, 2005, 15(4), 142–143
Synthesis of (R)- and (S)-isomers of 1-methylspermidine
Nikolay A. Grigorenko,a Jouko Vepsalainen,b Aki Jarvinen,c Tuomo Keinanen,c Leena Alhonen,c Juhani Jannec
and Alex R. Khomutov*a
a V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 1405; e-mail: alexkhom@genome.eimb.relarn.ru
b Department of Chemistry, University of Kuopio, P.O.Box 1627, FIN-70211, Kuopio, Finland
c A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O.Box 1627, FIN-70211, Kuopio, Finland
DOI: 10.1070/MC2005v015n04ABEH002120
Previously unknown (R)- and (S)-isomers of 1,8-diamino-5-azanonane were prepared starting from (R)- and (S)-2-aminopropanols.
The biogenic polyamines spermidine (Spd, 1,8-diamino-4-aza-
octane) and spermine (Spm, 1,12-diamino-4,9-diazadodecane)
occur in significant amounts in all mammalian cells and are
essential for their normal growth. A deficiency of Spm and Spd
leads to serious disorders of cellular metabolism and, finally, to
cell death.1 The consequences of the depletion of a polyamine
pool in vivo are quite complex.2 For example, the activation of
polyamine catabolism in transgenic rats dramatically reduces
Spd and Spm pools mainly in the pancreas and provokes acute
pancreatitis.3 Racemic 1,8-diamino-5-azanonane (1-methyl-
spermidine, 1-MeSpd) is metabolically stable, and it is the
only known polyamine analogue to completely prevent acute
pancreatitis caused by polyamine depletion in vivo.4
Boc-protected aminonitriles 1a and 1b were prepared accord-
ing to a published procedure5 starting from commercial enantio-
merically pure 2-aminopropanol via its N-Boc-protected mesylate.
The cyano group in 1a and 1b was smoothly reduced by LiAlH4
at –5 °C and afforded 2a and 2b† without racemization. The
above compounds were converted into o-nitrophenylsulfonyl
(Ns) derivatives 3a and 3b,‡ which were alkylated with N-(4-iodo-
butyl)phthalimide. Subsequent removal of the Ns group led to
bis(protected) 1-MeSpds 4a and 4b, which were isolated by
flash chromatography§. The target hydrochlorides of 6a and 6b
were obtained after the removal of Pht and Boct groups¶ with
†
To the cooled (–5 °C) suspension of LiAlH4 (0.96 g, 25 mmol) in Et2O
(20 ml), a solution of 1a (1.7 g, 9.2 mmol) in Et2O (15 ml) was added
with stirring for 20 min, and stirring was continued for 45 min at –5 °C.
The reaction was quenched with aqueous NaOH. The organic phase was
separated, the residue was treated with Et2O, combined Et2O extracts
were washed with brine and the solvent was evaporated in vacuo. The
residue was purified by flash chromatography [60 g SiO2, 1,4-dioxane–
25% NH4OH (98:2)] affording 1.56 g (90%) of (R)-N3-(tert-butyloxy-
carbonyl)-1,3-diaminobutane 2a; Rf 0.33 [1,4-dioxane–25% NH4OH
(95:5)]; [a]D20 –12.0° (c 2.0, CHCl3; lit.,5 [a]D20 –12.0°). 1H NMR (CDCl3)
d: 4.65 (br. s, 1H), 3.72 (m, 1H), 2.69 (m, 2H), 1.50 (m, 1H), 1.44 (m,
1H), 1.38 (s, 9H), 1.31 (br. s, 2H), 1.08 (d, 3H, JHH 6.54 Hz). 13C NMR
(CDCl3) d: 155.51, 78.89, 44.26, 40.99, 38.81, 28.34, 21.43. Starting
from 1b and following the same procedure, 2b was obtained (91%);
[a]D20 +12.0° (c 2.0, CHCl3; lit.,5 [a]D20 +12.0°).
However, it is unclear which of the two enantiomers of
1-MeSpd is the exact biochemical equivalent of Spd. Here we
describe the synthesis of earlier unknown (R)- and (S)-1-MeSpds.
Boc NH
CN
1a,b
a (R)
b (S)
i
Boc NH
NH2
‡
To the cooled (0 °C) solution of 2a (1.43 g, 7.6 mmol) and Et3N
2a,b
(1.21 ml, 8.8 mmol) in dry CH2Cl2 (15 ml) a solution of NsCl (1.77 g,
8.0 mmol) in dry CH2Cl2 (7 ml) was added with stirring for 30 min, and
stirring was continued for 1 h at 0 °C and for 3 h at 20 °C. The reaction
mixture was washed with H2O, 10% citric acid and brine and dried over
MgSO4. The solvent was removed in vacuo to afford (R)-N1-(o-nitro-
phenylsulfonyl)-N3-(tert-butyloxycarbonyl)-1,3-diaminobutane 3a (2.78 g,
98%); Rf 0.21 [EtOAc–n-hexane (1:2)]; [a]D20 –13.0° (c 5, CHCl3).
1H NMR (CDCl3) d: 8.09 (m, 1H), 7.80 (m, 1H), 7.70 (m, 2H), 6.23
(br. s, 1H), 4.33 (br. s, 1H), 3.71 (m, 1H), 3.24 (m, 1H), 3.01 (m, 1H),
1.69 (m, 1H), 1.37 (m, 10H), 1.07 (d, 3H, JHH 6.54 Hz). 13C NMR
(CDCl3) d: 155.91, 148.07, 134.24, 133.28, 132.49, 130.70, 125.06, 79.59,
43.81, 40.81, 38.10, 28.26, 21.37. Found (%): C, 48.28; H, 6.33; N,
11.35. Calc. for C15H23N3O6S (%): C, 48.25; H, 6.21; N, 11.25. Starting
from 2b and following the same procedure, 3b was obtained (99%);
[a]D20 +13.0° (c 5, CHCl3). Found (%): C, 48.17; H, 6.26; N, 11.28.
Calc. for C15H23N3O6S (%): C, 48.25; H, 6.21; N, 11.25.
ii
Boc NH
NH Ns
3a,b
iii, iv
Boc NH
NPht
NH2
NH
4a,b
v
Boc NH
§
The mixture of 3a (2.7 g, 7.2 mmol), N-(4-iodobutyl)phthalimide (2.6 g,
7.9 mmol) and K2CO3 (2.98 g, 21.5 mmol) in dry DMF (20 ml) was
stirred for 20 h at 20 °C, then PhSH (1.13 ml, 11.0 mmol) and K2CO3
(1.52 g, 11.0 mmol) were added and stirring was continued for 3 h at 20 °C.
The reaction mixture was evaporated to dryness in vacuo, the residue was
treated with a mixture of EtOAc and H2O (3:2, 50 ml) and the organic
layer was separated and washed with brine. The solvent was evaporated
in vacuo, and the residue was purified by flash chromatography [60 g of
SiO2, CHCl3–MeOH–25% NH4OH (100:2:0.2 to 100:4:0.4)] to afford
(R)-N1-(phthaloyl)-N8-(tert-butyloxycarbonyl)-1,8-diamino-5-azanonane
4a (2.49 g, 89%) as a white solid; Rf 0.37 (CHCl3–MeOH–25% NH4OH,
100:4:0.4); [a]2D0 –6.2° (c 1.0, CHCl3). 1H NMR (CDCl3) d: 7.79 (m, 2H),
7.67 (m, 2H), 4.90 (br. s, 1H), 3.67 (t, 3H, JHH 7.16 Hz), 2.61 (m, 4H),
1.65 (m, 3H), 1.48 (m, 4H), 1.38 (s, 9H), 1.09 (d, 3H, JHH 6.54 Hz).
13C NMR (CDCl3) d: 168.31, 155.52, 133.78, 132.14, 123.09, 78.80,
49.35, 46.50, 45.03, 37.77, 37.11, 28.37, 27.26, 26.35, 21.34. Starting
from 3b and following the same procedure, 4b was obtained (92%);
[a]D20 +6.4° (c 1.0, CHCl3).
NH
5a,b
vi
NH2
NH2·3HCl
NH
1-MeSpd 6a,b
SO2
Ns =
NO2
Scheme 1 Reagents and conditions: i, LiAlH4, Et2O, –5 °C; ii, NsCl,
Et3N, CH2Cl2; iii, PhtN(CH2)4I, K2CO3, DMF; iv, PhSH, K2CO3, DMF;
v, N2H4·H2O, EtOH, ∆; vi, HCl, MeOH.
142 Mendeleev Commun. 2005