An iterative approach to novel polyamines via nucleophilic ring-opening of aziridinium ions with β-amino alcohols

Article abstract of DOI:10.1039/b401447b

An iterative procedure for the synthesis of a novel class of synthetic polyamines has been developed, utilising the regioselective ring-opening of aziridinium ion intermediates; facile N-allyl deprotection of intermediate polyamines allows the rapid const

Full text of DOI:10.1039/b401447b

An iterative approach to novel polyamines via nucleophilic ring-opening
of aziridinium ions with b-amino alcohols†
Christopher McKay, Robert J. Wilson and Christopher M. Rayner*
Department of Chemistry, University of Leeds, Leeds, UK LS2 9JT. E-mail: chrisr@chem.leeds.ac.uk
Received (in Cambridge, UK) 2nd February 2004, Accepted 9th March 2004
First published as an Advance Article on the web 1st April 2004
An iterative procedure for the synthesis of a novel class of
synthetic polyamines has been developed, utilising the re-
gioselective ring-opening of aziridinium ion intermediates;
facile N-allyl deprotection of intermediate polyamines allows
the rapid construction of high molecular weight, stereochem-
ically defined compounds in a convergent manner.
We then used this work as a basis for developing the amino
alcohol homologation as a route to polyamine compounds (Scheme
3). Treatment of N-allyl-N-benzyl alaninol 5 with trifluromethane-
sulfonic anhydride at low temperature facilitated formation of the
intermediate aziridinium triflate 7. This was treated in situ with the
Polymethylene polyamines, their analogues and conjugates occur
naturally and show interesting biological activities. The distribution
of these compounds ranges from simple bacteria to plants, insects,
mammals and marine organisms, and in the last two decades, many
cellular functions have been shown to be polyamine dependent.1
Research on polyamines has resulted in numerous reports detailing
the preparation of a vast array of synthetic polyamine analogues
and conjugates.2,3
Herein, we present an initial report on the results of our efforts
towards the synthesis of a novel class of a-substituted poly-
methylene polyamines using an iterative aziridinium ion forma-
tion–ring opening protocol. Previous work by our group,4 and
others,5 has demonstrated the synthetic utility of aziridinium ion
intermediates for the synthesis of highly functionalised 1,2-amino
alcohols and 1,2-diamines. We reasoned that if attacked by a b-
amino alcohol nucleophile containing a secondary amine, this
would lead to formation of the corresponding tertiary amine, which
would allow the iterative strategy to proceed. Repetition of this
sequence could ultimately be used to construct a-substituted
polymethylene polyamines 1 (Scheme 1) with overall structure and
substitution patterns similar to those in a small peptide, but lacking
the amide carbonyl group.6 As such, we believe these stereochem-
ically defined polymers will have application in many different
areas (vide infra).
The b-amino alcohols required as starting materials could be
synthesised in high yield from the corresponding amino acids or
amino acid methyl esters via a combination of simple alkylation
and reduction reactions7 (Scheme 2). Initial studies focussed on the
regioselectivity of the ring-opening reaction when the aziridinium
ion was attacked by morpholine (entries 1, 2, 6 and 7, Table 1).
With both allyl- and benzyl-protected amino alcohols, the reaction
yielded a mixture of regioisomers. This behaviour has been noted
previously.8 Using secondary amino alcohols as nucleophiles
however (entries 3–5 and 8–10), we found that the aziridinium ion
intermediate was attacked with complete regioselectivity in good to
excellent yields, and with exclusive N-alkylation of the aminoalco-
hol nucleophile.
Scheme 2 Reagents and conditions: (a) 2.5 eq. NaBH4, 1.0 eq. I2, THF,
reflux 18 h; (b) 0.5 eq. RABr, neat or in MeCN; (c) (i) 1.0 eq. PhCHO, 1.0
eq. NEt3, MeOH, rt; (ii) 2.0 eq. NaBH4, MeOH, 0 °C ? rt; (d) 1.2 eq. allyl
bromide, 1.1 eq. NEt3, DMF, 65 °C, 48 h; (e) 2.5 eq. LiAlH4, THF, 0 °C ?
rt.
Table 1 Regioselectivity of aziridinium ion ring opening
Yield
(%)
Entry R1
R2
R3
Nu
Ratio A : B
1
2
3
4
5
6
7
8
9
allyl
Bn
allyl
Bn
Bn
allyl
Bn
Bn
Bn
Bn
allyl
Bn
allyl
Bn
allyl
allyl
Bn
Bn
allyl
allyl
Bn
Bn
Bn
Bn
Bn
Me
Me
Me
Me
Me
morpholine
morpholine
N-allyl Phe–OH 84
N-allyl Phe–OH 67
N-allyl Phe–OH 89
morpholine
morpholine
N-allyl Val–OH 30
80
69
88 : 12
95 : 5
> 95 : 5a
> 95 : 5a
> 95 : 5a
68 : 32
74
79
71 : 29
> 95 : 5a
> 95 : 5a
> 95 : 5a
6a
6b
69
94
10
a None of alternative regioisomer detected.
Scheme 1
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b4/b401447b/
Scheme 3 Reagents and conditions: (a) 1.3 eq. Tf2O, 1.5 eq. NEt3, DCM,
278 °C ? rt; (b) 1.1 eq. amino alcohol, rt, 2 h.
1080
C h e m . C o m m u n . , 2 0 0 4 , 1 0 8 0 – 1 0 8 1
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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secondary b-amino alcohols 6a or 6b which attacked the azir-
idinium ion at the methylene carbon, opening the ring to form the
diamines 8a or 8b in 94% and 69% yield, respectively.9 Diamine 8b
could then be reactivated under the same conditions to form the
aziridinium ion moiety 9, which was reacted with the secondary b-
complex polyamines in areas such as asymmetric catalysis and
molecular recognition,14 the results of which shall be reported in
due course.
In conclusion, we have developed a novel method of aziridinium
ion mediated coupling of b-amino alcohols, and utilised efficient
protocols for the selective deprotection of polyamines, leading to a
convergent synthesis of complex stereochemically defined octa-
meric polyamines, which we believe will have widespread use in a
diverse range of applications.
We are grateful to the EPSRC for funding. We also thank Dr.
Alison Ashcroft and Andrew Baron for MSMS and SPR studies
respectively, and Prof. P.G. Stockley for useful discussions
(Department of Biochemistry and Molecular Biology, University of
Leeds). We are also grateful to Dr. Sandra Monaghan and Pfizer
Ltd. for a CASE award (RJW).
amino alcohol 10, derived from -leucine, to form the triamine 11.
L
In an iterative manner, the triamine could then be treated with triflic
anhydride under the same conditions to form an aziridinium
intermediate that reacted with the -phenylalanine derived b-amino
L
alcohol 6a to form the tetramine 12.
At this point further extension of the polyamine chain became
difficult, and there was some evidence to suggest that as the
molecules grew larger, the aziridinium ion formed became less
reactive. Exploring alternative methods of elongating the poly-
amine chain, we decided that a convergent synthesis would be
desirable. Deprotecting the terminal nitrogen atom of a tetramine
such as 12 would unmask a nucleophilic secondary amine moiety
that could be used to attack an aziridinium ion formed from another
tetramine leading to our initial octamine targets. The removal of an
allyl group from nitrogen was easily accomplished via a metal-
catalysed rearrangement/enamine hydrolysis4a and we found that
this strategy worked well in the deprotection of polyamines. Initial
efforts using palladium on activated charcoal gave a poor recovery
of the polyamines from the catalyst. The use of Grubbs’ metathesis
catalysts10 was equally unsuccessful, but this was unsurprising in
light of recent literature reports.11 Efficient N-deprotection was
eventually achieved using ClRh(PPh3)3 in acetonitrile/water or,
more simply, tetrakis(triphenylphosphine)palladium(0) in di-
chloromethane with 1,3-dimethylbarbituric acid as an allyl group
scavenger (Scheme 4).12 After filtering the crude material through
a plug of silica, the deprotected polyamine 13 was isolated in over
90% yield when Wilkinson’s catalyst was used, and 15 could be
obtained in quantitative yield after reaction with the palladium-
based catalyst.
Notes and references
1 S. S. Cohen, Introduction to the Polyamines, Oxford University Press,
Oxford, 1998.
2 G. Karigiannis and D. Papaioannou, Eur. J. Org. Chem., 2000, 1841.
3 V. Kuksa, R. Buchan and P. K. T. Lin, Synthesis, 2000, 1189.
4 (a) Q. Liu, A. P. Marchington, N. Boden and C. M. Rayner, J. Chem.
Soc., Perkin Trans. 1, 1997, 511; (b) Q. Liu, A. P. Marchington, N.
Boden and C. M. Rayner, Synlett, 1995, 1037; (c) M. A. Graham, A. H.
Wadsworth, M. Thornton-Pett and C. M. Rayner, Chem. Commun.,
2001, 966.
5 D. R. Andrews, V. H. Dahanukar, J. M. Eckert, D. Gala, B. S. Lucas, D.
P. Schumacher and I. A. Zavialov, Tetrahedron Lett., 2002, 43, 6121; T.
H. Chuang and K. B. Sharpless, Org. Lett., 1999, 1, 1435 and references
cited therein. See also ref. 8.
6 Caesium-promoted alkylation of amines has been used to prepare
related systems, see: R. N. Salvatore, A. S. Nagle and K. W. Jung, J.
Org. Chem., 2002, 67, 674.
7 (a) M. J. McKennon and A. I. Meyers, J. Org. Chem., 1993, 58, 3568;
(b) J. Barluenga, F. Foubelo, F. J. Fananas and M. Yus, J. Chem. Res.
(M), 1989, 1524; (c) H. G. Aurich, C. Gentes and K. Harms,
Tetrahedron, 1995, 51, 10497; (d) G. Gerona-Navarro, M. A. Bonache,
R. Herranz, M. T. Garcia-Lopez and R. Gonzalez-Muniz, J. Org. Chem.,
2001, 66, 3538; (e) S. R. Hitchcock, G. P. Nora, C. Hedberg, D. M.
Casper, L. S. Buchanan, M. D. Squire and D. X. West, Tetrahedron,
2000, 56, 8799.
8 P. O’Brien and T. D. Towers, J. Org. Chem., 2003, 67, 304.
9 General procedure for aziridinium ion mediated b-amino alcohol
coupling: N,N-protected b-amino alcohol was dissolved in anhydrous
dichloromethane and the solution cooled to 278 °C. Triethylamine
(distilled from CaH2, 1.5 eq.) was added, followed by trifluor-
omethanesulfonic anhydride (1.3 eq.) then the solution was stirred at
278 °C for 1 h before being allowed to warm to rt. A secondary b-amino
alcohol (1.1 eq.) dissolved in anhydrous dichloromethane was then
added and the mixture stirred at rt for 2–12 h. The reaction was
quenched with either saturated aq. NaHCO3 solution or 1 M aq. NaOH
and the product extracted into dichloromethane. The organic extracts
were combined, dried (Na2SO4) and concentrated in vacuo. The product
was purified by silica gel flash chromatography, eluting with ethyl
acetate/n-hexane mixtures.
Polyamines 13 and 15 with N-terminal secondary amines could
then be coupled to tetramine-derived aziridinium ions to form the
octamines 16–18 in modest yields (Scheme 5). The octamines were
analysed by QTof MSMS, and showed characteristic fragmenta-
tions dependent on the sequence of the amino alcohol residues.13
We have recently demonstrated that these polyamines bind to
DNA using Surface Plasmon Resonance (SPR), and are currently
investigating this and other potential applications of these new
Scheme 4 Reagents and conditions: (a) 10–20 mol% (PPh3)3RhCl, 84 : 16
MeCN/H2O, reflux (90%); (b) 1 mol% Pd(PPh3)4, 3.0 eq. 1,3-dime-
thylbarbituric acid, DCM, rt, 12 h (99%).
10 (a) B. Alcaide, P. Almendros, J. M. Alonso and M. F. Aly, Org. Lett.,
2001, 3, 3781; (b) C. Cadot, P. I. Dalko and J. Cossy, Tetrahedron Lett.,
2002, 43, 1839.
11 See: A. E. Sutton, B. A. Seigal, D. F. Finnegan and M. L. Snapper, J.
Am. Chem. Soc., 2002, 124, 13390; B. Schmidt, Eur. J. Org. Chem.,
2003, 816. Isomerisation activity originates from an unidentified
ruthenium hydride species; when the catalyst is stringently purified
before use, no isomerisation is observed.
12 I. Brackenridge, S. G. Davies, D. R. Fenwick, O. Ichihara and M. E. C.
Polywka, Tetrahedron, 1999, 55, 533.
13 To the best of our knowledge, only two reports have detailed the
properties of polyamines of this type: (a) concerning the mass spectra of
polyamines derived from reduced peptides ( D. L. Lippstreu-Fisher and
M. L. Gross, Anal. Chem., 1985, 57, 1174) and (b) assessing the activity
of polyamine compounds towards k-opoid receptors: ( R. A. Houghten,
S. E. Blondelle, C. T. Dooley, B. Dörner, J. Eichler and J. M. Ostresh,
Mol. Diversity, 1996, 2, 41).
Scheme 5 Reagents and conditions: (a) (i) 1.1 eq. Tf2O, 1.3 eq. NEt3, DCM,
278 °C ? rt; (ii) 1.1 eq. amino alcohol, rt, 12 h.
14 C. McKay, L. Johnson and C. M. Rayner, unpublished results.
C h e m . C o m m u n . , 2 0 0 4 , 1 0 8 0 – 1 0 8 1
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