Regiocontrolled synthesis of enantiopure 3,3′-thiosubstituted biphenyls

Article abstract of DOI:10.1021/jo0157627

Sulfenylation of 6,6′-dimethoxy-2,2′-dihydroxybiphenyl, used as a racemic mixture and single enantiomers, by phthalimidesulfenyl chloride afforded the corresponding 3,3′-N,N'-dithiophthalimide with complete regioselectivity. Simple manipulations of the latter compound allowed access to the corresponding bis-thiol or o-thioquinone as useful intermediates for the synthesis of new sulfur-containing open-chain and macrocyclic C₂ enantiopure ligands. The application of this methodology to the preparation of a biphenyl bearing two cysteine units as potential HIV-1 protease inhibitor is also described.

Full text of DOI:10.1021/jo0157627

J . Org. Chem. 2002, 67, 2019-2026
2019
Regiocon tr olled Syn th esis of En a n tiop u r e 3,3′-Th iosu bstitu ted
Bip h en yls
Giuseppe Capozzi,*,† Giovanna Delogu,‡ Davide Fabbri,‡ Manuela Marini,†
Stefano Menichetti,*,§ and Cristina Nativi†
Centro CNR “Chimica dei Composti Eterociclici”, Dipartimento di Chimica Organica, Universita' di
Firenze, via G. Capponi 9, I-50121, Firenze, Italy, Istituto CNR “Applicazione Tecniche Chimiche
Avanzate ai Problemi Agrobiologici”, Via Vienna 2, I-07100 Sassari, Italy, and Dipartimento di Chimica
Organica e Biologica, Universita` di Messina, salita Sperone 31, I-98166, Messina, Italy
menichet@isengard.unime.it
Received May 16, 2001
Sulfenylation of 6,6′-dimethoxy-2,2′-dihydroxybiphenyl, used as a racemic mixture and single
enantiomers, by phthalimidesulfenyl chloride afforded the corresponding 3,3′-N,N′-dithiophthalimide
with complete regioselectivity. Simple manipulations of the latter compound allowed access to the
corresponding bis-thiol or o-thioquinone as useful intermediates for the synthesis of new sulfur-
containing open-chain and macrocyclic C2 enantiopure ligands. The application of this methodology
to the preparation of a biphenyl bearing two cysteine units as potential HIV-1 protease inhibitor
is also described.
In tr od u ction
strate their peculiar biocompatibility, making them a
stimulating subject of study.
Interest in the chemistry of atropisomeric biphenyls
is continuously expanding. Their preparation, in racemic1
or enantiopure2 form, and their use in asymmetric
synthesis,3 drug discovery,4 and material science5 are
fields of great development. Moreover the distribution of
biphenyls in plant extracts and the biological activities
related to several of these natural biphenyls6 demon-
We have reported an original method for introducing
an N-thiophthalimide group on electron-rich phenols that
uses phthalimidesulfenyl chloride 1 (PhthNSCl, Phth )
phthaloyl) as the key reagent.7-9 The N-thioarylphthal-
imides obtained with this procedure can be used for the
formation of the corresponding o-hydroxythiols7 and
o-thioquinones,8,9 two classes of very useful and versatile
intermediates in organic synthesis. Recently we com-
municated10 the possibility of applying this methodology
to racemic 6,6′-dimethoxy-2,2′-biphenol 2 which reacts
with sulfenyl chloride 1 to give the bis-thiophthalimide
3 with complete regioselectivity as shown in Scheme 1.
In this paper we report a detailed study on the reactivity
of racemic and enantiopure 311 (Scheme 1).
† Universita' di Firenze.
‡ Istituto CNR “Applicazione Tecniche Chimiche Avanzate ai Prob-
lemi Agrobiologici”.
§ Universita` di Messina.
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S.; Nativi, C.; Nuti, R. Tetrahedron Lett. 1999, 40, 4421.
(11) All the reactions described in this paper were previously
performed on racemic derivatives. Most of the transformations were
repeated using enantiopure biphenol (M)-2 (in some case and/or (P)-
2) as starting materials.12 The stereochemistry of biphenyls will be
indicated only when the corresponding compound has been actually
prepared as single enantiomer. “Flat” biphenyls state racemic mixtures.
10.1021/jo0157627 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/03/2002

2020 J . Org. Chem., Vol. 67, No. 7, 2002
Capozzi et al.
Sch em e 1
Sch em e 2
F igu r e 1. Top and side ORTEP view of racemic disulfide 5.
Resu lts a n d Discu ssion
The isolation of 5 as the sole product of the partial
reduction of 3 is an intriguing result. First, after the
formation of the first sulfur-sulfur bond, the intermedi-
ate open-chain mono-disulfide could give rise to a mixture
of cyclic and linear oligomers through a mix of inter- and
intramolecular formation of further disulfide linkages.
Instead, starting from 3 only an intramolecular reaction
occurs, and the cyclic dimer 5 is obtained as the only
product (Scheme 2).
The formation of 3, shown in Scheme 1, occurs smoothly
at room temperature in chloroform. Compound 3 can be
purified by flash chromatography on silica gel using
dichloromethane as eluent; however this procedure is
tedious, due to the poor solubility of 3 in the eluent as
well as in most of the common organic solvents. Thus,
for multigram-scale preparations, we realized that the
purification of 3 can be more conveniently achieved by
dissolving the byproducts in boiling chloroform, which
causes only a small loss of 3. When the sulfenylation was
performed on enantiopure (P)- and (M)-2,12 the obtained
thiophthalimides (P)- and (M)-3 surprisingly were much
more soluble in many solvents, including dichloromethane,
and even cold chloroform13 so that flash chromatography
is necessary for the purification of enantiopure thio-
phthalimides 3. Crystalline products 3 are perfectly
stable at room temperature and can be stored for months
with neither decomposition nor racemization.
As the first aspect of the reactivity of N-thiophthalim-
ide 3, we considered its transformation into the corre-
sponding thiol. The reduction of 3 was achieved using
an excess of LiAlH4 (5.5 equiv) in dry THF.14 Bis-thiol 4
was thus obtained as a racemic mixture, or as enan-
tiopure compounds, in near quantitative yield. When the
reaction was carried out using 1.5-2 equiv of LiAlH4 we
could isolate cyclic disulfide 5 as single compound in good
yield (Scheme 2).
Moreover, the formation of dimer 5, from racemic 3,
could afford different stereoisomers: a racemic mixture
and a meso form, depending on the chirality of the
biphenyl units link together (the same or the opposite
respectively). A single product was obtained from the
reduction of racemic 3, and X-ray analysis10 demon-
strated it was the racemic disulfide 5 (Figure 1). These
data seems to indicate that the two biphenyl units are
able to recognize each other during the formation of the
sulfur-sulfur bonds, which occurs preferentially between
two homochiral species affording (P,P)-5 and (M,M)-5.
These results can be rationalized by considering at
least two independent mechanisms. It is possible to
foresee the selective formation of the first sulfur-sulfur
bond between two homochiral biphenyls, followed by a
highly preferred intramolecular reaction that prevents
oligomerization. Alternatively, it can be suggested that
both racemic and meso compounds 5 are formed in the
mixture, and then a fast equilibration, carried out by
thiolate ions, occurs leading to the more stable species,
among those containing sulfur-sulfur linkages, repre-
sented by the homochiral derivatives 5.15 As a further
interesting aspect related to dimeric disulfide 5, the
reduction of (M)-3 afforded the corresponding (M,M)-5,
We have already reported7 the use of aryl N-thio-
phthalimides as a source for the corresponding diaryl
disulfides. Using a substoichiometric amount of hydride
ion, the partial reduction of the sulfenamide generates
in solution an intermediate thiolate ion, which is a good
nucleophile toward the residual starting sulfenamide
causing the formation of the disulfide linkage.
isolated in 86% yield, which showed [R]20 ) -735,
D
indicative of this species being an example of a “high
chirality”16 compound. The X-ray structure of disulfide
5 points out the smallness of its internal cavity, since
(12) Delogu, G.; Fabbri, D. Tetrahedron: Asymmetry 1997, 8, 759.
(13) The solubility differences between a racemate and the enan-
tiomers is
a known, although uncommon, phenomenon. See for
example: (a) J acques, J .; Gabard, J . Bull. Soc. Chim. Fr. 1972, 342.
(b) Cervinka, O.; Fabryova, A.; Sablukova, I. Collect. Czech. Chem.
Commun. 1986, 51, 401. In the case of derivative 3 the difference in
solubility is really remarkable, for example in chloroform at 20 °C
racemic 3 is about 20 times less soluble than (P)- or (M)-3, (4 vs 80
mg/mL).
(15) As a demonstration that 5 represents a particular favorite
situation, reacting 3 with 2 equiv of sodium methanethiolate or sodium
thiophenoxide, no trace of the expected unsymmetric disulfides were
detected, while the corresponding dimethyl or diphenyl disulfide and
5 were isolated, respectively. Reasonably in this case, a series of
thiolate-disulfide interchanges shifts the equilibrium towards the
thermodynamically favored symmetric disulfides.
(14) For the complete reduction of sulfenamide 3 to thiol 4, dry THF
was deoxygenated by bubbling N2 or Ar (vide infra).

Regiocontrolled Synthesis of 3,3′-Thiosubstituted Biphenyls
J . Org. Chem., Vol. 67, No. 7, 2002 2021
Sch em e 3
the four hydroxyl oxygens lay on the vertex of an almost
regular tetrahedron with a 3.0-3.2 Å side.17 Preliminary
attempts to use 5 as a cavitand18,19 for metal cations were
unsuccessful20 as well as our efforts to enlarge the
internal21 cavity which seems inadequate to accommodate
even very small metal ions.
The use of thiol 4 as an efficient nucleophile was then
exploited for the synthesis of 3,3′-thiosubstituted biphen-
yls. To avoid accidental oxidation of thiol 4 to disulfide
5, air was excluded from the reaction mixtures by
bubbling N2 or Ar. Thiol 4 was reacted in deoxygenated
dry THF or DMF, with electrophiles 7-10 and Et3N as
base, to give sulfides 11-14 in good yields. Bromo ester
9 and 2-picolyl chloride 10 also were reacted with
enantiopure (M)-4 to afford (M)-13 and (M)-14, respec-
tively, as reported in Scheme 3.
The electrophiles were chosen to demonstrate the
validity of this methodology in the synthesis of multido-
nor group containing C2 biphenyls, since the sulfur atom
in these compounds is a donor itself and a very practical
means to join the sidearms. Good yield of derivative 14
can be obtained only with excesses of both 2-picolyl
chloride 10 (3 equiv) and Et3N (6 equiv) in DMF. When
the reaction of (M)-4 and 10 was performed under the
in 1:1 ratio, suggesting for (M)-15 the structure shown
in Figure 2.
1
conditions suitable with the other electrophiles, the H
NMR analysis of the crude reaction mixture revealed,
besides the expected compound (M)-14, the presence of
disulfide (M,M)-5 and a third component 15, which were
isolated in 19%, 11%, and 24% yields, respectively (see
Experimental Section). 1H NMR showed that in the latter
compound the biphenyl unit and the pyridine ring were
We propose that compounds 14, 15, or 5 are formed
depending upon the relative rates of the nucleophilic
substitution vs the sulfur-sulfur bond formation (by
adventitious oxidation of thiol 4) this last becoming a
competitive side reaction when the substitution is less
efficient. A similar behavior can be observed in the case
of fast substitutions by modifying stoichiometry and
conditions of the reaction. By reacting thiol 4 with only
1.4 equiv of the bromo ester 9, after 4 h in nondeoxygen-
ated dry THF, compounds 13 and 1623 were isolated in
49% and 44% yields, respectively (with only traces of
disulfide 5), thus validating our previous hypothesis
(Figure 2).
(16) Kiupel, B.; Niederalt, C.; Nieger, M.; Grimme, S.; Vogtle, F.
Angew. Chem. Int. Ed. 1998, 37, 3031.
(17) X-ray structure of derivative 5 ruled out the possibility that
H-bonding is present between the OH’s in the cavity. Independent-
ly upon its presence in the final product, the possibility that H-bond-
ing could play a role in the recognition of the two homochiral bi-
phenyl units seems highly improbable since under the reaction
conditions required for the synthesis of 5 (see Scheme 2) we likely
have in the reaction mixture not the OH’s but the corresponding Li/Al
salts.
(18) (a) Koenig, K. E.; Lein, G. M.; Stuckler, P.; Kaneda, T.; Cram,
D. J . J . Am. Chem. Soc. 1979, 101, 3553. (b) Kaneda, T.; Umeda, S.;
Tanigawa, H.; Misumi, S.; Kai, Y.; Morii, H.; Miki, K.; Kasai, N. J .
Am. Chem. Soc. 1985, 107, 4802. (c) Ueda, T.; Adachi, T.; Sumiya, K.;
Yoshida, T. J . Chem. Soc., Chem. Commun. 1995, 935.
(19) A referee suggested that compound 5 resembles a calix[4]arene
more than a cavitand. Despite several examples of sulfur substituted
calixarens are available in the literature (see for example: Hosseini,
M., W. In Calixarenes 2001; Asfari, Z., Bohmer, V., Harrowfield, Vicens,
J . Eds.; Kluwer Academic Publisher: Dordrecht, The Netherlands,
2001; pp110-129 and references therein), compounds with calixarenes
containing biphenyl units are hardly ever reported: (a) Yamato, T.;
Saruwatari, Y.; Nagayama, S.; Meeda, K.; Tashiro, M. J . Chem. Soc.,
Chem. Commun. 1992, 861. (b) Yamato, T.; Hasegawa, K-i.; Saru-
watari, Y.; Doamekpor, L. K. Chem. Ber. 1993, 126, 1435.
(20) No trace of complexation between 5 and LiOH was detected by
1H NMR in CDCl3.
(21) Attempts to enlarge this cavity using the disulfide-thiolsulfi-
nate-trisulfide transforming methodology22 were unsuccessful. The
oxidation of 5 to the corresponding thiosulfinate 6 was achieved using
m-CPBA (see Experimental Section); however, the reaction of 6 with
bis(trimethylsilyl)sulfide in boiling chloroform22 did not afford the
expected mono-trisulfide but only a partial reduction back to the
disulfide 5.
F igu r e 2. Compounds 15 and 16 obtained from “mixed”
substitution and sulfur-sulfur bond formation.
Recently Reetz reported the synthesis of several amino
acids containing biphenyl or binaphthyl C2 symmetric
units and their ability to serve as HIV-1 protease
inhibitors.24 The affinity of these species toward the
(22) Capozzi, G.; Capperucci, A.; Degl’Innocenti, A.; Del Duce, R.;
Menichetti, S. Tetrahedron Lett. 1989, 30, 2991
(23) Compound 16 was obtained as single diastereomer, spectro-
scopic data did not allow the attribution of the relative stereochemistry
of the biphenyl units.

2022 J . Org. Chem., Vol. 67, No. 7, 2002
Capozzi et al.
Sch em e 4
F igu r e 3. Ratio and relative geometry of the three diaster-
eomers A, B, C of bis-benzoxathiin 20.
Sch em e 6
Sch em e 5
(between 5.4 and 5.0 ppm), one for each diastereomer in
a 1.7:1 ratio possessing the C2 axis (both homotopic acetal
protons in pseudoaxial or pseudoequatorial position,
diastereomers A and B, Figure 3) and two separated
singlets for the third diastereomer (one proton pseudo-
axial and one pseudoequatorial, diastereomer C, Figure
3). Column chromatography permitted the isolation of
one major isomer whose acetal protons resonate as a
single doublet of doublets at 5.18 ppm (J ) 5.8 and 2.4
Hz), indicating that the acetal protons are homotopic (i.e.,
C2 axis) and pseudoaxial (isomer A Figure 3).25 This
result allowed the attribution of the relative geometry
to the three diastereomers 20 as reported in Figure 3.
A promising result of this inverse electron demand
Diels-Alder reaction was obtained when bis-enol ethers
25-28 were used as dienophiles. In this case we had the
opportunity to verify whether an intramolecular cycload-
dition could occur after the initial intermolecular reac-
tion, leading to the formation of a macrocyclic compound.
The reactions, performed under the conditions reported
above (Et3N, CHCl3, 60 °C) but using 1 equiv of dieno-
philes 25-28, allowed the isolation of the monomeric
cycloadducts 29-32 as mixture of only two of the three
possible diastereomers (Scheme 6).
biological target is related to the presence of the C2
symmetry that is a critical requirement. We proved that
our approach is useful to create new potential inhibitors
by exploiting the reactivity of thiol 4. Thus tosylation of
(S)-N-Boc serine methyl ester gave the electrophile 17
that was reacted with racemic and (P)-thiol 4 to give the
biphenyl-linked cysteine amino acid 18 showing a struc-
ture directly related to that of previously mentioned
derivatives24 (Scheme 4).
The study of the reactivity of derivative 3 continued
with the evaluation of the possible generation in solution
of the corresponding o-thioquinone and its trapping as
electron-poor bis-heterodiene.8,9 A suspension in chloro-
form of thiophthalimide 3 was heated to 60 °C in the
presence of 3 equiv of Et3N and 3 equiv of ethyl vinyl
ether (19) as potential dienophile. After 24 h, we isolated
the cycloadduct 20 in 68% yield as a 1.7:1.7:1 mixture of
the three possible diastereomers (Scheme 5).
Bis-benzoxathiin 20 clearly can be derived from two
inverse electron demand Diels-Alder reactions of the
electron-rich alkene 19 with a dienic o-thioquinone
species generated “in situ”. The reaction was monitored
1
by H NMR, and after 5 h of heating, we could detect
These reactions likely proceeded through an interme-
diate thioquinone of type 33, bearing the tethered dieno-
phile, so that the intramolecular cycloaddition could be
associated with several intermolecular reactions which
result in the formation of cyclic and linear oligomers. For
cycloadditions carried out with vinyl ethers 26-28 (n )
1, 2, 3), 1H NMR analyses of the crude indicated the
presence of oligomeric species, although no compound
with molecular weight higher than 30-32 was isolated
from these mixtures. Since the formation of cyclic ethers
the presence of a biphenyl derivative of type 21 bearing
both a benzoxathiin ring and an o-hydroxy-N-thiophthal-
imide moiety. Although we cannot rule out the presence
of bis-o-thioquinone 22, a stepwise mechanism with the
formation of the final product 20 through two consecutive
cycloadditions carried out by the mono-o-thioquinones 23
and 24 seems to be the actual route (Scheme 5).
The ratio and relative geometry of the three stereo-
isomers 20 was obtained on the basis of the 1H NMR
spectra of the crude reaction mixture recorded in C6D6.
By decoupling the three, almost coincident, SCH2 groups,
the acetal protons appear as four separated singlets
(25) For
a discussion on the attribution of the pseudoaxial or
pseudoequatorial position for the acetal protons of similar oxathiins,
see: Capozzi, G.; Fratini, P.; Menichetti, S.; Nativi C. Tetrahedron
1996, 52, 12233. Ibid. 1996, 52, 12247.
(24) Reetz, M.; Merk, C.; Mehler, G. Chem. Commun. 1998, 2075.

Regiocontrolled Synthesis of 3,3′-Thiosubstituted Biphenyls
J . Org. Chem., Vol. 67, No. 7, 2002 2023
Con clu sion
The regioselective introduction of two sulfur atoms,
performed by applying the chemistry of phthalimides-
ulfenyl chloride 1, represents the key step for the further
functionalization of the biphenyl skeleton with preserva-
tion of the C2 symmetry. The versatility of the N-
thiophthalimide moiety offers a straightforward access
to a wide range of enantiopure 3,3′-thiosubstituted
substrates that represent interesting targets since many
thio-biphenyls28 have found application for their biologi-
cal activities.29 Moreover compounds such as biphenyl
dimer 5,18 C2 symmetry sulfides 11-14,30 biphenyl-
containing amino acid 18,24,31 1,4-dibenzoxathiin 20,32 and
macrocyclic polyethers 29-3233 are the thio-isosters of
several derivatives useful in asymmetric catalysis as well
as in medicinal chemistry. The potentials of the above-
described compounds as well as the extension of this
chemistry to further electron-rich biphenyls are under
investigation.
F igu r e 4. Relative and absolute stereochemistry for the two
diastereomers D and E of 12-membered ring oxathiin (M)-29.
30-32 occurred in roughly the same yields (Scheme 6)
the ratio of inter- vs intramolecular cycloaddition from
thioquinones 33b-d seems almost insensitive to the
length of the tethered dienophile (from n ) 1 to n ) 3).
Thus, cyclization to 15-, 18-, or 21-membered rings
(compounds 30, 31, and 32) takes place with similar
probability.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded (when not specified)
in CDCl3 at 200 and 50 MHz, respectively, using residual
CHCl3 at 7.26 ppm for 1H and central peak of CDCl3 at 77
ppm for 13C as reference lines. Mass spectra were recorded in
the electron impact ionization mode with an electron energy
of 70 eV or, when specified, by electron spray ionization (ESI).
Optical rotation were measured using a digital polarimeter
with a 10-cm cell. Melting point are uncorrected. CHCl3, CH2-
Cl2, THF, and DMF were dried following standard procedures,
all commercial reagents were used without further purifica-
tion. Phthalimidesulfenyl chloride 18 and biphenol 212 were
prepared as reported elsewhere. The following data described
only the reaction, when performed, of enantiopure compounds.
(M)-2-{3-[3-(1,3-Dioxoisoin d olin -2-ylth io)-2-h yd r oxy-6-
m e t h o x y p h e n y l]-2-h y d r o x y -4-m e t h o x y p h e n y lt h io }-
isoin d olin e-1,3-d ion e (3). To a solution of biphenol (M)-2 (470
mg, 1.90 mmol) in dry chloroform (15 mL) was added sulfenyl
chloride 1 (850 mg, 3.90 mmol), and the mixture was kept for
3 h at room temperature. The mixture was diluted with
dichloromethane (30 mL) and washed with saturated aqueous
NaHCO3 (1 × 30 mL) and with water (2 × 30 mL). The organic
layer was dried over Na2SO4 and the solvent removed under
reduced pressure. The crude which was purified by flash silica
gel chromatography to give bis(thiophthalimide) (M)-3 (935
mg, 82%) as a white solid (eluent: dichloromethane): mp 287
Remarkably, when ethylene glycol divinyl ether (25,
n ) 0) was the dienophile, the monomeric compound 29
was the unique cycloadduct in the crude reaction mixture,
indicating that the formation of the 12-membered ring
from thione 33a represents a highly favorite situation26
that prevents the oligomerization.27
When this reaction was repeated using enantiopure
sulfenamide (M)-3, derivative (M)-29 was isolated in 95%
yield, again as 3:1 mixture of two diastereomers isolated
by flash chromatography (Scheme 6, Figure 4). Following
the same consideration discussed for compound 20 (Fig-
ure 3), it has been possible to assign the relative and, in
this case, absolute stereochemistry of the two isomers
(M)-29. The major isomer D maintains the C2 axis with
both homotopic acetal protons in pseudoequatorial posi-
tion (apparent triplet at 5.28 ppm, J ) 3.0 Hz), while
the C2 axis is missed in the minor isomer E showing two
different signals for the diastereotopic acetal protons (see
Experimental Section) (Figure 4).
The same geometric attribution can be done for major
and minor diastereomers of derivatives 30-32, which in
turn were separated by flash chromatography (see Ex-
perimental Section). Thus the inter- plus intramolecular
cyclization favored the formation of the compounds
containing a C2 axis and with two pseudoaxial acetal
carbon-oxygen bonds. It is noteworthy that the same
geometry can be found in the minor diastereomer of
derivative 20 (see compound B, Figure 3), obtained from
two intermolecular cycloadditions. Moving from inter- to
intramolecular cycloaddition we observed an inversion
of the stereochemistry of the major isomers, which
however, maintains the C2 axis (compare isomer A of
compound 20, Figure 3, with isomer D of compound 29,
Figure 4).
(28) (a) Hanson, G.; Kemp, D. S. J . Org. Chem. 1981, 46, 5441. (b)
J igajinni, V. B.; Wightman, R. H.; Campbell, M. M. J . Chem. Res. (S)
1983, 187. (c) Shimuzu, H.; Matsuo, K.; Kataoka, T.; Hori, M. Chem.
Pharm. Bull. 1984, 32, 4360. (d) Cossu, S.; De Lucchi, O.; Fabbri, D.;
Valle, G.; Painter, G. F.; Smith, R. A. J . Tetrahedron 1997, 53, 6073.
(e) Delogu, G.; Fabbri, D. Dettori, M. A. Tetrahedron: Asymmetry 1998,
9, 2819.
(29) (a) Quan, M. L.; Liauw, A. Y.; Ellis, C. D.; Pruitt, J . R.; Carini,
D. J .; Bostrom, L. L.; Huang, P. P.; Harrison, K.; Knabb, R. M.; Thoolen,
M. J .; Wong, P. C.; Wexler, R. R. J . Med. Chem. 1999, 42, 2752. (b)
Green, B. G.; Toney, J . H.; Kozarich, J . W.; Grant, S. K. Arch. Biochem.
Biophys. 2000, 375, 355.
(30) (a) Chautemps, P.; Gellon, G.; Morin, B.; Pierre, J .-L.; Provent,
C.; Refaif, S. M.; Beguin, C. G.; El Marzouki, A.; Serratrice, G.; Saint-
Aman E. Bull. Soc. Chim. Fr. 1994, 131, 434. (b) Koning, B.; Hulst,
R.; Kellogg, R. M. Recl. Trav. Chim. Pays-Bas 1997, 115, 49.
(31) (a) Mazaleyrat, J .-P.; Gaucher, A.; Kavrda, J .; Wakselman, M.
Tetrahedron: Asymmetry 1997, 8, 619. (b) Carbonelle, A.-C.; Zhu, J .
Org. Lett. 2000, 2, 3477. (c) Boisnard, S.; Neuville, L.; Bois-Choussy,
M.; Zhu, J . Org. Lett. 2000, 2, 2459.
(26) No trace of oligomeric oxathiins were detected even using an
excess of bis-enol ether 25.
(27) As a referee suggests, the formation of 29 as the sole compound
is probably due to the “effective molarity” of the second reaction that
is much larger on account of the shorter chain holding the reactive
groups together. Reasonably with longer more flexible chains, more of
an entropic cost has to be paid to bring the reactive groups together,
thus allowing the oligomers to be formed during the formation of
derivatives 30-32.
(32) Pigini, M.; Brasili, L.; Giannella, M.; Giardina`, D.; Gulini, U.;
Quaglia, W.; Melchiorre, C. J . Med. Chem. 1988, 31, 2300.
(33) (a) Cram, D. Angew. Chem., Int. Ed. Engl. 1986, 25, 1039. (b)
Lindsten, G.; Wennerstro¨m, O.; Isaksson, R. J . Org. Chem. 1987, 52,
547. (c) Costero A. M., Pitarch, M. J . Org. Chem. 1994, 59, 2939. (d)
Costero A. M., Pitarch, M.; Andreu C.; Ochando L. E.; Amigo, J . M.;
Debaerdemaeker, T. Tetrahedron 1996, 52, 669.

2024 J . Org. Chem., Vol. 67, No. 7, 2002
Capozzi et al.
1
1
°C. [R]20 ) -7.7 (c 0.36, CHCl3). H δ: 8.26 (s, 2H, OH); 7.89
>300 °C H δ: 9.14 (s, 1H, OH); 7.69 (d, 1H, J ) 8.8 Hz); 7.65
(d, 1H, J ) 8.8 Hz); 7.41 (d, 1H, J ) 8.8 Hz); 7.24 (d, 1H, J )
8.8 Hz); 6.60 (d, 1H, J ) 8.8 Hz); 6.53 (d, 2H, J ) 8.8 Hz);
6.51 (d, 1H, J ) 8.8 Hz); 5.99 (s, 1H, OH); 5.71 (s, 1H, OH);
5.59 (s, 1H, OH); 3.69 (s, 3H); 3.68 (s, 3H); 3.67 (s, 3H); 3.66
(s, 3H). 13C δ: 162.1 (s); 161.5 (s); 160.6 (s); 160.4 (s); 158.4 (s);
157.9 (s); 157.3 (s); 156.5 (s); 142.8 (d); 137.9 (d); 136.9 (d);
125.0 (d); 118.7 (s); 115.7 (s); 114.8 (s); 108.8 (s); 107.7 (s); 104.2
(d); 104.0 (d); 103.7 (d); 103.0 (d);56.0 (q); 55.9 (q). Mass (ESI)
m/z: (633, MH+). Anal. Calcd for C28H24O9S4: C, 53.16; H, 3.83.
Found: C, 53.37; H, 4.16. Min or . Yellow solid, mp > 300 °C.
1H δ: 9.13 (s, 1H, OH); 7.69 (d, 1H, J ) 8.8 Hz); 7.65 (d, 1H,
J ) 8.8 Hz); 7.43 (d, 1H, J ) 8.8 Hz); 7.21 (d, 1H, J ) 8.8 Hz);
6.60 (d, 1H, J ) 8.8 Hz); 6.53 (d, 2H, J ) 8.8 Hz); 6.50 (d, 1H,
J ) 8.8 Hz); 5.99 (s, 1H, OH); 5.71 (s, 1H, OH); 5.42 (s, 1H,
OH); 3.71 (s, 3H); 3.69 (s, 3H); 3.68 (s, 3H); 3.66 (s, 3H) δ.
Typ ica l P r oced u r e for th e P r ep a r a tion of Su lfid es 11-
13. Nitrogen was bubbled for 5 min into a solution of thiol 4
in dry THF (roughly 10-2 M), the electrophiles 7-9 (2 equiv)
and Et3N (2 equiv) were added via syringe, and the mixture
kept at room temperature, under a positive nitrogen pressure,
until the complete disappearance of starting materials moni-
tored by TLC. Saturated aqueous NH4Cl (30 mL) was added,
and the mixture extracted with diethyl ether (3 × 20 mL),
organic phases recollected, dried over Na2SO4, and evaporated
to dryness. The crude mixtures were purified by silica gel flash
chromatography to isolate compounds 11-13.
D
(d, 2H, J ) 8.8 Hz); 7.87-7.68 (m, 8H); 6.55 (d, 2H, J ) 8.8
Hz); 3.72 (s, 6H). 13C δ: 168.6 (s); 162.6 (s); 157.8 (s); 139.4
(d); 134.7 (d); 132.0 (s); 124.3 (d); 124.1 (d); 110.8 (s); 103.8
(s); 56.1 (q) δ. Anal. Calcd for C30H20O8S2N2: C, 59.99; H, 3.36;
N, 4.66. Found: C 59.70; H, 3.36; N, 4.59.
In the same way was obtained derivative (P)-3, 94%, [R]20
D
) +7.7 (c 0.35, CHCl3). In the case of racemic biphenol 2 the
crude obtained after evaporation of the solvent was washed
with boiling CHCl3 (10 mL for 1 g) to give pure 3, 73% yield.
(M)-2-(2-Hydr oxy-6-m eth oxy-3-su lfan ylph en yl)-3-m eth -
oxy-6-su lfa n ylp h en ol (4). Nitrogen was bubbled for 10 min
in a solution of thiophthalimide M-3 (427 mg, 0.71 mmol) in
dry THF (40 mL), and then the mixture was cooled at 0 °C
and lithium aluminum hydride (149 mg, 3.92 mmol) added in
one portion. The green suspension obtained was kept under
nitrogen at 0 °C for 20 min and then at room temperature for
30 min. The mixture was adjusted at pH 2 with 3% aqueous
HCl and washed with diethyl ether (5 × 30 mL). The combined
organic solvent was dried over Na2SO4 and evaporated to
dryness. Silica gel flash chromatography (eluent: dichlo-
romethane) gave thiol (M)-4 (220 mg, 99%) as a white solid:
mp 158-160 °C. [R]20 ) -57 (c 0.34, CHCl3). IR (KBr pellet)
D
cm-1: 3437 (O-H stret.); 2254 (S-H stretch). H δ: 7.46 (dd,
1
2H, J ) 8.8 and 0.8 Hz); 6.57 (d, 2H, J ) 8.8 Hz); 6.14 (s, 2H,
OH); 3.74 (s, 6H); 3.12 (d, 2H, J ) 0.8 Hz, SH). 13C δ: 158.8
(s); 154.1 (s); 135.1 (d); 108.9 (s); 104.7 (s); 104.1 (d); 56.1 (q).
Mass m/z (rel int, %): 310 (M+•,100); 246 (23). Anal. Calcd for
2-(2-Hyd r oxy-6-m eth oxy-3-m eth ylth iop h en yl)-3-m eth -
oxy-6-m eth ylth iop h en ol (11). From thiol 4 (20 mg, 0.06
mmol), methyl iodide (7) (16 mg, 0.12 mmol), and Et3N (12
mg, 0.12 mmol) in dry THF (6 mL). After 30 min at room
temperature, workup and flash chromatography (eluent: dichlo-
romethane) gave compound 11 (20 mg, 99%) as a dark yellow
solid: mp 151-153 °C. 1H δ: 7.51 (d, 2H, J ) 8.8 Hz); 6.65 (s,
2H, OH); 6.59 (d, 2H, J ) 8.8 Hz); 3.75 (s, 6H); 2.32 (s, 6H).
13C δ: 159.4 (s); 154.9 (s); 135.0 (d); 113.1 (s); 109.2 (s); 104.0
(d); 56.0 (q); 20.1 (q). Mass m/z (rel int, %): 338 (M+•, 85); 290
(13); 276 (19); 83 (100). Anal. Calcd for C16H18O4S2: C, 56.78;
H, 5.36. Found: C, 56.65; H, 5.74.
2-[2-Hyd r oxy-6-m eth oxy-3-(m eth oxym eth ylth io)p h en -
yl]-3-m eth oxy-6-(m eth oxym eth ylth io)p h en ol (12): from
thiol 4 (46 mg, 0.15 mmol), bromo methyl methyl ether (8) (38
mg, 0.30 mmol), and Et3N (30 mg, 0.30 mmol) in dry THF (15
mL). After 30 min at room temperature, workup and flash
chromatography (eluent: dichloromethane) gave compound 12
C
14H14O4S2: C, 54.18; H, 4.55. Found C, 54.21; H, 4.60.
Analogously was obtained derivative (P)-4 (80%) [R]20
)
D
+54 (c 0.29. CHCl3).
(M,M)-3,12,15,24-Te t r a m e t h oxy-7,8,19,20-t e t r a t h ia -
pen tacyclo[19.3.1.1 2,6 .1 9,13 .1 14,18 ]octacosa-1(25),2,4,6-
(26),9(27),10,12,14(28),15,17,21,23-d od eca en e-25,26,27,28-
tetr a ol (5). To a solution of thiophthalimide M-3 (409 mg, 0.68
mmol) in dry THF (40 mL), kept at 0 °C, was added lithium
aluminum hydride (39 mg, 1.03 mmol) in one portion. The
yellow suspension obtained was kept under nitrogen at 0 °C
for 20 then at room temperature for 1 h. The mixture was
adjusted to pH 2 with 3% aqueous HCl and washed with
diethyl ether (5 × 30 mL). The combined organic solvent was
dried over Na2SO4 and evaporated to dryness. Silica gel flash
chromatography (eluent: dichloromethane) gave disulfide
(M,M)-5 (180 mg, 86%) as a yellow solid: mp 290-292 °C.
[R]20 ) -735 (c 0.29, CHCl3). 1H 7.65 (d, 4H, J ) 8.8 Hz);
D
1
6.55 (d, 4H, J ) 8.8 Hz); 5.97 (bs, 4H, OH); 3.69 (s, 12H). 13C
δ: 159.1 (s); 155.3 (s); 135.8 (d); 114.8 (s); 108.5 (s); 102.3 (d);
54.4 (q). Mass m/z (rel int, %): 616 (M+•, 40); 310 (55); 276
(100). Anal. Calcd for C28H24O8S4: C, 54.54; H, 3.93. Found:
C, 54.22; H, 4.12. Crystal data and structure refinement for
compound 5. (The following crystal structure has been depos-
ited at the Cambridge Crystallographic Data Centre: Ref.
Code LIVSEO, NBS ID: 723789). Molecular formula: C28H24O8-
S4; formula weight: 616.71; temperature: 293(2) K; wave-
length: 0.71070 Å; crystal system: orthorombic; space group:
Pbcn; unit cell dimensions: a ) 13.889(5) Å, b ) 17.615(5) Å,
c ) 12.871(5) Å, R ) 90°, â ) 90°, γ ) 90°; volume: 3148.9 (8)
Å3; Z: 4; density (calculated): 1.301 Mg/m3: absorption
coefficient: 0.316 mm-1; F(000): 1280; θ range for data
collection: 8.5 to 198.8°; index ranges: 0 e h e 15, 0 e k e
19, 0 e l e 14; reflections collected: 2343; R1 ) 0.007, wR )
0.062.
(59 mg, 99%) as a dark solid: mp 267-268 °C. H δ: 7.47 (d,
2H, J ) 8.8 Hz); 7.01 (s, 2H, OH); 6.56 (d, 2H J ) 8.8 Hz);
4.74 (s, 4H); 3.74 (s, 6H); 3.45 (s, 6H). 13C δ: 159.7 (s); 155.5
(s); 135.8 (d); 110.8 (s); 110.0 (s); 103.7 (d); 79.8 (t); 56.9 (q);
55.9 (q). Mass m/z (rel int, %): 398 (M+•, 46); 366 (23); 334
(48); 322 (100). Anal. Calcd for C18H22O6S2: C, 54.25; H, 5.56.
Found: C, 54.37; H, 5.86.
(M)-Eth yl-2-(3-{3-[(eth oxyca r bon yl)m eth ylth io]-2-h y-
d r oxy-6-m et h oxyp h en yl}-2-h yd r oxy-4-m et h oxyp h en yl-
th io)a ceta te (13): from thiol (M)-4 (38 mg, 0.12 mmol), bromo
ethyl acetate (9) (41 mg, 0.24 mmol), and Et3N (24 mg, 0.24
mmol) in dry THF (12 mL). After 1 h at room temperature,
workup and flash chromatography (eluent: petroleum ether:
ethyl acetate/1:1) gave compound (M)-13 (39 mg, 67%) as a
yellow solid: mp 129-130 °C. [R]20 ) -20 (c 0.54, CHCl3).
D
1H δ: 7.52 (d, 2H, J ) 8.8 Hz); 7.20 (s, 2H, OH); 6.55 (d, 2H J
) 8.8 Hz); 4.15 (q, 4H, J ) 7.0 Hz); 3.73 (s, 6H); 3.46 (s, 4H);
1.22 (t, 6H, J ) 7.0 Hz). 13C δ: 170.7 (s); 160.3 (s); 156.3 (s);
136.8 (d); 110.0 (s); 109.9 (s); 103.9 (d); 61.9 (t); 56.0 (q); 39.3
(t); 14.0 (q). Mass m/z (rel int, %): 482 (M+•, 5); 84 (100). Anal.
Calcd for per C22H26O8S2: C, 54.76; H, 5.44. Found: C, 54.79;
H, 5.84.
25,26,27,28-Tetr a h yd r oxy-3,12,15,24-tetr a m eth oxy-7,8,-
19,20-t et r a t h ia p en t a cyclo[19.3.1.1 2,6 .1 9,13 .1 14,18 ]-
octacosa-1(25),2,4,6(26),9(27),10,12,14(28),15,17,21,23-dode-
ca en -7-on e (6). To a solution of disulfide 5 (84 mg, 0.13 mmol)
in dry dichloromethane (14 mL) kept at 0 °C was added
m-CPBA (19 mg, 0.07 mmol), and the mixture was maintained
2 h at 0 °C and 3 h at room temperature. The mixture was
diluted with dichloromethane (25 mL), washed with saturated
aqueous NaHCO3, and dried over Na2SO4. The crude obtained
after evaporation of the solvent was purified by silica gel flash
chromatography (eluent: dichloromethane, dichloromethane/
methanol:100/1) to give sulfinate 6 (50 mg, 61%, overall) as a
6:1 mixture of 2 diastereoisomers. Ma jor . Yellow solid, mp
(M)-2-[2-Hyd r oxy-6-m eth oxy-3-(2-p yr id ylm eth ylth io)-
p h en yl]-3-m eth oxy-6-(2-p yr id ylm eth ylth io)p h en ol (14).
To a solution of thiol (M)-4 (39 mg, 0.13 mmol) and picolyl
chloride hydrochloride (10)(60 mg, 0.37 mmol) in dry DMF (5
mL) was bubbled nitrogen for 5 min and Et3N (65 mg, 0.65
mmol) added via a syringe. The mixture was kept under a
positive pressure of nitrogen for 24 h, saturated aqueous NH4-
Cl (50 mL) was added, and the mixture was extracted with

Regiocontrolled Synthesis of 3,3′-Thiosubstituted Biphenyls
J . Org. Chem., Vol. 67, No. 7, 2002 2025
dichloromethane (5 × 15 mL). The combined organic phase
dried over Na2SO4 and evaporated to dryness to give a crude
which was purified by flash chromatography (eluent: petro-
leum ether:ethyl acetate/2:3) to give (M)-14 (49 mg, 76%) as a
(s); 136.6 (d); 129.9 (s); 109.9 (s); 103.9 (d); 80.2 (s); 56.0 (q);
53.1 (d); 52.5 (q); 38.8 (t); 28.3 (q). Anal. Calcd for C32H44
-
N2O12S2: C, 53.92; H, 6.22; N, 3.93. Found: C, 54.13; H, 6.45;
N, 3.77.
yellow solid: mp 157-159 °C. [R]20 ) -35 (c 0.165, CHCl3).
2-Eth oxy-8-(2-eth oxy-7-m eth oxy(2H,3H-ben zo[e]1,4-ox-
ath iin -8-yl))-7-m eth oxy-2H,3H-ben zo[e]1,4-oxath ian e (20).
To a suspension of thiophthalimide 3 (100 mg, 0.17 mmol) in
dry chloroform (10 mL) were added ethyl vinyl (19) (37 mg,
0.51 mmol) and triethylamine (51 mg, 0.51 mmol), and the
mixture was kept for 40 h at 60 °C. The crude obtained after
evaporation of the solvent was purified by flash silica gel
chromatography (eluent: dichloromethane) to give compound
20 as the single A isomer and an unseparable mixture of B
and C isomers (52 mg, 68% overall). Ma jor (A). Mp 169-170
D
1H δ: 8.53 (ddd, 2H, J ) 5.2, 1.8, 0.8 Hz, HR Py); 7.58 (dt, 2H,
J ) 7.6 and 1.8 Hz, Hγ Py); 7.42 (d, 2H, J ) 8.8 Hz); 7.17-
7.06 (m, 4H, Hâ e Hâ′ Py); 6.49 (d, 2H, J ) 8.8 Hz); 4.06 (s,
4H); 3.71 (s, 6H). 13C δ: 160.1 (s); 157.2 (s); 156.9 (s); 147.9
(d); 138.0 (d); 136.7 (d); 123.7 (d); 122.5 (d); 11.2 (s); 110.6 (s);
103.4 (d); 56.0 (q); 42.3 (t). Mass m/z (rel int, %): 492 (M+•,2);
460 (1); 428 (4); 368 (20); 124 (24); 93 (100). Anal. Calcd for
C26H24N2O4S2: C, 63.39; H, 4.91; N, 5.69. Found: C, 63.56; H,
4.77; N, 5.55.
1
(M)-6-({2-Hydr oxy-3-[2-h ydr oxy-6-m eth oxy-3-(2-pyr idyl-
m et h ylt h io)p h en yl]-4-m et h oxyp h en yl}d isu lfa n yl)-2-[2-
h yd r oxy-6-m et h oxy-3-(2-p yr id ylm et h ylt h io)p h en yl]-3-
m eth oxyp h en ol (15). To a solution of thiol (M)-4 (33 mg, 0.11
mmol) and picolyl chloride hydrochloride 10 (36 mg, 0.22
mmol) in dry THF (11 mL) was added Et3N (22 mg, 0.22 mmol)
via a syringe. The mixture was kept under a positive pressure
of nitrogen for 22 h, saturated aqueous NH4Cl (40 mL) was
added, and the mixture was extracted with dichloromethane
(4 × 20 mL). The combined organic phase was dried over Na2-
SO4 and evaporated to dryness to give a crude which was
purified by flash chromatography (eluent: petroleum ether:
ethyl acetate/1:3) followed by preparative TLC (eluent dichlo-
romethane:methanol/40:1) to give disulfide (M,M)-5 (4 mg,
11%), sulfide (M)-14 (10 mg, 19%), and compound (M,M)-15
°C. H 7.03 (d, 2H, J ) 8.0 Hz); 6.57 (d, 2H, J ) 8.0 Hz); 5.18
(X part of an ABX system, dd, 2H, J ) 5.8 and 2.6 Hz); 3.68
(s, 6H); 3.68-3.35 (m, 4H); 3.05 (A part of an ABX system,
2H, J AB ) 12.5 Hz); 2.94 (B part of an ABX system 2H, J AB
)
12.5 Hz); 1.06 (t, 6H, J ) 7.4 Hz). 13C δ: 155.9 (s); 148.8 (s);
126.1 (d); 113.8 (s); 109.4 (s); 105.3 (d); 96.3 (d); 64.0 (t); 56.1
(q); 29.3 (t); 14.9 (q). Mass: m/z (rel int, %): 450 (M+•, 100);
422 (15); 404 (29). Anal. Calcd for C22H26O6S2: C, 58.64; H,
5.82. Found: C 58.49; H, 5.96.
1H NMR Da ta for Mixtu r e of Isom er s B + C: δ 7.04 (d,
2H, J ) 8.8 Hz); 6.58 (d, 2H, J ) 8.8 Hz); 5.24-5.12 (m, 2H);
3.71-3.40 (m, 4H); 3.66 (s, 6H); 3.09-2.93 (m, 4H); 1.13-1.05
(m, 6H) δ.
Typ ica l P r oced u r e for th e Syn th esis of Cycloa d d u cts
29-32. To a 10 mg/mL suspension of thiophthalimide 3 in dry
chloroform (a clear solution for (M)-3) were added bis-vinyl
ethers 25-28 (1 equiv) and triethylamine (3 equiv) and the
mixtures kept for 24 h at 60 °C. The crude obtained after
evaporation of the solvent was purified by flash silica gel
chromatography to give the corresponding cycloadducts 29-
32, see Scheme 6.
3,20-D im e t h o x y -10,13,22,23-t e t r a o x a -7,16-d it h ia -
h exa cyclo[12.6.2.2 2,6 .0 2,24 .0 9,23 .0 17,21 ]t et r a cosa -
1(21),2,4,6(24),17,19-h exa en e (29): from M-3 (70 mg, 0.12
mmol) and ethylene glycol divinyl ether 25 (14 mg, 0.12 mmol).
After 24 h at 60 °C, flash chromatography gave cycloadduct
25 (47 mg, 95% overall) as mixture of two diastereoisomers
(11 mg, 24%) as a yellow solid: mp 198-200 [R]20 ) -48 (c
D
0.45, CHCl3); 1H δ: 8.53 (d, 2H, J ) 5.0 Hz, HR Py); 7.58 (dt,
2H, J ) 7.6 and 1.8 Hz, Hγ Py); 7.46 (d, 2H, J ) 8.8 Hz); 7.39
(d, 2H, J ) 8.8 Hz); 7.15-7.04 (m, 4H, Hâ and Hâ′ Py); 6.47
(d, 2H, J ) 8.8 Hz); 4.03 (s, 4H); 3.68 (s, 6H); 3.67 (s, 6H).
Mass (ESI) m/z: (801, MH+). Anal. Calcd for C40H36N2O8S4:
C, 59.98; H, 4.53; N, 3.50. Found: C, 60.17; H, 4.38; N, 3.44.
Meth yl 2-(2-Hyd r oxy-3-{2-h yd r oxy-3-[(2-h yd r oxy-3-{2-
h yd r oxy-6-m et h oxy-3-[(m et h oxyca r b on yl)m et h ylt h io]-
ph en yl}-4-m eth oxyph en yl)disu lfan yl]-6-m eth oxyph en yl}-
4-m eth oxyp h en ylth io)a ceta te (16). To a solution of thiol 4
(22 mg, 0.07 mmol) in dry THF (7 mL) were added bromo
derivative 9 (14 mg, 0.08 mmol) and Et3N (14 mg, 0.14 mmol)
via a syringe. The mixture was kept under a positive pressure
of nitrogen for 1 h, saturated aqueous NH4Cl (40 mL) was
added, and the mixture extracted with diethyl ether (4 × 15
mL). The combined organic phase dried over Na2SO4 and
evaporated to dryness to give a crude which was purified with
two consecutives separations by flash chromatography (elu-
ent: dichloromethane:methanol/50:1 and petroleum ether:
ethyl acetate/2:1) to give compound 13 (16 mg, 49%) and
derivative 16 (12 mg, 44%) as a yellow solid. mp 230-232 °C.
1H δ: 7.54 (d, 2H, J ) 8.8 Hz); 7.35 (d, 2H, J ) 8.8 Hz); 7.20
(s, 2H, OH); 6.54 (d, 2H, J ) 8.8 Hz); 6.51 (d, 2H, J ) 8.8 Hz);
6.25 (s, 2H, OH); 4.15 (q, 4H, J ) 7.2 Hz); 3.74 (s, 6H); 3.71 (s,
3H); 3.67 (s, 3H); 3.46 (s, 4H); 1.22 (t, 6H, J ) 7.2 Hz). 13C δ:
170.7 (s); 161.1 (s); 160.3 (s); 156.3 (s); 155.6 (s); 136.9 (d); 136.8
(d); 112.8 (2s); 110.1 (s); 109.5 (s); 104.0 (2d); 61.9 (t); 56.0 (q);
53.4 (q); 39.3 (t); 14.0 (q). Mass (ESI) m/z: (791, MH+). Anal.
Calcd for C36H38O12S4: C, 54.67; H, 4.84. Found: C, 54.50; H,
5.07.
(eluent: dichloromethane). Ma jor (M, S, S-29). Mp 184-186
1
°C. [R]20 ) -147.6 (c 0.38, CHCl3). H δ: 7.07 (d, 2H, J ) 8.8
D
Hz); 6.65 (d, 2H, J ) 8.8 Hz); 5.28 (t, 2H, J ) 3.0 Hz); 4.10-
3.94 (m, 2H); 3.70 (s, 6H); 3.70-3.55 (m, 2H); 3.24 (dd, 2H, J
) 13.2 and 3.0 Hz); 2.89 (dd, 2H, J ) 13.2 and ) 3.0 Hz). 13C
δ: 156.5 (s); 146.7 (s); 126.7 (d); 114.5 (s); 109.9 (s); 106.1 (d);
93.6 (d); 68.3 (t); 56.4 (q); 28.8 (t). Mass m/z (rel int, %): 420
(M+•, 100); 375 (5). Anal. Calcd for C20H20O6S2: C, 57.13; H,
4.79. Found: C, 57.46; H, 5.00. Min or (M, S, R-29). Mp 98-
1
100 °C. [R]20 ) -94.4 (c 0.25, CHCl3). H δ: 7.07 (d, 2H, J )
D
8.6 Hz); 6.66 (d, 1H, J ) 8.6 Hz); 6.64 (d, 1H, J ) 8.6 Hz);
5.49 (t, 1H, J ) 2.0 Hz); 5.41 (dd, 1H, J ) 8.4 and 1.6 Hz);
4.14-3.88 (m, 4H); 3.70 (s, 6H); 3.28 (dd, 1H, J ) 11.2 and
8.4 Hz); 3.10-2.89 (m, 3H). 13C δ: 156.5 (s); 155.7 (s); 127.6
(d); 125.1 (d); 111.7 (s); 108.4 (s); 106.9 (d); 105.7 (d); 94.7 (d);
94.4 (d); 65.0 (t); 61.6 (t); 56.3 (q); 29.4 (t); 28.5 (t).
3,23-Dim et h oxy-10,13,16,25,26-p en t a oxa -7,19-d it h ia -
h exa cyclo[15.6.2.2 2,6 .0 2,27 .0 9,26 .0 20,24 ]h ep ta cosa -
1(24),2,4,6(27),20,22-h exa en e (30): from 3 (60 mg, 0.10
mmol) and diethylene glycol divinyl ether 26 (16 mg, 0.10
mmol). After 24 h at 60 °C, flash chromatography gave
cycloadduct 30 (23 mg, 50% overall) as mixture of two
diastereoisomers (eluent: dichloromethane/methanol:60/1).
Ma jor . Pale yellow solid, mp 162-164 °C. 1H δ: 7.08 (d, 2H
arom, J ) 8.6 Hz); 6.60 (d, 2H, J ) 8.6 Hz); 5.32 (dd, 2H, J )
4.8 and 2.6 Hz); 3.96-3.84 (m, 2H); 3.68 (s, 6H); 3.71-3.48
(m, 6H); 3.11 (dd, 2H, J ) 13.2 and 2.8 Hz); 2.88 (dd, 2H, J )
13.2 and 4.8 Hz). 13C δ: 156.5 (s); 147.7 (s); 127.0 (d); 113.7
(s); 109.7 (s); 105.5 (d); 95.1 (d); 69.2 (t); 68.4 (t); 56.4 (q); 29.4
(t). Mass m/z (rel int, %): 464 (M+•, 79); 375 (4); 84 (100). Anal.
Calcd for C22H24O7S2: C, 56.88; H, 5.21. Found: C, 56.92; H,
(P )-Meth yl-(2R)-3-[3-(3-{(2R)-2-[(ter t-bu toxy)ca r bon yl-
am in o]-2-(m eth oxycar bon yl)eth ylth io}-2-h ydr oxy-6-m eth -
oxyp h en yl)-2-h yd r oxy-4-m eth oxyp h en ylth io]-2-[(ter t-bu -
toxy)car bon ylam in o]pr opan oate (18). Nitrogen was bubbled
for 5 min into a solution of (P)-4 (32 mg, 0.10 mmol) and amino
acid 17 (79 mgr, 0.20 mmol) in dry DMF (5 mL), Et3N (20 mg,
0,20 mmol) was added via a syringe, and the mixture was kept
at room temperature for 5 h. The previous described workup
and flash chromatography (eluent: petroleum ether:ethyl
acetate/3:2) gave derivative (P,R,R)-18 (43 mg, 60%) as a pale
yellow glassy solid, mp 72-75 °C. [R]20 ) +80.8 (c 0.25,
D
CHCl3). 1H δ: 7.48 (d, 2H, J ) 8.8 Hz); 6.62 (bs, 2H, OH);
6.55 (d, 2H, J ) 8.8 Hz); 5.47-5.43 (m, 2H, NH); 4.52-4.46
(m, 2H); 3.74 (s, 3H); 3.57 (s, 6H); 3.18 (ad, 4H, J ) 4.8 Hz);
1.43 (s, 18H). 13C δ: 171.1 (s); 159.7 (s); 155.7 (s); 155.1
1
5.17. Min or . Mp 172-173 °C. H δ: 7.03 (d, 2H, J ) 8.4 Hz);
6.61 (d, 1H, J ) 8.4 Hz); 6.60 (d, 1H arom, J ) 8.4 Hz); 5.50
(dd, 1H, J ) 8.2 and 1.8 Hz); 5.29 (t, 1H, J ) 2.0 Hz); 3.71 (s,

2026 J . Org. Chem., Vol. 67, No. 7, 2002
Capozzi et al.
3H); 3.68 (s, 3H); 3.85-3.45 (m, 8H); 3.45-2.65 (m, 4H). 13C
δ: 156.4 (s); 156.1 8s); 149.1 (s); 146.6 (s); 126.6 (d); 125.4 (d);
114.1 (s); 113.7 (s); 109.2 (s); 108.8 (s); 106.1 (d); 105.8 (d);
96.5 (d); 91.6 (d); 71.9 (t); 69.4 (t); 67.2 (t); 64.5 (t); 56.6 (q);
56.4 (q); 29.4 (t); 28.9 (t).
tr itr ia con ta -1(30),2,4,6(33),26,28-h exa en e (32): from 3 (102
mg, 0.17 mmol) and tetraethylene glycol divinyl ether 28 (42
mg, 0.17 mmol). After 24 h at 60 °C, flash chromatography
gave cycloadduct 32 (43 mg, 46% overall) as mixture of two
diastereoisomers (eluent: dichloromethane/methanol:40/1).
1
3,26-D i m e t h o x y -10,13,16,19,28,29-h e x a o x a -7,22-
d it h ia h e xa cyclo[18.6.2.2 2,6 .0 2,30 .0 9,29 .0 23,27 ]-
tr ia con ta -1(27),2,4,6(30),23,25-h exa en e (31): from 3 (60
mg, 0.10 mmol) and triethylene glycol divinyl ether 27 (20 mg,
0.10 mmol). After 24 h at 60 °C, flash chromatography gave
cycloadduct 31 (27 mg, 52% overall) as mixture of two
diastereoisomers (eluent: petroleum ether/dichloromethane:
10/1). Ma jor . Pale yellow solid, mp 143-145 °C. 1H δ: 7.04 (d,
2H, J ) 8.8 Hz); 6.59 (d, 2H, J ) 8.8 Hz); 5.21 (dd, 2H, J )
5.4 and 2.1 Hz); 3.80-3.30 (m, 12H); 3.67 (s, 6H); 3.11 (dd,
2H, J ) 12.4 and 2.1 Hz); 2.99 (dd, 2H, J ) 12.4 and 5.4 Hz).
13C δ: 155.7 (s); 148.1 (s); 126.0 (d); 113.9 (s); 109.7 (s); 105.5
(d); 96.1 (d); 69.0 (t); 68.8 (t); 68.7 (t); 56.1 (q); 29.2 (t). Mass
m/z (rel int, %): 508 (M+•, 100); 463 (2). Anal. Calcd for
C24H28O8S2: C, 56.68; H, 5.55. Found: C, 56.36; H, 5.77.
Min or . Mp 167-169 °C 1H δ: 7.09 (d, 1H, J ) 8.4 Hz); 7.03
(d, 1H, J ) 8.4 Hz); 6.60 (d, 1H arom, J ) 8.4 Hz); 6.58 (d,
1H, J ) 8.4 Hz); 5.97 (dd, 1H, J ) 5.4 and 3.0 Hz); 5.29 (t, 1H,
J ) 1.8 Hz); 4.18 - 4.07 (m, 1H); 3.69 (s, 3H); 3.65 (s, 3H);
3.86 - 3.28 (m, 11H); 3.16 (dd, 1H, J ) 12.8 and 1.8 Hz); 3.07
(dd, 1H, J ) 12.9 and 3.0 Hz); 2.93-2.84 (m, 2H). 13C δ: 156.6
(s); 156.0 (s); 148.5 (s); 147.2 (s); 126.8 (d); 126.6 (d); 114.0 (s);
113.9 (s); 110.0 (s); 109.1 (s); 105.5 (d); 105.2 (d); 94.5 (d); 92.9
(d); 71.1 (t); 70.8 (t); 69.8 (t); 69.5 (t); 68.8 (t); 64.2 (t); 56.3 (q);
56.1 (q); 29.7 (t); 28.9 (t) .
Ma jor . Pale yellow solid, mp 135-138 °C. H δ: 7.04 (d, 2H,
J ) 8.4 Hz); 6.59 (d, 2H, J ) 8.4 Hz); 5.19 (dd, 2H, J ) 5.4
and 2.6 Hz); 3.74-3.29 (m, 16H); 3.69 (s, 6H); 3.11 (dd, 2H, J
) 12.8 and 2.6 Hz); 2.90 (dd, 2H, J ) 12.8 and 5.4 Hz). 13C δ:
156.2 (s); 148.1 (s); 126.3 (d); 114.1 (s); 110.2 (s); 105.6 (d);
96.4 (d); 70.6 (t); 70.4 (t); 69.9 (t); 68.3 (t); 56.3 (q); 29.3 (t).
Mass m/z (rel int, %): 552 (M+•, 100). Anal. Calcd for
C26H32O9S2: C, 56.50; H, 5.84. Found: C, 56.72; H, 5.63.
1
Min or . Mp 139 °C. H δ: 7.04 (d, 1H arom, J ) 8.6 Hz); 7.02
(d, 1H, J ) 8.6 Hz); 6.60 (d, 1H, J ) 8.6 Hz); 6.59 (d, 1H, J )
8.6 Hz); 5.84 (dd, 1H, J ) 5.6 and 2.6 Hz); 5.24 (dd, 1H, J )
3.2 and 2.2 Hz); 3.68 (s, 3H); 3.66 (s, 3H); 4.00-3.45 (m, 16H);
3.21-2.85 (m, 4H). 13C δ: 156.0 (s); 155.7 (s); 148.6 (s); 147.7
(s); 126.5 (d); 126.0 (d); 114.2 (s); 113.7 (s); 109.7 (s); 109.1 (s);
105.5 (d); 105.3 (d); 96.8 (d); 96.1 (d); 71.5 (t); 70.6 (t); 70.10
(t); 70.06 (t); 69.5 (t); 69.4 (t); 67.5 (t); 67.4 (t); 56.3 (q); 55.9
(q); 29.1 (t); 28.9 (t).
Ack n ow led gm en t. Work carried out in the frame-
work of the National Project: “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” supported by the
Ministero dell’Universita` e della Ricerca Scientifica e
Tecnologica, Rome, by the University of Florence and
by CNR-Rome
3,29-Dim eth oxy-10,13,16,19,22,31,32-h ep ta oxa -7,25-d i-
t h ia h e x a c y c lo [21.6.2.2 2,6 .0 2,33 .0 9,32 .0 26,30 ]-
J O0157627