Tuning the Chemoselectivity of Silyl Protected Rhamnals by Temperature and Br?nsted Acidity: Kinetically Controlled 1,2-Addition vs Thermodynamically Controlled Ferrier Rearrangement

Article abstract of DOI:10.1021/acs.orglett.9b00009

An acidity- and temperature-dependent chemoselective glycosylation of silyl-protected rhamnals with alcohols has been revealed. The reaction undergoes a 1,2-addition pathway with (±)-CSA as the catalyst at rt, affording kinetically controlled 2-deoxyl rhamnosides. In contrast, only thermodynamically controlled 2,3-unsaturated rhamnosides are formed via Ferrier rearrangement when elevating reaction temperature to 85 °C or using CF₃SO₃H instead. This tunable glycosylation allows facile and practical access to both 2-deoxyl and 2,3-unsaturated rhamnosides with excellent yields and high α-stereoselectivity.

Full text of DOI:10.1021/acs.orglett.9b00009

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Tuning the Chemoselectivity of Silyl Protected Rhamnals by
Temperature and Brønsted Acidity: Kinetically Controlled 1,2-
Addition vs Thermodynamically Controlled Ferrier Rearrangement
Jincai Wang,†,‡ Chuqiao Deng,†,‡ Qi Zhang,*,‡ and Yonghai Chai*,†,‡
†Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, Xi’an, Shaanxi 710119, P. R. China
‡School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an, Shaanxi 710119, P. R. China
S
* Supporting Information
ABSTRACT: An acidity- and temperature-dependent chemoselective glycosylation of silyl-protected rhamnals with alcohols
has been revealed. The reaction undergoes a 1,2-addition pathway with ( )-CSA as the catalyst at rt, affording kinetically
controlled 2-deoxyl rhamnosides. In contrast, only thermodynamically controlled 2,3-unsaturated rhamnosides are formed via
Ferrier rearrangement when elevating reaction temperature to 85 °C or using CF3SO3H instead. This tunable glycosylation
allows facile and practical access to both 2-deoxyl and 2,3-unsaturated rhamnosides with excellent yields and high α-
stereoselectivity.
Scheme 1. Acidity- and Temperature-Dependent
Chemoselective Glycosylation of Rhamnals
1,2-Glycals, a kind of important synthon, have attracted
increasing attention due to its easy preparation, good stability,
and ready functionalization into different chemo-, regio-, and
stereovarieties. They thus have been broadly employed in the
synthesis of a large number of carbohydrates and other useful
chiral compounds.1 The coupling reaction between 1,2-glycals
and alcohols under acidic conditions enables the preparation of
2-deoxy glycosides through 1,2-addition.2 The 2-deoxy sugars
are important structural frames found in many bioactive
natural products3 and drug molecules,4 such as the
anthracycline antibiotic daunorubicin,4b the anticancer drug
doxorubicin,4c and so on. Interestingly, the reaction of 1,2-
glycals with hydroxyl compounds can also lead to 2,3-
unsaturated glycosides via Ferrier rearrangement pathway
under certain acidic conditions.5 The olefinic moiety in the
pyran or furan rings of 2,3-unsaturated glycosides can be
further diversified, and they are consequently served as
important chiral intermediates in organic synthesis. Although
various catalytic systems have been developed to construct
either 2-deoxy glycosides2,6 or 2,3-unsaturated glycosides,5,7
there are only a few studies8 on the chemoselectivity for the
glycosylation of 1,2-glycals with nucleophiles which has two
competing reaction pathways, 1,2-addition and Ferrier
rearrangement, as well as influential factors on the selectivity.
Herein, we report an acidity- and temperature-dependent
chemoselective glycosylation of silyl protected rhamnals with
various alcohol acceptors (Scheme 1). 2-Deoxyl rhamnosides
3, which are key scaffolds in a wide spectrum of bioactivities,9
were predominantly formed via the kinetic 1,2-addition
pathway when a relatively weaker acid (( )-CSA) and lower
reaction temperature (rt) were applied. In contrast, a stronger
acid (CF3SO3H) or higher reaction temperature (85 °C) only
provided 2,3-unsaturated rhamnosides 4, versatile intermedi-
ates in organic synthesis,10 via a thermodynamic Ferrier
rearrangement pathway. This tunable glycosylation is facile and
practical for the synthesis of both 2-deoxyl and 2,3-unsaturated
rhamnosides with excellent yields and high α-stereoselectivity.
In addition, the kinetic addition products 3 can be converted
to the rearranged products 4 via glycals 1 when heated with
catalytic amounts of ( )-CSA.
Our study commenced by using bulky silyl TBDPS
protected rhamnal 1a as a glycosyl donor and menthol 2a as
an acceptor in the presence of various acid catalysts at rt
(Table 1). No reaction took place when thiourea (pKa 8.5)11a
Received: January 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00009
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Letter
without any formation of 3aa detected (entry 5). Further
exploration was conducted on different silyl protected donors
1b and 1c with menthol 2a. For TIPS-protected glycal 1b,
none of the addition product 3ba or rearranged product 4ba
was observed with AcOH as the acid catalyst (entry 6). As
expected, when using ( )-CSA as the catalyst, the 1,2-addition
product 3ba could be obtained as the major product (70%, α/
β 2.8:1) with the rearranged product 4ba as the minor product
(23%, α/β> 20:1, entry 7). When a catalytic amount of
CF3SO3H was applied, the rearranged product 4ba was formed
in 92% yield (α/β 16:1) with no formation of 3ba (entry 8).
Unfortunately, the reaction of TBS-protected glycal 1c with
menthol 2a led to complex mixtures under the current acidic
catalyst system (entry 9), presumably due to the acidic lability
of TBS protecting group. The outcomes of the above
experiments (entries 1−8) suggest that the silyl protected
rhamnal donors tend to undergo 1,2-addition to provide 2-
deoxyglycosides under the catalysis of an appropriate acid
(such as ( )-CSA). However, the competing Ferrier
rearrangement would progressively become the prevailing
reaction pathway with the increase of the acidity of the catalyst.
When the acid strength reaches a certain threshold (for
example, CF3SO3H, pKa −14), only Ferrier rearrangement
occurs with no 1,2-addition product observed. It should be
noted that this interesting phenomenon is only observed from
the silyl protected glycal donors (1a and 1b) while other
rhamnal donors, such as the acyl or benzyl protected one (1d
and 1e), does not show this acidity-dependent behavior
(entries 10−13).
Table 1. Catalyst Screening for Chemoselective
Rhamnosylation of Different Donors 1a−1e with Acceptor
a
2a
After exploring the effect of catalyst acidity on the
rhamnosylation, we next investigated the effect of the reaction
temperature. Various rhamnals 1a−1e were reacted with 2a in
the catalysis of ( )-CSA at different temperatures (Table 2). It
was observed that the increase of the reaction temperature led
to the sharp decrease of the ratio of the addition product 3aa
to the rearranged product 4aa using the TBDPS-protected
glycal 1a as the substrate (entries 1−7). When the temperature
rose to 85 °C, 4aa could be gained in excellent yields with high
α-selectivity without any 3aa observed (entry 7). The TIPS-
protected glycal 1b behaved similar to the case where low
temperature favors 1,2-addition and high temperature favors
Ferrier rearrangement (entries 8−11). To our surprise, no such
behavior was observed on acyl or benzyl protected glycal 2c or
2d (entries 12−15). It seems that the bulky silyl protecting
groups at C3 and C4 play significant roles in both the acidity-
and temperature-dependent chemoselectivity for the glyco-
sylation of rhamnals with acceptors, probably due to the steric
hindrance and stereoelectronic characteristics of the bulky silyl
groups. It has been reported that bulky silyl protecting groups
on glycosyl donors have great impact on the glycosylation,
such as enhancing the reactivity of donors12 and contributing
the stereoselectivity for anomers,13 by conformational change
or restriction. In our case, the silylation of the hydroxyl groups
in rhanmals probably induces a distinctive difference in the
activation energy of the two pathways and, as a result, leads to
the chemoselectivity between the 1,2-addition and Ferrier
rearrangement pathway.
a
Reaction of donor 1, acceptor 2a (1.2 equiv), and catalyst (0.1
b
equiv) in DCM at rt under Ar atmosphere. Isolated yield.
c
1
Determined by H NMR spectra of the reaction mixture.
or acetic acid (pKa 4.76)11b was used as an acid catalyst, and
the glycal donor 1a was recovered completely (entries 1−2).
When ( )-CSA (pKa 1.17)11c was taken as the acid catalyst, to
our delight, the 1,2-addition product, 2-deoxy rhamnoside 3aa,
was obtained as the major product in 88% yield with excellent
anomeric α-selectivity (α/β 18:1). Meanwhile, a small amount
of 2,3-unsaturated glycoside 4aa from the competing Ferrier
rearrangement was also observed (9%, α/β 15:1) (entry 3).
Interestingly, when the reaction was treated with catalytic
amounts of TsOH·H2O (pKa −2.8),11d the yield of the
addition product 3aa decreased (from 88% to 75%, entries 3
and 4) while that of 4aa increased remarkably (from 9% to
23%, entries 3 and 4). More interestingly, when strong acid
CF3SO3H (pKa −14)11c was employed, the Ferrier rearranged
product 4aa could be obtained in 85% yield (α/β 16:1)
Based on the above findings, we hypothesized that the
glycosylation of 3,4-silyl protected rhamnals with hydroxyl
compounds could undergo two competing pathways to deliver
different products. When a relatively weaker acid is used as the
catalyst at lower temperature, the 1,2-addition reaction
prevails, leading to the kinetically controlled product 2-deoxy
B
DOI: 10.1021/acs.orglett.9b00009
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Table 2. Investigation of the Effect of Temperature on
Chemoselective Rhamnosylation
Scheme 2. Investigation of the Transformation of α-3aa into
4aa through Variable-Temperature H NMR Experiments
a
1
Figure 1. Crude 1H NMR spectra (in toluene-D8) of the
transformation of α-3aa into 4aa at different temperatures: (a) rt
(black), (b) 40 °C for 1 h (blue), (c) 60 °C for 1 h (red), (d) 85 °C
for 2 h (green).
intermediate for the conversion of 3aa to 4aa, was also
detected during the variable-temperature 1H NMR experi-
ments (Figure 1b and c). When the temperature was further
elevated to 85 °C, most of α-3aa was transformed into 4aa in 2
h (Figure 1d). The results provide strong support for our
assumption that 2-deoxy rhamnosides 3 from 1,2-addition are
the kinetic products and are favored under kinetic control,
while 2,3-unsaturated rhamnosides 4 from Ferrier rearrange-
ment are the thermodynamic products and are favored under
thermodynamic control.
To examine the generality of our observation, various
acceptors 2a−2h were subjected to the glycosylation under the
kinetically controlled conditions of 0.1 equiv of ( )-CSA in
DCM at rt (Table 3, condition A). The reaction between 1a
and different nonsugar acceptors 2b−2d, regardless of primary
or second alcohol, steroidal or terpenoidal alcohol, performed
well and gave the corresponding kinetically controlled α-2-
deoxyl rhamnosides 3ab−3ad in excellent yields (entries 1−3,
condition A). The sugar-based acceptors 2e−2h, including
glucosyl, galactosyl, and rhamnosyl ones, were also smoothly
coupled with 1a to furnish the oligosaccharides 3ae−3ah in a
chemoselective manner with excellent yields and high α-
selectivity (entries 4−7, condition A). In all cases, the
kinetically controlled adducts 3 were obtained as the major
products (yields: 83−90%) with only a small ratio of
thermodynamic products 4 (ratio of 3/4: 7:1−36:1) observed,
demonstrating the usefulness of our findings in the synthesis of
2-deoxy rhamnosides and oligosaccharides.
a
Reaction of donor 1, acceptor 2a (1.2 equiv), and ( )-CSA (0.1
b
equiv) in DCM at rt under Ar atmosphere. Isolated yield.
c
d
Determined by 1H NMR spectra of the reaction mixture. 1,2-
DCE was used as solvent.
The glycosylations of 1a with 2a−2h were also evaluated
under the thermodynamically controlled conditions (Table 3,
conditions B and C). With the treatment of 0.1 equiv of
( )-CSA in 1,2-DCE at 85 °C, 2,3-unsaturated rhamnosides/
disaccharides 4 were formed in excellent yields with high α-
selectivity via the thermodynamically favored Ferrier rearrange-
ment, without formation of the addition products 3 (entries
1−7, condition B). Gratifyingly, this catalytic system tolerated
a number of commonly employed protecting groups, such as
isopropylidene acetals, bulky silyl ethers, benzoates, and allyl
ethers. When CF3SO3H was used as the catalyst, the Ferrier
rearrangement was still the dominant reaction pathway,
affording the corresponding 4 as major products (entries 1−
rhamnoside 3. In contrast, a stronger acid catalyst or higher
reaction temperature favors the pathway of Ferrier rearrange-
ment, resulting in the thermodynamically more stable product
2,3-unsaturated rhamnosides 4. To confirm our hypothesis,
variable-temperature 1H NMR experiments were carried out to
monitor the transformation of 3aa into 4aa in an NMR tube in
the presence of 0.1 equiv of ( )-CSA in toluene-D8 (Scheme
2 and Figure 1). After being placed at 40 °C for 1 h, 3aa
started to convert into 4aa (Figure 1b). More 4aa was formed
after the mixture was placed at 60 °C for 1 h. It should be
noted that 3,4-silyl protected glycal 1a, the key elimination
C
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In conclusion, we have developed a chemoseletive
glycosylation of rhamnals by controlling the acidity and the
reaction temperature. By using ( )-CSA as the catalyst at
lower temperature, the 1,2-addition reaction prevails and gives
the kinetic adducts as the major products. The Ferrier
rearrangement products are formed when strong acid catalyst
CF3SO3H or elevated temperature is employed. The protecting
groups on the glycals are also proven to affect the
chemoselectivity, and the bulky silyl group TBDPS gives the
best result. The reactions of TBDPS-protected rhamnals with
alcohol acceptors under kinetic or thermodynamic conditions
proceed efficiently to afford the corresponding products in
good to excellent yields with high stereoselectivity and should
therefore have widespread applications in the synthesis of
rhamnosides and disaccharides. To the best of our knowledge,
it is the first time it has been disclosed that the chemo-
selectivity of 1,2-rhamnals can be regulated by the change of
reaction temperature and Brønsted acidity of acid catalysts via
introducing bulky silyl protecting groups.
Table 3. Rhamnosylation of 1a with Various Hydroxyl
Acceptor 2 under Kinetic and Thermodynamic Control
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00009.
1
Experimental details, H and 13C NMR spectra for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: qiqizhang@snnu.edu.cn.
*E-mail: ychai@snnu.edu.cn.
ORCID
Qi Zhang: 0000-0002-9306-055X
Yonghai Chai: 0000-0003-3157-179X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21472119, 21302119), Ministry of
Science and Technology (No. 2012ZX09502-001-001), and
the Fundamental Research Funds for the Central Universities
(GK201701002, GK201603036). All of the financial support is
gratefully acknowledged.
a
Condition A: reaction of donor 1a, acceptor 2 (1.2 equiv), and
b
( )-CSA (0.1 equiv) in DCM at rt under Ar atmosphere. Condition
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