An Improved Synthesis of (3S,12S)-N1,N14-3,12-dihydroxyhomospermine, a Polyamine Analogue Therapeutic Agent

Article abstract of DOI:10.1055/s-2001-14570

The synthesis of a hydroxylated analogue of N¹,N¹⁴-diethylhomospermine, (3S,12S)-N¹,N¹⁴-diethyl-3,12-dihydroxyhomospermine, is described. The key step in the assembly of this homospermine derivative involves alk

Full text of DOI:10.1055/s-2001-14570

PAPER
1043
An Improved Synthesis of (3S,12S)-N1,N14-Diethyl-3,12-dihydroxy-
homospermine, a Polyamine Analogue Therapeutic Agent
I
mprove
d
Synthe
a
sis of
D
ihy
y
droxylated P
m
olyamine
A
nalogueond J. Bergeron,* Ralf Müller, James S. McManis, Guo Wei Yao, Guangfei Huang
Department of Medicinal Chemistry, University of Florida Health Science Center, Box 100485, Gainesville, Florida 32610–0485, USA
Fax +(352)3928406; E-mail: bergeron@mc.cop.ufl.edu
Received 20 November 2000; revised 19 February 2001
Abstract: The synthesis of a hydroxylated analogue of N1,N14-di-
ethylhomospermine, (3S,12S)-N1,N14-diethyl-3,12-dihydroxyho-
mospermine, is described. The key step in the assembly of this
homospermine derivative involves alkylation of N,N'-dibenzylpu-
trescine with two equivalents of N-[(3S)-3,4-epoxybutyl]-N-ethyl-
trifluoromethanesulfonamide.
+
BnHN
a
Cl
2
NHBn
O
2
3
OH Bn
N
Cl
N
Cl
Key words: antitumor agents, chiral alcohols, epoxides, Mitsunobu
4
Bn
OH
reaction, polyamine analogue
Bn Cl-
+
b
Because of the role polyamines play in a number of phys-
iological events, the polyamine metabolic network has at-
tracted considerable attention as a target in many
therapeutic strategies.1–3 A series of terminally N-alkylat-
ed polyamine analogues, which exhibit antineoplastic ac-
tivity against a number of murine and human tumor lines
both in vitro and in vivo, were assembled in our laborato-
ries.4–8
N
N
Cl
5
Bn
OH
HO
OH Bn
N
NC
+
N
CN
(R,S)-6
Bn
OH
(R,R)-6
c,d,e,f
In the course of our clinical studies with these analogues
as antineoplastics, we found N1,N14-diethylhomospermine
(DEHSPM), a polyamine analogue designed and synthe-
sized in these laboratories, to be a very potent gastrointes-
tinal antitransit and antisecretory agent.9,10 In one attempt
OH
H
N
H
N
N
H
N
H
OH
4 HCl
(R,R)-1
to ameliorate some metabolic problems associated with Scheme 1 Synthesis of (R,R)-(HO)2DEHSPM [(R,R)-1] from (S)-
(+)-Epichlorohydrin (2)12; Reagents and conditions: (a) MgSO4, Me-
OH, 68%; (b) KCN, 18-crown-6, MeCN, 65%; (c) H2, Ra Ni, NH3,
MeOH, 86%; (d) Ac2O, CH2Cl2, 73%; (e) LiAlH4, THF, 44%; (f) H2,
Pd-C, HCl, EtOH, 72%
DEHSPM,11 we raised the oxidation state of two of the
methylene groups of DEHSPM by introducing a single
hydroxyl in the (R) configuration at each of the external
aminobutyl fragments, resulting in (3R,12R)-N1,N14-di-
ethyl-3,12-dihydroxyhomospermine[(R,R)-
(HO)2DEHSPM, (R,R)-1].12
and hydrogenolysis of the benzyls furnished (R,R)-1 in
only 9% overall yield. Clearly, this sequence does not
Three synthetic routes to chiral N1,N14-diethyl-3,12-dihy-
droxyhomospermines [(HO)2DEHSPMs] have been pub-
lished from this laboratory. The first access to (R,R)-1
began with ring opening of (S)-(+)-epichlorohydrin (2)
(2 equivalents) by N,N’-dibenzylputrescine (3)
(Scheme 1).12 The homospermine chain was completed
by elaboration of the resulting dichloride 4 to the dinitrile
6. During scale-up of this step, varying amounts of race-
mization were observed, depending on the reaction condi-
tions. Loss of optical purity could arise from non-
stereoselective attack by cyanide ion at the 2-position of
an azetidinium intermediate such as 5.13 Transformation
of the cyano groups of 6 to terminally ethylated amines
lend itself to efficient scale-up.
A pivotal step in the second synthesis of (R,R)-114 was the
regiospecific alkylation of N-ethylmesitylenesulfonamide
(7) (NaH/DMF) by the ditosylate of (R)-2-benzyloxy-1,4-
butanediol (8), which was obtained from dimethyl
D-malate (Scheme 2). The resulting monotosylate (9)
(2 equivalents) was used in the bis-alkylation of N,N’-
bis(mesitylenesulfonyl)-1,4-butanediamine (10), provid-
ing fully protected polyamine 11 in 50% yield. Although
catalytic cleavage of the O-benzyl protecting groups of 11
occurred efficiently, deprotection of the amines of 12 by
sodium naphthalide gave (R,R)-1 in only 21% yield.
In our first route to (3S,12S)-N1,N14-diethyl-3,12-dihy-
droxyhomospermine [(S,S)-(HO)2DEHSPM, (S,S)-1], L-
malic acid was transformed into (3S)-N-(benzyloxycarbo-
Synthesis 2001, No. 7, 01 06 2001. Article Identifier:
1437-210X,E;2001,0,07,1043,1048,ftx,en;M03500SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1044
R. J. Bergeron et al.
PAPER
low yields of these routes to the (HO)2DEHSPMs may be
due to the stability of amine protecting groups: they were
either too labile during elaboration of the molecule or too
resistant to removal. The synthetic sequences to date are
certainly unsuitable for producing large quantities of
(HO)2DEHSPMs sufficient for biological evaluation.
OBn
NHSO2Mes
7
a
OTs
+
N
OBn
9
SO2Mes
OTs
TsO
+
8
MesSO2HN
NHSO2Mes
The current investigation describes the improvements in
accessing analogue (S,S)-1. The goal of the present route
to this polyamine was to increase the overall yield while
maintaining enantiomeric purity. Specifically, benzyl and
trifluoromethanesulfonyl (Tf)15 groups, which were uti-
lized for the synthesis of (2S,10S)-N1,N11-diethyl-2,10-di-
hydroxynorspermine,14 were selected as the amine
protecting groups. Methyl (S)-2,2-dimethyl-1,3-diox-
olane-4-acetate (17) was reduced to known primary alco-
hol 18 with lithium aluminum hydride in THF in 84%
yield (Scheme 4).16 Alkylation of ethyl trifluoromethane-
sulfonamide (19) under Mitsunobu conditions (diisopro-
pyl azodicarboxylate, triphenylphosphine, THF)17–19 with
carbinol 18 gave N,N-dialkyl sulfonamide 20 in 93%
yield. Hydrolysis of acetonide 20 (acetone, 1 N HCl, re-
flux) provided N-[(3S)-3,4-dihydroxybutyl]-N-ethyltrif-
luoromethanesulfonamide (21) in 88% yield. Reaction of
diol 21 with TsCl (1.1 equivalents) in pyridine at 0 °C pro-
vided primary tosylate 22 in 86% yield. Ring closure of 22
was promoted by K2CO3 in methanol, generating N-[(3S)-
3,4-epoxybutyl]-N-ethyltrifluoromethanesulfonamide
(23) in 79% yield. Triflate-protected epoxide derivative
23 was thus synthesized in 56% yield from compound 18,
a sequence with over 40% higher efficiency than that of
the Cbz-protected derivative.13 Alkylation of N,N'-diben-
zylputrescine (3) with epoxide 23 (2 equivalents) in re-
fluxing ethanol produced the protected tetraamine 24 in
virtually quantitative yield. Unmasking of the amines in
24 was accomplished in two steps. Removal of the Tf
groups in 24 was achieved with lithium aluminum hydride
in refluxing THF,20 giving (3S,12S)-N5,N10-dibenzyl-
N1,N14-diethyl-3,12-dihydroxyhomospermine (25) in
62% yield. Hydrogenolysis of 25 at 1 atmosphere over
10% Pd-C in ethanol and 1 N HCl (8 equivalents) cleaved
the N-benzyl moieties, providing (S,S)-(HO)2DEHSPM as
10
b
SO2Mes
RO
N
OR SO2Mes
N
11: R = Bn
12: R = H
N
N
c
SO2Mes
SO2Mes
d
(R,R)-1
Scheme 2 Synthesis of (R,R)-(HO)2DEHSPM [(R,R)-1] from Dito-
sylate 814; Reagents and conditions: (a) NaH, DMF, 77%; (b) NaH,
DMF, 50%; (c) H2, Pd-black, HOAc, H2O, 86%; (d) Na/naphthalene,
DME, then EtOH, HCl, 21%
Cbz
N
2
H2N
+
NH2
O
13
14
a
OH
Cbz
N
R
N
N
N
R
Cbz
OH
15: R = H
b
16: R = Cbz
c
OH
H
H
N
N
N
H
N
H
OH
(S,S)-1
4 HCl
Scheme 3 Synthesis of (S,S)-(HO)2DEHSPM [(S,S)-1] from Epoxi-
de 1314; Reagents and conditions: (a) EtOH; (b) benzyl chloroforma- its crystalline tetrahydrochloride salt [(S,S)-1] in 88%
te, Et3N, CHCl3, 22%; (c) H2, Pd-C, EtOH, HCl, 85%
yield. The proton NMR spectrum of (S,S)-1 matched pub-
lished values, and its optical rotation was within 5% error
of the literature value.14 The two-stage unmasking to the
target molecule proceeded in 36% higher yield than the
nyl)-N-ethyl-3,4-epoxybutylamine (13) (13% yield),14
corresponding sequence to (R,R)-1.14
which was used to alkylate putrescine (14) (0.5 equiva-
lent) (Scheme 3). Trapping the internal nitrogens of re-
Evaluation of the optical purity of (S,S)-1 was carried out
as before,14 by functionalizing the nitrogens with Cbz,
sulting diol 15 with benzyl chloroformate gave tetra-Cbz
giving 26, and then making the bis-Mosher’s ester 27
polyamine 16 in only 22% yield for the two steps. Facile
(Scheme 5). The 19F NMR spectrum showed approxi-
unmasking of the amines by hydrogenolysis provided
mately 3% contamination by the (R) stereocenter. There-
(S,S)-1.
fore, the enantiomeric purity of (S,S)-1 as accessed by the
present route was 94%. Assuming that no racemization
occurred in the final two steps, two-fold addition of ep-
oxide 23 to N,N'-dibenzylputrescine (3) led to 94% (97%
Although both (R,R)- and (S,S)-1 could now be synthe-
sized in enantiomerically pure states (Schemes 2 and 3),
as verified by 19F NMR spectral analysis of the bis-Mosh-
er’s esters of their N1,N5,N10,N14-tetra-Cbz derivatives, the
97%) of (S,S)-1, 6% (97% 3% 2) of the meso-com-
overall yields were only 7% and 2%, respectively.14 The
pound, and only 0.1% (3% 3%) of (R,R)-1. The spec-
Synthesis 2001, No. 7, 1043–1048 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Improved Synthesis of Dihydroxylated Polyamine Analogue
1045
We took measures to find the reaction step at which
epimerization occurred. Alcohol 18 was acylated with
(R)-(–)- and (S)-(+)-Mosher’s acid chlorides (Scheme 6),
OH
18
CO2CH3
a
b
O
O
O
O
+
17
1
and H NMR analysis showed that 18 was not stere-
ochemically compromised. Note, however, that the chiral
centers in respective derivatives 28 and 29 are separated
by four atoms; thus, the small amount of racemization in
the final product could have originated from the first step.
Epoxide 23 was reacted with chiral and racemic -meth-
Et
N
Tf
SO2CF3
N
H
O
O
20
19
1
ylbenzylamine (Scheme 7), and H NMR analysis of the
products 30 and rac-30 indicated approximately 1%
epimerization of the chiral center in 23. This level of race-
mization was slightly less than that in final product (S,S)-
1. Therefore, the diastereomeric derivatives of Schemes 6
and 7 do not pinpoint the origin of minor optical contam-
ination from Scheme 4.
c
Et
Et
N
N
Tf
e
Tf
O
23
RO
OH
+
21: R = H
22: R =Ts
BnHN
d
NHBn
F3C
O
OCH3
Ph
3
O
O
O
f
a
28
OH
18
OH Bn
N
R
O
O
N
N
R
N
b
H3CO
O
CF3
Ph
Bn
OH
24: R = Tf
25: R = H
g
O
O
O
29
h
Scheme 6 Reagents and conditions: (a) (R)-(–)-Mosher's acid chlo-
ride, pyridine, CCl4, 79%; (b) (S)-(+)-Mosher's acid chloride, Et3N,
DMAP
(S,S)-1
Scheme 4 Synthesis of (S,S)-(HO)2DEHSPM [(S,S)-1]; Reagents
and conditions: (a) LiAlH4, THF, 84%; (b) PPh3, diisopropyl azodi-
carboxylate, THF, 93%; (c) 1 N HCl, acetone, 90 °C, 88%; (d) TsCl,
pyridine, 86%; (e) K2CO3, MeOH, 79%; (f) EtOH, reflux, 98%; (g)
LiAlH4, THF, 62%; (h) H2, 10% Pd-C, 1 M HCl (8 equiv), EtOH,
88%
23
b
a
OH
OH
H
N
H
N
Et
Ph
Et
Ph
N
N
Tf
Tf
OR Cbz
N
Cbz
NEt
rac-30
30
a
(S,S)-1
EtN
Cbz
N
Scheme 7 Reagents and conditions: (a) (R)-(+)- -methylbenzyl-
amine, EtOH, reflux, 79%; (b) -methylbenzylamine, EtOH, reflux,
90%
Cbz OR
26: R = H
b
O
27: R =
The key to the improved synthesis of (S,S)-1 is in the
choice of protecting groups. Construction of a tetra pro-
tected polyamine from Tf-containing epoxide 23
(Scheme 4) occurred in 76% higher yield than that from
Cbz-protected amino epoxide 1314 (Scheme 3), likely due
to the greater stability of the Tf functionality. Removal of
the Tf blocking groups to make 25 was accomplished 41%
more efficiently than cleavage of the mesitylenesulfonyls
of 12 to generate (R,R)-1.14 Whereas the latter protecting
group has been effectively used in this laboratory in the
synthesis of terminally alkylated polyamine analogues,21
conditions of its removal using sodium naphthalide had to
be carefully controlled to avoid cleavage of the chiral al-
CH3O
Ph
CF3
Scheme 5 Reagents and conditions: (a) N-(benzyloxycarbonylo-
xy)succinimide, KHCO3, Et2O (aq), 83%; (b) (R)-(–)-Mosher's acid
chloride, pyridine, CCl4, quantitative
trum of Mosher’s ester 27 indicates only 3%
epimerization because the chemical shift of the stereogen-
ic center in the (S)-configuration in the meso-compound
would likely be identical to that of the Mosher’s ester of
26, due to the distance between the carbinol stereocenters.
Synthesis 2001, No. 7, 1043–1048 ISSN 0039-7881 © Thieme Stuttgart · New York

1046
R. J. Bergeron et al.
PAPER
vent removal in vacuo, purification by flash chromatography (88%
MeOH–CHCl3) gave 20.60 g of 21 (88%) as an oil.
[ ]23D –9.0 (c 1.88, CHCl3).
1H NMR: = 1.19 (t, 3H, J = 7.2 Hz), 1.68 (m, 2H), 3.41 (m, 5H),
3.56 (dd, 1H, J = 11.7, 3.0 Hz), 3.66 (m, 1H), 3.98 (br s, 2H).
cohols, which need not be protected during the present
route (Scheme 4).
Thus, the synthesis of the hydroxylated polyamine ana-
logue (S,S)-1 in 30% overall yield and in gram quantities
has been completed 15 times more efficiently than its pre-
vious synthesis.14 Also, this route is flexible in that (R,R)-
1 could be made, starting with the (R) enantiomer of 18.22
Moreover, the length of the central polyamine chain could
be varied by reacting N,N’-dibenzyldiamines other than 3
with the oxirane 23.
Anal. Calcd for C7H14F3NO4S: C, 31.70; H, 5.32; N, 5.28. Found:
C, 32.03; H, 5.40; N, 5.20.
N-Ethyl-N-[(3S)-3-hydroxy-4-p-toluenesulfonatobutyl]-
trifluoromethanesulfonamide (22)
A solution of 21 (20.12 g, 75.9 mmol) in pyridine (120 mL) was
cooled to 0 °C under N2, and TsCl (15.91 g, 83.45 mmol) in CH2Cl2
(80 mL) was added dropwise. The reaction mixture was stirred at
r.t. for 12 h, diluted with CHCl3 (600 mL), and extracted with 1 N
HCl (3 700 mL). The organic phase was dried (MgSO4), concen-
trated in vacuo, and purified by flash chromatography (5% acetone–
CHCl3) to yield 27.21 g of 22 (86%) as a liquid.
Methyl (S)-2,2-dimethyl-1,3-dioxolane-4-acetate (17) was obtained
from Synthon Co., Lansing, MI. Other reagents were purchased
from the Aldrich Chemical Co. (Milwaukee, WI). Fisher Optima-
grade solvents (Fisher Scientific, Pittsburgh, PA) were routinely
used, and THF was distilled from Na and benzophenone. Organic
extracts were dried over Na2SO4 unless otherwise indicated, and sil-
ica gel 32–63 (40 m “flash”) from Selecto Scientific, Inc. (Su-
wanee, GA) was used for flash column chromatography. 1H NMR
spectra were run at 300 MHz in a deuterated organic solvent (CDCl3
not indicated) or in D2O on a Varian Unity 300 with chemical shifts
in ppm downfield from TMS or 3-(trimethylsilyl)propionic-2,2,3,3-
d4 acid, sodium salt, respectively. A 19F NMR spectrum was run at
282 MHz in CDCl3 on the same instrument with chemical shifts in
ppm downfield from CFCl3. Optical rotations were measured at 589
nm (Na D line) with a Perkin Elmer 341 polarimeter. High resolu-
tion FAB mass spectra were run in a glycerol (26) or 3-nitrobenzyl
alcohol (30) matrix. Elemental analyses were performed by Atlantic
Microlabs, Norcross, GA.
[ ]24D –5.4 (c 1.00, CHCl3).
1H NMR (CD3OD): = 1.21 (t, 3H, J = 7.0 Hz), 1.64 (m, 1H), 1.76
(m, 1H), 2.45 (s, 3H), 3.44 (q, 2H, J = 7.0 Hz), 3.35–3.60 (m, 2H),
3.74 (m, 1H), 3.92 (dd, 1H, J = 10.3, 5.2 Hz), 3.95 (dd, 1H, J = 10.3,
4.8 Hz), 7.45 (m, 2H), 7.82 (m, 2H).
Anal. Calcd for C14H20F3NO6S2: C, 40.09; H, 4.81; N, 3.34. Found:
C, 40.19; H, 4.78; N, 3.27.
N-[(3S)-3,4-Epoxybutyl]-N-ethyltrifluoromethanesulfonamide
(23)
K2CO3 (4.48 g, 32.4 mmol) was added to a solution of 22 (12.35 g,
29.44 mmol) in MeOH (100 mL). The suspension was vigorously
stirred at r.t. for 3 h under Ar and was poured into a mixture of H2O
(200 mL), brine (200 mL), and CH2Cl2 (200 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3
100 mL). The organic phase was dried (MgSO4) and concentrated
in vacuo. Purification by flash chromatography (10% EtOAc–cy-
clohexane) gave 5.78 g of 23 (79%) as a colorless oil.
(S)-2,2-Dimethyl-1,3-dioxolane-4-ethanol (18)
Compound 17 (19.28 g, 0.111 mol) was reacted with LiAlH4 (1.0 M
in THF, 60 mL, 60 mmol) under Ar by a literature method.16 Distil-
lation (bp 72–73 °C/1.0 mbar) [Lit.16 bp 49–50 °C/0.47 mbar] gave
13.61 g (84%) of 18 as a colorless oil.
[ ]25D –15.9 (c 1.22, CHCl3).
[ ]28 –2.16 (c 9.80, MeOH) [Lit. [ ]D –2.23 (c 9.8, MeOH);23
D
[ ]21D –1.49 (c 9.83, MeOH);16 [ ]22D –3.2 (c 1.0, MeOH)22].
1H NMR: = 1.27 (t, 3H, J = 7.3 Hz), 1.72 (m, 1H), 2.05 (m, 1H),
2.53 (dd, 1H, J = 4.8, 2.6 Hz), 2.82 (dd, 1H, J = 4.8, 4.0 Hz), 2.96
(m, 1H), 3.48 (q, 2H, J = 7.3 Hz), 3.54 (m, 2H).
1H NMR data was essentially identical to reported values.22
N-{2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]ethyl}-N-ethyltri-
fluoromethanesulfonamide (20)
Anal. Calcd for C7H12F3NO3S: C, 34.01; H, 4.89; N, 5.67. Found:
C, 34.22; H, 4.86; N, 5.59.
Compound 18 (13.93 g, 95.3 mmol), PPh3 (dried in vacuo over
P2O5, 30.00 g, 0.114 mol), and 1918 (16.90 g, 95.4 mmol) were dis-
solved in THF (430 mL) under N2. Diisopropyl azodicarboxylate
(22.5 mL, 0.114 mol) was added dropwise over 35 min with inter-
mittent ice cooling, and the reaction mixture was stirred for 3.3 h at
r.t. Solids were filtered and washed with Et2O (3 50 mL). After
solvent removal in vacuo, purification by flash chromatography
(5% EtOAc–cyclohexane) furnished 27.07 g of 20 (93%) as a liq-
uid.
[ ]26D –2.5 (c 1.18, CHCl3).
1H NMR: = 1.27 (t, 3H, J = 7.3 Hz), 1.34 (s, 3H), 1.42 (s, 3H),
1.83–1.94 (m, 2H), 3.42–3.62 (m, 5H), 4.05–4.16 (m, 2H).
(3S,12S)-N1,N14-Bis(trifluoromethanesulfonyl)-N5,N10-
dibenzyl-N1,N14-diethyl-3,12-dihydroxyhomospermine (24)
A solution of 23 (5.74 g, 23.2 mmol) and 3 (3.10 g, 11.5 mmol) was
heated in EtOH (200 mL) at reflux for 44 h under N2. The solvent
was removed under reduced pressure. Purification by flash chroma-
tography (23% acetone–toluene) gave 8.58 g of 24 (98%) as a col-
orless oil.
[ ]24D +44.8 (c 1.32, CHCl3).
1H NMR: = 1.24 (t, 6H, J = 7.3 Hz), 1.42 (m, 4H), 1.50–1.78 (m,
4H), 2.30–2.60 (m, 8H), 3.36–3.67 (m, 14H), 3.78 (d, 2H, J = 13.5
Hz), 7.15–7.37 (m, 10H).
Anal. Calcd for C10H18F3NO4S: C, 39.34; H, 5.94; N, 4.59. Found:
C, 39.63; H, 6.05; N, 4.71.
Anal. Calcd for C32H48F6N4O6S2: C, 50.38; H, 6.34; N, 7.34. Found:
C, 50.25; H, 6.16; N, 7.30.
(3S,12S)-N5,N10-Dibenzyl-N1,N14-diethyl-3,12-dihydroxy-
homospermine (25)
N-[(3S)-3,4-Dihydroxybutyl]-N-ethyltrifluoro-
methanesulfonamide (21)
HCl (1 N, 210 mL) was added to a solution of 20 (27.04 g, 88.56
mmol) in acetone (105 mL). The reaction mixture was heated at 95
°C for 1 h and partially concentrated in vacuo. Brine (50 mL) was
added, and the mixture was extracted with EtOAc (3 100 mL).
The combined extracts were washed with brine (75 mL). After sol-
A solution of LiAlH4 (1.0 M in THF, 67 mL, 67 mmol) was cau-
tiously added to 24 (8.48 g, 11.1 mmol) in THF (340 mL) by syringe
under N2. The reaction mixture was heated to reflux for 2.8 days,
cooled to 0 °C, and carefully hydrolyzed with H2O (8 mL), 15%
NaOH (8 mL), and H2O (23 mL). The solids were filtered and
Synthesis 2001, No. 7, 1043–1048 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Improved Synthesis of Dihydroxylated Polyamine Analogue
1047
washed with Et2O (2 125 mL). The filtrate was concentrated in
vacuo, and the residue was purified by flash chromatography (5%,
then 10% concd NH4OH–MeCN), generating 3.43 g of 25 (62%) as
a white solid.
Anal. Calcd for C68H76F6N4O14: C, 63.44; H, 5.95; N, 4.35. Found:
C, 63.66; H, 6.00; N, 4.45.
2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]ethyl (S)- -Methoxy- -
(trifluoromethyl)phenylacetate (28)
[ ]22D +41.3 (c 1.15, CHCl3).
The reaction was carried out in an oven-dried 5- 175-mm NMR
tube, fitted with a rubber septum, under an Ar atmosphere. The re-
agents were injected via syringe in the following order: anhyd pyri-
dine (300 L), (R)-(–)-Mosher’s acid chloride (50 mg, 0.20 mmol),
CCl4 (200 L), and a solution of 18 (24.5 mg, 0.17 mmol) in CCl4
(500 L). The reaction was run and worked up by the method of 27.
The residue was purified by flash chromatography (10% EtOAc–
cyclohexane) to give 48 mg of 28 (79%) as a colorless oil.
1H NMR: = 1.31 (s, 3H), 1.39 (s, 3H), 1.94 (m, 2H), 3.50 (dd, 1H,
J = 8.1, 7.0 Hz), 3.54 (q, 3H, J = 1.2 Hz), 3.95 (dd, 1H, J = 8.1, 5.9
Hz), 4.08 (quintet, 1H, J = 6.4 Hz), 4.44 (t, 2H, J = 6.6 Hz), 7.40 (m,
3H), 7.52 (m, 2H).
1H NMR (CD3OD): = 1.09 (t, 6H, J = 7.3 Hz), 1.38–1.52 (m, 6H),
1.65–1.77 (m, 2H), 2.37–2.47 (m, 8H), 2.59 (q, 4H, J = 7.3 Hz), 2.65
(m, 4H), 3.54 (d, 2H, J = 13.4 Hz), 3.61 (d, 2H, J = 13.4 Hz), 3.69
(m, 2H), 7.15–7.34 (m, 10H).
Anal. Calcd for C30H50N4O2: C, 72.25; H, 10.10; N, 11.23. Found:
C, 72.02; H, 9.96; N, 11.36.
(3S,12S)-N1,N14-Diethyl-3,12-dihydroxyhomospermine
Tetrahydrochloride [(S,S)-1]
HCl (1 N, 27 mL) and 10% Pd-C (480 mg) were introduced into 25
(1.73 g, 3.47 mmol) in EtOH (150 mL). The reaction mixture was
stirred under H2 (1 atm) for 5 h, filtered through Celite, and concen-
trated in vacuo. Recrystallization of the concentrate from aq EtOH
gave 1.42 g of (S,S)-1 (88%) as white crystals.
2-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]ethyl (R)- -Methoxy- -
(trifluoromethyl)phenylacetate (29)
Et3N (11 mg, 0.11 mmol), DMAP (trace), and (S)-(+)-Mosher’s
acid chloride (13 mg, 51 mol) were added to 18 (6.4 mg, 44 mol)
in CDCl3 (400 L). The reaction mixture was stirred for 1 h at r.t.
and was transferred to an NMR tube.
[ ]23D +8.33 (c 1.14, 1 N HCl) [Lit.14 [ ]23D +8.7 (c 1.05, 1 N HCl)].
1H NMR (D2O): = 1.29 (t, 6H, J = 7.3 Hz), 1.72–2.02 (m, 8H),
2.98–3.30 (m, 16H), 4.05 (tt, 2H, J = 9.6, 3.2 Hz); essentially iden-
tical to lit.14 (S,S)-1.
1H NMR: = 3.99 (dd, 1H, J = 8.1, 6.0 Hz) (absent in the spectrum
of crude 28).
Anal. Calcd for C16H42Cl4N4O2: C, 41.39; H, 9.12; N, 12.07. Found:
C, 41.61; H, 9.22; N, 12.26.
N-Ethyl-N-[(3S)-3-hydroxy-4-[(1R)-1-phenylethylamino]-
butyl]trifluoromethanesulfonamide (30)
(3S,12S)-N1,N14-Diethyl-3,12-dihydroxy-N1,N5,N10,N14-tetra-
kis(benzyloxycarbonyl)homospermine (26)
KHCO3 (228 mg, 2.28 mmol) and N-(benzyloxycarbonyloxy)suc-
cinimide (128 mg, 0.51 mmol) were added to a mixture of (S,S)-1
(39.8 mg, 86 mol) in H2O (5 mL) and Et2O (5 mL) at 0 °C, and the
reaction mixture was stirred at r.t. for 5 h. H2O (20 mL) was added,
and the layers were separated. The aqueous layer was extracted with
A solution of 23 (25.1 mg, 0.10 mmol) and (R)-(+)- -methylbenzy-
lamine (24.6 mg, 0.20 mmol) in EtOH (5 mL) was heated to reflux
for 1 day under Ar. The solvent was removed, and the crude product
was purified by flash chromatography (5% MeOH–CHCl3) to give
29 mg of 30 (79%) as a colorless oil.
[ ]24D +39.3 (c 1.14, CHCl3).
Et2O (3
20 mL). The combined organic layers were dried
1H NMR (CDCl3/D2O): = 1.23 (t, 3H, J = 7.0 Hz), 1.37 (d, 3H,
J = 6.6 Hz), 1.50–1.75 (m, 2H), 2.28 (dd, 1H, J = 12.1, 9.2 Hz), 2.62
(dd, 1H, J = 12.1, 3.1 Hz), 3.36–3.57 (m, 4H), 3.63 (tt, 1H, J = 9.0,
3.3 Hz), 3.77 (q, 1H, J = 6.6 Hz), 7.22–7.38 (m, 5H); = 2.38 (dd,
integrates to 1% of dd at = 2.28, J = 12, 10 Hz).
(MgSO4) and concentrated in vacuo. Purification by flash chroma-
tography (75% EtOAc–cyclohexane) gave 61 mg of 26 (83%) as a
colorless, viscous oil.
[ ]22D +2.8 (c 1.00, MeOH) [Lit.14 [ ]21D +3.3 (c 0.97, MeOH)].
1H NMR (CD3OD): = 1.08 (m, 6H), 1.47 (m, 6H), 1.69 (m, 2H),
2.98–3.48 (m, 16H), 3.73 (m, 2H), 5.08 (m, 8H), 7.22–7.40 (m,
20H).
HRMS: calcd for C15H24F3N2O3S (M + H): 369.1460. Found:
369.1463.
HRMS: calcd for C48H63N4O10 (M + H): 855.4544. Found:
855.4625.
N-Ethyl-N-[(3S)-3-hydroxy-4-(1-phenylethylamino)butyl]-
trifluoromethanesulfonamide (rac-30)
A solution of 23 (25.0 mg, 0.10 mmol) and -methylbenzylamine
(24.5 mg, 0.20 mmol) in EtOH (5 mL) was heated to reflux for 19
h under N2. The product was purified by the method of 30 to pro-
duce 33 mg of rac-30 (90%) as a colorless oil.
1H NMR (CDCl3/D2O): = 2.28 (dd, 0.5H, J = 12.1, 9.5 Hz), 2.38
(dd, 0.5H, J = 12.3, 9.2 Hz).
(3S,12S)-3,12-Bis[(S)- -methoxy- -(trifluoromethyl)-
phenylacetoxy]-N1,N14-diethyl-N1,N5,N10,N14-tetrakis-
(benzyloxycarbonyl)homospermine (27)
The reaction was carried out in an oven-dried 5- 175-mm NMR
tube, fitted with a rubber septum, under an Ar atm. The reagents
were injected via syringe in the following order: anhyd pyridine
(300 L), (R)-(–)-Mosher’s acid chloride (37 L, 0.20 mmol), CCl4
(200 L), and a solution of 26 (45 mg, 53 mol) in CCl4 (500 L).
The reaction mixture was shaken and allowed to stand at r.t. for 20
h. CHCl3 (20 mL) was added, and the solution was washed with sat.
NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. Purification of the residue by
flash chromatography (33% EtOAc–cyclohexane) gave 68 mg of 27
(quantitative) as a colorless oil.
HRMS: calcd for C15H24F3N2O3S (M + H): 369.1460. Found:
369.1484.
Acknowledgement
These studies were supported by GelTex, Inc., Waltham, MA. We
would also like to acknowledge Dr. Eileen Eiler-McManis for her
assistance in the organization and editing of this manuscript.
[ ]20D –8.8 (c 1.28, CHCl3) [Lit.14 [ ]22D –7.7 (c 1.35, CHCl3)].
1H NMR (45 °C): = 1.05 (t, 6H, J = 7.3 Hz), 1.32 (m, 4H), 1.70–
1.95 (m, 4H), 2.80–3.52 (m, 16H), 3.43 (s, 6H), 5.09 (m, 8H), 5.22
(m, 2H), 7.20–7.54 (m, 30H).
References
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19F NMR (45 °C): = –71.57 (97 %), –71.81 (3%).
Synthesis 2001, No. 7, 1043–1048 ISSN 0039-7881 © Thieme Stuttgart · New York

1048
R. J. Bergeron et al.
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Synthesis 2001, No. 7, 1043–1048 ISSN 0039-7881 © Thieme Stuttgart · New York