Photoremovable NPEC group compatible with Ns protecting group in polyamine synthesis

Article abstract of DOI:10.1016/j.tetlet.2018.10.045

Herein, we disclose an efficient combination of NPEC and Ns protecting groups in the synthesis of polyamine, by showing the orthogonal reactivity using N-NPEC-N-Ns alkylamines prepared from NPEC-NHNs. Selective photodeprotection of NPEC group in 12-mer po

Full text of DOI:10.1016/j.tetlet.2018.10.045

Accepted Manuscript
Photoremovable NPEC group compatible with Ns protecting group in polya-
mine synthesis
Masayoshi Miyahara, Hiroki Shiozaki, Hideyuki Tukada, Yuichi Ishikawa,
Masato Oikawa
PII:
S0040-4039(18)31264-4
https://doi.org/10.1016/j.tetlet.2018.10.045
TETL 50355
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 August 2018
5 October 2018
22 October 2018
Please cite this article as: Miyahara, M., Shiozaki, H., Tukada, H., Ishikawa, Y., Oikawa, M., Photoremovable NPEC
group compatible with Ns protecting group in polyamine synthesis, Tetrahedron Letters (2018), doi: https://doi.org/
10.1016/j.tetlet.2018.10.045
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Photoremovable NPEC group compatible with Ns
protecting group in polyamine synthesis
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Masayoshi Miyahara, Hiroki Shiozaki, Hideyuki Tukada, Yuichi Ishikawa, Masato Oikawa*
NPEC
H
N
N
N
N
N
N
Boc
Boc
Ns
Boc
Boc
Ns
NNs
NNs
N
N
N
N
N
N
LED lamp
(365 nm)
Ns
Boc
Boc
Ns
Boc
Boc
N
N
N
N
N
N
Boc
Boc
Boc
Boc
N
N
N
N
N
N
N
N
MeOH
rt, 5  1 min
Ns
Boc
Boc
Ns
Ns
Boc
Boc
Ns
NHAlloc
NHAlloc
54%
MeO2C
MeO2C
Tetrahedron Letters
journal homepage: www.elsevier.com
Photoremovable NPEC group compatible with Ns protecting group in polyamine
synthesis
Masayoshi Miyahara, Hiroki Shiozaki, Hideyuki Tukada, Yuichi Ishikawa, Masato Oikawa*
Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Herein, we disclose an efficient combination of NPEC and Ns protecting groups in the synthesis
of polyamine, by showing the orthogonal reactivity using N-NPEC-N-Ns alkylamines prepared
from NPEC-NHNs. Selective photodeprotection of NPEC group in 12-mer polyamine and the
complex conjugate has been further demonstrated toward the synthesis of novel polyamine
natural product protoaculeine B.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Mitsunobu reaction
NPEC
Orthogonality
Photochemistry
Polyamine
1. Introduction
Methodology for selective construction of substituted amine plays an important role in the synthesis of nitrogen-containing
compounds. Classical methods include reductive alkylation of amines with aldehydes/ketones mediated by reducing agents such as
H2/catalyst [1], NaBH3CN [2], and NaBH(OAc)3 [3]. Reduction of amides has been also used for preparation of a variety of amines [4].
———
 Corresponding author. Tel.: +81-45-787-2403; fax: +81-45-787-2403; e-mail: moikawa@yokohama-cu.ac.jp

First in 1995 [5-9], Fukuyama et al reported the 2-nitrobenzenesulfonyl (Ns) strategy, which involves alkylation of NsNH-C(=O)-R
or NsNHR either with alcohol or R’-X (X = leaving group). The Ns strategy is now widely used as a reliable methodology for the
N
N
NHBoc
Ns
Ns
NNs
N
N
N
Ns
Ns
Ns
N
N
OH
Ns
Ns
N
N
N
Ns
Ns
Ns
2
Figure 2. Insoluble 12-mer polyamine 2 with eleven Ns groups,
synthesized in our first attempt toward pACU-B (1). The solubility
has been later improved in 12-mer polyamine 7a with less Ns
groups (see text and Table 4) [15].
synthesis of primary and secondary amines [10-13].
Since the discovery in 2014, we have been working on the synthetic study of protoaculeine B (pACU-B, 1, Figure 1) [14, 15], which
is the distal partial structure of novel marine natural peptide aculeine B (ACU-B). Structurally, pACU-B (1) is composed of the N-
terminal amino acid and the long-chain polyamine (LCPA) [16]. Toward synthesis of the LCPA of pACU-B (1), we first synthesized
N-terminal
amino acid
long-chain polyamine
(LCPA)
H2N
N
CO2H
H
N
H
N
NH2
11-14
1
protoaculeine B (pACU-B,
)
Figure 1. Protoaculeine B (1) as a polyamine natural product [14,
15]. The major homolog has a 14-mer polyamine.
12-mer poly(propanediamine) 2 with eleven Ns groups by the Ns strategy [5-9], using Boc group as “a temporary protecting group” for
amine (Figure 2, unpublished results). To our disappointment, however, 2 was found to be a solid insoluble in most of the organic
solvents, probably due to the poor molecular flexibility caused by multiple intramolecular aromatic π-π stacking interactions between
eleven Ns groups [17].
To improve the physical property, we planned to reduce the number of Ns group in the 12-mer polyamine, and decided to employ
Boc group as the second “persistent protecting group” in the synthesis, in addition to the Ns group. As “the temporary protecting group”
for amine, in the new synthesis plan, we decided to explore the possibility of 1-(2-nitrophenyl)ethoxycarbonyl (NPEC) group which had
been known to be photolabile and thus been used for caged compounds [18-20].
In this paper, we report our detailed results on the orthogonal reactivity of the two nitrophenyl-based protecting groups, NPEC and
Ns groups, which may be of use as a compatible tool for amine protection in the synthetic studies of highly nitrogenated compounds.
The photodegradation conditions of the NPEC group have been also screened. Furthermore, the photodegradation has been successfully
applied to structurally complex 12-mer poly(propanediamine) 7a and the conjugate 7b, which are the synthetic intermediates toward
pACU-B (1). From the examinations, it was found that the N-NPEC group can be selectively removed without affecting not only N-Ns
group but also N-Alloc, N-Boc, O-Tr groups and methyl ester, to show the feasibility of our protection strategy.
2. Results and discussion
To study the orthogonal reactivity of NPEC and Ns protecting groups, five N-NPEC-N-Ns alkylamines 4a-4e were synthesized from
NPEC-NHNs (3) [21] (for structure, see Table 1) either by 1) Mitsunobu reaction with alcohols (procedure A), or 2) coupling reaction
with alkyl bromide (procedure B) [7].

Table 1. N-Alkylation of NPEC-NHNs (3)
Entry R-OH or R-Br
(N-alkylation
agent)
Procedure
Aa
Time
15 h
Product and the
yield
NPEC
N-alkylation with
O2N
O
R-OH or R-Br
1
R
NPEC
H
HO C8H17
NPEC
N
O
N
N
C8H17
Ns
O2S
Ns
4a 4e
Ns
–
NPEC-NHNs
O2N
3
( )
4a, 92%
aProcedure A: R-OH (2 equiv), DEAD (2 equiv), PPh3 (2 equiv),
PhH, rt
2
Aa
16 h
bProcedure B: R-Br (1.5 equiv), K2CO3 (5 equiv), Bu4NI (0.2
80 °C
equiv), DMF,
NPEC
N
Ns
OH
As shown in Table 1 (entries 1-3), Mitsunobu
conducted with three alcohols using DEAD and PPh3 at
coupling reaction of 3 with 1-octanol provided N-
octylamine 4a in a good yield (92%, entry 1).
Naphthalenylethylamine 4b was also synthesized by the
procedure with 3 and 2-naphthalenethanol in an
yield (95%, entry 2). Mitsunobu reaction with even a
alcohol proceeded smoothly. Thus, alanine ester 4c was
constructed from 3 and ethyl lactate in 85% yield after
3).
reaction was
rt. First, the
NPEC-N-Ns
4b, 95%
3
Aa
17 h
same
NPEC
HO
excellent
secondary
smoothly
N
CO2Et
Ns
CO2Et
C7H15
Ph
17
h (entry
4c, 85%
dr = 57:43
Results for the coupling reaction with bromides
Bu4NI, DMF, 80 °C) are as follows (entries 4 and 5).
bromide and benzyl bromide, here, heptylamine 4d and
4e were readily synthesized in 77% yield (entry 4) and
(entry 5), respectively, by the reaction with NPEC-
The yields are comparable to those reported for popular
[7, 22] and Cbz-NHNs [7, 23], suggesting the good
NPEC-NHNs (3) for use in the synthetic study of
(K2CO3,
4
Bb
25 h
Br C7H15
NPEC
N
Ns
From heptyl
benzylamine
in 98% yield
NHNs
(3).
4d, 77%
Boc-NHNs
reactivity of
amines.
5
Bb
3 h
NPEC
Br
Ph
N
Ns
With N-NPEC-N-Ns alkylamines 4a-4e in hand, we
examined selective removal of Ns group. As shown in
treatment of 4a-4e with thiophenol and Cs2CO3 [6]
first
Table
afforded des-
2,
4e, 98%
N-Ns amines 5a-5e in good yields. All reactions were cleanly completed in 120 min, and no side reactions were observed. Thus it was
shown that the NPEC nitrophenyl group is enough stable under conditions for deprotection of Ns group.
Table 2. Selective removal of Ns group of N-NPEC-N-Ns alkylamines 4a-4e
Entry R (substrate)
Time
1.5 h
Product and
the yield
Selective photoremoval of NPEC group over Ns
group was next attempted using N-
PhSH (3 equiv)
Cs2CO3 (3 equiv)
1
5a, 91%
C8H17
R
R
NPEC
NPEC
N
N
H
(4a)
Ns
CH3CN, rt
2
1.5 h
5b, 88%
4a 4e
5a 5e
–
–
NPEC-N-Ns octylamine 4a as the substrate (Table
was conducted with a UV lamp (365 nm, 4 W) in
for 1.5 h, the substrate 4a was found to be partially
the reaction was terminated after 9 h (85% NMR
not completely consumed in entry 1, we changed
3). First, photodegradation of 4a
MeOH (entry 1). After irradiation
consumed from TLC analysis, and
yield). Since the substrate 4a was
(4b)
3
1 h
5c, 90%
dr = 57:43
the
solvent
to
2,2,2-
CO2Et
(4c, dr = 57:43)
trifluoroethanol
(TFE)
or
1,1,1,3,3,3-
hexafluoroisopropanol
(HFIP)
[24]. In both solvents, the reactions were
isolated yields were 92% for TFE, and 94% for
observed.
completed in 9 h (entry 2). The
HFIP. No side reactions were
4
2 h
5d, 88%
5e, 89%
C7H15
(4d)
5
1.5 h
Ph
(4e)

Table 3. Screening for selective photodegradation of NPEC group in N-NPEC-N-Ns octylamine 4a
aIsolated yields were satisfactory: 92% in TFE, and 94% in HFIP.
Entry Irradiation
source
Solvent
Time
Yield
photoirradiation
NPEC
N
H
1
2
3
UV lamp
(365 nm)
MeOH
9 h
85% (NMR)
100% (NMR)a
N
Ns
Ns
solvent (0.003 M)
4a
6
rt
UV lamp
(365 nm)
TFE or
HFIP
9 h
Then the photodegradation was examined with an LED lamp
3 W). Gratifyingly, the reaction was completed in much shorter
min) to give 6 in 95% isolated yield (entry 3). With an LED
longer wavelength (395 nm, 3 W), however, the conversion
(365 nm,
time (20
light of
yield was
(entry 4).
not
LED lamp
(365 nm)
MeOH
20 min
100% (NMR)
95% (isolation)
8.2% (NMR)
found to be quite low (8.2% NMR yield) in HFIP after 9 h 4
This obviously is due to the irradiation wavelength (395 nm) is
LED lamp
(395 nm)
HFIP
9 h
proper for 4a [19, 20]. Even lower NMR yields were observed
LED (395 nm) in MeOH (3.7% yield) and TFE (6.1% yield)
shown in Table 3).
with
(data not
5
high-pressure
Hg lamp
MeOH
20 min
100% (NMR)
91% (isolation)
Finally, the reaction was conducted with a high-pressure Hg lamp (435 W). In MeOH, the des-N-NPEC product 6 was cleanly
obtained in 91% isolated yield after 20 min (100% on NMR, entry 5). Complete conversion was also observed in TFE and HFIP (data
not shown in Table 3).
In all entries, the Ns nitrophenyl group of 4a was totally unaffected to show the specific reactivity of NPEC and Ns groups under
photoirradiation conditions. From the experiments shown in Table 3, it was shown that NPEC protecting group can be smoothly
removed in 20 min either by the LED lamp (365 nm, entry 3) or the high-pressure Hg lamp (entry 5), in MeOH.
It should be also noted here that the photoirradiation conditions in entry 3 (Table 3) were capable of complete removal (100% NMR
yield) of NPEC group in other N-NPEC-N-Ns alkylamines (4c-4e) prepared in Table 1 (data not shown). For aryl-rich substrate 4b, the
photodegradation was completed after two times (2 × 20 min) of irradiation with an LED lamp (365 nm, 3 W).
As noted above, we started this study to explore the usefulness of the combination of NPEC and Ns protecting groups, in the
synthesis of highly nitrogenated compounds such as polyamine. The results in Tables 2 and 3 here have suggested the feasibility, which
encouraged us to use them in polyamine synthesis. To our delight, the strategy using Boc and Ns groups for “persistent protection”, and
NPEC group for “temporary protection” of amino groups, was proven to be effective for iterative synthesis of fully protected 12-mer
polyamine 7a (for the structure, see Table 4) over 9 steps starting from 1,3-propanediamine, as reported prior to this paper [15].
Herein, we furthermore report selective deprotection of NPEC group of the 12-mer polyamine 7a and more complex conjugate 7b by
photoirradiation (Table 4). As shown in entry 1, the photodegradation of the 12-mer polyamine 7a was conducted using the high-
pressure Hg lamp for photoirradiation, according to the procedure shown in Table 3 (entry 5). The desired reaction (7a→8a) was found
to be smoothly completed in 5 min in a good yield (77%) without affecting other functional groups; eight N-Boc amines, four N-Ns
amines, and a Tr ether.
Table 4. Photodegradation of NPEC group in the 12-mer LCPA 7a and the conjugate 7b
We furthermore applied the photoreaction to 7b [15], which is the fully protected pACU-B with 12-mer LCPA (Table 4, entry 2).
photoirradiation
NPEC
H
N
N
Ns
Ns
MeOH, rt
7a
7b
8a
8b
Entry
1
N-NPEC amine substrate
Conditions
des-N-NPEC product
and the yield
We first found
that the
procedure using
the high-pressure
Hg lamp induces
high-pressure Hg lamp
MeOH (4.5 × 10-4 M)
rt, 5 min
8a (77%)
NPEC
N
N
N
Boc
Boc
Ns
NNs
N
N
N
Ns
Boc
Boc
not
only
N
N
OTr
Boc
Boc
deprotection of
the NPEC group,
N
N
N
Ns
Boc
Boc
12-mer poly(1,3-propanediamine) 7a [15]
but
complete
cleavage at the
C11-N bond
also
the
2
LED lamp (365 nm)
MeOH (0.003 M)
rt, 5 × 1 min
8b (54%)
NPEC
N
N
N
Boc
Boc
Ns
NNs
N
N
N
(data not shown).
As shown in
entry 2, however,
it was then found
Ns
Boc
Boc
12
N
N
N
N
11
Boc
Boc
N
N
N
Ns
Boc
Boc
Ns
that
undesirable
cleavage can be
somewhat
the
NHAlloc
MeO2C
fully protected pACU-B with 12-mer LCPA 7b [15]
suppressed when the light at 365 nm was irradiated by the LED lamp for 1 min (5 times), according to the procedure shown in Table 3
(entry 3). While the photoreaction still accompanied the bond cleavage at C11-N, the desired des-N-NPEC product 8b was successfully

generated in an acceptable yield (54%), to show that Alloc group and methyl ester are also compatible to NPEC group, in addition to
Boc and Ns groups.
3. Conclusion
In this paper, we have successfully shown the compatible use of two nitrophenyl-based protecting groups, NPEC and Ns groups, for
substituted amine synthesis, by studying with N-NPEC-N-Ns alkylamines 4a-4e prepared from NPEC-NHNs (3). Furthermore, selective
deprotection of NPEC group in the fully protected 12-mer poly(propanediamine) 7a and the conjugate 7b, over the other protecting
groups (Alloc, Boc, methyl ester, Tr), was successfully demonstrated to show the usefulness of our protection strategy. From 8b,
stepwise deprotections are expected to provide structurally defined pACU-B with 12-mer LCPA. Further application to the synthesis of
other polyamines including more complex protoaculeine A [14, 16] is also in progress, and the results will be reported in due course.
Acknowledgments
The authors are grateful to Prof. R. Sakai (Hokkaido University) for valuable discussions.
A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.tetlet.##.##.##.
References and notes
1.
2.
3.
4.
5.
6.
7.
8.
9.
J. Klankermayer, W. Leitner, Science 350 (2015) 629.
R.F. Borch, M.D. Bernstein, H.D. Durst, J. Am. Chem. Soc. 93 (1971) 2897.
A.F. Abdel-Magid, K.G. Carson, B.D. Harris, C.A. Maryanoff, R.D. Shah, J. Org. Chem. 61 (1996) 3849.
T. Mitsudome, K. Miyagawa, Z. Maeno, T. Mizugaki, K. Jitsukawa, J. Yamasaki, Y. Kitagawa, K. Kaneda, Angew. Chem. Int. Ed. 56 (2017) 9381.
T. Fukuyama, C.K. Jow, M. Cheung, Tetrahedron Lett. 36 (1995) 6373.
T. Fukuyama, M. Cheung, C.-K. Jow, Y. Hidai, T. Kan, Tetrahedron Lett. 38 (1997) 5831.
T. Fukuyama, M. Cheung, T. Kan, Synlett (1999) 1301.
Y. Hidai, T. Kan, T. Fukuyama, Chem. Pharm. Bull. 48 (2000) 1570.
T. Kan, T. Fukuyama, Chem. Commun. (2004) 353.
10. K.-i. Nihei, M.J. Kato, T. Yamane, K. Konno, Tetrahedron 62 (2006) 8335.
11. N.E. Golantsov, A.V. Karchava, M.A. Yurovskaya, Chem. Heterocycl. Compd. 44 (2008) 263.
12. L.K. Ottesen, C.A. Olsen, M. Witt, J.W. Jaroszewski, H. Franzyk, Chem. Eur. J. 15 (2009) 2966.
13. K. Kobayashi, S. Oishi, R. Hayashi, K. Tomita, T. Kubo, N. Tanahara, H. Ohno, Y. Yoshikawa, T. Furuya, M. Hoshino, N. Fujii, J. Med. Chem. 55
(2012) 2746.
14. S. Matsunaga, R. Kishi, K. Otsuka, M. Fujita, M. Oikawa, R. Sakai, Org. Lett. 16 (2014) 3090.
15. H. Shiozaki, M. Miyahara, K. Otsuka, K. Miyako, A. Honda, Y. Takasaki, S. Takamizawa, H. Tukada, Y. Ishikawa, R. Sakai, M. Oikawa, Org. Lett.
20 (2018) 3403.
16. S. Matsunaga, M. Jimbo, M.B. Gill, L.L. Lash-Van Wyhe, M. Murata, K.i. Nonomura, G.T. Swanson, R. Sakai, ChemBioChem 12 (2011) 2191.
17. P.C. Mbarushimana, Q.L. Liang, J.M. Allred, P.A. Rupar, Macromolecules 51 (2018) 977.
18. J.E. Corrie, A. DeSantis, Y. Katayama, K. Khodakhah, J.B. Messenger, D.C. Ogden, D.R. Trentham, J. Physiol. 465 (1993) 1.
19. F. Palma-Cerda, C. Auger, D.J. Crawford, A.C. Hodgson, S.J. Reynolds, J.K. Cowell, K.A. Swift, O. Cais, L. Vyklicky, J.E. Corrie, D. Ogden,
Neuropharmacology 63 (2012) 624.
20. M. Su, J. Wang, X. Tang, Chem. Eur. J. 18 (2012) 9628.
21. Preparation of NPEC-NHNs (3) is included in the Supplementary Data.
22. H. Aoki, T. Mukaiyama, Chem. Lett. 35 (2006) 456.
23. J. Taguchi, T. Ikeda, R. Takahashi, I. Sasaki, Y. Ogasawara, T. Dairi, N. Kato, Y. Yamamoto, J.W. Bode, H. Ito, Angew. Chem. Int. Ed. 56 (2017)
13847.
24. J.A. Karas, A. Noor, C. Schieber, T.U. Connell, F. Separovic, P.S. Donnelly, Chem. Commun. 53 (2017) 6903.
NPEC group is compatible with Ns and other protecting groups in polyamine synthesis.
Photoirradiation conditions for removal of N-NPEC group are optimized.
The precursor for marine natural product protoaculeine B is synthesized.