Synthesis, chromatographic separation, vibrational circular dichroism spectroscopy, and ab initio DFT studies of chiral thiepane tetraol derivatives

Article abstract of DOI:10.1021/jo048629y

(Chemical Equation Presented) Optically pure enantiomers of the chiral tetrahydroxythiepane derivative 3,6-dihydroxy-4,5-O-isopropylidene-thiepane (3) are obtained using a novel protocol in which a library of all possible stereoisomers of 3 is synthesized, followed by two-step stereoselective chromatography, using, first, conventional achiral and, then, chiral stationary phases. Configurational and conformational analysis of 3 are carried out using Vibrational Circular Dichroism (VCD) spectroscopy in conjunction with ab initio DFT calculations. The absolute configuration of 3 is shown to be 3R,4S,5R,6R-(+)/3S,4R,5S,6S-(-).

Full text of DOI:10.1021/jo048629y

Synthesis, Chromatographic Separation, Vibrational Circular
Dichroism Spectroscopy, and ab Initio DFT Studies of Chiral
Thiepane Tetraol Derivatives
Vanda Cere`,*,† Francesca Peri,† Salvatore Pollicino,† Alfredo Ricci,† Frank J. Devlin,‡
Philip J. Stephens,*,‡ Francesco Gasparrini,*,§ Romina Rompietti,§ and Claudio Villani§
Department of Organic Chemistry “A. Mangini”, University of Bologna, Viale Risorgimento 4,
I-40136 Bologna, Italy, Department of Chemistry, University of Southern California,
Los Angeles, California 90089-0482, and Dipartimento di Studi di Chimica e Tecnologia delle Sostanze
Biologicamente Attive, Universita` “La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy
cere@ms.fci.unibo.it; pstephen@usc.edu; francesco.gasparrini@uniroma1.it
Received August 6, 2004
Optically pure enantiomers of the chiral tetrahydroxythiepane derivative 3,6-dihydroxy-4,5-O-
isopropylidene-thiepane (3) are obtained using a novel protocol in which a library of all possible
stereoisomers of 3 is synthesized, followed by two-step stereoselective chromatography, using, first,
conventional achiral and, then, chiral stationary phases. Configurational and conformational
analysis of 3 are carried out using Vibrational Circular Dichroism (VCD) spectroscopy in conjunction
with ab initio DFT calculations. The absolute configuration of 3 is shown to be 3R,4S,5R,6R-(+)/
3S,4R,5S,6S-(-).
Introduction
ritols5 and diaminoconduritols6 from easily available
alcohol sugars, have been tested to investigate the
structural and stereochemical requirements for optimized
inhibitory activity against a variety of glycosidases.7
Interesting trends observed during the screening of these
derivatives prompted us to attempt the synthesis of
additional, previously unknown, tetrahydroxy thiepane
derivatives to further elucidate the stereochemistry-
activity relationship for these molecules as glycosidase
inhibitors. Since the required precursor alcohol sugars
are either very expensive or not available, the known
synthetic method,5 which maintains and transfers the
stereochemistry of the starting material to the thiepane,
could not be used. We have therefore developed a new
strategy in which a library containing all of the individual
Polyhydroxylated thiepane derivatives are of great
interest because of their potential therapeutic activity as
glycosidase inhibitors.1 This property has been tenta-
tively ascribed to the flexibility of the seven-membered
ring, which mimics the hypothetical transition state of
enzymatic glycosidic cleavage. A potent HIV-1 protease
inhibition2 and a low cytotoxicity3 have been reported for
a number of thiepane derivatives. Moreover, in recent
patents the use of some tri- and tetra-substituted thi-
epanes as immunogens, therapeutics, diagnostics, and for
other industrial purposes, has been disclosed.4 Recently,
new enantiopure tetrahydroxy thiepane derivatives, ob-
tained as intermediates during the synthesis of condu-
† University of Bologna.
(4) McGee, L. R.; Kim, C. U.; Bischofberger, N. W.; Krawczyk, S. H.
U.S. patent 1998, 81 pp; contained in part of U.S. Ser. No. 470,864.
Bischofberger, N. W.; Kim, C. U.; Krawczyk, S. H.; McGee, L. R.;
Postich, M. J.; Yang, W. U.S. patent 2000, 125 pp; contained in part
of U.S. Ser. No. 334,471.
‡ University of Southern California.
§ University of Roma.
(1) Le Merrer, Y.; Fouzier, M.; Dosbaa, I.; Foglietti, M. J.; Depezay,
J. C. Tetrahedron 1997, 53, 16731-16746.
(2) Quian, X.; Morris-Varas, F.; Fitzgerald, M. C.; Wong, C. H.
Bioorg. Med. Chem. 1996, 4, 2055-2069.
(5) Cere`, V.; Mantovani, G.; Peri, F.; Pollicino, S.; Ricci, A. Tetra-
hedron 2000, 56, 1225-1231.
(3) Kim, C. U.; McGee, L. R.; Krawczyk, S. H.; Harwood, E.; Harada,
Y.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Cherrington, J.
M.; Xiong, S. F.; Griffin, L.; Cundy, K. C.; Lee, A.; Yu, B.; Gulnik, S.;
Erickson, J. W. J. Med. Chem. 1996, 39, 3431-3434.
(6) Arcelli, A.; Cere`, V.; Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron
2001, 57, 3439-3444.
(7) Arcelli, A.; Cere`, V.; Peri, F.; Pollicino, S.; Ricci, A. Tetrahedron:
Asymmetry 2002, 13, 191-196.
10.1021/jo048629y CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/24/2004
664
J. Org. Chem. 2005, 70, 664-669

Studies of Chiral Thiepane Tetraol Derivatives
SCHEME 1. Synthesis of mix-4a
a Reagents and conditions: (i) acetone, pTSA (85%); (ii) mCPBA,
TBHMP, ClCH2-CH2Cl 3 h at 90 °C (89%); (iii) Na2S‚9H2O, EtOH
48 h at reflux (58%). pTSA ) p-toluenesulfonic acid; mCPBA )
m-chloroperoxybenzoic acid; TBHMP ) 5-tert-butyl-4-hydroxy-
methylphenyl sulfide.
FIGURE 1. Structures of the stereoisomeric isopropylidene
tetrahydroxy thiepane derivatives 1-6. Only one enantiomer
is shown for chiral derivatives 2-5.
stereoisomers of the target tetrahydroxy thiepane deriva-
tives are synthesized and a two-step chromatographic
procedure is then used for the isolation of the library
members. Simple elaboration of a commercially available
substrate leads to the library (Figure 1). Then, a first
chromatographic step over nonenantioselective stationary
phases affords the six diastereomers (two meso, 1 and 6,
and four chiral, 2, 3, 4, and 5, stereoisomers), and a
second step over enantioselective phases gives the indi-
vidual enantiomers of the four chiral stereoisomers, 2-5.
The new method greatly reduces the synthetic effort
required to obtain all the distinct components of the
library and overcomes the difficulties encountered in
obtaining precursor materials with the correct stereo-
chemistry. The stereochemical identities of enantiopure
materials obtained by chromatographic separation of the
thiepane derivative enantiomers are established by a
combination of experimental Vibrational Circular Dichro-
ism (VCD) spectroscopy and ab initio Density Functional
Theory (DFT) calculations,8 in addition to FT-IR, 1H
NMR, and 13C NMR spectroscopies.
the (R,R), (S,S), and meso-divinyl diols mix-1,9 which was
easily converted into the related isopropylidene deriva-
tives mix-2. Oxidation with m-CPBA at 90 °C for 3 h in
the presence of a radical inhibitor afforded the corre-
sponding diepoxy derivatives mix-3, with the two ad-
ditional stereocenters. Intramolecular thiacyclization
upon treatment with Na2S‚9H2O yielded the mixture of
10 stereoisomeric thiepanes mix-4 in 44% yield. Thi-
epane derivatives (+)-3, (-)-3, (+)-4, 1, and 6, to our
knowledge, were previously unreported.
With the mixture of the whole set of stereoisomers in
hand, we started a chromatographic study aimed at
finding a method capable of affording the individual
components in high yield and purity. We first examined
the ability of several nonenantioselective HPLC station-
ary phases to resolve the six diastereoisomeric compo-
nents of the mixture of thiepane derivatives. Despite
careful optimization of the experimental parameters we
found that none of the available stationary phases (bare
silica, diol-silica, cyanopropyl-silica, aminopropyl-silica)
was able to effect the complete resolution of the mixture.
Next, we tried using two columns in tandem containing
different stationary phases and found that the combina-
tion of a column packed with bare silica with a column
packed with the racemic version of a chiral stationary
phase10 successfully achieved the required selectivity and
efficiency. With this approach the six diastereoisomers
As far as we can determine, this protocol has not been
previously employed in the synthesis and stereochemical
characterization of chiral molecules. The new protocol is
exemplified here by the synthesis and stereochemical
characterization of thiepane 3, whose enantiomers have
not previously been characterized from the stereochem-
ical and chiroptical points of view.
Results and Discussion
The library of thiepane stereoisomers was prepared
(Scheme 1) from the commercially available mixture of
(8) (a) Stephens, P. J.; Devlin, F. J. Chirality 2000 12, 172-179. (b)
Aamouche, A.; Devlin, F. J.; Stephens, P. J. J. Am. Chem. Soc. 2000,
122, 2346-2354. (c) Stephens, P. J.; Aamouche, A.; Devlin, F. J.;
Superchi, S.; Donnoli, M. I.; Rosini, C. J. Org. Chem. 2001, 66, 3671-
3677. (d) Devlin, F. J.; Stephens, P. J.; Scafato, P.; Superchi, S.; Rosini,
C. Tetrahedron: Asymmetry 2001, 12, 1551-1558. (e) Devlin, F. J.;
Stephens, P. J.; Scafato, P.; Superchi, S.; Rosini, C. Chirality 2002,
14, 400-406. (f) Devlin, F. J.; Stephens, P. J.; Oesterle, C.; Wiberg, K.
B.; Cheeseman, J. R.; Frisch, M. J. J. Org. Chem. 2002, 67, 8090-
8096.
(9) The prefix “mix” denotes here a mixture of all the possible
stereoisomers.
J. Org. Chem, Vol. 70, No. 2, 2005 665

Cere` et al.
solvating eluents were obtained on a new polymeric chiral
stationary phase containing a covalently bound oligomer
of the (R,R)-diaminocyclohexane diacryloylamide.13 Itera-
tive enantioselective HPLC of 400 mg of racemic 3 on a
1 cm column afforded 170 mg of the pure (+)-3 enanti-
omer (first eluted, [R]25 +9.76 ( 0.10 (c 1.0 in CHCl3,
D
ee >99%)) and 180 mg of the (-)-3 enantiomer (second
eluted, [R]25 -9.06 ( 0.10 (c 1.0 in CHCl3, ee 95%)).14
D
VCD spectroscopy and DFT calculations were per-
formed to establish the Absolute Configuration (AC) of
3 and to gain insight into its conformational preferences.8
The structures, energies, and VCD spectra of the stable
conformations of 3, whose relative energies permit sig-
nificant population at room temperature, were predicted
by using DFT and the conformationally averaged VCD
spectrum was obtained thence. Then, the predicted VCD
spectra of the two enantiomers of 3 were compared to
the experimental VCD spectrum of (+)-3 and its absolute
configuration deduced. The mid-IR IR and VCD spectra
of 3 in CHCl3 solution are shown in Figure 3.
Conformational analysis (see Supporting Information)
of 3 at the B3LYP/TZ2P level led to five stable conforma-
tions within a range of 3 kcal/mol, 3a-e (Table 1). Their
structures for (3R,4S,5R,6R)-315 are given in Figure 4.
In 3a, the lowest energy conformer, the thiepane ring, is
in a chair conformation and the dioxolane ring exhibits
an envelope conformation. The two OH groups are
oriented such that one hydrogen is hydrogen bonded to
the adjacent oxygen atom of the dioxolane ring (H‚‚‚O )
2.31 Å) and the other is hydrogen bonded to the sulfur
atom (H‚‚‚S ) 2.40 Å). All other stable conformations of
3 were predicted to be more than 1 kcal/mol higher in
energy than conformer 3a. In 3b and 3c the thiepane
ring is again in a chair conformation, whereas in 3d the
thiepane ring is in a boat conformation. In 3e, the highest
energy of the five conformations, the thiepane ring is
substantially twisted. As in conformer 3a, in conformers
3b-e both OH groups are internally hydrogen bonded.
H‚‚‚O and H‚‚‚S distances are given in Figure 4. The
B3LYP/TZ2P and B3PW91/TZ2P VCD spectra of con-
formers 3a-e have been calculated. Thence, the spectra
of the equilibrium mixture of conformers have been
obtained, weighting the spectrum of each conformer by
its equilibrium population, which was calculated from
relative free energies using Boltzmann statistics and T
) 298K (Table 1 and Table 1S of the Supporting
Information).
FIGURE 2. Analytical HPLC separation of thiepane deriva-
tives 1-6 over nonenantioselective stationary phases. Two
columns connected in series, one packed with LiChrosorb Si-
60, 5 µm ,and one with (rac)-DACH-DNB Si-100, 5 µm; eluent
hexane/2-propanol 90/10; flow rate 1.0 mL/min; room temper-
ature (25 °C); refractive index detection (k′1 ) 1.36, k′2 ) 1.58,
k′3 ) 1.80, k′4 ) 2.06, k′5 ) 2.31, k′6 ) 2.73; R1,2 ) 1.16, R2,3
)
1.14, R3,4 ) 1.14, R4,5 ) 1.12, R5,6 ) 1.18). Bottom trace: peak
purity check of the pooled fractions containing 3, after semi-
preparative HPLC.
of the thiepane derivative mixture were completely
resolved in less than 30 min (Figure 2) at the analytical
level.
Scaling-up to semipreparative levels was straightfor-
ward, and 60 replicate separations (62 mg of sample each
run) carried out on 1 cm internal diameter columns in
tandem afforded the six stereoisomers with de greater
than 98% and overall recovery of about 90%. In particu-
lar, 400 mg of (()-3 with de > 99% was obtained by
pooling the proper fractions collected in this stage. When
monitored by RI, the HPLC resolved mixture showed an
uneven distribution of the six stereoisomers, with the
stereoisomers 3 and 4 giving the most intense signals.
However, the amounts of isolated products showed that
the library was slightly enriched in the stereoisomers 4,
5, and 6 (26%, 19%, and 19%, respectively) at the expense
of stereoisomers 1, 2, and 3 (8%, 16%, and 12%, respec-
tively).11
A second screening procedure was then started for the
chiral thiepane derivatives 2-5 to find a chromato-
graphic method for the isolation of sizable amounts of
enantiopure materials. The enantiomers of chiral thi-
epane derivatives 2-5 were well separated by HPLC on
cellulose chiral stationary phases.12 However, the ana-
lytical HPLC resolution of compound 3 was not scalable
to preparative levels as the sample showed very limited
solubility in the mobile phase. On the other hand,
satisfactory enantioseparation values for 3 using good
The conformationally averaged B3LYP/TZ2P VCD
spectrum of (3R,4S,5R,6R)-3 and of its mirror-image
enantiomer are shown in Figure 5, together with the
experimental VCD spectrum of (+)-3. As delineated in
Figure 5, convincing assignment of the majority of the
bands of the experimental spectrum can be made if the
absolute configuration of (+)-3 is taken to be (3R,4S,5R,6R)
(10) Silica stationary phase: LiChrosorb Si 60. Chiral stationary
phase, racemic version: DACH-DNB stationary phase. Analytical
separations: columns 4.0 × 250 and 3.9 × 300 mm, respectively.
Eluent: hexane/2-propanol 90/10. Flow rate: 1.0 mL/min. Preparative
separations: columns 10 × 250 mm. Eluent: hexane/2-propanol 90/
10. Flow rate: 5.0 mL/min. Columns are available from Merck,
Darmstadt, Germany and from Regis Chemical Company, Morton
Groove, IL.
(11) Stereochemical identities of the separated species were estab-
lished by FT-IR, 1H NMR, and 13C NMR spectroscopies and by
co-injection of samples of known stereochemistry available from
previous studies.5
(13) Chiral stationary phase: (R,R)-P-CAP containing a polymeric
derivative of (R,R)-1,2-diaminocyclohexane. Columns: 4.6 × 250 mm
(analytical) and 10 × 250 mm (preparative). Eluent: hexane/2-
propanol/acetonitrile/dichloromethane
74/4/3/19.
Flow
rate:
2.0 mL/min (F. Gasparrini, D. Misiti, C. Villani, Italian Patent no.
RM2002A000155, 20.03.2002; International Patent no. WO 03/079002
A2, 25.09.2003). Columns available from Astec Inc, Wippany, NJ.
(14) We used the individual enantiomers (+)-3 and (-)-3 for the
synthesis of enantiopure conduritol derivatives (unpublished results).
(15) For the atom numbering used here see above. For the IUPAC
nomenclature, see the Supporting Information.
(12) Chiral stationary phases: Chiralcel OJ (thiepanes 2, 3, and 4)
and Chiralcel OD (thiepane 5). Columns: 4.6 × 250 mm. Eluent:
hexane/2-propanol 90/10. Flow rate 1.0 mL/min. Columns are available
from Chiral Technologies, Illkirch, France.
666 J. Org. Chem., Vol. 70, No. 2, 2005

Studies of Chiral Thiepane Tetraol Derivatives
FIGURE 4. B3LYP/TZ2P structures of conformers a-e of
(3R,4S,5R,6R)-3. The molecules are viewed along the C4-C5
bond (the atom numbering used is detailed in the text).
Hydrogen atoms are not shown, except for those on the OH
groups and on the C4 and C5 carbon atoms. Internal hydrogen-
bonding distances are the following: (a) H9‚‚‚O14 ) 2.31 Å,
H11‚‚‚S ) 2.40 Å; (b) H9‚‚‚S ) 2.42 Å, H11‚‚‚O12 ) 2.32 Å;
(c) H9‚‚‚O14 ) 2.31 Å, H11‚‚‚O12 ) 2.28 Å; (d) H9‚‚‚O14 )
2.25 Å, H11‚‚‚O12 ) 2.24 Å; (e) H9‚‚‚O14 ) 2.32 Å, H11‚‚‚
O12 ) 2.24 Å.
FIGURE 3. Experimental IR and VCD spectra of 3 in CHCl3
solution. The IR spectrum (a) is of (()-3. The VCD spectrum
(b) is the “half-difference” spectrum: 1/2[∆ꢀ(+) - ∆ꢀ(-)].
Solution concentrations were the following: (()-3, 0.066 M;
(+)-3, 0.059 M; and (-)-3, 0.068 M. Enantiomeric excesses of
(+)- and (-)-3 were >99% and 95%, respectively. Path length
was 597 µm. The gaps are due to CHCl3 absorption.
novel combination of synthetic and stereoselective ana-
lytical strategies with advanced spectroscopic methodolo-
gies is of general use for the production and structural
characterization of the individual members of small
stereoisomer libraries, and additional applications will
be reported soon.
TABLE 1. B3LYP/TZ2P Energies, Free Energies, and
Populations of the Conformations of 3a
B3LYP/TZ2P
Experimental Section
conformer
∆E
∆G
P
2,2-Dimethyl-4,5-di(2-oxiranyl)-1,3-dioxolane (mix-3).
0.452-g (2.9 mmol) of the d,l- and meso-2,2-dimethyl-4,5-
divinyl-1,3-dioxolane (mix-2)16 and 0.208 g (0.58 mmol) of
5-tert-butyl-4-hydroxy-2-methylphenyl sulfide were dissolved
in 40 mL of ClCH2CH2Cl. The reaction mixture was stirred
for 10 min and then, after addition of 2 g (5.8 mmol) of 50%
m-CPBA, was warmed at 90 °C under stirring for 3 h, using a
previously reported procedure.17 To the solution, cooled to 0
°C, was added a saturated solution of NaHSO3 to destroy the
unreacted m-CPBA, using a starch iodide paper to monitor
the complete disappearance of the peracid. The mixture was
filtered and the organic layer was extracted with a saturated
solution of NaHCO3 (3×15 mL) and washed with brine.
Evaporation of the solution, dried with MgSO4, gave 0.479 g
(88.9%) of a crude product as a yellow oil, which was used
without any purification to prevent possible diastereomeric
separations. The spectroscopic data of the complex mixture
are the following: 1H NMR (300 MHz, CDCl3) δ 3.98-3.52 (m,
a
b
c
d
e
0.00
1.18
1.49
1.82
2.51
0.00
0.81
1.47
1.66
2.58
72.1
17.9
5.8
4.2
0.0
a ∆E and ∆G are in kcal/mol; populations P are in %.
and cannot be made for the mirror-image structure. It
follows that the absolute configuration of (+)-3 is
(3R,4S,5R,6R). The same conclusion follows from the
B3PW91/TZ2P VCD spectrum (see the Supporting In-
formation).
Conclusion
In summary, the procedure described offers an easy
access to enantiomerically pure tetrahydroxy thiepane
derivatives with unambiguously assigned stereochemis-
try. In view of its inherent flexibility, we believe that the
(16) Wiberg, K. B.; Snoonian, J. R. J. Org. Chem. 1998, 63, 1402-
1407.
(17) Kishi, Y.; Aratani, M.; Tanino, H.; Fukuyama, T.; Goto, T. J.
Chem. Soc., Chem. Commun. 1972, 64-65.
J. Org. Chem, Vol. 70, No. 2, 2005 667

Cere` et al.
preparative HPLC, was obtained as a pale yellow deliquescent
1
solid. H NMR (300 MHz, CDCl3) δ 4.20 (dd, 2H, J ) 1.9, 5.9
Hz), 4.05 (br t, 2H, J ) 6.0-8.0 Hz), 3.05 (br s, 2H, 2OH),
2.89 (d, 2H, J ) 14.2 Hz), 2.57 (dd, 2H, J ) 8.54, 14.4 Hz),
1.50 (s, 3H), 1.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ108.6
(C), 80.8 (2CHO), 73.3 (2CHO), 33.4 (2CH2S), 27.2 (CH3), 24.4
(CH3); IR (KBr) (cm-1) 3368, 2974, 2909, 1377, 1208, 1091,
1045, 896; ESI-MS 221 (MH+). Anal. Calcd for C9H16O4S: C,
49.07; H, 7.32. Found: C, 49.06; H, 7.30.
(3R,4S,5R,6S)-3,6-Dihydroxy-4,5-O-isopropylidene-thi-
epane (6, meso form). The title compound, isolated by
preparative HPLC, was obtained as a white crystalline product
(mp 176 °C). 1H NMR (300 MHz, CDCl3) δ 4.35 (br s, 2H), 4.14
(t, 2H, J ) 8.1 Hz), 3.35 (d, 2H, 2OH, J ) 8.2 Hz), 2.97 (dd,
2H, J ) 8.5, 14.7 Hz), 2.61 (d, 2H, J ) 14.7 Hz), 1.58 (s, 3H),
1.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 108.8 (C), 79.5
(CHO), 70.6 (CHO), 33.0 (CH2S), 26.1 (CH3), 23.8. (CH3); IR
(KBr) (cm-1) 3333, 2936, 1421, 1250, 1184, 1013, 909; m/z 59
(100), 71 (50), 89 (25), 101 (41), 161 (39), 202 (38), 205 (33),
220 (10). Anal. Calcd for C9H16O4S: C, 49.07; H, 7.32. Found:
C, 49.00; H, 7.29.
Compounds (()-2,19 (-)-4,20 and (()-519 have spectroscopic
data in agreement with those reported in the literature.
Compound (+)-4 {[R]25 +36.2 (c 1.0 in CHCl3)} has spectro-
D
scopic data in perfect agreement with those of the correspond-
ing enantiomer (-)-4.
(+)-(3R,4S,5R,6R)-3,6-Dihydroxy-4,5-O-isopropylidene-
thiepane ((+)-3). The title compound, enantiomerically pure
after enantioselective HPLC separation, was obtained as a
white solid (mp 119-120 °C). 1H NMR (300 MHz, acetone-d6)
δ 4.38 (m, 1H, CHO), 4.20 (m, 3H, 1CHO and 2OH), 3.87 (m,
2H, 2CHO), 3.03-2.42 (m, 4H, 2CH2), 1.43 (s, 3H, CH3), 1.28
(s, 3H, CH3); 13C NMR (75 MHz, acetone-d6) δ 108.2 (C), 81.3
(CHO), 80.3 (CHO), 72.7 (CHO), 72.3 (CHO), 33.7 (CH2), 33.3
(CH2), 26.8 (CH3), 24.2 (CH3); IR (KBr) (cm-1) 3288, 2986, 2917,
1383, 1259, 1211, 1166, 1085, 1057, 1007, 893; [R]25D +9.76 (c
1.0 in CHCl3, ee >99%); m/z 59 (100), 71 (52), 89 (26), 101 (41),
161 (40), 202 (38), 205 (32), 220 (13). Anal. Calcd for
C9H16O4S: C, 49.09; H, 7.34. Found: C, 49.11; H, 7.34.
Chromatographic Procedures. For the analytical HPLC
experiments the following equipment was used: pump Waters
600E, Refractive Index detector Waters R401, UV detector
Waters 448, Rheodyne 20 µL loop injector. Preparative separa-
tions: pump Waters Delta Prep 3000, RI detector Waters 410,
Rheodyne 0.5 mL loop injector. Preparative separations:
samples were dissolved in the mobile phase at a concentration
of about 0.1 g/mL and injected through a 0.5 mL loop.
Vibrational Circular Dichroism Spectroscopy and
DFT Calculations. IR and VCD spectra of 3 were measured
in CHCl3 solution. IR spectra were measured using a Nicolet
MX-1 FTIR instrument at 1 cm-1 resolution. VCD spectra were
measured using a Bomem/BioTools ChiralIR spectrometer at
4 cm-1 resolution. VCD data acquisition times were 1 h.
Solutions of (+)- and (-)-3 were ∼0.06 M. Enantiomeric
excesses of (+)- and (-)-3 were >99% and >95%, respectively.
Solutions of (()-3 of comparable concentration were used to
obtain VCD baselines. VCD spectra are reported as “half-
difference” spectra: 1/2[∆ꢀ(+) - ∆ꢀ(-)].
FIGURE 5. Calculated and experimental VCD spectra of 3.
The calculated spectra (3R,4S,5R,6R)-3 and (3S,4R,5S,6S)-3
are the conformationally averaged B3LYP/TZ2P spectra for
the (3R,4S,5R,6R) and (3S,4R,5S,6S) enantiomers of 3. The
experimental spectrum is from Figure 3. Numbers indicate
corresponding features in the calculated spectrum (3R,4S,
5R,6R)-3 and the experimental spectrum of (+)-3.
2H), 3.18-2.88 (m, 2H), 2.83-2.56 (m, 4H), 1.45-1.23 (ss, 6H);
13C NMR (75 MHz,CDCl3) δ 110.5, 110.3, 110.1, 109.9, 80.1,
78.3, 78.1, 77.6, 51.5, 51.3, 51.1, 50.2, 49.6, 49.4, 46.4, 45.9,
45.5, 44.1, 43.7, 43.6, 43.5, 43.3, 29.2, 28.7, 27.4, 27.1, 26.9,
26.8, 26.6, 26.5, 25.1, 24.9.
2,2-Dimethylhexahydrothiepino[4,5-d][1,3]dioxole-4,8-
diol (mix-4). Following a literature procedure,18 to 400 mL
of EtOH, refluxing under nitrogen, was added 4.5 g of Na2S‚
9H2O (18.7 mmol) dissolved in 75 mL of EtOH. To this
refluxing solution was simultaneously added dropwise 2.4 g
(12.9 mmol) of the dioxiranyl derivative mix-3 dissolved in
150 mL of EtOH and 4.5 g of Na2S‚9H2O (18.7 mmol) dissolved
in 75 mL of EtOH. After 48 h refluxing, the crude product,
obtained from evaporation of the solvent, was extracted
repeatedly with CH2Cl2. The dried organic layer was purified
by flash chromatography (SiO2; Et2O) yielding 1.64 g (57.8%)
of a mixture with the diastereoisomeric ratio of the crude
product. 1H NMR (300 MHz, CDCl3) δ 4.30-3.75 (m, 4H), 3.32
(br s, 2H), 3.00-2.38 (m, 4H), 1.45-1.22 (ss superimposed 6H);
13C NMR (75 MHz, CDCl3) δ 109.4, 109.1, 108.8, 108.6, 108.0,
81.4, 80.7, 79.8, 79.1, 78.7, 78.6, 75.9, 73.9, 73.2, 71.6, 70.9,
66.2, 66.0, 38.1, 38.0, 37.6, 37.2, 33.5, 33.0, 32.8, 32.5, 27.2,
27.0, 26.9, 26.7, 26.4, 26.0, 23.8.
Conformational analysis of 3 was carried out using the
Spartan 0221 and Gaussian 9822 programs, using the following
protocol. A Monte Carlo conformational search was initially
carried out using the MMFF94 molecular mechanics force field
via the Spartan 02 program. All structures found within a 10
kcal/mol window were reoptimized, first using the AM1
semiempirical method and then using the Hartree-Fock (HF)/
6-31G* ab initio method. Finally, all structures within a 3.0
kcal/mol window at the HF/6-31G* level were reoptimized
using Density Functional Theory (DFT), the functionals
(3R,4R,5S,6S)-3,6-Dihydroxy-4,5-O-isopropylidene-thi-
epane (1, meso form). The title compound, isolated by
(19) Kuszmann, J.; Soha`r, P. Carbohydr. Res. 1977, 56, 105-115.
(20) Kuszmann, J.; Soha`r, P.; Horva`th, G. Carbohydr. Res. 1976,
50, 45-52
(18) Fuzier, M.; LeMerrer, Y.; Depezay, J. C. Tetrahedron Lett. 1995,
36, 6443-46.
(21) Spartan 02, Wavefunction Inc., Irvine, CA.
668 J. Org. Chem., Vol. 70, No. 2, 2005

Studies of Chiral Thiepane Tetraol Derivatives
B3LYP and B3PW91, and the basis sets 6-31G* and TZ2P.23
The procedure was then repeated, beginning with a Monte
Carlo search using the AM1 method.
Acknowledgment. The financial support by the
University of Bologna (Funds for Selected Research
Topics, A.A. 1999-2001), by the National Projects
“Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni” and “Engineering of high performance
separation systems, sensors and arrays based on chemo-
and stereoselective molecular recognition” (2003-2004),
by the ex-60% MIUR-Funding 2002, by Centro di
Eccellenza-Molecular Biology and Medicine (BEMM)
of the University “La Sapienza” of Rome, and by the
U.S. National Science Foundation (grant CHE-0209957)
is gratefully acknowledged. We are also grateful to the
USC Center for High Performance Computing for
computer time.
The harmonic frequencies, dipole strengths, and rotational
strengths of the stable conformations of 3 were calculated
using DFT,24 the functionals B3LYP and B3PW91, and the
basis set TZ2P at the corresponding equilibrium geometries
via the Gaussian 98 program. IR and VCD spectra were
obtained thence using Lorentzian line shapes,25 with γ ) 4.0
cm-1
.
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.,
Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.;
Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.;
Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen,
W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.;
Pople, J. A. Gaussian 98 and 03; Gaussian, Inc.: Pittsburgh, PA.
(23) Stephens, P. J.; Jalkanen, K. J.; Amos, R. D.; Lazzeretti, P.;
Zanasi, R. J. Phys. Chem. 1990, 94, 1811-1830.
Supporting Information Available: Structures of thi-
epanes 1-6, general experimental synthetic procedures, chro-
matographic plots on preparative and analytical columns,
comparison of relative energies of conformations a-e of 3,
B3LYP/TZ2P dihedral angles of conformations a-e of 3,
experimental and calculated VCD spectra of 3 at the B3LYP/
TZ2P and B3PW91/TZ2P levels, and text files containing
B3LYP/TZ2P optimized geometries in Cartesian coordinates
of conformers a-e of 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
(24) Cheeseman, J. R.; Frisch, M. J.; Devlin, F. J.; Stephens, P. J.
Chem. Phys. Lett. 1996, 252, 211-220.
(25) Devlin, F. J.; Stephens, P. J.; Cheeseman, J. R.; Frisch, M. J.
J. Phys. Chem., 1997, 101, 6322-6333. Devlin F. J.; Stephens P. J.;
Cheeseman J. R.; Frisch M. J. J. Phys. Chem. 1997, 101, 9912-9924.
JO048629Y
J. Org. Chem, Vol. 70, No. 2, 2005 669