Angewandte
Chemie
Table 2: Regioselective radical mono-de-O-benzylation of benzylated
xanthyl methylsilyl ethers.[a]
Initially, when a solution of the xanthate 6 and dilauroyl
peroxide (DLP, 1.2 equiv)[16] in refluxing 1,2-dichoroethane
was heated at reflux under argon and treated successively
with acid and TBAF,[17] regioselective de-O-benzylation at C3
cleanly occurred, thus affording the 1,2-diol 11[18] in 62%
yield (entry 1, Table 1). Increasing the amount of the pro-
moter to 2 equivalents ensured a complete conversion of the
starting xanthate (entries 2 and 3). This transformation,
resulting from an apparent unexpected 1,7-HAT, was not
the result of a more favorable pathway including two
successive 1,5-HATs through the relay of the syn-axial
anomeric hydrogen atom. This was readily seen by trans-
formation of the a-anomer 2 (anti-equatorial anomeric
hydrogen) under the optimized reaction conditions to the
diol 12 with a similar efficiency (entry 4). Interestingly,
benzylidene acetal (as in 8) and alkyne (as in 9) functionalities
are compatible under these radical conditions (entries 5 and
6). In contrast to many debenzylation procedures, our
methodology also applies to sulfide-containing compounds,
as with the thiophenyl glycoside 10, thus affording the product
15 in 80% yield (entry 7).
Entry
Substrate
Product
Yield [%][b]
1
75
16
17
2
61
18
20
19
21
3
4
86
47[c]
This procedure was then extended to other representative
benzylated monosaccharides (Table 2). Treatment of the
xanthates 16 and 18 provided vicinal benzyl ether cleavage
at O3 to give the diols 17 and 19, respectively (entries 1 and
2). These results indicated that a 1,7-HAT is largely favored
over a 1,8-HAT process which would provide debenzylation
at O6 in both substrates. However, when the 1,8-HAT is the
only possible choice as in the xanthate 26, debenzylation
occurs to provide the diol 27 (entry 6), although with much
less efficiency under the general reaction conditions (40%
yield). The methodology operates with 1,2-trans-oriented
alkoxy groups (d-gluco examples) as well as with a 1,2-cis
orientation found in the d-galacto and d-manno substrates 18
and 20 to afford, respectively, 19 (61% yield) and 21 (86%
yield; entries 2 and 3). Interestingly, the azido functionality in
the xanthate 22 was unaffected under these radical conditions
(entry 4), a moderate yield obtained for the diol 23 (40%)
resulted from the hydrolysis of the acid-sensitive 1,6-anhydro
group during workup. Finally, regioselective debenzylation at
O2 occurred by treatment of both the anomeric xanthates 24
(a/b ratio of 1:5), thus providing the product 25 in 58% yield
(or 63% from the corresponding hemi-acetal of 24; entry 5).
Again, 1,7-HAT was favored over other 1,n-HAT options.
The sequence of transformations was studied in detail for
the xanthate 6. Careful chromatographic as well as mass
spectrometry analysis of the reaction indicated the formation,
in sequence, of the two intermediates D (MS = 757 [M+Na]+)
and E (MS = 469 [M+Na]+), both converted into the diol 11
after suitable workup. We believe that the sequence of
reactions proceeded as shown in Scheme 1. The silylmethyl
radical A produced by thermal decomposition of the initiator
probably adds quickly to the xanthate 6 to provide the
stabilized radical F which can only regenerate the starting
xanthate and the same radical A. This very powerful way of
increasing the effective lifetime of a radical, identified and
reported on many occasions by Zard and co-workers,[9] makes
it possible to obtain a 1,7-HAT giving the benzylic radical B.
With no other external trap than dilauroyl peroxide, B
22
24
26
23
25
27
5
6
58 (63[d])
40[e]
[a] General reaction conditions: DLP (2 equiv), ClCH2CH2Cl, reflux, 2 h;
H2O/AcOH (1:1), RT then 1m TBAF solution in THF (2 equiv) at RT.
[b] Yield after silica gel chromatography. [c] 2-Azido-2-deoxy-d-glucose
resulting from 1,6-anhydro hydrolytic ring opening of the product diol 23
was also formed (20-30% estimated yield) and separated in the aqueous
phase. [d] Yield of isolated product obtained over two steps from the
corresponding hemiacetal of 24. [e] Hydrolysis of unreacted substrate 26
also occured in about 30% yield. Xa=S(CS)OEt.
obviously undergoes an oxidation to the stabilized benzylic
cation C, which is quenched in the form of the acyl acetal D.
In situ acetal cleavage to E and desilylation then provided the
debenzylated product 11. The electron transfer from B to
DLP, thus providing the benzylic cation C, was readily
demonstrated by an intramolecular nucleophilic trapping of
the cationic intermediate using the xanthate 29, equipped
with a cis hydroxy group, which is accessible in one step from
diol 28[19] (Scheme 2). Trapping of the benzylic cation resulted
in the formation of the benzylidene acetal 30.
Moreover, the conclusive advantage of this xanthate
chemistry over the more conventional bromomethylsilyl
ether chemistry is readily seen with the bromomethyl
dimethyl ether 31 (analogous to the xanthate 9; Table 1)
which only provided the reduction product 32 by a standard
tin hydride treatment (slow addition of Bu3SnH). These
results also suggested that a slight change in the workup
procedure can provide a new way to perform an overall
regioselective exchange of a protecting group from the
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3
These are not the final page numbers!
Attouche, Angie
