2-Naphthylmethyl (NAP) as a Versatile Amino Protecting Group, Chemoselective Removal under Mild Conditions

Article abstract of DOI:10.1055/s-2003-41465

The use of 2-naphthalenemethyl (NAP) as a versatile amino protecting group is reported. Highly efficient and chemoselective cleavage of protected tertiary amines using DDQ in CH₂Cl₂-MeOH (4:1) has been observed in the presence of various functionalities such as hydroxyl, acetal, alkene, ester, benzyloxy and N-benzyl groups.

Full text of DOI:10.1055/s-2003-41465

LETTER
2065
2-Naphthylmethyl (NAP) as a Versatile Amino Protecting Group, Chemo-
selective Removal under Mild Conditions
2
-Naphthylmethyl
u
(N
A
P) as a
V
i
e
rsatil
l
e
A
min
l
o
Prote
a
cting
G
rou
u
p
me Godin, Philippe Compain,* Olivier R. Martin*
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, rue de Chartres, BP 6759, 45067 Orléans, France
Fax +33(2)38417281; E-mail: Philippe.compain@univ-orleans.fr; E-mail: olivier.martin@univ-orleans.fr
Received 4 July 2003
Firstly, we were pleased to find that our initial synthetic
Abstract: The use of 2-naphthalenemethyl (NAP) as a versatile
strategy,3 could be applied successfully to the 2-naphtha-
lenemethyl protected imine 5 instead of the corresponding
N-benzyl derivative 1 (Scheme 2). Chain extension of the
amino protecting group is reported. Highly efficient and chemo-
selective cleavage of protected tertiary amines using DDQ in
CH2Cl2–MeOH (4:1) has been observed in the presence of various
functionalities such as hydroxyl, acetal, alkene, ester, benzyloxy imine 5 with allyl- or vinylmagnesium bromide was found
and N-benzyl groups.
to proceed in good yield and high diastereoselectivity. In
contrast with the behaviour of the allyl- or 4-methoxyben-
zyl (PMB) group, the NAP group was not cleaved during
the deprotection of the acetal function in aqueous TFA.5
Intramolecular reductive amination and acylation of the
resulting piperidinols 7 afforded the expected protected
nojirimycin C-glycosides 8 in overall yields comparable
to those obtained following the benzyl amino protection
strategy.
Key words: protecting group, amine, 2-naphthalenemethyl (NAP)
group, oxidative cleavage, DDQ
The benzyl group is one of the most popular protecting
group in organic synthesis for alcohols and amines be-
cause of the mild conditions involved in its removal by
catalytic hydrogenolysis.1 In connection with our studies
on azaglycoside mimics,2 we needed to remove chemose-
lectively the N-benzyl group in 3, an iminosugar C-glyco-
side obtained efficiently in 11 steps and 40% overall yield
from L-sorbose (Scheme 1).3 After various attempts, the
best conditions found made use of 4 equivalents of ammo-
nium cerium (IV) nitrate (CAN) in a biphasic system
(THF–H2O)4 to provide in modest yield the secondary
amine 4 as the only isolated product. This disappointing
result prompted us to seek a new protecting group for the
endocyclic amine that could fulfill the following require-
ments according to our synthetic strategy: introduction via
an imine function, stability under strongly acidic
conditions5 and chemoselective removal in the presence
of alkene and of benzyloxy groups. Recently, Matta and
Spencer reported independently the efficient cleavage of a
new benzyl-type protecting group for hydroxyl and car-
boxyl functions, the 2-naphthalenemethyl (NAP) group,6,7
using 2,3-dichloro-5,6-dicyanoquinone (DDQ).8 This in-
spiring work incited us to study the synthetic potential of
NAP as a suitable amino protecting group. To our knowl-
edge, only one example of a N-NAP amine has been re-
ported in the literature.9 It is noteworthy that, in that case,
the NAP group was removed by hydrogenolysis over 10%
activated palladium on carbon. In this communication, we
wish to report our preliminary exploration of the synthetic
utility of the NAP group as an amino protecting group and
its cleavage under mild conditions using DDQ.
Scheme 1 (a) AllylMgBr (3 equiv), Et2O, 0 °C to 20 °C, 24 h; (b)
TFA–H2O (9:1), 30 h; (c) NaBH3CN (4 equiv), AcOH (1 equiv), Me-
OH, 30 h; (d) Ac2O (6 equiv), Py, 5 h, (e) CAN (4 equiv), THF–H2O.
At this stage, we investigated the chemoselective depro-
tection of the endocyclic amine in 8. The N-NAP pro-
tecting group was efficiently removed at room
temperature in the presence of 3 equivalents of DDQ at a
good rate (1–2 h) in 83–89% yield (Table 1, entries 1 and
2).10 To further explore the chemoselectivity of this meth-
odology, we tested this protocol on piperidinols 7 as it is
SYNLETT 2003, No. 13, pp 2065–2067
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-41465; Art ID: G15803ST.pdf
© Georg Thieme Verlag Stuttgart · New York

2066
G. Godin et al.
LETTER
known that hindered secondary alcohols could be oxi- DDQ was found to cleave very selectively the NAP group
dized by DDQ11 (entries 3 and 4). Treatment of 7 with 2.5 over the benzyl group. Protection of the secondary amine
equivalents of DDQ afforded the expected secondary afforded the N-Boc piperazine 12 in 59% yield for the two
amines 10 in acceptable yields. To assess the relative re- steps. A further competitive experiment was carried out
activities of the benzyl and the NAP groups, we per- with the sorbofuranose derivative 13,12 bearing on the
formed an intramolecular competition experiment using a same nitrogen atom a NAP and a benzyl group. As for
piperazine linker12 (entry 5).
compound 11, the NAP group was selectively cleaved us-
ing DDQ to afford the mono-deprotected N-benzyl amine
14 (entry 6). This result further highlights the fact that
benzyl and NAP groups could be combined in new or-
thogonal protection strategies for the synthesis of com-
plex products containing various amine functions.
Oxidative cleavage of the NAP group could be also ap-
plied to aromatic heterocyclic frameworks as it was
shown by deprotection of the N-NAP indole 15 (entry 7).
We then tested our protocol on secondary amine 17 pro-
tected with the NAP group. Reaction of 17 with 3 equiva-
lents of DDQ led to almost complete recovery of the
starting material after 24 h (entry 8). This result suggested
that it might be possible to perform chemoselective oxida-
tive mono-deprotection of tertiary amines di-protected
with NAP groups.13 Further investigations on the scope of
the oxidative cleavage using DDQ as well as other appli-
cations of the NAP group in organic synthesis are current-
ly in progress in our laboratory.
Table 1 Chemoselective Removal of the NAP Group by Oxidative
Cleavage Using 3 equivalents of DDQ in CH2Cl2–MeOH (4:1) at
room temperature10
En- Substrate
try
Time Product
(h)
Yield
(%)a
1
1
89
8a
4
2
2
83
8b
9
3
1
61b
56b
7a
10a
4
2
7b
10b
5
3
59b,c
11
12
6
0.5
88
13
14
7
1
57
16
–
15
d
d
Scheme 2 (a) AllylMgBr or vinylMgBr (3 equiv), Et2O, 0 °C to
20 °C, 24 h; (b) TFA–H2O (9:1), 30 h; (c) NaBH3CN (4 equiv), AcOH
(1 equiv), MeOH, 30 h; (d) Ac2O (6 equiv), Py, 5 h.
8
24
–
In conclusion, we have described a mild and selective
cleavage of N-NAP protected tertiary amines using DDQ
in CH2Cl2–MeOH. The above results highlight the appli-
cation of the NAP amino protection strategy to the syn-
thesis of highly functionalized molecules such as
carbohydrates or peptides. The NAP group was indeed
17
a Isolated yield after flash chromatography on silica gel.
b 2.5 Equivalents of DDQ were used (1.5 + 1 after 15 min).
c Isolated yield from 11 after protection by a BOC group.
d No conversion of compound 17 was observed.
Synlett 2003, No. 13, 2065–2067 © Thieme Stuttgart · New York

LETTER
2-Naphthylmethyl (NAP) as a Versatile Amino Protecting Group
2067
(7) For selected examples of total synthesis using the O-NAP
group see: (a) Xia, J.; Alderfer, J. L.; Piskorz, F.; Matta, K.
L. Chem.–Eur. J. 2001, 7, 356. (b) Inoue, M.; Uehara, H.;
Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551.
(c) Csávás, M.; Borbás, A.; Szilágyi, L.; Lipták, A. Synlett
2002, 887. (d) Yvin, J.-C.; Jamois, F.; Ferrières, V.;
Plusquellec, D. PCT Int. Appl. WO 0157053, 2001; Chem.
Abstr. 2001, 135, 137673.
chemoselectively removed in the presence of a number
of protecting groups and chemical functions including
hydroxyl, alkene, ester, acetal, benzyloxy and N-benzyl
groups.
Acknowledgment
(8) (a) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C. F.;
Alderfer, J. L.; Matta, K. L. Tetrahedron Lett. 2000, 41,
169. (b) Wright, J. A.; Yu, J.; Spencer, J. B. Tetrahedron
Lett. 2001, 42, 4033.
Financial support of this study by grants from CNRS and the as-
sociation ‘Vaincre les Maladies Lysosomales’ is gratefully ack-
nowledged. G. G. thanks the council of Région Centre and the
CNRS for a fellowship.
(9) Ishihara, K.; Kuroki, Y.; Yamamoto, H. Synlett 1995, 41.
(10) Typical experimental procedure: To a solution of 8b (1.7
g, 2.86 mmol) in a 4:1 mixture of CH2Cl2–MeOH (220 mL)
was added DDQ (1.95 g, 8.59 mmol, 3 equiv) under Ar. The
solution was stirred at r.t. for 2 h. The crude mixture was
evaporated to dryness and then taken into CH2Cl2. The
solution was washed with sat. aq NaHCO3 (5 ×). The organic
layer was dried (MgSO4) and concentrated under reduced
pressure. Purification on silica gel (petroleum ether–EtOAc,
3:2) afforded the secondary amine 9 as a colorless oil (1.08
g, 83%).
References
(1) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999.
(2) (a) Iminosugars: Recent Insights into their Bioactivity and
Potential as Therapeutic Agents In Current Topics in
Medicinal Chemistry; Martin, O. R.; Compain, P., Eds.;
Bentham: Hilversum Netherlands, 2003, 3, issue 5.
(b) Tezuka, K.; Compain, P.; Martin, O. R. Synlett 2000,
1837. (c) Rambaud, L.; Compain, P.; Martin, O. R.
Tetrahedron: Asymmetry 2001, 12, 1807. (d) Martin, O. R.;
Saavedra, O. M.; Xie, F.; Liu, L.; Picasso, S.; Vogel, P.;
Kizu, H.; Asano, N. Bioorg. Med. Chem. 2001, 9, 1269.
(e) Bordier, A.; Compain, P.; Martin, O. R.; Ikeda, K.;
Asano, N. Tetrahedron: Asymmetry 2003, 14, 47.
(3) (a) Godin, G.; Compain, P.; Masson, G.; Martin, O. R. J.
Org. Chem. 2002, 67, 6960. (b) Masson, G.; Compain, P.;
Martin, O. R. Org. Lett. 2000, 2, 2971.
(4) Cipolla, L.; Palma, A.; La Ferla, B.; Nicotra, F. J. Chem.
Soc., Perkin Trans. 1 2002, 2161.
(5) In our case, N-allyl or N-PMB groups were found to be
partially or totally cleaved during the deprotection of the
acetal function in aq TFA (Scheme 1).
(6) (a) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998,
63, 4172. (b) Gaunt, M. J.; Boschetti, C. E.; Yu, J.; Spencer,
J. B. Tetrahedron Lett. 1999, 40, 1803.
(11) Iwamura, J.; Hirao, N. Tetrahedron Lett. 1973, 2447.
(12) Compounds 11, 13 and 15 were synthesized by alkylation of
the corresponding secondary amines with 2-bromo-
methylnaphthalene.
Typical experimental procedure: To a solution of N-
benzyl piperazine (510 mg, 2.89 mmol) in anhyd THF (30
mL) was added NaH in oil (60%, 140 mg, 3.5 mmol) at 0 °C.
After 30 min, commercial 2-bromomethylnaphthalene (660
mg, 3 mmol) was added and the mixture was stirred for 24 h
at r.t. The reaction was then quenched with a mixture of
MeOH (5 mL) and ice (10 g). The product was extracted
with CH2Cl2 (50 mL). The organic phase was washed with
sat. aq NaHCO3 (2 × 40 mL), dried (MgSO4) and
concentrated under reduced pressure. Purification on silica
gel (petroleum ether–EtOAc, 95:5) afforded the tertiary
amine 11 (645 mg, 71%).
(13) For oxidative mono-debenzylation of tertiary amines
incorporating two N-benzyl substituents using DDQ or CAN
see: Hungerhoff, B.; Samanta, S. S.; Roels, J.; Metz, P.
Synlett 2000, 77.
Synlett 2003, No. 13, 2065–2067 © Thieme Stuttgart · New York