The tertiary-butyl group: Selective protection of the anomeric centre and evaluation of its orthogonal cleavage

Article abstract of DOI:10.1016/j.tetlet.2018.04.048

The tertiary-butyl group has not been examined extensively as a protecting group. In this work, we describe the synthesis of tert-butyl glycosides via the Fischer glycosylation protocol. Furthermore, its utility as a temporary anomeric protecting group was evaluated. A range of differentially protected monosaccharides was used to investigate the stability of the tert-butyl group upon the introduction of other protecting groups; and compatibility of its cleavage in the presence of the latter.

Full text of DOI:10.1016/j.tetlet.2018.04.048

Accepted Manuscript
The tertiary-butyl group: Selective protection of the anomeric centre and eval-
uation of its orthogonal cleavage
Afraz Subratti, Nigel Kevin Jalsa
PII:
S0040-4039(18)30518-5
https://doi.org/10.1016/j.tetlet.2018.04.048
TETL 49911
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Accepted Date:
22 March 2018
18 April 2018
Please cite this article as: Subratti, A., Jalsa, N.K., The tertiary-butyl group: Selective protection of the anomeric
centre and evaluation of its orthogonal cleavage, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2
018.04.048
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Graphical Abstract
The tertiary-butyl group: Selective protection of the
anomeric centre and evaluation of its orthogonal cleavage
Leave this area blank for abstract info.
Afraz Subratti
Nigel Kevin Jalsa*

1
Tetrahedron Letters
journal homepage: www.els evier.com
The tertiary-butyl group: Selective protection of the anomeric centre and
evaluation of its orthogonal cleavage
*
Afraz Subratti, Nigel Kevin Jalsa
Department of Chemistry, The University of the West Indies, Trinidad and Tobago
ARTICLE INFO
ABSTRACT
Article history:
Received
The tertiary-butyl group has not been examined extensively as a protecting group. In this work,
we describe the synthesis of tert-butyl glycosides via the Fischer glycosylation protocol.
Furthermore, its utility as a temporary anomeric protecting group was evaluated. A range of
differentially protected monosaccharides was used to investigate the stability of the tert-butyl
group upon the introduction of other protecting groups; and compatibility of its cleavage in the
presence of the latter.
Received in revised form
Accepted
Available online
Keywords:
Tertiary-butyl
Glycoside
2
017 Elsevier Ltd. All rights reserved.
Anomeric centre
Regioselectivity
Orthogonal
Carbohydrates are well known for their complexity and
diversity in nature. This facilitates their roles in biological
groups listed, the methyl, allyl and benzyl allow for selective
introduction on a free sugar via a Fischer glycosylation pathway.
This acid catalyzed reaction in the presence of excess alcohol is
1
systems and hence makes them attractive synthetic targets for a
variety of medicinal purposes. In constructing mimics of
2
,3
18
attractive and indispensable, due to its anomeric selectivity.
naturally occurring glycoconjugates and oligosaccharide1s,4,
The tert-butyl group, like most ethers, is stable to many
conditions encountered. It can however be cleaved under milder
conditions when compared to other alkyl ethers. Despite this, it is
glycoside bond formation is
Consequently, there is always
a
common challenge.
demand for alternative
a
glycosylation strategies and a critical step in such techniques is
the choice of protection for the anomeric centre on the donor
molecule. Some anomeric protecting groups are bifunctional
since they can also act as a leaving group upon activation to
1
9
not among the more popular protecting groups. Its utility has
been demonstrated for the protection of alcohols in non-
carbohydrate systems, using isobutylene together with different
5
20
facilitate glycosylation. More commonly however, the anomeric
combinations of reagents such as: (1) BF .Et O, H PO ; (2)
3
2
3
4
2
Amberlyst H-15; as well as using t-
1
22
protection is removed, subsequent to which an appropriate
leaving group is installed. In this latter case, an ideal candidate
should be: (1) selectively and easily installed; (2) stable to further
modifications on the molecule and; (3) deprotected relatively
easily, yielding the hemiacetal while preserving the remaining
(3) H SO ;
2
4
2
3
BuOC(=NH)CCl and BF .Et O. The systems protected include
3
3 2
cyclic ketones, halohydrins, acetylenic alcohols, esters and
ethers. Various methods have also been developed for its
selective cleavage under acidic conditions. Some of these
6
groups.
24
25
include: (1) anhydrous CF COOH; (2) HBr/AcOH; (3)
3
2
6
27 28
2 3
TBDMSOTf; (4) HCO H; and CeCl /NaI. There exist very
Currently, there are a number of anomeric protecting groups
that are employed in oligosaccharide synthesis. Some of the more
9
little precedent for its usage in carbohydrate derivatives. In most
cases, tert-butanol has been employed as an acceptor in
evaluating new glycosylation protocols. Lindberg described the
synthesis of a tert-butyl glucoside via the Koenigs-Knorr method
7
8
popular ones include the O-methyl, O-allyl, p-methoxyphenyl,
1
0
11
p-nitrobenzyl, n-pentenyl, TMSEt, thioglycosides, O-
12
13
14
15
benzyl, and more recently the N,O-dimethylhydroxylamine,
2
9
16
of glycosylation using Hg(O₂CCH₃)₂ as the promoter. Further
work done in investigating the action of strong acids on these
acetylated glucosides indicated that selective deprotection of the
and the 1-methyl 1’-cyclopropylmethyl. Each of these has their
relative advantages and associated drawbacks. The lack of an
ideal anomeric protecting group is what spurs research in this
area. One of the major problems encountered with many of these
groups involves the need to perform multistep protocols to allow
for their installation with differential protection around the
3
0
3
tert-butyl group was achieved using BCl in moderate yields. A
similar study was also undertaken using instead silver salicylate
as the promoter, and selective cleavage of the glycoside was
3
1
achieved with CF COOH. Other activators also investigated
1
7
3
molecule. Depending on the nature of the reactions involved,
this can result in a significantly low overall yield. Among the
29 32 33
include:
Ag
2
O;
HgO;
and
2 2
Hg(CN) /HgBr .

2
Tetrahedron
Table 1
Synthesis of Tert-butyl Glycosides
o
1
. (CH ) COH, AcCl, 150 C, 48h
3 3
O
O
t
OH
O Bu
HO
AcO
Yield %
2
. Ac O, C H N, rt, 24h
2 5 5
Entry
Substrate
Product
Ratio α:β
5
8 (1a)
(1b)
3:1 (1a)
1
D-Glucose
8
α exclusively
tBuO
AcO
AcO
AcO
OAc
O
OAc
O
6
5 (2a)
0 (2b)
2
D-Mannose
α exclusively
1
AcO
AcO
2a
2b
t
t
O Bu
O Bu
3
4
L-Rhamnose
L-Fucose
61
64
β exclusively
0.7: 1
5
6
D-Xylose
D-Lyxose
65
61
1: 0.5
α exclusively
In glycosylations which employ the anomeric acetate as a leaving
group, the formation of ortho esters inevitably results in low
Man and as a result, a larger volume of the alcohol was required
for solvation. The other sugars exhibited poor solubility in the t-
BuOH. In an attempt to facilitate their dissolution and hence
reaction, an equal volume of DMF was added. With D-Gal, D-
Maltose and D-Gentiobiose, homogenous solutions were formed
3
4
yields of the target glycoside. Pavia et al. described the
synthesis of tert-butyl glycosides in yields of 60-90% using
3
5
isobutylene on acetylated reducing sugars. Cleavage of the
glycosides was effected using FeCl , both in the presence and
absence of acetic anhydride.
3
2
within 2 h. However, with D-GlcNAc and D-GlcNH .HCl, no
3
5
apparent solubilization was observed, even when DMSO was
used instead. This is not surprising as solubility problems exist
36
with these sugars even with the simpler alcohols.
We report herein a straightforward synthesis of tert-butyl
glycosides via the Fischer glycosylation method; using tert-butyl
alcohol with catalytic amounts of Lewis acid. Its stability under
conditions necessary for the introduction of common protecting
groups was also investigated. Furthermore, we evaluated its
selective removal in the presence of these protecting group
patterns. To the best of our knowledge this is the first report: (i)
detailing the synthesis of tert-butyl glycosides using the Fischer
glycosylation; and (ii) functionalizes the remaining hydroxyls on
the tert-butyl glycoside beyond an ester protection and testing for
the latter’s orthogonal cleavage.
Acetylation of the crude mixture was undertaken to aid in
37
purification of anomers (Table 1). The α anomer of the
glucopyranoside 1a was the major product, with minor quantities
of the β anomer and furanosides being detected. Recrystallization
from methanol afforded the pure β anomer. The mannoside, 2a,
was obtained exclusively in the α configuration. It is likely that
the bulkiness of the tert-butyl group destabilizes the cis-
38
glycosidic linkage, a common observation with D-Man.
Interestingly, both these hexopyranoses yielded the 1,6 di-
substituted compound, 1b and 2b respectively. Such products
have never been reported under typical Fischer conditions. A
plausible explanation revolves around the stability of a tert-butyl
carbocation which is unfavourable with the simple commonly
used alcohols. Nucleophilic attack by the 6-OH on the cation is
facilitated because of the former’s sterically accessible nature.
The impact of temperature, time, equivalents of catalyst, as
o
well as the volume of the alcohol were examined. Below 150 C,
extended reaction times (> 48h) were required for solubilization
of the free sugar. Refluxing beyond 48h did not yield any
appreciable improvement in product yield. The deoxy sugars, L-
Rha and L-Fuc, were the most soluble in the tert-butanol followed
by D-Xyl. D-Glc demonstrated a much lower solubility than D-

3
Table 2
Deprotection Conditions Attempted
No Reaction
Non-selective Cleavage
InCl
KB(CH
3
/TMSCl; NBS; ZnCl ; ZnI ; VCl
COOH; CCl
HCl.
2
2
3
; NaOH; NaH; KOH;
BCl
; BF .OEt
3 3
2
4 3 3 3
; TMSOTf; TfOH; NIS/TMSOTf; SnCl ; FeCl ; AlBr ; AlCl ;
3
)
3
H; TBAF; CH
3
3
COOH; Cu(OTf)
2
; LiCl;
3
CF COOH; HBr/AcOH.
Table 3
Cleavage of Tert-butyl Glycosides
CeCl , NaI
3
O
O
t
O Bu
OH
PO
o
PO
CH CN, 150 C, 24h
3
Entry
Substrate
Product
Yield %
1
1a
70
2
3
2a
3a
72
76
OH
O
AcO
AcO
OAc
3b
4
4a
74
5
6
5a
6a
75
65
7
8
9
73
74
60
65
10

4
Tetrahedron
The rhamnopyranoside, 3a, was obtained exclusively as the β
2). Compound 11a was subjected to the same deprotection
conditions and desilylation was observed selectively in over 70
% yield. With base labile groups present on a compound, it
provides a mild route to silyl ether deprotection. This is
especially advantageous since the existing strongly basic
anomer in 61 % yield. L-Fuc yielded both anomers with the β
being higher yielding. Xyloside, 5a was obtained in 43 % yield
of the α isomer and 22 % of the β. The resulting glycoside of D-
Lyx, 6a, was produced only as the α anomer. Though the D-Gal
was soluble in the t-BuOH/DMF system, no reaction occurred.
For the disaccharides, hydrolysis of the glycoside bond took
precedence over formation of the Fischer product. Significant
amounts of glucose were produced indicating that hydrolysis was
faster than glycoside formation. Glycosides 1a-6a were obtained
in yields ranging from 58-65 % (Table 1). These lower than usual
yields (for a Fischer Glycosylation) are likely due to the lability
of the existing tert-butyl protection under these conditions,
43
conditions may deprotect the anomeric acetate.
3
Scheme 2: Desilylation using CeCl /NaI
39
arising as a result of the stability of the tertiary carbocation.
Two possible mechanisms are likely. The first being the
proposal by Bartoli and co-workers in which an iodide ion
attacks the tertiary carbon resulting in tert-butyl iodide as the
byproduct. A second pathway may exist with carbohydrates,
which involves iodide attacking the anomeric centre of 13,
instead of the tertiary carbon, to yield the glycosyl halide 14
Deacetylation of compounds 1a and 2a was performed using
K
2
CO in methanol to give the free sugar, which was then further
functionalized. Substrates: 7a, 8a, 9a, and 10a, were synthesized
3
28
4
0
from the resulting glycosides. We were pleased to observe the
stability of the tert-butyl group under conditions necessary for the
introduction of O-Benzyl, O-Benzylidene and silyl protecting
groups. A variety of reagents were evaluated in order to achieve
selective cleavage of the tert-butyl group (Table 2). Even though
the tert-butyl protection is well known to be highly resistant
toward strong basic conditions, we speculated that isobutylene
(
Figure 1). Under these conditions the glycosyl halide will
44
readily hydrolyze to yield the hemiacetal, 15. We estimate that
the relative stability of the glycosyl cation will be greater than the
tertiary cation and hence our thoughts are more in favour with the
latter mechanism for these glycosides.
4
0
liberation may have been favoured in this case. Some of the
reagents produced no observable reactions while others, though
deprotecting the tert-butyl group, also caused removal of other
protecting groups present.
Bartoli and co-workers described the CeCl
the deprotection of tert-butyl ethers from a range of aliphatic and
3
/NaI protocol for
2
8
aromatic systems. Employing these reaction conditions gave no
reaction after 24 h. Cerium is highly oxophilic and owing to the
number of oxygen atoms on the sugar, excess cerium chloride
2
8
was added to compensate for this. We also found that using the
fully hydrated CeCl .7H O gave very sluggish reactions and as
Figure 1: Proposed mechanism of anomeric tert-butyl
cleavage
3
2
28
such, the anhydrous form was used. After 24 h almost complete
conversion of starting material was observed. Leaving the
reaction for a further 12 h resulted in no significant progression.
An examination was also undertaken to assess which of the tert-
butyl groups from 2b would be the most reactive under these
conditions. Results indicated that the primary tert-butyl was
selectively removed; however 4→6 O-acyl migration took place
subsequently under these conditions (Scheme 1). This type of
migration is known to occur under both acidic and basic
In summary, we have successfully demonstrated an efficient
method for the synthesis of tert-butyl glycosides. This route is
advantageous as it allows for selective installation on an
unprotected monosaccharide. Our method of deprotection allows
for selective cleavage with both acetate and benzyl protecting
groups present. It is a relatively cheap and simple procedure that
does not require any aqueous work up. Furthermore, in light of
the results obtained from the silylated substrate, we present a
method that selectively removes silyl ethers and which is also
orthogonal to both the acetate and benzyl groups.
4
1
conditions.
Acknowledgements
This work was supported by The University of the West Indies,
St. Augustine.
Supplementary data
Scheme 1: Tert-butyl cleavage and 4→6 O-acyl migration
Supplementary data (NMR data and spectra data) associated
with this article can be found….
Per-O-acetylated derivatives 1a-6a were deprotected
selectively to their corresponding hemiacetals in good yields of
over 70% (Table 3). Benzylated substrates 7a and 8a gave
slightly higher yields of deprotection. Unfortunately, these
conditions proved to be too harsh for both the benzylidene acetal
References:
,
,
1
.
Wang, C.C; Lee J.-C.; Luo S.-Y.; Kulkarni, S.S.;
Huang, Y.W.; Lee, C.C.; Chang, K.; Hung, S. Nature
2007, 446, 896-899.
9
a as well as the silyl ether 8a. Similar to Pavia’s method of tert-
35
butyl introduction using a glycosyl acetate; an alternative route
to synthesizing tert-butyl glycosides of the insoluble sugars was
2. Muthana, S.; Cao, H.; Chen, X. Curr. Opin. Chem.
Biol. 2009, 13, 573-581.
3. Shukla, R.K.; Tiwari, A. Crit. Rev. Ther. Drug 2011,
28, 255-292.
4
0
demonstrated with D-Glc.NH
trichloroacetimidate protocol.
2
.
This pathway utilized Schmidt’s
4
2
4
.
Nigudkar, S.S.; Demchenko, A.V. Chem. Sci. 2015, 6,
687-2704.
As a result of the above observation, we also attempted to
remove a silyl group from a protected monosaccharide (Scheme
2

5
5
6
.
.
Ye, X.S.; Guo, J. Molecules 2010, 15, 7235-7265.
Osborn, H.M.I. Carbohydrates: Best Synthetic
Methods; Academic Press: Reading, U.K., 2003; pp 10.
Kumar, A.; Doddi, V.R.; Vankar, Y.D. J. Org. Chem.
36. Wang, J.; Chang, C.T. Glycobiology and Drug
Design; American Chemical Society, 2012, pp 265–
286.
37. Ali, S.P.; Jalsa, N.K. J. Carbohydr. Chem. 2014, 33,
185-196.
38. Crich D. J. Carbohydr. Chem. 2002, 21, 667–690.
39. Alamiddine, Z.; Humbel. S. Front. Chem. 2013, 1, 37-
47.
7
8
9
1
1
.
.
.
2
008, 73, 5993-5995.
Wang, Y.; Liang, X.; Wang, P. Tetrahedron Lett. 2011,
2, 3912-3915.
Zhang, Z.Y.; Magnusson, G. Carbohydr. Res. 1996,
95, 41-55.
5
2
40. Details in supplementary data.
41. Dias, E.L.; Hettenbach, K.W.; Ende, D.J. Org. Process
Res. Dev. 2005, 9, 39–44.
42. Schmidt, R.R.; Michel, J. Angew. Chem. Int. Ed. Engl.
1980, 19, 731-732.
0. Fukase, K.; Yasukochi, T.; Nakai, Y.; Kusumoto, S.
Tetrahedron Lett. 1996, 37, 3343-3344.
1. Fraser-Reid, B.; Konradsson, P.; Mootoo, D.R.;
Udodong, U. J. Chem. Soc. Chem. Commun. 1988, 823-
8
25.
43. Corey, E.J.; Snider, B.B. J. Am. Chem. Soc. 1972, 94,
2549–2550.
44. Gervay-Hague, J. Acc. Chem. Res. 2016, 49, 35-47.
1
1
2. Jansson, K,; Ahlfors, S.; Frejd, T.; Kihlberg, J.;
Magnusson, G.; Dahmen, J.; Noorl, G.; Stenvall, K. J.
Org. Chem. 1988, 53, 5629-5647.
3. Seeberger, P.H.; Haase, W.C. Chem. Rev. 2000, 100,
4
349-4394.
4. Jalsa, N.K. Tetrahedron Lett. 2011, 52, 6587-6590.
5. Dasgupta, S.; Nitz, M. J. Org. Chem. 2011, 76, 1918-
1
1
1
921.
6. Yu, S.H.; Whitfield, D.M. Tetrahedron 2011, 67, 5750-
761.
7. Codee, J.D.C.; Ali, A.; Overkleeft, H.S.; van der Marel,
G.A. C. R. Chimie 2011, 14, 178-193.
1
1
5
1
1
8. Fischer, E. Chem. Ber. 1893, 26, 2400–2412.
9. Greene, T.W.; Wuts, P.G. Protective Groups in
Organic Synthesis; Wiley: New York, 1991; pp 82.
0. Micheli, R.A.; Hajos, Z.G.; Cohen, N.; Parrish, D.R.;
Portland, L.A.; Sciamanna, W.; Scott, M.A.; Wehrli,
P.A. J. Org. Chem. 1975, 40, 675-681.
2
2
2
2
2
2
2
2
2
1. Alexakis, A.; Duffault, J.M. Tetrahedron Lett. 1988, 29,
6
243-6246.
2. Beyerman, H.C.; Bontekoe, J.S. Proc. Chem. Soc. 1961,
49-253.
2
3. Armstrong, A.; Brackenridge, I.; Jackson, R.F.W.; Kirk,
J.M. Tetrahedron Lett. 1988, 29, 2483-2486.
4. Beyerman, H.C.; Heiszwolf, G.L. J. Chem. Soc. 1963,
7
55-757.
5. Callahan, F.M.; Anderson, G.W.; Paul, R.; Zimmerman,
J.E. J. Am. Chem. Soc. 1963, 85, 201-207.
6. Franck, X.; Figadere, B.; Cave, A. Tetrahedron Lett.
1
995, 5, 711-714.
7. Paulsen, H.; Adermann, K. Liebigs Ann. Chem. 1989, 8,
51-769.
7
8. (a) Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.;
Marcantoni, E.; Melchiorre, P.; Sambri, L. Adv. Synth.
Catal. 2006, 348, 905–910. (b) Bartoli, G.; Giuliani,
A.; Marcantoni, E.; Massaccesi, M.; Melchiorre, P.;
Lanari, S.; Sambri, L. Adv. Synth. Catal. 2005, 347,
1
673-1679. (c) Bartoli, G.; Bosco, M.; Giuliani, A.;
Marcantoni, E.; Palmieri, A.; Petrini, M.; Sambri, L. J.
Org. Chem. 2004, 69, 1290-1297.
2
3
3
9. Lindberg, B. Acta Chem. Scand. 1949, 3, 151-156.
0. Lindberg, B. Acta Chem. Scand. 1948, 2, 426-429.
1. Van Heeswijk, W.A.R.; Hendrick, G.J.V.; Vliegenthart,
J.F.G. Carbohydr. Res. 1977, 58, 494-497.
3
2. Pavia, A.A.; Rakotomanomana, N.; Lacombe, J.M.
Carbohydr. Res. 1988, 181, 246-252.
3
3
3. Helferich, B.; Ost, W. Chem. Ber. 1962, 95, 2612-2615.
4. Risbood, P.A.; Reed, L.A.; Goodman, L. Carbohydr.
Res. 1981, 88, 245-251.
3
5. Pavia, A.A.; Rakotomanomana, N.; Lacombe, J.M.
Carbohydr. Res. 1990, 9, 93-99.

6
Tetrahedron
Synthesis of tert-butyl glycosides in a single
•
step from the free sugars
•
•
•
Addition of popular protecting groups at
other positions in tert-butyl glycosides
Deprotection conditions of anomeric tert-
butyl group investigated
Tert-butyl group removal is compatible with
acetate and benzyl groups