synthesis of polyamines, their derivatives, analogues and ......vladimir kuksa, robert buchan, paul...

REVIEW 1189

Synthesis 2000, No. 9, 1189–1207 ISSN 0039-7881 © Thieme Stuttgart · New York

Synthesis of Polyamines, Their Derivatives, Analogues and ConjugatesVladimir Kuksa, Robert Buchan, Paul Kong Thoo Lin*The Robert Gordon University, School of Applied Sciences, St. Andrew Street, Aberdeen, AB25 1HG, Scotland, UKFax +44(1224)262828; E-mail: [email protected] 21 December 1999; revised 24 May 2000

Abstract: The role of polyamines in biological systems is now wellrecognised. In this review an introduction to polyamines and theirbiological significance is first outlined. The main focus of this re-view is on the chemical strategies used in the synthesis ofpolyamines, their derivatives, analogues and conjugates. Recent de-velopments in solid phase synthesis of more complex polyaminemolecules is also covered.

1 Introduction2 Synthesis of Polyamines2.1 Alkylation Reactions2.2 Reduction Methods2.2.1 Reduction of Amide, Nitrile and Nitro Groups2.2.2 Reduction of Azides2.2.3 Reduction of Schiff’s Bases2.3 Michael Addition Reactions2.4 The Mitsunobu Reaction3 Solid-phase Synthesis of Polyamines4 Synthesis of Polyamine Conjugates5 Synthesis of Oxa-polyamines5.1 Synthesis of Primary Aminooxy-polyamines5.2 Synthesis of Oxa-polyamines with Secondary Aminooxy

Groups6 Conclusion

Key words: polyamines, analogues, conjugates, synthesis, method-ology

1 Introduction

Biogenic amines are widely distributed in the plant andanimal kingdom. Many of these bases and their deriva-tives play key roles in a number of biological processesand possess a variety of pharmacological properties.1 Be-ing natural products of amino acid metabolism, thepolyamines, putrescine, spermidine and spermine (Figure1) are found in all living cells in substantial quantities.

Figure 1 Biogenic polyamines

A simplified polyamine biosynthetic2 pathway is depictedin Figure 2. Urease converts arginine to ornithine which is

decarboxylated by the enzyme ornithine decarboxylase(ODC) to putrescine, the simplest of the naturalpolyamines.

Figure 2 Polyamine biosynthetic pathway

The formation of putrescine is the rate-limiting step in thebiosynthetic pathway. The aminopropyl groups in spermi-dine and spermine are derived from dcSAM (decarboxy-lated S-adenosylmethionine decarboxylase), which isformed from SAM (S-adenosylmethionine decarboxy-lase) in a reaction catalysed by SAMDC (S-adenosylme-thionine decarboxylase). The aminopropyl transferreactions are catalysed by spermidine and spermine syn-thases, generating 5’-methylthioadenosine (MTA) in addi-tion to spermidine and spermine.

In the last two decades, many functions of prokaryotic andeukaryotic cells have been shown to be polyamine depen-dent.3 Although the precise role of polyamines is not fullyunderstood, the concentrations of such low molecularweight compounds are strictly regulated. Rapid cellgrowth (e.g. cancer cells) is usually accompanied by highpolyamine concentration.4

Polyamines are cations at physiological pH and thereforethey can interact with nucleic acids, proteins, and phos-pholipids. These compounds affect DNA conformation in

H2N

HN NH2

NH

HN NH2

H2N

H2NNH2

Putrescine Spermidine

Spermine

NH

COOH

NH2

H2N

NH

H2NCOOH

NH2

NH2H2N

NH2NH

H2N

H2NHN

NH

NH2

HH

Arginine

Urease

Ornithine

ODC

Putrescine

MTA

Spermidine

Spermine

SAMdcSAM

MTA SAMdcSAM

1190 V. Kuksa et al. REVIEW


vitro and in vivo, and thus influence many biological pro-cesses, such as transcription, regulation and cell recombi-nation.5,6

Polyamines may act as carcinogenesis promoting factors.The connection between polyamines and cancer growthhas been established by biological and molecular tech-niques.7,8 Polyamines have been shown to accumulate incancer tissues and the concentration of polyamines andtheir derivatives increases in cancer patient fluids.9−13

Polyamines are also important in biological systems, forexample, in order to elucidate their precise role,polyamine analogues such as α-difluoromethyl ornithine(DFMO) and 3-aminooxypropylamine (APA) (Figure 3)have been synthesised and used to suppress the activity ofthe enzyme ornithine decarboxylase (ODC),14−16 which is

the first enzyme involved in polyamine biosynthesis incells. Bis-benzyl polyamine analogues were also found tobe potent inhibitors of both chloroquine-resistant andchloroquine-sensitive strains of human malaria parasitePlasmodium falciparum in vitro.17

Figure 3 Inhibitors of ODC

H2NNH2

COOH

CHF2

O NH2H2N

α-Difluoromethyl Ornithine (DFMO) 3-Aminooxypropylamine (APA)

Biographical Sketches

Paul Kong Thoo Lin wasborn in Mauritius in 1959and is a reader in Bio-organ-ic Chemistry at the school ofApplied Sciences, The Rob-ert Gordon University, Ab-erdeen, Scotland. Heobtained his BSc Hons. inphysical sciences majoringin chemistry at The RobertGordon Institute of Tech-nology, Aberdeen in 1984.

In 1987 he received his PhDin Heterocyclic Chemistryat this institute and in thesame year obtained fullmembership to the RoyalSociety of Chemistry. Be-tween 1987 and 1992, hecarried out his postdoctoralwork at the Laboratory ofMolecular Biology, Cam-bridge, UK working on thesynthesis and properties of

nucleosides, oligonucle-otides and polyamines. Hismain teaching areas are or-ganic chemistry, spectros-copy, bioanalysis andmedicinal chemistry. Hiscurrent research interestsare in the synthesis, reactiv-ity and biological activitiesof novel nucleosides, oligo-nucleotides, oxapolyaminesand oxa-azamacrocycles.

Robert Buchan was born inPeterhead, Scotland andstudied chemistry at Aber-deen university where heobtained his Bachelor ofScience (1st Class) in 1959and his Ph.D. in 1972. Heheld the post of lecturer inorganic chemistry at The

Robert Gordon Institute ofTechnology from 1959 to1984. He was promoted tosenior lecturer position from1984−1998. His main teach-ing areas are organic chem-istry, spectroscopy, polymerscience and medicinalchemistry. His research in-

terests are in the synthesisand reactivity of heterocy-clic compounds and medici-nal chemistry.

Vladimir Kuksa was bornin Protvino, Russia in 1973.He studied at Moscow StateAcademy of Fine ChemicalTechnology, Russia be-tween 1990−1996 where heobtained a Diploma ofHigher Education in Engi-neering Biotechnology withdistinction. In 1995 he re-ceived the prestigiousScholarship of the RussianPresident. Between 1996−

1999 he carried out his post-graduate studies at The Rob-ert Gordon University,United Kingdom, on aproject which entailed thedevelopment of syntheticpathways to novelpolyamine analogues andtheir derivatives, and inves-tigation into the biologicalactivity of synthesised com-pounds. This project also in-cluded the synthesis of

novel oxa-azamacrocyclesand the study of their metalcomplexation properties. Heis currently a Senior Fellowat the Department of Oph-thalmology, University ofWashington, School ofMedicine, USA, where he isinvolved in the research ofthe chemistry and biochem-istry of the visual cycle, in-cluding synthesis of vitaminA analogues.

REVIEW Synthesis of Polyamines, Their Derivatives, Analogues and Conjugates 1191


Over the last decade a few reviews on the chemistry andbiological activity of polyamines have been published.For example the reviews published by Ganem18 andBergeron19 focused on the selective modification of natu-rally occurring polyamines and homologues while themore recent reviews by Blagbrough et al.20 and Hesse etal.21 elegantly presented the biological activities of natu-rally occurring polyamine conjugates, polyamine amidesand analogues. No reviews covering the main syntheticaspects of polyamines have yet been published.

This review summarises the synthetic approaches topolyamine chemistry and includes the synthesis of select-ed polyamine conjugates. The last part of the review is de-voted to the synthesis of novel oxa-polyamines.

2 Synthesis of Polyamines

The general synthetic pathways used in polyamine chem-istry can be classified into several groups viz. (i) methodsusing alkylation reactions, (ii) reduction methods, (iii)Michael addition reactions, and (iv) Mitsunobu reactions.

2.1 Alkylation Reactions

The most widely used reaction in polyamine synthesis isN-alkylation of amines. This method readily allows theextension of the polyamine chain. Alkylation of a primaryamino group can lead progressively to the formation ofsecondary, tertiary amines and quaternary amine salts asshown in Figure 4.

Figure 4 Alkylation of amines

To effect solely mono-alkylation of an amino group, ex-cess amine may be used, or the amine may be protectedwith a suitable protecting group in order to avoid the for-mation of undesirable tertiary and quaternary amines. Se-lected examples of alkylation reactions are given below.

Mono-acylated triamines 1 have been synthesised by thealkylation of the unprotected amino group of diaminoal-kanes with excess of bromoamides in ethanol to giveproducts in yields varying from 49 to 68% (Scheme 1).22

Scheme 1

N-Alkylation has been used respectively in the synthesisof a number of spider toxins.23 For example in the synthe-sis of spider toxin Agel 489a,24 a protected penta-aminewas prepared by the sequence of reactions shown inScheme 2. The monoamino protected diamine was alky-lated with N-(3-bromopropyl)phthalimide in the presenceof potassium fluoride on Celite. The product was subse-quently protected with Boc anhydride (Boc2O) and thephthaloyl group was removed with hydrazine to give thetriamine which was repetitively subjected to alkylationand deprotection to yield the penta-amine derivative 2which was further elaborated to obtain the spider toxin.

An efficient synthesis of polyamines was carried out byIwata and Kuzuhara25 starting from N,N-phthaloyl-1,3-propanediamine hydrochloride (Scheme 3). The phthaloyl

R NH2 R N

R'

R N

R'

R'

R N

R'

R'

R'

H

Primaryamine

Secondaryamine

Tertiaryamine

Quaternary amine (salt)

R'-X R'-X R'-X

X-

HN Br

O

RHN

HN

O

RNH2H2N

NH2( )n

+ ( )n

n = 3,4, m = 3,41

( )m( )m

TrocHN NH2

TrocHN N NPhth

Boc

TrocHN N NH2

Boc

Cl3CO

O

TrocHN N NH2

Boc

TrocHN N NH2

Boc

NH

HN N

HN

HN N

CH3

O

OH CH3

H

Troc =

25 %

100 %

iii

i, ii

i, ii, iii

45 %

i, ii, iii

44 %

1

2

3

+

Toxin Agel 489a

2

Reagents and conditions: i) PhthN(CH2)3Br/KF-Celite/MeCN, 40 °C,18 h; ii) Boc2O/CH2Cl2, r.t., 3 h; iii) N2H4/MeOH, 50 °C, 18 h

Scheme 2

PhthN NH2.HCl PhthN NHTs

N NHTsOHC

H

N NOHC

H Ts

N NTs

H Ts

NPhth

NPhth

Br96 %

ii

98 %

i

84 %

iv, v

92 %

iii

3

Phth+ ( )4

Reagents and conditions: i) TsCl/Py/Et3N, r.t., 4 h; ii) N2H4/H2O/DMF, 75 °C, 18 h; iii) Cs2CO3/DMF, r.t., 2 d; iv) 2 M HCl/EtOH, 80°C, 4 h; v) TsCl/Py/Et3N, r.t., 4 h

Scheme 3



group was transformed into the acid sensitive formylgroup which allowed the regioselective chain elongationto give the orthogonally protected triamine 3.

A further synthesis of orthogonally protected triamineswas described by Bergeron et al. 26 The method involvedfirstly the synthesis of mono-benzylated putrescine(Scheme 4) which was achieved by means of reductiveamination in the presence of formic acid. The putrescinederivative was protected with a Boc group and subsequentalkylation with 4-chlorobutyronitrile gave the nitrile 4 inhigh yield. Reduction of 4 with Raney Nickel followed bytrifluoroacylation afforded the orthogonally protected tri-amine 5. All the protecting groups of compound 5 can beselectively removed thus allowing mono-, di- or tri-func-tionalisation of this spermidine homologue.

Another orthogonally protected synthetic intermediate forthe preparation of substituted tetraamines27 was preparedstarting from mono-benzylated propandiamine. Sulfona-tion with mesitylene sulfonyl chloride and subsequentalkylation with N-(3-bromopropyl)phthalimide gave theprotected triamine 6 (Scheme 5).

This intermediate 6, on reaction with the iodide 7 gave ul-timately the unsymmetrically substituted tetraaminesshown in Scheme 6.

Another synthesis of alkylated tetraamines was performedby reacting two segments at a time to form a longerpolyamine chain.28 Firstly, reagents 8 and 9 were preparedas shown in Scheme 7. These were reacted together asshown in Scheme 8 to give a series of substitutedpolyamine analogues 10 all of which show anticancer ac-tivity. Similar procedures have been used to obtain otherbiologically active polyamine analogues and deriva-tives.29,30

Ph H

O

H2NNH2

Ph NH

NH2 Ph NH

NHBoc

NNHBoc

Ph

NC

NNHBoc

Ph

H2N

NNHBoc

Ph

HNF3C

O

+

4

5

81 %

i

92 %

95 %

iii

97 %

iv

91 %

v

ii

Reagents and conditions: i) HCO2H, 0 °C, then ∆; ii) Boc-ON/THF,0 °C, 8 h; iii) Cl(CH2)3CN/BuOH/KI/Na2CO3, heat, 48 h; iv) H2/Ra-ney Ni/NaOH/EtOH, r.t., 28 h; v) (CF3CO)2O/CH2Cl2/Et3N, r.t., 16 h

Boc-ON = 2-{[(tert-butoxycarbonyl)oxy]imino}-2-phenylacetonit-rile

Scheme 4

H2N NH

Ph

NH

N

Ph

NPhth

NH

NH

PhMts

Mts

6

92 %

i

75 %

ii

Reagents and conditions: i) MtsCl/CH2Cl2, 10% NaOH, 0 °C, 90min; ii) PhthN(CH2)3Br/BuOH, 80 °C, 24 h

Scheme 5

Mts-HN N

Ph

NPhthH3C N I

Mts

N N

Ph

NPhthNH3C

MtsMts

N N

Mts

NPhthNH3C

MtsMts

N N

Mts

NNH3C

MtsMts

H

Mts

N N

H

NNH3C

HH

R

H

6

+

7

4 HBr

46 %

ii, iii

50 %

iv, iii

62, 40 %

v, vi

96 %

i

R =

Reagents and conditions: i) NaH/DMF, 0 °C, 30 min; ii) H2/Pd-C/MeOH, r.t., 2 d; iii) MtsCl/CH2Cl2/10% NaOH, r.t., 2 h; iv) N2H4/MeOH, 50 °C, 18 h; v) RBr/NaH/DMF, 0 °C, 30 min; vi) 30% HBr/AcOH/PhOH/EtOAc, r.t., 15 h

Scheme 6

MtsN

H

Boc

MtsN

Boc

CN

MtsN

Boc

MtsN

BocHNNH2

Mts

RNH2

RN X

Mts

8

( )n

9

75 %

i

100 %

ii

87 %

iii

30-96 %

iii, ivX = Cl, Brn = 3,4R = Me, Et, i-Pr, tert-Bu

Reagents and conditions: i) Cl(CH2)3CN/NaH/DMF, 70 °C, 1 d; ii)H2/NH3/Raney Ni/MeOH, r.t., 6 h; iii) MtsCl/CH2Cl2/1 N NaOH, r.t.1 d; iv) NaH/X(CH2)nX/DMF, r.t. to 80 °C, 12 h

Scheme 7



An efficient method of alkylation which proceeds withgood chain chemoselectivity and prevents polyalkylationproducts involves the reaction between an azide and analkyl dichloroborane.31 This method has been used for thesynthesis of symmetrical diamines and tetramines(Scheme 9).32

An example of the use of C-alkylation in polyamine chainextension has also been demonstrated in the synthesis of(2R,5R)-hept-6-yne-2,5-diamine,33 an irreversible inhibi-tor of the enzyme ODC. This procedure involved the alky-lation of 11 with the N-Boc-protected alkyl iodide in thepresence of an excess of strong base to give the Boc-pro-tected diamine as shown in Scheme 10. The Boc groupswere removed by acid to afford the final product.

2.2 Reduction Methods

One of the simplest methods for the synthesis of aminesinvolves the complete reduction of a variety of functionalgroups to the amino group using a range of reducingagents. A selection of reduction reactions to producepolyamine derivatives are presented here.

2.2.1 Reduction of Amide, Nitrile and Nitro Groups

The reduction of amides, nitriles and nitro compoundsprovides a simple and convenient synthesis forpolyamines. For example the triamine 1334 was preparedby reduction of the dimethylcyanoacetamide 12. Here(Scheme 11) both the amide and nitrile groups are reducedunder the same conditions using borohyhride in THF.

A similar method34 (Scheme 12) initially involved thecondensation between 4-methyl-4-nitrovaleric acid and β-aminopropionitrile in the presence of dicyclohexyl carbo-diimide (DCC) to give the corresponding amide 14. Boththe amido and cyano groups of 14 were reduced with bo-rane-THF complex and the nitro group was reduced usingsodium borohydride to afford triamine 15 in 70% yield.

The synthesis of a diformyl polyamine35 is depicted inScheme 13. The reaction was performed by the condensa-tion of diacyl chloride with two equivalents of 3-amino-1,1-diethoxypropane in the presence of Et3N. Reductionof the diamide with LiAlH4 followed by hydrolysis of theacetal gave the diformyl derivative 16.

2.2.2 Reduction of Azides

The reduction of azides is another convenient method forthe preparation of polyamines. The method normally in-

MtsN

H

N

Mts

NR

Mts

N

Mts

N

Mts

NR

Mts

NR

Mts

N

H

N

H

NR

H

NR

H

8 9+ ( )n

9, i

( )n( )m

( )n( )m

10

i

18-85 %

iii

Reagents and conditions: i) NaH/DMF, 70 °C, 12 h; ii) TFA/CH2Cl2,r.t., 1 h; iii) 30% HBr/AcOH/PhOH/CH2Cl2, r.t., 1 d

Scheme 8

N3

Br NH

NH

Br.2HCl

N3 NH

NH

N3.3HCl

H2N NH

NH

NH2.4HCl

89 %

i, ii

71 %

iii, iv

81 %

v

+ Br BCl2( )2

Reagents and conditions: i) CH2Cl2, r.t., 18 h; ii) MeOH/Et2O; iii)NaN3/H2O, 80 °C, 15 h; v) H2/Pd-C/HCl, r.t., 18 h

Scheme 9

NHBoc

TMS

I NHBoc

CH3

NHBoc

TMS

NHBoc

CH3

NH2.2HCl

NH2

CH3

+

11 61 %

i

69 %

ii

Reagents and conditions: i) BuLi/hexane/i-Pr2NH/TMEDA/THF,−78 °C, 30 min; ii) MeONa/MeOH, r.t., 1 h; iii) HCl/Et2O, r.t., 24 hTMEDA = tetramethylethylenediamine

Scheme 10

NC COOH

H3C CH3

NC

H2NNH2

O

HN

NH2

HN

NH2H2N

H3CCH3

H3CCH3

+

12

13

59 %

i

49 %

ii

Reagents and conditions: i) Et3N/THF/ClCO2Et, 0 °C, 12 h;ii) BH3∑THF, ∆, 2 h

Scheme 11



volves mild reaction conditions, but a disadvantage is theuse of the highly toxic sodium azide. The followingschemes illustrate some examples.

4-Bromobutylamine on condensation with acyl chlorides(Scheme 14) gave the corresponding N-acyl-N-alkyl bro-mides. Reaction with sodium azide gave the amino azidewhich on hydrogenation in the presence of Lindlar’s cata-lyst produced the acylated diamines 17.36

Reagents and conditions: i) CHCl3/Et3N, r.t., 10 min; ii) NaN3/EtOH,reflux, 2 h; iii) H2/Lindlar catalyst/EtOH, r.t., 2 h

Scheme 14

The synthesis of alkyl substituted spermine was accom-plished by condensing putrescine with two equivalent of3-azido-3-methylbutyric acid using ethyl chloroformateas a condensing agent. Reduction of both the azide andamino groups with BH3-THF yielded methylatedpolyamine 18 in 28% yield (Scheme 15).34

Reagents and conditions: i) Et3N/ClCO2Et/THF, r.t., 16 h;ii) BH3∑THF, reflux, 2 h

Scheme 15

The synthesis of spider neurotoxins (e.g. NPTX-11) hasbeen achieved by employing an azide intermediate(Scheme 16).37 Protection of aminopentanol with a Bocgroup and introduction of an easy-leaving sulfonate fol-lowed by treatment with sodium azide produced the ami-no protected azide 19. Deprotection of 19 followed by aseries of reactions involving N-Boc-L-asparagine p-nitro-phenyl ester and indole-3-acetic acid p-nitrophenyl esterfurnishes 20. The azide group from 20 was reduced onpalladium catalyst to afford the amine, which was coupledwith an amino acid active ester to obtain the target mole-cule.

Reagents and conditions: i) Boc2O/aq Na2CO3, r.t., 12 h; ii) MsCl/Py/CH2Cl2, 0 °C, 1 h; iii) NaN3/DMF, r.t., 12 h

Scheme 16

OHO2N

O

H2NCN

CNNH

O2N

O

NH

O2NNH2

NH

H2NNH2

H3CCH3

H3C CH3

H3C CH3

H3C CH3

+

15

1495 %

ii

70 %

iii

97 %

i

Reagents and conditions: i) DCC/CH2Cl2, 0 °C, 2 h, then r.t., 10 h;ii) BH3•THF, ∆, 2 h; iii) NiCl2•6H2O/NaBH4, r. t., 2 h

Scheme 12

C2H5O NH2

C2H5O

Cl Cl

O O

O O

C2H5O NH

C2H5O

OC2H5NH

OC2H5

O NH

ONH

+( )n

2

( )n

90 %

i

52-53 %

ii-v

( )n n = 2,7

16

Reagents and conditions: i) Et3N/benzene, ∆, 12 h; ii) LiAlH4/THF,∆, 12 h; iii) H2O/H+; iv) aq oxalic acid, r.t., 5 h; v) aq BaCl2, 30 min

Scheme 13

BrHBr . H2N

R Cl

O

R NH

O

BrR N

H

O

N3

R NH

O

NH2

+

17

79-91 %

i

52-76 %

ii

95-97 %

iii

H2NNH2

HO2C

NH

OHN

O

NH

HN

NH2

H3CCH3

H3C CH3

N3

H3C CH3

N3

N3

CH3

CH3

H3CCH3

H2N

95 %

i+

28 %

(ii)

18

H2N OH BocHN OH

BocHN OMs BocHN N3

NH

HN

NH

O

N3

O

NH2

O

NH

HN

NH

O

O

NH2

O O

NH2

H2N

19

99 %( )3 ( )3

( )3 ( )3

i

98 %

ii

99 %

iii

52 %

4 steps

45 %

4 steps

NPTX-11

20



2.2.3 Reduction of Schiff’s Base

The synthesis of polyamines by the reduction of Schiff’sbases has also been applied in polyamine chemistry. Thegeneral reaction involves the condensation between a pri-mary amine and a carbonyl compound to afford theSchiff’s base, which is then reduced to give a substitutedamine. The general approach of this method is shown inFigure 5.

Figure 5 Formation of amines by the reduction of Schiff’s bases

For example, treatment of an excess of diamine 21(Scheme 17)38 with azidopropanal afforded the corre-sponding iminoazide which was reduced with sodium bo-rocyanohydride to give the azido alkyne. Reduction of thealkyne with LiAlH4 gave the triamine alkene 22 whereasreduction with triphenylphosphine yielded the triaminoalkyne 23.

Selectively protected N8-benzyloxycarbonyl-N1-Boc-spermidine was obtained by the method shown in Scheme18.39 The amino acetal 24 was protected with the Bocgroup and then acid hydrolysis gave the corresponding al-dehyde. Coupling of the aldehyde with Z-mono-protecteddiaminobutane gave the imine 25 which was then reducedto the protected spermidine 26.

Schiff’s bases may also be formed via an aza-Wittig reac-tion.40 This is illustrated in Scheme 19 where an azide isformed from N-benzyloxycarbonylbutanol using hydra-

zoic acid. Reaction of the resulting azide with triphe-nylphosphine followed by the addition of the aldehydegives the corresponding imine which is reduced by sodi-um borohydride to the protected diamine which on depro-tection afforded the target amine 27.

Golding’s method for the synthesis of secondary amineshas been adopted for the synthesis of polyamines usingdibenzyltriazone (DBT) as the amino-protecting group(Scheme 20).41 The reaction of azide 28 with trimeth-ylphosphine gave the corresponding iminophosphorane.Aza-Wittig reaction of the iminophosphorane with a pro-tected aldehyde followed by reduction of the imine in thepresence of sodium borohydride gave the protected sper-midine 29 in one step. DBT deprotection with aqueous pi-peridine afforded spermidine.

H2N R''R

NH

R''R'

R

N

R''R'

R

O

R'+

[H]

R, R', R'' = H, Alkyl, Aryl, etc.

H2NNH2 OHC

N3

H2NN N3

H2N

HN N3

H2N

HN NH2

H2N

HN NH2

+

21

22 23

60 %

62 % 98 %iii iv

i

ii

Reagents and conditions: i) MeOH, r.t.; ii) NaBH3CN/MeOH, pH 6,r.t., 18 h; iii) LiAlH4/THF, r.t., then reflux, 6 h; iv) Ph3P/THF/H2O,r.t., 18 h

Scheme 17

BocHNO

BocHNN

NHZ

BocHNNH

NHZ

H2NOEt

OEt

25

26

( )2

( )2

( )2

32 %

iv

( )2

iH2N

ii iii24

NHZ( )4

Reagents and conditions: i) Boc2O/dioxane/Et3N; ii) AcOH/H2O; iii)THF, mol. sieves, r.t., 1 h; iv) NaBH3CN/THF/TsOH (ph 6−7), r.t.,12 h

Z = benzyloxycarbonyl

Scheme 18

ZNHOH

ZNHN3

ZNHN

PPh3

ZNHN R

ZNH

HN R

H2N

HN R

95 %

27

i

v

iv

ii iii

63 %

Reagents and conditions: i) HN3/CH2Cl2/benzene/Ph3P/DEAD, r.t.,20 h; ii) Ph3P/Et2O, r.t.; 1 h; iii) RCHO, r.t., 5 h; iv) NaBH4, r.t., 12 h;v) H2/10% Pd-C/EtOH

Scheme 19



2.3 Michael Addition Reactions

The addition of amines to alkenes provides another gener-al method for the synthesis of polyamines. The tetra-amines 30 and 31 have been prepared by the addition di-amines with acrylonitrile. Subsequent reduction gives thetetraamines as illustrated in Scheme 21.42

A similar methodology has been used to obtain modifiedtetraamine.43,44 The reaction between benzyl(Bn)-protect-ed diamine 32 and methyl vinyl ketone afforded the dike-tone which on conversion to the dioxime followed by

reduction and deprotection gave the tetraamine 33(Scheme 22). These compounds have been shown to ex-hibit anti-malarial activity.45

Dimethyl spermidine 35 was synthesised by the Michaeladdition of azide 34 to acrylonitrile followed by reductionwith Raney nickel (Scheme 23).31

An example of stepwise extension of the polyamine chainusing a Michael addition reaction is shown in Scheme24.46 Reaction of the Boc protected diamine with acry-lonitrile gave the protected nitrile which on further protec-tion and reduction gave the triamine 36.

DBT OH DBT N3

DBT NPMe3

DBT NDBT

DBT NH

DBT

H2N NH

NH2N

N

N

O

PhPh

28

29

Spermidine

87 %

69 %

DBT =

i, ii iii

v

90 %

vi

iv

OHC-(CH2)3DBT

Reagents and conditions: i) MsCl/i-Pr2EtN/CH2Cl2, 0 °C, 10 min;ii) NaN3/DMF, 80 °C, 75 min; iii) PMe3/THF, 3Å mol. sieves, r.t.,45 min; iv) THF, 30 min, r.t.; v) NaBH4/EtOH, r.t., 20 h; vi) 20% aqpiperidine/MeOH, pH 3, 65 °C

Scheme 20

H3CCN

HN

HN

CH3 CH3

HN

HN

CH3 CH3

NC CN

H2N NH2

CN

N N

N N

NC CN

H2N NH2

CH3 CH3

CH3 CH3

30

96 %

2

31

i

30 %

ii

90 %

iii+

7 %

ii

H2N NH2( )8+ 2

( )8

( )8

CH3NH NHCH3( )8

( )8

( )8

Reagents and conditions: i) EtOH, r.t., 48 h; ii) H2/PtO2/AcOH/HCl,r.t., iii) NaOH/EtOH, r.t., 72 h

Scheme 21

CH3

O

N N

Bn Bn

H3C CH3

O O

N N

Bn Bn

H3C CH3

N NHO OH

HN

HNH3C CH3

NH2 NH2

N N

Bn Bn

H3C CH3

NH2 NH2

BnNH

32

33

2

.4 HCl

96 %

i

38 %

ii

33 %

iii

6 %

iv, v

NHBn( )8

+

( )8

( )8

( )8

( )8

Reagents and conditions: i) MeOH, r.t., 18 h; ii) NH2OH•HCl/NaOH/MeOH, 0 °C, r.t., 12 h; iii) LiAlH4/THF, ∆, 48 h; iv) H2/Pd(OH)2/C/EtOH, r.t.; v) HCl

Bn = Benzyl

Scheme 22

Reagents and conditions: i) EtOH, r.t., 30 h; ii) H2/Raney Ni/NH3, r.t.,15 h

Scheme 23

NHCH3

CH3

CN

N3N

N3

CH3

CH3

CN

H2NN

CH3

CH3

NH2

82 %+

35

34

i

72 %

ii



Further chain extension may be carried out by repeatingthe process as illustrated below (Scheme 25). All the stepsin this series of reactions were carried out in high yield.47

Reagents and conditions: i) KF/Celite/MeCN, r.t., 16 h, then 70 °C,24 h; ii) Boc2O/CH2Cl2, r.t., 68 h; iii) H2/Pd(OH)2-C/AcOH, r.t., 2 h;iv) MeOH, r.t., 12 h

Scheme 25

The Michael addition reaction involving primary aminesand acrylonitrile can sometimes lead to mixtures of mono-and bis-cyanoethylated amines48 as illustrated in Scheme26.

2.4 The Mitsunobu Reaction

The Mitsunobu reaction49 is a condensation reaction be-tween a compound containing an acidic hydrogen (e.g.sulphonamide) and a primary or secondary alcohol in thepresence of diethylazodicarboxylate (DEAD) and triphe-nylphosphine. This reaction has been used successfully toproduce substituted polyamines.

For example, N-methyl p-toluenesulfonamide and N-BOC p-toluenesulfoamide can be condensed with primaryand secondary alcohols under Mitsunobu conditions to af-ford a number of sulfoamide-protected amines50 as shownin Scheme 27.

Reagents and conditions: i) N-methyl-p-toluenesulfonamides:DEAD/Ph3P/THF, r.t; ii) N-Boc-p-toluenesulfonamides: DEAD/Ph3P/THF, r.t.

Scheme 27

Another example is the stereospecific reaction between N-trifluoromethanesulfonyl(Tf)-N-methylaminobutanol andN1,7-bis-Tf-aminoheptane under Mitsunobu conditionsfollowed by deprotection to afford the optically active tet-raamine 37 (Scheme 28).51

H2NNH2

H2N

HN

Boc

NH

HN

BocNC N

HN

BocNC

Boc

N

HN

Boc

Boc

H2N

86 %

i

ii

90 %

iii

96 %

iv

CH2=CHCN

36

Reagents and conditions: i) Boc2O/dioxane, r.t., 3 d; ii) MeOH, r.t.,2 d; iii) Boc2O/CH2Cl2, r.t., 3 h; iv) H2/Raney Ni/NaOH/EtOH, r.t.,23 h

Scheme 24

NC

HN

NH2

NC

HN

NH

NHBoc

NN NHBoc

Boc

Boc

H2N

NN NHBoc

Boc

Boc

NNC

Boc

NN NHBoc

NH2N

Br NHBoc

Boc

BocBoc

+

91 %

ii, iii

60 %

i

ii (90 min)

iii, H2C=CHCN,iv

H2C=CHCN,iv

iii

R NH2

CNR N

H

R NCN

CN

CN+

62 %

11 %

+

i

Reagents and conditions: i) MeOH, 0 °C

Scheme 26

Ph Me

OH

Ph Me

N

Ph Me

N BocTsMe Ts

55% 92%

i ii

NH

NH

CH3H3C

NH NH.4HClH3C H3C

H3C OH

NH3C Tf

TfNH

NH

Tf

N N

TfTf

NNH3C Tf H3C Tf

2

( )5

37

+ ( )5

( )5

80 %

i

31 %

ii-iv

Reagents and conditions: i) DEAD/Ph3P/THF, 10 min, r.t.; ii) Na/NH3/THF/t-BuOH,-70 °C, 30 min; iii) Boc2O/H2O, r.t., 1 h; iv) HCl/MeOH

Scheme 28



3. Solid Phase Synthesis of Polyamines

The demand for more complex polyamines, mono-func-tionalised polyamines, unsymmetrical polyamines andpolyamine chemical libraries has led recently to the appli-cation of the solid phase approach to the synthesis of thesecompounds. This method offers many advantages over theconventional solution phase synthesis particularly in thesimplification of reaction procedures, ease of purificationsteps and the application to automated systems.

The spermine alkaloid Kukoamine A52 has been efficient-ly synthesised on a solid support of 2-chlorotrityl resin,PCTr (Scheme 29). The procedure involved firstly, theformation of the carbon framework of spermine from pu-trescine and activated esters in the presence of the cou-pling agent benzotriazol-1-yloxytris(dimethylami-no)phosphonium hexafluorophosphate (BOP). The result-ing amide groups were reduced using diborane. The otherthree isomers of Kukoamine A were prepared using a sim-ilar strategy.

Synthesis of unsymmetrically funtionalised polyamineswere obtained from commercially available symmetricalsubstrates. In this method (Scheme 30), O-chlorotritylwas used to generate the corresponding bromoacetyl resinusing bromoacetic acid in the presence of N,N-diisopro-pylethylamine (DIEA). Subsequent reaction with differ-ent polyamines, Boc-protection and cleavage from theresin afforded a number of mono-functionalisedpolyamines (all the amino groups are protected). These

compounds have potential use as novel non-viral vectorsfor DNA delivery in gene therapy.53

trityl-Cl trityl- O C

O

Br

OH

N

N

N

O

NHBOC

BOC

BOC

BOC

DdeHN

N

N

NHDde

BOC

O

OH

OH

N

N

N

O

NHDde

BOC

BOC

BOC

NH

N

N

NHBOC

BOC

BOC

O

OH

N

N

NHBOC

BOCHN

BOCN

BOCHN

O

OH

i, ii, iii i, ii, iii i, ii,v, iii i, ii,v, iii vi, iii, ii

P P

Reagents and conditions: spermine in CH2Cl2; ii) (Boc)2CO2; iii) TFA/CH2Cl2; iv) DdeOH; v) tetra(3-aminopropyl)diaminobutane; iv) tris(2-aminoethyl)amine

Scheme 30

PNH

OBt

O

H2NNH2

NH

O

NH

NH2Trt

HNSuO

O

NH

O

NH

Trt

HN

HN

O

NH

NH

Trt

HN

HN

NH

HN NHR

RHN

OH

OHO

P

P

P

P

+

+

i

ii

overall65 %

R =

5 steps

Kukoamine A

= 2-Chlorotrityl resin

BOP

Reagents and conditions: i) Et3N; ii) B2H6•THF, ∆, 2 d

Scheme 29



The solid phase method was also used in the synthesis ofmono-functionalised putrescine and spermine derivatives.On this occasion the Wang resin (hydroxymethyl resin)was used as the solid support (Scheme 31) which was re-acted with 4-nitrophenyl chloroformate to the give thecorresponding carbonate. Reaction with putrescine orspermine yielded the corresponding resin bound carbam-ate. Mono-functionalisation proceeded and the cleavageof the products off the solid support was effected with tri-fluoroacetic acid in dichloromethane. Interestingly all pu-trescine derivatives prepared, showed no anti-canceractivity while the spermine derivatives exhibited an IC50

in the range of 1.7−5.8 µM against Leukaemic L1210cells.54

The efficient use of the solid phase method has beenapplied55 to generate peptidomimetics since natural pep-tides are limited as pharmaceutical drugs due to their lowbioavailability and rapid enzymatic degradation. Thepeptidomimetic libraries were generated as shown inScheme 32 by applying the standard solid phase peptidesynthesis method. The resulting peptides were chemicallytransformed by peralkylation and/or reduction.

Recently the synthesis of trypanothione and analogueshave been carried out by the solid phase method (Scheme33).56,57 These compounds have been screened for theiractivity against trypanothione reductase, an enzyme in thetrypanosomal parasites responsible for many tropical dis-eases such as African Sleeping Sickness and Chagas Dis-ease.58

In a more recent publication Bradley et al.59 extended theabove methodology to the synthesis of symmetrical sper-mine conjugates. This has led to the successful synthesisof the natural product Kukoamine as depicted in Scheme34.

4 Synthesis of Polyamine Conjugates

Polyamines are constituents of many natural productsboth in the plant and animal kingdom. Because of theirpotential application as pharmaceutical drugs, a lot of ef-fort has been focused on the chemical synthesis ofpolyamine-containing natural products and conjugates. Aselection of these compounds is presented below.

MBHA NH2MBHA NH

O

NTtr

H

R3

MBHA N

O

NTtr

H

R3R4

MBHA N

O

N

H

R3R4

NTtr

O

R1

H

MBHA N

O

N

R2

R3R4

NTtr

O

R1

H

HN

O

N

R2

R3R4

NH2

O

R1

P P

P

P

P

i

iiiii

iv

v

MBHA = p-methylbenzhydrylamine

Reagents and conditions: Fmoc-CHR3OH/HOBt/DIC/DMF, 20%piperidine/DMF/TtrCl/DIEA/CH2Cl2; ii) LiOBu-t in THF/alkyl hal-ide (R4X)/DMSO; iii) 2% TFA in CH2Cl2, Fmoc-CHR1-OH/HOBt/DIC in DMF, 20% piperidine in DMF/TtrCl/DIEA/CH2Cl2; iv) LiO-Bu-t/THF/alkyl halide (R2X) in DMSO; v) HF cleavage (anisole asscavenger)

Scheme 32

OH O O

ONO2

O NH

O

NH2

H3NNHR1

O NH

O

NN NH2

BOC

BOC

H3NHN

NH

NHR2

P P

P

+

P

+

R1 = - CONHPh, 68 % - CH2Ph, 64 % - CONHCH2Ph, 68 % - CO-Ph-NO2, 71 % - CO-CH(PhCH2)NH3

+, 75 %

R2 = - PhNHCO, 70 % - CH2Ph, 50 % - PhCH2NHCO, 71 % - 4-NO2-C6H6-CO, 70 % - Phe, 58 % - Dansyl, 56 %

Scheme 31



For example, the preparation of the nucleoside-polyamineconjugate 3860 involved the stepwise alkylation of N1-Boc-N3-benzyl protected diaminopropane with chloroace-tonitrile in the presence of KF/Celite as outlined inScheme 35. Attachment of the polyamine chain to the pro-tected purine was performed using N-alkylation. The aimfor the synthesis of this polyamine conjugate is to study itseffect on the uptake of nucleosides and modified oligonu-cleotide in cells.

A synthesis of a peptide-polyamine conjugate containingthe phosphinate group within the polyamine chain was re-ported by Chen et al. (Scheme 36).61,62 Starting frommono-trifluoroacetylputrescine the polyamine chain was

extended by first protecting the primary amino group fol-lowed by alkylation and introduction of the phosphinateresidue using the Abramov reaction to give 39 which withSchiff’s base Ph3CN=CH2 afforded the key phosphinateintermediate. In order to avoid any deprotection problems,the phthaloyl and trifloroacetyl groups were removed byhydrazinolysis and the free amino groups were protectedwith carbamate (Z). Before coupling with the dipeptide,the trityl protecting group was removed with acid to givethe protected triamine 40 which was coupled with thedipeptide before removing all the protecting groups togive the peptide-polyamine conjugate 41. The latter com-pound was found to be a potent inhibitor of gluathionyl-

NH2

N N NHFmoc

HN

HN

NH

NH

OH

OH

O

O OH

OH

O Ot-ButO

O

O CO2H

N N NHFmoc

O Ot-ButO

O

O NH

OP

P

Aminomethylresin

+ FmocNH

i

ii, iii

FmocNH

Reagents and conditions: i) DIC/HOBt/CH2Cl2; ii) 20% piperidine/DMF or NH2NH2•H2O/EtOH, 80 °C; iii) HO2CCH2Ph-3,4-(OH)2/DIC/HOBt/CH2Cl2

Scheme 34

COOCH3

O

O

O

NO2

NHNH

HN

Boc

Boc

NNH

HN

Boc

Boc

O

O

COOH

NNH

HN

Boc

Boc

O

O

C

O

HN P

(Boc)Glu(OtBu)-Cys(Trt)-Gly

(Boc)Glu(OtBu)-Cys(Trt)-Gly

N

O

O

C

O

HN P

N

H

NH

Glu-Cys-Gly

Glu-Cys-Gly

N

O

O

C

O

HN P

N

H

NH

S

S

+76-80 %

i, ii( )n

( )m

( )n

( )m

iii

( )n

( )m

iv-vii

( )n

( )m

( )n

( )m

Nortrypanothione: m = n = 1Trypanothione: m = 1, n = 2Homotrypanothione: m = n = 2

Reagents and conditions: i) DMF/Et3N, r.t., then 50 °C, 2.5 h; ii) aq NaOH/dioxane, r.t., 2 h, then 50 °C, 2.5 h; iii) DIC/HOBt/aminomethylresin/DMF; iv) Boc deprotection; v) coupling with FmocGlyOH, then Fmoc deprotection; vi) coupling with FmocCys(Trt)OH, then Fmoc de-protection; vii) coupling with BocGlu(OH)OBu-t; viii) TFA/TFMSA/ethanedithiol/PhSMe; ix) I2/MeOH

Scheme 33



spermidine synthase/amidase, a key enzyme thatparticipates in trypanothione biosynthesis.

The synthesis of chlorambucil-polyamine conjugate 42was reported by Cullis et al. (Scheme 37).63 This synthesisinvolved first terminal protection of spermidine with theacid labile Boc group, Michael addition of acrylonitrile tothe secondary nitrogen and finally, reduction of the cyanogroup on Raney nickel. Attachment of the resultingbranched tetraamine to (R)-chlorambucil was performedvia an acyl chloride. Removal of the Boc group with acidfrom 42 gave chlorambucil-spermidine conjugate whichshowed more efficient cross-linking with DNA thanchlorambucil itself.

Boron-containing polyamines 44 have been developed aspotential agents for neutron capture therapy of brain tu-mours.64 The method of synthesis involves an alkylationreaction between terminally Boc-protected spermidineand the iodide 43 in the presence of K2CO3/DMF followedby removal of Boc groups (Scheme 38).

A number of polyamines 46 with a thiophene unit incor-porated in the chain have been prepared.65 Starting fromtheir homologous dicarboxylic acids 45 as shown inScheme 39. The acids were converted into their aciddichlorides with oxalyl chloride to avoid formation ofpolymeric products. Introduction of gaseous ammonia ledto the formation of amides which were then reduced to the

NH

NH

BocPh

NH

NBoc

Ph

HN

Ph

NH

NBoc

CN

Ph

NH

N

Ph

HN

PhBoc

ON

N

N

NH

O

O

O

Cl

H2N N

Ph

HN

Ph

ON

N

N

NH

O

O

O

NH

N

Ph

HN

Ph

ON

N

N

NH

HO

HO

O

NH

NH

NH2

Si

Si

OH3C

H3C

CH3

H3C

H3C

H3C

CH3

Si

SiO

H3CCH3

H3C

H3C

CH3

H3C

H3C

CH3CH3

87 %

82 %

i

ii, iii, iv1. i-iv2. i-iv

3

23 %

v

3

+ 87 %

vi

3

3 steps

3

38

Reagents and conditions: i) ClCH2CN/KF-Celite/MeCN, 85 °C, 12h; ii) H2/Raney Ni/EtOH/NaOH, r.t., 12 h; iii) PhCHO/MeOH/MgSO4, r.t., 4 h; iv) NaBH4/MeOH, r.t., 12 h; v) TFA/CH2Cl2, r.t.,30 min; vi) MeOCH2CH2OH, 80 °C, 12 h

Scheme 35

H2NNHCOCF3

PhthNNHCOCF3

PhthNN

I

COCF3

PhthNN

P

COCF3O

OEt

H

PhthNN

P

COCF3O

OEt

HN CPh3

ZHNN

P

ZO

OEt

HN CPh3

ZHNN

P

ZO

OEt

NH2

H3N

HN

NH

P

CO2

O

OO

O

NH2

NH3CH3

93 %

i

55 %

iii, iv, v

76 %

81 %

vii, viii

72 %

approx. 90 %

ix

Z = benzyloxycarbonyl

x, xi

62 %

39

40

41

Ph3CN=CH2, vi

I(CH2)4I, ii

Reagents and conditions: i) PhthNCO2Et/TEA/THF, ∆; ii) KH/18-crown-6/THF; iii) NH4H2PO2/HMDS, 110 °C, 1.5 h; iv) toluene, 105°C, 12 h; v) PyBOP/EtOH/DIEA; vi) BF3•OEt2/toluene, ∆; vii)N2H4•H2O/MeOH; viii) Z-Cl/DIEA/CH2Cl2; ix) 1 M HCl/MeOH, ∆,20 min; x) Z-Glu(Ala-OH)-OBn/PyBOP/DIEA/CH2Cl2; xi) 30%HBr/AcOH, r.t, 48 h

Scheme 36

Reagents and conditions: i) Boc-ON; ii) H2/Raney Ni; iii) RCOCl

Scheme 37

H2N NH

NH2

BocHN NH

NHBoc

BocHN NNHBoc

BocHN NNHBocH2N

RCOHN 42

72 %

i

CH2=CHCN

iii

ii

R = Chlorambucil



diamines. Compounds such as 46 have been useful in theelucidation of the physiological significance of polyamineregulatory site of the NMDA receptor complex.

A number of conformationally restricted polyamines 47incorporating cyclopropyl, cyclobutyl, alkyne and o-C6H4

units have been prepared (Scheme 40)67 for their use asnovel anticancer agents.

A practical synthesis of lipid polyamine conjugates hasbeen reported by Blagbrough and Geall (Scheme 41).68

The synthesis first included preparation of tri-Cbz or tri-Boc protected spermine from the mono-trifluoroacetylprotected spermine. Mono-functionalisation of the termi-nal amino group followed by deprotection afforded lipo-spermine 4868 or cholesterol-polyamine conjugate 49from the analogously obtained pentaamine.69

The polyamino side chain of the antibiotic squalamine70

was introduced by reductive amination of the ketone 50with di-Boc protected spermidine as shown in Scheme 42.Removal of Boc and TBDMS protecting groups was ac-

H2N NH

HN NH2

NH

NN NH2

R

R

R

H2N NH

HN

HN

O

C15H31

NH

N NH2Boc

Boc

O

O

H2N

HN NH

i, ii, iii

R = Cbz R = Boc

48-50 %

57 %

iv, v

48

41 %

vi, v

3

3

49

Reagents and conditions: i) CF3CO2Et/MeOH, −78 °C, 1 h, r.t., 1 h;ii) Cbz2O or Boc2O, 0 °C to r.t., 1 h; iii) concd NH4OH, r.t., 15 h;iv) C15H31CO2H/DCC/HOBt/DMF, 40 °C, 12 h; v) TFA/CH2Cl2

(9:1), r.t., 1 h; vi) 3-cholesteryl chloroformate/Et3N/CH2Cl2, 0 °C, 10min, 25 °C, 12 h

Scheme 41

BocHN NH

NBoc

B10H10

NHBocI

R

H2N NNH

R

B10H10

NH2-(CH2)3NH2 65 %

+

R = H 52 %

R =

i, ii

43

44

Reagents and conditions: i) K2CO3/DMF; ii) 3 M HCl

Scheme 38

S

SNH2H2N

O O

HO OH

S

O O

H2N NH2

( )n-1 ( )m-1

( )n ( )m

45

46

m = 4-8,10n = 4-10

59-88 %

i

51-81 %

ii

( )n-1 ( )m-1

Reagents and conditions: i) oxalyl chloride/benzene/NH3 (g);ii) LiAlH4/THF, ∆, 12 h

Scheme 39

Reagents and conditions: i) NaH/DMF, 70 °C, 4 h; ii) HBr/AcOH/PhOH/CH2Cl2, r.t., 48 h

Scheme 40

X

OMts

MtsOMtsHN N CH3

Mts

X

N N CH3

Mts

NNH3C

Mts

Mts

Mts

X

N N CH3

H

NNH3C

H

H

H

+ 2

47

X =

40-92 %

i

75-87 %

ii

NH

N NH2Boc

Boc

OBnO

OTBDMS

OBn

OTBDMS

H2N

HN

HN

+

i, ii 60 %

50

51

Reagents and conditions: i) NaBH3CN/MeOH, r.t., 12 h; ii) TFA/CHCl3, r.t.

Scheme 42



complished with TFA to give a mixture of the α- and β-isomers 51.

An example of the synthesis of a site-specific oligonucle-otide-polyamine conjugate 52 was reported by Ganesh etal. (Scheme 43).71 Incorporation of spermine at the C4 po-sition yielded the conjugate where the polyamine is linkedthrough the primary amino group. In the synthesis, the oli-gonucleotide amino functions were protected with trifluo-roacetyl groups which were shown to be suitable for theoligonucleotide synthesis by the phosphoramidite meth-od.

A number of terminally and internally alkylated and acy-lated spermidines 53 possessing anti-trypanosomal activ-ities have been prepared using a one-step selectiveprotection with trifluoroethyl acetate (Scheme 44). Alkyl-ation of terminally protected polyamines with the corre-sponding halides gave internally alkylated products. Pro-tection of the intermediate with Boc2O, selective removalof the COCF3 groups followed by alkylation, acyl-ationand deprotection gave the terminally alkylated or acylatedderivatives. Furthermore, the corresponding spermine de-rivatives were obtained using the same strategy.72

5. Synthesis of Oxapolyamines

Polyamines bearing an aminooxy group have demonstrat-ed bacteriostatic properties.73 These compounds have alsoproved to be a useful tool in generating further informa-tion on the role of polyamines in biological systems.74,75

The synthetic polyamine methods requiring reductiveconditions, are not appropriate to synthesise compoundscontaining aminooxy (ONH) groups because of the facilecleavage of the N−O bond. Suitably N-protected hydrox-ylamines readily react with electrophiles to generate

oxyamines as shown in Figure 6.76,77 Commonly used re-agents are ethyl acethydroxyamate and N-hydroxyphthal-imide.

Figure 6 Routes to oxapolyamines

5.1 Synthesis of Primary Aminooxypolyamines

The alkylation of ethyl acethydroxamate with 4-bro-mopropylamine hydrobromide gave the ethoxyeth-ylidene-protected oxyamine (Scheme 45). Removal ofthis protecting group by acid hydrolysis gave the dihydro-chloride salt of 3-aminooxypropylamine (APA). Alterna-tively APA may be prepared from 1,3-bromochloropropane followed by aminolysis.77

The reaction between ethyl acethydroxamate and dibro-moethane gave a bromoaminooxy derivative which on re-action with diaminobutane followed by deprotectionafforded oxa-spermidine (Scheme 46).77

ON

N

O

OH

DMTO

O

H2N NH

HN NH2

ON

N

OH

DMTO

H3C

O

HN NH

HN NH2

H3C

CH3

H3C

+

Py, 60 oC, 16 h

52

Scheme 43

H2N O R'

N

O

O

OH

SN

SHO

OO

OO

O

N

H3C

OH H2N O SO3Ar

R' XR' X

R' OH

NH

OH

O

R' X

H3CH2C

H2N

HN NH2

CF3CONH

HN NHCOCF3

CF3CONHN NHCOCF3

R

H2NN NH2

R

H2NN NH2

Boc

NH

HN

HN

RR

i

ii

iii

2iv, iii v or ii, vi

53

R = PhCH2OCONaphthalyl-CH2PhCO, PhCH2, Ph(CH2)3

Reagents and conditions: i) CF3CO2Et/H2O/MeCN, ∆; ii) R-Hal/base;iii) K2CO3/MeOH/H2O or NH4OH/MeOH; iv) Boc2O/Et3N/THF;v) RCHO/MeCN, 3 h, then NaBH4/EtOH; vi) TFA

Scheme 44



Reagents and conditions: i) i-PrOH, r.t., 24 h; ii) concd HCl/MeOH/i-PrOH, −10 °C, 12 h

Scheme 46

An oxa-spermine analogue74 has been synthesised by themethod shown in Scheme 47. Alkylation of aminobutanolafforded the aminooxy derivative which was protectedwith benzyloxycarbonyl chloride (Cbz). Conversion ofthe hydroxy group into the tosylate followed by treatmentwith diaminopropane and subsequent deprotection afford-ed aminooxyspermine.

Ethyl acethydroxamate has also been used to prepare hy-droxy derivatives of oxyamines.78 Reaction between ethylacethydroxamate and epichlorohydrin gave a mixture ofmono-54 and bis-55 products. Reaction of 55 with variousamines followed by deprotection produced the hydroxy-monooxyamines. Deprotection of 55 gave bis-aminooxy-hydroxypropane (Scheme 48).

The reaction between potassium phthalimide and a dibro-moalkane gave the bromoalkylphthalimide, which reactedwith N-hydroxyphthalimide to give the diphthaloyl deriv-ative. After the removal of both phthaloyl groups fromthese derivatives, the α-aminooxy-ω-aminoalkanes 56were obtained (Scheme 49).79

A library of oxapolyamine derivatives 59 was synthesisedusing the combinatorial chemistry approach80 as depictedin Scheme 50. Protected diamine alcohol 58 was con-densed with PhthN-OH under the Mitsunobu conditionsto give the fully protected oxapolyamine. Subsequentdeprotection of the phthaloyl groups afforded the Boc-protected oxa-polyamine 59.

Benzohydroxamic acid has also been used for theoxyamine synthesis.81 Benzohydroxamic acid reacts withbromoalkylnaphthalimide to give the corresponding hy-droxamates which upon deprotection, gave aminooxy-alkylamines 60 (Scheme 51).

5.2 Synthesis of Oxapolyamines with Secondary Aminooxy Group

Until recently no polyamines with an N−O bond withinthe aliphatic chain have been reported. In 1994 oxa-sper-midine and oxa-spermine analogues were first reported.82

H3C

EtO

N OH

H2NO NH2

.2HClH3C

EtO

NO NH2

H3C

EtO

NO ClH3C

EtONOH

Br+

APA

+

44 %

i

90 %

ii

50 %

i

63 %iii

NH2. HBr( )3

Br Cl( )3

Reagents and conditions: i) NaOEt/EtOH, r.t.; ii) i-PrOH/concdHCl, r.t., 15 min; iii) NH3/EtOH, 80 °C, 18 h

Scheme 45

H3C

EtO

NO

Br

H3C

EtO

NO

NH

NH2

H2NO

NH

NH2.3HCl

NH2(CH2)4NH2+62 %

i

87 %

ii

H3C

EtO

NO

Br

H3C

EtO

NO

NH

OH

H3C

EtO

NO

NOTs

Cbz

H2NO

NH

HN NH2

.4HCl

NH2(CH2)4OH+i

ii, iii

iv-vi

Total17.5 %

Reagents and conditions: i) i-PrOH/K2CO3, 80 °C; ii) Cbz-Cl;iii) TsCl; iv) NH2(CH2)3NH2; v) H2/Pd; vi) HCl/H2O

Scheme 47

H3C

EtO

N

O

Cl

H3C

EtO

N

CH3

OEtN

H3C

EtO

N

O

OH

O

H2N O NH2.2HClO

OH

N

OH

R'NR

OH

H3C

EtO

N

R

R' .2HCl

OHO

O

O

OH2N

++

55

54

55

i

46 %

R = CH3, R' = H; R = R' = CH3

R = (CH3)2CH, R' = H

R = CH2CH=CH2, R' = H; R = HC≡CCH2, R' = H

54ii iii

51-99 % 34-98 %

iii

35 %

Reagents and conditions: i) 10 N NaOH/acetone, 60 °C, 20 h; ii) RN-HR’, 20−85 °C, 5−18 h; iii) 2 M HCl, ∆, 1 h

Scheme 48



These compounds have been obtained using a Mitsunobureaction. 3-Aminooxypropylphthalimide was obtained viaa rearrangement reaction which occurred during thedeprotection of Fmoc-aminoprotected alkoxyphthal-imide83 (Scheme 52).

Reagents and conditions: i) PHthNOH/DEAD/Ph3P/THF, r.t., 30min; ii) DBU/MeCN

Scheme 52

When 3-aminooxypropylphthalimide was sulfonated withpentamethylchromanesulfonyl chloride (Pmc-Cl) the cor-responding sulfonamide which upon condensation withBpoc-protected aminopropanol under Mitsunobu condi-tions gave the fully protected oxa-spermidine analogue(Scheme 53). Subsequent deprotection afforded oxa-sper-midine 61.

Reagents and conditions: i) Pmc-Cl; ii) HO(CH2)3NHBpoc/DEAD/Ph3P/THF; iii) N2H4; iv) HCl/MeOH; v) HCl/AcOH

Scheme 53

In a similar reaction, a spermine oxa-analogue83 was ob-tained starting from bis(aminooxy)ethane which was pre-pared by the reaction between dibromoethane and N-hydroxyphthalimide. Sulfonation of bis-oxyamine, andMitsunobu condensation with 2-fold excess of Bpoc-ami-nopropanol gave the fully protected oxa-spermine ana-logue which after deprotection afforded thedioxaspermine analogue 62 (Scheme 54).

The methodology described in Scheme 53 and Scheme 54was further developed to synthesise a number of oxa-sper-midine analogues and homologues84 starting from 3-bro-mopropylamine as shown in Scheme 55.

During the investigation of these reactions, interesting ob-servations were made on the reactivity of the aminooxygroup. Firstly, it was found that when the sulfonation re-action of aminooxy propylphthalimide was carried out inthe presence of an excess of sulfonyl chloride in the pres-

FmocHN ONPhth

H2NO NPhth

FmocHN OHi

ii

82-90%

45-80%

PhthN ONH2 PhthN O

HN

Pmc

PhthN ON

PmcHN

Bpoc

H2N O

HN NH2

.3HCl

61

i

ii iii-v

65-75%

57-97% 45-83%

N-K+

O

O

N

O

O

(CH2)nBr

H2N (CH2)n NH2.2HClO

O

O

O-N(CH2)nN

O

O

Br(CH2)nBr

1. N2H42. HCl

+DMF

PhthN-OH, Et3N, DMF

n = 2,4

56

Scheme 49

HN OHPhthNBr

Ph

OH

Ph

PhthNN

OHPhthN

HN

OHPhthN

N

Boc

ONPhthPhthN

N

Boc

ONH2H2N

N

Boc

+i

ii

58

v

59

56 %

81 %

75 %

98 %

68 %

iv

iii

Reagents and conditions: i) K2CO3/KI/DMF, 65 °C, 6 h; ii) H2/Pd-C/MeOH/AcOH, r.t., 4 h; iii) Boc2O/Et3N/CH2Cl2, r.t., 4 h; iv) Phth-NOH/Ph3P/DEAD/THF, r.t., 12 h; v) N2H4/EtOH, 45 °C, 4 h

Scheme 50

NHOH

O

NH

O

O NPhth H2NO NH2

.2HCl

PhthN(CH2)nBr+

( )n( )n

60

i

ii, iii

Reagents and conditions: i) NaOMe/DMF; ii) NH2NH2; iii) HCl

Scheme 51



ence of Et3N, a product of N,N-bis-sulfonation formed inmany cases84 (Scheme 56). However the reaction between3-chloropropyloxyamine and Mts-Cl under these condi-tions resulted in cyclisation to give N-Mts-isoxazoli-dine.85

6 Conclusion

A wide variety of methods are avaiable for the synthesisof polyamines and polyamine conjugates, the most gener-al method being the alkylation of amines. Increasing use

is being made of the solid phase method as this has manypotential advantages leading to diversity and higheryields. Orthogonal protection allows selective removal ofthe protecting groups and hence selective functionalisa-tion of the polyamine chain. Only a limited number ofmethods are available for the synthesis of oxa-polyamines.

References and Notes

(1) Morris, D. R.; Marton, L. J. Polyamines In Biology And Medicine; Marcel Dekker: New York, 1981.

(2) Zubay, G. Biochemistry, 3rd Edition; Wm. C. Brown Publishers: Dubuque, Iowa; Oxford 1993.

(3) Cohen, S. S. A Guide to the Polyamines; Oxford University Press: Oxford, 1998.

(4) Basu, H. S.; Feuerstein, B. G.; Marton, L. J. In Polyamines in the Gastrointestinal Tract; Kluwer: Lancaster, 1992 pp 35−47.

(5) Pegg, A. E. Cancer Res. 1988, 48, 759. (6) Algranati, I. D.;Goldemberg, S.H. TIBS 1977, 272. (7) Williamson, J. D.; Tyms, A.S. Medical Microbiology 1984, 4,

239. (8) Janne, J.; Alhonen, L.; Leinonen, P. Ann. Med. 1991, 3, 241. (9) Russell, A. H. Nature New Biol. 1971, 233, 144.(10) Cipolla, B.; Moulinoux, J. P.; Quemener, V.; Havouis, R.;

Martin, L. A.; Guille, F.; Lobel, B. J. Urol. 1990, 144, 1164.(11) Matsumoto, T.; Suzuki, O. In The Physiology Of Polyamines;

Bachrach, U.; Heimer, Y. M. Eds.; CRC Press: Boca Raton, 1989, Vol. 2, pp 219−234.

(12) Bachrach, U. In The Physiology of Polyamines; Bachrach, U.; Heimer, Y.M., Eds.; CRC Press: Boca Raton, 1989, Vol. 2, pp 235−250.

(13) Porter, C. W.; Pera, P. J.; Kramer, P. L. Anticancer Res. 1986, 6, 1148.

(14) Mamont, P. S.; Duchesne, M.-C.; Grove, J.; Bey, P. Biochem. Biophys. Res. Commun. 1978, 81, 58.

(15) Bey, P.; Gerhart, F.; Van Dorsseler, V.; Danzin, C. J. Med. Chem. 1983, 26, 1551.

(16) Mett. H.; Stanek, J.; Lopez-Ballester, J. A.; Janne, J.; Alhonen, L.; Sinervirta, R.; Frei, J.; Reganass, U. Cancer Chemother. Pharmacol. 1993, 32, 39.

(17) Bitonti A. J.; Dumont, J. A.; Bush, T. L.; Edwards, M. L.; Stemerick, D. M.; McCann, P. P.; Sjoerdsma, A. Proc. Natl. Acad. Sci., USA, Medical Sciences 1989, 86, 651.

(18) Ganem, B. Acc. Chem. Res. 1982, 15, 290.(19) Bergeron, R. Acc. Chem. Res. 1986, 19, 105.(20) Blagbrough, I. S.; Carrington, S.; Geall, A. J. Pharmaceutical

Sciences 1997, 3, 223.(21) Geneste, H.; Hesse, M. Chem. unserer Zeit 1998, 32, 206.(22) Ramiandrasoa, F.; Milat, M.-L. Tetrahedron Lett. 1989, 30,

1365.(23) Jasys, V. J.; Kelbaugh, P. R.; Nason, D. M.; Phillips, D.;

Saccomano, N. A.; Stroh, J. G.; Volkmann, R. A. Tetrahedron Lett. 1988, 29, 6223.

(24) Jasys, V. J.; Kelbaugh, P. R.; Nason, D. M.; Phillips, D.; Rosnack, K. J.; Forman, J. T.; Saccomano, N. A.; Stroh, J. G.; Volkmann, R. A. J. Org. Chem. 1992, 57, 1814.

(25) Iwata, M.; Kuzuhara, H. Bull. Chem. Soc. Jpn. 1989, 62, 1102.(26) Bergeron, R. J.; Garlich, J. R.; Stolowich, N. J. J. Org. Chem.

1984, 49, 2997.(27) Saab, N. D.; West, E. E.; Bieszk, N. C.; Preuss, C. V.; Mank,

A. M.; Casero, R. A. Jr.; Woster, P. M. J. Med. Chem. 1993, 36, 2998.

BrBr H2NO

ONH2.2HCl

PmcHNOONHPmc

BpocHN NO

ON NHBpoc

Pmc

Pmc

H2N NH

OO

HN NH2

.4HCl

62

i, ii iii

iv

v, vi

40-73%

55-59%

55-60%

Reagents and conditions: i) PhthNOH/Et3N/DMF; ii) HCl/AcOH;iii) Pmc-Cl; iv) HO(CH2)3NHBpoc/DEAD/Ph3P/THF; v) HCl/Me-OH; vi) HCl/AcOH

Scheme 54

Br NH2.HBrPhthN OH

PhthN ONH2

PhthN O

HN

Mts

PhthN ON NPhth

Mts

H2N ON NH2

.3HBr

H

+72 %

i

75 %

ii

57-91 %

iii44-68 %

iv, v

( )n

RO

R'O

NH2 N

SO2Mes

SO2Mes

ONH2

ClO

N SO2Mes

i

R = Cl(CH2)n-, PhthNCH2-, NH2O-R' = Cl(CH2)n-, PhthNCH2-, MesSO2NHO-

n = 0,2,3

i

11-22%

92-96%

Reagents and conditions: i) MesSO2Cl/Et3N/CH2Cl2, r.t., 24 h

Scheme 56

Reagents and conditions: i) PhthN-OH/DBU/DMF, 60 °C, 24 h;ii) Mts-Cl/Et3N/CH2Cl2, r.t., 24 h; iii) PhthN(CH2)n+2Br/K2CO3/DMF, 80 °C, 12 h; iv) N2H4•H2O/EtOH, r.t., 24 h; v) 30% HBr/AcOH/CH2Cl2, r.t., 24 h

Scheme 55



(28) Bergeron, R. J.; McManis, J. S.; Liu, C. Z.; Feng, Y.; Weimar, W. R.; Luchetta, G. R.; Wu, Q.; Ortiz-Ocasio, J.; Vinson, J. R. T.; Kramer, D.; Porter, C. J. Med. Chem. 1994, 37, 3464.

(29) Bergeron, R. J.; Weimar, W. R.; Wu, Q., Feng, Y.; McManis, J. S. J. Med. Chem. 1996, 39, 5257.

(30) Bergeron, R. J.; Feng, Y.; Weimar, W. R.; McManis, J. S.; Dimova, H.; Porter, C.; Raisler, B.; Phanstiel, O. J. Med. Chem. 1997, 40, 1475.

(31) Carboni, B., Benalil, A., Vaulter, M. J. Org. Chem. 1993, 58, 3736.

(32) Vaulter, M.; Carboni, B.; Martinez-Freshneda, P. Synth. Commun. 1992, 22, 665.

(33) Casara, P.; Danzin, C.; Metcalf, B.; Jung, M. J. Chem. Soc., Perkin Trans. 1 1985, 2201.

(34) Nagarajan, S.; Ganem, B. J. Org. Chem. 1986, 51, 4856.(35) Israel, M.; Zoll, E. C.; Muhammad, N.; Modest, E. J. J. Med.

Chem. 1973, 16, 1.(36) Kunesch, G. Tetrahedron Lett. 1983, 24, 5211.(37) Miyashita, M.; Sato, H.; Yoshikoshi, A.; Toki, T.; Matsushita,

M.; Irie, H.; Yanami, T.; Kikuchi, Y.; Takasaki, C.; Nakajima, T. Tetrahedron Lett. 1992, 33, 2833.

(38) Nagarajan, S.; Ganem, B. J. Org. Chem. 1987, 52, 5044.(39) Levchine, I.; Pajan, P.; Borloo, M.; Bollaert, W.; Haemers, A.

Synthesis 1994, 37.(40) Golding, B.T.; O’Sullivan, M.C.; Smith, L.L. Tetrahedron

Lett. 1988, 29, 6651.(41) Knapp, S.; Hale, J. J.; Bastos, M.; Molina, A.; Chen, K. Y. J.

Org. Chem. 1992, 57, 6239.(42) Edwards, M. L.; Prakash, N. J.; Stemerick, D. M.; Sunkara, S.

P.; Bitonti, A. J.; Davis, G. F.; Dumont, J. A.; Bey, P. J. Med. Chem. 1990, 33, 1369.

(43) 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.

(44) Edwards, M. L.; Snyder, R. D.; Stemerick, D. M. J. Med. Chem. 1991, 34, 2414.

(45) Bellevue III, F. H.; Boahbedason, M.; Wu, R.; Woster, P. M.; Casero, R. A. Jr.; Rattendi, D.; Lane, S.; Bacchi, C. J. Bioorg. Med. Chem. Lett. 1996, 6, 2765.

(46) Lochner, M.; Geneste, H.; Hesse, M. Helv. Chim. Acta 1998, 81, 2270.

(47) Jasys, V. J.; Kelbaugh, P. R.; Nason, D. M.; Phillips, D.; Rosnack, K. J.; Saccomano, N.A.; Stroh, J.G.; Volkmann, R.A. J. Am. Chem. Soc. 1990, 112, 6696.

(48) Kumar, V. V.; Singh, S. K.; Sharma, S.; Bhaduri, A. P.; Gupta, S.; Zaidi, A.; Tiwari, S.; Katiyar, J. C. Bioorg. Med. Chem. Lett. 1997, 7, 675.

(49) Hughes, D. L. Org. React. 1992, 42, 335. (50) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.;

Harris, G. D. Jr.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709.

(51) Edwards, M. L.; Stemerick, D. M.; McCarthy, J. R. Tetrahedron Lett. 1990, 31, 3417.

(52) Karigiannis, G.; Mamos, P.; Balayiannis, G.; Katsoulis, I.; Papaioannou, D. Tetrahedron Lett. 1998, 39, 5117.

(53) Byk, G.; Frederic, M.; Scherman, D. Tetrahedron Lett. 1997, 38, 3219.

(54) Tomasi, S.; Le Roch, M.; Renault, J.; Corbel, J.-C.; Uriac, P.; Carboni, B.; Moncoq, D.; Martin, B.; Delcros, J.-G. Bioorg. Med. Chem. Lett. 1998, 8, 635.

(55) Dörner, B.; Husar, G. M.; Ostresh, J. M.; Houghten, R. A. Bioorg. Med. Chem. 1996, 4, 709.

(56) Marsh, I. R.; Smith, H.; Bradley, M. Chem. Commun. 1996, 941.

(57) Marsh, I. R.; Bradley, M. Tetrahedron 1997, 53, 17317.

(58) Fairlamb, A. H.; Blackburn, P.; Ulrich, P.; Chait, B. T.; Cerami, A. Science 1985, 227, 1485.

(59) Page, P.; Burrage, S.; Baldock, L.; Bradley, M. Bioorg. Med. Chem. Lett. 1998, 8, 1751.

(60) Ramasamy, K.S.; Bakir, F.; Baker, B.; Cook, P.D. J. Heterocycl. Chem. 1993, 30, 1373.

(61) Chen, S.; Lin, C.-H.; Walsh, C. T.; Coward, J. K. Bioor . Med. Chem. Lett. 1997, 7, 505.

(62) Chen, S.; Lin, C.-H.; Kwon, D. S.; Walsh, C. T.; Coward, J. K. J. Med. Chem. 1997, 40, 3842.

(63) Cohen, G. M.; Cullis, P. M.; Hartley, J. A.; Mather, A.; Symons, M. C. R.; Wheelhouse, R. T. J. Chem. Soc., Chem. Commun. 1992, 298.

(64) Zhuo, J.-C.; Cai, J.; Soloway, A. H.; Barth, R. F.; Adams, D. M.; Ji, W.; Tjarks, W. J. Med. Chem. 1999, 42, 1282.

(65) Berger, M. L.; Schödl, C.; Noe, C. R. Eur. J. Med. Chem. 1998, 33, 3.

(66) Reddy, V. K.; Valasinas, A.; Sarkar, A.; Basu, H. S.; Marton, L. J.; Frydman, B. J. Med. Chem. 1998, 41, 4723.

(67) Blagbrough, I. S.; Geall, A. J. Tetrahedron Lett. 1998, 39, 439.(68) Geall, A. J.; Blagbrough, I. S. Tetrahedron Lett. 1998, 39, 443.(69) Geall, A. J.; Taylor, R. J.; Earll, M. E.; Eaton, M. A. W.;

Blagbrough, I. S. Chem. Commun. 1998, 1403.(70) Pechilus, A. D.; Bellevue, F. H. III; Cioffi, C. L.; Trapp, S. G.;

Fojtik, J. P.; McKitty, A. A.; Kinney, W. A.; Frye, L. L. J. Org. Chem. 1995, 60, 5121.

(71) Prakash, T. P.; Barawkar, D. A.; Kumar, V.; Ganesh, K. N. Bioorg. Med. Chem. Lett. 1994, 4, 1733.

(72) O’Sullivan, M. C.; Zhou, Q. Bioorg. Med. Chem. Lett. 1995, 5, 1957.

(73) Schumann, E. L.; Heinzelman, R. V.; Greig, M. E.; Veldkamp, W. J. Am. Chem. Soc. 1964, 7, 329.

(74) Khomutov, A. R.; Shvetsov, A. C.; Vepsalainen, J.; Kramer, D. L.; Hyvönen, T., Keinanen, T.; Eloranta, T. O.; Porter, C. W.; Khomutov, R. M. Bioorg. Khim. 1996, 22, 557; Chem. Abstr. 1997, 126, 18709.

(75) Hyvonen, T.; Keinanen, T. A.; Khomutov, A. R.; Khomutov R. M.; Eloranta, T. O. Life Sciences 1994, 56, 349.

(76) Pearce, A.J.; Walter, D.S.; Frampton, C.S.; Gallagher, T. J. Chem. Soc. Perkin Trans. 1 1998, 847.

(77) Khomutov, A. R.; Khomutov R. M. Bioorg. Khim. 1989, 15, 698; Chem. Abstr. 1989, 111, 194441

(78) Stanek, J.; Frei, J.; Mett, H.; Schneider, P.; Regenass, U. J. Med. Chem. 1992, 35, 1339.

(79) Mikola, H.; Hänninen, E. Bioconjugate Chem. 1992, 3, 182.(80) Kung, P.-P.; Bharadwaj, R.; Fraser, A. S.; Cook, D. R.;

Kawasaki, A. M.; Cook, P. D. J. Org. Chem. 1998, 63, 1846.(81) Pankaskie, M. C.; Scholtz, S. A. Synth. Commun. 1989, 19,

339.(82) Kong Thoo Lin, P.; Maguire, N. M.; Brown, D.M.

Tetrahedron Lett. 1994, 35, 3605.(83) Kong Thoo Lin, P.; Kuksa, V. A.; Maguire, N.M. Synthesis

1998, 859.(84) Kuksa, V.A. Ph.D. Thesis 1999, The Robert Gordon

University, Aberdeen, UK.(85) Kuksa, V. A.; Kong Thoo Lin, P.; Wardell, S. Abstr. of pap.

7th Blue Danube Symposium on Heterocyclic Chemistry, Eger, Hungary, June 7−10, 1998, CD-Rom collection ISBN 9630350955.

Article Identifier:1437-210X,E;2000,0,09,1189,1207,ftx,en;E03699SS.pdf

synthesis of polyamines, their derivatives, analogues and ......vladimir kuksa, robert buchan, paul...

Documents