Tuning the stereoelectronic properties of 1-sulfanylhex-1-enitols for the sequential stereoselective synthesis of 2-deoxy-2-iodo-β- d -allopyranosides

Article abstract of DOI:10.1021/jo5001912

The preparation of challenging 2-deoxy-2-iodo-β-d-allo precursors of 2-deoxy-β-d-ribo-hexopyranosyl units and other analogues is reported using a robust olefination-cyclization-glycosylation sequence. Here, we particularly focus on tuning the stereoelectronic properties of the alkenyl sulfides intermediates in order to improve the diastereoselectivity of the cyclization step and, hence, the efficiency of the overall transformation. Phosphine oxides with the general formula Ph₂P(O)CH₂SR (R = t-Bu, Cy, p-MeOPh, 2,6-di-ClPh, and 2,6-di-MePh) were easily synthesized and subsequently used in the olefination reaction with 2,3,5-tri-O-benzyl-d-ribose and -d-arabinose. The corresponding sugar-derived alkenyl sulfides were submitted to a 6-endo [I⁺]-induced cyclization, and the resulting 2-deoxy-2-iodohexopyranosyl-1-thioglycosides were used as glycosyl donors for the stereoselective synthesis of 2-deoxy-2-iodohexopyranosyl glycosides. Among the different S-groups studied, t-Bu derivative was the best performer for the synthesis of cholesteryl 2-deoxy-2-iodomannopyranosides, whereas for the synthesis of 2-deoxy-2-iodoallopyranosides none of the derivatives here studied proved superior to the phenyl analogue previously described. Glycosylation of cholesterol with different d-allo and d-manno derivatives produced 2-deoxy-2-iodoglycosides with stereoselectivities in the same order in each case, reinforcing the involvement of an oxocarbenium ion as the common intermediate of this crucial glycosylation step.

Full text of DOI:10.1021/jo5001912

Article
pubs.acs.org/joc
Tuning the Stereoelectronic Properties of 1‑Sulfanylhex-1-enitols for
the Sequential Stereoselective Synthesis of 2‑Deoxy-2-iodo-
β‑D‑allopyranosides
Andrea Kover, Omar Boutureira,* M. Isabel Matheu, Yolanda Díaz,* and Sergio Castillon
́
́
̈
Departament de Química Analítica i Química Organ
Spain
̀
ica, Universitat Rovira i Virgili, C/Marcel·lí Domingo s/n, 43007 Tarragona,
S
* Supporting Information
ABSTRACT: The preparation of challenging 2-deoxy-2-iodo-β-D-allo precursors of 2-deoxy-β-D-ribo-hexopyranosyl units and
other analogues is reported using a robust olefination−cyclization−glycosylation sequence. Here, we particularly focus on tuning
the stereoelectronic properties of the alkenyl sulfides intermediates in order to improve the diastereoselectivity of the cyclization
step and, hence, the efficiency of the overall transformation. Phosphine oxides with the general formula Ph2P(O)CH2SR (R = t-
Bu, Cy, p-MeOPh, 2,6-di-ClPh, and 2,6-di-MePh) were easily synthesized and subsequently used in the olefination reaction with
2,3,5-tri-O-benzyl-D-ribose and -D-arabinose. The corresponding sugar-derived alkenyl sulfides were submitted to a 6-endo [I+]-
induced cyclization, and the resulting 2-deoxy-2-iodohexopyranosyl-1-thioglycosides were used as glycosyl donors for the
stereoselective synthesis of 2-deoxy-2-iodohexopyranosyl glycosides. Among the different S-groups studied, t-Bu derivative was
the best performer for the synthesis of cholesteryl 2-deoxy-2-iodomannopyranosides, whereas for the synthesis of 2-deoxy-2-
iodoallopyranosides none of the derivatives here studied proved superior to the phenyl analogue previously described.
Glycosylation of cholesterol with different D-allo and D-manno derivatives produced 2-deoxy-2-iodoglycosides with
stereoselectivities in the same order in each case, reinforcing the involvement of an oxocarbenium ion as the common
intermediate of this crucial glycosylation step.
was further refined to develop a one-pot procedure13 directly
INTRODUCTION
■
from the corresponding alkenes, and it was also applied to the
synthesis of pyranoid glycals of restricted availability14 (e.g., D-
allal, D-gulal) and 2-iodoglycals15 to access unnatural 2-C-sugar
mimetics16 and further extended to other electrophiles (e.g.,
PhSe+) leading to 2-deoxy-2-phenylselenenylglycosides.17
Alternative methods for fine-tuning the reactivity of such
vinyl chalcogenides by replacing the sulfur atom with a
selenium to alter the stereochemical properties of this moiety
toward the electrophile-induced cyclization were also ex-
plored.18 This would ultimately promote the mild activation
of the anomeric leaving group at lower temperatures, which has
proven to be a key issue to afford better selectivities in the
glycosylation step. In all these studies, we observed that during
the iodonium-induced cyclization of alkenes, the Z-alkene
cyclizes much more slowly than the E-isomer or does not
cyclize at all, limiting the efficiency of the cyclization step.
Attempts to improve this E-selectivity by using metal-mediated
cross-metathesis protocols were recently explored in our group
2-Deoxy- and 2,6-dideoxy-β-D-ribo-hexopyranosyl units are
structural motifs present in many natural products of plant
origin.1 They are present in cardiac glycosides,2 appetite
suppressants,3 and synthetic, biologically active nucleosides and
nucleotides.4 Despite recent advances in the preparation of 2-
deoxy- and 2,6-dideoxyglycosides,5 those with an all-cis C2−
C3−C4 β-D-ribo configuration (directly accessed from 2-deoxy-
2-iodo-β-D-allo)6 remain challenging structures. Methods
typically employed for their preparation involve the use of D-
allal derivatives with Ph3P·HBr7 or Re(V)8 catalysts, 2-deoxy9
and other specialized 2,6-anhydro-2,6-dideoxy-2,6-dithio glyco-
syl donors,10 and de novo metal-mediated protocols.11 In this
context, our group developed a general two-step procedure for
synthesizing 2-deoxy-2-iodo-1-thioglycosides from furanoses
which were used as glycosyl donors for the synthesis of 2-
deoxyglycosides, being particularly efficient for those with β-D-
allo and xylo configurations12 (Scheme 1). The first step is an
olefination of furanoses to obtain a Z/E mixture of sulfanyl
alkene derivatives, which undergo an NIS-induced cyclization
reaction in a second step to give 2-deoxy-2-iodo-1-thioglyco-
sides in a regio- and stereoselective manner. This methodology
Received: January 25, 2014
Published: March 10, 2014
© 2014 American Chemical Society
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(HWE), and Peterson olefination.12 The best results in terms
of chemoselectivity and yield of alkene were obtained under
WH conditions, that is, using phosphine oxide carbanions
formed by Li−bases, although, as expected for semistabilized
carbanions, the alkene product was always obtained as a Z/E
mixture, which was inseparable (Scheme 1).
Scheme 1. General Strategy for the Preparation of
Representative (C-3eq/ax) 2-Deoxy-2-iodo-D-manno- and
-allopyranosyl Glycosides after Fine Tuning the
Stereoelectronic Properties of Key 1-Sulfanylhex-1-enitol
Intermediates
To increase the E stereoselectivity of the olefination and the
efficiency of the cyclization, and eventually the overall 2-
deoxyglycoside synthesis, we decided to study the influence of
substituents at sulfur on the stereoselectivity of the olefination
using a phenyl, substituted phenyl, tert-butyl, cyclohexyl, etc.
RESULTS AND DISCUSSION
■
Synthesis and Reactivity of Phosphine Oxides with
Model Carbonyl Compounds. For this study to be done, we
first needed to have in our hands a series of (sulfanylmethyl)-
diphenylphosphine oxides. The most common procedure for
preparing phosphine oxide derivatives is the Michaelis−
Arbuzov reaction,21 which consists of reacting an O-ethyl
diphenylphosphinite with an electrophilic reagent, typically an
alkyl halide. (Sulfanylmethyl)diphenylphosphine oxides22 have
been prepared by the Arbuzov reaction with available
chloromethyl thioethers23 (e.g., phenylsulfanyl 3a with R =
Ph), although these halides are usually unstable and difficult to
prepare. An alternative procedure for synthesizing these
phosphine oxides involves reacting methyldiphenylphosphine
oxide with n-BuLi in the presence of an electrophilic
heteroatomic reagent. These reagents, however, are rarely
available and must be specifically prepared.24 (Sulfanylmethyl)-
diphenylphosphine oxides can also be accessed from
(tosyloxymethyl)diphenylphosphine oxide 225 (directly ob-
tained from 1) by a substitution reaction with sulfur
nucleophiles22 (Scheme 2).
This method was considered the procedure of choice for the
preparation of a variety of (sulfanylmethyl)diphenylphosphine
oxides since the most common thiolates can be easily prepared
in situ by deprotonation of readily available thiols. Thus,
starting from (tosyloxymethyl)diphenylphosphine oxide 2,
phosphine oxides 3b−g were prepared in excellent yields (up
to 98%). We first explored the olefination of benzaldehyde 4
using phosphine oxides 3b−g to give sulfanyl alkenes 7b−g.
Highly hindered sulfanyl alkenes 7b,c and 7e,f were obtained
with good to excellent yields (up to 93%). High stereo-
selectivities (Z/E ≥ 1:9) were obtained when aliphatic alkyl
but resulted unsuccessful in terms of selectivity (1:1 Z/E
mixtures were typically obtained).19 Various reagents had been
utilized in the olefination of furanoses, including Wittig,12,20
Wittig−Horner12 (WH), Horner−Wadsworth−Emmons12
Scheme 2. Synthesis of (Sulfanylmethyl)diphenylphosphine Oxides 3b−g and Their Reactivity toward Model Carbonyl
a
Compounds 4−6
a
Reagents and conditions: (a) TsCl, DMAP, CH2Cl2, reflux, 4 h, 95% (see ref 25); (b) LDA was used as a base; (c) isolated yield; (d) Z/E ratio.
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groups and 2,6-disubstituted aryl substituents were used. Only
the p-methoxyphenylsulfanyl derivative 3d furnished alkene
product 7d with low stereoselectivity. The formation of α-
hydroxyphosphine oxide intermediates was not observed in
these syntheses. Phosphine oxide 3b, which bears a tert-
butylsulfanyl group, was made to react with acetophenone 5 to
give sulfanyl alkene 8 with excellent yield (92%) and
stereoselectivity (Z/E 1:10). The configurational assignment
Particularly relevant are the Z/E ratios ranging from 1:25 up
to 1:50 obtained with phosphine oxides 3b and 3e (Table 1,
entries 2 and 4). Olefination of 2,3,5-tri-O-benzyl-D-arabinofur-
anose 13 with (sulfanylmethyl)diphenylphosphine oxides
3a,b,d−f was further explored (Table 1, entries 6−10).
Obtaining a high E-stereoselectivity in the olefination reaction
of arabino derivatives is especially important as in the
cyclization step of the Z/E-alkene of such a configuration
only the E-alkene cyclizes, thus limiting the efficiency of the
entire process.12 WH olefination of 13 with tert-butyl derivative
3b afforded compound 14b in excellent yield (93%) and with
an improved E-selectivity (Table 1, entry 7) compared to those
obtained with phenyl derivative 3a (Table 1, entry 6). WH
reaction with p-methoxy derivative 3d produced sulfanyl alkene
14d with poor yield and stereoselectivity (Table 1, entry 8). In
this case, the best stereoselectivity (Z/E = 1:12) was obtained
with 2,6-dimethylphenyl derivative 3e, although the isolated
yield of 14e was comparably lower than that for 14b (Table 1,
entries 7 vs 9). WH olefination with dichlorophenyl derivative
3f furnished sulfanyl alkene 14f with a practical 78% yield and
stereoselectivity (Table 1, entry 10). Thus, all sulfanylmethyl
phosphine oxides led to the corresponding alkenes with
improved E-stereoselectivity related to that of the reference
phenylsulfanyl-substituted olefinating agent 3a (Table 1, entry
6). Among the different derivatives, tert-butyl derivative 3b
seems to combine better yield and stereoselectivity followed by
the 2,6-dimethylphenyl derivative 3e.
1
of 8 was carried out by comparison with the experimental H
NMR data reported, where the chemical shift for the vinyl
proton geminal to the sulfur moiety in the E alkene is
unshielded related to that of the Z alkene.26 Phosphine oxides
3c and 3e were also treated with cyclohexanone 6 in the
presence of n-BuLi to give sulfanyl alkenes 9 and 10 in excellent
93% and 89% yields, respectively.
Olefination of Furanoses. With these results in hand, we
turned our attention to the olefination of furanoses. First, 2,3,5-
tri-O-benzyl-D-ribose 11 was allowed to react with
(sulfanylmethyl)diphenylphosphine oxides 3a−c,e,f in the
presence of n-BuLi or LDA at −78 °C (Table 1, entries 1−
a
Table 1. Olefination of Furanoses 11, 13 to 12, 14
Cyclization Reaction. The sulfanylhex-1-enitols prepared
were tested in electrophile-induced cyclization reactions to
study whether the presence of the different S-alkyl or S-aryl
groups influence the yield and the selectivity of the 6-endo
cyclization reaction. To this end, we selected S-2,6-
dimethylphenyl- and S-tert-butyl-substituted ribo-hex-1-enitols
12b and 12e, which were obtained with the best Z/E ratio in
the previous olefination experiments. The cyclization reactions
were performed under standard conditions, with NIS in the
presence of sodium bicarbonate in dichloromethane, starting at
−60 °C, and allowing the temperature to increase until the
cyclization reactions started. The results are summarized in
Table 2.
b
entry furanose phosphine oxide (R3) product yield (%) Z/E ratio
c
1
2
3
4
5
6
7
8
9
11
11
11
11
11
13
13
13
13
13
3a (Ph)
12a
12b
12c
12e
12f
72
65
47
1:4
3b (t-Bu)
1:25
1:7
d
c
3c (Cy)
3e (2,6-di-MePh)
3f (2,6-di-ClPh)
3a (Ph)
83
1:50
1:2
e
17 (62)
14a
14b
14d
14e
14f
100
93
2:3
3b (t-Bu)
1:8
e
3d (p-MeOPh)
3e (2,6-di-MePh)
3f (2,6-di-ClPh)
32 (50)
1:3
e
64 (93)
1:12
1:6
10
78
a
General conditions: phosphine oxide (2 equiv), n-BuLi (3.5 equiv),
and furanose (1 equiv) in dry THF unless otherwise indicated.
Determined by integration of the olefinic proton signals in the H
NMR spectrum of the crude reaction mixture. See ref 12. LDA (3.5
equiv) was used as a base. Yield in round brackets is based on
Starting from 12b, reaction with NIS/NaHCO3 led to 6-endo
cyclization product 2-deoxy-2-iodo-1-thioallopyranoside 15b in
57% yield as an anomeric α/β mixture of 1:13 (Table 2, entry
2). The reaction was comparatively slower than the reference
b
1
c
d
e
recovered starting material. Cy = cyclohexyl, LDA = lithium
diisopropylamide.
a
Table 2. Iodonium-Induced Cyclization of 12 to 15
5). The yields and stereoselectivities obtained were compared
to those observed for the reference reaction with phenyl-
sulfanyl-substituted derivative 3a (Table 1, entry 1). WH
olefination of 11 with tert-butylsulfanyl derivative 3b produced
sulfanyl alkene 12b with a 65% yield and an excellent Z/E ratio
of 1:25 (Table 1, entry 2). Cyclohexyl derivative 3c furnished
the desired sulfanyl alkene 12c with a 47% yield and a
moderate-to-good stereoselectivity (Table 1, entry 3). Better
yield (83%) and stereoselectivity (Z/E 1:50) were obtained
from 2,6-dimethyl derivative 3e to give sulfanyl alkene 12e
(Table 1, entry 4). WH reaction with 2,6-dichlorophenyl
derivative 3f generated the corresponding product in low yield
and selectivity (Table 1, entry 5). Thus, compared to the
phenylsulfanylmethyl)diphenylphosphine oxide 3a (Table 3,
entry 1), increased stereoselectivities were obtained in almost
all WH reactions with phosphine oxides 3b,c and 3e,f.
hex-1-enitol
b
T
time
(h)
Yield
(%)
α/β
b
entry (Z/E ratio )
(°C)
product
ratio
c
1
2
3
12a (1:2)
12b (1:8)
−30 to rt
−78 to −10
15
18
18
15a
15b
15e
77
57
49
1:9
1:13
1:25
12e (1:50) −78 to −10
a
General conditions: hex-1-enitol (1 equiv), NIS (1.5 equiv), and
NaHCO3 (1.5 equiv) in dry CH2Cl2 unless otherwise indicated.
b
Determined by integration of the olefinic and anomeric proton
signals in the 1H NMR spectrum of the crude reaction mixture,
c
respectively. See ref 12; reaction performed in dry CH3CN as a
solvent.
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reaction from 12a (Table 2, entry 1) and required slightly lower
temperatures. The moderate yield of 15b might be a
consequence of partial decomposition of the cyclized product
under the forced reaction conditions. The steric bulk of the t-
BuS group might be responsible for the low reactivity of alkene
12b toward cyclization, probably increasing the hindrance of
the complex alkene−I+ system toward intramolecular attack of
the hydroxyl group. The reductance to cyclization could also be
associated to a stereoelectronic issue; the coplanarity of the
alkene system with the sulfur atom (nS(3pz)→π* conjugation) in
the most reactive conformation for cyclization may be
disrupted due to 1,2- and 1,3-allylic (A1,2 and A1,3) strain
between the t-Bu and the olefinic protons, lowering the
electronic density of the double bond and consequently slowing
down the electrophilic cyclization (Scheme 3). Additional
manno-pyranoside 16b was obtained in 57% yield together
with 3,4,6-tri-O-benzyl-D-glucal byproduct (25%). A similar
elimination reaction had been observed previously in our group
during the preparation of 2-deoxy-2-iodo-15,28 and 2-deoxy-2-
phenylselenenyl-1-thiohexopyranoses.17 Subsequent glycosyla-
tion of cholesterol 17 starting from tert-butyl thiomannopyr-
anoside 16b rendered 18 as a 37:1 α/β mixture in 69% yield,
which is in line with the results obtained starting from phenyl
derivative 16a (71%, 37:1 α/β).12 Cyclization of 14e did not
proceed, even at room temperature after several days of
reaction.
The results obtained from the cyclization of the different S-
substituted sulfanyl alkenes are in agreement with those
previously reported by our group12−19 and may be summarized
as follows: (a) the cyclization reaction is completely
regioselective toward 6-endo cyclization products, (b) the
relative stereochemistry of sulfany group at C-1 and the C-2
iodo group in the thioglycosides obtained is conditioned by the
Z/E composition of the starting alkenes and their relative
reactivity, and (c) the formation of the cyclized products with a
cis arrangement between the C-2 iodo group and the alkoxy
group at C-3 is of general application to alkenols with an allylic
alkoxy group. It is a consequence of a stereoelectronic effect
that dictates the more reactive conformation of the alkene,
known as inside-alkoxy effect,29 and (d) relative energy
difference between the preferred conformation and the most
reactive one dictates the relative reactivities between the E- and
the Z-alkenes isomers so that, for the arabino derivatives 14a,b,
only the E-alkenes cyclize to give the corresponding thioglyco-
sides as a single α-anomer, whereas for the ribo derivatives
12a,b and 12e both the E and Z alkenes cyclize, although at
different rates, to give an anomeric mixture of thioglycosides.
This fact also accounts for the lower reactivity of the arabino
alkenes toward cyclization compared to those of the ribo
alkenes.30
Scheme 3. Stabilizing and Destabilizing Effects in
Substituted Vinyl Sulfides (R = 2,6-di-MePh, t-Bu)
Glycosylation Reaction. Glycosylation reactions of
cholesterol 17 using derivatives 15a,b and 15e were carried
out under typical glycosylation conditions for thioglycosides
using NIS and TfOH as a promoter system (Table 3). The
reaction was started at −78 °C and then allowed to warm until
glycosylation was finished (ca. −40 °C). When tert-butyl 1-
thioglycoside 15b was used as a glycosyl donor, glycosylation
proceeded readily at low temperature (−60 °C) to give
compound 19 in an excellent 95% yield (Table 3, entry 2). The
β-stereoselectivity, though, was of the same order than that
obtained when starting from the phenyl 1-thio-glycoside 15a
(Table 3, entry 1). Similar results were obtained in the
glycosylation of cholesterol 17 with glycosyl donor 15e, but in
this case the yield was slightly lower (Table 3, entry 3).
features that may also account for this reduced electronic
density include the inductive and polarizability effects of the SR
group together with hyperconjugative effects such as 3d-orbital
interactions and negative hyperconjugation (π→σ*C−S) that
may play a minor role if any.27 A similar result was obtained in
the cyclization of 12e to give 1-thioglycoside 15e (Table 2,
entry 1), although yields were even lower in this case, probably
suggesting the presence of even more serious A1,2 and A1,3
strains with the flat arylsulfanyl framework.
We then studied the cyclization reactions of arabino-hex-1-
enitols 14b and 14e, which had produced the best results in the
olefination reaction (Scheme 4). When compound 14b was
submitted to cyclization conditions, 2-deoxy-2-iodo-thio-
Scheme 4. Cyclization−Glycosylation Sequence for 14a (See ref 12), 14b, and 14e
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a
synthesis of 2-deoxy-2-iodoglycosides from furanoses in three
steps: Wittig−Horner olefination of furanoses with
(sufanylmethyl)diphenylphosphine oxides to give sulfanylal-
kenes, electrophilic iodine−induced cyclization, and glycosyla-
tion. In particular, we have gained insight into the stereo-
electronic effect of substitutions on sulfur in terms of yield and
stereoselectivity of olefination, cyclization, and glycosylation
reactions compared to previous results obtained with SPh
derivatives. The use of phosphine oxide derivatives Ph2P(O)-
CH2X (X = t-Bu, 2,6-di-Me-Ph) provided good yields and
excellent E selectivities in the WH olefination reaction of both
ribo- and arabinofuranoses. The presence of bulky S-
substituents generally decreases the rate and yield of cyclization
reactions starting from ribo-hex-1-enitols and seems to slightly
increase the cyclization yield of the tert-butyl arabino-hex-1-
enitol derivative. However, no cyclization product was obtained
starting from the 2,6-dimethylphenyl arabino-hex-1-enitol
derivative. Glycosylation reactions were studied starting from
2-deoxy-2-iodo-1-thio-allo-glycosides 15b and 15e, which have
t-Bu and 2,6-di-Me-Ph groups at sulfur and from unstable 2-
deoxy-2-iodo-1-thio-manno-glycoside 16b, and their results
were compared with the reference compounds 15a and 16a
(SPh). Moreover, no aglycon transfer of any of the leaving
groups (Ph, t-Bu, etc.) was noticed under the conditions
tested.32 The stereoselectivity of the glycosylation is independ-
ent of the anomeric sulfanyl group present in the glycosyl
donor, which is in agreement with the intermediacy of an
oxocarbenium ion, and only moderate changes in the
glycosylation yields were observed. Scheme 5 summarizes the
performance of the different sulfanyl derivatives in the synthetic
route toward 2-deoxy-2-iodopyranosides that involves olefina-
tion, cyclization, and glycosylation. The use of t-BuS group
does not appear advantageous over the PhS group for the ribo
series especially because the yield for cyclization step is
considerably lower than for PhS, probably due to the high steric
hindrance on sulfur. On the contrary, the tert-butyl derivative
was superior to the phenyl analogue for the arabino series. In
this case, an increase in the E stereoselectivity of the olefination
step was crucial for obtaining a moderately good yield of thio-
manno-pyranoside product and eventually of the final glycoside,
since the Z alkene is completely resistant to cyclization.
Table 3. Glycosylation of 17 to 19
1-
thioglycoside
T
(°C)
time
(h)
yield
(%)
α/β
b
b
entry (α/β ratio )
product
ratio
c
1
2
3
15a (1:9)
−40
2.5
4
19
19
19
81
95
60
1:9
1:7
15b (1:13) −78 to −40
15e (1:25) −78 to −40
4
1:10
a
General conditions: 1-thioglycoside (1 equiv), Cholesterol 17 (2
equiv), NIS (2.2 equiv), TfOH (20 mol %), and 4 Å MS in dry
b
CH2Cl2 unless otherwise indicated. Determined by integration of the
anomeric proton signals in the 1H NMR spectrum of the crude
c
reaction mixture. See ref 12.
As already described in previous studies, glycosylations from
2-deoxy-2-iodo-1-thiopyranosides seem to proceed via for-
mation of an oxocarbenium ion intermediate and subsequent
nucleophilic attack of the glycosyl acceptor. The stereo-
selectivity of this attack is determined by the reactivity/
conformational profile of the oxocarbenium ion intermediate.31
Hence, glycosylations starting from glycosyl donors of the same
configuration (allo) but differing only in the anomeric sulfanyl
substituent (15a,b and 15e), are supposed to proceed through
the same oxocarbenium intermediate and, therefore, should all
render glycoside 19 with virtually the same stereoselectivty, as it
happens to be. Differences in the yield might derive from their
activation profiles due to the electronic/steric properties of the
substituent at the anomeric sulfanyl moiety. The same
interpretation can be inferred for the synthesis of manno
glycoside 18 from glycosyl donors 16a,b.
CONCLUSION
■
A concise synthetic strategy has been developed for the
preparation of 2-deoxy-2-iodo-β-allopyranosides precursors of
2-deoxy-β-D-ribo-hexopyranosyl units commonly found in
antibiotics and natural products. We have explored the
Scheme 5. Summary of the Results for the Olefination−Cyclization−Glycosylation Sequence of Vinyl Sulfides 12a,b,e and
14a,b,e with R = Ph (See ref 12), t-Bu, and 2,6-di-MePh
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1
FTIR (ATR, νmax) 1436.7, 1189.9; H NMR (400 MHz, CDCl3) δ
EXPERIMENTAL SECTION
■
7.77−6.96 (m, 13H), 3.44 (d, JHP = 9.6 Hz, 2H), 2.35 (s, 6H); 13C
2
General Remarks. Proton (1H NMR), carbon (13C NMR), and
phosphorus (31P NMR) nuclear magnetic resonance spectra were
recorded on a 400 MHz (for 1H), 100.6 MHz (for 13C), and 162 MHz
(for 31P) spectrometer. Spectra were fully assigned using COSY,
HSQC, HMBC, and NOESY. All chemical shifts are quoted on the δ
scale in ppm using either Me4Si (1H NMR: CDCl3 = 0.00) or the
NMR (100.6 MHz, CDCl3) δ 142.7, 132.2−128.1, 34.1 (d, 1JCP = 67.9
Hz), 21.6; 31P NMR (162 MHz, CDCl3) δ 28.89. Anal. Calcd for
C21H21OPS: C, 71.57; H, 6.01; S, 9.10. Found: C, 71.93; H, 5.96; S,
9.73.
(2,6-Dichlorophenylsulfanylmethyl)diphenylphosphine oxide
(3f): white crystalline solid; yield 2.84 g (72%); mp 181.5−183 °C;
residual solvent as internal standard (1H NMR: CDCl3 = 7.26 and 13
C
1
FTIR (ATR, νmax) 1436.7, 1188.9; H NMR (400 MHz, CDCl3) δ
NMR: CDCl3 = 77.23) and 85% H3PO4 as external standard (31P
NMR: CDCl3 = 0.00). Coupling constants (J) are reported in hertz
with the following splitting abbreviations: s = singlet, d = doublet, t =
triplet, q = quartet, quin = quintet and app = apparent. Melting points
were determined on a melting point apparatus and are uncorrected.
Infrared (IR) spectra were recorded on a FTIR-ATR spectropho-
tometer. Absorption maxima (νmax) are reported in wavenumbers
(cm−1). Elemental analyses (C, H, N, and S) were performed with the
corresponding analyzer. Thin-layer chromatography (TLC) was
carried out using commercial aluminum-backed sheets coated with
silica gel. Visualization of the silica plates was achieved using a UV
lamp (λmax = 254 nm) and/or 6% H2SO4 in EtOH and/or 2% PdCl2
and 15% H2SO4 in water. Flash column chromatography was carried
out using silica gel (230−400 mesh). Radial chromatography was
performed on 1, 2, or 4 mm plates of silica gel, depending on the
amount of product. Mobile phases are reported in relative composition
(e.g., 1:1 EtOAc/hexane v/v). HPLC-grade dichloromethene (DCM),
tetrahydrofuran (THF), and dimethylformamide (DMF) were dried
using a solvent purification system. All reagents were used as received
from commercial suppliers. All reactions using anhydrous conditions
were performed using a flame-dried apparatus under an atmosphere of
argon.
2
7.82−7.12 (m, 13H), 3.74 (d, JHP = 9.2 Hz, 2H); 13C NMR (100.6
MHz, CDCl3) δ 141.0, 132.3−128.6, 33.3 (d, JCP = 67.1 Hz); 31P
1
NMR (162 MHz, CDCl3) δ 28.55. Anal. Calcd for C19H15Cl2OPS: C,
58.03; H, 3.84; S, 8.15. Found: C, 57.92; H, 3.57; S, 8.06.
(Ethylsulfanylmethyl)diphenylphosphine oxide34 (3g): white
crystalline solid; yield 2.18 g (79%); mp 88−89 °C; FTIR (ATR,
1
νmax) 1436.7, 1178.3; H NMR (400 MHz, CDCl3) δ 7.82−7.46 (m,
10H), 3.26 (d, 2JHP = 9.6 Hz, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.20 (t, J =
7.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 141.0, 132.3−128.8,
31.1, 29.9 (d, JCP = 70.9 Hz), 14.4; 31P NMR (162 MHz, CDCl3) δ
1
30.05. Anal. Calcd for C15H17OPS: C, 65.20; H, 6.20; S, 11.60. Found:
C, 65.4; H, 5.94; S, 11.36.
General Procedure for Wittig−Horner Olefination. nBuLi (3.5
mmol, 1.6 M in hexanes) was slowly added to a cold (−78 °C)
solution of (alkylsulfanyl- or arylsulfanylmethyl)diphenylphosphine
oxide (2 mmol) in anhydrous THF (13 mL) under argon atmosphere,
and the mixture was stirred at the same temperature for 30 min. A
solution of the corresponding aldehyde (1.0 mmol) in anhydrous THF
(5 mL) was subsequently added via cannula and warmed to room
temperature. The reaction progress was monitored by TLC. After 24
h, the reaction mixture was quenched with a saturated solution of
aqueous NH4Cl and extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by chromatographic techniques. A second fraction was
obtained during the olefination of pyranoses when a mixture of the
corresponding β-hydroxyphosphine oxide intermediate and unreacted
(alkylsulfanyl- or arylsulfanylmethyl)diphenylphosphine oxide, ob-
tained after purification, was dissolved in anhydrous THF and treated
with either KH or t-BuOK at 40 °C for 30 min.
General Procedure for the Synthesis of Diphenylphosphine
Oxides. Thiol (1.1 mmol) was added to a suspension of sodium
hydride (60% in mineral oil, 1.1 mmol) in anhydrous THF (4 mL) at
0 °C under argon atmosphere. The reaction mixture was warmed to
room temperature and stirred for 1 h. A solution of 225 (1 mmol) in
anhydrous THF (2 mL) was added at 0 °C. The reaction mixture was
warmed to room temperature and stirred for 2 h. After being
quenched with a saturated solution of aqueous NH4Cl, the reaction
mixture was extracted with ethyl acetate. The combined organic layers
were washed with water and brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. The white solid typically
obtained was purified by recrystallization from ethyl acetate and
hexane solvent mixtures.
(Z/E)-tert-Butyl(styryl)sulfane35 (7b): colorless oil; yield 179 mg
(93%) as an inseparable 1:9 Z/E mixture; Rf (1:8 EtOAc/hexane)
0.53. Anal. Calcd for C12H16S: C, 74.94; H, 8.39; S, 16.67. Found: C,
74.75; H, 8.33; S, 16.53. Data for Z-7b: 1H NMR (400 MHz, CDCl3)
δ 7.78 (m, 2H), 7.52 (m, 1H), 7.23 (m, 2H), 6.45 (d, J = 11.2 Hz,
1H), 6.36 (d, J = 11.2 Hz, 1H), 1.42 (s, 9H); 13C NMR (100.6 MHz,
CDCl3) δ 135.3, 131.2, 129.7, 128.5, 127.9, 124.2, 43.2, 31.0. Data for
(tert-Butylsulfanylmethyl)diphenylphosphine oxide22 (3b): white
crystalline solid; yield 1.08 g (89%); mp 155.5−157 °C; FTIR (ATR,
1
νmax) 1436.7, 1183.1; H NMR (400 MHz, CDCl3) δ 7.81−7.46 (m,
1
2
10H), 3.31 (d, JHP = 12.4 Hz, 2H), 1.27 (s, 9H); 13C NMR (100.6
E-7b: H NMR (400 MHz, CDCl3) δ 7.78 (m, 2H), 7.52 (m, 1H),
MHz, CDCl3) δ 143.1, 132.3, 131.3, 128.8, 128.4, 34.4 (d, 1JCP = 67.2
Hz), 30.4, 21.9; 31P NMR (162 MHz, CDCl3) δ 30.12. Anal. Calcd for
C17H21OPS: C, 67.08; H, 6.95; S, 10.53. Found: C, 67.37; H, 7.01; S,
10.35 S.
7.23 (m, 2H), 6.87 (d, J = 15.6 Hz, 1H), 6.72 (d, J = 15.6 Hz, 1H),
1.40 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 135.6, 131.5, 129.7,
128.5, 127.9, 122.0, 44.3, 31.1.
(Z/E)-Cyclohexyl(styryl)sulfane35 (7c): LDA (3.5 mmol) was used
as a base; colorless oil; yield 188 mg (86%) as an inseparable 1:12 Z/E
mixture; Rf (1:6 EtOAc/hexane) 0.83. Anal. Calcd for C14H18S: C,
77.01; H, 8.31; S, 14.68. Found: C, 76.95; H, 8.35; S, 14.54. Data for
Z-7c: 1H NMR (400 MHz, CDCl3) δ 7.49−7.17 (m, 5H), 6.42 (d, J =
11.2 Hz, 1H), 6.32 (d, J = 11.2 Hz, 1H), 2.89 (m, 1H), 2.02 (m, 2H),
1.79 (m, 2H), 1.63 (m, 1H), 1.55−1.27 (m, 5H); 13C NMR (100.6
MHz, CDCl3) δ 137.4, 128.8, 127.9, 125.8, 128.4, 125.2, 48.0, 34.0,
(Cyclohexylsulfanylmethyl)diphenylphosphine oxide22 (3c): white
crystalline solid; yield 3.25 g (98%); mp 100−101 °C; FTIR (ATR,
1
νmax) 1436.7, 1183.1; H NMR (400 MHz, CDCl3) δ 7.82−7.49 (m,
10H), 3.29 (d, 2JHP = 9.6 Hz, 2H), 2.69 (m, 1H), 1.91−1.57 (m, 5H),
1.20 (m, 5H); 13C NMR (100.6 MHz, CDCl3) δ 132.2, 131.6, 131.4,
128.8, 128.7, 45.6, 33.2, 28.5 (d, 1JCP = 94.5 Hz), 26.1, 25.9; 31P NMR
(162 MHz, CDCl3) δ 29.87. Anal. Calcd for C19H23OPS: C, 69.06; H,
7.02; S, 9.70. Found: C, 68.95; H, 7.11; S, 9.73.
1
33.9, 26.0, 25.9. Data for E-7c: H NMR (400 MHz, CDCl3) δ 7.28
(4-Methoxyphenylsulfanylmethyl)diphenylphosphine oxide33
(3d): white crystalline solid; yield 3.16 g (89%); mp 71−72 °C;
FTIR (ATR, νmax) 1436.8, 1185; 1H NMR (400 MHz, CDCl3) δ
7.79−7.43 (m, 10H), 7.27 (d, J = 8.8 Hz, 2H), 6.74 (d, J = 8.8 Hz,
2H), 3.76 (s, 3H), 3.63 (d, 2JHP = 9.2 Hz, 2H); 13C NMR (100.6 MHz,
CDCl3) δ 159.6, 134.1, 132.2, 131.5, 131.4, 128.8, 128.7, 114.8, 55.5,
35.9 (d, 1JCP = 67.9 Hz); 31P NMR (162 MHz, CDCl3) δ 28.74. Anal.
Calcd for C20H19O2PS: C, 67.78; H, 5.40; S, 9.05. Found: C, 67.44; H,
5.24; S, 8.93.
(m, 4H), 7.17 (m, 1H), 6.76 (d, J = 15.6 Hz, 1H), 6.56 (d, J = 15.6 Hz,
1H), 2.97 (m, 1H), 2.02 (m, 2H), 1.79 (m, 2H), 1.63 (m, 1H), 1.45−
1.27 (m, 5H); 13C NMR (100.6 MHz, CDCl3) δ 137.4, 128.8, 127.9,
125.8, 124.3, 45.5, 33.9, 26.3, 25.9.
(Z/E)-4-Methoxyphenyl(styryl)sulfane35 (7d): yellow oil; yield 225
mg (93%) as an inseparable 2:3 Z/E mixture; Rf (1:6 EtOAc/hexane)
0.83. Anal. Calcd for C15H14OS: C, 74.34; H, 5.82; S, 13.23. Found: C,
74.04; H, 5.94; S, 13.36. Data for Z-7d: 1H NMR (400 MHz, CDCl3)
δ 7.51−6.42 (m, 7H), 6.90 (d, J = 10.8 Hz, 2H), 6.43 (d, J = 10.8 Hz,
1H), 6.33 (d, J = 10.8 Hz, 1H), 3.82 (s, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 159.5, 136.1, 132.9, 128.7, 128.4, 127.6, 125.7, 114.7, 55.2.
(2,6-Dimethylphenylsulfanylmethyl)diphenylphosphine oxide
(3e): white crystalline solid; yield 2.74 g (78%); mp 119−120 °C;
3065
dx.doi.org/10.1021/jo5001912 | J. Org. Chem. 2014, 79, 3060−3068

The Journal of Organic Chemistry
Article
1
Data for E-7d: H NMR (400 MHz, CDCl3) δ 7.40−7.22 (m, 7H),
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-cyclohexylsulfanyl-D-ribo-
hex-1-enitol (12c): LDA (3.5 mmol) was used as a base; yellowish
syrup; yield 253 mg (47%) as an inseparable 1:7 Z/E mixture; Rf (1:3
EtOAc/hexane) 0.63. Anal. Calcd for C33H40O4S: C, 74.40; H, 7.57; S,
6.02. Found: C, 74.03; H, 7.52; S, 6.07. Data for E-12c: 1H NMR (400
MHz, CDCl3) δ 7.27−7.13 (m, 15H), 6.23 (d, J = 15.2 Hz, 1H), 5.61
(dd, J = 15.2, 8.4 Hz, 1H), 4.67 (d, J = 11.2 Hz, 1H), 4.55 (d, J = 11.2
Hz, 1H), 4.48 (d, J = 11.2 Hz, 1H), 4.41 (d, J = 11.2 Hz, 2H), 4.27 (d,
J = 11.2 Hz, 1H), 4.10 (dd, J = 8.4, 4.4 Hz, 1H), 3.72 (m, 1H), 3.49−
3.66 (m, 2H), 2.77 (m, 1H), 2.70 (d, J = 4.8 Hz, 1H), 1.89 (m, 2H),
1.66 (m, 2H), 1.53 (m, 1H), 1.33−1.13 (m, 5H); 13C NMR (100.6
MHz, CDCl3) δ 138.6, 138.5, 138.1, 129.5, 128.6, 128.5, 128.42,
128.36, 128.3, 128.03, 127.98, 127.9, 127.83, 127.79, 127.74, 127.66,
125.0, 82.1, 81.1, 74.4, 73.5, 71.1, 70.3, 44.8, 33.64, 33.58, 26.1, 25.8.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-(2,6-dimethylphenyl)-
sulfanyl-D-ribo-hex-1-enitol (12e): yellowish syrup; yield 403 mg
(83%) as an inseparable 1:50 Z/E mixture; Rf (1:3 EtOAc/hexane)
0.65. Anal. Calcd for C35H38O4S: C, 75.78; H, 6.90; S, 5.78. Found: C,
75.63; H, 6.85; S, 5.67. Data for E-12e: 1H NMR (400 MHz, CDCl3)
δ 7.32−7.10 (m, 18H), 6.23 (d, J = 15.2 Hz, 1H), 5.17 (dd, J = 15.2,
8.8 Hz, 1H), 4.65 (d, J = 11.6 Hz, 1H), 4.57 (d, J = 11.6 Hz, 1H), 4.48
(d, J = 11.6 Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 4.43 (d, J = 11.6 Hz,
1H), 4.29 (d, J = 11.6 Hz, 1H), 4.10 (dd, J = 8.8, 4.4 Hz, 1H), 3.76 (m,
1H), 3.59−3.55 (m, 3H), 2.82 (d, J = 3.6 Hz, 1H), 2.45 (s, 6H); 13C
NMR (100.6 MHz, CDCl3) δ 143.2, 138.6, 138.3, 138.1, 129.8, 129.4,
129.3, 128.50, 128.47, 128.3, 127.9, 127.9, 127.8, 127.7, 127.62,
127.56, 122.3, 81.4, 81.1, 74.0, 73.4, 71.10, 71.07, 70.2, 21.8.
6.76 (d, J = 15.6 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 3.83 (s, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 159.5, 136.1, 133.9, 131.7, 128.7, 128.4,
127.6, 125.7, 124.3, 114.6, 55.2.
(Z/E)-2,6-Dimethylphenyl(styryl)sulfane36 (7e): colorless oil; yield
180 mg (75%) as an inseparable 1:12 Z/E mixture; Rf (1:6 EtOAc/
hexane) 0.80. Anal. Calcd for C16H16S: C, 79.95; H, 6.71; S, 13.34.
1
Found: C, 80.02; H, 6.94; S, 13.35. Selected data for Z-7e: H NMR
(400 MHz, CDCl3) δ 7.60−7.00 (m, 8H), 6.61 (d, J = 11.2 Hz, 1H),
6.43 (d, J = 11.2 Hz, 1H), 2.47 (s, 6H). Data for E- 7e: 1H NMR (400
MHz, CDCl3) δ 7.60−7.00 (m, 8H), 6.65 (d, J = 15.2 Hz, 1H), 5.96
(d, J = 15.2 Hz, 1H), 2.49 (s, 6H); 13C NMR (100.6 MHz, CDCl3) δ
143.6, 143.5, 137.2, 134.9, 128.6, 128.4, 128.5, 128.1, 127.3, 125.3,
124.7, 21.9.
(Z/E)-2,6-Dichlorophenyl(styryl)sulfane (7f): white solid; yield 177
mg (63%) as an inseparable 1:16 Z/E mixture; Rf (1:6 EtOAc/hexane)
0.83. Anal. Calcd for C14H10Cl2S: C, 59.80; H, 3.58; S, 11.40. Found:
C, 59.75; H, 3.55; S, 11.45. Selected data for Z-7f: H NMR (400
MHz, CDCl3) δ 7.43−7.21 (m, 8H), 6.57 (d, J = 11.2 Hz, 1H), 6.00
(d, J = 11.2 Hz, 1H). Data for E-7f: H NMR (400 MHz, CDCl3) δ
7.43−7.21 (m, 8H), 6.67 (d, J = 15.2 Hz, 1H), 6.40 (d, J = 15.2 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) δ 141.1, 136.6, 131.3−125.6,
122.5.
1
1
(Z/E)-Ethyl(styryl)sulfane37 (7g): colorless oil; yield 184 mg (96%)
as an inseparable 1:10 Z/E mixture; Rf (1:8 EtOAc/hexane) 0.63. Anal.
Calcd for C10H12S: C, 73.12; H, 7.36; S, 19.52. Found: C, 72.95; H,
7.33; S, 19.53. Selected data for Z-7g: 1H NMR (400 MHz, CDCl3) δ
7.78−7.35 (m, 5H), 6.45 (d, J = 10.8 Hz, 1H), 6.26 (d, J = 10.8 Hz,
1H), 2.80 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). Data for E- 7g:
1H NMR (400 MHz, CDCl3) δ 7.78−7.35 (m, 5H), 6.73 (d, J = 15.2
Hz, 1H), 6.46 (d, J = 15.2 Hz, 1H), 2.82 (q, J = 7.2 Hz, 2H), 1.35 (t, J
= 7.2 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 137.2, 131.6, 128.6,
128.5, 128.2, 125.0, 26.7, 14.7.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-(2,6-dichlorophenyl)-
sulfanyl-D-ribo-hex-1-enitol (12f): yellowish syrup; yield 103 mg
(17%, 62% based on recovered starting material) as an inseparable 1:2
Z/E mixture; Rf (1:3 EtOAc/hexane) 0.65. Anal. Calcd for
C33H32Cl2O4S: C, 66.55; H, 5.42; S, 5.38. Found: C, 66.48; H, 5.32;
S, 5.30. Data for Z-12f: 1H NMR (400 MHz, CDCl3) δ 7.43−7.15 (m,
18H), 6.22 (d, J = 10.4 Hz, 1H), 5.90 (appt, J = 10.4, 10.4 Hz, 1H),
4.82 (d, J = 11.2 Hz, 1H), 4.74 (d, J = 11.2 Hz, 1H), 4.68 (d, J = 11.2
Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 4.35 (d,
J = 11.2 Hz, 1H), 4.06 (dd, J = 10.4, 4.4 Hz, 1H), 3.95 (m, 1H), 3.69−
3.53 (m, 3H), 2.89 (d, J = 4.0 Hz, 1H); 13C NMR (100.6 MHz,
CDCl3) δ 140.6, 138.5, 138.21, 138.15, 130.54, 130.48, 129.9, 129.8,
120.0, 128.6, 128.4, 128.2, 128.02, 127.98, 127.9, 127.7, 127.3, 81.4,
(Z/E)-(tert-Butyl-2-phenylprop-1-enyl)sulfane (8): colorless oil;
yield 189 mg (92%) as an inseparable 1:10 Z/E mixture; Rf (1:10
EtOAc/hexane) 0.70. Anal. Calcd for C13H18S: C, 75.67; H, 8.79; S,
1
15.54. Found: C, 75.75; H, 8.83; S, 15.53. Selected data for Z-8: H
NMR (400 MHz, CDCl3) δ 7.31−7.12 (m, 5H), 6.11 (s, 1H), 2.10 (s,
1
3H), 1.28 (s, 9H). Data for E- 8: H NMR (400 MHz, CDCl3) δ
7.31−7.12 (m, 5H), 6.42 (s, 1H), 2.06 (s, 3H), 1.34 (s, 9H); 13C NMR
(100.6 MHz, CDCl3) δ 142.7, 135.1, 128.5−125.4, 120.0, 44.3, 31.3,
17.9.
1
81.1, 77.42, 74.38, 71.35, 71.3, 71.2. Data for E-12f: H NMR (400
MHz, CDCl3) δ 7.43−7.15 (m, 18H), 6.25 (d, J = 15.2 Hz, 1H), 5.50
(dd, J = 15.2, 8.4 Hz, 1H), 4.82 (d, J = 11.2 Hz, 1H), 4.74 (d, J = 11.2
Hz, 1H), 4.68 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 4.50 (d,
J = 11.2 Hz, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.14 (dd, J = 8.4, 4.4 Hz,
1H), 3.82 (m, 1H), 3.69−3.53 (m, 3H), 2.78 (d, J = 4.0 Hz, 1H); 13C
NMR (100.6 MHz, CDCl3) δ 141.2, 138.5, 138.2, 138.1, 130.9, 129.1,
128.60, 128.58, 128.53, 128.46, 128.1, 128.0, 127.93, 127.90, 127.78,
127.77, 125.7, 81.4, 81.0, 74.3, 73.6, 71.2, 71.1, 70.5.
Cyclohexyl(cyclohexylidenemethyl)sulfane38 (9): colorless oil;
1
yield 202 mg (93%); Rf (1:6 EtOAc/hexane): 0.75; H NMR (400
MHz, CDCl3) δ 5.60 (s, 1H), 2.69−2.63 (m, 1H), 2.23 (m, 2H), 2.10
(m, 2H), 1.95−1.89 (m, 2H), 1.73−1.71 (m, 2H), 1.57−1.20 (m,
12H); 13C NMR (100.6 MHz, CDCl3) δ 143.0, 113.1, 45.7, 37.4, 33.7,
30.4, 28.4, 27.2, 26.5, 26.1, 25.8. Anal. Calcd for C13H22S: C, 74.22; H,
10.54; S, 15.24. Found: C, 74.34; H, 10.47; S, 15.33.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-tert-butylsulfanyl-D-arabi-
no-hex-1-enitol (14b): yellowish syrup; yield 472 mg (93%) as an
inseparable 1:8 Z/E mixture; Rf (1:3 EtOAc/hexane) 0.60. Anal. Calcd
for C31H38O4S: C, 73.48; H, 7.56; S, 6.33. Found: C, 73.39; H, 7.32; S,
Cyclohexylidenemethyl-2,6-dimethylphenylsulfane (10): yellow-
ish oil; yield 207 mg (89%); Rf (1:9 EtOAc/hexane) 0.90; H NMR
1
(400 MHz, CDCl3) δ 7.23−6.99 (m, 3H), 5.36 (s, 1H), 2.49 (s, 6H),
2.23−2.10 (m, 4H), 1.58−1.25 (m, 6H); 13C NMR (100.6 MHz,
CDCl3) δ 143.6, 142.7, 142.3, 129.5, 128.5, 115.2, 36.4, 30.3, 28.5,
27.4, 26.7, 22.3, 21.9; Anal. Calcd for C15H20S: C, 77.53; H, 8.67; S,
13.80. Found: C, 77.45; H, 8.53; S, 13.59.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-tert-butylsulfanyl-D-ribo-
hex-1-enitol (12b): colorless syrup; yield 288 mg (65%) as an
inseparable 1:25 Z/E mixture; Rf (1:3 EtOAc/hexane) 0.60. Anal.
Calcd for C31H38O4S: C, 73.48; H, 7.56; S, 6.33. Found: C, 73.37; H,
1
6.27. Selected data for Z-14b: H NMR (400 MHz, CDCl3) δ 7.35−
7.23 (m, 15H), 6.49 (d, J = 9.6 Hz, 1H), 5.83 (appt, J = 9.6, 9.6 Hz,
1H), 4.66 (dd, J = 9.6, 4.0 Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 4.61 (d,
J = 11.2 Hz, 1H), 4.52 (d, J = 11.2 Hz, 1H), 4.47 (s, 1H), 4.36 (d, J =
11.2 Hz, 1H), 4.00 (m, 1H), 3.63−3.55 (m, 2H), 2.96 (d, J = 5.2 Hz,
1
1H), 1.34 (s, 9H). Data for E-14b: H NMR (400 MHz, CDCl3) δ
7.35−7.23 (m, 15H), 6.39 (d, J = 15.2 Hz, 1H), 5.89 (dd, J = 15.2, 7.6
Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 4.61 (d, J = 11.2 Hz, 1H), 4.61 (d,
J = 11.2 Hz, 1H), 4.52 (d, J = 11.2 Hz, 1H), 4.47 (s, 1H), 4.14 (dd, J =
7.6, 4.0 Hz, 1H), 4.00 (m, 1H), 3.63−3.55 (m, 3H), 2.79 (d, J = 5.2
Hz, 1H), 1.34 (s, 9H); 13C NMR (100.6 MHz, CDCl3) δ 138.24,
138.17, 138.0, 129.0, 128.53, 128.49, 128.4, 128.31, 128.25, 128.2,
128.0, 127.9, 127.8, 126.6, 80.9, 79.6, 74.4, 73.5, 71.1, 70.9, 70.7, 44.0,
31.1.
1
7.43; S, 6.27. Data for E-12b: H NMR (400 MHz, CDCl3) δ 7.33−
7.21 (m, 15H), 6.44 (d, J = 15.2 Hz, 1H), 5.90 (dd, J = 15.2, 8.4 Hz,
1H), 4.76 (d, J = 11.2 Hz, 1H), 4.65 (d, J = 11.2 Hz, 1H), 4.56 (d, J =
11.2 Hz, 1H), 4.49 (d, J = 11.2 Hz, 1H), 4.48 (d, J = 11.2 Hz, 1H),
4.36 (d, J = 11.2 Hz, 1H), 4.17 (dd, J = 8.4, 4.2 Hz, 1H), 3.81 (m, 1H),
3.68 (dd, J = 8.4, 4.2 Hz, 1H), 3.61 (m, 2H), 2.89 (bs, 1H), 1.35 (s,
9H); 13C NMR (100.6 MHz, CDCl3) δ 138.5, 138.4, 138.1, 129.0,
128.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.82, 127.75, 127.7, 81.7,
81.0, 74.3, 73.4, 71.1, 71.0, 70.3, 43.8, 31.0.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-(4-methoxyphenyl)-
sulfanyl-D-arabino-hex-1-enitol (14d): yellowish syrup; yield 176 mg
(32%, 50% based on recovered starting material) as an inseparable 1:3
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Article
Z/E mixture; Rf (1:3 EtOAc/hexane) 0.53. Anal. Calcd for C34H36O5S:
2,6-Dimethylphenyl 3,4,6-tri-O-benzyl-2-deoxy-2-iodo-1-thio-α/
β-D-allopyranoside (15e): yellowish syrup; yield 123 mg (49%) as
an inseparable 1:25 α/β mixture; Rf (1:3 EtOAc/hexane) 0.45. Anal.
Calcd for C35H37IO4S: C, 61.76; H, 5.48; S, 4.71. Found: C, 62.03; H,
C, 73.35; H, 6.52; S, 5.76. Found: C, 73.19; H, 6.35; S, 5.56. Selected
1
data for Z-14d: H NMR (400 MHz, CDCl3) δ 7.38−7.19 (m, 17H),
6.88 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 9.2 Hz, 1H), 5.85 (appt, J = 9.2,
9.2 Hz, 1H), 4.92−4.44 (m, 6H), 4.28 (dd, J = 9.2, 4.8 Hz, 1H), 3.96
(m, 1H), 3.81 (s, 3H), 3.71−3.58 (m, 3H), 3.00 (d, J = 4.4 Hz, 1H).
Data for E- 14d: 1H NMR (400 MHz, CDCl3) δ 7.38−7.19 (m, 17H),
6.87 (d, J = 8.8 Hz, 2H), 6.38 (d, J = 15.2 Hz, 1H), 5.60 (dd, J = 15.2,
8.0 Hz, 1H), 4.92−4.44 (m, 5H), 4.38 (d, J = 11.2 Hz, 1H), 4.13 (dd, J
= 8.0, 4.0 Hz, 1H), 3.98 (m, 1H), 3.80 (s, 3H), 3.63−3.49 (m, 3H),
2.75 (d, J = 4.8 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) δ 159.8,
138.18, 138.15, 138.1, 137.4, 134.1, 130.2, 128.5−127.7, 125.3, 115.1,
80.9, 79.4, 74.4, 73.5, 71.9, 71.0, 70.7, 55.5.
1
5.32; S, 4.66. Data for β-15e: H NMR (400 MHz, CDCl3) δ 7.42−
7.04 (m, 18H), 4.90 (d, J = 11.2 Hz, 1H), 4.89 (ddd, J = 10.0, 9.6, 6.4
Hz, 1H), 4.88 (d, J = 10.8 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.63 (d,
J = 11.2 Hz, 1H), 4.53 (d, J = 11.2 Hz, 1H), 4.47 (d, J = 11.2 Hz, 1H),
4.41 (d, J = 11.2 Hz, 1H), 4.27 (dd, J = 10.8, 2.0 Hz, 1H), 4.17 (dd, J =
2.0, 1.6 Hz, 1H), 3.76 (dd, J = 10.0, 1.6 Hz, 1H), 3.57 (m, 2H), 2.58
(s, 6H); 13C NMR (100.6 MHz, CDCl3) δ 144.7, 138.48, 138.46,
137.8, 131.6, 129.1, 128.7, 128.5, 128.31, 128.26, 128.14, 128.08,
128.0, 127.9, 127.8, 127.7, 86.6, 79.0, 76.5, 75.9, 75.8, 73.7, 72.4, 69.6,
31.4, 23.0.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-(2,6-dimethylphenyl)-
sulfanyl-D-arabino-hex-1-enitol (14e): yellowish syrup; yield 357 mg
(64%, 93% based on recovered starting material) as an inseparable
1:12 Z/E mixture; Rf (1:3 EtOAc/hexane) 0.65. Anal. Calcd for
C35H38O4S: C, 75.78; H, 6.90; S, 5.78. Found: C, 75.62; H, 6.87; S,
tert-Butyl 3,4,6-Tri-O-benzyl-2-deoxy-2-iodo-1-thio-α/β-D-man-
nopyranoside (16b). The isolated product decomposed in solution
and was therefore quickly subjected to the next reaction without
further characterization: yellowish syrup; yield 179 mg (57%) as an
inseparable >49:1 α/β mixture; Rf (1:3 EtOAc/hexane) 0.46. Anal.
Calcd for C31H37IO4S: C, 58.86; H, 5.90; S, 5.07. Found: C, 58.67; H,
5.89; S, 4.99. Selected data for α-16b: 1H NMR (400 MHz, CDCl3) δ
7.42−7.16 (m, 15H), 5.73 (s, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.81 (d, J
= 3.9 Hz, 1H), 4.77 (d, J = 12.1 Hz, 1H), 4.69 (d, J = 11.4 Hz, 1H),
4.48 (m, 3H), 4.30 (ddd, J = 9.0, 3.9, 1.6 Hz, 1H), 4.01 (dd, J = 9.0, 8.6
Hz, 1H), 3.87 (dd, J = 11.0, 3.9 Hz, 1H), 3.68 (dd, J = 11.0, 1.6 Hz,
1H), 3.04 (dd, J = 8.6, 3.9 Hz, 1H), 1.36 (s, 9H); 13C NMR (100.6
MHz, CDCl3) δ 138.3−127.7, 89.9, 77.8, 76.8, 75.6, 73.6, 73.6, 71.3,
68.9, 44.7, 35.0, 31.6.
General Procedure for Glycosylation. A solution of the glycosyl
donor (1 mmol) and cholesterol 17 (2 mmol) in anhydrous CH2Cl2
(4 mL) was stirred with 4 Å molecular sieves (1 g) at −78 °C for 2 h.
NIS (2.2 mmol) and TfOH (0.2 mmol) were then added, and the
reaction temperature was allowed to increase depending on the
reactivity of the substrate. The reaction progress was monitored by
TLC. The mixture was diluted with CH2Cl2 and washed with saturated
aqueous Na2S2O3 and NaHCO3. The combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by chromatographic techniques.
Cholesteryl 3,4,6-tri-O-benzyl-2-deoxy-2-iodo-α/β-D-mannopyr-
anoside12 (18): yellowish foam; yield 174 mg (69%) as an inseparable
37:1 α/β mixture; Rf (1:3 EtOAc/hexane) 0.63. Anal. Calcd for
C54H73IO5: C, 69.81; H, 7.92. Found: C, 69.79; H, 7.92. Data for α-18:
1H NMR (400 MHz, CDCl3) δ 7.49−7.15 (m, 15H), 5.38 (s, 1H),
5.28 (d, J = 5.2 Hz, 1H), 4.85 (d, J = 10.8 Hz, 1H), 4.73 (d, J = 12.0
Hz, 1H), 4.71 (d, J = 11.6 Hz, 1H), 4.53−4.46 (m, 4H), 3.96−3.87
(m, 2H), 4.81 (dd, J = 10.8, 4.4 Hz, 1H), 3.71 (dd, J = 10.8, 1.2 Hz,
1H), 4.48 (m, 1H), 3.36 (dd, J = 8.0, 4.0 Hz, 1H), 2.40−0.67 (m,
43H); 13C NMR (100.6 MHz, CDCl3) δ 140.6, 138.6−138.0, 129.1−
127.1, 122.2, 99.6, 77.6, 77.2, 76.1, 75.6, 73.4, 72.2, 71.0, 69.0, 56.3−
12.0, 34.6.
1
5.72. Selected data for Z-14e: H NMR (400 MHz, CDCl3) δ 7.39−
7.10 (m, 18H), 6.03 (d, J = 10.0 Hz, 1H), 5.78 (dd, J = 10.0, 8.8 Hz,
1H), 4.72 (dd, J = 8.8, 6.8 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 4.47 (d,
J = 11.6 Hz, 1H), 4.42 (s, 2H), 4.41 (d, J = 11.6 Hz, 1H), 4.30 (d, J =
11.6 Hz, 1H), 3.91 (m, 1H), 3.74 (dd, J = 6.8, 3.6 Hz, 1H), 3.65 (d, J =
4.0 Hz, 2H), 3.02 (d, J = 5.6 Hz, 1H), 2.46 (s, 6H). Data for E-14e: 1H
NMR (400 MHz, CDCl3) δ 7.39−7.10 (m, 18H), 6.20 (d, J = 15.2 Hz,
1H), 5.12 (dd, J = 15.2, 8.8 Hz, 1H), 4.58 (d, J = 11.6 Hz, 1H), 4.47
(d, J = 11.6 Hz, 1H), 4.42 (s, 2H), 4.41 (d, J = 11.6 Hz, 1H), 4.30 (d, J
= 11.6 Hz, 1H), 4.06 (dd, J = 8.8, 3.6 Hz, 1H), 3.91 (m, 1H), 3.52 (d, J
= 4.4 Hz, 2H), 3.47 (dd, J = 7.2, 3.6 Hz, 1H), 2.66 (d, J = 5.6 Hz, 1H),
2.47 (s, 6H); 13C NMR (100.6 MHz, CDCl3) δ 143.4, 138.21, 138.17,
138.0, 129.6, 129.0, 128.7, 128.59, 128.57, 128.4, 128.3, 128.2, 128.1,
127.93, 127.89, 127.8, 121.7, 81.4, 79.6, 74.5, 73.5, 71.0, 70.32, 70.31,
21.8.
(Z/E)-3,4,6-Tri-O-benzyl-1,2-dideoxy-1-(2,6-dichlorophenyl)-
sulfanyl-D-arabino-hex-1-enitol (14f): yellowish syrup; yield 464 mg
(78%) as an inseparable 1:6 Z/E mixture; Rf (1:3 EtOAc/hexane)
0.45. Anal. Calcd for C33H32Cl2O4S: C, 66.55; H, 5.42; S, 5.38. Found:
C, 66.61; H, 5.32; S, 5.27. Data for E-14f: 1H NMR (400 MHz,
CDCl3) δ 7.42−7.17 (m, 18H), 6.21 (d, J = 15.2 Hz, 1H), 5.40 (dd, J
= 15.2, 8.4 Hz, 1H), 4.62 (d, J = 11.2 Hz, 1H), 4.54 (d, J = 11.2 Hz,
1H), 4.45 (d, J = 11.2 Hz, 1H), 4.46 (s, 2H), 4.34 (d, J = 11.6 Hz, 1H),
4.11 (dd, J = 8.4, 7.2 Hz, 1H), 3.97 (m, 1H), 3.54−3.52 (m, 2H), 3.51
(dd, J = 7.2, 3.6 Hz, 1H), 2.62 (d, J = 5.2 Hz, 1H); 13C NMR (100.6
MHz, CDCl3) δ 141.3, 138.2, 138.1, 137.8, 131.0, 130.0, 129.2, 129.0,
128.9, 128.7, 128.5, 128.4, 128.1, 128.0, 127.9, 127.84, 127.8, 127.76,
126.4, 125.0, 81.2, 79.1, 74.4, 73.4, 71.3, 70.7, 70.1.
General Procedure for Iodonium-Induced Cyclization.
NaHCO3 (1.5 mmol) was added to a cold (−78 °C) solution of
alkenyl sulfide (1 mmol) in anhydrous CH2Cl2 (2 mL) under argon
atmosphere and the mixture stirred at the same temperature for 5 min.
NIS (1.5 mmol) was then added, and the reaction temperature was
allowed to increase depending on the reactivity of the substrate. The
reaction progress was monitored by TLC. The mixture was diluted
with CH2Cl2 and washed with saturated aqueous Na2S2O3. The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
chromatographic techniques.
Cholesteryl 3,4,6-tri-O-benzyl-2-deoxy-2-iodo-α/β-D-allopyrano-
side12 (19): yellowish foam; yield from 15b: 202 mg (95%) as an
inseparable 1:7 α/β mixture; yield from 15e 81 mg (60%) as an
inseparable 1:10 α/β mixture; Rf (1:3 EtOAc/hexane) 0.62. Anal.
Calcd for C54H73IO5: C, 69.81; H, 7.92. Found: C, 69.87; H, 7.89.
1
Data for β-19: H NMR (400 MHz, CDCl3) δ 7.47−7.06 (m, 15H),
5.35 (d, J = 5.2 Hz, 1H), 4.87 (d, J = 10.4 Hz, 1H), 4.86 (d, J = 9.0 Hz,
1H), 4.77 (d, J = 10.4 Hz, 1H), 4.66−4.50 (m, 4H), 4.18−4.01 (m,
3H), 3.73−3.64 (m, 3H), 3.48 (m, 1H), 2.39−0.67 (m, 43H); 13C
NMR (100.6 MHz, CDCl3) δ 143.6−127.7, 122.0, 99.3, 79.9, 78.6,
76.9, 75.8, 73.5, 73.2, 72.4, 69.6, 57.0, 56.3, 50.3, 42.5, 40.0, 39.7, 38.7,
37.4, 36.9, 36.4, 36.0, 33.4, 32.2, 32.0, 29.7, 28.4, 28.2, 24.5, 24.0, 23.0,
22.8, 21.2, 19.6, 18.9, 12.05.
tert-Butyl 3,4,6-tri-O-benzyl-2-deoxy-2-iodo-1-thio-α/β-D-allopyr-
anoside (15b): yellowish syrup; yield 181 mg (57%) as an inseparable
1:13 α/β mixture; Rf (1:3 EtOAc/hexane) 0.45. Anal. Calcd for
C31H37IO4S: C, 58.86; H, 5.90; S, 5.07. Found: C, 59.02; H, 5.72; S,
1
5.03. Data for β-15b: H NMR (400 MHz, CDCl3) δ 7.53−7.23 (m,
15H), 5.05 (d, J = 10.8 Hz, 1H), 4.92 (d, J = 11.2 Hz, 1H), 4.78 (d, J =
11.2 Hz, 1H), 4.64 (d, J = 11.2 Hz, 1H), 4.58 (d, J = 11.2 Hz, 1H),
4.52 (d, J = 11.2 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 4.19 (dd, J = 3.4,
2.8 Hz, 1H), 4.16 (ddd, J = 10.0, 9.6, 6.4 Hz, 1H), 3.69 (m, 2H), 2.89
(dd, J = 10.0, 3.4 Hz, 1H), 1.37 (s, 9H); 13C NMR (100.6 MHz,
CDCl3) δ 138.5, 138.4, 137.7, 134.2, 129.7, 128.7, 128.5, 128.3,
128.20, 128.16, 128.0, 127.8, 127.9, 127.3, 81.8, 78.8, 76.8, 75.9, 75.7,
73.6, 72.3, 69.8, 44.8, 32.3, 31.6.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H, 13C, and 31P NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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Article
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: omar.boutureira@urv.cat.
*E-mail: yolanda.diaz@urv.cat.
■
(25) Silveira, C. C.; Rinaldi, F.; Guadagnin, R. C. Eur. J. Org. Chem.
2007, 4935.
Notes
The authors declare no competing financial interest.
(26) Trost, B. M.; Tanigawa, Y. J. Am. Chem. Soc. 1979, 101, 4743.
(27) (a) Greenway, K. T.; Bischoff, A. G.; Pinto, B. M. J. Org. Chem.
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ACKNOWLEDGMENTS
We thank the Ministerio de Economıa y Competitividad, Spain
(CTQ2011-22872BQU), for generous financial support. O.B.
thanks the Ministerio de Ciencia e Innovacion, Spain (Juan de
́
la Cierva Fellowship), and the European Commission (Marie
Curie Career Integration Grant).
■
́
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