A highly selective mono-C-allylation of DTPA pentaethyl ester

Article abstract of DOI:10.1055/s-0030-1259545

A highly selective mono-C-allylation of pentaethyl diethylenetriaminepentaacetate was achieved with allyl bromide and potassium carbonate via a newly developed elaborate procedure based on Stevens rearrangement. It is contrastive that the conservative one

Full text of DOI:10.1055/s-0030-1259545

LETTER
615
A Highly Selective Mono-C-allylation of DTPA Pentaethyl Ester
M
ono-C-allylation
i
of
D
T
s
e
a
thyl Ester o Nemoto,* Kenji Yatsuzuka, Shin-ya Tamagawa, Naoko Hirao, Masaki Kamiya, Tomoyuki Kawamura
Department of Pharmaceutical Chemistry, Institute of Health Biosciences, Graduate School of The University of Tokushima,
Tokushima 770-8505, Japan
Fax +81(88)6337284; E-mail: nem@ph.tokushima-u.ac.jp
Received 3 December 2010
The loss of large amounts of halogen salts, however,
makes these processes unsustainable.
Abstract: A highly selective mono-C-allylation of pentaethyl di-
ethylenetriaminepentaacetate was achieved with allyl bromide and
potassium carbonate via a newly developed elaborate procedure
based on Stevens rearrangement. It is contrastive that the conserva-
tive one-pot procedure gave a complicated mixture.
In contrast, fundamental molecule 1 has been prepared in
a highly sustainable industrial-scale process via addition–
dehydration reactions followed by hydrolysis of penta-
nitrile 5.6 We recently developed a carbon–carbon bond-
forming reaction that enables addition of a side chain di-
rectly onto the DTPA framework to afford 6.5 However,
poor reproducibility on a large scale has remained prob-
lematic. In this process, highly moisture- or air-sensitive
carbanion species must be generated with strict stoichio-
metric control because of the five reacting groups in the
DTPA framework. Similar procedures were reported by
Keana et al.7 and Muller et al.8 to afford 7 in only 32–36%
yield. Accordingly, the efficient methods for the synthesis
of DTPA-hybrid molecules have not yet been developed.
Key words: MRI, Stevens rearrangement, chelating agent,
Mizoroki–Heck reaction
Diethylenetriaminepentaacetic acid (DTPA, 1) is a well-
known chelating agent of heavy-metal cations
(Scheme 1).1 To design the hybrid molecules possessing
both a peculiarity of the metal cations and an orthogonal
property such as a specific affinity for particular organs or
cells, a number of DTPA derivatives have been synthe-
sized.2–5,7,8 A major molecular design is shown as 2, which
can be synthesized from commercially available DTPA
dianhydride and an amine (H2NR1). Despite the simplicity
of this synthetic strategy, it should be reconsidered; the
loss of one of the five carboxylates decreases the binding
ability.3,9
In this paper, we report a highly practical and reproducible
mono-C-allylation reaction of 85 using allyl bromide (9)
in DMF in the presence of potassium carbonate (K2CO3)
as an essential base (Scheme 2). Importantly, excessively
strict control of the quantity of each reagent is not re-
quired. It is believed that this key reaction proceeds via
the Stevens rearrangement,10 N-allylation followed by C-
migration.11 However, results of our preliminary attempts,
conservative procedures of Stevens rearrangement report-
ed in a number of previous papers,10 were described at
Recently, syntheses of DTPA derivatives with five free
carboxylates that contain a linker-and-functionality group
at a carbon of the framework, such as in 3 and 4, have been
reported via a number of C–N bond-formation reactions.4
HCN, NH3, HCHO
R2
O
O
highly sustainable synthetic route for DTPA (1) via 5
– none of X
(only for non-substituted DTPA)
LiAlH4
H2N
N
H
NH2
– 5X
1 R2 = R3 = R4 = H, XA = CO2H (DTPA)
R2
R4
N
2 R2 = R3 = R4 = H, XA = CO2H, CONHR1 (4:1)..
3 R2 - H, R3 = R4 = H, XA = CO2H
4 R3 - H, R2 = R4 = H, XA = CO2H
5 R2 = R3 = R4 = H, XA = CN
XA
XA
XA
5 mol
– 6X
X
CO2R5
N
N
XA
6 R2 = R3 = H, R4 = XA = CO2Et
R3
4 mol
XA
7 R2 = R3 = H, R4 = H, XA = CO2Me
X
X
NH2
– 1 X
amide base
+ R4X
H2N
R5O2C
NH2
R5O2C
R5O2C
CO2R5
CO2R5
N
N
N
R3
R5O2C
Scheme 1 Previous synthetic routes of DTPA derivatives for candidates of MRI agents
SYNLETT 2011, No. 5, pp 0615–0618
x
x.
x
x.
2
0
1
1
Advanced online publication: 11.02.2011
DOI: 10.1055/s-0030-1259545; Art ID: U10710ST
© Georg Thieme Verlag Stuttgart · New York

616
H. Nemoto et al.
LETTER
first for comparison. Those conservative procedures were have two (Figure 1). The higher nucleophilicity increases
the same as a newly developed condition except ‘one-pot’ the central nitrogen’s ability to form an ammonium cat-
and ‘stepwise’. The conservative conditions gave mix- ion.
tures of mono-C-allylated products 10 and 11, recovered
8, and an unidentified complex mixture of byproducts 12–
14 (likely di- and triallylated compounds) were obtained
less nucleophilic by TWO
neighboring CO2Et groups
in irreproducible yields. The values of chemical yield
EtO2C
EtO2C
CO2Et
CO2Et
shown in Scheme 2 are the best of all we have attempted
by the conservative procedure. Although the reaction pro-
cedure was easy and simple, isolated yield of the desired
one was low, and it was very unpractical to purify the de-
sired one in pure form.
N
N
N
EtO2C
more nucleophilic by ONE
neighboring CO2Et group
8
Figure 1 Considerable difference of nucleophilicity between the
central nitrogen atom and the edge nitrogen atoms
In contrast, the newly developed elaborate procedure re-
ported herein gave 1012 in 63% isolated yield along with
1112 and 8 in 5% and 10% yields, respectively. The chem-
ical yield and selectivity were significantly increased by
inserting a ‘vacuum operation’ between the N-allylation13
and C-migration steps. First, a mixture of 8 and nine
equivalents of 9 was heated in DMF without base for 39
hours. The mixture was then concentrated in vacuo to ex-
haustively remove any excess 9. The residue was dis-
solved in DMF, and K2CO3 was added. Heating the
suspension with stirring for 70 hours afforded 10 with
high selectivity.14,15 This procedure was highly reproduc-
ible even when 50 grams of 8 were used.
Compound 10 was then further reacted to form a DTPA-
hybrid molecule (Scheme 3). Via the Mizoroki–Heck
reaction,16 the allylic moiety of 10 was converted to a link-
er-and-functionality group using aryl iodide 15,17 which
was hydrogenated to afford 16 in 84% overall yield. Acid
hydrolysis of 16 led to formation of the hydrochloride salt
of all-carboxylate-free DTPA derivative 1718 bearing an
amino terminal group in 92% yield.
In conclusion, we have developed a highly selective
mono-C-allylation reaction for functionalizing the DTPA
framework via an elaborately modified Stevens rearrange-
ment and demonstrated the synthesis of a DTPA deriva-
tive bearing a linkage and functionality at the central
carbon atom. Detail exploration of the mechanism of the
allylation reaction and synthesis of various key synthetic
intermediates such as 17 are now in progress.
It is noteworthy that the central-selectivity of our new pro-
cedure contrasts with the edge-selectivity of the carbon–
carbon bond-forming reaction that afforded 65 and 7.7,8
We propose that the central nitrogen is more nucleophilic
than the two edge nitrogens because it has only one elec-
tronegative substituent (CH2CO2Et), while edge nitrogens
a newly developed
EtO2C
EtO2C
CO2Et
elaborate step-wise
procedure
EtO2C
EtO2C
CO2Et
CO2Et
N
N
N
N
N
N
CO2Et
9 only
+ K2CO3
in DMF
EtO2C
10
EtO2C
8
"vacuum"
93% chemoselectivity, 63% isolated yield
+ 11 5% isolated yield
+ 8 10% recovered
a representative example of
conservative one-pot procedure
EtO2C
CO2Et
CO2Et
N
N
N
10 20% yield
8 20% recovered yield
EtO2C
EtO2C
11 14% yield
EtO2C
N
CO2Et
CO2Et
EtO2C
EtO2C
CO2Et
CO2Et
EtO2C
EtO2C
CO2Et
CO2Et
N
N
N
N
N
N
N
N
EtO2C
EtO2C
EtO2C
EtO2C
14 2% yield
12 + 13 27% yield
Scheme 2 A representative example of conservative one-pot procedure and a newly developed elaborate procedure of mono-C-allylation of
8. Reagents and conditions: a) allyl bromide (9), DMF, 40 °C, 39 h; then evaporation for removal of allyl bromide; b) K2CO3, DMF, 70 h, 80 °C.
Synlett 2011, No. 5, 615–618 © Thieme Stuttgart · New York

LETTER
Mono-C-allylation of DTPA Pentaethyl Ester
617
(10) (a) Stevens, T. S.; Creighton, E. M.; Gordon, A. B.;
a, b
+
10
I
(CH2)2NHBoc
MacNicol, M. J. Chem. Soc. 1928, 3193. (b) Vanecko,
J. A.; Wan, H.; West, F. G. Tetrahedron 2006, 62, 1043.
(c) Tayama, E.; Orihara, K.; Kimura, H. Org. Biomol. Chem.
2008, 6, 3673.
15
R6O2C
R6O2C
CO2R6
CO2R6
(11) Studies of the C-migration process were reported:
(a) Honda, K.; Inoue, S.; Sato, K. J. Am. Chem. Soc. 1990,
112, 1999. (b) Honda, K.; Inoue, S.; Sato, K. J. Org. Chem.
1992, 57, 428. (c) Honda, K.; Igarashi, D.; Asami, M.;
Inoue, S. Synlett 1998, 685. (d) Workman, J. A.; Garrido,
N. P.; Sançon, J.; Roberts, E.; Wessel, H. P.; Sweeney, J. B.
J. Am. Chem. Soc. 2005, 127, 1066. (e) Sweeney, J. B.
Chem. Soc. Rev. 2009, 38, 1027.
N
N
N
R6O2C
NHR7
16 R6 = Et, R7 = CO2t-Bu
17 R6 = H, R7 = H (4HCl salt)
c
Scheme 3 Synthesis of a DTPA derivative bearing amino terminal
group at C-branched side chain. Reagents and conditions: a)
Pd(OAc)2, P(o-Tol)3, i-Pr2NEt, MeCN–H2O, 60 °C, 8 h, 87% yield;
b) Pd/C, H2, EtOH, r.t., 11 h, 97% yield; c) aq HCl (4.1 mol/L)–THF
(4:1), reflux, 12.5 h, 92% yield. Boc = tert-butoxycarbonyl.
(12) Analytical Data for Compound 10
Colorless oil. FT-IR (neat): 3628, 3448, 3077, 2981, 2366,
2055, 1732, 1642, 1446, 1370, 1343, 1188, 1029, 917, 856,
808, 733 cm–1. 1H NMR (400 MHz, CDCl3): d = 5.80 (ddt,
J = 16.8, 10.0, 6.8 Hz, 1 H, inside of terminal olefin), 5.08
(d, J = 16.8 Hz, 1 H, an edge of terminal olefin), 5.03 (dt,
J = 10.0, 0.4 Hz, 1 H, an edge of terminal olefin), 4.20–4.13
(m, 10 H, 5 × OCH2CH3), 3.57 (s, 8 H, 4 × NCH2CO2Et),
3.50 (t, J = 7.6 Hz, 1 H, allyl-CHCO2Et), 2.88–2.77 [m, 6 H,
N(CH2CHAN)2], 2.71–2.66 [m, 2 H, N(CH2CHBN)2], 2.51
(ddd, J = 14.0, 7.6, 6.8 Hz, 1 H, CHACH=CH2), 2.35 (ddd,
J = 14.0, 7.6, 6.8 Hz, 1 H, CHBCH=CH2), 1.285 (t, J = 6.8
Hz, 12 H, 4 × OCH2CH3), 1.276 (t, J = 6.8 Hz, 3 H,
OCH2CH3). 13C NMR (100 MHz, CDCl3): d = 172.2 (C),
170.9 (4 × C), 134.9 (CH, olefinic), 116.5 (CH2, olefinic),
63.6 (CH, allyl-CHCO2Et), 60.2 (4 × CH2, OCH2CH3), 60.0
(CH2, OCH2CH3), 55.1 (4 × CH2, NCH2CO2Et), 53.3 [2 ×
CH2, N(CH2CH2N)2], 50.2 [2 × CH2, N(CH2CH2N)2], 34.3
(CH2, CH2CH=CH2), 14.3 (CH3, OCH2CH3), 14.1 (4 × CH3,
OCH2CH3). ESI-HRMS: m/z [M + H]+ calcd for
Acknowledgment
This work was partly supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology of Japan (Grant No. 22590101 in 2010–2012).
References and Notes
(1) Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B.
Chem. Rev. 1999, 99, 2293.
(2) (a) Hanaoka, K.; Kikuchi, K.; Terai, T.; Komatsu, T.;
Nagano, T. Chem. Eur. J. 2008, 14, 987. (b) Yu, K.;
Hamdan, Y.; Wan, F.; Li, Y.; Huang, K.; Zhou, J. Aust. J.
Chem. 2006, 60, 218. (c) Broekema, M.; van Eerd, J. J. E.
M.; Oyen, W. J. G.; Corstens, F. H. M.; Liskamp, R. M. J.;
Boerman, O. C.; Harris, T. D. J. Med. Chem. 2005, 48,
6442. (d) Johannes, P.; Ulrich, N. WO 2002059076, 2002.
(e) Ge, P.; Selvin, P. R. Bioconjugate Chem. 2004, 15, 1088.
(f) Arano, Y.; Uezono, T.; Akizawa, H.; Ono, M.; Wakisaka,
K.; Nakayama, M.; Sakahara, H.; Konishi, J.; Yokoyama, A.
J. Med. Chem. 1996, 39, 3451.
(3) Deshpande, S. V.; Subramanian, R.; McCall, M.; DeNardo,
S. J.; Denardo, G. L.; Meares, C. F. J. Nucl. Med. 1990, 31,
218.
(4) (a) Anelli, P. L.; Fedeli, F.; Gazzotti, O.; Lattuada, L.; Lux,
G.; Rebasti, F. Bioconjugate Chem. 1999, 10, 137.
(b) Williams, M. A.; Rapoport, H. J. Org. Chem. 1993, 58,
1151. (c) Anelli, P. L.; Lattuada, L.; Lorusso, V.; Lux, G.;
Morisetti, A.; Morisini, P.; Serleti, M.; Uggeri, F. J. Med.
Chem. 2004, 41, 3629. (d) Corson, D. T.; Meares, C. F.
Bioconjugate Chem. 2000, 11, 292.
C27H48O10N3: 574.3340; found: 574.3331.
Analytical Data for Compound 11
Colorless oil. FT-IR (neat): 3626, 3542, 3453, 3077, 2981,
2938, 2907, 2873, 2386, 2350, 2057, 1883, 1731, 1643,
1465, 1446, 1371, 1344, 1189, 1029, 919, 861, 807, 725, 574
cm–1. 1H NMR (400 MHz, CDCl3): d = 5.83 (ddt, J = 16.8,
10.0, 6.8 Hz, 1 H, inside of terminal olefin), 5.08 (d, J = 16.8
Hz, 1 H, an edge of terminal olefin), 5.03 (d, J = 10.0 Hz,
1 H, an edge of terminal olefin), 4.19–4.12 (m, 10 H, 5 ×
OCH2CH3), 3.60–3.45 (m, 9 H, 4 × NCH2CO2Et and allyl-
CHCO2Et), 2.90–2.77 [m, 8 H, N(CH2CH2N)2], 2.49 (ddd,
J = 10.0, 6.8, 6.8 Hz, 1 H, CHACH=CH2), 2.40 (ddd,
J = 10.0, 6.8, 6.8 Hz, 1 H, CHBCH=CH2), 1.29–1.26 (m, 15
H, 5 × OCH2CH3). 13C NMR (100 MHz, CDCl3): d = 172.3
(C), 171.7 (C), 171.4 (C), 171.1 (2 × C), 134.5 (CH,
olefinic), 116.9 (CH2, olefinic), 64.3 (CH, allyl-CHCO2Et),
60.43 (2 × CH2, CH2, OCH2CH3), 60.40 (CH2, OCH2CH3),
60.3 (CH2, OCH2CH3), 60.2 (CH2, OCH2CH3), 55.3 (2 ×
CH2, NCH2CO2Et), 55.1 (CH2, NCH2CO2Et), 53.2 (CH2,
NCH2CO2Et), 52.8 (CH2, NCH2CH2N), 52.7 (CH2,
NCH2CH2N), 52.3 (CH2, NCH2CH2N), 50.7 (CH2,
NCH2CH2N), 34.9 (CH2, CH2CH=CH2), 14.5 (CH3,
OCH2CH3), 14.34 (CH3, OCH2CH3), 14.31 (2 × CH3,
OCH2CH3), 14.28 (CH3, OCH2CH3). ESI-HRMS: m/z [M +
Na]+ calcd for C27H47O10N3Na: 596.3159; found: 596.3152.
(13) During the reaction of 8 (retention time tR = 0.91 min) and 9
in DMF without K2CO3, a newly generated peak (tR = 1.24
min) was observed by UPLC® [BEH C18 1.7 mm column (2.1
mm id. × 50 mm length), linear gradient of MeCN (0.1%
TFA) in H2O (0.1% TFA), 40–50% over 5 min, detected by
UV at 220 nm]. The new peak was disappeared after the
addition of K2CO3, and 10 (tR = 1.65 min) was produced.
Accordingly, the new peak may indicate the generation of
N-allylated ammonium intermediate (s). Unfortunately,
(5) Nemoto, H.; Cai, J.; Yamamoto, Y. Tetrahedron Lett. 1996,
37, 539.
(6) (a) HN(CH2CN)2 from HCHO, HCN, and NH3: Miller, W.
R.; Falls, N. US 2794044, 1957. (b) Diethylenetriamine
from HN(CH2CN)2 and H2: Ansmann, A.; Benisch, C.;
Funke, F.; Ohlbach, F.; Merger, M. US 0058841, 2002.
(c) Compound 5 from diethylenetriamine, HCHO, and
HCN: Singer, J. J.; Mass, W.; Weisberg, M. US 2855428,
1958. (d) Compound 1 from 5 via hydrolysis: Busch, C. L.;
Meier, H. P.; Cemona, A. WO 83/04020, 1983.
(7) Keana, J. F.; Mann, J. S. J. Org. Chem. 1990, 55, 2868.
(8) Laurent, S.; Botteman, F.; Elst, L. V.; Muller, R. N. Helv.
Chim. Acta 2004, 87, 1077.
(9) Deal, K. A.; Motekaitis, R. J.; Martell, A. E.; Welch, M. J.
J. Med. Chem. 1996, 39, 3096.
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618
H. Nemoto et al.
LETTER
purification of the intermediate (s) was unsuccessful because
of the instability. HPLC separation afforded a mixture of
unidentified polar materials along with unreasonably small
amounts of 8.
NHBoc), 4.18–4.11 (m, 10 H, 5 × OCH2CH3), 3.54 (s, 8 H,
4 × NCH2CO2Et), 3.39–3.33 (m, 3 H, NCHCO2Et and
CH2NHBoc), 2.86–2.56 [m, 12 H, N(CH2CH2N)2 and
CH2C6H4CH2], 1.80–1.56 (m, 4 H, NCHCH2CH2), 1.44 [s, 9
H, C(CH3)3], 1.258 (t, J = 7.2 Hz, 12 H, 4 × OCH2CH3),
1.250 (t, J = 7.2 Hz, 3 H, OCH2CH3). 13C NMR (100 MHz,
CDCl3): d = 172.9 (C, OC=O), 170.8 (4 × C, OC=O), 155.5
(C, NC=O), 139.9 (C, arom.), 136.0 (C, arom.), 128.4 (2 ×
CH, arom.), 128.2 (2 × CH, arom.), 78.6 (C, OCMe3), 63.4
(CH, NCHCO2Et), 60.0 (4 × CH2, OCH2CH3), 59.7 (CH2,
OCH2CH3), 54.9 (4 × CH2, NCH2CO2Et), 53.4 [2 × CH2,
N(CH2CH2N)2], 50.0 [2 × CH2, N(CH2CH2N)2], 41.5 (CH2,
CH2NHBoc), 35.5 (CH2, one of CH2CH2CH2C6H4CH2),
34.9 (CH2, one of CH2CH2CH2C6H4CH2), 29.3 (CH2, one of
CH2CH2CH2C6H4CH2), 28.1 (3 × CH3C(CH3)3], 27.9 (CH2,
one of CH2CH2CH2C6H4CH2), 14.1 (CH3, OCH2CH3), 13.9
(4 × CH3, OCH2CH3). ESI-HRMS: m/z [M + H]+ calcd for
C40H67N4O12: 795.4755; found: 795.4746.
(14) Details of Initial Conditions until Optimization
Under the same conditions except for the amount of 9, 10
was obtained in 23% with 3.0 equiv, 36% with 5.0 equiv,
55% with 7.0 equiv, 63% with 9.0 equiv, 62% with 10.0
equiv, 63% with 11.0 equiv, and 61% yield with 12.0 equiv.
Thus, the use of 9 equiv of 9 was adequate. When the
reaction period of the first process (N-allylation) was shorter
than 39 h, not only was the recovery yield of 8 pointlessly
increased, but the formation of unignorable amount of
isomers 11, di- and tri-allylated compounds was also
observed. At this moment, we considered that N-allylation is
reversible and the mono-(central-N)-allylated cation to
afford 10 is thermodynamically most stable of all the other
N-allylated ammonium cations. The final process (C-
migration) was terminated when the peak corresponding to
the N-allylated cations by UPLC® was disappeared. The
reaction at higher temperature than 80 °C gave a larger
amount of unidentified polar materials. At lower
Analytical Data for Compound 17
Hygroscopic colorless solid. FT-IR (KBr): 3420, 2955,
2361, 1734, 1647, 1636, 1507, 1457, 1418, 1214, 1057, 954,
899, 814, 667 cm–1. 1H NMR (400 MHz, D2O,
temperature than 80 °C, much longer reaction period was
required to consume the N-allylated intermediates.
(15) When we attempted the same reaction with crotyl bromide,
a mixture of inseparable complicated compounds was
obtained probably because of the presence of various
isomers. Accordingly, the selectivity (a- or g-selectivity of
C–N bond formation for the first step and [2,3]- or [1,2]-
sigmatropy for the second step) could not be discussed.
(16) (a) Bräse S., de Meijere A.; Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, 2004; Vol 1:
217-315. (b) de la Escosura A., Marínez-Diaz M. V.,
Thorarson P., Rowan A. E., Nolte R. J. M., Torres T.; J. Am.
Chem. Soc.; 2003, 125: 12300. (c) Trost B. M., Toste F. D.;
J. Am. Chem. Soc.; 2003, 125: 3090. (d) Jeffery T.;
Tetrahedron Lett.; 1994, 35: 3051.
TMSCH2CH2CO2Na as an internal standard): d = 7.28 (d,
J = 7.2 Hz, 2 H, arom.), 7.26 (d, J = 7.2 Hz, 2 H, arom.), 3.96
(s, 8 H, 4 × N+CH2CO2D), 3.56–3.53 (m, 1 H, N+CHCO2D),
3.43 [t, J = 6.8 Hz, 4 H, N+(CH2CH2N+)2], 3.26 (t, J = 6.8
Hz, 2 H, CH2N+D3], 3.19–3.09 [m, 4 H, N+(CH2CH2N+)2],
2.97 (t, J = 6.8 Hz, 2 H, C6H4CH2CH2N+D3), 2.67 (t, J = 6.8
Hz, 2 H, CH2CH2CH2C6H4), 1.87–1.78 (m, 1 H,
CHACH2CH2C6H4), 1.76–1.69 (m, 2 H, CH2CH2CH2C6H4),
1.64–1.58 (m, 1 H, CHBCH2CH2C6H4). 13C NMR (100 MHz,
D2O, TMSCH2CH2CO2Na as an internal standard): d =
177.8 (C, CO2D), 171.8 (4 × C, CO2D), 143.6 (C, arom.),
137.1 (C, arom.), 132.0 (2 × CH, arom.), 131.9 (2 × CH,
arom.), 66.2 (CH, N+CHCO2D), 58.0 (4 × CH2,
N+CH2CO2D), 56.0 [2 × CH2, N+(CH2CH2N+)2], 49.5
[2 × CH2, N+(CH2CH2N+)2], 43.5 (CH2, CH2N+D3), 37.1
(CH2, one of CH2CH2CH2C6H4CH2), 35.2 (CH2, one of
CH2CH2CH2C6H4CH2), 30.5 (CH2, one of
(17) Preparation of 15: Sakurai M., Washizuka K., Hamashima
H., Tomishima Y., Imanishi M., Kayakiri H., Taniguchi K.,
Takamura F.; WO 2002094770, 2002.
CH2CH2CH2C6H4CH2), 30.2 (CH2, one of
(18) Analytical Data for Compound 16
CH2CH2CH2C6H4CH2). ESI-HRMS: m/z [M – H]– calcd for
C25H37N4O10: 553.2510; found: 553.2520. Anal. Calcd for
C25H38N4O10·(HCl)4·(H2O)4.5: C, 38.42; H, 6.58; N, 7.17.
Found: C, 38.32; H, 6.33; N, 7.19..
Colorless oil. FT-IR (neat): 3627, 3396, 2980, 2367, 2054,
1733, 1699, 1508, 1164, 868, 810, 775 cm–1. 1H NMR (400
MHz, CDCl3): d = 7.10 (s, 4 H, arom.), 4.62–4.52 (m, 1 H,
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