Facile diastereoselective synthesis of carbohydrate-based thiochromans

Article abstract of DOI:10.1080/07328303.2012.762103

An efficient and novel diastereoselective thiochroman synthesis using the carbohydrate chiral pool via intramolecular Friedel-Crafts alkylation is presented. The scope and limitations of the method are investigated.Copyright Taylor and Francis Group, LLC.

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Facile Diastereoselective Synthesis of
Carbohydrate-Based Thiochromans
Henok H. Kinfe a , Paseka T. Moshapo a , Felix L. Makolo a & Alfred
Muller a
a Department of Chemistry, University of Johannesburg, Auckland
Park, 2006, South Africa
Published online: 12 Feb 2013.
To cite this article: Henok H. Kinfe , Paseka T. Moshapo , Felix L. Makolo & Alfred Muller (2013)
Facile Diastereoselective Synthesis of Carbohydrate-Based Thiochromans, Journal of Carbohydrate
Chemistry, 32:2, 139-157, DOI: 10.1080/07328303.2012.762103
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Journal of Carbohydrate Chemistry, 32:139–157, 2013
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Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2012.762103
Facile Diastereoselective
Synthesis of
Carbohydrate-Based
Thiochromans
Henok H. Kinfe, Paseka T. Moshapo, Felix L. Makolo,
and Alfred Muller
Department of Chemistry, University of Johannesburg, Auckland Park, 2006,
South Africa
An efficient and novel diastereoselective thiochroman synthesis using the carbohydrate
chiral pool via intramolecular Friedel-Crafts alkylation is presented. The scope and
limitations of the method are investigated.
Keywords Thiochroman; Carbohydrate; Friedel-Crafts Alkylation
INTRODUCTION
3,4-Dihydro-2H-1-benzothiopyranas, commonly known as thiochromans, are
privileged fused rings that have received special attention due to their pres-
ence as substructures in many interesting biologically active compounds, such
as those used in the treatment of depression, schizophrenia, Alzheimer’s dis-
ease, and Parkinson’s disease, as well as those with anticancer activity.[1–3]
Due to their important role in medicinal chemistry, these types of com-
pounds have attracted significant interest from synthetic organic chemists,
resulting in the development of a number of synthetic methodologies for the
synthesis of such compounds. The two strategies commonly employed for
the synthesis of thiochromans are (1) the thio-Claisen rearrangement of ally
phenyl sulfides[4,5] and (2) acid-catalyzed intermolecular cycloaddition of α,β-
unsaturated aldehydes with arylthiols.[2,6–10] Stereoselective thiochroman syn-
thesis can be achieved either via stereoselective derivitazation of a thiochro-
man[11–13] or through stereoselective cycloaddition reactions.[3,14–17] Although
Received July 31, 2012; accepted December 20, 2012.
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
139

H.H. Kinfe et al.
140
Figure 1: General structure of proposed carbohydrate-based thiochromans.
these strategies are efficient in terms of selectivity, the need for special cata-
lysts that are not readily or commercially available calls for the development of
new alternative strategies. These alternatives should be highly stereoselective
and utilize cheap and readily available substrates and/or catalysts to supple-
ment the existing methodologies. A possible strategy of the aforementioned
alternatives would involve the use of readily available chiral building blocks
such as carbohydrates, which are abundant renewable chiral building blocks
and employed extensively in the synthesis of valuable organic molecules.[18]
However, to the best of our knowledge, their use in the stereoselective syn-
thesis of thiochromans has not been explored and herein we report the first
example for diastereoselective synthesis of carbohydrate-based thiochromans
whose general structures are depicted in Figure 1.
In this context, we envisioned that the tricyclic unit of the thiochromans in
the general structures (Fig. 1) might be assembled starting from the glycosyl
iodoacetate, readily constructed using the protocol reported by Gammon and
coworkers for ring opening of cyclopropanated sugars,[19] followed by substitu-
tion of the iodide with a suitably substituted arylthiolate and intramolecular
Friedel-Crafts alkylation at the anomeric center as shown in Scheme 1. It was
expected that a glycosyl starting material would afford thiochroman 1 while a
mannosyl substrate would result in the formation of thiochroman 2.
Scheme 1: i) NaH, ArSH, DMF, rt, 5 min (see Table 1 for yields); ii) BF3·Et2O, DCM, 0◦C, 5 min
(see Table 1 for yields); iii) oxone, wet alumina, DCM, rt, overnight, 78%.
RESULT AND DISCUSSION
In achieving our goals, we started with glycosyl iodoacetate 3 synthesized from
α-1,2-cyclopropanated sugar[19] and thiophenol to establish optimum reaction

Synthesis of Carbohydrate-Based Thiochromans
141
conditions for the synthesis of the target thiochromans. Thus, sulfide 4a
(R1 = R2 = H) was prepared in 83% yield by reaction of glycosyl iodoacetate
3 with freshly prepared sodium thiophenolate in DMF at rt for 5 min (Sch. 1).
It is important to mention that prolonged reaction time of more than 10 min
resulted in formation of several by-products, lowering the yield of the desired
product. Treatment of sulfide 4a with BF3·Et2O in dry DCM in the presence of
molecular sieves at 0◦C for 5 min afforded thiochroman 5a in 69% yield as a
white solid having the glucose configuration (Sch. 1).
The structure of thiochroman 5a was established using 1H, 13C, and
NOESY NMR spectroscopies. The decrease in the integration of the aromatic
protons from 20 in iodoacetate 4a to 19 in thiochroman 5a, coupled with the
upfield shift of the anomeric proton to δH 5.13 and the disappearance of the
acetate group signal in the absence of any external nucleophile during the cy-
clization reaction, reasonably indicates intramolecular alkylation at C-1. This
was supported by 13C NMR spectroscopy, which displayed an upfield shift of
3
C-1. The anomeric configuration was determined by measuring the JH-1,H-2
3
coupling constant. The JH-1,H-2 coupling constant was found to be 5.6 Hz for
thiochroman 5a and corresponds to a gauche relationship between the H-1
and H-2 protons. Since the stereochemistry at C-2 is fixed, a gauche relation-
ship between H-1 and H-2 is possible if the H-1 proton is equatorially oriented
and, thus, confirms that the anomeric configuration of thiochroman 5a is α-
anomer.[20] Attempts to grow crystals of thiochroman 5a for absolute structure
determination using X-ray crystallography were unsuccessful. However, oxida-
tion of thiochroman 5a using excess oxone in the presence of wet alumina[21]
resulted in formation of sulfone 6 in 78% yield as white crystals. As only one
pure isomer is present from the synthesis, the compound crystallizes in the
noncentrosymmetric P212121 space group, with the Flack parameter indicat-
ing the correct isomer refined (Fig. 2). Ring puckering analysis[22] for the pyra-
◦
˚
˚
˚
nosyl ring gave q2 = 0.033(7) A, q3 = −0.584(6) A, Q = 0.585(6) A, θ = 177.1(7) ,
and ϕ = 263(11)◦, proving that it is a chair conformation, whereas the puck-
˚
ering analysis for the thiochroman ring gave q2 = 0.365(7) A, q3 = 0.332(6)
◦
◦
˚
˚
A, Q = 0.585(6) A, θ = 47.8(8) , and ϕ = 251.4(9) , proving an envelope con-
formation. The crystal structure is stabilized by several C-H . . . O and CH . . . π
interactions.[23]
To investigate the generality and scope of the synthetic methodology, sev-
eral ortho and para substituted arylthiols were tested. These provided the cor-
responding thiochromans in good to excellent yields. The results are summa-
rized in Table 1 (entries 1–6) with the products identified by 1H and 13C NMR
spectroscopy. Unfortunately, the cyclization resulted in a difficult-to-separate
mixture of products when para halide or meta substituted arylthiols were used.
A possible explanation for this could be due to the ortho-meta and ortho-para
directing competitions between the sulfur and the respective aryl substituents,
resulting in competitive Friedel-Crafts alkylations.

H.H. Kinfe et al.
142
Figure 2: Single X-ray crystal structure of sulfone 6, showing atom labeling and thermal
ellipsoids drawn at 50% probability.
Under similar reaction conditions and sequences, thiochromans 10a–e
(Table 1, entries 7–11), which have opposite stereochemistry at positions
C-1 and C-2 to those of thiochromans 5a–f (Table 1, entries 1–6), were obtained
as pure isomers with mannosyl iodoacetate 8 as starting material (Sch. 2). The
mannosyl iodoacetate 8 was prepared by opening of a β-1,2-cyclopropanated
sugar 7 with NIS in the presence of water as a nucleophyl.[24] This was fol-
lowed by acetylation of the anomeric hydroxyl group (Sch. 2). The structures
of the products were established the same way as thiochroman 5a. However,
it was not possible to determine the anomeric configuration of thiochromans
10a–e by simply measuring the 3JH-1,H-2 coupling constant since in both possi-
ble anomers, the H-1 and H-2 protons possess the gauche relationship, which
results in a small J value.[20] One way of proving the anomeric configuration is

Synthesis of Carbohydrate-Based Thiochromans
143
Scheme 2: i) a. NIS, H2O, THF, 50◦C, 12 h; b. Ac2O, DMAP, Et3N, rt, 30 min, 93%; ii) NaH, ArSH,
DMF, rt, 5 min (see Table 1 for yields); iii) BF3·Et2O, DCM, 0◦C, 5 min (see Table 1 for yields).
the size of the hetero-coupling constant 1JC-1,H-1 (>170 Hz for α-mannoside and
<160 Hz for β-mannoside).[20] Unfortunately, the C-1 of thiochromans 10a–e
overlapped with the other carbon signals, making it difficult to measure the
1
hetero-coupling constant JC-1,H-1. Therefore, crystals of thiochroman 10a–e
were grown from different solvent systems and the absolute structures and
anomeric configurations were determined using X-ray crystallography. The
anomeric configuration was proved to be a β-mannoside for all thiochromans
10a–e.
Concerning the proposed mechanism of the reaction, the formation of a
single thiochroman isomer product suggests the formation of an oxocarbenium
intermediate III formed via activation of the OAc leaving group by BF3·Et2O.
It is possible that the arylthiol moiety undergoes resonance[25] and attacks the
electrophilic anomeric center intramolecularly to form a six-membered ring as
shown in Scheme 3.
Selectivity in favor of the α-anomeric configuration for thiochromans 5a–f
could be explained in terms of the preference in the oxocarbenium intermedi-
ate for the 4H3 conformation VI (Sch. 4).[26] In this conformation the thiophenyl
Table 1: Results of the arylthiolate substitution and thiochroman syntheses.
Sulfides
Thiochromans
Product % Yield
Entry
Aromatic substituent
Product
% Yield
1
2
3
4
5
6
7
8
R1=R2= H
R1= H, R2= CH3
R1= CH3, R2= H
R1= H, R2= But
R1= H, R2= OCH3
naphtalene-2-thiol
R1=R2= H
4a
4b
4c
4d
4ea
4f
9a
9b
9c
9d
9e
83
87
87
93
—
86
95
80
93
93
78
5a
5b
5c
5d
5e
5f
10a
10b
10c
10d
10e
69
71
73
69
70
68
75
83
94
70
92
R1= H, R2= CH3
R1= CH3, R2= H
R1= H, R2= But
R1= H, R2= OCH3
9
10
11
aSulfide 4e was unstable on standing and thus it was immediately cyclized without purification.

H.H. Kinfe et al.
144
Scheme 3: Proposed mechanism for the formation of the carbohydrate-based
thiochromans.
Scheme 4: Preferred conformation of oxocarbenium intermediate of a glucosyl pyranose.
moiety is prepositioned for intramolecular delivery from the α-face of the
sugar.
In the case of the mannose analog, the selectivity for the β-anomer could
be due to the intramolecular thiophenyl delivery to the β-face of the preferred
3H4 oxocarbenium conformer VIIb (Sch. 5).[26,27] The formation of the β-anomer
Scheme 5: Possible conformations of oxocarbenium intermediate of a mannosyl pyranose.

Synthesis of Carbohydrate-Based Thiochromans
145
thiochromans 10a–e and the absence of formation of a twisted boat thiochro-
4
man as a result of nucleophilic attack at the β-face of the H3 conformer VIIa
suggests that the preferred conformation of the oxocarbenium intermediate in
the mannose analogs is the 3H4 conformer. This preference of the oxocarbenium
conformation is in agreement with the literature reports.[26,27] The stability of
3
the H4 conformer is attributed to the stabilization of the positive charge by
the C-3, C-4, and C-5 axially oriented alkoxy groups.[27a]
CONCLUSION
In conclusion, we have demonstrated an efficient synthetic protocol for di-
astereoselective preparation of novel carbohydrate-based thiochromans in
which the orientation of the substituent at C-2 of the starting pyranosyl ac-
etate induces the stereochemistry of the thiochroman products. 1α,2α-aryl-C-
glycoside and 1β,2β−aryl-C-mannoside-type thiochromans (1 and 2 in Fig. 1)
were successfully synthesized as pure isomers from glycosyl and mannosyl
iodoacetate substrates, respectively. To the best of our knowledge, this is the
first report whereby a carbohydrate chiral pool is employed in diastereoselec-
tive synthesis of thiochromans. Besides the investigation of the synthesized
thiochromans and their derivatives in medicinal chemistry, we are currently
also investigating their use in the Corey-Chaykovsky reaction for asymmetric
epoxidation and in the synthesis of the rather difficult cis-2-C-branched-aryl-
C-glycosides and mannosides.
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 monitored by
thin layer chromatography (TLC) on aluminum-backed Merck 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% sulfuric 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 Thermovar hot-stage microscope and are uncorrected. Optical rotations
were determined 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 standard

H.H. Kinfe et al.
146
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
1
shifts are reported in ppm. Anomeric ratios are calculated from the H NMR
spectroscopy of the crude product. Mass spectrometers were recorded on a
Walters API Quattro Micro spectrometer at the University of Stellenbosch,
South Africa.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-C-iodomethyl-α and-β-D-gluco
pyranoses (3)
This was synthesized according to the protocol reported by Gammon et al.
and the spectroscopic data were in agreement with the literature reports.[19]
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-C-iodomethyl-α-D-mannopyra
nose (8)
To a solution of the β-1,2-cyclopropanated sugar 7 (2.55 mg, 5.92 mmol)
in 30 mL of THF-H2O (2:1), NIS (1.91 mg, 7.89 mmol) was added. The result-
ing mixture was stirred at 50◦C for 12 h.[23] The residue was then taken up in
ethyl acetate; washed successively with 10% Na2S2O3, water, and brine; and
dried over MgSO4. The crude product was redissolved in DCM (20 mL) and
treated with Et3N (3 mL), a catalytic amount of DMAP, and Ac2O (3 mL),
and the resulting solution was then stirred at rt. After 30 min, the reaction
mixture was diluted with DCM, washed successively with water and brine,
and then dried over MgSO4. The crude product was purified by column chro-
matography (ethyl acetate/petroleum ether, 5:95) to give the title compound in
93% yield as a colorless oil; [α]D = +13.7 (c 0.5, CHCl3); IR (neat, cm−1): 1752,
1
1496, 1453, 1226, 1096, 1026, 954, 735, 695.3; H NMR (CDCl3, 400 MHz):
δ 7.40–7.10 (m, 15H, aromatic), 6.32 (s, 1H, H-1), 4.78 (d, J = 10.8 Hz, 1
H, CHAHBPh), 4.70–4.56 (m, 3H, CHAHBPh), 4.53–4.40 (m, 2H, CHAHBPh),
4.00–3.88 (m, 1H, H-3), 3.83–3.55 (m, 5H, H-5, H-4, H-6a, H-6b and H-7a), 3.11
(t, J = 10.8 Hz, 1H, H-7b), 2.60–2.45 (m, 1H, H-2), 2.05 (s, 3H, OCOCH3); 13C
NMR (CDCl3, 100 MHz): δ 168.9 (OCOCH3), 138.1, 137.9, 128.5, 128.4, 128.4,
128.0, 127.8, 127.7 (aromatic), 93.9 (C-1), 79.1 (C-3), 74.9 (CH2Ph), 73.8 (C-4),
73.5 (CH2Ph), 73.4 (C-5), 72.0 (CH2Ph), 68.5 (C-6), 45.8 (C-2), 21.0 (OCOCH3),
0.2 (C-7); HRMS (ESI): m/z [M+Na]+ Calcd 639.1220; found: 639.1224.
General procedure for the substitution of the iodoacetates
with arylthiols
To a solution of arylthiol (1.62 mmol) in DMF (20 mL), sodium hydride
(60% dispersion on oil, 47 mg, 1.62 mmol) was added and the mixture was

Synthesis of Carbohydrate-Based Thiochromans
147
vigorously stirred at rt for 5–10 min under nitrogen. A solution of iodoacetate
3 or 8 (900 mg, 1.35 mmol) in DMF (2 mL) was then added and after 5-min
stirring of the reaction mixture, methanol (3 mL) was added dropwise and the
resulting clear solution was concentrated in vacuo. The solution was directly
submitted to silica gel chromatography (ethyl acetate/petroleum ether, 2:8) to
give the corresponding sulfides:
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-phenylthiomethyl-D-gluc
opyranosyl (4a): 83% yield, 1:3 α:β anomeric mixture; colorless oil; IR
(CHCl3, cm−1): 1752, 1483, 1452, 1137, 699; 1H NMR (CDCl3, 400 MHz) for β-
anomer: δ 7.46–7.03 (m, 20H, aromatic), 5.66 (d, J = 9.2 Hz, 1H, H-1), 4.93 (d,
J = 10.8 Hz, 1H, CHAHBPh), 4.79 (d, J = 10.4 Hz, 1H, CHAHBPh), 4.75–4.40
(m, 4H, the rest of the CH2Ph), 3.90–3.70 (m, 5H, H-3, H-4, H-5, H-6a and
H-6b), 3.27 (dd, J = 3.6 and 13.2 Hz, 1H, H-7a), 3.18 (d, J = 13.2 Hz, 1H, H-7b),
2.32–2.18 (m, 1H, H-2), 1.98 (s, 3H, OCOCH3); 13C NMR (CDCl3, 100 MHz) for
β-anomer: δ 168.9 (OCOCH3), 138.1, 137.9, 137.8, 136.7, 129.8, 129.0, 128.4,
128.3, 127.9, 127.8, 127.7, 126.4 (aromatic), 93.1 (C-1), 80.3 (C-4), 79.0 (C-3),
75.4 (C-5), 74.9 (CH2Ph), 73.6 (CH2Ph), 73.5 (CH2Ph), 73.0 (C-6), 46.1 (C-2),
1
31.4 (C-7), 20.9 (OCOCH3); H NMR (CDCl3, 400 MHz) for α-anomer: δ 6.42
(s, 1H, H-1), 4.98 (d, J = 11.2 Hz, 1H, CHAHBPh), 3.44 (d, J = 13.2 Hz, 1H,
H-7a), 2.57 (t, J = 12.4 Hz, 1H, H-7b), 2.05 (s, 3H, OCOCH3); 13C NMR (CDCl3,
100 MHz) for α-anomer: δ 168.9 (OCOCH3), 137.7, 135.6, 128.9, 128.5, 128.3,
128.0, 127.7, 127.6, 126.0 (aromatic), 92.0 (C-1), 80.2 (C-4), 78.8 (C-3), 75.3 (C-
5), 74.9 (CH2Ph), 73.7 (CH2Ph), 73.5 (CH2Ph), 68.1 (C-6), 44.4 (C-2), 30.6 (C-7),
20.9 (OCOCH3); HRMS (ESI): m/z [M+Na]+ Calcd 621.2287; found: 621.2289.
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-(4-methylphenyl)thiomet
hyl-D-glucopyranosyl (4b): 87% yield; 1:3 α:β anomeric mixture; colorless
oil; IR (CHCl3, cm−1): 1749, 1494, 1454, 1091, 699; 1H NMR (CDCl3, 400 MHz)
for α-anomer: δ 7.51–7.05 (m, 19H, aromatic), 6.43 (bs, 1H, H-1), 4.96 (d, J =
11.2 Hz, 1H, CHAHBPh), 4.79 (d, J = 10.4 Hz, 1H, CHAHBPh), 4.75–4.42 (m,
4H, the rest of the CH2Ph), 3.95–3.62 (m, 5H, H-3, H-4, H-5, H-6a and H-6b),
3.40 (d, J = 13.2 Hz, 1H, H-7a), 2.58 (t, J = 12.4 Hz, 1H, H-7b), 2.32 (s, 3H,
ArCH3), 2.95–2.18 (m, 1H, H-2), 2.05 (s, 3H, OCOCH3); 13C NMR (CDCl3,
100 MHz) for α-anomer: δ 169.0 (OCOCH3), 138.1, 137.9, 137.7, 136.2, 131.8,
130.6, 129.7, 128.4, 128.3, 127.9, 127.8, 127.7 (aromatic), 92.0 (C-1), 78.9
(C-4), 78.8 (C-3), 75.3 (C-5), 74.9 (CH2Ph), 73.5 (CH2Ph), 73.0 (CH2Ph), 68.1
1
(C-6), 44.3 (C-2), 31.4 (C-7), 20.9 (OCOCH3), 20.8 (ArCH3); H NMR (CDCl3,
400 MHz) for β-anomer: δ 5.68 (d, J = 8.8 Hz, 1H, H-1), 3.27 (d, J = 11.6 Hz,
1H, H-7a), 3.15 (d, J = 12.8 Hz, H-7b), 1.98 (s, 3H, OCOCH3); 13C NMR (CDCl3,
100 MHz) for β-anomer: δ 169.0 (OCOCH3), 137.8, 136.5, 132.9, 129.7, 128.4,
128.5, 128.3, 128.1, 128.0, 127.8, 127.7, 127.6 (aromatic), 93.1 (C-1), 80.3 (C-4),
79.8 (C-3), 75.4 (C-5), 75.2 (CH2Ph), 74.6 (CH2Ph), 73.4 (CH2Ph), 46.1 (C-2),
32.1 (C-7), 20.9 (OCOCH3) 20.8 (ArCH3); HRMS (ESI): m/z [M+Na]+ Calcd
635.2444; found: 635.2444.

H.H. Kinfe et al.
148
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-(2-methylphenyl)thiomet
hyl-D-glucopyranosyl (4c): 87% yield; 1:3 α:β anomeric mixture; colorless
oil; IR (CHCl3, cm−1): 1752, 1496, 1455, 1130, 698; 1H NMR (CDCl3, 400 MHz)
for β-anomer: δ 7.45–7.05 (m, 19H, aromatic), 5.70 (d, J = 8.8 Hz, 1H, H-1),
4.94 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.80 (d, J = 10.4 Hz, 1H, CHAHBPh),
4.75–4.40 (m, 4H, the rest of the CH2Ph), 3.95–3.55 (m, 5H, H-3, H-4, H-5,
H-6a and H-6b), 3.24 (d, J = 10.8 Hz, 1H, H-7a), 3.17 (d, J = 12.8 Hz, 1H, H-7b),
2.40 (s, 3H, ArCH3), 2.30–2.21 (m, 1H, H-2), 2.00 (s, 3H, OCOCH3); 13C NMR
(CDCl3, 100 MHz) for β-anomer: δ 169.0 (OCOCH3), 138.0, 137.9, 137.8, 135.8,
130.2, 128.4, 128.3, 128.0, 127.9, 127.8, 126.5, 126.1 (aromatic), 93.2 (C-1),
80.5 (C-4), 79.0 (C-3), 75.4 (C-5), 75.4 (CH2Ph), 74.7 (CH2Ph), 73.5 (CH2Ph),
68.1 (C-6), 45.9 (C-2), 30.6 (C-7), 20.9 (OCOCH3), 20.5 (ArCH3); 1H NMR
(CDCl3, 400 MHz) for α-anomer: δ 6.40 (bs, 1H, H-1), 4.98 (d, J = 10.8 Hz, 1H,
CHAHBPh), 3.41 (d, J = 13.2 Hz, 1H, H-7a), 2.56 (t, J = 12.2 Hz, 1H, H-7b),
2.32 (s, 3H, ArCH3), 2.06 (s, 3H, OCOCH3); 13C NMR (CDCl3, 100 MHz) for
α-anomer: δ 169.0 (OCOCH3), 137.9, 137.8, 137.4, 134.9, 129.0, 128.5, 127.7,
127.6, 127.4, 126.5, 126.4, 125.6 (aromatic), 92.0 (C-1), 80.3 (C-4), 78.9 (C-3),
75.4 (C-5), 74.9 (CH2Ph), 73.6 (CH2Ph), 73.0 (CH2Ph), 68.1 (C-6), 44.2 (C-2),
29.7 (C-7), 20.9 (OCOCH3), 20.3 (ArCH3); HRMS (ESI): m/z [M+Na]+ Calcd
635.2444; found: 635.2444.
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-(4-tert-butylphenyl)thio
methyl-D-glucopyranosyl (4d): 93% yield; 1:3 α:β anomeric mixture; col-
1
orless oil; IR (CHCl3, cm−1): 1750, 1498, 1454, 1130, 698; H NMR (CDCl3,
400 MHz) for β-anomer: δ 7.45–7.21 (m, 19H, aromatic), 5.67 (d, J = 8.8 Hz,
1H, H-1), 4.92 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.80 (d, J = 10.4 Hz, 1H,
CHAHBPh), 4.75–4.38 (m, 4H, the rest of the CH2Ph), 3.92–3.55 (m, 5H, H-3,
H-4, H-5, H-6a and H-6b), 3.29 (d, J = 12.0 Hz, 1H, H-7a), 3.20–3.11 (m, 1H, H-
7b), 2.37–2.18 (m, 1H, H-2), 1.96 (s, 3H, OCOCH3), 1.28 (s, 9H, ArC(CH3)3); 13
C
NMR (CDCl3, 100 MHz) for β-anomer: δ 169.0 (OCOCH3), 149.3, 142.2, 138.1,
137.9, 137.7, 130.2, 129.4, 128.5, 128.4, 128.3, 128.0, 127.8, 126.0 (aromatic),
93.2 (C-1), 80.6 (C-4), 80.4 (C-3), 75.9 (C-5), 75.3 (CH2Ph), 74.9 (CH2Ph), 74.2
(CH2Ph), 70.6 (C-6), 44.6 (C-2), 34.4 (ArC(CH3)3), 32.0 (C-7), 31.2 (ArC(CH3)3),
20.9 (OCOCH3); 1H NMR (CDCl3, 400 MHz) for α-anomer: δ 6.42 (bs, 1H, H-1),
4.97 (d, J = 11.2 Hz, 1H, CHAHBPh), 3.45 (d, J = 13.2 Hz, 1H, H-7a), 2.57 (t, J
= 12.2 Hz, 1H, H-7b), 2.04 (s, 3H, OCOCH3), 1.30 (s, 9H, ArC(CH3)3); 13C NMR
(CDCl3, 100 MHz) for α-anomer: δ 168.8 (OCOCH3), 149.7, 138.2, 138.1, 137.9,
133.1, 132.0, 131.2, 128.8, 128.3, 128.0, 127.7, 127.6, 126.0, 125.8 (aromatic),
92.1 (C-1), 80.4 (C-4), 79.0 (C-4), 75.5 (C-5), 75.2 (CH2Ph), 74.6 (CH2Ph), 73.6
(CH2Ph), 68.3 (C-6), 44.6 (C-2), 36.6 (ArCCH3), 32.0 (C-7), 31.3 (ArC(CH3)3),
20.9 (OCOCH3); HRMS (ESI): m/z [M+Na]+ Calcd 677.2913; found: 677.2899.
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-(2-naphtalene)thiometh
yl-D-glucopyranosyl (4f): 86% yield; 1:3 α:β anomeric mixture; yellow oil;
1
IR (CHCl3, cm−1): 1723, 1497, 1453, 1130, 695; H NMR (CDCl3, 400 MHz)

Synthesis of Carbohydrate-Based Thiochromans
149
for β-anomer: δ 7.85–7.12 (m, 22H, aromatic), 5.72 (d, J = 8.8 Hz, 1H, H-1),
4.94 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.79 (d, J = 10.4 Hz, 1H, CHAHBPh),
4.74–4.42 (m, 4H, the rest of CH2Ph), 3.95–3.51 (m, 5H, H-3, H-4, H-5, H-6a
and H-6b), 3.34 (d, J = 13.2 Hz, 1H, H-7a), 3.26 (d, J = 12.8 Hz, 1H, H-7b),
2.39–2.24 (m, 1H, H-2), 1.90 (s, 3H, OCOCH3); 13C NMR (CDCl3, 100 MHz) for
β-anomer: δ 169.1 (OCOCH3), 138.0, 137.9, 134.1, 133.7, 133.1, 131.8, 128.4,
128.3, 127.8, 127.7, 127.1, 126.6, 125.8 (aromatic), 93.2 (C-1), 80.4 (C-4), 79.0
(C-3), 75.4 (C-5), 74.9 (CH2Ph), 73.6 (CH2Ph), 73.1 (C-6), 46.0 (C-2), 31.2 (C-
1
7), 20.9 (OCOCH3); H NMR (CDCl3, 400 MHz) for α-anomer: δ 6.46 (bs, 1H,
H-1), 5.01 (d, J = 11.2 Hz, 1H, CHAHBPh), 2.70–2.59 (m, 1H, H-7b), 2.05 (s,
3H, OCOCH3); 13C NMR (CDCl3, 100 MHz) for α-anomer: δ 169.1 (OCOCH3),
138.0, 137.9, 134.1, 133.7, 133.1, 131.8, 128.4, 128.3, 127.8, 127.7, 127.1, 126.6,
125.8 (aromatic), 92.0 (C-1), 80.2 (C-4), 79.0 (C-3), 75.3 (C-5), 74.7 (CH2Ph),
73.5 (CH2Ph), 73.1 (C-6), 44.4 (C-2), 30.4 (C-7), 20.9 (OCOCH3); HRMS (ESI):
m/z [M+Na]+ Calcd 671.2444; found: 671.2439.
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-phenylthiomethyl-α-D
-mannopyranosyl (9a): 95% yield, colorless oil; [α]D = +49.6 (c 0.5, CHCl3);
1
IR (neat, cm−1): 1749, 1496, 1454, 1363, 1096, 1025, 695; H NMR (CDCl3,
400 MHz): δ 7.50–7.10 (m, 20H, aromatic), 6.44 (s, 1H, H-1), 4.83 (d, J =
10.4 Hz, 1H, CHAHBPh), 4.64 (d, J = 12.0 Hz, 1H, CHAHBPh), 4.55–4.35 (m,
4H, the rest of the CH2Ph), 4.10–3.96 (m, 1H, H-3), 3.88–3.72 (m, 3H, H-5, H-4
and H-6a), 3.65 (d, J = 10.4 Hz, 1H, H-6b), 3.52 (d, J = 14.0 Hz, 1H, H-7a),
2.90–2.78 (m, 1H, H-7b), 2.45–2.30 (m, 1H, H-2), 2.04 (s, 3H, OCOCH3); 13C
NMR (CDCl3, 100 MHz): δ 169.0 (OCOCH3), 138.1, 138.0, 137.9, 135.5, 130.2,
128.9, 128.4, 128.3, 128.0, 127.8, 127.7, 127.6, 127.5, 126.4 (aromatic), 93.3 (C-
1), 78.3 (C-3), 75.0 (CH2Ph), 73.9 (C-4), 73.6 (CH2Ph), 73.5 (CH2Ph), 71.8 (C-5),
68.5 (C-6), 41.7 (C-2), 29.7 (C-7), 21.0 (OCOCH3); HRMS (ESI): m/z [M+Na]+
Calcd 621.2287; found 621.2287.
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-(4-methylphenyl)thiome
thyl-α-D-mannopyranosyl (9b): 80% yield; colorless oil; [α]D = +19.9 (c 0.5,
1
CHCl3); IR (neat, cm−1): 1749, 1494, 1454, 1367, 1094, 1026, 697; H NMR
(CDCl3, 400 MHz): δ 7.45–6.95 (m, 19H, aromatic), 6.43 (s, 1H, H-1), 4.81 (d,
J = 10.8 Hz, 1H, CHAHBPh), 4.62 (d, J = 12.4 Hz, 1H, CHAHBPh), 4.60–4.30
(m, 4H, the rest of the CH2Ph), 4.01–3.90 (m, 1H, H-3), 3.85–3.55 (m, 4H, H-5,
H-4, H-6a and H-6b), 3.44 (d, J = 13.6 Hz, 1H, H-7a), 2.80–2.72 (m, 1H, H-7b),
2.40–2.23 (m, 4H, H-2 and ArCH3), 2.02 (s, 3H, OCOCH3); 13C NMR (CDCl3,
100 MHz): δ 169.0 (OCOCH3), 138.2, 138.1, 137.9, 136.7, 131.7, 131.2, 129.8,
128.4, 128.4, 128.3, 128.0, 127.8, 127.7, 127.7, 127.6, 127.5 (aromatic), 93.4
(C-1), 78.3 (C-3), 75.0 (CH2Ph), 73.9 (C-4), 73.6 (CH2Ph), 73.5 (CH2Ph), 71.5
(C-5), 68.6 (C-6), 41.6 (C-2), 30.5 (C-7), 21.1 (ArCH3), 21.0 (OCOCH3); HRMS
(ESI): m/z [M+Na]+ Calcd 635.2443; found 635.2446.
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-(2-methylphenyl)thiomet
hyl-α-D-mannopyranosyl (9c): 93% yield; colorless oil; [α]D = +23.0 (c 0.5,

H.H. Kinfe et al.
150
1
CHCl3); IR (neat, cm−1): 1749, 1496, 1454, 1366, 1098, 1026, 697; H NMR
(CDCl3, 400 MHz): δ 7.50–6.90 (m, 19H, aromatic), 6.45 (s, 1H, H-1), 4.83 (d,
J = 10.4 Hz, 1H, CHAHBPh), 4.63 (d, J = 12.0 Hz, 1H, CHAHBPh), 4.60–4.35
(m, 4H, the rest of the CH2Ph), 4.10–3.94 (m, 1H, H-3), 3.90–3.70 (m, 3H,
H-4, H-5 and H-6a), 3.64 (d, J = 10.0 Hz, 1H, H-6b), 3.48 (d, J = 13.2 Hz, 1H,
H-7a), 2.88–2.76 (m, 1H, H-7b), 2.45–2.20 (m, 4H, H-2 and ArCH3), 2.03 (s,
3H, OCOCH3); 13C NMR (CDCl3, 100 MHz): δ 169.0 (OCOCH3), 138.6, 138.1,
138.0, 137.9, 134.7, 130.3, 129.2, 128.4, 128.4, 128.0, 127.9, 127.8, 127.8, 127.7,
127.6, 127.5, 126.4, 126.2 (aromatic), 93.3 (C-1), 78.4 (C-3), 75.1 (CH2Ph), 74.0
(C-4), 73.6 (CH2Ph), 73.5 (CH2Ph), 71.8 (C-5), 68.5 (C-6), 41.6 (C-2), 28.7 (C-7),
21.1 (ArCH3), 20.4 (OCOCH3); HRMS (ESI): m/z [M+Na]+ Calcd 635.2443;
found 635.2438.
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-(4-tert-butylphenyl)thio
methyl-α-D-mannopyranosyl (9d): 93% yield; colorless oil; [α]D = +25.8 (c
0.5, CHCl3); IR (neat, cm−1): 1750, 1496, 1454, 1364, 1099, 1025, 697; 1H NMR
(CDCl3, 400 MHz): δ 7.45–7.05 (m, 19H, aromatic), 6.42 (s, 1H, H-1), 4.82 (d,
J = 10.4 Hz, 1H, CHAHBPh), 4.62 (d, J = 12.0 Hz, 1H, CHAHBPh), 4.55–4.30
(m, 4H, the rest of the CH2Ph), 4.04–3.91 (m, 1H, H-3), 3.85–3.72 (m, 3H, H-5,
H-4 and H-6a), 3.64 (d, J = 10.4 Hz, 1H, H-6b), 3.46 (d, J = 14.0 Hz, 1H, H-7a),
2.81–2.75 (m, 1H, H-7b), 2.45–2.25 (m, 1H, H-2), 2.03 (s, 3H, OCOCH3), 1.27
(s, 9H, (ArC(CH3)3); 13C NMR (CDCl3, 100 MHz): δ 169.0 (OCOCH3), 149.8,
138.2, 138.1, 137.9, 132.0, 130.5, 128.4, 128.4, 128.0, 127.8, 127.7, 127.7, 127.6,
127.6, 126.0 (aromatic), 93.4 (C-1), 78.3 (C-3), 75.0 (CH2Ph), 73.9 (C-4), 73.6
(CH2Ph), 73.5 (CH2Ph), 71.5 (C-5), 68.6 (C-6), 41.7 (C-2), 34.4 (ArC(CH3)3),
31.2 (ArC(CH3)3), 30.2 (C-7), 21.1 (OCOCH3); HRMS (ESI): m/z [M+Na]+
Calcd 677.2913; found 677.2910.
1-O-Acetyl-3,4,6-tri-O-benzyl-2-deoxy-2-C-(4-methoxyphenyl)thiom
ethyl-α-D-mannopyranosyl (9e): 78% yield; colorless oil; [α]D = +12.0
(c 0.5, CHCl3); IR (neat, cm−1): 1746, 1591, 1493, 1454, 1366, 1096, 1026,
697; 1H NMR (CDCl3, 400 MHz): δ 7.50–7.05 (m, 17H, aromatic), 6.79 (d,
J = 8.4 Hz, 2H, aromatic), 6.45 (s, 1H, H-1), 4.80 (d, J = 10.8 Hz, 1H,
CHAHBPh), 4.61 (d, J = 12.0 Hz, 1H, CHAHBPh), 4.60–4.47 (m, 2H, 2 ×
CHAHBPh), 4.35 (d, J = 11.4 Hz, 1H, CHAHBPh), 4.26 (d, J = 11.4 Hz, 1H,
CHAHBPh), 4.05–3.90 (m, 1H, H-3), 3.85–3.70 (m, 6H, H-5, H-4, ArOCH3
and H-6a), 3.63 (d, J = 10.4 Hz, 1H, H-6b), 3.34 (d, J = 14.0 Hz, 1H, H-7a),
2.84–2.62 (m, 1H, H-7b), 2.36–2.24 (m, 1H, H-2), 2.03 (s, 3H, OCOCH3); 13C
NMR (CDCl3, 100 MHz): δ 169.0 (OCOCH3), 159.2, 138.1, 138.1, 137.9, 134.2,
128.4, 128.4, 128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 127.6, 127.6, 127.5,
125.6, 114.6 (aromatic), 93.4 (C-1), 78.3 (C-3), 75.1 (CH2Ph), 73.9 (C-4), 73.6
(CH2Ph), 73.5 (CH2Ph), 71.2 (C-5), 68.6 (C-6), 55.3 (ArOCH3), 41.3 (C-2), 31.7
(C-7), 21.0 (OCOCH3); HRMS (ESI): m/z [M+Na]+ Calcd 651.2392; found
651.2394.

Synthesis of Carbohydrate-Based Thiochromans
151
General procedure for the synthesis of the thiochromans
A sulfide, 4a–f or 9a–e (0.69 mmol), was dissolved in dry dichloromethane
˚
(3 mL) under an atmosphere of nitrogen and stirred together with 4A molec-
ular sieves at rt for 1 h. The mixture was cooled down to 0◦C and then
treated dropwise with BF3·Et2O (1 mL of 48% BF3 solution in diethylether,
8.02 mmol). After stirring at this temperature for 5 min, Et3N (0.7 mL) was
added and the solids removed by filtration through a Celite bed. The solution
was then diluted with water (10 mL) and the aqueous phase was extracted
with dichloromethane. The combined organic phases were successively washed
with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, fil-
tered, and evaporated. The residue was purified by column chromatography
on silica gel (ethyl acetate/petroleum ether, 1:9) to yield the corresponding
thiochromans:
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-2,3,4,
4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (5a): 69% yield; white
solid; mp 91–95◦C; [α]D = −125.0 (c 0.1, CHCl3); IR (neat, cm−1): 1452, 1082,
694; 1H NMR (CDCl3, 400 MHz): δ 7.53 (d, J = 7.2 Hz, 1H, aromatic), 7.42–7.30
(m, 13H, aromatic), 7.13–7.03 (m, 5H, aromatic), 5.13 (d, J = 5.6 Hz, 1H, H-1),
4.96 (d, J = 11.0 Hz, 1H, CHAHBPh), 4.85 (d, J = 11.0 Hz, 1H, CHAHBPh),
4.78 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.70 (d, J = 12.0 Hz, 1H, CHAHBPh),
4.60–4.58 (m, 2H, the rest of the CHAHBPh), 4.03 (t, J = 13.2 Hz, 1H, H-3),
3.88–3.69 (m, 3H, H-4, H-6a and H-6b), 3.47 (d, J = 9.2 Hz, 1H, H-5), 3.35 (bd,
J = 13.2 Hz, 1H, H-7a), 3.19 (dd, J = 3.6 and 13.6 Hz, 1H, H-7b), 2.62–2.50
(m, 1H, H-2); 13C NMR (CDCl3, 100 MHz): δ 138.7, 138.0, 134.4, 131.4, 128.5,
127.9, 127.8, 127.7, 127.6, 126.3, 124.8 (aromatic), 80.0 (C-4), 78.7 (C-3), 75.9
(CH2Ph), 74.8 (CH2Ph), 73.5 (CH2Ph), 72.8 (C-5), 72.4 (C-1), 68.9 (C-6), 38.4
(C-2), 26.4 (C-7); HRMS (ESI): m/z [M+H]+ Calcd 539.2256; found: 539.2259.
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-met
hyl-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (5b): 71% yield;
white solid; mp 105–107◦C; [α]D = +91.0 (c 0.1, CHCl3); IR (neat, cm−1):
1
1453, 1108, 695; H NMR (CDCl3, 400 MHz): δ 7.45–7.20 (m, 14H, aromatic),
7.18–7.06 (m, 2H, aromatic), 7.02–6.88 (m, 2H, aromatic), 5.09 (d, J = 5.6 Hz,
1H, H-1), 4.95 (d, J = 11.0 Hz, 1H, CHAHBPh), 4.85 (d, J = 11.0 Hz, 1H,
CHAHBPh), 4.78 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.71 (d, J = 9.2 Hz, 1H,
CHAHBPh), 4.60–4.48 (m, 2H, the rest of the CHAHBPh), 4.03 (t, J = 9.8 Hz,
1H, H-3), 3.80–3.68 (m, 3H, H-4, H-6a and H-6b), 3.59–3.49 (m, 1H, H-5), 3.33
(bd, J = 11.2 Hz, 1H, H-7a), 3.18 (dd, J = 3.8 Hz and 13.6 Hz, 1H, H-7b),
2.60–2.49 (m, 1H, H-2), 2.23 (s, 3H, ArCH3); 13C NMR (CDCl3, 100 MHz): δ
138.1, 134.5, 131.2, 130.6, 128.6, 128.5, 128.4, 128.0, 127.8, 127.7, 127.6, 126.2
(aromatic), 80.1 (C-4), 78.8 (C-3), 75.9 (CH2Ph), 74.8 (CH2Ph), 73.4 (CH2Ph),
72.8 (C-5), 72.5, (C-1) 69.1 (C-6), 38.6 (C-2), 26.5 (C-7), 21.0 (ArCH3) HRMS
(ESI): m/z [M+H]+ Calcd 553.2412; found: 553.2410.

H.H. Kinfe et al.
152
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-7-met
hyl-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (5c): 73% yield;
white solid; mp 119–121◦C; [α]D = +127.0 (c 0.1, CHCl3); IR (neat, cm−1): 1496,
1
1406, 1140, 694; H NMR (CDCl3, 400 MHz): δ 7.50–7.20 (m, 14H, aromatic),
7.18–7.19 (m, 2H, aromatic), 7.05–6.95 (m, 2H, aromatic), 5.17 (d, J = 5.2 Hz,
1H, H-1), 4.97 (d, J = 11.0 Hz, 1H, CHAHBPh), 4.88 (d, J = 11.0 Hz, 1H,
CHAHBPh), 4.79 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.71 (d, J = 12.0 Hz, 1H,
CHAHBPh), 4.62–4.48 (m, 2H, the rest of the CHAHBPh), 4.04 (t, J = 9.8 Hz,
1H, H-3), 3.80–3.60 (m, 3H, H-4, H-6a and H-6b), 3.47 (d, J = 9.2 Hz, 1H,
H-5), 3.38–3.20 (m, 2H, H-7a and H-7b), 2.60–2.52 (m, 1H, H-2), 2.23 (s, 3H
ArCH3); 13C NMR (CDCl3, 100 MHz): δ 138.7, 138.0, 137.9, 134.3, 133.9, 131.4,
128.7, 128.5, 128.4, 127.9, 127.8, 127.7, 125.0, 124.0 (aromatic), 79.9 (C-4), 78.6
(C-3), 75.8 (CH2Ph), 74.7 (CH2Ph), 73.4 (CH2Ph), 72.7 (C-5), 72.6 (C-1), 68.8
(C-6), 37.9 (C-7), 26.0 (C-2), 20.1 (ArCH3); HRMS (ESI): m/z [M+H]+ Calcd
553.2412; found: 553.2415.
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-tert
-butyl-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (5d): 69%
yield; white solid; mp 157–159◦C; [α]D = +92.0 (c 0.1, CHCl3); IR (neat, cm−1):
1
1478, 1134, 1103, 697; H NMR (CDCl3, 400 MHz): δ 7.61 (s, 1H, aromatic),
7.42–7.21 (m, 13H, aromatic), 7.18–7.07 (m, 3H, aromatic), 6.97 (d, J =
8 Hz, 1H, aromatic), 5.13 (d, J = 5.6 Hz, 1H, H-1), 4.96 (d, J = 11.2 Hz, 1H,
CHAHBPh), 4.87 (d, J = 11.2 Hz, 1H, CHAHBPh), 4.77 (d, J = 10.8 Hz, 1H,
CHAHBPh), 4.68 (d, J = 12.0 Hz, 1H, CHAHBPh), 4.56 (d, J = 12.0 Hz, 1H,
CHAHBPh), 4.48 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.04 (t, J = 9.8 Hz, 1H, H-3),
3.79–3.18 (m, 3H, H-4, H-6a and H-6b), 3.55–3.48 (m, 1H, H-5), 3.34 (bd, J =
13.6 Hz, 1H, H-7a), 3.18 (dd, J = 3.6 and 13.2 Hz, 1H, H-7b), 2.10–2.08 (m,
1H, H-2), 1.24 (s, 9H, ArC(CH3)3); 13C NMR (CDCl3, 100 MHz): δ 148.0, 138.8,
138.0, 137.9, 130.7, 128.5, 128.4, 128.0, 127.9, 127.8, 127.7, 125.9, 124.8,
124.6 (aromatic), 80.3 (C-4), 78.8 (C-3), 75.9 (CH2Ph), 74.9 (CH2Ph), 73.6
(CH2Ph), 73.0 (C-5), 72.7 (C-1), 69.1 (C-6), 38.7 (C-7), 34.4 (ArC(CH3)3), 31.2
(ArC(CH3)3), 26.3 (C-2); HRMS (ESI): m/z [M+H]+ Calcd 595.2882; found:
595.2880.
(2R,3S,4R,4aS,10bS)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-met
hoxy-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (5e): 70%
yield; white solid; mp 130–132◦C; [α]D = +111.0 (c 0.1, CHCl3); IR (neat,
cm−1): 1472, 1134, 1103, 698; 1H NMR (CDCl3, 400 MHz): δ 7.42–7.20 (m, 13H,
aromatic), 7.17–7.11 (m, 3H, aromatic), 6.96 (d, J = 8.4 Hz, 1H, aromatic),
6.71 (d, J = 8.4 Hz, 1H, aromatic), 5.09 (d, J = 5.6 Hz, 1H, H-1), 4.96 (d, J =
11.0 Hz, 1H, CHAHBPh), 4.87 (d, J = 11.0 Hz, 1H, CHAHBPh), 4.79 (d, J =
10.8 Hz, 1H, CHAHBPh), 4.66 (d, J = 12.0 Hz, 1H, CHAHBPh), 4.52 (m, 2H,
the rest of the CHAHBPh), 4.05 (t, J = 9.8 Hz, 1H, H-3), 3.80–3.72 (m, 3H,
H-4, H-6a and H-6b), 3.66 (s, 3H, ArOCH3), 3.53 (m, 1H, H-5), 3.33 (bd, J =
13.2 Hz, 1H, H-7a), 3.18 (dd, J = 3.6 and 13.6 Hz, 1H, H-7b), 2.62–2.51 (m, 1H,

Synthesis of Carbohydrate-Based Thiochromans
153
H-2); 13C NMR (CDCl3, 100 MHz): δ 157.5, 138.7, 138.0, 132.5, 128.4, 128.3,
128.0, 127.7, 127.3, 124.8, 115.2, 112.0 (aromatic), 80.2 (C-4), 78.8 (C-3), 75.9
(CH2Ph), 74.8 (CH2Ph), 73.6 (CH2Ph), 73.0 (C-5), 72.6 (C-1), 69.2 (C-6), 55.3
(ArOCH3), 38.6 (C-7), 26.5 (C-2); HRMS (ESI): m/z [M+H]+ Calcd 569.2361;
found: 569.2354.
(2R,3S,4R,4aS,10bS) - 3,4 - bis(benzyloxy) - 2 - (benzyloxymethyl) - 2,
3,4,4a,5,12c-hexahydro-1H-dibenzo[c,f ]thiochromeno[4,3-b]pyran (5f):
68% yield; yellow solid; mp 154–156◦C; [α]D = +91.0 (c 0.1, CHCl3); IR (neat,
cm−1): 1496, 1363, 1124, 1071, 697; 1H NMR (CDCl3, 400 MHz): δ 8.00 (d, J =
8.4 Hz, 1H, aromatic), 7.69 (d, J = 7.6 Hz, 1H, aromatic), 7.57 (d, J = 8.8 Hz,
1H, aromatic), 7.49–7.18 (m, 17H, aromatic), 7.10 (d, J = 8.4 Hz, 1H, aromatic),
4.98 (d, J = 10.8 Hz, 1H, H-1), 4.96–4.72 (m, 2H, CHAHBPh), 4.69 (d, J =
11.0 Hz, 1H, CHAHBPh), 4.61 (d, J = 11.0 Hz, 1H, CHAHBPh), 4.54 (d, J =
11.6 Hz, CHAHBPh), 4.48 (d, J = 11.6 Hz, CHAHBPh), 4.00–3.91 (m, 1H, H-3),
3.85 (d, J = 10.4 Hz, 1H, H-6a), 3.80–3.63 (m, 2H, H-4 and H-6b), 3.60–3.52
(m, 1H, H-5), 3.12 (d, J = 12.4 Hz, 1H, H-7a), 2.73 (t, J = 12.4 Hz, 1H, H-
7b), 2.65–2.50 (m, 1H, H-2); 13C NMR (CDCl3, 100 MHz): δ 138.0, 128.7, 128.6,
128.5, 128.5, 128.2, 128.0, 127.8, 127.5, 126.2, 125.6, 125.2, 124.5 (aromatic),
85.0 (C-4), 80.4 (C-3), 80.3 (C-1), 76.2 (CH2Ph), 75.3 (CH2Ph), 75.0 (CH2Ph),
73.4 (C-5), 69.6 (C-6), 46.3 (C-7), 25.3 (C-2); HRMS (ESI): m/z [M+H]+ Calcd
589.2412; found: 589.2402.
(2R,3S,4R,4aR,10bR)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-2,3,
4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (10a): 75% yield; white
solid; mp 87–89◦C; [α]D = +35.2 (c 0.5, CHCl3); IR (neat, cm−1): 1454, 1361,
1
1075, 1010, 694; H NMR (CDCl3, 400 MHz): δ 7.45–6.95 (m, 19H, aromatic),
4.88 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.75 (d, J = 11.6 Hz, 1H, CHAHBPh),
4.68–4.40 (m, 4H, the rest of the CH2Ph), 4.35 (s, 1H, H-1), 4.00–3.85 (m, 1H,
H-3), 3.80–3.55 (m, 4H, H-6a, H-6b, H-5 and H-4), 3.26 (t, J = 12.6 Hz, 1H, H-
7a), 2.96 (bd, J = 12.4 Hz, 1H, H-7b), 2.70–2.50 (m, 1H, H-2); 13C NMR (CDCl3,
100 MHz): δ 138.4, 138.3, 138.0, 134.1, 133.3, 131.2, 128.7, 128.5, 128.3, 128.3,
127.9, 127.8, 127.7, 127.6, 127.5, 126.4, 124.1 (aromatic), 82.9 (C-3), 79.9 (C-
4), 75.1 (CH2Ph), 74.6 (C-1), 74.3 (C-5), 73.4 (CH2Ph), 71.3 (CH2Ph), 69.4 (C-
6), 39.0 (C-2), 21.3 (C-7); HRMS (ESI): m/z [M+Na]+ Calcd 539.2256; found
539.2260.
(2R,3S,4R,4aR,10bR) - 3,4 - bis(benzyloxy) - 2 - (benzyloxymethyl) - 9
-methyl-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (10b): 83%
yield; white solid; mp 101–103◦C; [α]D = +29.9 (c 0.5, CHCl3); IR (neat, cm−1):
1485, 1455, 1369, 1072, 1027, 698; 1H NMR (CDCl3, 400 MHz): δ 7.45–6.90 (m,
18H, aromatic), 4.87 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.74 (d, J = 11.6 Hz,
1H, CHAHBPh), 4.68–4.40 (m, 4H, the rest of the CH2Ph), 4.31 (s, 1H, H-1),
4.00–3.85 (m, 1H, H-3), 3.82–3.55 (m, 4H, H-6a, H-6b, H-5 and H-4), 3.25 (t,
J = 12.6 Hz, 1H, H-7a), 2.94 (bd, J = 12.4 Hz, 1H, H-7b), 2.70–2.50 (m, 1H,
H-2), 2.27 (s, 3H, ArCH3); 13C NMR (CDCl3, 100 MHz): δ 138.3, 138.2, 138.0,

H.H. Kinfe et al.
154
133.8, 130.9, 130.4, 129.8, 128.5, 128.4, 128.3, 128.0, 127.8, 127.7, 127.5, 126.2
(aromatic), 83.0 (C-3), 79.8 (C-4), 75.1 (CH2Ph), 74.5 (C-1), 74.4 (C-5), 73.4
(CH2Ph), 71.2 (CH2Ph), 69.4 (C-6), 39.1 (C-2), 21.2 (C-7), 20.7 (ArCH3); HRMS
(ESI): m/z [M+Na]+ Calcd 553.2413; found 553.2422.
(2R,3S,4R,4aR,10bR) - 3,4 - bis(benzyloxy) - 2 - (benzyloxymethyl) - 7
-methyl-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (10c): 94%
yield; white solid; mp 82–84◦C; [α]D = +25.2 (c 0.5, CHCl3); IR (neat, cm−1):
1455, 1361, 1072, 1029, 696; 1H NMR (CDCl3, 400 MHz): δ 7.50–6.90 (m,
18H, aromatic), 4.88 (d, J = 10.8 Hz, 1H, CHAHBPh), 4.75 (d, J = 11.6 Hz,
1H, CHAHBPh), 4.68–4.42 (m, 4H, the rest of the CH2Ph), 4.37 (s, 1H, H-1),
4.40–3.85 (m, 1H, H-3), 3.81–3.55 (m, 4H, H-6a, H-6b, H-5 and H-4), 3.24 (t,
J = 12.8 Hz, 1H, H-7a), 3.03 (bd, J = 12.4 Hz, 1H, H-7b), 2.70–2.50 (m, 1H,
H-2), 2.25 (s, 3H, ArCH3); 13C NMR (CDCl3, 100 MHz): δ 138.3, 138.2, 138.0,
134.3, 133.4, 131.0, 130.8, 130.0, 128.5, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6,
127.5, 123.5 (aromatic), 82.8 (C-3), 79.8 (C-4), 75.1 (CH2Ph), 74.7 (C-1), 74.5 (C-
5), 73.4 (CH2Ph), 71.2 (CH2Ph), 69.4 (C-6), 38.5 (C-2), 21.2 (C-7), 19.3 (ArCH3);
HRMS (ESI): m/z [M+Na]+ Calcd 553.2413; found 553.2411.
(2R,3S,4R,4aR,10bR)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-te
rt-butyl-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (10d): 70%
yield; white solid; mp 83–84◦C; [α]D = +32.4 (c 0.5, CHCl3); IR (neat, cm−1):
1454, 1361, 1072, 1030, 696; 1H NMR (CDCl3, 400 MHz): δ 7.50–7.00 (m,
18H, aromatic), 4.91 (d, J = 10.4 Hz, 1H, CHAHBPh), 4.77 (d, J = 11.6 Hz,
1H, CHAHBPh), 4.70–4.45 (m, 4H, the rest of the CH2Ph), 4.37 (s, 1H, H-1),
4.00–3.60 (m, 5H, H-3, H-6a, H-6b, H-5 and H-4), 3.29 (t, J = 12.6 Hz, 1H,
H-7a), 2.98 (bd, J = 12.4 Hz, 1H, H-7b), 2.70–2.50 (m, 1H, H-2), 1.31 (s, 9H,
(ArC(CH3)3); 13C NMR (CDCl3, 100 MHz): δ 147.1, 138.3, 138.3, 138.0, 130.6,
130.6, 130.0, 128.4, 128.3, 128.2, 128.0, 127.7, 127.7, 127.7, 127.6, 127.4, 126.3,
126.0 (aromatic), 83.0 (C-3), 79.9 (C-4), 75.1 (CH2Ph), 74.6 (C-1), 74.6 (C-5),
73.4 (CH2Ph), 71.2 (CH2Ph), 69.4 (C-6), 39.2 (C-2), 34.2 (ArC(CH3)3), 31.2
(ArC(CH3)3), 21.2 (C-7); HRMS (ESI): m/z [M+Na]+ Calcd 595.2882; found
595.2888.
(2R,3S,4R,4aR,10bR)-3,4-bis(benzyloxy)-2-(benzyloxymethyl)-9-met
hoxy-2,3,4,4a,5,10b-hexahydrothiochromeno[4,3-b]pyran (10e): 92%
yield; yellow solid; mp 106–108◦C; [α]D = +30.5 (c 0.5, CHCl3); IR (neat, cm−1):
1483, 1454, 1369, 1062, 1028, 698; 1H NMR (CDCl3, 400 MHz): δ 7.50–7.10 (m,
15H, aromatic), 7.03 (d, J = 8.8 Hz, 1H, aromatic), 6.86 (s, 1H, aromatic) 6.78
(d, J = 8.4 Hz, 1H, aromatic), 4.87 (d, J = 10.4 Hz, 1H, CHAHBPh), 4.75 (d,
J = 11.6 Hz, 1H, CHAHBPh), 4.68–4.40 (m, 4H, the rest of the CH2Ph), 4.32
(s, 1H, H-1), 4.00–3.55 (m, 8H, H-3, ArOCH3, H-6a, H-6b, H-5 and H-4), 3.24
(t, J = 12.6 Hz, 1H, H-7a), 2.94 (bd, J = 12.4 Hz, 1H, H-7b), 2.70–2.50 (m, 1H,
H-2); 13C NMR (CDCl3, 100 MHz): δ 156.7, 138.3, 138.2, 138.0, 132.0, 128.5,
128.3, 128.3, 128.0, 127.8, 127.7, 127.5, 127.3, 124.8, 117.6, 116.2 (aromatic),
82.9 (C-3), 79.9 (C-4), 75.1 (CH2Ph), 74.5 (C-1 and C-5), 73.4 (CH2Ph), 71.2

Synthesis of Carbohydrate-Based Thiochromans
155
(CH2Ph), 69.4 (C-6), 55.4 (ArOCH3), 39.3 (C-2), 21.3 (C-7); HRMS (ESI): m/z
[M+Na]+ Calcd 569.2362; found 569.2357.
Sulfone 6
The sulphide 5a (130 mg, 0.24 mmol) was added to a vigorously stirring
suspension of wet alumina (650 mg wetted with 70 μL of water) and OXONE
(1.19 g, 1.92 mmol) and the reaction mixture was stirred at rt overnight. Af-
ter allowing the mixture to cool to rt, it was filtered to remove the adsorbent.
Evaporation of the solvent and flash-chromatographic purification on silica gel
(ethyl acetate/petroleum ether, 2:8) gave sulfone 6 in 78% yield; white solid;
crystallization from the DCM-hexane solvent system gave clear crystals; 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 7.56 (d, J = 8.4 Hz, 1H, aromatic), 7.63–7.48
(m, 3H, aromatic), 7.40–7.20 (m, 13H, aromatic), 7.18–7.10 (m, 2H, aromatic),
5.19 (d, J = 4.0 Hz, 1H, H-1), 4.85 (d, J = 10.6 Hz, 1H, CHAHBPh), 4.80
(d, J = 10.6 Hz, 1H, CHAHBPh), 4.72 (d, J = 11.2 Hz, 1H, CHAHBPh), 4.66
(d, J = 12.0 Hz, 1H, CHAHBPh), 4.62–4.54 (m, 2H, the rest of the CHAHBPh),
4.11–3.96 (m, 2H, H-3, H-4), 3.84 (m, 1H, H-5), 3.78–3.67 (m, 3H, H-6a, H-6b
and H-7a), 3.42 (bd, J = 14.4 Hz, 1H, H-7b), 2.95–2.80 (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-3 and C-4), 74.3
(CH2Ph), 74.1 (CH2Ph), 74.0 (CH2Ph), 73.4 (C-5), 69.4 (C-1), 68.2 (C-6), 49.3
(C-2), 39.5 (C-7); HRMS (ESI): m/z [M+Na]+ Calcd 593.1974; found: 593.1740.
ACKNOWLEDGMENT
We thank the University of Johannesburg for financial support and Prof. CW
Holzafel for valuable discussions and advice on this manuscript.
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