Organic Letters
Letter
without the need for hydroxyl protecting groups. The scope of
this approach was then explored (Scheme 3). Selective
dehydration was carried out with an array of sugar dithioacetals
derived from aldose sugars, in moderate to excellent yields
(48−99%) for several pentose and hexose sugars (6a, 6b, 6e,
6f). However, some thioacetals, such as those derived from D-
ribose (5c), L-rhamnose (5d) and D-mannose (5g), gave little
to no conversion to the alkene. A common feature of the
unsuccessful substrates is anti-stereochemistry at the C-2 and
C-3 positions. This potentially provides a useful insight into
the mechanism of the reaction, which is likely to occur via
(reversible) formation of a cyclic carbonate at C-2/C-3,
through reaction of the polyol with dimethyl carbonate. This
then subsequently undergoes elimination by removal of the
acidic C-1 proton (Scheme 4).
Scheme 1. (a) Reductive cyclization of Silyl-Protected
Sugars;11−13 (b) Chiral THF Formation via the
Dehydration of Pentose Sugars;14,15 (c) This Work:
Regioselective Dehydration of Sugar Thioacetals
The stereochemical relationship between the C-2 and C-3
alcohols may well affect the ease with which the carbonate can
be formed (Scheme 4). As shown in structure 7c, sugars with
anti stereochemistry at C-2/C-3 (e.g., D-rib) will have to form
the more sterically hindered syn-cyclic carbonate. This
hindered carbonate may also disfavor alignment of the C-1
proton into the correct orientation for the subsequent E-2
elimination. In contrast, sugars with syn-stereochemistry at C-
2/C-3 (L-ara) will form the less hindered anti-cyclic carbonate
(e.g., 7a) which can easily adopt the required conformation for
E-2 elimination to generate the alkene. DFT calculations at the
M06-2X/6-31G(d,p) level confirmed that the free energy
change in going from 5a to 7a in methanol solution is ca. 21 kJ
mol−1 more negative than that going from 5c to 7c.
both pentoses and hexoses. In this paper, we describe methods
for the regioselective dehydration of sugar thioacetals at C-2
and C-3 under mild and scalable conditions to provide access
to novel chiral polyols and heterocycles (Scheme 1c).
Using L-arabinose, which is available from waste sugar beet
pulp,15,16 as a test substrate, the corresponding ethyl and
phenyl thioacetals were prepared via the reported proce-
dures.17,18 Treatment of the ethyl thioacetal with K2CO3/
dimethyl carbonate (DMC) led to the formation of a complex
mixture of products. However, reaction of the readily formed
phenyl thioacetal 5a18 under similar conditions led to the
formation of the ketene thioacetal 6a as a single product. In
addition, purification of the phenyl thioacetal derivative could
be achieved via recrystallization, avoiding the need for column
chromatography. Interestingly, unlike the reactions of the
corresponding hydrazones, the THF was not formed, and a
selective dehydration took place exclusively at the C-2 position
to give alkene 6a in near-quantitative yield on a 5 g scale
(Scheme 2).
Attempts to use more reactive electrophiles such as
carbonyldiimidazole with 5c failed to give any improvement
in the yield, indicating that the stereochemical relationship in
these starting materials presents a significant barrier to
successful dehydration under mild reaction conditions. An
alternative strategy was therefore considered for anti-sugars
which did not rely on the formation of a cyclic intermediate. It
was envisaged that conversion of the thioacetal 5c to the
corresponding peracetate could lead to sufficient activation of
the C-2 alcohol for it to act as a leaving group, facilitating
dehydration under basic conditions. Formation of the
peracetate derivatives with pyridine/Ac2O,21 prior to treatment
with a base was explored for the D-ribose, L-rhamnose, and D-
mannose thioacetal derivatives (Scheme 5). Following
acetylation, the protected sugars were stirred under basic
conditions and monitored for ketene thioacetal formation.
Although unreactive with K2CO3, the use of the stronger bases
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), TBD (1,5,7-
Scheme 2. Thioacetal Protection of L-Arabinose Followed
by Selective Dehydration under Mild Conditions14,18
t
triazabicyclo[4.4.0]dec-5-ene), and BuOK led to formation
of the desired products 8c, 8d, and 8g in 47−96% yields.
Different bases proved to be preferable for each example
studied.
With a series of sugar-derived ketene dithioacetals in hand,
we then went on to explore the reactivity of these novel
compounds (Scheme 6). We envisaged that reductive
desulfurization of the ketene acetal group could lead to
valuable chiral polyols containing a stereogenic center bearing
an ethyl group. Thus, reduction of the L-arabinose derivative
6a with Raney-Ni gave a triol 9, which was isolated as the
corresponding benzoate ester derivative 10 in 94% overall yield
(Scheme 6). Depending on the sugar used, chiral polyols of
this general structure could be useful in the synthesis of natural
products such as eicosatetraenoic acid (precursor 11),22
polysaccharides found in Gram-negative bacteria 12,23 and
The PhS groups in 5a make the C-1 proton fairly acidic, and
hence, it is clear that an elimination reaction can take place
readily when the C-2 hydroxyl group is activated by DMC.14
The formation of similar ketene dithioacetals has previously
been reported as a problematic side reaction in reactions of
protected derivatives with strong bases (e.g., sodium
methylsulfinylmethylide or n-BuLi).19,20 Given that our
reaction conditions are very mild, and that the reaction is
selective and high yielding, this potentially offers a readily
scalable method for the selective C-2 deoxygenation of sugars
2489
Org. Lett. 2021, 23, 2488−2492