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doi.org/10.1002/chem.202005102
Chemistry—A European Journal
the 3-O position of the novioside. To avoid their formation, an
anhydrous HCl solution in methanol was added after comple-
tion of the glycosylation which delivered targeted product 39a
in a 81% yield with complete b-stereocontrol. The reaction
was also carried out with the more complex alcohol 34, a syn-
thetic precursor of the aglycone fragment A2. The formation
of the silaketal was performed as with (À)-menthol which pro-
Table 2. Glycosylation conditions of donors D (41–42) with different ac-
ceptors.
D (equiv.)
A
Conditions[a]
P, Yield [%][b]
a/b[c]
1
2
3
4
5
6
41 (1.3)
41 (1.3)
41 (1.3)
42 (1.3)
42 (2.1)
42 (2.1)
33
34
34
33
34
26
DMTST[d]
43, 83
44, 11
44, 21
43, 66
44, 62
45, 68
1:5
n.d.
n.d.
>1:20
1:20
>1:20
DMTST[d]
NIS, TfOH[e]
Tf2O, À708C[f]
Tf2O, À708C[g]
Tf2O, À708C[g]
1
duced 36 exclusively in a C4 chair conformation and a good
76% yield. Using the glycosylation conditions described previ-
ously and acid treatment, the corresponding adduct 40 was
obtained in 41% yield also as a single b-anomer. As for 39, the
[a] Reaction performed in CH2Cl2 (0.01m) with 4 MS unless otherwise
stated. [b] After chromatography on silica gel. [c] Ratio and stereochemis-
try determined by 1H NMR analysis of the crude mixture and by measur-
4
obtained glycosylated compound 40 adopted a C1 conforma-
1
1
ing JC1,H1 coupling. [d] With 2.3 equiv. of the promotor in DCE (0.02m)
tion with a measured JC-1,H-1 of 159 Hz. Despite this unsatisfac-
from 08C to RT. [e] With 1.4 equiv. of NIS and 1.8 equiv. of TfOH from
À408C to RT. [f] With 1.5 equiv. of Tf2O and 3 equiv. of DTBMP. [g] With
1.9 equiv. of Tf2O, 4.7 equiv. of DTBMP and 4.2 equiv. of ADMB.
tory result, we decided to attempt the reaction with the semi-
glycosylated tiacumicin B 26. In this case we failed at preparing
the silaketal using Montgomery’s conditions but good results
were obtained with the preliminary formation of the chloroalk-
oxysilane[44a] that reacted with 26 providing the corresponding
dialkoxysilane 37 in 73% yield. Unfortunately, glycosylation
using NIS and TMSOTf in CH2Cl2 at À408C followed by an HCl
treatment led to degradation of the compound without evi-
dence of the formation of the targeted glycosylated adduct.
We then shifted to another strategy based this time on a
HAD approach involving the use of noviosyl donor 41 bearing
a Pico group at the 3-position (Scheme 8). Following esterifica-
in 66% yield (Table 2, entry 4). With alcohol 34, the use of the
sulfoxide approach proved to be more efficient as well provid-
ing b-glycosylation product 44 in a 62% yield (Table 2, entry 5).
Moreover, these reaction conditions applied to the hemiglyco-
sylated tiacumicin B 26 delightfully furnished the desired nov-
iosylated product 45 in 68% yield, with high facial selectivity
(Table 2, entry 6, a/b>1:20).
Final deprotection stages
The last steps consisting in the removal of all protective
groups (2 MPM, 3 Nap, 1 Pico and 1 TBS) from compound 45
proved unpleasantly more difficult than expected (Scheme 9).
Using HF·NEt3 in THF allowed us to remove first the TBS group
located on the rhamnosyl moiety giving the corresponding al-
cohol. The 2 MPM as well as the Nap located on the novioside
were then oxidized with DDQ in CH2Cl2/H2O. At this stage, the
two Nap groups protecting the phenol functions of the rham-
nosyl moiety resisted these conditions at 08C, and a longer re-
action time at 208C led to an intractable mixture of products.
The removal of the picoloyl was then cleanly carried out using
Cu(OAc)2 in CH2Cl2/MeOH at 08C to produce 46. This deprotec-
tion sequence order was important as the Pico group had to
be removed after its neighboring Nap group to avoid the
DDQ-promoted formation of a 2,3-O-naphthylmethylidene on
the novioside. These three operations were performed with no
intermediate purifications providing an overall yield of 74% of
46. However, the unexpected problem of cleavage of the two
Nap groups located on the two phenol functions remained to
be addressed. Lewis acid-mediated treatment of the Nap led
only to the degradation of the molecule. Pd-catalyzed hydro-
genation (Pd/C, cyclohexene) allowed the phenol deprotection
but along with the reduction of the C4=C5 alkene.[49] As above
mentioned, we observed a partial loss of the Nap groups locat-
ed on the phenol moiety during the Pd-catalyzed Suzuki reac-
tion of 23 with phenyl vinylboronic acid (see Scheme 4 and
text). Exploiting this observation, we finally discover a new and
selective method of deprotection of Nap ether on phenol.
After a few optimizations, we found that using Pd2(dba)3 as a
catalyst in combination with PPh3 along with 1,3-dimethylbar-
Scheme 8. Preparation of the noviosyl donors D (41 and 42) and glycosyla-
tion (structure of R1OH in Scheme 7).
tion of 32 with picolinic acid, the corresponding sulfide 41 was
engaged in a glycosylation reaction with (À)-menthol as the
acceptor (Table 2, entry 1). The reaction was carried out with
DMTST as the promoter and led predominantly to the b-com-
pound 43 (a/b: 1:5) in 83% yield. With elaborated unsaturated
alcohol 34, this approach led to poor yields (11 to 21%) either
with DMTST (Table 2, entry 2) or NIS/TfOH (Table 2, entry 3) and
unfortunately turned out unsuccessful with macrolactonic ac-
ceptor 26 since no glycosylated adduct was detected. The suc-
cess of the above-mentioned rhamnosylation led us to consid-
er that sulfoxide 42 derived from sulfide 41 could be a far
more reactive donor. A first trial with (À)-menthol as acceptor
under Tf2O activation at À708C revealed the potency of this
method, as the b-anomer 43 was obtained as the only adduct
Chem. Eur. J. 2021, 27, 5230 –5239
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