New carbohydrate-derived S,S -dioxothiochroman derivatives and their unexpected easy epimerization at the anomeric position

Article abstract of DOI:10.1080/07328303.2013.789106

An efficient and stereoselective procedure is developed for high-yield preparation of novel S,S-dioxothiochroman carbohydrate derivatives 5a-e from their corresponding sulfone epimers 3a-e via anomeric epimerization in the presence of sodium hydride. Copy

Full text of DOI:10.1080/07328303.2013.789106

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New Carbohydrate-Derived S,S-
Dioxothiochroman Derivatives and Their
Unexpected Easy Epimerization at the
Anomeric Position
Henok H. Kinfe a , Felix L. Makolo a , Paseka T. Moshapo a & Zanele
H. Phasha a
a Department of Chemistry , University of Johannesburg , Auckland
Park , South Africa
Published online: 24 May 2013.
To cite this article: Henok H. Kinfe , Felix L. Makolo , Paseka T. Moshapo & Zanele H. Phasha
(2013) New Carbohydrate-Derived S,S-Dioxothiochroman Derivatives and Their Unexpected Easy
Epimerization at the Anomeric Position, Journal of Carbohydrate Chemistry, 32:3, 193-204, DOI:
10.1080/07328303.2013.789106
To link to this article: http://dx.doi.org/10.1080/07328303.2013.789106
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Journal of Carbohydrate Chemistry, 32:193–204, 2013
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2013.789106
New Carbohydrate-Derived
S,S-Dioxothiochroman
Derivatives and Their
Unexpected Easy
Epimerization at the
Anomeric Position
Henok H. Kinfe, Felix L. Makolo, Paseka T. Moshapo,
and Zanele H. Phasha
Department of Chemistry, University of Johannesburg, Auckland Park, South Africa
An efficient and stereoselective procedure is developed for high-yield preparation of
novel S,S-dioxothiochroman carbohydrate derivatives 5a–e from their corresponding
sulfone epimers 3a–e via anomeric epimerization in the presence of sodium hydride.
Keywords Dioxothiochroman; Epimerization; Sulfone
INTRODUCTION
Thiochromans, 3,4-dihydro-2H-1-benzothiopyrans, continue to attract signifi-
cant interest from organic and medicinal chemists due to their presence as key
components in biologically active compounds against cancer,[1] HIV,[2] mala-
ria,[3] and bacteria,[4] as well as in the treatment of depression,[5] schizophre-
nia,[5a] Alzheimer’s disease,[6] and Parkinson’s disease.[5a] Moreover, the en-
hanced biological activity exhibited by thiochromans in comparison to their
corresponding oxygen analogs[5b,7] (chromans) and the ease of derivatizing
them into different analogs as shown in Scheme 1, thus generating libraries
of compounds for structure-activity relationship studies, make thiochromans
one of the sought-after compounds. Several strategies for the synthesis of
Received January 30, 2013; accepted March 20, 2013.
Address correspondence to Henok H. Kinfe, Department of Chemistry, University of Jo-
hannesburg, P.O. Box 524, Auckland Park, 2006, South Africa. E-mail: hhkinfe@uj.ac.za
193

H. H. Kinfe et al.
194
thiochromans, which include thio-Claisen rearrangement of allyl phenyl sul-
fides and stereoselective cycloaddition reactions, have been reported in the lit-
erature.[6b,8–19]
Scheme 1: Possible derivatization of thiochromans into useful synthetic intermediates.
We recently reported an efficient protocol for the diastereoselective prepa-
ration of carbohydrate-based thiochromans in which the orientation of the sub-
stituent at C-2 of a pyranosyl substrate induces the stereochemistry of the
thiochroman products. More specifically, 1α,2α-aryl-C-glycoside 1 and 1β,2β-
aryl-C-mannoside 2 were synthesized by this protocol (Fig. 1).[20] In this paper
we report that the stereoselective access to these types of compounds can be
expanded via the treatment of sulfone derivatives of the 1α,2α-aryl-C-glycoside
1 with sodium hydride.
Figure 1: Structures of the carbohydrate-based thiochromans 1 and 2.

New Carbohydrate-derived S,S-dioxothiochroman Derivatives
195
RESULTS AND DISCUSSION
This discovery resulted from our attempts to synthesize derivatives of 1α,2α-
aryl-C-glycoside 1 for structure-activity relationship studies against cancer
(breast, colon, and prostate cancers). It was envisaged that oxidation of 1 would
result in a sulfone derivative,[20] which, upon deprotonation of the acidic proton
α to the sulfur with a base followed by treatment with an alkyl halide, would
provide an alkylated product. Thus, sulfide 1a was oxidized to sulfone 3a,[20]
which was then successively treated with sodium hydride and methyl iodide
as an alkylating[21] agent in the hope of obtaining 4a via deprotonation at H-7
as shown in Scheme 2. Thin layer chromatography (TLC) analysis of the reac-
tion showed formation of a slightly more polar product relative to the starting
sulfone. However, structural analysis of the new product confirmed the forma-
tion of the unexpected sulfone epimer 5a instead of the alkylated sulfone 4a.
Carrying out the same reaction in the absence of methyl iodide resulted in the
Scheme 2: (i) Oxone, wet alumina, DCM, rt, 12 h, 69%; (ii) NaH, DMF, rt, 30 min followed with
CH3I, rt, 1 h, 68% (5a); (iii) NaH, DMF, rt, 15 min, 87%.

H. H. Kinfe et al.
196
Figure 2: Single x-ray crystal structure of sulfone 5a (color figure available online).
formation of the same epimer. The shift of the anomeric proton signal and in-
3
crease in the JH-1,H-2 coupling constant of the sulfone epimer 5a from 4.0 Hz
in sulfone 3a to 10.4 Hz indicates a trans-diaxial relationship between H-1
and H-2, and this could be achieved if the configuration of the anomeric proton
is α.[22] The absolute structure of the sulfone epimer 5a was also determined
using x-ray crystallography (Fig. 2).[23]
By varying the amount of NaH used, it was established that 1.5 equiva-
lents are sufficient to fully epimerize the starting sulfone 3a to 5a in short reac-
tion time at room temperature. Treatment of various sulfones 3b–e (Table 1) in
this way provided efficient access to the new sulfone epimers 5b–e. In all cases

New Carbohydrate-derived S,S-dioxothiochroman Derivatives
197
Table 1: Results of the oxidation of sulfide 1a–e to sulfone 3a–e and of the
epimerization reaction
Sulfone 3a–e
Sulfone epimer 5a–e
Entry
Aromatic substituent
Product
% Yield
Product
% Yield
1
2
3
4
5
R1 = R2 = H
R1 = H, R2 = CH3
R1 = CH3, R2 = H
R1 = H, R2 = But
R1 = H, R2 = OCH3
3a
3b
3c
3d
3e
69
71
73
69
70
5a
5b
5c
5d
5e
87
88
85
94
92
complete conversion of the starting sulfones to their corresponding epimers
1
was achieved in short reaction time, and products were identified by H and
13C NMR spectroscopy after chromatographic purification.
The transformation from the starting sulfone to its epimer probably in-
volves deprotonation at the benzylic (allylic) position relative to the sulfone,
thus giving rise to the preferred resonance-stabilized anion VIII (Sch. 3) in con-
trast to the relatively less stabilized resonance anion VI from deprotonation at
H-7 (Sch. 2). The possibility of both anions (VI and VIII) forming initially can-
not be excluded but with time equilibrium moves to species VIII, which is then
protonated at the anomeric center via internal or external hydrogen transfer
from C-7. In this regard, the sp2 hybridized anomeric center in VIII is pro-
tonated from the α side to form the equatorially substituted stable epimer in
Scheme 3: Proposed mechanism of the epimerization reaction via intramolecular
deprotonation at C-7.

H. H. Kinfe et al.
198
order to avoid the 1,3-diaxial strain of the phenyl group. Species IX is then pro-
tonated upon workup to give the epimerized product. To confirm which anion
was finally trapped during the workup, the reaction was quenched with D2O
1
(Sch. 3). The H NMR spectrum of the product so obtained indicated that the
integrations of the H-7a and H-7b signals reduced by almost 50% while the in-
tegration of the H-1 signal remained intact (Sch. 3), supporting the formation
of anion IX (via either inter- or intramolecular deprotonation). The decrease in
the integration of H-7a and H-7b by 50% also indicates that compound X is a
mixture of diastereomers.
CONCLUSION
In conclusion, we have demonstrated that access to new stereoisomers of the
carbohydrate-based thiochroman derivatives could be achieved efficiently via
epimerization at the anomeric center. Currently we are investigating the effect
of stereochemistry on the biological activity of these compounds and results
will be reported in due course.
EXPERIMENTAL
All the solvents used were freshly distilled. Dichloromethane was distilled
over phosphorous pentoxide in a condenser fitted with a drying tube contain-
ing calcium chloride. Other solvents were dried by appropriate techniques.
All reagents were purchased from Sigma Aldrich. All reactions were moni-
tored by TLC on aluminum-backed Merck silica gel 60 F254 plates using an
ascending technique. The plates were visualized by spraying with a 1:1 solu-
tion of 5% p-anisaldehyde in ethanol and 10% sulphuric acid in ethanol baking
at 150◦C. Gravity column chromatography was done on Merck silica gel 60
(70–230 mesh). Melting points were determined using a Reichert-Jung Ther-
movar hot-stage microscope and are uncorrected. Optical rotations were de-
termined on a Perkin-Elmer 141 polarimeter in chloroform solutions at 25◦C.
The concentration c refers to g/100 mL. Infrared spectra were recorded using
Tensor 27 Bruker and Perkin Elmer FT-IR spectrum BX.
All proton nuclear magnetic resonance (1H NMR) spectra were recorded
as deuteriochloroform solutions using tetramethylsilane as an internal stan-
dard on a Bruker Ultrashield (400 MHz) spectrometer. Carbon-13 nuclear mag-
netic resonance (13C NMR) spectra were recorded on the same instrument at
100 MHz using tetramethylsilane as an internal standard. All chemical shifts
1
are reported in ppm. Anomeric ratios are calculated from the H NMR spec-
troscopy of the crude product. Mass spectrometers were recorded on a Wal-
ters API Quattro Micro spectrometer at the University of Stellenbosch, South
Africa.

New Carbohydrate-derived S,S-dioxothiochroman Derivatives
199
General Procedure for the Synthesis of Sulfones 3a–e
A sulfide 1a–e[24] (0.28 mmol) was added to a vigorously stirring suspen-
sion of wet alumina (852 mg wetted with 90 μL of water) and OXONEꢀR (1.4 g,
2.28 mmol) in DCM (5 mL). The reaction mixture was stirred at rt for 12 h.
The reaction mixture was then filtered to remove the adsorbent. Evaporation
of the solvent and flash chromatographic purification on silica gel (ethyl ac-
etate/hexane, 3:7) afforded the corresponding sulfones 3a–e.
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-2,3,4,4a,5,
10b-hexahydro-S,S-dioxothiochromeno[4,3-b]pyran (3a):
69% yield; white solid; mp 116–118◦C; [α]D = +53.0 (c 0.1, CHCl3); IR
(neat, cm−1): 1453, 1305, 1101, 696; 1H NMR (CDCl3, 400 MHz): δ 7.92
(d, 1H, J = 7.6 Hz, Aromatic), 7.63–7.47 (m, 3H, Aromatic), 7.42–7.21 (m,
13H, Aromatic), 7.29–7.10 (m, 2H, Aromatic), 5.19 (d, 1H, J = 4.0 Hz, H-
1), 4.90–4.78 (m, 2H, CH2Ph), 4.74–4.62 (m, 2H, CH2Ph), 4.59–4.48 (m, 2H,
CH2Ph), 4.10–3.98 (m, 2H, H-3, H-7a), 3.84–3.66 (m, 4H, H-4, H-5, H-6a, H-6b)
3.42 (bd, 1H, J = 14.4 Hz, H-7b), 2.93–2.84 (m, 1H, H-2); 13C NMR (CDCl3,
100 MHz): δ 139.4, 138.1, 137.8, 137.6, 134.0, 132.9, 129.5, 128.5, 128.4, 128.3,
127.9, 127.8, 127.6, 123.7 (Aromatic), 78.1 (C-4), 77.3 (C-3) 74.3 (C-5), 74.1,
74.0, 73.4 (CH2Ph), 69.4 (C-1), 68.2 (C-6), 49.3 (C-7), 39.5 (C-2). The spectro-
scopic data were in agreement with the literature.[20]
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-methyl-2,
3,4,4a,5,10b-hexahydro-S,S-dioxothiochromeno[4,3-b]pyran (3b):
71% yield; white solid; mp 115–117◦C; [α]D = +6.5 (c 0.1, CHCl3); IR (neat,
1
cm−1): 1454.6, 1300.3, 1105.4, 754.1, 695.6 cm−1; H NMR (CDCl3, 400 MHz):
δ 7.79 (d, 1H, J = 8.0 Hz, Aromatic), 7.44–7.08 (m, 17H, Aromatic), 5.13 (d,
1H, J = 4.4 Hz, H-1), 4.89–4.50 (m, 6H, CH2Ph), 4.10–3.98 (m, 2H, H-3, H-
7a), 3.89–3.60 (m, 4H, H-4, H-5, H-6a, H-6b), 3.37 (bd, 1H, J = 3.0 Hz, H-7b),
2.93–2.80 (m, 1H, H-2), 2.36 (s, 3H, PhCH3); 13C NMR (CDCl3, 100 MHz):
δ 143.7, 138.1, 137.9, 137.6, 136.5, 133.9, 130.3, 128.6, 128.5, 128.4, 127.9,
127.8, 127.6, 123.7 (Aromatic), 78.0 (C-4), 77.3 (C-3), 74.3 (C-5), 74.1, 73.9, 73.4
(CH2Ph), 69.3 (C-1), 68.4 (C-6), 49.4 (C-7), 39.5 (C-2), 21.6 (PhCH3); HRMS
(ESI): m/z [M+Na]+ Calcd: 607.2131; Found: 607.2130.
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-7-methyl-2,
3,4,4a,5,10b-hexahydro-S-S-dioxothiochromeno[4,3-b]pyran (3c):
73% yield; white solid; mp 94–96◦C; [α]D = +21.5 (c 0.1, CHCl3); IR (neat,
1
cm−1): 454.3, 1300.1, 1149.9, 734.6, 695.3 cm−1; H NMR (CDCl3, 400 MHz):
δ 7.56–7.08 (m, 18H, Aromatic), 5.15 (d, 1H, J = 4.8 Hz, H-1), 4.90 (d, 1H, J
= 10.4 Hz, CHAHBPh), 4.83 (d, 1H, J = 10.4 Hz, CHAHBPh). 4.74 (d, 1H, J =
11.2 Hz, CHAHBPh), 4.66 (d, 1H, J = 12.0 Hz, CHAHBPh), 4.62–4.48 (m, 2H,
the rest of the CHAHBPh), 4.14–3.99 (m, 2H, H-3, H-7a), 3.79–3.65 (m, 4H, H-4,
H-5, H-6a, H-6b), 3.42 (dd, 1H, J = 3.2 Hz and 14.4 Hz, H-7b), 2.85–2.70 (m, 4H,

H. H. Kinfe et al.
200
H-2, PhCH3); 13C NMR (CDCl3, 100 MHz): δ 138.3, 137.8, 137.6, 137.4, 137.2,
134.4, 132.6, 132.3, 128.5, 128.4, 128.0, 127.8, 127.6, 125.9 (Aromatic), 78.9
(C-4), 74.6 (C-3), 74.2 (C-5, CH2Ph), 73.8, 73.5 (CH2Ph), 70.5 (C-1), 68.4 (C-
6), 51.3 (C-7), 39.7 (C-2), 19.6 (PhCH3); HRMS (ESI): m/z [M+NH4+]+ Calcd:
602.2571; Found: 602.2577.
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-tert-
butyl-2,3,4,4a,5,10b-hexahydro-S,S-dioxothiochromeno[4,3-b]
pyran (3d):
69% yield; white solid; 114–116◦C; [α]D = +44.0 (c 0.1, CHCl3); IR (neat,
1
cm−1): 1455.0, 1299.2, 1105.2, 749.9, 695.7 cm−1; H NMR (CDCl3, 400 MHz):
δ 7.83 (d, 1H, J = 8.4 Hz, Aromatic), 7.65 (s, 1H, Aromatic), 7.52 (d, 1H, J =
8.0 Hz, Aromatic), 7.40–7.08 (m, 15H, Aromatic), 5.18 (d, 1H, J = 4.8 Hz, H-1),
4.88 (d, 1H, J = 10.8 Hz, CHAHBPh), 4.81 (d, 1H, J = 10.8 Hz, CHAHBPh),
4.72 (d, 1H, J = 11.2 Hz, CHAHBPh), 4.64 (d, 1H, J = 12.0 Hz, CHAHBPh),
4.57 (d, 1H, J = 12.0 Hz, CHAHBPh), 4.51 (d, 1H, J = 11.2 Hz, CHAHBPh),
4.05 (dd, 1H, J = 7.8 Hz and 9.4 Hz, H-3), 3.98 (dd, 1H, J = 5.8 Hz and
14.2 Hz, H-7a), 3.83–3.56 (m, 4H, H-4, H-5, H-6a, H-6b), 3.41 (dd, 1H, J =
3.8 Hz and 14.2 Hz, H-7b), 2.88–2.69 (m, 1H, H-2), 1.28 (s, 9H, Ph(CH3)3);
13C NMR (CDCl3, 100 MHz): δ 156.8, 138.2, 137.8, 137.5, 136.5, 133.4, 128.5,
128.4, 128.0, 127.9, 127.7, 126.7, 125.0, 123.6 (Aromatic), 78.9 (C-4), 77.4 (C-3),
74.5 (C-5), 74.3, 74.1, 73.6 (CH2Ph), 70.1 (C-1), 68.6 (C-6), 49.6 (C-7), 40.1 (C-
2), 35.2 (PhC(CH3)3), 30.9 (PhC(CH3)3); HRMS (ESI): m/z [M+NH4+]+ Calcd:
644.3040; Found: 644.3038.
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-methoxy-
2,3,4,4a,5,10b-hexahydro-S-S-dioxothiochromeno[4,3-b]pyran (3e):
70% yield; white solid; 99–101◦C; [α]D = +39.5 (c 0.1, CHCl3); IR (neat,
1
cm−1): 1600.5, 1299.5, 1290.4, 1089.5, 744.8, 696.1 cm−1; H NMR (CDCl3,
400 MHz): δ 7.82 (d, 1H, J = 8.8 Hz, Aromatic), 7.50–7.04 (m, 16H, Aromatic),
7.00 (d, 1H, J = 9.2 Hz, Aromatic), 5.15 (d, 1H, J = 5.2 Hz, H-1), 4.91–4.70 (m,
3H, CH2Ph), 4.66–4.49 (m, 3H, CH2Ph), 4.07 (t, 1H, J = 8.8 Hz, H-3), 3.95 (dd,
1H, J = 5.2 Hz and 14.4 Hz, H-7a), 3.88–3.57 (m, 7H, H-4, H-5, H-6a, H-6b,
PhOCH3), 3.42 (dd, 1H, J = 3.2 Hz and 14.4 Hz, H-7b), 2.91–2.78 (m, 1H, H-2);
13C NMR (CDCl3, 100 MHz): δ 163.0, 138.2, 137.7, 137.6, 136.2, 131.3, 128.5,
128.4, 128.0, 127.8, 127.6, 125.8, 116.3, 111.6 (Aromatic), 79.1 (C-4), 77.4 (C-
3), 74.6 (C-5), 74.3, 74.1, 73.6 (CH2Ph), 70.2 (C-1), 68.7 (C-6), 55.5 (PhOCH3),
49.6 (C-7), 40.2 (C-2); HRMS (ESI): m/z [M+H+]+ Calcd: 601.2261; Found:
601.2272.
General Procedure for the Synthesis of Sulfones 5a–e
A solution of sulfone 3a–e (0.25 mmol) in DMF (1 mL) was added to a vig-
orously stirring suspension of sodium hydride (60% dispersion on oil, 15 mg,

New Carbohydrate-derived S,S-dioxothiochroman Derivatives
201
0.38 mmol) in DMF (1 mL) and the mixture was stirred at rt. After 15 min stir-
ring of the reaction mixture, water (10 mL) was added and the aqueous phase
was extracted with ethyl acetate (3 × 30 mL). The combined organic phases
were washed with brine and dried over MgSO4. After filtration and evapo-
ration of the solvent in vacuo, the crude product was purified by flash chro-
matography on silica gel (ethyl acetate/hexane, 3:7) to give the corresponding
epimerized sulfones 5a–e.
(2R,3S,4R,4aS,10bR)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-2,3,4,4a,5,
10b-hexahydro-S,S-dioxothiochromeno[4,3-b]pyran (5a):
87% yield; white solid; mp 98–100◦C; [α]D = +5.8 (c 0.5, CHCl3); IR (neat,
cm−1): 1304, 696; 1H NMR (CDCl3, 400 MHz): δ 7.95–7.05 (m, 19H, Aromatic),
4.96 (d, J = 11.2 Hz, 1H, CHAHBPh), 4.83 (d, J = 10.8 Hz, 1H, CHAHBPh),
4.75–4.50 (m, 4H, the rest of the CH2Ph), 4.38 (d, J = 10.4 Hz, 1H, H-1),
3.95–3.35 (m, 6H, H-6a, H-6b, H-4, H-5, H-7a, H-3), 2.91 (t, J = 13.0 Hz, 1H,
H-7b), 2.78–2.55 (m, 1H, H-2); 13C NMR: (CDCl3, 100 MHz): δ 137.9, 137.7,
137.4, 137.4, 135.0, 132.6, 129.0, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9,
127.8, 127.7, 127.0, 123.3 (Aromatic), 82.0 (C-3), 79.8 (C-5), 79.2 (C-4), 75.1
(CH2Ph), 75.0 (CH2Ph), 75.0 (C-1), 73.5 (CH2Ph), 68.8 (C-6), 50.8 (C-7), 42.2
(C-2); HRMS (ESI): m/z [M+NH4+]+ Calcd: 588.2420; Found: 588.2427.
(2R,3S,4R,4aS,10bR)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-methyl-
2,3,4,4a,5,10b-hexahydro-S,S-dioxothiochromeno[4,3-b]pyran (5b):
88% yield; white solid; mp 94–96◦C; [α]D = +3.5 (c 0.5, CHCl3); IR (neat,
1
cm−1): 1304, 697; H NMR (CDCl3, 400 MHz): δ 7.73 (d, J = 8.0 Hz, 1H, Aro-
matic), 7.52 (s, 1H, Aromatic), 7.45–7.10 (m, 16H, Aromatic), 4.96 (d, J =
11.2 Hz, 1H, CHAHBPh), 4.84 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.75–4.50 (m,
4H, the rest of the CH2Ph), 4.35 (d, J = 10.4 Hz, 1H, H-1), 3.95–3.40 (m, 6H, H-
6a, H-6b, H-4, H-5, H-7a, H-3), 2.91 (t, J = 12.8 Hz, 1H, H-7b), 2.75–2.55 (m, 1H,
H-2), 2.40 (s, 3H, PhCH3); 13C NMR: (CDCl3, 100 MHz): δ 143.4, 138.0, 137.7,
137.4, 134.9, 134.7, 129.7, 128.7, 128.5, 128.4, 128.2, 128.1, 127.9, 127.9,127.8,
127.7, 127.3, 123.4 (Aromatic), 82.1 (C-3), 79.8 (C-5), 79.3 (C-4), 75.1 (CH2Ph),
75.1 (CH2Ph), 75.0 (C-1), 73.4 (CH2Ph), 68.7 (C-6), 50.8 (C-7), 42.3 (C-2), 21.7
(PhCH3); HRMS (ESI): m/z [M+NH4+]+ Calcd: 602.2577; Found: 602.2569.
(2R,3S,4R,4aS,10bR)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-7-methyl-
2,3,4,4a,5,10b-hexahydro-S-S-dioxothiochromeno[4,3-b]pyran (5c):
85% yield; white solid; mp 151–152◦C; [α]D = +4.5 (c 0.5, CHCl3); IR (neat,
1
cm−1): 1304, 699; H NMR (CDCl3, 400 MHz): δ 7.60 (d, J = 7.6 Hz, 1H, Aro-
matic), 7.50–7.10 (m, 17H, Aromatic), 4.97 (d, J = 11.2 Hz, 1H, CHAHBPh),
4.84 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.75–4.50 (m, 4H, the rest of the CH2Ph),
4.30 (d, J = 10.4 Hz, 1H, H-1), 3.95–3.35 (m, 6H, H-6a, H-6b, H-4, H-5, H-7a,
H-3), 2.90 (t, J = 13.2 Hz, 1H, H-7b), 2.80–2.50 (m, 4H, H-2, PhCH3); 13C NMR:

H. H. Kinfe et al.
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(CDCl3, 100 MHz): δ 138.0, 137.7, 137.5, 136.6, 135.7, 135.3, 132.3, 131.7,
128.7, 128.5, 128.4, 128.2, 128.2, 127.9, 127.9, 127.8, 127.7, 125.1 (Aromatic),
82.0 (C-3), 79.8 (C-5), 79.2 (C-4), 75.5 (CH2Ph), 75.1 (CH2Ph), 75.0 (C-1), 73.5
(CH2Ph), 68.8 (C-6), 52.5 (C-7), 41.6 (C-2), 19.7 (PhCH3); HRMS (ESI): m/z
[M+NH4+]+ Calcd: 602.2571; Found: 602.2583.
(2R,3S,4R,4aS,10bR)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-tert-but-
yl-2,3,4,4a,5,10b-hexahydro-S,S-dioxothiochromeno[4,3-b]pyran
(5d):
94% yield; white solid; mp 159–161◦C; [α]D = +4.8 (c 0.5, CHCl3); IR (neat,
1
cm−1): 1301, 696; H NMR (CDCl3, 400 MHz): δ 7.85–7.68 (m, 2H, Aromatic),
7.49 (d, J = 8.4 Hz, 1H, Aromatic), 7.45–7.15 (m, 15H, Aromatic), 4.96 (d, J
= 11.6 Hz, 1H, CHAHBPh), 4.85 (d, J = 11.2 Hz, 1H, CHAHBPh), 4.75–4.50
(m, 4H, the rest of the CH2Ph), 4.37 (d, J = 10.4 Hz, 1H, H-1), 3.95–3.40 (m,
6H, H-6a, H-6b, H-4, H-5, H-7a, H-3), 2.90 (t, J = 13.2 Hz, 1H, H-7b), 2.75–2.55
(m, 1H, H-2), 1.31 (s, 9H, PhC(CH3)3); 13C NMR: (CDCl3, 100 MHz): δ 156.3,
138.1, 137.7, 137.4, 134.6, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.7,
127.7, 126.3, 123.6, 123.2 (Aromatic), 82.2 (C-3), 79.9 (C-5), 79.4 (C-4), 75.2
(CH2Ph), 75.1 (CH2Ph), 75.0 (C-1), 73.6 (CH2Ph), 68.9 (C-6), 50.8 (C-7), 42.4 (C-
2), 35.3 (PhC(CH3)3), 31.0 (PhC(CH3)3); HRMS (ESI): m/z [M+NH4+]+ Calcd:
644.3040; Found: 644.3049.
(2R,3S,4R,4aS,10bR)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-methoxy-
2,3,4,4a,5,10b-hexahydro-S-S-dioxothiochromeno[4,3-b]pyran (5e):
92% yield; white solid; mp 132–134◦C; [α]D = +3.6 (c 0.5, CHCl3); IR (neat,
1
cm−1): 1321, 646; H NMR (CDCl3, 400 MHz): δ 7.78 (d, J = 8.4 Hz, 1H, Aro-
matic), 7.50–7.10 (m, 16H, Aromatic), 6.96 (d, J = 8.4 Hz, 1H, Aromatic), 4.96
(d, J = 11.2 Hz, 1H, CHAHBPh), 4.75 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.75–4.50
(m, 4H, the rest of the CH2Ph), 4.36 (d, J = 10.4 Hz, 1H, H-1), 3.95–3.40 (m,
9H, PhOCH3, H-6a, H-6b, H-4, H-5, H-7a, H-3), 2.90 (t, J = 12.8 Hz, 1H, H-
7b), 2.75–2.55 (m, 1H, H-2); 13C NMR: (CDCl3, 100 MHz): δ 162.8, 138.0, 137.7,
137.4, 137.4, 129.5, 128.7, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.7, 125.5,
114.9, 111.6 (Aromatic), 82.2 (C-3), 79.8 (C-5), 79.3 (C-4), 75.1 (CH2Ph), 75.0
(CH2Ph), 74.9 (C-1), 73.5 (CH2Ph), 68.8 (C-6), 55.5 (PhOCH3), 50.9 (C-7), 42.4
(C-2); HRMS (ESI): m/z [M+NH4+]+ Calcd: 618.2526; Found: 618.2516.
ACKNOWLEDGMENT
We thank the University of Johannesburg for financial support.
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