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S. Ciceri et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Scheme 1. Usual synthetic routes of capecitabine.
b-
D
-ribose 3c into a halogen6 or into a tosylate,7 after the suitable
The hydrolytic conditions, generally, require the use of a cosol-
vent, for dissolving the substrate, a careful pH control and the
recovery of the final product from an aqueous medium. We chose
the alcoholysis conditions that also in the past gave us best results
both on steroidal compounds12 and on macrolactams.13 Under
alcoholysis conditions the final product is recovered by simple sol-
vent evaporation after the enzyme removal by filtration.
protection (usually as methylglycoside of the 1-hydroxy group and
as acetonide of the 2- and 3-hydroxy groups, respectively). The
treatment with a reducing agent furnishes the 5-deoxy sugar. Acidic
removal of protective groups followed, for example, by acetylation
of 1-, 2-, and 3-hydroxy groups affords 1,2,3-tri-O-acetyl-5-deoxy
derivative 3b, the starting material of the N-glycosidation of the
suitable silyl derivative of the 5-fluorocytosine, compound 5. The
synthesis is then accomplished by the formation of the N4-carba-
mate and basic removal of protecting groups (Scheme 1).
N4-Pentylcarbamate 7 was treated with some common com-
mercially available lipases, in ethanol. Pseudomonas fluorescens
lipase (PFL) did not transform the substrate even after changing
the alcohol (see Table 1). Candida cylindracea (CCL) and Candida
antartica (CAL B) lipases showed a low selectivity affording 50-hy-
droxy-20,30-diacetate 8 in 40–50% amount together with other
deacetylated products, even at low conversion extent (see Table 1).
Better results were observed in the case of a different commercially
available preparation of CAL B, the CAL B CLEA, that is, the enzyme
cross linked aggregate (CLEA Technologies). According to this tech-
nology, physical aggregates of an enzyme are cross-linked by
means of a bifunctional compound furnishing a preparation char-
acterized by improved stability, activity, and tolerance to organic
solvents.14 CAL B CLEA-catalyzed alcoholysis in ethanol of triac-
etate 7 afforded mainly (82% by HPLC) 50-hydroxy-20,30-diacetate
8, at 93% conversion.
In order to avoid the laborious preparation of 1,2,3-tri-O-acetyl-
5-deoxy-
D-ribose 3b, we decided to N-glycosidate 5-fluoro pyrim-
idine silyl derivative 5 with peracetylated b-
D-ribose 3d obtaining
5-fluorocytidine nucleoside 6 (Scheme 2) that was easily trans-
formed into the corresponding N4-pentylcarbamate 7 in 59% yield
from 3d.
The contemporary presence of three acetyl groups at position
20-, 30-, and 50-O, together with the N4-carbamate and the N1-glyco-
sidic bond, required the selective removal of ester at position 50,
under mild conditions. This result, in a 2005 paper,8 has been
achieved, in the case of some similar nucleosides, by means of
iodine in methanol. In our hands this method afforded desired
50-deoxy compound 8 together with a complex mixture of products
while 6, that is, the compound lacking the carbamate function, was
transformed, under the same conditions, only in a little amount
(10–20%), into the corresponding 50-deoxy derivative.
The enzymatic approach, already reported under hydrolytic
conditions9 or in alcoholysis10 in the case of other, less functional-
ized, acetyl esters of deoxyribonucleosides or ribonucleosides,
seemed to be suitable in order to easily obtain 8, considering the
mild reaction conditions. The selective hydrolysis of 50-ester of
compounds 6 or 7, to give 50-deoxy intermediates, has been previ-
ously described in a 2008 patent, by means of several native
enzymes,11a or by means of a recombinant lipase from Candida
rugose, for compound 6, as reported in a later article by the same
authors.11b
This encouraging result, the very easy work-up and the subse-
quent high yields prompted us to treat triacetate 7 also with the
Alcalase CLEA (the Alcalase is the alkaline protease from Bacillus
licheniformis, also known as subtilisin). This enzymatic preparation
gave us, in the past, very good results in the case of the resolution
of a racemic not-proteogenic aminoacid, useful optically pure syn-
thon of the antithrombotic clopidogrel.15 When applied to nucle-
oside 7 it showed an excellent selectivity removing, almost
exclusively, the 50-acetate (91%) at 96% conversion of the alcohol-
ysis in ethanol.
Pure 50-hydroxy-20,30-diacetate 8, recovered after column chro-
matography, seemed the suitable advanced intermediate for the
capecitabine synthesis: indeed, only the reductive treatment of the
Scheme 2. Reagents: (i) Hexamethyldisilazane, (NH4)2SO4. (ii) 3d, SnCl4, CH2Cl2. (iii) n-C5H11OCOCl, CH2Cl2, py.