The 2,2-Dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) Group: A Novel Protecting Group in Carbohydrate Chemistry

Article abstract of DOI:10.1021/acs.orglett.9b03025

The 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) group was introduced to synthetic carbohydrate chemistry as a protecting group (PG) for the first time. Benefiting from a unique chemical structure and novel deprotection conditions, the DMNPA group can be cleaved rapidly and mutually orthogonal to other PGs. Orchestrated application of the DMNPA group with other PGs led to the highly efficient synthesis of the glycan of thornasterside A.

Full text of DOI:10.1021/acs.orglett.9b03025

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
The 2,2-Dimethyl-2‑(ortho-nitrophenyl)acetyl (DMNPA) Group: A
Novel Protecting Group in Carbohydrate Chemistry
Hui Liu,† Si-Yu Zhou,† Guo-En Wen,† Xu-Xue Liu,† De-Yong Liu,† Qing-Ju Zhang,†
Richard R. Schmidt,*,†,‡ and Jian-Song Sun*,†
†National Research Centre for Carbohydrate Synthesis, Jiangxi Normal University, 99 Ziyang Avenue, Nanchang 330022, China
‡Department of Chemistry, University of Konstanz, D-78457, Konstanz, Germany
S
* Supporting Information
ABSTRACT: The 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) group was introduced to synthetic carbohydrate
chemistry as a protecting group (PG) for the first time. Benefiting from a unique chemical structure and novel deprotection
conditions, the DMNPA group can be cleaved rapidly and mutually orthogonal to other PGs. Orchestrated application of the
DMNPA group with other PGs led to the highly efficient synthesis of the glycan of thornasterside A.
backbone may render the DMNPA group with the same
etour protecting group (PG) manipulations and unsat-
Disfactory efficiency thereof seriously compromise the cleavage mechanism to the NPA group, guaranteeing the
overall efficiency of glycoside synthesis.1 To tackle this problem,
orthogonality of DMNPA to other PGs. (2) The enhanced steric
hindrance resulting from the gem-dimethyl group as well as the
elimination of two acidic protons3 α to the ester carbonyl group
can improve the stability of the DMNPA group to basic
conditions; thus, the highly desired mutual orthogonality to
other PGs especially the ester-type PGs is expected. (3)
Benefiting from the favorable Thorpe−Ingold effect4 of the
gem-dimethyl group, a rapid deprotection of the DMNPA group
can be anticipated, potentially toppling the chronic notion that
steric PGs suffer from sluggish/difficult deprotection.5 Through
systematic investigations, the assumption was successfully
reduced to practice, leading to the determination of the
DMNPA group as a potent PG in carbohydrate chemistry.
The DMNPA group has been used in prodrug design,6 but its
use as a PG with synthetic purpose has only been tested once in
the masking of an amino group in amino acids.7 As no protocol
for the efficient installation/cleavage of the DMNPA group in
the carbohydrate context is available, the study commenced with
the optimization of these conditions.
great efforts have been devoted to the development of novel PGs
orthogonal and more ideally mutually orthogonal to the
generally applied PGs, leading to the introduction of a variety
of new PGs to synthetic carbohydrate chemistry.2 Inspired by
the (2-nitrophenyl)acetyl (NPA) group,2g which enjoys broad
orthogonality to other PGs due to the unique deprotection
mechanism of the successive nitro group reduction and
lactamization, the 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl
(DMNPA) group was considered as an ideal PG in carbohydrate
chemistry under the assumption that the DMNPA group may
keep or upgrade the merits while eliminating the drawbacks of
the NPA group (Figure 1). The assumption was made based on
the unique chemical structure of DMNPA: (1) The NPA
Effected by the bulkiness, the introduction of the DMNPA
group proved to be difficult with 4 as the model substrate (Table
1). The dehydrative esterification of 4 with DMNPAOH 16
Received: August 24, 2019
Figure 1. Chemical structures of NPA and DMNPA groups.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03025
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Organic Letters
Letter
Table 1. Optimization of DMNPA Installation Conditions
Table 2. Optimization of DMNPA Removal Conditions
Acylating reagents
a
Entries
Conditions
Yield
Entries (equivalents to 4)
Conditions
Results
NR
1
2
Zn (5.0 equiv), NH4Cl (3.0 equiv), MeOH, rt, 4 h
Zn (5.0 equiv), NH4Cl (3.0 equiv), MeOH/CH2Cl2 = 3:1,
rt, 4 h
30%
50%
1
1 (1.5)
EDCI (2.4 equiv), DMAP (2.0
equiv), DIPEA (4.0 equiv),
CH2Cl2, rt
2
3
4
5
6
1 (1.2)
1 (2.0)
1 (5.0)
1 (1.2)
2 (3.0)
EDCI (2.4 equiv), HOBt (2.0 equiv), NR
DIPEA (4.0 equiv), CH2Cl2, rt
DCC (1.1 equiv), DMAP (3.0 equiv) NR
CH2Cl2, rt
3
4
5
6
7
Zn (5.0 equiv), NH4Cl (3.0 equiv), MeOH/dioxane = 3:1,
rt, 4 h
Zn (10.0 equiv), NH4Cl (5.0 equiv) MeOH/dioxane = 1:1, 55%
rt, 4 h
Zn (10.0 equiv), NH4Cl (10.0 equiv), dioxane/H2O = 1:1, 65%
rt, 4 h
Zn (10.0 equiv), NH4Cl (5.0 equiv), CuSO4 (1.0 equiv)
dioxane/H2O = 1:1, rt, 4 h
60%
a
HATU (1.5 equiv), DIPEA (5.0
equiv) DMF, 50 °C
NR
MNBA (1.2 equiv), Et3N (4.0 equiv) NR
DMAP (0.25 equiv), CH2Cl2, rt
93%
TMEDA (2.2 equiv), 4A MS,
CH2Cl2 (−78 °C)
Trace
Zn (10.0 equiv), HOAc (5.0 equiv), CuSO4 (1.0 equiv)
dioxane/H2O = 1:1, rt, 4 h
98%
7
8
9
2 (4.0)
3 (1.5)
3 (1.5)
Pyridine, 50 °C
DMAP, pyridine, rt
DIPEA (4.0 equiv), PPY (0.3 equiv) 45%
toluene, reflux
Sc(OTf)3 (2.0 equiv), CH3CN, rt
TMSOTf (0.5 equiv), CH2Cl2, rt
TMSOTf (2.0 equiv), 5A MS,
CH2Cl2, −36 °C, 40 min
NR
NR
a
Isolated yield.
b
be attributed to the in situ generated Cu/Zn couple, which
shows improved reductive potential; while the isolation and
characterization of lactam A10 as the departure form of the
DMNPA group testifies the proposed mechanism of the
successive nitro group reduction/lactamization.
With the optimal conditions for installation and cleavage of
the DMNPA group settled, the substrate scope was
subsequently checked (Table 3). Under the standard acylation
conditions, both the primary (4 and 6) and secondary (7−9, 13,
and 16) hydroxy groups were successfully acylated, furnishing
DMNPA decorated monosaccharides 5, 21, 22−24, 28, and 31
with excellent yields (above 87%). Thanks to the mild acylation
conditions, carbohydrates containing acid-labile protecting
10
11
12
3 (5.0)
3 (1.5)
3 (1.5)
NR
86%
91%
b
b
a
b
The DMNPAOH was transformed to DMNPAA cleanly. Isolated
yield.
under the effect of conventional dehydrative reagents did not
afford even a trace amount of the acylated product 5 (entries 1−
4), as was the case for the Shiina esterification (entry 5).8
Interestingly, though the combination of DCC and 4-
dimethylaminopyridine (DMAP) did not lead to the desired
acylation, it converted DMNPAOH to DMNPA anhydride
(DMNPAA) 3 (CCDC 1819242) quantitatively, which proved
stable enough to be purified by silica gel chromatography and
stored in a refrigerator for months (entry 3). After attempts to
acylate 4 with DMNPA chloride (DMNPACl) 26 met with
failure (entries 6 and 7), the acylation with DMNPAA was tried
under basic and acidic conditions, respectively, with the
TMSOTf providing the most promising results (entries 8−
11).9 Further optimizations by lowering the reaction temper-
ature (−36 °C), increasing the amounts of TMSOTf (2.0
equiv), and adding molecular sieves bestowed the acylation with
mildness, swiftness, and efficiency, thus leading to a 91% yield of
5 in 40 min (entry 12).
Table 3. Substrate Scopes for DMNPA Installation/Cleavage
Conditions
In searching for the optimal conditions for DMNPA cleavage,
the conditions used for the NPA group deprotction were tried
first to remove the DMNPA group in 5. However, under the
effect of Zn/NH4Cl in methanol only 30% yield of 4 was isolated
(Table 2, entry 1), presumably due to the low solubility of the
starting material and the product in methanol. Addition of
dichloromethane or dioxane as cosolvent alone or in
combination with the increasing of the applied Zn and NH4Cl
amounts indeed brought about the yield amelioration, but only
to a limited extent (entries 2−5). Additional screening entailed
the addition of CuSO4 (1.0 equiv), leading to a steep rise in
chemical yield (from 65% to 93%, entries 5 vs 6), which was
further improved by taking HOAc in lieu of NH4Cl as acid (98%,
entry 7). The beneficial effect of CuSO4 on the conversion can
B
DOI: 10.1021/acs.orglett.9b03025
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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
DOI: 10.1021/acs.orglett.9b03025
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Organic Letters
Letter
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 1. Synthesis of 54 via the Orchestrated Application of
the DMNPA and Other PGs
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jssun@jxnu.edu.cn.
*E-mail: richard.schmidt@uni-konstanz.de.
ORCID
Richard R. Schmidt: 0000-0001-6398-9053
Jian-Song Sun: 0000-0001-6413-943X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (21572081, 21762024, and
21877055) and Natural Science Foundation of Jiangxi Province
(20161ACB20005, 20171BCB23036, and 20171BAB203008).
The Innovative Fund of Jiangxi Province to H. L. (YC-2018-
B031) was also appreciated.
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03025.
Detailed experimental procedure and NMR spectra
copies of all new compounds (PDF)
Accession Codes
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(16) See Supporting Information.
CCDC 1819242 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
D
DOI: 10.1021/acs.orglett.9b03025
Org. Lett. XXXX, XXX, XXX−XXX