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Synthesis of novel oxa-isosteres of spermidine and spermine
Tetmhedmn Lmcrs, Vol. 35, No. 21, pp. 36053608, 1994 Hseti science Ltd Printed in Great Britain oO404039194 s7.00+0.00
Synthesis of Novel Oxadsosteres
hII1
Kong Thaw Lin',
of Spermidine and &ermine
Nuala hf. Maguire
and Daniel M. Brown+ ABl
TheRobatGorQlru~oivasity.SchooldApplmdSci +MRC Labontory
lHG.uK.
Biology,Hius Road,CambridgeCB2 2QH.UK
of M
AWJU& f-Bmma9ropylamii hydnhrdde reacts with N-hydroxypblhalimidein the ~WUKZC of but N-(3-aminooxypropyl)DBU to give, mt the expected N-(3-aokmpmpyloxy)i&, pMhhi&, 6, fomd by an onuaal Mamolecular ltanmgment. Coupling of the pcrlmlnuhylchranaa-6-sugaoayt (Pmc)derivativeaof 9 and W with N-Bpoc-eminopropenol affavh a dWau&lly aaaaapamidinelOd69-dioaaspamine14respccti~y6mmwhichthcpotactinggroups meltmoved”, mtly.
Polyamines fue essential for the normal growth processes of mammalian cells. Their biosynthesis is accelerated during cell division, in cancerous tissues and in infected cells during viral replication.lsa3 Polyamiae
analogues are of considerable interest as anticancer and, recently, as antimaltuial
agents.4~5 In
looking for analogues with antivital activity we investigated the synthesis of some oxyamine derivatives.6 particularly with the intention of introducing differentially removable protecting groups for further synthetic elaboration.
During this work we encountered chemistry that revealed a facile rearrangement
oxyamine as an inkrme&te.
coupling with anN-protected amino alcohol gave novel oxa-analogues of qermidk Fmoc-Aminopropan-3-01
1 was coupled under Mitsunobu conditions
form 2. On deprotection with DBU followed by uifluomacetylation that formed from 3-aminopropyl displacement
with IV-hydroxyphthalimide.7
then ethyl aifluoroacetate. with tosyl chloride followed by
The structure of 3 has recently been confikmed
FmocNHmONPhth
-
3605
to
the product was found to be identical to
CrystalloglYlphically.* FmacNHwOH
and spamine.
with N-hydroxyphthslkide
bromide and N-hydroxyphthalimide/DBU
However it differed from 3 formed by tteating uifluoroacetamidopropanol nucleophilic
to give an
Activating the oxyamine with an arenesulphonyl group followed by Mitsunobu
3606
It became clear that deprotecting the Fmoc-derivative 2 gave, not the expected N-(3-aminopropyloxy)phthaIimide. 4. but the isomeric N-(3- aminooxypropy0phthalimide 6.9 We account for this by two sequential acyl transfer reactions, the first giving rise to the presumed large ring intermediate, 5. Each step in the rearrangement leads to the replacement of an hydmxamic phtha.limidooxyalkyl
derivatives
by an amidic residue.
undergo very much more facile aminolysis
It is known10 that
than the corresponding
phthalimides and this must cotrelate with the direction that the potentially reversible reaction takes. The aminolysis is evidently rate-determining since neither 4 nor 5 is observed.
Conversion of 6 to the TFA
derivative gives 7 as the sole product (95%). The C2 homologue of 4 foamedfrom lmnnoethylamine hydrobromide and N-hydroxyphthabmkk derivatives
and the Co. Cs and Q homologues released from their Fmoc-
by DBU all undergo rearrangement to give only the corresponding N-(aminooxyalkyl)-
phthaIMde.11 The rearrangement is being investigated further, particularly with a view to halting the Fess
at the
large ring intermediate. We note that it bears formal analogy to other ester-amide and amide-amide transfer reactions, the latter however requiring very strong base catalysis. 12J3 An acetyl transfer in an acetamidooxyalkylaminehasalsobeenmpated.14 0
7
-
(9
8pec~“-O~‘00 8 0
ti
fwc‘N-O-N
01
30
0
9
1,
lint10
BpocN”-pJ’O-N
0
I
ZxJ
0
(ii), (iii), (iv)
To extend the polyamine chain further N-Bpoc-aminopropanol
(N-[2-(biphenylyl)-prop-2-yloxy-
carbonyl]aminoptopanol) was coupled with the TFA derivative, 7, using the Mltsunobu reaction. The single pmduet was not the result of N-alkylation that might bave been expected from mparted equivalent syntheses of N-uifkomacetyl
secondary amines,15~16but instead the isomeric imidate 8, treament of the latter with IW3-
MeOH gave an amidine and the original alcohol. crystallographically trifluoroacetamide.17 satisfactory,
The formation of an imidate was confirmed
on the product derived from 4-nitrobenzyl
alcohol and N-(4-nitrobenzyloxy)-
However, srenesulphonyl activating groups for the aminooxy-functionality
undergoing
coupling,
pentamethyMroman-6-sulphonyl
rapid compared with the corresponding
sulphonamides.1a
were The
(Pmc) derivative 9, not heretofore used in this connection, was preferred
3607
because of its considerably aminopropauol
Thus, 9 was coupled to N-Bpoc-
greater acid lability during deprotecrion.l~
yield to give the fully protected targeL 10. Removal of the phthaloyl group
in quantitative
(80%) then the Bpoc residue (86%) gave the Ng-Pmc derivative. which with HCl-AcOH afforded 6-oxaspermidine 11 as its a+hydrochloride as sole product (76%). 20 Removal of the Bpoc and phthaloyl residues couldalsobe&ectedintherevuse&. Further elabmuion of the Mitsunobu reaction allowed us to synthesise a 6,9dioxa-analog&t spermine
by coupling the 1.2~bis-(Pmc-aminooxy)ethan~
sequential
depmmxion
13 with IV-Bpoc-aminopropanol
16 of
followed
by
as shown in scheme below. The synthesis of other spemineanaloguesbasedonthe
double Mitsunobu reaction are presently being investigated in our laboramy.
PIllc
(0. (ii), (iii)
Bf Br/\/
pm:
-
O-N’
\ *N-O-
‘H
H
12
/
WI
13
7
HZN-N,O~O/N~NY A
.41xc1
16
(i) N-hydroxyphtimbi&@BU in DMF at &‘C for 2 hrs, (ii) IF&X in COIIC.HCI/~~ A&El (iii) Rnccltpyridinc (iv) N-Bpoc-amimprqmm l/Ph~jDEAD ill THP (v) MeOH/Hcl (vi) Hcl/glacial AeoH
We have been able to w an interesting rearrangement
the synthesis of novel analogues of spemidk
Research
oxa-analogues. Institute,
the fanner via
and, as far as we m aware, involving the first use of an arenesulphonyl activated
oxyamine in a Mitsunobu coupling reaction. We are currently polyamine
and s-e,
using the above strategy to synthesise
Biological evaluation of the above compounds
Aberdeen,
in collaboration
other
is being camied out at the Rowett
with Dr. Susan Bardocz and the results will be rcportcd
elsewhere. Acknowledgements:
We thank the MRC Aids Directed Programme Robert Gordon University (to N.M.M.) for financial support .
(to P.K.T.L. and D.M.B.) and The
3608
Referencesnnd Notes 1.
Peg8. A.E. Biochcm. J. 1985234.240-262.
2.
Janne, I., Paso, H. and Raina, A. Biockinr. Bbphys.
3.
Cohen, S.S. and McCormick, F.P. A&. V&r&rRes., 1979,24*
4.
Bardocz. S. in Physiology
Acta, 1978,473,241-293. 331-387.
of Po&am;Jm?s Vol. II, (I% Bachrach and Y.&I. Heimer e&s.), 1989.96
106, CRC Press, Boca Raton FL USA. 5.
Bdwa&,
ML., Stemetick, D.M., Bitoni, A.J., Dumont, J.A., McCanu, P.P., Bcy, P. and Sjoedsma,
A.J. J. Med. Chem. 1991, 34, 569-574. 6.
Khomutov~ R.M., HyvGnen, T., Karvonen, E., sudden,
L., Paalanen, T., Paulin, L., Eloranta, T., Eiophys. Res. Comm., 19?% 130, 596402.
Pajula, R-L., Andersson. L.C. and P&6. H., B&hem. 7.
cbmpounds mfened to have been chamct&sed by n.mr. and mass specuometry.
8. 9.
Van Meervelt, L. Acta Cryst. 1993, c49,624-626. 8~ in &-DMSO: 7,12.8 br (CF3COl’WO}- ; 3,9Sbr
10.
Brown, D.M.. Coe, P.F. and Green, D.P.L. J. C&em. Sot., 1971,C, 867-869.
11.
Cq, Cs and c(j homologues of 6 were isolated as their hydrochloride salts. They all showed in dg-
(CF3COl’W).
DMSO a broad peak at -(&I$ 11.1 (NffGO-) compared with a normal Primary amiue which usually exhibits a peak at -8.2
@I$-)
as, for example, in comPound 11.
12.
Bruice, T-C, and Benkovic, SJ. ~~rg~c
I3.
Guggisberg,
Me&u&~
Vol. 1, Benjamin Iuc. 1966, p. 195.
14.
Lee, B.H. and Miller, MI. J. Org. Chem. 1983,48,24.
A., Dabrowski, B., Kramer, U., Heidelberger,
Claim. Acta, 1978.61,
C., Hesse, M. and S&mid,
X. X&v.
1039.
I5.
Tsunoda, T,, Yamamiya, Y., Ito, S. Tet. Le#s. W3,
16,
Macor, J.E., Blank, D.H., Post, R.J. and Ryan, K Tel: Letts., 1992, 52, 8011-8014.
17.
Brown, D.M., Kong Thoo Lin, P. and Van Meervelt, L. Acta C?yst. 1993, c49,1209-1211.
18.
Roemmele, R.C. and Rapoport, H. J. Org. Chem. 1988,53,2367-2371.
19. 20.
Ramage, R, Green, J. and Blake, A. J. Tetrahedron, 1991,6353-6371. 8H in de-DMSO: 11, 1.76-2.13 (4H, m, 2x -CH2CH2CH2), 2.71-3.07 (4H. m, 2xH2NCH2).
21.
3.34 @I-I, t, -ONHCH2-), 4.08-4.27 @II, t, -f&ONH.), 7.90-8.40 (8H, broad, amino mx%ons). 8R in d&DMSO: 16, 1.88-2.22 (4H, m, 2x -CI-l~C&$H~), 2.70-3.10 (4H1 2x -C&WH2), 3.18-3.45
22.
&..Iin & DMSO: 15, 1.30 (12I-L s, Pmc 2x CI-I3), 1.70-2.10 (14H, m, Pmc CH2. HzNCH2CH2-
(4H, m, 2x-ONHC&-). Pmc CH3),
34, 1639-1642.
4.35 (4H, s, 2x -C~2ONH-],7.90-8.50
2.35 (12H, s, Pmc 2x CH3).
2.50-2.65
H2NCH2), 3.10-3.40 @II, m, -C&NHOCH2-1.
(Received in UK 19 November 1993; accepted 24 March 1994)
3.10-
(6H, broad s, 2x -NH3+).
(4H. m, Pmc CH2).
2.75-2.95
and
(4H, m,
Synthesis of Novel Oxadsosteres
hII1
Kong Thaw Lin',
of Spermidine and &ermine
Nuala hf. Maguire
and Daniel M. Brown+ ABl
TheRobatGorQlru~oivasity.SchooldApplmdSci +MRC Labontory
lHG.uK.
Biology,Hius Road,CambridgeCB2 2QH.UK
of M
AWJU& f-Bmma9ropylamii hydnhrdde reacts with N-hydroxypblhalimidein the ~WUKZC of but N-(3-aminooxypropyl)DBU to give, mt the expected N-(3-aokmpmpyloxy)i&, pMhhi&, 6, fomd by an onuaal Mamolecular ltanmgment. Coupling of the pcrlmlnuhylchranaa-6-sugaoayt (Pmc)derivativeaof 9 and W with N-Bpoc-eminopropenol affavh a dWau&lly aaaaapamidinelOd69-dioaaspamine14respccti~y6mmwhichthcpotactinggroups meltmoved”, mtly.
Polyamines fue essential for the normal growth processes of mammalian cells. Their biosynthesis is accelerated during cell division, in cancerous tissues and in infected cells during viral replication.lsa3 Polyamiae
analogues are of considerable interest as anticancer and, recently, as antimaltuial
agents.4~5 In
looking for analogues with antivital activity we investigated the synthesis of some oxyamine derivatives.6 particularly with the intention of introducing differentially removable protecting groups for further synthetic elaboration.
During this work we encountered chemistry that revealed a facile rearrangement
oxyamine as an inkrme&te.
coupling with anN-protected amino alcohol gave novel oxa-analogues of qermidk Fmoc-Aminopropan-3-01
1 was coupled under Mitsunobu conditions
form 2. On deprotection with DBU followed by uifluomacetylation that formed from 3-aminopropyl displacement
with IV-hydroxyphthalimide.7
then ethyl aifluoroacetate. with tosyl chloride followed by
The structure of 3 has recently been confikmed
FmocNHmONPhth
-
3605
to
the product was found to be identical to
CrystalloglYlphically.* FmacNHwOH
and spamine.
with N-hydroxyphthslkide
bromide and N-hydroxyphthalimide/DBU
However it differed from 3 formed by tteating uifluoroacetamidopropanol nucleophilic
to give an
Activating the oxyamine with an arenesulphonyl group followed by Mitsunobu
3606
It became clear that deprotecting the Fmoc-derivative 2 gave, not the expected N-(3-aminopropyloxy)phthaIimide. 4. but the isomeric N-(3- aminooxypropy0phthalimide 6.9 We account for this by two sequential acyl transfer reactions, the first giving rise to the presumed large ring intermediate, 5. Each step in the rearrangement leads to the replacement of an hydmxamic phtha.limidooxyalkyl
derivatives
by an amidic residue.
undergo very much more facile aminolysis
It is known10 that
than the corresponding
phthalimides and this must cotrelate with the direction that the potentially reversible reaction takes. The aminolysis is evidently rate-determining since neither 4 nor 5 is observed.
Conversion of 6 to the TFA
derivative gives 7 as the sole product (95%). The C2 homologue of 4 foamedfrom lmnnoethylamine hydrobromide and N-hydroxyphthabmkk derivatives
and the Co. Cs and Q homologues released from their Fmoc-
by DBU all undergo rearrangement to give only the corresponding N-(aminooxyalkyl)-
phthaIMde.11 The rearrangement is being investigated further, particularly with a view to halting the Fess
at the
large ring intermediate. We note that it bears formal analogy to other ester-amide and amide-amide transfer reactions, the latter however requiring very strong base catalysis. 12J3 An acetyl transfer in an acetamidooxyalkylaminehasalsobeenmpated.14 0
7
-
(9
8pec~“-O~‘00 8 0
ti
fwc‘N-O-N
01
30
0
9
1,
lint10
BpocN”-pJ’O-N
0
I
ZxJ
0
(ii), (iii), (iv)
To extend the polyamine chain further N-Bpoc-aminopropanol
(N-[2-(biphenylyl)-prop-2-yloxy-
carbonyl]aminoptopanol) was coupled with the TFA derivative, 7, using the Mltsunobu reaction. The single pmduet was not the result of N-alkylation that might bave been expected from mparted equivalent syntheses of N-uifkomacetyl
secondary amines,15~16but instead the isomeric imidate 8, treament of the latter with IW3-
MeOH gave an amidine and the original alcohol. crystallographically trifluoroacetamide.17 satisfactory,
The formation of an imidate was confirmed
on the product derived from 4-nitrobenzyl
alcohol and N-(4-nitrobenzyloxy)-
However, srenesulphonyl activating groups for the aminooxy-functionality
undergoing
coupling,
pentamethyMroman-6-sulphonyl
rapid compared with the corresponding
sulphonamides.1a
were The
(Pmc) derivative 9, not heretofore used in this connection, was preferred
3607
because of its considerably aminopropauol
Thus, 9 was coupled to N-Bpoc-
greater acid lability during deprotecrion.l~
yield to give the fully protected targeL 10. Removal of the phthaloyl group
in quantitative
(80%) then the Bpoc residue (86%) gave the Ng-Pmc derivative. which with HCl-AcOH afforded 6-oxaspermidine 11 as its a+hydrochloride as sole product (76%). 20 Removal of the Bpoc and phthaloyl residues couldalsobe&ectedintherevuse&. Further elabmuion of the Mitsunobu reaction allowed us to synthesise a 6,9dioxa-analog&t spermine
by coupling the 1.2~bis-(Pmc-aminooxy)ethan~
sequential
depmmxion
13 with IV-Bpoc-aminopropanol
16 of
followed
by
as shown in scheme below. The synthesis of other spemineanaloguesbasedonthe
double Mitsunobu reaction are presently being investigated in our laboramy.
PIllc
(0. (ii), (iii)
Bf Br/\/
pm:
-
O-N’
\ *N-O-
‘H
H
12
/
WI
13
7
HZN-N,O~O/N~NY A
.41xc1
16
(i) N-hydroxyphtimbi&@BU in DMF at &‘C for 2 hrs, (ii) IF&X in COIIC.HCI/~~ A&El (iii) Rnccltpyridinc (iv) N-Bpoc-amimprqmm l/Ph~jDEAD ill THP (v) MeOH/Hcl (vi) Hcl/glacial AeoH
We have been able to w an interesting rearrangement
the synthesis of novel analogues of spemidk
Research
oxa-analogues. Institute,
the fanner via
and, as far as we m aware, involving the first use of an arenesulphonyl activated
oxyamine in a Mitsunobu coupling reaction. We are currently polyamine
and s-e,
using the above strategy to synthesise
Biological evaluation of the above compounds
Aberdeen,
in collaboration
other
is being camied out at the Rowett
with Dr. Susan Bardocz and the results will be rcportcd
elsewhere. Acknowledgements:
We thank the MRC Aids Directed Programme Robert Gordon University (to N.M.M.) for financial support .
(to P.K.T.L. and D.M.B.) and The
3608
Referencesnnd Notes 1.
Peg8. A.E. Biochcm. J. 1985234.240-262.
2.
Janne, I., Paso, H. and Raina, A. Biockinr. Bbphys.
3.
Cohen, S.S. and McCormick, F.P. A&. V&r&rRes., 1979,24*
4.
Bardocz. S. in Physiology
Acta, 1978,473,241-293. 331-387.
of Po&am;Jm?s Vol. II, (I% Bachrach and Y.&I. Heimer e&s.), 1989.96
106, CRC Press, Boca Raton FL USA. 5.
Bdwa&,
ML., Stemetick, D.M., Bitoni, A.J., Dumont, J.A., McCanu, P.P., Bcy, P. and Sjoedsma,
A.J. J. Med. Chem. 1991, 34, 569-574. 6.
Khomutov~ R.M., HyvGnen, T., Karvonen, E., sudden,
L., Paalanen, T., Paulin, L., Eloranta, T., Eiophys. Res. Comm., 19?% 130, 596402.
Pajula, R-L., Andersson. L.C. and P&6. H., B&hem. 7.
cbmpounds mfened to have been chamct&sed by n.mr. and mass specuometry.
8. 9.
Van Meervelt, L. Acta Cryst. 1993, c49,624-626. 8~ in &-DMSO: 7,12.8 br (CF3COl’WO}- ; 3,9Sbr
10.
Brown, D.M.. Coe, P.F. and Green, D.P.L. J. C&em. Sot., 1971,C, 867-869.
11.
Cq, Cs and c(j homologues of 6 were isolated as their hydrochloride salts. They all showed in dg-
(CF3COl’W).
DMSO a broad peak at -(&I$ 11.1 (NffGO-) compared with a normal Primary amiue which usually exhibits a peak at -8.2
@I$-)
as, for example, in comPound 11.
12.
Bruice, T-C, and Benkovic, SJ. ~~rg~c
I3.
Guggisberg,
Me&u&~
Vol. 1, Benjamin Iuc. 1966, p. 195.
14.
Lee, B.H. and Miller, MI. J. Org. Chem. 1983,48,24.
A., Dabrowski, B., Kramer, U., Heidelberger,
Claim. Acta, 1978.61,
C., Hesse, M. and S&mid,
X. X&v.
1039.
I5.
Tsunoda, T,, Yamamiya, Y., Ito, S. Tet. Le#s. W3,
16,
Macor, J.E., Blank, D.H., Post, R.J. and Ryan, K Tel: Letts., 1992, 52, 8011-8014.
17.
Brown, D.M., Kong Thoo Lin, P. and Van Meervelt, L. Acta C?yst. 1993, c49,1209-1211.
18.
Roemmele, R.C. and Rapoport, H. J. Org. Chem. 1988,53,2367-2371.
19. 20.
Ramage, R, Green, J. and Blake, A. J. Tetrahedron, 1991,6353-6371. 8H in de-DMSO: 11, 1.76-2.13 (4H, m, 2x -CH2CH2CH2), 2.71-3.07 (4H. m, 2xH2NCH2).
21.
3.34 @I-I, t, -ONHCH2-), 4.08-4.27 @II, t, -f&ONH.), 7.90-8.40 (8H, broad, amino mx%ons). 8R in d&DMSO: 16, 1.88-2.22 (4H, m, 2x -CI-l~C&$H~), 2.70-3.10 (4H1 2x -C&WH2), 3.18-3.45
22.
&..Iin & DMSO: 15, 1.30 (12I-L s, Pmc 2x CI-I3), 1.70-2.10 (14H, m, Pmc CH2. HzNCH2CH2-
(4H, m, 2x-ONHC&-). Pmc CH3),
34, 1639-1642.
4.35 (4H, s, 2x -C~2ONH-],7.90-8.50
2.35 (12H, s, Pmc 2x CH3).
2.50-2.65
H2NCH2), 3.10-3.40 @II, m, -C&NHOCH2-1.
(Received in UK 19 November 1993; accepted 24 March 1994)
3.10-
(6H, broad s, 2x -NH3+).
(4H. m, Pmc CH2).
2.75-2.95
and
(4H, m,