The Synthesis of Oxa-Analogues and Homologues of Naturally Occuring Polyamines

Article abstract of DOI:10.1055/s-1998-2073

A number of polyamine oxa-analogues 14a-d, 19 have been synthesized.Spermidine oxa-analogues and homologues 14 were made from N-(aminooxypropyl)phthalimide 8a which was obtained either from the Fmoc-deprotection of N-<3-(Fmoc-amino)propoxy>phthalimide 4a or from the reaction between 3-bromopropylamine and N-hydroxyphthalimide, both reactions involving an unusual rearrangement mechanism.Sulphonated derivatives 9, 16, upon Mitsunobu condensation with N-protected 3-aminopropanol or N-alkylation with N-(bromoalkyl)phthalimides, afforded the fully protected spermidine and spermine oxa-analogues.Subsequent sequential deprotection gave spermidine analogues 14.Using the same strategy, spermine oxa-analogues 19 was synthesised. - Keywords: polyamines; oxa-analogues of polyamines; polyamine homologues; rearrangement; synthesis

Full text of DOI:10.1055/s-1998-2073

June 1998
SYNTHESIS
859
The Synthesis of Oxa-Analogues and Homologues of Naturally Occurring Polyamines
P. Kong Thoo Lin,* V. A. Kuksa, N. M. Maguire
School of Applied Sciences, The Robert Gordon University, St. Andrew Street, Aberdeen AB25 1HG, Scotland, UK
Fax +44(1224)262828; E-mail: p.kong@rgu.ac.uk
Received 23 June 1997; revised 8 August 1997
In the memory of Romeo V. Yordanov
Abstract: A number of polyamine oxa-analogues 14a–d, 19 have (APA), N-(2-aminooxyethyl)butane-1,4-diamine and 3-
been synthesised. Spermidine oxa-analogues and homologues 14
were made from N-(aminooxypropyl)phthalimide 8a which was
obtained either from the Fmoc-deprotection of N-[3-(Fmoc-
amino)propoxy]phthalimide 4a or from the reaction between 3-
aminooxy-N-(3-aminopropyl)propylamine, have interest-
ing biological activity.4–16 Furthermore, analogues of
APA have also been evaluated as potential anticancer
agents.17 At physiological pH these drugs are partially
bromopropylamine and N-hydroxyphthalimide, both reactions
involving an unusual rearrangement mechanism. Sulphonated
derivatives 9, 16, upon Mitsunobu condensation with N-protected
3-aminopropanol or N-alkylation with N-(bromoalkyl)phthalim-
ides, afforded the fully protected spermidine and spermine oxa-
analogues and homologues. Subsequent sequential deprotection
gave spermidine analogues 14. Using the same strategy, spermine
oxa-analogue 19 was synthesised.
deprotonated since the pKa values of the oxyamino group
are in the region of 4.5–5.016 and this may facilitate their
transport through the cell membrane. Other workers have
synthesised polyamine analogues with electron-with-
drawing groups either on or adjacent to the nitrogen to
generate the same effect.18, 19
Key words: polyamines, oxa-analogues of polyamines,
polyamine homologues, rearrangement, synthesis
In this paper we report the synthesis of a number of
polyamine oxa-analogues and homologues with the ami-
nooxy group located within the polyamine chain.
Natural polyamines such as putrescine [NH2(CH2)4NH2],
spermidine [NH2(CH2)3NH(CH2)4NH2] and spermine
[NH2(CH2)3NH(CH2)4NH(CH2)3NH2] are ubiquitous
biomolecules in living cells. Their presence is vital for the
proper function and proliferation of cells.1–3 During the
last decade there has been intense interest in developing
specific inhibitors to target enzymes which take part in
polyamine biosynthesis, in order to elucidate the precise
biological function of cellular polyamines and to develop
new anticancer agents.4 For example, a number of N-al-
kylated polyamine analogues such as N1 ,N14-diethylsper-
mine demonstrated very good in vitro and in vivo activity
against cancer cells5–9 while dibenzylpolyamine ana-
logues have been shown to be potential antimalarial and
antitrypanosomal drugs.10–13 More recently a number of
reports have revealed that polyamine analogues bearing
an oxyamino moiety, for example aminooxypropylamine
In a recent publication20 we reported the facile synthesis
of N-(aminooxypropyl)phthalimide starting from 3-bro-
mopropylamine hydrobromide (7) and N-hydroxyphthal-
imide in the presence of base (DBU), as shown in Scheme
1. This reaction involves firstly the nucleophilic substitu-
tion of bromine by the N-hydroxyphthalimide anion. Sub-
sequent intramolecular rearrangement affords N-(amino-
oxypropyl)phthalimide (8a) in 72% yield. It is interesting
to note that the N-(aminooxyalkyl)phthalimides with four,
five, and six carbon chains cannot be obtained from the
corresponding aminoalkyl bromide salts, In these reac-
tions with N-hydroxyphthalimide, no characterisable
product was isolated. However, N-(aminooxyalkyl)phthal-
imides 8b–d were successfully obtained by the deprotec-
tion and rearrangement of the corresponding N-[w-
(Fmoc-amino)alkoxy]phthalimides 4 by DBU. The reac-
Scheme 1

860
Papers
SYNTHESIS
tion mechanism proposed for the formation of the N-(ami- groups adjacent to the aminooxy and phthalimido groups
nooxyalkyl)phthalimides is depicted in Scheme 2. The showed two groups of triplets between d = 4.0 and 4.5
reaction mechanism proposed for the deprotection of 4a to while the central methylene groups were usually located
form 8a is analogous to the reaction between aminopropyl in the region of d = 1.0–2.0. The IR spectra of 8 showed
bromide and N-hydroxyphthalimide discussed above. characteristic absorption bands at 3460, 3320, 1710 cm–1.
However for the formation of 8b–d, the nucleophilic ad-
In the synthesis of the spermidine analogue 14a and ho-
dition of two molecules of N-(aminoalkoxy)phthalimide
mologues 14b–d, N-(aminooxypropyl)phthalimide (8a)
to give large ring intermediates 6b–d is suggested; this in-
was used as the precursor. The aminooxy group was first
termediate subsequently undergoes ring opening to give
activated by sulphonation and extension of the chain was
the corresponding N-(aminooxyalkyl)phthalimides 8b–d.
effected by two methods (Scheme 3).
This proposal is supported by the isolation and character-
isation of macrocycle 6d. During deprotection of 4d, if
glacial acetic acid was added to the reaction mixture soon
after the addition of DBU, this resulted in the formation of
a precipitate in 9% yield. The mass spectrum of the pre-
cipitate gave a molecular ion at 525 m.u. and the 13C NMR
spectrum showed resonances at d = 167.4, 165.2, 136.6,
133.5, 129.5, 129.3, 127.6, 127.4, suggesting two differ-
ent spatial arrangements of the phthaloyl groups. This
spectroscopic evidence suggests that 6d is a macrocycle.
Compound
n
Ra
R¢
Compound
n
Ra
10a
10b
10c
10d
11
1
2
3
4
1
Mts
Mts
Mts
Mts
Pmc
NPhth
NPhth
NPhth
NPhth
NHBpoc
12a
12b
12c
12d
13
1
2
3
4
1
Mts
Mts
Mts
Mts
Pmc
a Mts = SO2Mes,
a: RCl, Et3N, CH2Cl2, r.t., 24 h. b: PhthN(CH2)nBr, K2CO3, DMF,
80°C, 12 h. c: 2, DEAD, Ph3P, THF, r.t., 2 h. d: N2H4·H2O, EtOH,
r.t., 24 h. e: HBr/HOAc, CH2Cl2, r.t., 24 h. f: HCl, MeOH, r.t., 2 h.
g: HCl/HOAc, 80°C, 12 h.
Scheme 3
Firstly N-(sulphonylaminooxypropyl)phthalimide 9b was
condensed with Bpoc-amino-protected propyl alcohol 2
under Mitsunobu conditions to give the fully protected
polyamine oxa-analogue 11. Subsequent deprotection
with alcoholic hydrazine hydrate, HCl/diethyl ether and
then HCl/HOAc gave the parent compound 14a. The sec-
ond method involved direct N-alkylation of 9a with the
appropriate N-(bromoalkyl)phthalimide22 in the presence
of K2CO3 in anhydrous DMF. Removal of the phthaloyl
groups followed by treatment with HBr/HOAc gave 14.
Scheme 2
Typically the 1H NMR spectrum of N-(aminooxy-
alkyl)phthalimides 8 showed a broad signal at d ~5.5
which disappeared in the presence of D2O and was hence
assigned as the aminooxy group (ONH2). The methylene
For the oxa-analogue of spermine 19 (Scheme 4), 1,2-
bis(aminooxy)ethane dihydrochloride (15) was prepared

June 1998
SYNTHESIS
861
1
trophotometer. H and 13C spectra were recorded on a JEOL JNM-
EX90 FT NMR spectrometer. FAB-MS were obtained on a VG Ana-
lytical AutoSpec (25 kV) spectrometer, EI/CI-MS spectra were per-
formed on Micromass Quattro II (low resolution) or VG Analytical
ZAB-E instruments (accurate mass). DMF was distilled prior to use.
CH2Cl2 and THF were distilled over P2O5. Compounds 1,2-bis(ami-
nooxy)ethane(15),21 w-bromoalkylphthalimides,22 1-(biphenyl-4-yl)-
1-methylethyl 4-methoxycarbonylphenyl carbonate (Bpoc-carbon-
ate),23 and 2,2,5,7,8-pentamethyl-3,4-dihydro-2H-chromen-6-ylsulpho-
nyl chloride (Pmc-Cl)24 were synthesised as described in the literature.
3-[1-(Biphenyl-4-yl)-1-methylethoxycarbonylamino]propanol (2):
To a solution of 3-aminopropanol (1a) (1.08 g, 14.4 mmol) in THF
(32 mL), Bpoc-carbonate (5.61 g, 14.4 mmol) was added and the mix-
ture was stirred at r.t. for 24 h. Solvent was removed under reduced
pressure, and the residue was dissolved in CHCl3 (30 mL) and washed
with 1 M NaOH (5 ´ 50 mL), water (100 mL), and dried (Na2SO4).
Evaporation of CHCl3 gave 4.03 g (89%) of product which was used
without further purification; mp 118–119 °C (MeCN).
a
Mixture DMF-THF was used. b Reaction conditions and reagents
1H NMR (CDCl3): d = 7.33–7.61 (m, 9H), 5.03 (s, 1H, NH), 3.60 (t,
2H), 3.14–3.35 (m, 2H), 2.51 (s, 1H, OH), 1.79 (s, 6H), 1.55–1.69 (m,
2H).
used were the same as shown in Scheme 3.
Compound
R
Compound
R
R¢
13C NMR (CDCl3): d = 157.6 (C=O), 145.4, 140.6, 139.5, 128.6,
127.0, 126.9, 126.8, 124.5 (arom. C), 80.6, 59.2, 38.2, 32.4, 28.9.
IR (Nujol): n = 3290 (NH), 3240 (OH), 1678 cm–1 (C=O).
16a, 18a
16b, 18b
Mts
Pmc
17a
17b
Mts
Pmc
NPhth
NHBpoc
N-(9-Fluorenylmethoxycarbonyl)-w-amino Alcohols 3; General
Procedure:
a: RCl, Et3N, CH2Cl2, r.t., 24 h. b: PhthN(CH2)nBr, K2CO3, DMF, 80
°C, 12 h. c: 2, DEAD, Ph3P, DMF, THF, r.t., 12 h. d: N2H4·H2O,
EtOH, r.t., 24 h. e: HCl, MeOH, r.t., 2 h. f: HBr/HOAc, CH2Cl2, r.t.,
24 h. g: HCl/HOAc, 80 °C, 12 h.
Amino alcohol, (11 mmol) was dissolved in aq acetone (1:1, 20 mL)
followed by the addition of sat. aq Na2CO3 (2.5 mL) and a solution of
9-fluorenylmethyl chloroformate (Fmoc-Cl) (10 mmol) in acetone
(10 mL). The mixture was stirred for 6 h at r.t. and the solvent was
then removed under reduced pressure. The crude product was dis-
solved in CHCl3 (40 mL) and was washed with water (2 ´ 40 mL); the
organic layer was dried (anhyd Na2SO4) and filtered. After removal
of solvent in vacuo, Fmoc-protected amino alcohol was obtained as a
white solid which was used without further purification. An analytical
sample was prepared by recrystallisation from MeCN (Table 1).
Scheme 4b
from the reaction between 1,2-dibromoethane and N-hy-
droxyphthalimide followed by acid hydrolysis.21 Exten-
sion from both sides of the chain was done via
condensation under Mitsunobu conditions or N-alkylation
as discussed above.
In this paper we have introduced a new method to synthe-
sise N-(aminooxyalkyl)phthalimides 8, versatile precur-
sors to oxa-analogues and homologues of naturally
occurring polyamines. The synthetic strategies we have
employed have generated polyamine oxa-analogues with
orthogonal protection. For example the phthaloyl groups
in compounds 10 can be selectively removed with hydra-
zine, leaving the mesityl group intact, thus introducing the
w-[N-(9-Fluorenylmethoxycarbonyl)amino]-O-phthalimido Al-
cohols 4 (Mitsunobu Reaction); General Procedure:
A solution of DEAD (5.57 mg, 32 mmol) in anhyd THF (10 mL) was
added dropwise with stirring to a suspension of Fmoc-amino alcohol
3 (16 mmol), N-hydroxyphthalimide (PhthN-OH) (5.22 g, 32 mmol),
and Ph3P (8.39 g, 32 mmol). The mixture was stirred for 2 h at r.t. and
after removal of solvent under reduced pressure, the residue was tak-
en up into CHCl3 (100 mL) and washed with sat. NaHCO3 (4 ´ 100
mL) and water (100 mL). The organic layer was dried (Na2SO4) and
possibility of extending the chain from both sides. In com- evaporation of solvent followed by the addition of MeOH (100 mL)
afforded a white precipitate. The latter was filtered off, washed with
cold MeOH and dried to give the product. For analytical purposes a
sample was recrystalised from MeCN (Table 1).
pound 11 the Bpoc group can be selectively removed with
acid thereby allowing chain extension on one side. Fur-
thermore, oxa-analogues of polyamines are a new family
of compounds which can be used in the design of a num-
ber of biologically active compounds and they can be also
applied to the synthesis of novel oxa-azamacrocycles, an
area in which we are currently working.
N-[w-(Aminooxy)alkyl]phthalimides 8 (Fmoc-Deprotection);
General Procedure:
A solution of DBU (0.85 g, 5.58 mmol) in anhyd MeCN (7 mL) was
added dropwise with stirring to a suspension of Fmoc-amino-O-
phthalimido alcohol 4a–d (5.58 mmol) in MeCN (10 mL). The mix-
Unless otherwise stated all reagents were purchased from Aldrich, ture was allowed to stir for 12–20 h at r.t. Removal of the solvent in
Fluka and Lancaster and were used without further purification. Mps vacuo followed by column chromatography on silica gel (CHCl3) af-
were determined on a Gallenkamp melting point apparatus in open forded the pure oxyamine as a yellow oil (Table 2).
capillaries and are uncorrected. TLC was performed on Kieselgel
plates (Merck) 60 F254 in either CHCl3/MeOH (97:3 or 99:1) or hex-
ane/acetone (3:1). Plates were visualised using UV-light or an iodine
vapour bath. Silica gel Kieselgel 60 (230–400 mesh ASTM) was used
N-[3-(Aminooxy)propyl]phthalimide (8a) (O-Alkylation of N-Hy-
droxyphthalimide):
DBU (10.6 g, 69.5 mmol) was added dropwise to stirred mixture of 3-
for column chromatography. IR spectra were recorded on a Nicolet bromopropylamine hydrobromide (7) (6.92 g, 31.6 mmol), and N-hy-
droxyphthalimide (5.51 g, 33.8 mmol) in anhyd DMF (60 mL). The re-
5ZDX FT-IR spectrophotometer or on a Perkin–Elmer 781 IR spec-

862
Papers
SYNTHESIS
5,18), 28.9, 27.5, 26.0, 25.2 (C-6,7,8,9,19,20,21,22).
IR (Nujol): n = 3252, 3115 (N–H), 1627 cm–1 (C=O).
action was left at 60°C for 24 h. DMF was removed under reduced
pressure and the residue was dissolved in CHCl3 (50 mL), washed with
sat. NaHCO3 (4 ´ 50 mL) and brine (50 mL), dried (Na2SO4), and filtered
through silica gel. Removal of solvent in vacuo yielded 5.00 g (72%) of
a yellow oil, which crystallised on standing (mp 67–69°C). The com-
pound obtained showed spectroscopic properties identical to 8a.
Anal.: Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C,
59.90; H, 5.57; N, 12.86.
LRMS (FAB): calcd for C28H36N4O6 524.62, found 525.00 [MH]+.
N-{3-[(Mesitylsulphonyl)aminooxy]propyl}phthalimides 9; Gen-
eral Procedure:
Mesitylsulphonyl chloride (26.2 mmol) was added portionwise to a
stirred solution of 8a (5.49 g, 24.9 mmol) and Et3N (2.68 g,
26.5 mmol) in anhyd CH2Cl2 (20 mL) at 0°C. After 24 h at r.t., CHCl3
(50 mL) was added and the solution was washed with 1 M HCl
(50 mL), sat. NaHCO3 (2 ´ 50 mL), and brine (50 mL). The organic
layer was dried (Na2SO4), filtered through silica gel and, after remov-
al of solvent under reduced pressure, Et2O (40 mL) was added to the
residue. The mixture was allowed to stir for 30 min and then cooled;
the crystals formed were filtered off, washed with cold Et2O, and
dried to give the product as a white solid.
Cyclic Amide 6d:
To a suspension of 4d (2.34 g, 4.82 mmol) in anhyd MeCN (20 mL)
was added DBU (0.73 g, 4.79 mmol). After all the precipitate had dis-
solved, glacial HOAc (0.58 g, 9.66 mmol) was added. The precipitate
formed was filtered off, washed with MeCN and dried to give 0.23 g
(9%) of macroheterocycle 6d, which was recrystallised from DMF.
1H NMR (CDCl3): d = 7.91–8.20 (m, 8H, phthaloyl), 3.97 (m, 4H,
CH2-11,24), 3.39 (m, 4H, CH2-5,18), 1.47 (m, 16H, CH2-
6,7,8,9,19,20,21,22).
N-{3-[(Mesitylsulphonyl)aminooxy]propyl}phthalimide (9a): yield:
75%; mp 137–138°C (Et2O/THF).
13C NMR (CDCl3): d = 167.4, 165.2 (C=O), 136.6, 133.5, 129.5,
129.3, 127.6, 127.4 (phthaloyl C and CH), 75.0 (C-11,24), 39.1 (C-
1H NMR (CDCl3): d = 7.67–7.91 (m, 4H), 7.55 (s, 1H, ONH), 6.97 (s,

June 1998
SYNTHESIS
863
2H), 3.94 (t, 2H), 3.72 (t, 2H), 2.67 (s, 6H), 2.32 (s, 3H), 1.78–2.13 13C NMR (CDCl3): d = 167.6, 155.3 (C=O), 145.4, 140.3, 138.9,
(m, 2H).
138.8, 138.7, 133.5, 131.4, 128.2, 126.6, 126.5, 124.6, 124.5, 124.4,
13C NMR (CDCl3): d = 168.1 (C=O), 143.2, 140.5, 133.8, 131.9, 122.7, 118.4 (arom. C), 80.0, 73.9, 73.8, 47.5, 38.5, 34.7, 32.1, 28.7,
130.8, 123.1 (arom. C), 74.3, 34.7, 27.1, 22.9, 20.9.
27.0, 26.2, 25.2, 21.0, 18.2, 17.2, 11.7.
IR (Nujol): n = 3244 (N–H), 1695 (C=O), 1338, 1162 cm–1 (SO2).
IR (Nujol): n = 3400 (N–H), 1710 (C=O), 1340; 1160 cm–1 (SO2).
N-{3-[(2,2,5,7,8-Pentamethyl-3,4-dihydro-2H-chromen-6-ylsulpho-
nyl)aminooxy]propyl}phthalimide (9b): yield: 65%; mp 129–130°C eral Procedure (Removal of the Phthaloyl Protecting Group):
a,w-Diamino-5-(mesitylsulphonyl)-4-oxa-5-azaalkanes 12; Gen-
(Et2O/THF).
Phthaloyl-protected oxapolyamine 10 (1.94 mmol) was dissolved in
1H NMR (CDCl3): d – 7.70–7.93 (m, 4H), 7.41 (s, 1H, NH), 4.02 (t, EtOH (30 mL) at 70°C and N2H4·H2O (0.20 g, 4.00 mmol) was add-
2H), 3.77 (t, 2H), 2.61 (s, 6H), 2.40–2.82 (t, 2H), 2.18 (s, 3H), 1.61– ed. The reaction was left to stir at r.t. for 24 h. The precipitate formed
2.18 (m, 4H), 1.40 (s, 6H).
was filtered off and the filtrate was evaporated in vacuo. The residue
13C NMR (CDCl3): d = 167.9 (C=O), 155.1, 137.9, 137.7, 133.6, was treated with CHCl3 (20 mL), filtered, and the filtrate was evapo-
131.6, 125.7, 124.4, 122.8, 118.3 (arom. C), 74.0, 73.9, 34.6, 32.2, rated again to yield the compound as a yellow oil in quantitative yield
27.0, 26.4, 21.0, 18.3, 17.3, 11.9.
(Table 3). To form the dihydrochloride salt, diamine was dissolved in
Et2O/MeOH (5:1, 10 mL) and sat. HCl/Et2O (3 mL) was added. The
mixture was then cooled, precipitate formed was filtered off and
IR (Nujol): n = 3220 (N–H), 1710 (C=O), 1322, 1162 cm–1 (SO2).
5-(Mesitylsulphonyl)-a,w-diphthalimido-4-oxa-5-azaalkanes 10; washed with cold Et2O and dried to afford the dihydrochloride salt as
General Procedure (Alkylation Reaction):
a white solid.
Amixture ofmesitylsulphonyl amide 9a (3.13 mmol), N-(bromoalkyl)-
phthalimide (3.13 mmol), and anhyd K2CO3 (0.91 g, 6.58 mmol) in an- 5-(2,2,5,7,8-Pentamethyl-3,4-dihydro-2H-chromen-6-ylsulpho-
hyd DMF (8 mL) was allowed to stir at 80°C for 12 h. DMF was re- nyl)-4-oxa-5-azaoctane-1,8-diamine Dihydrochloride (13):
moved under reduced pressure and the residue was taken up in CHCl3 8-[I-(Biphenyl-4-yl)-1-methylethoxycarbonylamino]-5-(2,2,5,7,8-
(50 mL), washed with 2 M HCl (2 ´ 50 mL), sat. NaHCO3 (50 mL), and pentamethyl-3,4-dihydro-2H-chromen-6-ylsulphonyl)-4-oxa-5-aza-
water (2 ´ 50 mL), dried (Na2SO4), and filtered through silica gel. Sol- octan-1-amine:
vent was removed in vacuo followed by the addition of Et2O (30 mL). The phthaloyl group of 11 was removed using the same procedure as
The mixture was allowed to stir for 20 min, cooled, and the crystals for 12 to give the product as a yellow oil; yield: 86%.
formed were filtered off, washed with cold Et2O, and dried to give the 1H NMR (CDCl3): d = 7.3–7.9 (m, 9H), 3.0–3.8 (m, 6H), 2.3–3.0 (m,
product as a white solid, which was used without further purification. 10H), 2.2 (s, 3H), 1.4–2.1 (m, 4H), 1.86 (s, 6H), 1.38 (s, 6H).
AnanalyticalsamplewaspreparedbyrecrystallizationfromEt2O/THF 13C NMR (CDCl3): d = 155.7, 155.2, 145.4, 140.6, 139.3, 139.0,
(Table 3).
128.5, 126.9, 126.8, 126.8, 124.8, 124.6, 118.6 (arom. C), 80.4, 74.2,
73.5, 38.6, 38.4, 38.3, 32.3, 28.9, 27.2, 26.5, 21.2, 18.4, 17.4, 12.0.
8-[1-(Biphenyl-4-yl)-1-methylethoxycarbonylamino]-5-(2,2,5,7,8-
pentamethyl-3,4-dihydro-2H-chromen-6-ylsulphonyl)-1-phthal-
imido-4-oxa-5-azaoctane (11) (Mitsunobu Reaction):
5-(2,2,5,7,8-Pentamethyl-3,4-dihydro-2H-chromen-6-ylsulphonyl)-
4-oxa-5-azaoctane-1,8-diamine Dihydrochloride (13):
11 was obtained from 2 and 9b using the Mitsunobu method de- The NPhth-deprotected material was used directly for the deprotec-
scribed above and was purified by column chromatography on silica tion of the Bpoc group. To a suspension of the amine (2.38 g, 3.6
gel (CHCl3) to give pure product as a yellow oil; yield 80%.
mmol) in MeOH (15 mL) was added a solution of sat. HCl in MeOH
1H NMR (CDCl3): d = 7.2–8.1 (m, 13H), 5.38 (t, 1H, NH), 3.1–3.9 (m, (10 mL) and the mixture stirred for 2 h min. After removal of most of
8H), 1.5–3.0 (m, 8H), 2.61 (s, 6H), 2.18 (s, 3H), 1.89 (s, 6H), 1.35 (s,6H). the MeOH, cold EtOAc was added to precipitate the product. After

864
Papers
SYNTHESIS
filtration, washing and drying the diamine salt 13 was obtained as a
white powder (Table 3).
ture was stirred for 24 h at r.t. The precipitate formed was filtered off,
washed with EtOAc (5 ´ 10 mL) and dried in a desiccator ovemight to
give the trihydrobromide salt as a yellow hygroscopic powder (Table 4).
a,w-Diamino-4-oxa-5-azaalkanes 14; General Procedure (Re-
moval of the Mesitylsulphonyl Protecting Group):
4-Oxa-5-azaoctane-1,8-diamine Trihydrochloride (14a); Typical
Procedure (Removal of the Pmc Protecting Group):
To a solution of mesitylsulphonyl-protected oxapolyamine 12 (5.89
mmol) in CH2Cl2 (5 mL) 30% HBr in HOAc (5mL) was added and mix-
The dihydrochloride salt of 13 (0.52 g, 1.00 mmol) was suspended in
a solution of HCl in glacial HOAc (20 mL) in a screwtop bottle and

June 1998
SYNTHESIS
865
Table 4. a,w-Diamino-4-oxa-5-azaalkanes 14 and 5,8-Dioxa-4,9-diazadodecane-1,12-diamine (19)
Prod-
uct
Yield
(%)
IR (Nujol)
1H NMR
d
13C NMR
d
LRMS (FAB)
m/z
n (cm–1)
14a
47–71
3070, 2680, 2480,
2000, 1600, 1273,
1169, 1060, 955,
850, 787
4.27 (t, 2H), 3.51 (t, 2H),
3.07–3.24 (m, 4H), 1.95–
2.33 (m, 4H) (D2O)
80.1, 54.9, 45.3, 45.0, 33.8,
30.0 (D2O)
Calcd (C6H20Br3N3O)
389.956. Found 148
[M–3HBr+H+]
14b
14ca
14d
19
68
3080, 2730, 2505,
2495, 1600, 1310,
995, 895, 760
–
72.2, 49.5, 39.8, 37.5, 24.9,
24.8, 21.2 (D2O)
Calcd (C7H22Br3N3O)
403.983. Found 162
[M–3HBr+H+]
83
–
3.66 (t, 2H), 2.40–2.82 (m,
6H), 1.04–1.80 (m, 8H)
71.6, 51.7, 41.7, 39.2, 33.3,
32.4, 26.9, 24.2 (CDCl3)
(CDCl3)
(EI/CI): Calcd (C8H21N3O)
175.284. Found 176 [M+H+]
46
–
3.67 (t, 2H), 2.40–2.90 (m,
6H), 1.20–1.78 (m, 10H)
(CDCl3)
2.2, 52.2, 42.2, 39.7, 33.9,
32.9, 27.5, 27.3, 27.0
(CDCl3)
Calcd (C9H24Cl3N3O)
298.683. Found 192
[M–2HCl+3H+]
40–73 –
7.9–8.5 (br s, 6H), 4.35 (s,
4H), 3.1–3.45 (m, 4H), 2.7–
3.1 (m, 4H), 1.8–2.22 (m,
4H) (DMSO-d6)
70.29, 45.51, 36.28, 21.61
(DMSO-d6)
Calcd (C8H26Br4N4O2)
529.936. Found 228.2
[M–4HBr+Na+]
a Product was isolated as the free base.
1H NMR (CDCl3): d = 7.70–7.93 (m, 8H), 7.01 (s, 4H), 3.83 (t, 4H), 3.55
(s, 4H), 3.35 (t, 4H), 2.66 (s, 12H), 2.37 (s, 6H), 1.79–2.46 (m, 4H).
13C NMR (CDCl3): d = 168.0 (C=O), 143.7, 141.9, 133.9, 132.0,
129.6, 123.1 (arom. C), 73.5, 47.5, 35.7, 25.6, 23.1, 21.0.
the suspension heated for 24 h at 80 °C. The mixture was cooled, con-
centrated in vacuo and the residue treated with MeOH, EtOAc and
Et2O to precipitate a fawn-coloured solid. After filtration and drying,
0.13 g (47%) of the salt was obtained. Spectroscopic properties were
consistent to those of the trihydrobromide salt (Table 4).
IR (Nujol): n = 3100, 1710 (C=O), 1600, 1325, 1165 cm–1 (SO2).
LRMS (FAB): calcd for C42H46N4O10S2 830.98, found 831 [MH]+.
1,2-Bis[(mesitylsulphonyl)aminooxy]ethane (16a):
A mixture of 15 (3.30 g, 20 mmol), mesitylsulphonyl chloride (8.75
g, 40 mmol) and Et3N (4.05 g, 40 mmol) in CH2Cl2 (15 mL) was left
to stir at r.t. for 24 h. The mixture was worked up as for 9a to give
crude product which was recrystallised from toluene to give 16a as a
white solid; yield: 55%; mp 116–117°C (dec).
1,12-Bis[1-(biphenyl-4-yl)-1-methylethoxycarbonylamino]-4,9-
bis(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-chromen-6-ylsulpho-
nyl)-5,8-dioxa-4,9-diazadodecane (17b) (bis-Mitsunobu Reaction):
The bis-Pmc-oxyamine 16b (2.81 g, 4.5 mmol) was dissolved in an-
hyd DMF (40 mL) at 100 °C. After cooling to r.t., anhyd THF
(125 mL), Bpoc-aminopropanol 2 (3.37 g, 10.7 mmol), Ph3P (3.54 g,
13.5 mmol), and DEAD (2.12 mL, 13.5 mmol) were added. After stir-
ring for 1 h, more DEAD (2.34 g, 13.5 mmol) and Ph3P (3.54 g,
13.5 mmol) were added and the mixture was stirred overnight. The
THF was then removed in vacuo and the residue taken up in CHCl3
(40 mL) and washed with sat. Na2CO3 (2 ´ 50 mL), sat. NH4Cl
(50 mL), water (50 mL), and brine (50 mL), dried (Na2SO4) and con-
centrated in vacuo to give the crude product. This was treated with
Et2O and cooled to 0°C to precipitate out Ph3PO. After removal of
this, the filtrate was concentrated in vacuo and purified by column
chromatography (MeOH/CHCl3, 1.5:98.5 and then Et2O/CH2Cl2,
5:95) to provide the pure mono-Mitsunobu product and a mixture of
the mono- and bis-Mitsunobu products. These products (3.48 g) were
together resubjected to the Mitsunobu reaction in anhyd THF (30 mL)
using 2 (2.02 g, 6.44 mmol), Ph3P (2.12 g, 8.08 mmol) and DEAD
1.40 g (8.06 mmol) for 3 h. Following the usual workup the crude
product was subjected to column chromatography, eluting with
(Et2O/CH2Cl2) as above, to obtain the pure bis-Mitsunobu product
17b in 55% (3.00 g) yield as a yellow oil.
1H NMR (CDCl3): d = 7.04 (s, 4H), 7.32 (s, 2H, NH), 4.00 (s, 4H),
2.65 (s, 12H), 3.49 (s, 6H).
13C NMR (CDCl3): d = 143.6, 140.8, 132.1, 130.8 (arom. C), 73.8,
22.9, 21.0.
IR (Nujol): n = 3250, 1600 (N–H), 1350, 1160 cm–1 (SO2).
1,2-Bis[(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-chromen-6-ylsul-
phonyl)aminooxy]ethane (16b):
Reaction conditions were the same as for 16a. The precipitate formed
after reaction was filtered off and washed with water (100 mL), and
MeCN (50 mL), and dried to provide the title compound as a white
powder in 59% yield; mp 198–199 °C (dec) (DMF).
1H NMR (CDCl3): d = 3.97 (s, 4H), 3.43 (s, 6H), 2.69 (s, 6H), 2.49
(s, 12H), 2.14 (s, 6H), 1.89 (t, 4H), 1.38 (s, 12H).
13C NMR (CDCl3): d = 154.8, 138.1, 137.9, 127.2, 123.8, 118.8
(arom. C), 74.4, 73.7, 32.2, 26.6, 21.0, 18.6, 17.6, 12.2.
IR (Nujol): n = 3230, 1665 (N–H), 1540, 1320 (SO2), 1298, 1154
(SO2), 1103 cm–1.
1H NMR (CDCl3): d = 7.3–7.9 (m, 18H), 5.00 (s, 2H, NH), 3.42 (s,
4H), 3.33 (t, 4H), 3.21 (m, 4H), 2.4–2.9 (m, 8H), 2.65 (s, 6H), 2.3 (s,
3H), 1.79–2.37 (m, 4H), 1.89 (s, 6H), 1.4 (s, 6H).
4,9-Bis(mesitylsulphonyl)-1,12-diphthalimido-5,8-dioxa-4,9-di-
azadodecane (17a):
17a was obtained from 16a and N-(3-bromopropyl)phthalimide using
the procedure for 10 in 60% yield as a white solid; mp 183–184°C
(dec) (EtOH).
13C NMR (CDCl3): d = 155.7, 155.1, 145.5, 140.7, 139.4, 139.1, 139.0,
128.5, 126.8, 126.8, 124.74, 124.7, 124.6, 118.6 (arom. C), 80.4, 74.2,
73.5, 47.2, 38.4, 32.3, 28.9, 27.0, 26.6, 21.1, 18.4, 17.4, 12.0.

866
Papers
SYNTHESIS
4,9-Bis(mesitylsulphonyl)-5,8-dioxa-4,9-diazadodecane-1,12-di-
amine Dihydrochloride (18a):
(5) Bergeron, R. J.; Neims, A. H.; McManis, J. S.; Hawthorne, T.
R.; Vinson, J. R. T.; Bortell, R.; Ingeno, M. J. J. Med. Chem.
1988, 31, 1183.
(6) Bernacki, R. J.; Bergeron, R. J.; Porter C. W. Cancer Res. 1992,
52, 2424.
(7) Bergeron, R. J.; McManis, J. S.; Weimer, W. R.; Schreier, K.
M.; Gao, F.; Wu, Q.; Ortiz-Ocasio, J.; Luchetta, G. R.; Porter,
C.; Vinson, J. R. T. J. Med. Chem. 1995, 38, 2278.
(8) Bergeron, R. J.; Weimar, W. R.; Wu, Q.; Feng, Y.; McManis, J.
S. J. Med. Chem. 1996, 39, 5257.
(9) Chang, B. K.; Bergeron, R. J.; Porter, C. W.; Vinson, J. R. T.;
Liang, Y.; Libby, P. R. Cancer Chemother. Pharmacol. 1992,
30, 183.
(10) Bitonti, A. J.; Dumont, J. A.; Bush, T. L.; Edwards, M. L.; Ste-
merick, D. M.; McCann, P. P.; Sjoerdsma, A. Proc. Natl. Acad.
Sci. U.S.A. 1989, 86, 651.
(11) Bacchi, C. J.; Nathan, H. C.; Hunter, S. H.; McCann, P. P.; Sjo-
erdsma, A. Science 1980, 210, 332.
(12) Bitonti, A. J.; Byers, T. L.; Bush, T. L.; Casara, P. J.; Bacchi, C.
J.; Clarkson, Jr, A. B.; McCann, P. P.; Sjoerdsma, A. Anti-
microb. Agents Chemother. 1990, 34, 1485.
(13) Edwards, M. L.; Stemerick, D. M.; Bitonti, A. J.; Dumont, J. A.;
McCann, P. P.; Bey, P.; Sjoerdsma, A. J. Med. Chem. 1991, 34,
569.
18a was obtained according to the procedure for 12a–d as a white sol-
id with 56% yield of the dihydrochloride salt.
1H NMR (DMSO-d6): d = 8.32 (br s, 6H, 2 ´ NH3+), 7.17 (s, 4H), 4.26
(s, 4H), 2.78–3.35 (m, 8H), 2.57 (s, 12H), 2.36 (s, 6H), 1.52–2.16 (m,
4H).
13C NMR (DMSO-d6): d = 143.9, 141.1, 131.9, 129.1 (arom. C), 73.0,
46.8, 37.3, 24.2, 22.5, 20.5.
IR (Nujol): n = 3400 (N–H), 1950 (NH3+), 1600, 1340, 1165 cm–1
(SO2).
4,9-Bis(2,2,5,7,8-pentamethyl-3,4-dihydro-2H-chromen-6-ylsul-
phonyl)-5,8-dioxa-4,9-diazadodecane-1,12-diamine Dihydrochlo-
ride (18b):
The dihydrochloride salt was obtained according to the procedure for
Bpoc removal for 13 in 84% yield as a white solid.
1H NMR (DMSO-d6): d = 2.95–4.4 (m, 14H), 2.85 (s, 4H), 2.6 (m,
4H), 2.35 (s, 12H), 2.05 (s, 6H), 1.94 (m, 4H), 1.8 (m, 4H), 1.3 (s,
12H).
13C NMR (DMSO-d6): d = 155.4, 139.2, 138.8, 124.8, 124.3, 119.2
(arom. C), 74.65, 73.4, 46.8, 37.1, 32.0, 21.0, 24.5, 26.6, 18.4, 17.5,
12.1.
5,8-Dioxa-4,9-diazadodecane-1,12-diamine (19):
(14) Eloranta, T. O.; Khomutov, A. R.; Khomutov, R. M.; Hyvönen,
T. J. Biochem. 1990, 108, 593.
(15) Keinänen, T.; Hyvönen, T.; Pankaskie, M. C.; Vepsäläinen, J.
J.; Eloranta, T. O. J. Biochem. 1994, 116, 1056.
(16) Hyvönen, T.; Keinänen, T. A.; Khomutov, A. R.; Khomutov, R.
M.; Eloranta, T. O. Life Sci. 1994, 56, 349.
The tetrahydrobromide salt was prepared from 18a using HBr/HOAc
as described for the preparation of 14. The tetrahydrochloride salt was
prepared from 18b using HCl/HOAc (procedure 13 to 14a). Both
compounds showed identical spectroscopic properties (Table 4).
(17) Baillon, J. G.; Kolb, M.; Mamont, P. S. Eur. J. Biochem. 1989,
179, 17.
(18) Baillon, J. G.; Mamont, P. S.; Wagner J.; Gerhart, F.; Lux, P.
Eur. J. Biochem. 1988, 176, 237.
(19) Mett, H.; Stanek, J.; Lopez-Ballester, J. A.; Jänne, J.; Alhonen,
L.; Sinervirta, R.; Frei, J.; Reganass, U. Cancer Chemother.
Pharmacol. 1993, 32, 39.
We thank Drs. R. Buchan and M. Fraser for their critical comments
on this paper, Russian President Scholarship, The Robert Gordon
University, CVCP Award for financial support and the Centre of
Mass Spectrometry at the University of Wales, Swansea, for mass
spectroscopic analyses.
(1) Jänne, J.; Pösö, H.; Raina, A. Biochim. Biophys. Acta 1978, 473,
241.
(20) Kong Thoo Lin, P.; Maguire N. M.; Brown, D. M. Tetrahedron
Lett. 1994, 35, 3605.
(2) Tabor, C. W.; Tabor, H. Annu. Rev. Biochem. 1984, 53, 747.
(3) Pegg, A. E. Biochem. J. 1986, 234, 249.
(21) Shirayev, A.; Kong Thoo Lin, P.; Moiseev, I. K. Synthesis 1997,
38.
(4) Porter, C. W.; Regenass, U.; Bergeron, R. G. In Polyamines in
Gastrointestinal Tract; Chapter 31; p 301; Dowling, R. H.;
Folsch, U. R.; Loser, C. H. R., Eds.; as part of the Proceedings
of the Falk Symposium 62; Kluwer Academic Publisher: Am-
sterdam, 1991.
(22) Gilman, H. Org. Synth. Coll. Vol. 1 1964, 120.
(23) Schnabel, E.; Schmidt, G.; Klauke, E. Liebigs Ann. Chem. 1971,
743, 69.
(24) Ramage, R.; Green, J.; Blake, A. J. Tetrahedron 1991, 6353.

June 1998
SYNTHESIS
867