Organic Letters
Letter
groups, including 10−12, and 17, were also proven to be vital
substrates for the acylation reaction, and the desired DMNPA
protected compounds 25−27, and 32, were obtained with good
to excellent yields (75−96%). In particular, taking advantage of
the bulkiness of the DMNPA group and the power of the
acylating conditions, the monoacylation of 14 and biacylation of
15 were successfully achieved simply by adjusting the amounts
of the acylating agents to deliver 29 and 30 (80% and 93% yields,
respectively). It should be pointed out that only 40 min are
required for all acylation reactions to reach completion.
Table 4. Selective Removal of the Generally Applied PGs in
the Presence of the DMNPA Group
Similarly, the deprotection conditions also enjoyed a quite
broad substrate scope (Table 3). Thus, upon treatment with the
optimized cleavage conditions, all DMNPAs located either at
the primary hydroxy groups such as 5, 21, and 29 or at the
secondary hydroxy groups including 22−24, and 28, could be
efficiently removed, and above 88% yields of 4, 6, 7−9, 13, and
14 were isolated. Despite the acidic deprotection conditions, the
desired 10−12 were secured smoothly from the acid-labile
substrates 25−27 at room temperature (83−98% yields),
verifying the mildness of the deprotection protocol. With 30
as a substrate, the simultaneous removal of two DMNPAs was
feasible when the amounts of the applied reagents were doubled,
yielding 15 quantitatively. Furthermore, the conditions of
DMNPA removal reconcile quite well with the chloroacetyl
(CA), levulinoyl (Lev), and 2-(azidomethyl)benzoyl (AZMB)11
groups, thus converting 33−35 to 18−20 efficiently (83−95%).
Of particular interest is the selective DMNPA cleavage in the
presence of the AZMB group, as a metal zinc has been used for
azido group reduction.12 Thus, shortening the reaction time to
15 min and reducing the reagents amounts by half (5 equiv of
Zn, 2.5 equiv of HOAc, and 0.5 equiv of CuSO4) were required
to suppress the undesired AZMB deprotection to provide 20
efficiently (83%).
The rapid conversion of 35 to 20 prompted us to recheck the
DMNPA deprotections, allowing the observation that all the
deprotection reactions could be finished within 30 min.
Strikingly, at least 2 h were required for the departure of the
NPA group.2g The high deprotection rate of the DMNPA group
subverts the notion that bulky PGs inevitably have sluggish/
difficult deprotection processes, and can be attributed to the
favorable Thorpe−Ingold effect of the gem-dimethyl moiety.
In combination with the selective DMNPA removal listed in
Table 3, if the coexisting PGs on sugar residues could be
removed without affecting the DMNPA group, the mutual
orthogonality of the DMNPA group to the generally applied
PGs could then be established. Hence, the selective removal of
the generally applied PGs in the presence of the DMNPA group
was subsequently tested (Table 4). The mutual orthogonality of
the DMNPA group to PGs not belonging to the ester-type was
checked first. Expectedly, removals of the TBDPS group from
26, the allyl group from 31, and the MP group from 32
proceeded uneventfully under the standard conditions to
generate 39−41 (80−94% yields, entries 5−7). Distinguishing
the benzyl group (Bn) from DMNPA is by no mean a trivial
problem since the DMNPA group cannot survive the hydro-
genolysis debenzylation conditions. Thus, the oxidative
debenzylation conditions (NaBrO3/Na2S2O4) were chosen,13
converting 22 to 38 fluently (85% yield, entry 3).
a
Isolated yield.
were smoothly removed to furnish 36, keeping the DMNPA
group intact (82%, entry 1). Encouraged by this result, the
selective removal of the two acetyl groups in 22 and the two
benzoyl groups in 23 was also examined. Again, good yields of
37 were recorded (86% and 80% yields from 22 and 23, entries 2
and 4). To avoid the overdeprotection side reaction, K2CO3 was
used in control amounts in all these reactions (1.0 equiv of
K2CO3 for one acyl group). Finally, the selective removal of the
CA, Lev, and AZMB groups was evaluated with 33, 34, and 35,
respectively (entries 8−10). Pleasantly, the commonly used
conditions worked efficiently to distinguish the CA, Lev, and
AZMB groups, keeping the coexisting DMNPA group
untouched (29 was obtained in 91%, 89%, and 84% yields,
entries 8−9). The broad mutual orthogonality of the DMNPA
group to other PGs is extremely attractive, since it can be
exploited to improve the efficiency of complex glycosides
synthesis by raising the efficiency of PG manipulation and
reducing the steps thereof.
Taking advantage of the broad mutual orthogonality of the
DMNPA group to other PGs, the highly efficient synthesis of the
pentasaccharide glycan of thornasterside A 54 was investigated
(Scheme 1).14 The synthetic endeavor commenced with the
coupling between 42 and 43 under the catalysis of the Au(I)
complex15 to afford the disaccharide 44 (85%). Surprisingly,
when the corresponding Schmidt donor was applied, no desired
glycosylation product was detected. Selective removal of the
AZMB group in 44 afforded 45 (86%), which was then
glycosylated with Schmidt donor 4614 to yield the trisaccharide
47 (98%). Then 47 was converted to 48 via a sequence of MP
group removal and Yu donor formation (66%, 2 steps), which
was further subjected to sugar chain extension with 4914 under
the effect of Ph3PAuOTf, delivering the tetrasaccharide 50
(95%). Selective cleavage of the DMNPA group in 50 furnished
the tetrasaccharide acceptor 51 (98%), which was then coupled
with 5215 to provide the fully protected pentasaccharide 53
(80%). Finally, the global deprotection was achieved by
The most challenging task in the mutual orthogonality
determination is the selective removal of the ester-type PGs
without affecting the DMNPA group of the same type.
Fortunately, upon treatment with the conventional saponifica-
tion conditions (K2CO3/MeOH), the three benzoyl groups in 5
C
Org. Lett. XXXX, XXX, XXX−XXX