Stereoselective synthesis of thiochromenes via intramolecular tandem thio-michael addition of in situ generated α,β-unsaturated aldehydes

Article abstract of DOI:10.1021/jo5002164

An efficient and highly stereoselective strategy for the synthesis of 2,3-substituted thiochromenes having a complex and easily transformable group at the stereogenic center has been developed via a tandem thio-Michael addition reaction of an in situ generated α,β-unsaturated aldehyde sugar derivative. The protocol is superior to reported protocols in that the carbohydrate-derived substituent at the stereogenic center of the thiochromene is versatile and is amenable for further transformation.

Full text of DOI:10.1021/jo5002164

Article
pubs.acs.org/joc
Stereoselective Synthesis of Thiochromenes via Intramolecular
Tandem Thio-Michael Addition of in Situ Generated α,β-Unsaturated
Aldehydes
Henok Hadgu Kinfe,* Fanuel Mesfin Mebrahtu, Felix Loka Makolo, Paseka Thendo Moshapo,
and Mandlenkosi Maxwell Manana
Department of Chemistry, University of Johannesburg, P.O. Box 524, Auckland Park 2006, South Africa
S
* Supporting Information
ABSTRACT: An efficient and highly stereoselective strategy
for the synthesis of 2,3-substituted thiochromenes having a
complex and easily transformable group at the stereogenic
center has been developed via a tandem thio-Michael addition
reaction of an in situ generated α,β-unsaturated aldehyde sugar
derivative. The protocol is superior to reported protocols in
that the carbohydrate-derived substituent at the stereogenic
center of the thiochromene is versatile and is amenable for further transformation.
α,β-unsaturated aldehyde making use of thiochroman 3 as a
camouflaged hemithioacetal and as is illustrated in Scheme 2.
INTRODUCTION
■
2H-1-Benzothiopyrans 1, commonly known as thiochromenes,
are an important heterocyclic class of compounds found in a
number of pharmaceutical agents1−5 including anticancer,6,7
anticonvulsant,8 anti-HIV,9 and antibacterial agents.7 Owing to
their pharmacological importance, a number of synthetic
protocols have been reported for the synthesis of thiochro-
menes.10−15 However, there have been very few literature reports
on stereoselective synthetic approaches to such compounds.
Kobayashi and co-workers reported on the synthesis of thio-
chromenes in 92−93% ee via condensation of 2-mercaptoben-
zophenone and α,β-unsaturated carboxylates in the presence
of (diisopropylamino)magnesium reagent followed by dehy-
RESULT AND DISCUSSION
■
To determine the optimal reaction conditions, thiochroman 3a
was used as a model substrate. Thus, it was oxidized with cerium
ammonium nitrate to provide the sulfoxide 5a as a diastereo-
meric mixture in 68% combined yield. Pummerer rearrangement
of the diastereomeric mixture of sulfoxides 5a with NaOAc in
acetic anhydride under refluxing conditions21,22 followed by
suspension of the crude product in a 1:1 mixture of methanol and
dichloromethane in the presence of a catalytic amount of
NaOMe at room temperature for 10 min afforded thiochromene
4a in 80% yield over two steps (Scheme 2). Similar results were
obtained when other milder bases such as NaHCO3, KHCO3,
and K2CO3 were employed. The substituent at C-2 of the thio-
chromene was the open sugar chain moiety with its stereo-
chemistry intact.
dration.16 Cοrdova et al. and Wang et al. have independently
́
reported on a highly stereoselective (91−98% ee) chiral
pyrrolidine catalyzed domino thia-Michael/aldol reaction of
2-mercaptobenzaldehydes and α,β-unsaturated aldehydes for
the synthesis of thiochromene derivatives.17−19 Although these
methods are efficient, they are limited to providing chiral thio-
chromenes with simple n-alkyl or phenyl substituents at the C-2
stereogenic center. As a result of this limitation, the search for the
development of stereoselective synthetic protocols, which can
provide thiochromenes having versatile substituents and are
amenable for further functionalization at the stereogenic center,
are crucial. We recently reported on the stereoselective synthesis
of carbohydrate-based thiochroman 3 via Lewis acid catalyzed
intramolecular Friedel−Crafts alkylation whereby the stereo-
chemistry at the C-2 position of the sugar moiety determines the
stereochemical outcome of the product (Scheme 1).20 As an
extension of this early report, we now wish to report a highly
diastereoselective synthesis of a series of novel 2,3-substituted
chromene-3-carbaldehydes 4 (Figure 1) via intramolecular
tandem Michael addition-type reaction of an in situ generated
The structure of thiochromene 4a was established using NMR
spectroscopy and HRMS. The appearance of the aldehydic
proton signal at δH 9.51 and carbon signal at δC 193.6 confirmed
the presence of an aldehyde functional group. The appearance
of H-2 as a doublet at δH 4.39 due to coupling to H-1′ only and
the C-4 and H-4 signals downfield in the aromatic region (as
evidenced from HMBCAD spectrum due to coupling to the
aldehydic proton) suggested the presence of a double bond
between C-3 and C-4. To confirm the presence and position
of the OH group, thiochromene 4a was transformed into the
acetylated product 6a in quantitative yield (Scheme 2). The
downfield shift of H-2′ from around δH 3.50 in thiochromene 4a
to the region of δH 5.20−5.03 in thiochromene 6a coupled with
Received: February 3, 2014
Published: March 7, 2014
© 2014 American Chemical Society
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Scheme 1. Proposed Mechanism for the Formation of the Carbohydrate-Based Thiochroman 320
Scheme 3. Possible Staggered Conformations of
Thiochromene 4a
Figure 1. General structure of thiochromene 1, carbohydrate-based
thiochroman 3, and chromene-3-carbaldehyde derivatives 4.
preferred conformers, and this would have resulted in a larger
3JH‑2, H‑1′ coupling constant. In thiochromene 6a, the absence of
the hydrogen-bonding stabilization in the staggered conforma-
tions was confirmed from the relatively higher 3JH‑2, H‑1′ coupling
constant (5.7 Hz inferred from the signal of H-1′) which resulted
from the average of all the possible conformers.
With the optimized reaction conditions in hand, the scope of
this diastereoselective thiochromene synthesis with various
thiochroman 3 derivatives was examined. Following the devel-
oped protocol, several thiochromans 3a−e were transformed
stereoselectively to thiochromene-3-carbaldehydes 6a−e, and
the results are summarized in Table 1.
The proposed mechanism is illustrated in Scheme 4. The sulf-
oxide is transformed into the acetate 7 via Pummerer re-
arrangement. Hydrolysis of the acetate results in formation of the
hemimercaptal derivative 8 which equilibrates with the mercap-
toaldehyde 9.24 Deprotonation of the acidic α-hydrogen gives an
enolate 10, which then undergoes cleavage of the benzyloxy
under the alkaline conditions to provide the α,β-unsaturated
the appearance of the OAc signals at δH 2.06, δC 169.9 and 21.1
confirmed acetylation of the OH group at C-2′ (C-2′ in 6a
corresponds to C-2 in 5a), which indirectly indicated an opening
of the sugar ring. Moreover, the integration of the methylene
signals of the benzyl protecting groups was found to be four,
confirming the cleavage of one benzyl group from the starting
thiochroman.
The S-configuration at the C-2 stereogenic center was deter-
mined by measuring the 3JH‑2,H‑1′ coupling constant. The 3JH‑2,H‑1′
coupling constant was found to be 3.4 Hz for thiochromene 4a
and corresponds to a gauche relationship between the H-2 and
H-1′ protons.23 In the S-configuration at C-2, thiochromene 4a
would possibly adopt two favored staggered conformations (IV
and V) due to hydrogen bonding and a less favored conformation
VI (Scheme 3) having a gauche and anti relationship between the
3
H-2 and H-1′ protons, respectively. Hence, a smaller JH‑2,H‑1′
coupling constant was observed. Had the configuration at C-2
been R, thiochromene 4a would have adopted a conformation
having anti relationship between H-2 and H-1′ as one of its
a
Scheme 2
a
Key: (i) CAN, wet silica, KBr, CH2Cl2/CH3CN (1:1), rt, 30 min, 68%; (ii) (a) NaOAc, Ac2O, 140 °C, 3 h; (b) NaOMe, CH2Cl2/CH3OH (1:1), rt,
10 min, 80%; (iii) Ac2O, Et3N, DMAP, rt, 30 min, 79%.
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Table 1. Formation of Thiochromenes 6a−e and 20a−e Using Sulfoxides 5a−e and 13a−e
entry
sulfoxide substrate (diastereomeric ratio)
thiochromene product
isolated yield (%)
1
2
3
4
5
6
7
8
9
10
5a R1 = R2 = H (1:1.5)
6a R1 = R2 = H
79
69
69
75
72
63
86
60
66
85
5b R1 = H, R2 = CH3 (1:1.8)
5c R1 = H, R2 = OCH3 (1:2)
5d R1 = H, R2 = C(CH3)3 (1:1.2)
5e R1 = CH3, R2 = H (1:1.5)
13a R1 = R2 = H (1:2.3)
6b R1 = H, R2 = CH3
6c R1 = H, R2 = OCH3
6d R1 = H, R2 = C(CH3)3
6e R1 = CH3, R2 = H
20a R1 = R2 = H
13b R1 = H, R2 = CH3 (1:2.3)
13c R1 = H, R2 = OCH3
13d R1 = H, R2 = C(CH3)3 (1:2.6)
13e R1 = CH3, R2 = H (1:2)
20b R1 = H, R2 = CH3
20c R1 = H, R2 = OCH3
20d R1 = H, R2 = C(CH3)3
20e R1 = CH3, R2 = H
Scheme 4. Proposed Mechanism of the One-Pot Tandem Michael Addition-Type Reaction for the Stereoselective Synthesis of
Thiochromene 4
aldehyde 11 in accordance with the literature report by
Yamakawa et al.25 Attack by the thiolate at the β-position of
the double bond provides the desired thiochromene 4 via tandem
Michael addition-type reaction.
Selectivity in favor of the S-configuration at the C-2 position of
thiochromenes 4 could be explained in terms of the preference in
the α,β-unsaturated aldehyde intermediate 11 for the OH5
conformation (Figure 2).26 In this conformation, the thiolate
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by the acetate ion followed by rearrangement of the aryl-C-
glycoside 18 to the corresponding aryl S-glycoside 20 as shown
in Scheme 5. The possibility of this rearrangement occurring
during workup and isolation cannot be excluded. The
abstraction of the β-hydrogen might have been favored by
the possible coplanar arrangement of the H−C and CS
bonds in a similar fashion to an E2 elimination reaction. The
structure of thiochromene 20 was determined using single-
crystal X-ray crystallography.27
Figure 2. Preferred OH5 conformation of α,β-unsaturated aldehyde
intermediate 11.
CONCLUSION
■
moiety is prepositioned for intramolecular delivery from the
α-face of the sugar unit to give the stereochemistry depicted in
thiochromene 4.
In conclusion, we have shown an efficient and highly stereo-
selective strategy for the synthesis of 2,3-substituted thiochro-
menes via a tandem thio-Michael addition reaction. The current
protocol is superior to reported protocols in that the carbohydrate-
derived substituent at the stereogenic center of the thiochromene
is versatile and is amenable for further transformation. Application
of this methodology for the synthesis of biologically important
molecules is under way.
After the successful stereoselective synthesis of thiochromenes
6a−e, we envisioned the potential synthesis of thiochromene 16
(with opposite stereochemistry at C-2 to that of 4) using the
same reaction sequences but starting with thiochroman 12 as
proposed in Scheme 5. However, treatment of the sulfoxide 13
under Pummerer reaction conditions failed to provide the
hemithioacetal derivative 15 via acetate attack at the α-carbon of
the sulfonium intermediate 14. Instead, the reaction provided
thiochromene 20 (entries 6−10 in Table 1) presumably by
abstraction of the β-hydrogen of the sulfonium intermediate 17
EXPERIMENTAL SECTION
General Methods. All of the solvents used were freshly distilled.
Dichloromethane was distilled over phosphorus pentoxide in a
■
a
Scheme 5
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condenser fitted with a drying tube containing calcium chloride. Other
solvents were dried by appropriate techniques reported in Purification of
Laboratory Chemicals.28 Thiochromans 3a−e and 12a−e were
synthesized according to previously published protocols.20 All reactions
were monitored by thin-layer chromatography (TLC) on an aluminum-
backed silica gel 60 F254 plates using an ascending technique. The plates
were visualized by spraying with a 1:1 solution of 5% p-anisaldehyde in
ethanol and 10% performed on silica gel 60 (70−230 mesh). Melting
points were determined using a hot-stage apparatus and are uncorrected.
Optical rotations were determined in chloroform solutions at 25 °C.
The concentration c refers to g/100 mL. All proton and carbon-13
nuclear magnetic resonance spectra were recorded as deuteriochloro-
form solutions using tetramethylsilane as an internal standard. All
chemical shifts are reported in ppm.
General Procedure for the Synthesis of Thiochroman
Sulfoxide Derivatives 5a−e. KBr (0.15 mmol), 0.5 g of wet silica
(50% w/w), and CAN (0.6 mmol) were consecutively added to the
stirring solution of sulfides (3a−e) (0.5 mmol) dissolved in a 1:1
solution of CH2Cl2/CH3CN (10 mL). The reaction was stirred for
30 min, and the solids were filtered through a pad of Celite. The solvents
were removed under reduced pressure, and the diastereomeric mixture
of sulfoxides was separated by column chromatography on silica gel
using hexane and ethyl acetate as eluent (1:1) to afford sulfoxides 5a−e.
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-
2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran (5a, first
diastereomer): 110.9 mg, 40% yield; white solid; mp 103−105 °C; IR
(neat cm−1) 1454, 1090, 1025, 734, 695; [α]D (c 0.1, CHCl3) +84.0; 1H
NMR (400 MHz, CDCl3) δ: 7.84 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 7.6 Hz,
1H), 7.60−7.44 (m, 2H), 7.42−7.07 (15H), 5.04 (d, J = 5.6 Hz, 1H),
4.96 (d, J = 10.4 Hz, 1H), 4.85−4.72 (m, 2H), 4.65 (d, J = 12.0 Hz, 1H),
4.61−4.48 (m, 2H), 4.21 (dd, J = 7.6 and 10.0 Hz, 1H), 3.82−3.60 (m,
5H), 3.09 (dd, J = 3.8 and 14.6 Hz, 1H), 2.72−2.60 (m, 1H); 13C{1H}
NMR (100 MHz, CDCl3) δ 139.5, 138.8, 138.0, 133.5, 132.0, 129.1,
128.4, 128.0, 127.7, 127.6, 127.5, 79.4, 78.9, 74.2, 73.9, 73.5, 71.2, 68.8,
44.8, 35.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C34H35O5S
555.2205, found 555.2207.
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-
2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran (5a, sec-
ond diastereomer): 74.9 mg, 27% yield; white solid; mp 68−70 °C; IR
(neat cm−1) 1454, 1049, 1024, 730, 696; [α]D (c 0.1, CHCl3) −4.0; 1H
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.2 Hz, 1H), 7.58−7.43 (m,
3H), 7.40−7.12 (m, 15H), 5.17 (d, J = 4.4 Hz, 1H), 4.79−4.50 (m, 6H),
3.94−3.84 (m, 2H), 3.82−3.71 (m, 2H), 3.70−3.58 (m, 2H,), 3.06−
2.96 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 137.8, 137.7, 137.6,
134.2, 131.9, 130.0, 129.7, 129.3, 128.5, 128.4, 128.0, 127.8, 127.7, 127.6,
78.2, 76.6, 74.1, 74.0, 73.5, 73.4, 68.8, 68.0, 46.7, 34.9; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C34H35O5S 555.2205, found 555.2207.
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
methyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran
(5b, first diastereomer): 135.1 mg, 44% yield; white solid; mp 103−
105 °C; IR (neat cm−1) 1077, 1049, 740, 695; [α]D (c 0.1, CHCl3) −9.0;
1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H),
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
methoxy-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-
b]pyran (5c, first diastereomer): 154.7 mg, 49% yield; white solid; mp
106−108 °C; IR (neat cm−1) 1596, 1071, 1022, 735, 697; [α]D (c 0.1,
CHCl3) −1.0; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 1H),
7.48−7.10 (m, 16H), 7.00 (d, J = 8.4 Hz, 1H), 5.11−4.99 (m, 2H), 4.80
(d, J = 10.4 Hz, 1H), 4.67−4.50 (m, 3H), 4.37 (t, J = 9.8 Hz, 1H), 3.85−
3.62 (m, 7H), 3.61−3.50 (m, 1H), 2.99 (dd, 1H, J = 3.2 and 14.8 Hz),
2.73−2.61 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 139.0,
138.0, 137.9, 134.5, 133.6, 130.6, 128.4, 128.3, 128.0, 128.0, 127.7, 127.6,
127.5, 127.4, 115.8, 111.4, 80.3, 78.6, 74.4, 74.3, 73.8, 73.6, 72.1, 69.3,
55.4, 44.1, 36.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H37O6S
585.2311, found 585.2302.
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
methoxy-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-
b]pyran (5c, second diastereomer): 75.8 mg, 23% yield; colorless oil;
IR (neat cm−1) 1594, 1083, 1018, 738, 697; [α]D (c 0.1, CHCl3) +91.5;
1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.4 Hz, 1H), 7.50−7.12 (m,
15H), 7.05 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 2.4 and 8.8 Hz, 1H), 5.14 (d,
J = 4.0 Hz, 1H), 4.80−4.50 (m, 6H), 3.93−3.70 (m, 7H), 3.65−3.52 (m,
2H), 3.06−2.92 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.4,
137.9, 137.7, 137.6, 136.3, 132.0, 128.6, 128.5, 128.4, 128.0, 127.9, 127.8,
127.7, 115.8, 114.0, 78.5, 77.0, 74.2, 74.0, 73.5, 73.4, 68.8, 68.3, 55.5,
46.8, 34.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H37O6S
585.2311, found 585.2308.
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-
tert-butyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-
b]pyran (5d, first diastereomer): 128.6 mg, 39% yield; white solid; mp
113−115 °C; IR (neat cm−1) 1453, 1064, 735, 696; [α]D (c 0.1, CHCl3)
−0.5; 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.65 (d, J = 8.4 Hz,
1H), 7.40 (dd, J = 1.6 and 8.4 Hz, 1H), 7.35−7.08 (m, 13H), 7.05−6.95
(m, 2H), 5.00−4.88 (m, 2H), 4.78−4.63 (m, 2H), 4.54 (d, J = 12.0 Hz,
1H), 4.46 (d, J = 12.0 Hz, 1H), 4.38 (d, J = 11.2 Hz, 1H), 4.20 (dd, J = 8.4
and 10.8 Hz, 1H), 3.70−3.40 (m, 5H), 2.92 (dd, J = 3.8 and 15.0 Hz,
1H), 2.65−2.50 (m, 1H); 1.19 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 156.0, 138.9, 137.8, 135.8, 132.2, 131.4, 128.0, 127.7, 127.6,
127.5, 126.3, 124.3, 80.2, 78.6, 74.5, 74.3, 73.7, 73.6, 72.0, 69.0, 44.2,
36.1, 35.1, 31.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H43O5S
611.2831, found 611.2821.
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
tert-butyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-
b]pyran (5d, second diastereomer): 108.8 mg, 33% yield; white solid;
mp 115−117 °C; IR (neat cm−1) 1455, 1085, 1039, 749, 695; [α]D (c
0.1, CHCl3) +72.5; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.0 Hz,
1H), 7.59 (s, 1H), 7.48 (dd, J = 1.6 and 8.0 Hz, 1H), 7.41−7.10 (m,
15H), 5.19 (d, J = 4.4 Hz, 1H), 4.80−4.49 (m, 6H), 3.95−3.85 (m, 2H),
3.80−3.70 (m, 2H), 3.65−3.57 (m, 2H), 3.04−2.94 (m, 2H), 1.28 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.6, 138.0, 137.8, 137.6,
136.4, 133.7, 129.9, 128.6, 128.5, 128.4, 128.0, 127.9, 127.8, 127.7, 126.6,
126.5, 78.5, 77.0, 74.1, 73.7, 73.5, 69.2, 68.4, 46.9, 35.4, 35.0, 31.0;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H43O5S 611.2831, found
611.2835.
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-7-
methyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran
(5e, first diastereomer): 132.1 mg, 43% yield; white solid; mp 99−
101 °C; IR (neat cm−1) 1594, 1070, 736, 697; [α]D (c 0.1, CHCl3)
+38.5; 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 7.6 Hz, 1H), 7.48−
7.09 (m, 17H), 5.11 (d, J = 10.8 Hz, 1H), 5.05 (d, J = 5.6 Hz, 1H), 4.83
(d, J = 11.2 Hz, 1H), 4.67 (d, J = 12.0 Hz, 2H), 4.60−4.47 (m, 3H), 3.84
(dd, J = 3.2 and 15.2 Hz, 1H), 3.80−3.50 (m, 4H), 2.94 (dd, J = 3.0 and
15.0 Hz, 1H), 2.80−2.14 (m, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ
141.4, 139.1, 138.1, 137.9, 136.5, 133.8, 132.1, 131.2, 128.4, 128.3, 128.1,
127.8, 127.7, 127.5, 127.4, 127.3, 124.9, 80.6, 78.3, 74.4, 74.3, 73.5, 73.4,
72.9, 68.8, 43.0, 35.3, 19.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C35H37O5S 569.2362, found 569.2362.
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-7-
methyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran
(5e second diastereomer): 86.0 mg, 28% yield; colorless oil; IR (neat
cm−1) 1453, 1089, 1028, 730, 695; [α]D (c 0.1, CHCl3) −24.0; 1H NMR
(400 MHz, CDCl3) δ 7.65 (d, J = 7.6 Hz, 1H), 7.50−7.06 (17H), 5.10
(d, J = 10.4 Hz, 1H), 5.04 (d, J = 6.0 Hz, 1H), 4.87−4.76 (m, 2H), 4.66
7.41−7.10 (m, 16H), 5.04−4.97 (m, 2H), 4.78 (d, J = 10.8 Hz, 1H), 4.66
(d, J = 12.0 Hz, 1H), 4.61−4.50 (m, 2H), 4.26 (t, J = 9.2 Hz, 1H), 3.81−
3.59 (m, 5H), 3.04 (dd, J = 3.6 and 14.8 Hz, 1H), 2.70−2.59 (m, 1H),
2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 142.7, 138.8, 138.0,
136.3, 133.2, 131.2, 129.9, 128.4, 128.3, 128.0, 127.8, 127.7, 127.6, 127.5,
127.4, 79.6, 78.8, 74.2, 73.8, 73.4, 71.4, 67.0, 44.6, 35.9, 21.6; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C35H37O5S 569.2362, found 569.2354.
(2R,3S,4R,4aS,10bS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
methyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran
(5b ,second diastereomer): 73.7 mg, 24% yield; white solid; mp 104−
106 °C; IR (neat cm−1) 1454, 1049, 1026, 731, 696; [α]D (c 0.1, CHCl3)
−11.5; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 1H), 7.42−
7.13 (m, 15H), 5.11 (bs, 1H), 4.78−4.50 (m, 6H), 4.00−3.73 (m, 4H),
3.69−3.59 (m, 2H), 3.10−2.95 (m, 2H), 2.36 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 142.6, 137.9, 137.7, 137.6, 134.0, 130.4, 130.2,
130.1, 128.5, 128.4, 127.9, 127.8, 127.7, 127.6, 78.2, 76.2, 74.1, 73.8,
73.3, 68.2, 68.0, 46.4, 33.9, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C35H37O5S 569.2362, found 569.2363.
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(d, J = 12.0 Hz, 1H), 4.58−4.45 (m, 3H), 3.84 (dd, J = 3.6 and 15.2 Hz,
1H), 3.75−3.68 (m, 2H), 3.72 (t, J = 2.0 Hz, 1H), 3.58−3.50 (m, 1H),
2.94 (dd, J = 3.8 and 15.0 Hz, 1H), 2.85−2.60 (m, 4H); 13C{1H} NMR
(100 MHz, CDCl3) δ 141.4, 139.2, 138.2, 138.0, 133.9, 132.2, 131.2,
128.4, 128.3, 128.1, 127.8, 127.7, 127.5, 127.4, 127.3, 124.9, 80.7, 78.3,
74.4, 74.3, 73.5, 72.9, 68.9, 43.1, 35.3, 19.4; HRMS (ES+-TOF) m/z
[M + H]+ calcd for C35H37O5S 569.2362, found 569.2364.
(Ar, C-3 and C-4), 81.4 (C-1′), 74.4 (CH2Ph), 73.2 (CH2Ph), 72.3
(C-2′), 68.0 (C-3′), 35.2 (C-2), 21.2 (OCOCH3), 20.7 (CH3); HRMS
(ESI-TOF) m/z [M + H]+ calcd for C30H31O5S 503.1892, found
503.1878.
(1R,2R)-1,3-Bis(benzyloxy)-1-((S)-3-formyl-6-methoxy-2H-thio-
chromen-2-yl)propan-2-yl acetate (6c): 114.2 mg, 69% yield; IR
(neat cm−1) 1737, 1676, 1596, 1477, 1370, 1229, 1164, 1025, 731, 697;
[α]D (c 0.1, CHCl3) +12.5; 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H,
CHO), 7.39−7.12 (m, 10H, Ar and H-4), 6.93−6.72 (m, 4H, Ar), 5.14−
5.01 (m, 1H, H-2′), 4.63−4.24 (m, 5H, 2 × CH2Ph and H-2), 3.86−3.79
(m, 2H, H-1′ and H-3′a), 3.76 (s, 3H, OMe), 3.69 (dd, J = 6.4 and
12.0 Hz, 1H, H-3′b), 2.01 (s, 3H, OAc); 13C{1H} NMR (100 MHz,
CDCl3) δ 191.1 (CHO), 170.2 (OCOCH3), 158.2, 145.6, 138.2, 133.4,
131.6, 128.3, 128.1, 127.9, 127.7, 127.6, 127.5, 125.1, 117.7, 115.8 (Ar,
C-3 and C-4), 81.2 (C-1′), 74.4 (CH2Ph), 73.2 (CH2Ph), 72.4 (C-2′),
68.0 (C-3′), 55.5 (OMe), 35.1 (C-2), 21.2 (OCOCH3); HRMS (ESI-
TOF) m/z [M + H]+ calcd for C30H31O6S 519.1841, found 519.1833.
(1R,2R)-1,3-Bis(benzyloxy)-1-((S)-6-tert-butyl-3-formyl-2H-thio-
chromen-2-yl)propan-2-yl acetate (6d): 125.1 mg, 75% yield; IR
(neat cm−1) 2958, 1738, 1674, 1622, 1365, 1229, 1138, 1069, 733, 696;
[α]D (c 0.1, CHCl3) +16.3; 1H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H,
CHO), 7.38−7.12 (m, 12H, Ar and H-4), 6.89−6.57 (m, 2H, Ar), 4.98−
4.88 (m, 1H, H-2′), 4.49−4.36 (m, 5H, 2 × CH2Ph and H-2), 3.91 (dd,
J = 5.2 and 6.4 Hz, 1H, H-1′), 3.80 (dd, J = 4.4 and 10.8 Hz, H-3′a), 3.70
(dd, J = 4.4 and 10.8 Hz, 1H, H-3′b), 2.03 (s, 3H, OAC), 1.29 (s, 9H,
C(CH3)3); 13C{1H} NMR (100 MHz, CDCl3) δ 191.3 (CHO), 170.0
(OCOCH3), 148.9, 146.9, 138.0, 137.6, 131.9, 131.3, 130.2, 128.9,
128.4, 128.2, 128.1, 128.0, 127.7, 127.6, 127.5, 126.8 (Ar, C-3 and C-4),
81.7 (C-1′), 74.7 (CH2Ph), 73.2 (CH2Ph), 72.2 (C-2′), 68.0 (C-3′),
35.3 (C-2), 34.4 (C(CH3)3), 31.2 (C(CH3)3), 21.2 (OCOCH3); HRMS
(ESI-TOF) m/z [M + H]+ calcd for C33H37O5S 545.2362, found
545.2362.
(1R,2R)-1,3-Bis(benzyloxy)-1-((S)-3-formyl-8-methyl-2H-thiochro-
men-2-yl)propan-2-yl acetate (6e): 118.5 mg, 72% yield; IR (neat cm−1)
1737, 1674, 1629, 1566, 1366, 1228, 1143, 1027, 733, 696; [α]D (c
0.1, CHCl3) +14.0; 1H NMR (400 MHz, CDCl3) δ 9.55 (s, 1H, CHO),
7.49−7.08 (m, 12H, Ar and H-4), 6.91−6.89 (m, 2H, Ar), 5.19−5.01
(m, 1H, H-2′), 4.58−4.37 (m, 4H, CHAHBPh, CHAHBPh and H-2), 4.31
(d, J = 11.2 Hz, 1H, CHAHBPh), 3.84−3.77 (m, 2H, H-1′ and H-3′a),
3.70 (dd, J = 5.2 and 10.8 Hz, 1H, H-3′b), 2.35 (s, 3H, CH3), 1.98 (s, 3H,
OAc); 13C{1H} NMR (100 MHz, CDCl3) δ 191.2, (CHO), 170.0
(OCOCH3), 146.3, 138.0, 137.5, 135.9, 133.9, 132.9, 131.8, 130.3,
128.9, 128.3, 128.1, 127.9, 127.6, 127.5, 124.8 (Ar, C-3 and C-4), 81.4
(C-1′), 74.5 (CH2Ph), 73.2 (CH2Ph), 72.4 (C-2′), 68.0 (C-3′), 35.2
(C-2), 21.1 (OCOCH3), 20.3 (CH3); HRMS (ESI-TOF): m/z
[M + H]+ calcd for C30H31O5S 503.1892, found 503.1883.
(S)-2-((1R,2R)-1,3-Bis(benzyloxy)-2-hydroxypropyl)-2H-thiochro-
mene-3-carbaldehyde (4a). A stirred mixture of sulfoxide 5a (160 mg,
0.29 mmol) and sodium acetate (4.1 mg, 0. 05 mmol) in acetic anhy-
dride (1 mL) was refluxed at 140 °C for 3 h. The reaction was allowed to
cool to room temperature. Diethyl ether (5 mL) and methanol (1 mL)
were added to the reaction mixture and stirred for 1 h. The solution
was concentrated at reduced pressure. The residue was diluted with
dichloromethane and washed several times with saturated aqueous
sodium bicarbonate solution. The organic layer was dried over MgSO4
and concentrated in vacuo to give orange oil. To a solution of this oil in
CH2Cl2 and CH3OH (5 mL, 1:1) was added a catalytic amount of
sodium methoxide, and the mixture was stirred at room temperature for
10 min. Water was added, and the mixture was extracted with CH2Cl2
(3 × 10 mL). The combined organic layer was dried, concentrated in
vacuo, and flash chromatographed on silica gel (ethyl acetate/hexane,
1:9) to obtain thiochromene 4a as a yellow syrup: 119.7 mg, 80% yield;
[α]D (c 0.1, CHCl3) +26.5; IR (neat cm−1) 3446, 1656, 1622, 1453,
1362, 1206, 1143, 1070, 732, 696; 1H NMR (400 MHz, CDCl3) δ 9.51
(s, 1H, CHO), 7.38−6.90 (m, 13H, Ar and H-4), 6.44−6.56 (m, 2H, 2H,
Ar), 4.34 (d, J = 10.6 Hz, 1H, CHACHBPh), 4.28 (d, J = 10.6 Hz, 1H,
CHACHBPh), 4.39 (d, J = 3.6 Hz, 1H, H-2), 4.50 (d, J = 12.0 Hz, 1H,
CHACHBPh), 4.44 (d, J = 12.0 Hz, 1H, CHACHBPh), 3.73 (dd, J = 3.2
and 8.4 Hz, 1H, H-1′), 3.61 (bd, J = 4.4 Hz, 1 H, OH), 3.60−3.35 (m,
3H, H-2′, H-3′a, and H-3′b); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6
(CHO), 149.7, 138.0, 137.4, 135.7, 131.7, 131.3, 131.0, 130.7, 128.4,
128.0, 127.9, 127.6, 127.5, 126.7, 125.5 (Ar, C-3 and C-4), 85.6 (C-1′),
75.5 (CH2Ph), 73.5 (CH2Ph), 70.4 (C-2′), 69.8 (C-3′), 35.5 (C-2);
HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H27O4S 447.1630, found
447.1624.
General Procedure for the Synthesis of Thiochromene
Derivatives 6a−e. Thiochromenes 6a−e were synthesized using the
same conditions described for the synthesis of 4a. However, prior to
column purification, the thiochromenes so obtained were dispersed in
CH2Cl2 (5 mL) and treated with acetic anhydride (1 mL), triethylamine
(0.5 mL), and a catalytic amount of DMAP. The solution was stirred at
room temperature until completion of the reaction (monitored by
TLC). The solution was diluted with CH2Cl2, washed with water, and
dried over MgSO4. The residue was then purified by flash column chro-
matography on silica gel (ethyl acetate/hexane, 1:9) to afford thio-
chromene 6a−e as a yellow syrup:
(1R,2R)-1,3-Bis(benzyloxy)-1-((S)-3-formyl-2H-thiochromen-2-yl)-
propan-2-yl acetate (6a): 129.2 mg, 79% yield; IR (neat cm−1) 1737,
1674, 1626, 1367, 1231, 1140, 1069,732, 696; [α]D (c 0.1, CHCl3)
+15.2; 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H, CHO), 7.43−7.10
(m, 13H, Ar and H-4), 6.92−6.80 (m, 2H, Ar), 5.20−5.03 (m, 1H,
H-2′), 4.61−4.34 (m, 5H, 2 × CH2Ph and H-2), 3.88 (t, J = 5.7 Hz, 1H,
H-1′), 3.82 (dd, J = 3.5 and 11.0 Hz, 1H, H-3′a), 3.70 (dd, J = 4.8 and
11.0 Hz, 1H, H-3′b), 2.06 (s, 3H, OAc); 13C{1H} NMR (100 MHz,
CDCl3) δ 191.1 (CHO), 169.9 (OCOCH3), 145.8, 137.9, 137.4, 134.5,
132.2, 131.3, 131.0, 130.3, 128.3, 128.0, 127.6, 127.5, 127.1, 125.6 (Ar,
C-3 and C-4), 81.3 (C-1′), 74.5 (CH2Ph), 73.1 (CH2Ph), 72.1 (C-2′),
67.8 (C-3′), 35.1 (C-2), 21.12 (OCOCH3); HRMS (ESI-TOF) m/z
[M + H]+ calcd for C29H29O5S 489.1732, found 489.1732.
General Procedure for the Synthesis of Thiochroman
Sulfoxide Derivatives 13a−e. To a vigorously stirring suspension
of wet alumina (1.11 g wetted with 117 μL of water) and Oxone
(332 mg, 0.54 mmol) in DCM was added thiochroman 12 (0.54 mmol).
After 3 h of stirring at room temperature, the adsorbent was filtered over
a Celite bed and washed several times with DCM. The filtrate was
evaporated in vacuo. The residue was purified by column chromatog-
raphy on silica gel (ethyl acetate/hexane, 4:6) to give the corresponding
diastereomeric sulfoxides:
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-
2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran (13a,
first diastereomer): 134.8 mg, 45% yield; colorless oil; [α]D
1
(c 0.1, CHCl3) −33.5; IR (neat, cm−1) 1028, 696; H NMR (CDCl3,
400 MHz) δ 7.75 (d, J = 7.2 Hz, 1H), 7.65−7.00 (m, 18H), 4.91 (d,
J = 10.8 Hz, 1H), 4.80 (d, J = 11.6 Hz, 1H), 4.65−4.30 (m, 5H), 4.10−
3.90 (m, 1H), 3.80−3.50 (m, 5H), 3.36 (d, J = 13.2 Hz, 1H), 3.15 (t, J =
13.0 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 137.6, 133.4, 132.7,
132.3, 131.6, 130.0, 128.5, 128.4, 128.3, 128.0, 128.0, 127.8, 127.7, 127.6,
81.0, 79.8, 75.2, 74.5, 73.5, 73.4, 70.8, 69.2, 40.2, 28.3; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C34H35O5S 555.2205, found 555.2200.
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-
2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran (13a
second diastereomer). 59.9 mg, 20% yield; white solid; mp 115−
117 °C; [α]D (c 0.1, CHCl3) +24.5; IR (neat, cm−1) 1026, 695; 1H NMR
(CDCl3, 400 MHz) δ 7.85 (d, J = 7.6 Hz, 1H), 7.70−7.00 (m, 18H), 4.86
(1R,2R)-1,3-Bis(benzyloxy)-1-((S)-3-formyl-6-methyl-2H-thiochro-
men-2-yl)propan-2-yl acetate (6b): 120.1 mg, 73% yield; IR (neat
cm−1) 1737, 1674, 1629, 1566, 1366, 1228, 1143, 1027, 733, 696; [α]D (c
0.1, CHCl3) +18.5; 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H, CHO),
7.40−6.98 (m, 12H, Ar and H-4), 6.91−6.81 (m, 2H, Ar), 5.13−4.96
(m, 1H, H-2′), 4.55−4.27 (m, 5H, 2 × CH2Ph and H-2), 3.87−3.78 (m,
2H, H-1′ and H-3′a), 3.69 (dd, J = 4.8 and 10.8 Hz, 1H, H-3′b), 2.28 (s,
3H, CH3), 2.00 (s, 3H, OAc); 13C{1H} NMR (100 MHz, CDCl3) δ
191.2 (CHO), 170.0 (OCOCH3), 146.0, 138.0, 137.6, 135.5, 132.4,
132.3, 131.6, 131.0, 130.5, 128.3, 128.0, 127.9, 127.7, 127.6, 127.4, 127.1
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(d, J = 10.8 Hz, 1H), 4.70 (s, 2H), 4.60−4.30 (m, 4H), 4.00−3.50 (m,
6H), 3.40−3.20 (m, 1H), 2.60−2.40 (m, 1H); 13C{1H} NMR (CDCl3,
100 MHz) δ 142.5, 138.1, 138.1, 137.7, 133.6, 131.8, 130.6, 130.0, 128.6,
128.4, 128.3, 128.1, 128.0, 127.8, 127.7, 127.7, 127.6, 127.0, 81.5, 80.4,
75.2, 74.6, 73.6, 73.5, 72.1, 69.2, 42.3, 34.4; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C34H35O5S 555.2205, found 555.2205.
(d, J = 11.2 Hz, 1H), 4.65−4.35 (m, 5H), 4.10−3.90 (m, 1H), 3.80−3.50
(m, 5H), 3.43 (d, J = 14.0 Hz, 1H), 3.06 (t, J = 13.4 Hz, 1H), 2.72 (s,
3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 140.3, 138.3, 138.1, 137.6,
135.6, 133.6, 132.0, 130.9, 128.5, 128.3, 128.3, 128.1, 127.9, 127.8, 127.8,
127.7, 127.6, 81.0, 79.7, 75.2, 74.5, 73.8, 73.4, 70.7, 69.2, 39.3, 27.5, 18.8;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H37O5S 569.2362, found
569.2366.
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-7-
methyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran
(13e, second diastereomer): 76.8 mg, 25% yield; oil; [α]D (c 0.1,
CHCl3) +11.6; IR (neat, cm−1) 1026, 696; 1H NMR (CDCl3, 400 MHz)
δ 7.50−7.00 (m, 18H), 4.85 (d, J = 10.4 Hz, 1H), 4.69 (s, 2H), 4.60−
4.40 (m, 3H), 4.31 (s, 1H), 3.95−3.30 (m, 6H), (m, 1H), 2.67 (s, 3H),
2.55−2.40 (m, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 140.4, 139.1,
138.2, 138.1, 137.8, 134.5, 132.6, 130.3, 128.6, 128.4, 128.3, 128.0, 128.0,
127.8, 127.6, 127.5, 81.6, 80.4, 75.2, 74.5, 74.4, 73.5, 71.9, 69.2, 42.6,
34.4, 21.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H37O5S
569.2362, found 569.2366.
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
methyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran
(13b, first diastereomer): 153.6 mg, 50% yield; colorless oil; [α]D
1
(c 0.1, CHCl3) −20; IR (neat, cm−1) 1027, 695; H NMR (CDCl3,
400 MHz) δ 7.62 (d, J = 8.4 Hz, 1H), 7.50−7.00 (m, 17H), 4.91 (d,
J = 10.8 Hz, 1H), 4.81 (d, J = 11.2 Hz, 1H), 4.65−4.35 (m, 5H), 4.10−
3.90 (m, 1H), 3.80−3.50 (m, 5H), 3.36 (d, J = 13.6 Hz, 1H), 3.11 (t, J =
13.0 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 143.0,
138.3, 138.1, 137.6, 134.7, 133.3, 133.2, 131.6, 130.7, 128.6, 128.5, 128.4,
128.3, 128.0, 127.9, 127.8, 127.7, 127.6, 81.1, 79.8, 75.2, 74.6, 73.5, 73.4,
70.7, 69.3, 40.1, 28.2, 21.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C35H37O5S 569.2362, found 569.2365.
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
methyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran
(13b, second diastereomer): 67.6 mg, 22% yield; white solid; mp 99−
101 °C; [α]D (c 0.1, CHCl3) +7.5; IR (neat, cm−1) 1026, 696; 1H NMR
(CDCl3, 400 MHz) δ 7.75 (d, J = 8.0 Hz, 1H), 7.50−7.10 (m, 17H), 4.88
(d, J = 10.8 Hz, 1H), 4.73 (s, 2H), 4.65−4.42 (m, 3H), 4.37 (s, 1H),
3.90−3.50 (m, 6H), 3.40−3.20 (m, 1H), 2.60−2.43 (m, 1H), 2.40 (s,
3H,); 13C{1H} NMR (CDCl3, 100 MHz) δ 141.0, 138.5, 138.1, 138.0,
137.7, 133.4, 132.3, 130.9, 128.6, 128.4, 128.3, 128.0, 127.8, 127.7, 127.6,
127.0, 81.6, 80.3, 75.2, 74.6, 73.7, 73.4, 72.1, 69.2, 42.4, 34.5, 21.2;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H37O5S 569.2362, found
569.2365
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
methoxy-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-
b]pyran (13c): 94.7 mg, 30% yield; colorless oil; [α]D (c 0.1, CHCl3)
−15.5; IR (neat, cm−1) 1028, 697; 1H NMR (CDCl3, 400 MHz) δ 7.59
(d, J = 8.4 Hz, 1H), 7.40−7.05 (m, 15H), 7.00−6.80 (m, 2H), 4.85 (d,
J = 10.8 Hz, 1H), 4.74 (d, J = 11.6 Hz, 1H), 4.60−4.30 (m, 5H), 4.10−
3.90 (m, 1H), 3.85−3.45 (m, 8H), 3.30 (d, J = 13.6 Hz, 1H), 3.00 (t, J =
13.2 Hz, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 126.5, 138.2, 138.1,
137.6, 135.3, 133.5, 128.4, 128.3, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6,
117.6, 115.8, 81.0, 79.8, 75.1, 74.5, 73.6, 73.4, 70.7, 69.3, 55.6, 40.0, 27.9;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H37O6S 585.2311, found
585.2313.
General procedure for the Synthesis of Thiochromene
Derivatives 20a−e. NaOAc (4 mg, 0.03 mmol) was added to a
solution of sulfoxide 13 (0.30 mmol) in acetic anhydride (2 mL), and
the reaction mixture was stirred overnight at 140 °C. The reaction
mixture was then allowed to cool to room temperature and diluted
with DCM. The resulting solution was washed successively with
saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and
evaporated. The residue was purified by column chromatography
on silica gel (ethyl acetate/hexane, 5:95) to yield the corresponding
thiochromene 20:
(2R,3S,4R,10aS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-
2,3,4,10a-tetrahydrothiochromeno[2,3-b]pyran (20a): 161.0 mg,
63% yield; white solid; mp 66−68 °C; [α]D (c 0.5, CHCl3) −96.5; IR
(neat, cm−1) 696; 1H NMR (CDCl3, 400 MHz) δ 7.60−7.00 (m, 19H,
Ar), 6.75 (d, J = 1.2 Hz, 1H, H-5), 5.25 (s, 1H, H-10a), 5.00−4.80 (m,
2H, CH2Ph), 4.71 (d, J = 11.6 Hz, 1H, CH2Ph), 4.60−4.40 (m, 3H,
CH2Ph), 4.26 (dd, J = 1.6 and 8.4 Hz, 1H, H-4), 3.80−3.40 (m, 4H, H-3,
H-1′a, H-1′b, H-2); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.0, 137.8,
129.6, 128.6, 128.5, 128.4, 128.3, 128.3, 128.3, 128.2, 128.0, 128.0, 127.9,
127.8, 127.8, 127.8, 127.7, 127.6, 125.6, 125.2 (Ar and C-4a), 120.4
(C-5), 85.1 (C-4), 82.2 (C-3), 80.6 (C-2), 75.4 (C-10a), 75.2, 73.5, 72.8
(CH2Ph), 69.1 (C-1′); HRMS (ESI-TOF) m/z [M + H]+ calcd for
C34H33O4S 537.2100, found 537.2100.
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
tert-butyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-
b]pyran (13d, first diastereomer): 214.4 mg, 65% yield; colorless oil;
(2R,3S,4R,10aS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-7-meth-
yl-2,3,4,10a-tetrahydrothiochromeno[2,3-b]pyran (20b): 142.1 mg,
86% yield; white solid; mp 109−111 °C; [α]D (c 0.5, CHCl3) −95.5; IR
(neat, cm−1) 696; 1H NMR (CDCl3, 400 MHz) δ 7.60−6.90 (m, 18H,
Ar), 6.72 (s, 1H, H-5), 5.23 (s, 1H, H-10a), 5.00−4.80 (m, 2H, CH2Ph),
4.72 (d, J = 11.6 Hz, 1H, CH2Ph), 4.60−4.40 (m, 3H, CH2Ph), 4.27 (d, J
= 8.4 Hz, 1H, H-4), 3.80−3.50 (m, 4H, H-3, H-1′a, H-1′b, H-2), 2.30 (s,
3H, ArCH3); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.0, 137.9, 134.9,
130.2, 129.2, 128.5, 128.3, 128.2, 128.0, 127.9, 127.9, 127.7, 127.5, 127.4,
125.4, 125.0 (Ar and C-4a), 120.5 (C-5), 85.1 (C-4), 82.2 (C-3), 80.5
(C-2), 75.5 (C-10a), 75.2, 73.4, 72.7 (CH2Ph), 69.1 (C-1′), 20.8
(ArCH3); HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H35O4S
551.2256, found 551.2258. The compound was crystallized from a
mixture of ethyl acetate and hexane for X-ray analysis.
1
[α]D (c 0.1, CHCl3) −28.5; IR (neat, cm−1) 1051, 683; H NMR
(CDCl3, 400 MHz) δ 7.66 (d, J = 8.0 Hz, 1H), 7.60−7.10 (m, 17H), 4.91
(d, J = 10.8 Hz, 1H), 4.80 (d, J = 11.6 Hz, 1H), 4.65−4.35 (m, 5H),
4.10−3.90 (m, 1H), 3.80−3.50 (m, 5H), 3.36 (d, J = 12.4 Hz, 1H), 3.13
(t, J = 13.0 Hz, 1H), 1.31 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ
156.0, 138.3, 138.1, 137.6, 134.7, 132.9, 131.4, 129.7, 128.5, 128.4, 128.3,
128.0, 128.0, 127.8, 127.7, 127.7, 127.6, 127.3, 81.1, 79.8, 75.2, 74.6,
73.8, 73.4, 70.7, 69.2, 40.2, 35.1, 31.1, 28.4; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C38H43O5S 611.2831, found 611.2828.
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-
tert-butyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-
b]pyran (13d, second diastereomer): 82.4 mg, 25% yield; white solid;
mp 136−138 °C; [α]D (c 0.1, CHCl3) +10.0; IR (neat, cm−1) 1051, 683;
1H NMR (CDCl3, 400 MHz) δ 7.76 (d, J = 8.4 Hz, 1H), 7.60−7.10 (m,
17H), 4.86 (d, J = 10.8 Hz, 1H), 4.70 (s, 2H), 4.60−4.40 (m, 3H), 4.37
(s, 1H), 3.90−3.50 (m, 6H), 3.40−3.20 (m, 1H), 2.60−2.40 (m, 1H),
1.31 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ 154.1, 139.4, 138.2,
138.1, 137.7, 133.3, 128.7, 128.6, 128.4, 128.3, 128.0, 127.8, 127.8, 127.6,
127.5, 127.3, 126.9, 81.6, 80.4, 75.2, 74.7, 73.9, 73.4, 72.1, 69.2, 42.4,
34.8, 34.6, 31.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H43O5S
611.2831, found 611.2828.
(2R,3S,4R,10aS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-7-me-
thoxy-2,3,4,10a-tetrahydrothiochromeno[2,3-b]pyran (20c): 102.0
mg, 60% yield; white solid; mp 126−128 °C; [α]D (c 0.5, CHCl3) −99.5;
1
IR (neat, cm−1) 697; H NMR (CDCl3, 400 MHz) δ 7.50−7.00 (m,
16H, Ar), 6.85−6.75 (m, 2H, Ar), 6.70 (d, J = 1.6 Hz, 1H, H-5), 5.20 (s,
1H, H-10a), 4.95−4.80 (m, 2H, CH2Ph), 4.72 (d, J = 11.6 Hz, 1H,
CH2Ph), 4.60−4.35 (m, 3H, CH2Ph), 4.27 (dd, J = 1.2 and 8.4 Hz, 1H,
H-4), 3.90−3.40 (m, 7H, OCH3, H-3, H-1′a, H-2′b, H-2); 13C{1H}
NMR (CDCl3, 100 MHz) δ 157.6, 138.1, 137.9, 129.1, 128.6, 128.4,
128.3, 128.0, 128.0, 127.9, 127.8, 127.6, 126.6, 120.5, 119.3, 115.0, 114.6
(Ar, C-4a and C-5), 85.1 (C-4), 82.3 (C-3), 80.6 (C-2), 75.6 (C-10a),
75.3, 73.5, 72.8 (CH2Ph), 69.1 (C-1′), 55.5 (OCH3); HRMS (ESI-
TOF) m/z [M + H]+ calcd for C35H35O5S 567.2205, found 567.2209.
The compound was crystallized from ethanol for X-ray analysis.
(2R,3S,4R,4aR,10bR)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-7-
methyl-2,3,4,4a,5,10b-hexahydro-S-oxothiochromeno[4,3-b]pyran
(13e, first diastereomer): 153.6 mg, 50% yield; colorless oil; [α]D
1
(c 0.1, CHCl3) −24.6; IR (neat, cm−1) 1027, 695; H NMR (CDCl3,
400 MHz) δ 7.50−7.00 (m, 18H), 4.92 (d, J = 10.4 Hz, 1H), 4.81
3117
dx.doi.org/10.1021/jo5002164 | J. Org. Chem. 2014, 79, 3111−3118

The Journal of Organic Chemistry
Article
́
́
(10) Sipos, A.; Tοth, M.; Mueller, F. K. U.; Lehmann, J.; Berenyi, S.
(2R,3S,4R,10aS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-7-tert-
butyl-2,3,4,10a-tetrahydrothiochromeno[2,3-b]pyran (20d): 117.3
mg, 66% yield; white solid; mp 122−124 °C; [α]D (c 0.5, CHCl3)
−164.0; IR (neat, cm−1) 696; 1H NMR (CDCl3, 400 MHz) δ 7.60−7.00
(m, 18H, Ar), 6.75 (s, 1H, H-5), 5.22 (s, 1H, H-10a), 4.92 (d, J = 12.0
Hz, 2H, CH2Ph), 4.72 (d, J = 112.0 Hz, 1H, CH2Ph), 4.60−4.40 (m, 3H,
CH2Ph), 4.26 (d, J = 8.4 Hz, 1H, H-4), 3.80−3.40 (m, 4H, H-3, H-1′a,
H-1′b, H-2), 1.30 (s, 9H, (C(CH3)3); 13C{1H} NMR (CDCl3, 100
MHz) δ 148.4, 138.1, 138.0, 128.6, 128.4, 128.3, 128.1, 128.0, 128.0,
127.9, 127.7, 127.5, 127.2, 126.7, 125.7, 125.3, 125.1 (Ar and C-4a),
121.0 (C-5), 85.1 (C-4), 82.3 (C-3), 80.6 (C-2), 75.5 (C-10a), 75.2,
73.5, 72.8 (CH2Ph), 69.2 (C-1′), 34.4 (C(CH3)3), 31.3 (C(CH3)3);
HRMS (ESI-TOF) m/z [M + H]+ calcd for C38H41O4S 593.2726, found
593.2720. The compound was crystallized from a mixture of ethyl
acetate and hexane for X-ray analysis.
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(2R,3S,4R,10aS)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-9-meth-
yl-2,3,4,10a-tetrahydrothiochromeno[2,3-b]pyran (20e): 140.0 mg,
1
85% yield; oil; [α]D (c 0.5, CHCl3) −88.0; IR (neat, cm−1) 696; H
(19) Bhanja, C.; Jena, S.; Nayak, S.; Mohapatra, S. Beilstein J. Org. Chem.
2012, 8, 1668−1694.
NMR (CDCl3, 400 MHz) δ 7.60−6.90 (m, 18H, Ar), 6.74 (d, J = 1.6 Hz,
1H, H-5), 5.34 (s, 1H, H-10a), 5.00−4.80 (m, 2H, CH2Ph), 4.71 (d, J =
11.6 Hz, 1H, CH2Ph), 4.60−4.40 (m, 3H, CH2Ph), 4.25 (dd, J = 1.2, and
8.4 Hz, 1H, H-4), 3.80−3.40 (m, 4H, H-3, H-1′a, H-1′b, H-2), 2.32 (s,
3H, ArCH3); 13C{1H} NMR (CDCl3, 100 MHz) δ 138.1, 138.0, 137.9,
133.7, 130.0, 128.6, 128.4, 128.3, 128.0, 127.9, 127.9, 127.8, 127.8, 127.7,
127.6, 127.6, 127.2, 124.4, 121.0 (Ar, C-4a and C-5), 85.0 (C-4), 82.1
(C-3), 80.6 (C-2), 75.3 (C-10a), 75.2, 73.4, 72.8 (CH2Ph), 69.1 (C-1′),
19.5 (ArCH3); HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H35O4S
551.2256, found 551.2260.
(20) Kinfe, H. H.; Moshapo, P. T.; Makolo, F. L.; Muller, A. J.
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ASSOCIATED CONTENT
* Supporting Information
■
Soc. Jpn. 1987, 60, 301−310.
̌
S
(26) Ruzic-
́
Toros,
̌
Z.; Rogic,
́
V.; Kojic-
́
Prodic,
́
B. Acta Crystallogr. 1980,
̌
Copies of 1H and 13C{1H} NMR spectra for products 4a, 5a−e,
6a−e, 13a−e, and 20a−e; COSY and HSQC spectra for 4a, 6a,
and 20a; crystallographic data for the structures of 20b−d (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
B36, 607−611.
(27) Crystallographic data for the structures of 20b, 20c, and 20d have
been deposited with the Cambridge Crystallographic Data Centre as
deposition nos. CCDC 989920, 990238, and 989921, respectively.
(28) Perrin, D. D.; Armarego, L. F. Purification of Laboratory Chemicals,
3
rd ed.; Pergamon Press: Oxford, 1988.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hhkinfe@uj.ac.za.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Johannesburg and the Research
Centre for Synthesis and Catalysis of the Department of Chem-
istry at UJ for funding this project and Mrs. Z. Phasha and Dr. C.
Arderne for solving the crystal structures of the thiochromenes.
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