An easy and efficient approach for the installation of alkoxycarbonyl protecting groups on carbohydrate hydroxyls

Article abstract of DOI:10.1016/S0040-4039(00)01673-7

Alkoxycarbonyl groups can be readily installed on carbohydrates by reaction with the corresponding chloroformates in the presence of TMEDA at low temperature. The mild reaction conditions can be modulated to attain regioselective protections. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01673-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9305–9309
An easy and efficient approach for the installation of
alkoxycarbonyl protecting groups on carbohydrate
hydroxyls
Matteo Adinolfi, Gaspare Barone, Luigi Guariniello and Alfonso Iadonisi*
Dipartimento di Chimica Organica e Biologica, Universita` degli Studi di Napoli Federico II, Via Mezzocannone 16,
I-80134 Naples, Italy
Received 31 July 2000; revised 20 September 2000; accepted 27 September 2000
Abstract
Alkoxycarbonyl groups can be readily installed on carbohydrates by reaction with the corresponding
chloroformates in the presence of TMEDA at low temperature. The mild reaction conditions can be
modulated to attain regioselective protections. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: alkoxycarbonyl group; N,N,N%,N%-tetramethylethylenediamine; carbohydrates; protecting groups.
In the course of our efforts for the solid phase synthesis of oligosaccharides1 we intended to
prepare the imidate 1, equipped in position 6 with a protecting allyl group selectively removable
after the incorporation of this sugar unit into a polymer-bound growing saccharidic chain.
During the synthesis of 1, allylation of the intermediate 2 turned out to be problematic both
under basic and acidic conditions. Thus, we considered the use of allyloxycarbonyl as an
alternative transient protecting group, whose mild and selective removal in the presence of esters
was known.2,3 At the same time, we became aware of the efficiency of TMEDA in promoting the
reactivity of acyl chlorides towards alcohols in CH2Cl2.4 We envisaged that an analogous role as
nucleophilic catalyst could be played by this diamine in the activation of the less reactive
alkylchloroformates. As a matter of fact allyloxycarbonylation of compound 2 was smoothly
performed at 0°C in CH2Cl2 in 20 min with 0.6 equiv. of TMEDA and a small excess of
allylchloroformate to give 3 quantitatively after a simple extractive work-up (Fig. 1).
Encouraged by this result we explored the application of this approach for the installation of
allyloxy- and benzyloxycarbonyl groups on several differently functionalized saccharidic sub-
strates. Alkoxycarbonyl groups are widely employed for the protection of amino functionalities,5
whereas they are much less commonly used in the derivatization of hydroxyl groups and only
* Corresponding author. Fax: +39 081 5521217; e-mail: iadonisi@unina.it
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01673-7

9306
OR2
O
BnO
BzO
R1
BzO
1 R1 = α-OC(=NH)CCl3,
R2 = All
2 R1 = OBz, R2 = H
3 R1 = OBz,
R2 = COOAll
Figure 1.
rare examples of their exploitation in carbohydrate chemistry can be found, especially for the
case of benzyloxycarbonyl groups.6 They are typically introduced by treatment of the alcohol
with the suitable chloroformate in the presence of a mild (DMAP, TEA, DIPEA, pyridine) or
even harsh (NaH, NaOH) base. However, no general procedure was established to date. In this
regard, TMEDA was reported in a single example to promote allyloxycarbonylation of an allylic
hydroxyl group in an ether solvent.7
The general efficiency of the procedure exploited for the preparation of 3 was tested with
several saccharidic substrates. High yields were achieved8 in short reaction times (less than 1
hour) in all cases (Table 1), even at very low temperatures (Table 2) and in the presence of other
protecting groups commonly used in carbohydrate chemistry.
The approach proved effective also in the installation of Troc (trichloroethoxycarbonyl), and
Fmoc (9-fluorenylmethoxycarbonyl) protecting groups (Table 1, entries 6 and 7). In spite of the
high reactivity of the ROCOCl/TMEDA system, a good regioselectivity was obtained when
diols 4, 5 and 6 were treated with 1.1 equiv. of benzyl- or allylchloroformate and 0.6 equiv. of
TMEDA at low temperature (−78°C) (Table 2). In the cases examined the mono alkoxycarbonyla-
ted derivative at the most reactive position was the major product. No detectable amounts of the
alternative mono derivative were produced, whereas substantial amounts of the fully protected
product were also isolated. Interestingly, allyloxycarbonylation of 4 was reported to proceed
with no regioselectivity when allylchloroformate was used in combination with TEA, whereas a
comparable regioselectivity and a higher yield can be attained by using the less reactive allyl
1-benzotriazoyl carbonate.6e
In conclusion, we have shown that allyloxy- or benzyloxycarbonyl groups, typically employed
in the protection of amino functionalities, can be conveniently introduced on primary and
secondary carbohydrate hydroxyl groups. The procedure described could contribute to increase
the practical usefulness of these protecting groups,9 in view of the specificity and mild conditions
required for their removal.2,6
Acknowledgements
Financial support by MURST (PRIN 1999-2000), CNR and Universita` di Napoli (Progetto
Giovani Ricercatori 2000) is acknowledged. NMR spectra were performed at the ‘‘Centro di
Metodologie Chimico-Fisiche dell’Universita` di Napoli’’.

9307
Table 1
Alkoxycarbonylation of carbohydrate alcoholsa
Entry
Substrate
Product and isolated yields
Ph
Ph
O
O
Ph
O
O
O
O
HO
ROCOO
AcO
AcO
OMe
OMe
1
2
R = Bn
R = All
86%
>95%
O
Ph
O
O
O
O
O
AcO
AcO
HO
ROCOO
OMe
OMe
3
4
R = Bn
R = All
86%
>95%
Ph
O
O
Ph
O
O
O
O
HO
ROCOO
BnO
BnO
OMe
OMe
82%
88%
5
6
R = Bn
R = CH2CCl3
R = 9-fluorenylmethyl 92%
7
OTBDMS
O
OTBDMS
O
AcO
AcO
AcO
AcO
8
>95%
HO
BnOCOO
OMe
OMe
OCOOAll
O
AllOCOO
O
HO
BnOCOO
91%
9
BzO
BzO
BzO
OBz
BzO
OBz
Ph
O
Ph
O
O
O
O
O
10
11
86%
OMe
BnO
BnO
BnOCOO
HO
OMe
OBn
O
OBn
O
HO
BnOCOO
83%
OMe
AcO
AcO
AcO
AcO
OMe
Ph
O
O
Ph
O
O
O
O
R2OCOO
HO
R1OCOO
HO
OMe
OMe
>95%
>95%
12
13
R1 = R2 = Bn
R1 = R2 = Al
a Reaction conditions: see Ref. 7.

9308
Table 2
Regioselective allyloxy- and benzyloxy-carbonylation of carbohydrate diolsa
Entry
Product and isolated yields
Substrate
Ph
O
O
Ph
O
R2O
O
O
O
HO
R1O
HO
OMe
OMe
4
1
2
R1 = R2 = COOBn
21%
65%
R1 = COOBn, R2 = H
R1 = R2 = COOAll
15%
R1 = COOAll, R2 = H 67%
OR2
OH
R1O
O
O
HO
AcO
AcO
AcO
AcO
OMe
OMe
5
3
4
R1 = R2 = COOBn
R1 = H, R2 = COOBn
15%
71%
R1 = R2 = COOAll
R1 = H, R2 = COOAll
20%
68%
OR2
R1O
O
OH
O
HO
BzO
BzO
BzO
OBz
BzO
OBz
6
5
R1 = R2 = COOAll
R1 = H, R2 = COOAll
traces
72%
a Reaction conditions: see Ref. 7.
References
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2607–2610 and references cited therein.
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6. For instance see: (a) Teshima, T.; Nakajima, K.; Takahashi, M.; Shiba, T. Tetrahedron Lett. 1992, 33, 363–366;
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9309
7. Cvetovich, R. J.; Kelly, D. H.; DiMichele, L. M.; Shuman, R. F.; Grabowski, E. J. J. Org. Chem. 1994, 59,
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8. Typical procedure: TMEDA (0.06 mmol for each hydroxyl to be protected) and chloroformate (0.11 mmol for
each hydroxyl to be protected) are added, under argon and at 0°C, to a solution of the saccharidic substrate (0.10
mmol) in anhydrous CH2Cl2 (1 mL). After completion of the reaction (30–60 min, TLC), the mixture is diluted
with CH2Cl2, washed with water, dried, evaporated and chromatographed on silica gel if necessary. Regioselective
protections were performed at −78°C. Satisfactory spectral data were obtained for all products.
9. We have recently disclosed orthogonal conditions for the removal of benzyl- and benzyloxycarbonyl protecting
groups: Adinolfi, M.; Guariniello, L.; Iadonisi, A.; Mangoni, L. Synlett 2000, 1277–1278.
.