Macrocyclic polyamine lactam synthesis by diphenyl ether closure of 23-, 24- And 28-membered rings

Article abstract of DOI:10.1039/a806688d

Novel 23-, 24- and 28-membered cyclic polyamine amides (cinnamamides) have been prepared by closure of diphenyl ethers; functionalized conjugates of spermidine and spermine underwent intramolecular aromatic nucleophilic substitution to afford nitro-substituted analogues of cadabicine class (24-membered polyamine lactam) alkaloids.

Full text of DOI:10.1039/a806688d

Macrocyclic polyamine lactam synthesis by diphenyl ether closure of 23-, 24-
and 28-membered rings
Simon Carrington,a Alan H. Fairlambb and Ian S. Blagbrough*a†
a Department of Pharmacy and Pharmacology, University of Bath, Bath, UK BA2 7AY
b Department of Biochemistry, University of Dundee, Dundee, UK DD1 5EH
Received (in Cambridge, UK) 26th August 1998, Accepted 10th September 1998
Novel 23-, 24- and 28-membered cyclic polyamine amides
(cinnamamides) have been prepared by closure of diphenyl
ethers; functionalized conjugates of spermidine and sper-
mine underwent intramolecular aromatic nucleophilic sub-
stitution to afford nitro-substituted analogues of cadabicine
class (24-membered polyamine lactam) alkaloids.
spermidine 1, from Cadaba farinosa Forsk. The regiochemical
substitution of the diphenyl ether moiety is reversed with
respect to the unsymmetrical spermidine moiety in 6 and 7.11
We are unaware of a synthesis2,8 of a cadabicine 8 class
alkaloid, although a regiocontrolled synthesis of the Lunaria
diphenyl ether alkaloid codonocarpine 6 has been reported.12
Macrocycles containing diphenyl ethers are of chemical and
biological interest as they occur in vancomycin and ristocetin
antibiotic families.13–15 Also, these substitution patterns are
found in anti-cancer peptide conjugate RA-VII and ACE
inhibitor K-13.15,16 Macrocyclic polyamine lactams incorporat-
ing a diphenyl ether have been prepared using intermolecular
Ullmann diaryl ether synthesis followed by lactam forma-
tion.8,12 Herein we report the first design and synthesis of 23-,
24- and 28-membered ring polyamine lactam conjugates that
are nitro-substituted analogues of cadabicine 8 class alkaloids.
The required substituted cinnamic acids were prepared from
the corresponding benzaldehydes by Knoevenagel condensa-
tion.17,18 Isoferulic acid (3-hydroxy-4-methoxycinnamic acid) 9
was prepared in good yield (92%) under standard conditions
starting with malonic acid (EtOH, piperidine, pyridine, 3 h,
reflux).17 4-Fluorobenzaldehyde was similarly converted into
4-fluorocinnamic acid 10 (85%). Nitration ortho to fluorine, in
order to activate the final intramolecular nucleophilic substitu-
tion (SNiAr) reaction, achieved with conc. nitric acid, afforded
4-fluoro-3-nitrocinnamic acid 11 (1 h, 0 °C, 72%).
Polyamines such as triamine spermidine 1 and tetraamine
spermine 2 are widely distributed in nature and display a variety
of biological activities.1 Cinnamic acid (3-phenylpropenoic
acid) conjugates are commonly isolated as the corresponding N-
substituted amides from plant sources.2 Ferulic acid (4-
hydroxy-3-methoxycinnamic acid) 3 is found as feruloyl-
putrescine, a conjugate of 1,4-diaminobutane.3 N1,N3-Di-(E)-
feruloylspermidine 4 has been isolated from Corylus avellana
L.3,4 Spermidine conjugates have also been found asymmet-
rically substituted with both ferulic and caffeic (3,4-dihydrox-
ycinnamic) acids 5.3 Maytenine,5 from Maytenus chuchuhua-
sha, is the unsubstituted dicinnamamide of spermidine 1.
Dicinnamamides of spermine 2 include kukoamine A, a
biologically active bis(dihydrocaffeoyl) conjugate.6,7
Cyclic polyamine amide containing cinnamamides are less
common natural products whose biological activities are largely
unknown.2,8 Spermine 2 containing macrocyclic polyamine
lactams include inter alia chaenorhine and ephedradine A.8
Spermidine 1 containing polyamine lactams include codono-
carpine 6, from Codonocarpus australis,9 and capparisinine 7.10
Cadabicine 8 is a diphenyl ether 24-membered ring containing
For the 23-membered ring 12, N-(3-aminopropyl)-1,3-di-
aminopropane was protected with trifluoroacetyl groups on the
O
H
R2
NH2
N
NH2
OH
H2N
N
H2N
N
H
H
1
R1
2
3 R1 = OH, R2 = OMe
9 R1 = OMe, R2 = OH
OH
10 R1 = F, R2 = H
11 R1 = F, R2 = NO2
O
H
N
R2
R1
N
H
N
H
OMe
O
4 R1 = OH, R2 = OMe
5 R1 = OH, R2 = OH
H
N
N
H
N
H
N
H
N
H
H
O
N
H
O
O
H
O
H
N
R
N
O
N
n
N
H
O
O
O
R1
O
R1
R2
R2
OH
OMe
NO2
8 n = 1, R1 = OH, R2 = H
15
6 R1 = H, R2 = OMe
7 R1 = OMe, R2 = H
12 n = 0, R1 = OMe, R2 = NO2
13 n = 1, R1 = OMe, R2 = NO2
14 n = 1, R1 = OH, R2 = NO2
Chem. Commun., 1998, 2335–2336
2335

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primary amino groups (2 equiv. CF3CO2Et, THF, 10 min,
25 °C).19–21 This was followed by immediate Boc protection of
the central, secondary amine (Boc2O, THF, 18 h, 25 °C). Conc.
aq. ammonia was added to the solution of tri-protected triamine
until the pH was greater than 11 to remove the trifluoroacetyl
protecting groups (24 h). Mono-Boc protected amine was
isolated and purified by flash column chromatography (15 : 5: 1,
CH2Cl2–MeOH–conc. aq. NH3, v/v/v, Rf 0.13). The cinnamic
acid moieties17,18 were coupled sequentially (first the iso-
feruloyl 9 then the 4-fluoro-3-nitro 11) to the primary amines by
pre-activation with 2-mercaptothiazoline (2-thiazoline-2-thiol,
thiazolidine-2-thione)5 (DCC, 0.01 equiv. DMAP, CH2Cl2, 1 h,
25 °C, followed by filtration to remove the urea). Mono-Boc
protected triamine was added to the yellow CH2Cl2 solution of
the N-acylated 2-mercaptothiazoline and the coupling was
typically complete after 3 h (ca. 50% each acylation). Cyclisa-
tion was brought about by stirring with 5 equiv. CsF in
anhydrous DMF (18 h) to give 23-membered ring polyamine
lactam 12 (79% isolated yield). O-Arylation has occurred by
intramolecular aromatic nucleophilic substitution (SNiAr) reac-
tion of o-nitro-activated fluoride by the remote phenol.
For the 24-membered ring 14, spermidine 1 was reacted with
formalin to give a hexahydropyrimidine adduct (0.95 equiv.
37% w/w aq. formaldehyde, H2O, 1 h, 91%) as developed
independently by Ganem and Hesse and their co-workers.22,23
Isoferulic acid 917,18 was coupled to the primary amine of this
regioselectively protected spermidine through the 2-mercapto-
thiazoline activated intermediate (278 to 25 °C, 55%). After
chromatography, this hexahydropyrimidine was deprotected by
heating with malonic acid and pyridine (EtOH, reflux, 2 h,
79%).22 4-Fluoro-3-nitrocinnamic acid 11 was coupled to the
uncovered primary amine and then the secondary amine was
protected by a Boc group (1.1 equiv. Boc2O, MeOH, 18 h,
25 °C, 89%) to afford a linear precursor of cadabicine analogue
13. Cyclisation was carried out by stirring with 3 equiv. CsF in
anhydrous DMF (18 h, 71% isolated yield), final purification by
RP-HPLC (5 mm C8 inertpak column eluting with 1:4 aq. TFA
(0.1%)–MeOH, v/v, l = 250 nm). TFA catalysed deprotection
(1:1 TFA–CH2Cl2, v/v, 45 min, 0 °C, 90%) of the Boc group in
diaryl ether 15 was followed by O-demethylation with BBr3
(1.2 equiv., CH2Cl2, 3 h, 278 °C) to give 2A-nitrocadabicine 14
in 60% isolated yield.
For the 28-membered ring 15, spermine 2 was protected in a
similar fashion to N-(3-aminopropyl)-1,3-diaminopropane vide
supra. Trifluoroacetyl groups were used to block the two
primary amines then two Boc groups were introduced at the
secondary amines. Conc. aq. ammonia was used to remove the
trifluoroacetyl protecting groups and the N2,N3-diBoc spermine
was then purified by chromatography. The two cinnamic acid
moieties17,18 were introduced in a stepwise fashion using
2-mercaptothiazoline activation to yield the cyclisation pre-
cursor. Cyclisation was carried out in anhydrous DMSO with 3
equiv. K2CO3 and 10 equiv. 18-crown-6, the oxygen nucleophi-
licity was found to be too low without the crown ether. The
cyclisation reaction did not proceed to completion at 25 °C
(starting material still present after 24 h). However, heating the
mixture to 50 °C, in the presence of 18-crown-6, led to complete
reaction after 5 h, yielding the desired macrocycle 15 (66%).
The previously proposed mechanism of cyclisation involved
bringing the two sites of reaction into proximity by p-orbital
stacking interactions between the electron rich guaiacol (2-
methoxyphenol) ring and the electron deficient o-fluoro-
nitrophenyl ring.15 However, macrocycle formations of this
type have recently been demonstrated to proceed in good yield
when the aryl hydroxy group is replaced by an alkyl hydroxy
group, proving that such p–p interactions are not necessary for
successful cyclisation.24 As the isolated yields are high, this
practical approach by aromatic nucleophilic substitution (intra-
molecular SNiAr reaction) should find ready application in the
synthesis of natural products and their analogues with particular
reference to cyclic spermidine and spermine alkaloids of the
codonocarpine 6 and cadabicine 8 classes.
We thank the Department of Pharmacy and Pharmacology,
University of Bath, for a studentship (to S. C.). We acknowl-
edge useful discussions with Dr William N. Hunter (University
of Dundee), Professor Manfred Hesse (University of Zürich)
and Dr Ian S. Haworth (University of Southern California).
I. S. B. and I. S. H. are recipients of a NATO grant (CRG
970290). A. H. F. is funded by the Wellcome Trust.
Notes and references
† E-mail: prsisb@bath.ac.uk
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Communication 8/06688D
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Chem Commun., 1998