-
cessfully separated into the respective enantiomers (A and B) by
HPLC on a chiral stationary phase and isolated using preparative
HPLC. The chromatogram of chiral HPLC of the enantiomers is
shown in Figure 5. The absolute configuration (conformation) of
enantiomers (A and B) was determined by comparison of the
HPLC data with those of the oxidation products (8I-A, 8II-A,
9-A, and the B-series enantiomers) of the enantiomerically pure
(aS)- and (aR)-1,5-benzothiazepin-4-one (5-A and 5-B)8b
(Scheme 2a). In the oxidation, no isomeric products were
detected, indicating that the reaction proceeded without rotation
around the axis. The circular dichroism (CD) spectra and optical
rotation ([α]D) data of the separated enantiomers are shown in
Figure 6. It is interesting to note that the chiroptical properties of
8II-A/B differed from those of 5-A/B,8b 8I-A/B, and 9-A/B; for
example, the [α]D value of 8II-A (aS,1R) was positive (+42), and
that of 5-A (aS), 8I-A (aS,1S), and 9-A (aS) was negative (−16,
−61, and −37, respectively) (Figure 6). The CD spectral pattern
of 8II-A also differed from those of 5-A, 8I-A, and 9-A as shown
in Figure 6. The unique chiroptical properties of 8II-A, compared
with those of 5-A, 8I-A, and 9, indicate that the absolute
stereochemistry at the 1S affects the chiroptical properties as
observed in the 1,5-benzodiazepin-2-one nucleus (7-A).8b,18
Isomerization of Enantiomeric Sulfoxides (8I-A/B and
8II-A/B) and Sulfone (9A/B). Using the enantiomerically pure
lactams (8I-B and 8II-B), the mechanism of the interconversion
between 8I and 8II was investigated by chiral HPLC analysis
(Scheme 2b). Thus, when heated at 50 °C in CHCl3, the
enantiomerically pure 8I-B was converted into the atropisomer
8II-A with the ΔG⧧ values of 109 kJ/mol (the equillibrium state
of 8I-B/8II-A ≈5:1), whereas 8II-B was converted to 8I-A at
37 °C with the ΔG⧧ values of 100 kJ/mol (the equillibrium state
of 8II-B/8I-A ≈1:5), which clearly indicates the rotation around
the axis (without isomerization of the chiral center at the S-oxide)
during the conversion process. The stereochemical stability of
the atropisomeric sulfone (9-A/B) was also examined at 37 °C in
toluene. The ΔG⧧ value was shown to be 100 kJ/mol
(conversion from 9-A to 9-B), and the time required for
racemization was approximately 7 h. The lower stability of 9-A/B
compared with that of 5-A/B (105 kJ/mol, 7 h at 50 °C in
toluene for racemization)8b may be ascribed to the presence of
the axial S-oxygen in 9-A/B, which may cause instability of the
lactam ring.
Scheme 2. (a) S-Oxidation of (aS)- and
(aR)-1,5-Benzothiazepin-4-ones (5-A and 5-B) with mCPBA
and (b) Interconversion between the Enantiomers of Sulfoxide
(8I-A, 8I−B, 8II-A, and 8II−B) and Sulfone (9-A and 9-B)
CONCLUSION
■
In summary, the stereochemistry of 1,5-benzothiazepin-4-one
sulfoxide (4/8) was first elucidated from the viewpoint of the
Figure 6. CD spectra and [α]D data of the enantiomers (A and B) of 5, 8I, 8II, and 9 measured in MeOH.
D
dx.doi.org/10.1021/jo401020y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ESI-TOF) m/z [M + Na]+ calcd for C24H18N2O2F4SNa 497.0917,
found 497.0920.
Oxidation Products of N-(4-Fluoro-2-trifluoromethylphenyl)-
2-(4-oxo-6-phenyl-3,4-dihydro-2H-1,5-benzothiazepin-5-yl)-
acetamide (5): The Sulfoxide Isomers (8I, 8II) and Sulfone (9).
relation between two stereogenic elements at the sulfur atom and
axis. The sterically controlled reaction observed in the S-oxidation
of 1,5-benzothiazepin-4-one (5) was shown to be caused by the
remote stereogenic axis. Furthermore, using the enantiomerically
pure lactams, interconversion between the diastereomers was
unequivocally clarified to originate from rotation around the axis.
These results indicate that axial chirality plays an important role
in controlling the stereochemistry and chemical reactivity of
the 1,5-benzothiazepin-4-one nucleus. The stereochemistry of
S-oxides revealed in this study is also important for understanding
the metabolism of the biologically active sulfide derivatives. We
hope that this study will contribute to drug design of phar-
maceutically important 1,5-benzothiazepin-4-one molecules.
EXPERIMENTAL SECTION19
■
2-Bromo-N-(4-fluoro-2-trifluoromethylphenyl)acetamide.
To a solution of bromoacetic acid (695 mg, 5.0 mmol) and 4-fluoro-2-
trifluoromethylaniline (690 mg, 3.85 mmol) in THF (25 mL) at 23 °C
under argon was added N,N′-dicyclohexylcarbodiimide (DCC) (1.34 g,
6.5 mmol) portionwise with stirring. After being stirred at 23 °C for 24 h,
the mixture was filtrated to remove N,N′-dicyclohexylurea. The filtrate
was concentrated, and ethyl acetate was added to the concentrate. The
mixture was washed successively with dilute HCl, H2O, saturated
NaHCO3, and H2O and dried. The solvent was evaporated, and the
residue was treated with diisopropyl ether to afford 2-bromo-N-(4-
fluoro-2-trifluoromethylphenyl)acetamide as colorless crystals (465 mg,
1.55 mmol, 40%): mp 105−107 °C; 1H NMR (600 MHz, CDCl3) δ 4.06
(s, 2H, CH2), 7.30 (1H, dt, J = 8.4, 2.8 Hz, H5), 7.37 (1H, dd, J = 8.4, 2.8
Hz, H3), 8.12 (1H, dd, J = 8.4, 4.8 Hz, H6), 8.51 (1H, br, NH); 13C
NMR (150 MHz, CDCl3) δ 29.1 (Br−C), 113.7 (dq, C3), 119.7 (d,
C5), 122.9 (dq, C2), 122.9 (q, CF3), 126.7 (d, C6), 130.5 (C1), 159.2
(d, C4), 163.9 (CO); IR (KBr) 3275, 1670, 1315, 1176, 1122 cm−1;
HRMS (ESI-TOF) m/z [M − H]− calcd for C9H6NOF4Br 297.9496,
found 297.9502.
To a solution of 5 (15.4 mg, 0.032 mmol) in CH2Cl2 (0.3 mL) at 23 °C
under argon was added dropwise a solution of meta-chloroperoxy-
benzoic acid (mCPBA) (9.0 mg, 0.034 mmol) in CH2Cl2 (0.24 mL).
After being stirred at 23 °C for 0.5 h, the mixture was treated with
saturated aq NaHCO3 and extracted with ethyl acetate. The extract was
washed with brine, dried, and concentrated. The concentrate was
purified by column chromatography (silica gel, ethyl acetate/hexane =
1:4) to afford sulfoxide (8) (14.4 mg, 91%) and sulfone (9) (6.8 mg,
4%). The sulfoxide (8) was separated by preparative HPLC using a
nonchiral column (YMC SIL-06) to give the diastereomers 8I and 8II in
a ratio of ≈5:1. See the Supporting Information for the HPLC
chromatogram. The oxidation at −78 °C gave similar results, affording 8
(89%) (8I/8II ≈ 5:1) and 9 (4%), although the reaction proceeded
slowly, taking approximately 3 h to complete. The product ratio of the
oxidation reaction was also confirmed by HPLC analysis using an aliquot
of the reaction mixture before work up.
N-(4-Fluoro-2-trifluoromethylphenyl)-2-(4-oxo-6-phenyl-
3,4-dihydro-2H-1,5-benzothiazepin-5-yl)acetamide (5).8b
Major Sulfoxide (8I): Colorless crystals; mp 220−221 °C; 1H NMR
(600 MHz, CDCl3) δ 2.76 (1H, ddd, J = 12.0, 7.2, 1.4 Hz, H3b), 2.93
(1H, ddd, J = 11.5, 8.9, 1.4 Hz, H2a), 2.98 (1H, ddd, J = 12.0, 10.8, 8.9
Hz, H3a), 4.14 (1H, ddd, J = 11.5, 10.8, 7.2 Hz, H2b), 3.22 (1H, d, J =
14.9 Hz, −CH2CO−), 4.28 (1H, d, J = 14.9 Hz, −CH2CO−), 7.21 (1H,
dt, J = 8.4, 2.7 Hz, H5″), 7.3 (1H, m, H3″), 7.30 (2H, d, J = 7.6 Hz, H2′,
H6′), 7.42 (1H, t, J = 7.6 Hz, H4′), 7.46 (2H, t, J = 7.6 Hz, H3′, H5′),
7.62 (1H, dd, J = 7.6, 1.4 Hz, H7), 7.71 (1H, t, J = 7.6 Hz, H8), 7.90 (1H,
dd, J = 8.4, 4.8 Hz, H6″), 7.92 (1H, dd, J = 7.6, 1.4 Hz, H9), 8.26 (1H, br,
NH); 13C NMR (150 MHz, CDCl3) δ 29.8, 52.9, 54.7, 113.5 (d), 119.6
(d), 123.8, 127.2 (d), 128.2 (2 × C), 128.9, 129.5 (2 × C), 129.7, 134.4,
134.6, 136.7, 137.1, 138.9, 158.9 (d), 165.5, 171.0 (signals due to C2″−
CF3 were not determined); IR (KBr) 3161, 1686, 1321, 1175, 1132,
1049, 1036 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C24H18N2O3F4SNa 513.0866, found 513.0868.
To a solution of 2,3-dihydro-6-phenyl-1,5-benzothiazepin-4(5H)-one8a
(120 mg, 0.47 mmol) in DMF (1.0 mL) at 0 °C under argon was added
sodium hydride (60% in oil) (20 mg, 0.5 mmol). The mixture was stirred
at 23 °C for 30 min, cooled to 0 °C, and treated with 2-bromo-N-(4-
fluoro-2-trifluoromethylphenyl)acetamide (120 mg, 0.4 mmol). After
being stirred at 23 °C for 20 h, the mixture was treated with H2O and
extracted with ethyl acetate. The extract was washed with brine, dried,
and concentrated. The concentrate was purified by column chromatog-
raphy (silica gel, ethyl acetate/hexane = 1/2) to afford 5 as colorless
crystals (87 mg, 39%): mp 113−115 °C; 1H NMR (600 MHz, CDCl3) δ
2.85−2.90 (2H, m, H3a, H3b), 3.30 (1H, d, J = 16.3 Hz, −CH2CO−),
3.37 (1H, ddd, J = 11.7, 11.1, 8.1 Hz, H2b), 3.48 (1H, ddd, J = 11.7, 5.9,
2.9 Hz, H2a), 4.25 (1H, d, J = 16.3 Hz, −CH2CO−), 7.20 (1H, dt, J =
8.4, 2.8 Hz, H5″), 7.32 (1H, dd, J = 8.4, 2.8 Hz, H3″), 7.35 (2H, d, J = 7.6
Hz, H2′, H6′), 7.41 (1H, dt, J = 7.6, 1.4 Hz, H4′), 7.42 (1H, t, J = 7.6 Hz,
H8), 7.46 (2H, t, J = 7.6 Hz, H3′, H5′), 7.51 (1H, dd, J = 7.6, 1.4 Hz,
H7), 7.58 (1H, dd, J = 8.4, 4.8 Hz, H6″), 7.69 (1H, dd, J = 7.6, 1.4 Hz,
H9), 9.19 (1H, br, NH); 13C NMR (150 MHz, CDCl3) δ 33.5, 33.9,
53.3, 113.6 (d), 119.4 (d), 122.6 (q), 125.8 (dd), 128.1 (2 × C), 128.6,
128.8, 129.1, 129.4 (2 × C), 130.4 (d), 130.5, 133.4, 135.0, 137.8, 138.0,
142.8, 159.7 (d), 167.3, 173.0; IR (KBr) 3277, 1681 cm−1; HRMS
1
Minor Sulfoxide (8II): Colorless crystals; mp 224−225 °C; H
NMR (600 MHz, CDCl3) δ 2.85−2.90 (2H, m, H3a, H3b), 3.47 (1H,
ddd, J = 14.8, 6.0, 2.9 Hz, H2a), 3.65 (1H, ddd, J = 14.8, 10.5, 7.4 Hz,
H2b), 3.36 (1H, d, J = 16.6 Hz, −CH2CO−), 4.25 (1H, d, J = 16.6 Hz,
−CH2CO−), 7.16 (1H, dt, J = 8.4, 2.8 Hz, H5″), 7.27 (1H, dd, J = 8.4,
2.8 Hz, H3″), 7.3 (1H, m, H6″), 7.32 (2H, d, J = 7.6 Hz, H2′, H6′), 7.44
(1H, t, J = 7.6 Hz, H4′), 7.49 (2H, t, J = 7.6 Hz, H3′, H5′), 7.55 (1H, t,
J = 7.6 Hz, H8), 7.63 (1H, dd, J = 7.6, 1.4 Hz, H7), 7.71 (1H, dd, J = 7.6,
1.4 Hz, H9), 10.20 (1H, br, NH); 13C NMR (150 MHz, CDCl3) δ 31.0,
52.9, 53.6, 113.7 (d), 119.3 (d), 128.1 (2 × C), 128.2, 129,0 129.1, 129.7
(2 × C), 132.1 (d), 134.4, 134.6, 137.3, 137.4, 139.6, 139.8, 160.3 (d),
167.7, 173.0 (signals due to C2″−CF3 were not determined); IR (KBr)
3127, 1679, 1319, 1167, 1137, 1048, 1023 cm−1; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C24H18N2O3F4SNa 513.0866, found 513.0863.
E
dx.doi.org/10.1021/jo401020y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
20
Sulfone (9): Colorless crystals; mp 219−220 °C; H NMR (600
MHz, CDCl3) δ 2.95 (1H, ddd, J = 12.2, 12.0, 6.8 Hz, H3a), 3.00 (1H,
ddd, J = 12.0, 7.2, 2.2 Hz, H3b), 3.60 (1H, ddd, J = 13.8, 6.8, 2.2 Hz,
H2a), 3.90 (1H, ddd, J = 13.8, 12.2, 7.2 Hz, H2b), 3.54 (1H, d, J = 15.4
Hz, −CH2CO−), 4.15 (1H, d, J = 15.4 Hz, −CH2CO−), 7.17 (1H, dt,
J = 8.4, 2.8 Hz, H5″), 7.28 (1H, dd, J = 8.4, 2.8 Hz, H3″), 7.33 (2H, d,
J = 7.6 Hz, H2′, H6′), 7.40 (1H, t, J = 7.6 Hz, H4′), 7.45 (2H, t, J = 7.6
Hz, H3′, H5′), 7.68 (1H, t, J = 7.6 Hz, H8), 7.69 (1H, dd, J = 8.4, 5.5 Hz,
H6″), 7.79 (1H, dd, J = 7.6, 1.4 Hz, H7), 8.14 (1H, dd, J = 7.6, 1.4 Hz,
H9), 8.94 (1H, br, NH); 13C NMR (150 MHz, CDCl3) δ 30.7, 54.6,
56.5, 113.3 (d), 119.3 (d), 122.7 (q), 124.8 (dd), 128.3 (2 × C), 128.6,
128.8, 129.2, 129.6 (2 × C), 129.3 (d), 130.8, 133.3, 136.7, 138.5, 138.6,
139.3, 159.4 (d), 165.8, 170.8; IR (KBr) 3313, 1685, 1320, 1163, 1122
cm−1; HRMS (ESI-TOF) m/z [M − H]− calcd for C24H18N2O4F4S
505.0851, found 505.0858.
peak (8I-B), white solids; retention time = 57.2 min; [α]D +57 (c
0.245, MeOH). The retention time of 8I-A was 11.7 min and that of
8I-B was 7.9 min under the following analytical conditions:
CHIRALPAK IA (0.46 cm ϕ × 25 cm); eluent, hexane:IPA (9:1);
flow rate, 1.2 mL/min; temperature, 23 °C; detection, 254 nm.
Atropisomers (A and B) of Minor Sulfoxide (8II). CHIRALPAK
IA (0.46 cmϕ × 15 cm): eluent, hexane/IPA (5/1); flow rate, 1.2 mL/min;
temperature, 22 °C; detection, 254 nm; former peak (8II-A), white solids;
retention time = 15.6 min; [α]D20 +42 (c 0.085, MeOH); latter peak (9-B),
white solids; retention time = 35.0 min; [α]D20 −40 (c 0.135, MeOH).
Atropisomers (A and B) of Sulfone (9). CHIRALPAK IA (1.0
cmϕ × 25 cm): eluent, hexane/IPA (5/1); flow rate, 4.0 mL/min;
temperature, 22 °C; detection, 254 nm; former peak (9-A), white solids;
retention time = 34.0 min; [α]D20 −37 (c 0.07, MeOH); latter peak (9-B),
white solids; retention time = 57.3 min; [α]D20 +34 (c 0.04, MeOH).
Stereochemical (Thermodynamic) Stability of Diastereomers (8I
and 8II) and Atropisomers (8I-B, 8II-B, and 9-A) (Determination of
ΔG⧧ Value). To examine the thermal stability of diastereomers and
enantiomers, the time-dependent conversion rate (%) was estimated from
chiral or nonchiral HPLC analysis of a solution of the diastereomers or
enantiomer in toluene (or CHCl3) after it was allowed to stand at
designated temperatures. The ΔG⧧ value was determined according to a
calculation method reported in the literature.17 The details, including the
figures of conversion profiles, are shown in the Supporting Information.
Separation of the Oxidation Products of 5 (aS/aR) into the
Enantiomers (8I-A, 8I-B, 8II-A, 8II-B, 9-A, and 9-B) by Chiral
HPLC. The oxidation of 58b with mCPBA was performed by the
procedure described above (at 23 °C for 0.5 h), and the products were
analyzed by a chiral column (CHIRALPAK IA). All the enantiomers
(8I-A, 8I-B, 8II-A, 8II-B, 9-A, and 9-B) were separated as shown in
Figure 5.
Oxidation of 5-A (aS) with mCPBA. Oxidation of 5-A (aS)8b with
mCPBA by the procedure described above (at 23 °C for 0.5 h) afforded
the sulfoxide (8I-A, 8II-A) and sulfone (9-A) with the (aS)-form. The
chiral HPLC chromatogram of the reaction is shown in the Supporting
Information.
ASSOCIATED CONTENT
* Supporting Information
■
S
Oxidation of 5-B (aR) with mCPBA. Oxidation of 5-B (aR)8b with
mCPBA by the procedure described above (at 23 °C for 0.5 h) afforded
the sulfoxide (8I-B, 8II-B) and sulfone (9-B) with the (aR)-form. The
chiral HPLC chromatogram of the reaction is shown in the Supporting
Information.
General experimental procedure, 1H, 13C, and 2D (CH and HH
COSY) NMR spectra for new compounds, figures of thermal
isomerization rate of diastereomers (8I and 8II) and
atropisomers (8I-B, 8II-B, and 9-A), and X-ray data (CIF) for
compounds 8I and 9. This material is available free of charge via
the Internet at http://pubs.acs.org.
Single-Crystal X-ray Analysis. All measurements were made on an
imaging plate area detector graphite monochromated Cu Kα radiation.
The data were collected at a temperature of −100 °C. The structure was
solved by direct method SIR92 and expanded using Fourier techniques.
The non-hydrogen atoms were refined anisotropically. All calculations
were performed using the Crystal Structure 3.8 crystallographic software
package. Typical crystal data of 5-A, 8I, and 9 are as follows.
Crystal Data for 5-A.8b C24H18O2N2F4S: mp 113−115 °C, Mr =
474.47; Cu Kα (λ = 1.54187 Å); orthorhombic, P212121, colorless prism
0.30 × 0.25 × 0.20 mm; crystal dimensions, a = 8.25733(15) Å, b =
14.0039(3) Å, c = 18.1857(3) Å, α = 90°, β = 90°, γ = 90°, T = 173 K, Z =
4, V = 1565.41(12) Å3, Dcalcd = 1.499 g·cm−3, μCu Kα = 19.188 cm−1,
F000 = 976.00, GOF = 1.003, Rint = 0.025, R1 = 0.0263, wR2 = 0.0578,
Flack parameter = 0.001(13), CCDC-831104.
Crystal Data for 8I. C24H18N2O3F4S: mp 220−221 °C, Mr =
490.47; Cu Kα (λ = 1.54187 Å); monoclinic, P21/n, colorless prism 0.20 ×
0.15 × 0.10 mm; crystal dimensions, a = 12.8334(2) Å, b = 7.98785(14)
Å, c = 20.8843(7) Å, α = 90°, β = 99.1302(9)°, γ = 90°, T = 173 K, Z = 4,
V = 2113.75 (7) Å3, Dcalcd = 1.541 g·cm−3, μCu Kα = 19.668 cm−1,
F000 = 1008.00, GOF = 1.585, Rint = 0.040, R1 = 0.0429, wR2 = 0.1198,
CCDC-933115.
Crystal Data for 9. C24H18N2O4F4S: mp 219−220 °C; Mr = 506.47;
Cu Kα (λ = 1.54187 Å); monoclinic, P21/c, colorless prism 0.20 × 0.15 ×
0.05 mm; crystal dimensions, a = 12.4476(2) Å, b = 25.6010(4) Å, c =
8.0385(1) Å, α = 90°, β = 94.3930°, γ = 90°, T = 173 K, Z = 4, V = 2554.11
(7) Å3, Dcalcd = 1.317 g·cm−3, μCu Kα = 16.755 cm−1, F000 = 1040.00,
GOF = 3.496, Rint = 0.0371, R1 = 01517, wR2 = 0.3664, CCDC-941996.
Separation of Sulfoxides (8I and 8II) and Sulfone (9) into the
Enantiomers (A and B) and Characterization of the Separated
Enantiomers. The sulfoxides (8I and 8II) and sulfone (9) were
obtained by the procedure described above and were separated into the
respective atropisomers (A and B) by preparative HPLC using a chiral
column. The separation conditions and the physicochemical data are
described below.
AUTHOR INFORMATION
Corresponding Author
*E-mail: natsu@pharm.teikyo-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by a Grant-in-Aid for Scientific
Research (C) (21590124) and a Grant-in-Aid for Young Scientists
(B) (21790025) from the Japan Society for the Promotion of
Sciences.
REFERENCES
■
(1) (a) Kugita, H.; Inoue, H.; Ikezaki, M.; Konda, M.; Takeo, S. Chem.
Pharm. Bull. 1971, 19, 595−602. (b) Bariwal, J. B.; Upadhyay, K. D.;
Manvar, A. T.; Trivedi, J. C.; Singh, J. S.; Jain, K. S.; Shah, A. K. Eur. J.
Med. Chem. 2008, 43, 2279−2290.
(2) (a) Krapcho, J.; Spitzmiller, E. R.; Turk, C. F. J. Med. Chem. 1963, 6,
544−546. (b) Krapcho, J.; Turk, C. F. J. Med. Chem. 1966, 9, 191−195.
(c) Krapcho, J.; Turk, C. F.; Piala, J. J. J. Med. Chem. 1968, 11, 361−364.
(3) DeVita, R. J.; Schoen, W. R.; Doldouras, G. A.; Fisher, M. H.;
Wyvratt, M. J.; Cheng, K.; Chan, W. W.-S.; Butler, B. S.; Smith, R. G.
Bioorg. Med. Chem. Lett. 1995, 5, 1281−1286.
(4) (a) Slade, J.; Stanton, J. L.; Ben-David, D.; Mazzenga, G. C. J. Med.
Chem. 1985, 28, 1517−1521. (b) Itoh, K.; Kori, M.; Inada, Y.; Nishikawa,
K.; Kawamatsu, Y.; Sugihara, H. Chem. Pharm. Bull. 1986, 34, 1128−1147.
(5) Skiles, J. W.; Sorcek, R.; Jacober, S.; Miao, C.; Mui, P. W.; McNeil,
D.; Rosenthal, A. S. Bioorg. Med. Chem. Lett. 1993, 3, 773−778.
(6) Campiani, G.; Nacci, V.; Fiorini, I.; De Filippis, M. P.; Garofalo, A.;
Greco, G.; Novellino, E.; Altamura, S.; Di Renzo, L. J. Med. Chem. 1996,
39, 2672−2680.
Atropisomers (A and B) of Major Sulfoxide (8I). CHIRALPAK
IA (1.0 cmϕ×25 cm): eluent, hexane/EtOH (9/1); flow rate, 4.0 mL/min;
temperature, 24 °C; detection, 254 nm; former peak (8I-A), white
solids; retention time = 41.7 min; [α]D20 −61 (c 0.155, MeOH); latter
(7) For representative reports, including review articles on the relation
between axial chirality and biological activity, see the following:
F
dx.doi.org/10.1021/jo401020y | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(a) Natsugari, H.; Ikeura, Y.; Kamo, I.; Ishimaru, T.; Ishichi, Y.;
Fujishima, A.; Tanaka, T.; Kasahara, F.; Kawada, M.; Doi, T. J. Med.
Chem. 1999, 42, 3982−3993. (b) Albert, J. S.; Aharony, D.; Andisik, D.;
Barthlow, H.; Bernstein, P. R.; Bialecki, R. A.; Dedinas, R.; Dembofsky,
B. T.; Hill, D.; Kirkland, K.; Koether, G. M.; Kosmider, B. J.; Ohnmacht,
C.; Palmer, W.; Potts, W.; Rumsey, W.; Shen, L.; Shenvi, A.; Sherwood,
S.; Warwick, P. J.; Russell, K. J. Med. Chem. 2002, 45, 3972−3983.
(c) Clayden, J. Tetrahedron 2004, 60, 4335. (d) Guile, S. D.; Bantick, J.
R.; Cooper, M. E.; Donald, D. K.; Eyssade, C.; Ingall, A. H.; Lewis, R. J.;
Martin, B. P.; Mohammed, R. T.; Potter, T. J.; Reynolds, R. H.; St-
Gallay, S. A.; Wright, A. D. J. Med. Chem. 2007, 50, 254−263. (e) Lee, S.;
Kamide, T.; Tabata, H.; Takahashi, H.; Shiro, M.; Natsugari, H. Bioorg.
Med. Chem. 2008, 16, 9519−9523. (f) Tabata, H.; Akiba, K.; Lee, S.;
Takahashi, H.; Natsugari, H. Org. Lett. 2008, 10, 4871−4874. (g) Porter,
J.; Payne, A.; Whitcombe, I.; de Candole, B.; Ford, D.; Garlish, R.; Hold,
A.; Hutchinson, B.; Trevitt, G.; Turner, J.; Edwards, C.; Watkins, C.;
Davis, J.; Stubberfield, C. Bioorg. Med. Chem. Lett. 2009, 19, 1767−1772.
(h) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew.
Chem., Int. Ed. 2009, 48, 6398−6401. (i) LaPlante, S. R.; Edwards, P. J.;
Fader, L. D.; Jakalian, A.; Hucke, O. Chem. Med. Chem 2011, 6, 505−
513. (j) Takahashi, H.; Wakamatsu, S.; Tabata, H.; Oshitari, T.; Harada,
A.; Inoue, K.; Natsugari, H. Org. Lett. 2011, 13, 760−763. (k) Tabata,
H.; Nakagomi, J.; Morizono, D.; Oshitari, T.; Takahashi, H.; Natsugari,
H. Angew. Chem., Int. Ed. 2011, 50, 3075−3079.
(8) (a) Tabata, H.; Wada, N.; Takada, Y.; Oshitari, T.; Takahashi, H.;
Natsugari, H. J. Org. Chem. 2011, 76, 5123−5131. (b) Tabata, H.; Wada,
N.; Takada, Y.; Nakagomi, J.; Miike, T.; Shirahase, H.; Oshitari, T.;
Takahashi, H.; Natsugari, H. Chem.Eur. J. 2012, 18, 1572−1576.
(9) Numbering for 1,5-benzothiazepin-4-ones includes 1, 4, 5, 8, and 9.
The number 6 corresponds to 9 for compounds with other nuclei (2/6
and 3/7).
(10) Breitschuh, R.; Seebach, D. Synthesis 1992, 1170−1178.
(11) The relative configuration (cis−trans) of the racemic 1,5-
benzothiazepin-4-one S-oxide with a substituent at C2 has been
reported. Patonay, T.; Adam, W.; Jeko, J.; Kover
́
, K. E.; Lev
́
ai, A.;
̈
Nem
́
eth, M.; Peters, K. Heterocycles 1999, 51, 85−94 Although not
mentioned in the report, it should be recognized that the molecule has
axial chirality due to the sp2−sp2 axis at Ar−N(CO), which exists in
the latent form and is moving together like a gear with the
stereochemistry specified by the two chiral centers at 1S and 2C.
(12) The terms aS and aR (chiral axis nomenclature) correspond to P
and M (helix nomenclature), respectively.
(13) For a recent paper on the 1H chemical shifts in NMR for
sulfoxides and sulfones in general, see: Abraham, R. J.; Byrne, J. J.;
Griffiths, L. Magn. Reson. Chem. 2008, 46, 667−675.
(14) See the Supporting Information for detailed NMR analysis of the
methylene protons for 5, 8I, 8II, and 9, including the torsion angles
around the 1S−2C−3C moiety, obtained from the X-ray structures. The
values of the vicinal coupling (3J) correspond well with those estimated
from the torsion angles by the Karplus equation. Karplus, M. J. Am.
Chem. Soc. 1963, 85, 2870−2871.
(15) For review articles on the hydrogen bond, see: (a) Steiner, T.
Angew. Chem., Int. Ed. 2002, 41, 48−76. (b) Jeffrey, G. A. An Introduction
to Hydrogen Bonding; Oxford University Press: Oxford, U.K., 1997.
(16) (a) Axelrod, M.; Bickart, P.; Jacobus, J.; Green, M. M.; Mislow, K.
J. Am. Chem. Soc. 1968, 90, 4835−4842. (b) Korpiun, O.; Lewis, R. A.;
Chickos, J.; Mislow, K.; Rayner, D. R.; Gordon, A. J.; Mislow, K. J. Am.
Chem. Soc. 1968, 90, 4854−4860. (c) Miller, E. G.; Rayner, D. R.;
Thomas, H. T.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4861−4868.
(d) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow, K. J. Am.
Chem. Soc. 1968, 90, 4869−4876.
(17) For determination of ΔG⧧ values, see: Petit, M.; Lapierre, A. J. B.;
Curran, D. P. J. Am. Chem. Soc. 2005, 127, 14994−14995.
(18) For an informative study on the correlation of absolute
configuration and the chiroptical properties of alkyl aryl sulfoxides,
see: Rosini, C.; Donnoli, M. I.; Superchi, S. Chem.Eur. J, 2001, 7, 72−
79.
(19) For general experimental methods, see the Supporting
Information.
G
dx.doi.org/10.1021/jo401020y | J. Org. Chem. XXXX, XXX, XXX−XXX