Novel selectivity in carbohydrate reactions, IV: DABCO-mediated regioselective primary hydroxyl protection of carbohydrates

Article abstract of DOI:10.1080/00397910802656067

An efficient procedure for the regioselective tritylation of primary hydroxyl group of aldohexopyranosides and nucleosides using trityl chloride in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in dichloromethane has been developed. Subsequent acetylation of the tritylated products in the same pot has been made possible, thereby providing an efficient route to the fully protected carbohydrate derivatives that can be discriminated chemoselectively.

Full text of DOI:10.1080/00397910802656067

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Novel Selectivity in
Carbohydrate Reactions,
IV: DABCO-Mediated
Regioselective Primary
Hydroxyl Protection of
Carbohydrates
Bharat Kacheshwar Gadakh a , Premanand Ramrao
Patil a , Satish Malik a & K. P. Ravindranathan Kartha
a
a Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Research,
Punjab, India
Version of record first published: 01 Jun 2009.
To cite this article: Bharat Kacheshwar Gadakh , Premanand Ramrao Patil , Satish
Malik & K. P. Ravindranathan Kartha (2009): Novel Selectivity in Carbohydrate
Reactions, IV: DABCO-Mediated Regioselective Primary Hydroxyl Protection of
Carbohydrates, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:13, 2430-2438
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Synthetic Communications1, 39: 2430–2438, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802656067
Novel Selectivity in Carbohydrate Reactions, IV:
DABCO-Mediated Regioselective Primary
Hydroxyl Protection of Carbohydrates
Bharat Kacheshwar Gadakh, Premanand Ramrao Patil,
Satish Malik, and K. P. Ravindranathan Kartha
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Punjab, India
Abstract: An efficient procedure for the regioselective tritylation of primary
hydroxyl group of aldohexopyranosides and nucleosides using trityl chloride in
the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) in dichloromethane has
been developed. Subsequent acetylation of the tritylated products in the same
pot has been made possible, thereby providing an efficient route to the fully
protected carbohydrate derivatives that can be discriminated chemoselectively.
Keywords: DABCO-mediated alkylations, pyridine=DMF-free tritylation,
regioselective tritylation
INTRODUCTION
In continuation of our previous research,[1] a mechanochemical method
for the regioselective primary hydroxyl protection of hexosides and
nucleosides was recently reported from this laboratory.[2] The method
is solvent-free, thus eliminating the need for often-used solvents such as
pyridine and dimethylformamide (DMF).[3] However, we felt that until
the mixer mills like the planetary ball mill used in that work become a
Received October 3, 2008.
Address correspondence to K. P. Ravindranathan Kartha, Department of
Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research, Sector 67, S.A.S. Nagar, Punjab 160 062, India. E-mail: rkartha@
niper.ac.in
2430

DABCO-Mediated Regioselective Tritylation
2431
common feature of chemical laboratories worldwide, finding an more
environmentally favorable alternative to pyridine and DMF as solvent
for this reaction was needed. Moreover, some of the standard protocols
that have been in use by chemists and biochemists worldwide for the tri-
tylation reaction in pyridine often suffer from long reaction times and
by-product formation in addition to the requirement for above-ambient
reaction temperature.[4] Also, most of the frequently used systems, such
as triphenylmethylium perchlorate and 2,4,6-tri-tert-butylpyridine,[5]
trityl chloride and 4-N,N-dimethyl aminopyridine,[6] DBU,[7] and N-trityl
pyridiniumfluoroborate,[8] for this class of reactions are somewhat expen-
sive and are often required in stoichiometric proportions or in excess.
Therefore, investigations of a relatively cheaper reagent such as 1,4-
diazabicyclo[2.2.2]octane (DABCO) as an alternative to these would also
be desirable. With these points in mind, an examination of the suitability
of some of the other common organic solvents for regioselective trityla-
tion in the presence of bases such as DABCO was carried out.
RESULTS AND DISCUSSION
Based on our observation that regioselective 6-O-tritylation of methyl
a-D-glucoside (1) was most effective when conducted using 2.5 mol equiv
of each of TrCl (2) and DABCO (3) in the ball mill and from the fact that
the tritylated product obtained in the reaction possessed good solubility
in dichloromethane (DCM), our initial focus was on wet chemistry
experiments involving glucoside 1 as the substrate in the presence of 3
in DCM. Thus, when glucoside 1 was treated with 2 and 3 under the opti-
mized conditions for the solvent-free reactions in the ball mill in DCM at
rt, the tritylation reaction proceeded smoothly (as judged by thin-layer
chromatography (TLC): eluent, DCM–MeOH, 9:1). Complete consump-
tion of 2 occurred in 2 h, leading to the formation of the expected 6-O-
trityl glucoside 4 in virtually quantitative yield as a crystalline solid
(entry 1, Table 1) upon isolation by chromatographic filtration (silica
gel; eluent, EtOAc–n-hex, 4:1). The structure was confirmed by compar-
ison of the physical constants and spectral data obtained for the product
with those of authentic 4. As expected, no reaction was observed in the
absence of the base (entry 2, Table 1). Encouraged by these results, the
optimization of the reagent requirement for the reaction to proceed at
high efficiency was carried out (entries 3–7, Table 1). Thus, 1.5–2.0 mol
equiv each of TrCl and DABCO were found to be sufficient for the
tritylation product 4 to be obtained in yields of 90–98%.
The reaction using 2.0 mol equiv each of 2 and 3 as described
previously was then repeated in the presence of 10 mol% of DMAP to

2432
B. K. Gadakh et al.
Table 1. Regioselective tritylation of methyl-a-D-glucopyranoside (1): Optimiza-
tion of reaction conditiona
Reaction condition
TrCl (3) Yield of 4
(mol equiv) Time (h) (%, isolated)
Entry
Base (mol equiv)
DABCO (2.5)
None
DABCO (1.1)
DABCO (1.5)
DABCO (2.0)
DABCO (1.5)
DABCO (2.0)
DABCO (2) þ DMAP (5, 0.1)
DMAP (2.0)
1
2
3
4
5
6
7
8
9
2.5
2.5
1.1
1.5
2.0
2.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
24
24
24
3.5
3.5
6.5
3.5
50
98
No reaction
50
90
98
96
90
98
5–10
5–10
80
10
11
12
DMAP (2.0) þ TEA (5)
120
24
24
DBU (2.0)
Collidine (2.0)
84
aAll reactions were carried out using 1 mmol of glucoside 1 in CH2Cl2 (4mL) at rt.
study its effect, if any, on the reaction time (entry 8, Table 1) and no
perceivable rate-enhancement was observed. Also, dimethylaminopyride
(DMAP) either alone or in combination with triethylamine (TEA) was
also ineffective for the reaction (entries 9 and 10, Table 1). Other hindered
bases such as DBU and collidine gave good yields of the product but were
not as efficient as DABCO (entries 11 and 12, Table 1). Further, common
inorganic bases such as sodium hydroxide (NaOH) and potassium
hydroxide (KOH) were found to be completely ineffective (no reaction
was observed; results not shown).
As the solvent could be expected to influence the rate and outcome of
the reaction, the reactions were subsequently tried using various solvents.
Acetonitrile possesses better solubilization characteristics toward both
the expected product as well as its precursor and was found to be highly
efficient, giving the 6-O-tritylated product 4 in 96% yield in 2 h at rt.
Aromatic solvents such as toluene (no perceivable reaction up to 40 h
at rt) and oxygenated solvents such as Et2O (5–10% yield of 4 in 72 h

DABCO-Mediated Regioselective Tritylation
2433
at rt), THF (5–10% yield of 4 in 72 h at rt), dioxane (18% yield of 4 in 40 h
at rt), and EtOAc (5–10% yield of 4 in 72 h at rt) were unsuitable for the
reaction, as was seen from the very low yields obtained in the respective
cases. The 6-O-tritylation of glucoside 1 was also done in DMF, the con-
ventional solvent, in the presence of DABCO, and it was found that
although the desired product could be isolated in reasonably good yield
(79% yield of 4 in 50 h at rt), the alkylation was characteristically slow,
requiring more than 2 days for the reaction. Thus, the greatest and best
yields were obtained when the tritylation was carried out in MeCN or
DCM.
Several aldohexose derivatives were subsequently subjected to trityla-
tion reaction under the conditions optimized as before, and excellent
results were obtained in all cases. Thus, although the O-=S-galactosides
6, 8, and 10 as well as the mannoside 12 and the acetonides 16 and 18
reacted with TrCl in DCM in the presence of DABCO to afford the
respective tritylated products 7, 9, 11, 13, 17, and 19 in 90–98% yields
in 1–8 h at rt, the glucosamine derivative 14 required 24 h to give the cor-
responding 6-O-tritylated product 15 in 71% of isolated yield. See
Scheme 1. As expected, the secondary OH group in the di-O-isopropyli-
dene derivative 20 was extremely sluggish toward tritylation at rt, and
only 23% of the tritylated product 21 could be obtained after allowing
the reaction to take place for 60 h, thereby proving the high degree of
regioselectivity observed in other instances. The reaction of uridine (22)
with 3 as well as dimethoxytrityl (DMT) chloride in DCM in the presence
of DABCO was also highly successful, yielding the respective 50-O-ethers
23 and 24 in good yields after purification.
Scheme 1. Chemical structures 6–24.

2434
B. K. Gadakh et al.
As the overall objective was to develop an alternate procedure for the
fully acetylated 6-O-trityl-aldosides that did not require the use of pyridi-
ne=DMF for the reaction, the one-pot tritylation–acetylation protocol
was subsequently attempted on glucoside 1, and the results are summar-
ized in Table 2. As CH3CN was proved best suited for the initial trityla-
tion step in the two-step sequence, its suitability for the sequential
reaction was first investigated. Thus, after completion of the initial trity-
lation, the acetylation reaction was allowed to take place by adding Ac2O
(2 mol equiv per OH group) and DMAP (0.1 mol equiv) to the reaction
mixture. Complete acetylation was achieved in 6 h at rt as was shown
by TLC (EtOAc–n-hex, 1:3). Aqueous workup and purification on a
silica-gel column (eluent, EtOAc–n-hex, 1:4) afforded the expected pro-
duct 25 in 85% yield (entry 1, Table 2). A similar reaction carried out
in DCM (entry 2, Table 2), on the other hand, resulted in the formation
of 25 in nearly quantitative yield (98%). The acetylation reaction thus
proceeded significantly faster when DCM was employed as the solvent.
Reducing the amounts of DABCO and Ac2O (for the consecutive steps)
from 2 mol equiv to 1.5 mol equiv resulted in increased time for the acet-
ylation reaction as could be expected, although the product was obtained
in ꢀ96% yield (entries 3 and 4, Table 2) after extractive isolation and
Table 2. One-pot tritylation–acetylation: Optimization of reagent concentrationa
Reaction condition, step 1
Reaction condition, step 2
TrCl
(2, mol
Entry equiv)
DABCO
(3, mol
equiv)
DMAP
Time (5, mol
Ac2O
(mol
equiv)
Yield
(25,
%)
Time
(h)
Solvent (h)
equiv)
1
2
3
4
5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
2.0
MeCN 2.0
DCM 3.5
DCM 3.5
DCM 3.5
0.1
0.1
0.1
0.1
—
6.0
6.0
6.0
4.5
6.0
6
1
4
10
1
85
98
96
98
98
2.0 þ 5 (0.1) DCM 3.5
aAll reactions were performed using 1 mmol of the glucoside 1 in the respective
solvent (4 ml) at rt.

DABCO-Mediated Regioselective Tritylation
2435
Scheme 2. Chemical structures 26–28.
chromatographic purification. By the addition of DMAP (10 mol%) at the
beginning of the initial step, the subsequent acetylation could be effected
without having to add any additional quantities of DMAP (entry 5,
Table 2). Under the optimized conditions, the disaccharide substrate 26
could be converted first to the 60-O-trityl ether 27 and further to the
tri-O-acetate 28 in 92% overall yield. See Scheme 2.
In conclusion, a simple, highly efficient, and convenient protocol for
the regioselective tritylation of aldohexose derivatives has been developed.
The subsequent global acetylation (in the same pot) of any remaining
hydroxyl groups in the molecule has been proved practical by the current
method, thereby making chemoselective discrimination of hydroxyl groups
in such molecules possible. The method eliminates the need for the use of
hazardous solvents such as pyridine and DMF for such reactions.
EXPERIMENTAL
General Procedure for Tritylation
The sugar to be tritylated was suspended (or dissolved as the case may be)
in anhydrous DCM (2 ml=100 mg of substrate), and DABCO (2 mol
equiv) and TrCl (2 mol equiv) were added. The mixture was stirred at
rt (approximately 30ꢁC) until the reaction was complete (as monitored
by TLC; eluent, CH2Cl2–MeOH, 9:1, or another suitable solvent system
depending upon the nature of the substrate). The solvent was then
removed by evaporation under reduced pressure, and the product was
isolated by column chromatography (silica gel; eluent, EtOAc–n-Hex,
4:1, or another as appropriate depending upon the compound). All the
compounds, except 27 and 28, reported here have been reported pre-
viously.[2] Many are commercially available, and therefore analytical data
for compounds 27 and 28 only have been listed here. The physical con-
stants obtained for the known compounds agreed with the literature data,
and their spectral data were in agreement with the values expected for

2436
B. K. Gadakh et al.
their respective structures. Compound 27 was prepared by the general
procedure described previously in 94% yield as a colorless solid; mp
88–90ꢁC; [a]D ¼ ꢂ26.52 (C 1 in CHCl3); dH (CDCl3, 300 MHz)
7.54–7.15 (m, 20H, ArH), 4.93–4.89 (d, 1H, CH2Ph, J 11.5 Hz),
4.80–4.77 (d, 1H, J 10.2 Hz, CH2Ph), 4.74–4.70 (d, 1H, J 10.2 Hz, CH2Ph),
4.67 (s, 2H, CH2Ph), 4.67–4.63 (d, 1H, J1,2 9.6 Hz, H-1), 4.61–4.57 (d, 1H,
0
0
0
J 11.5 Hz, CH2Ph), 4.27–4.24 (d, 1H, J1 ,2 7.6 Hz, H-1 ), 3.94–3.80 (m, 4H,
H-2, H-4, H-30, H-40), 3.65–3.62 (t, 1H, J 5.7 Hz, H-50), 3.58–3.54 (dd, 1H,
J2,3 9.6 Hz, J3,4 5.7 Hz, H-3), 3.51–3.27 (m, 6H); MALDI-TOF MS
C58H58O10S [M]þ calcd. m=z 947.140; found m=z 970.154 (M þ Naþ),
986.160 (M þ Kþ), and 243.122 (Trþ).
General Procedure for One-Pot Tritylation-Acetylation
The initial tritylation reaction was carried out as described previously.
When the reaction was complete, acetic anhydride (2 mol equiv perꢂOH
group) and DMAP (0.1 mol equiv) were added, and the stirring was
continued until completion of acetylation as judged by TLC (eluent,
EtOAc–n-hex, 1:3). The mixture was then diluted with DCM and washed
successively with cold dilute aqueous HCl, dilute aqueous Na2CO3 solu-
tion, and water. The organic layer was then dried and concentrated to
dryness, and the residue was purified on a column of silica gel (eluent,
EtOAc–n-hex, 1:9) to obtain the desired product (see Table 2). Com-
pound 28 was prepared by the general procedure described previously
in 92% yield as a colorless solid; mp 79–80ꢁC; [a]D ¼ 14.01 (C 1 in
CHCl3); dH (CDCl3, 300 MHz) 7.55–7.17 (m, 20H, ArH), 5.21–5.15
(dd, 1H, J3 ,4 9.1 Hz, J2 ,3 8.6 Hz, H-30), 5.11–5.05 (dd, 1H, J4 ,5
0
0
0
0
0
0
9.3 Hz, J3 ,4 9.1 Hz, H-40), 5.02–4.96 (dd, 1H, J2 ,3 8.6 Hz, J1 ,2 7.5 Hz,
H-20) 4.96–4.92 (d, 1H, J 12.0 Hz, CH2Ph), 4.84–4.73 (2d, 2H, J
10.2 Hz, CH2Ph), 4.68 (s, 2H, CH2Ph), 4.68–4.63 (m, 2H, CH2Ph, H-1),
0
0
0
0
0
0
4.54–4.51 (d, 1H, J1 ,2 7.5 Hz, H-10), 3.95–3.85 (m, 3H, H-2, H-4,
H-6a), 3.72–3.65 (dd, 1H, J2,3 9.4 Hz, J3,4 2.7 Hz, H-3), 3.65–3.58 (m,
2H, H-6b, H-60a), 3.47–3.44 (m, 1H, H-5), 3.31–3.28 (d, 1H), 3.08–3.03
(dd, H-60b), 1.99, 1.91, 1.73 (3s, 9H, 3 ꢃ COCH3); MALDI-TOF MS
C64H64O13S [M]þ calcd. m=z 1073.250, found m=z 1096.581 (M þNaþ),
1112.593 (M þ Kþ), and 243.122 (Trþ).
0
0
ACKNOWLEDGMENTS
B. K. Ghadakh and P. R. Patil thank NIPER, and S. Malik and K. P. R.
Kartha thank the University Grants Commission, New Delhi, India, and

DABCO-Mediated Regioselective Tritylation
2437
the Department of Science and Technology, New Delhi, India, respec-
tively, for providing financial support.
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