Participation of compact planar 1,3,5-tri(buta-2,3-dien-1-yl)-1,3,5- triazinane-2,4,6-trione in Pd(0) catalysed seven component cascade reactions delivers novel tunable molecular architecture

Article abstract of DOI:10.1016/j.tet.2014.05.025

We report the spatially controlled, protecting group free, catalytic assembly of a library of nineteen 7-component cascade products generated from a novel planar trisallenyl 1,3,5-triazinane-2,4,6-trione core in combination with aryl iodides and amines with excellent regio and good stereoaselectivity for Z,Z,Z-isomers.

Full text of DOI:10.1016/j.tet.2014.05.025

Accepted Manuscript
Participation of Compact Planar 1,3,5-Tri(buta-2,3-dien-1-yl)-1,3,5-triazinane-2,4,6-
trione in Pd(0) Catalyzed Seven Component Cascade Reactions Delivers Novel
Tunable Molecular Architecture
Zeynep Gültekin , Elghareeb E. Elboray , Moustafa F. Aly , Hussien H. Abbas-
Temirek , Helena J. Shepherd , Ronald Grigg
PII:
S0040-4020(14)00697-8
10.1016/j.tet.2014.05.025
TET 25574
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 March 2014
Revised Date: 29 April 2014
Accepted Date: 12 May 2014
Please cite this article as: Gültekin Z, Elboray EE, Aly MF, Abbas-Temirek HH, Shepherd HJ, Grigg
R, Participation of Compact Planar 1,3,5-Tri(buta-2,3-dien-1-yl)-1,3,5-triazinane-2,4,6-trione in Pd(0)
Catalyzed Seven Component Cascade Reactions Delivers Novel Tunable Molecular Architecture,
Tetrahedron (2014), doi: 10.1016/j.tet.2014.05.025.
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Participation of Compact Planar 1,3,5-
Tri(buta-2,3-dien-1-yl)-1,3,5-triazinane-
2,4,6-trione in Pd(0) Catalyzed Seven
Component Cascade Reactions Delivers
Novel Tunable Molecular Architecture
Leave this area blank for abstract info.
Zeynep Gültekina,d , Elghareeb E. Elborayb,d, Moustafa F. Alyb, Hussien H. Abbas-Temirekb, Helena J.
Shepherd,c Ronald Griggd,
a Çankırı Karatekin University, Department of Chemistry, 18100, Çankırı, Turkey.
b Department of Chemistry, Faculty of Science at Qena, South Valley University, Qena, Egypt.
c Department of Chemistry, Bath University, Bath AB2 7AY, UK.
dMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, University of
Leeds. Leeds, LS6 9JT, UK.

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1
E2NC-2013
Paper Submission Template
Participation of Compact Planar 1,3,5-Tri(buta-2,3-dien-1-yl)-1,3,5-triazinane-2,4,6-
trione in Pd(0) Catalyzed Seven Component Cascade Reactions Delivers Novel
Tunable Molecular Architecture
Zeynep Gültekina,d, Elghareeb E. Elborayb,d, Moustafa F. Alyb, Hussien H. Abbas-Temirekb, Helena J.
Shepherd,c Ronald Griggd,
a Çankırı Karatekin University, Department of Chemistry, 18100, Çankırı, Turkey.
b Department of Chemistry, Faculty of Science at Qena, South Valley University, Qena, Egypt.
c Department of Chemistry, Bath University, Bath BA2 7AY, UK.
d Molecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry, University of Leeds. Leeds, LS6 9JT, UK.
ARTICLE INFO
ABSTRACT
Article history: (Office Use Only)
Received
Received in revised form
Accepted
We report the spatially controlled, protecting group free, catalytic assembly of a library of
nineteen 7-component cascade products generated from a novel planar trisallenyl 1,3,5-
triazinane-2,4,6-trione core in combination with aryl iodides and amines with excellent regio
and good stereoselectivity for Z,Z,Z-isomers.
Available online
Keywords:
Palladium
Stereoselective
Tunable
Multidirectional
Peptides
1. Introduction
of the hitherto unknown, trisallene 3 via Scheme 1. The
intermediate trisalkyne 2 crystallised as colourless plates from
A wide variety of central core compounds that promote
attachment, assembly and spatial distribution of multiple
attendant molecules have been developed which generate
moderate to large superstructures with tuneable properties or
multiple recognition sites. The initial core compound may be
planar and/or non-planar and possess intrinsic recognition sites.1a-
1:1 v/v CHCl3/MeOH and displayed the expected planar central
core (Fig 1). The trisallene 3, which to our knowledge has not
been reported before, was prepared from 2 by a modified Crabbe
reaction3a-c and obtained as a pale yellow viscous oil.
g
Typical examples for the former are the long known planar
benzene-1,3,5-tricarboxamides and porphyrins.1c More recently
dendrimers1d and adamantanes have attracted considerable
attention. The latter can display a fixed orthogonal spatial
disposition of four reactive arms and we recently used this to
achieve 3- and 9-component Pd(0) catalysed cascade assembly of
allenes, aryl iodides and N-nucleophiles with concomitant
installation of one to four trisubstituted Z-alkene functionalities.2a
Aditionally we have engineered novel tridirectional exploration
of biochemical space built from 5-component cascades of
heterocyclic bisallenes.2b
Scheme 1. Synthesis of 1,3,5-tri(buta-2,3-dien-1-yl)1,3,5-
triazinane-2,4,6-trione 3.
Related cores have been reported previously4a,b but their
participation in protecting group free multicomponent catalytic
cascade processes is unexplored although the road is signposted
by the elegant and extensive studies referred to in references1a-g,2
spanning nanotechnology, polymer processing and biomedical
applications. For example compounds which deliver multiple
2. Results and discussion
The success of these latter cascades, which are protecting
group free, prompted us to develop the synthesis and application
———
Corresponding author. Tel.: +44 113 343 6401; Fax: +44 113 343 6501; e-mail address: r.grigg@leeds.ac.uk (R. Grigg).

ACCEPTED MANUSCRIPT
2
Tetrahedron
targets often exhibit superior efficacy against complex
the slower process for the amino acid ester cascades of 7 and 8
(Table 1, entries 1-6). In all cases only trace amounts of the
corresponding Z,Z,E-isomer were detected. Additionally, the
presence of iodides with para- or meta- electron withdrawing
groups was not deleterious and the aliphatic hydroxyl group of 8
(Table 1, entry 6) was not competitive.
diseases.1e-g A recent review by Weerapana et al summarized the
importance and versatility of the related 1,3,5-triazine scaffolds
as a source of diverse molecular libraries.5
Next, we evaluated an analogous cascade series involving 1-
aminoadamantane
9 which continues to attract multiple
applications in drug discovery.6a-g In this case, we employed the
higher loading faster reacting catalyst combination of Pd2(dba)3
(7.5 mol%) and TFP (30 mol%) at 80 °C. Reaction times ranged
from 1.5 to 2.5 h and product yields ranged from 57-91% whilst
isomer ratios were typically 87:13 of Z,Z,Z- versus Z,Z,E- (Table
1, entries 7-13). In the case of entry 11, involving the 4-
trifluoromethyliodobenzene, the selectivity was lower although
the yield of the mixed isomers was high.
Figure 1. X-ray crystal structure of trisalkyne 2.
A third series (Table 1, entries 14-18) employing 8-fluoro-
2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole
nucleophile produced products with Z,Z,Z- to Z,Z,E- ratios of 87-
13 apart from entry 18 which was lower.
10
as
A series of aryl iodides and primary and secondary amines
was selected for evaluation of the trisallene 3 (Chart 1). In
comparison with our 9-component adamantyl cascade where the
cascade process involves populating four distinctly different non-
competitive areas of space2 the planar nature of the trisallene is
potentially more significantly compromised by buttressing effects
(Scheme 2). The conditions, catalyst, solvent and temperature
employed are noted in Scheme 2.
The final cascade (Table 1, entry 19) employed the sterically
demanding bridged ring 3-(3-isopropyl-5-methyl-4H-1,2,4-
triazol-4-yl)-8-azabicyclo[3.2.1]-octane 11 together with high
loading catalyst combination at 80 °C. As expected, this was the
least selective cascade generating a 62:38 mixture of Z,Z,Z- and
Z,Z,E-isomers.
I
I
I
(a) R = H
(b) R = Me
Table 1. Seven component cascade selectivity.
(c) R = OMe
(d) R = CF3
(e) R = 1-pyrrolyl
N
F3C
NH2
CF3
Time
(h)
Z,Z,Z:
Z,Z,Ea
Yield
(%)b
74c
R
4
5
F
6
Entry
1
Ar-I
Nu-H
Product
Me
CO2Me
NH3Cl
NH
Me
H
6
OH
HN
N
N
N
MeO2C
NH3Cl
8
N
12
>99:1
H
N
Me
H
18
82d
9
10
11
7
4a
7
7
Chart 1. Aryl iodides and amines used in 7-component cascades.
2
24
13
>99:1
73d
4c
O
.
.
Pd2(dba)3
TFP, K2CO3
MeCN, 80 °C
N
N
,
3 Nu-H
7-11
3 Ar-I
4-6
O
N
O
3
4
7
7
19
19
14
15
>99:1
>99:1
79d
79d
3
.
4d
Nu
Ar
Nu
Ar
Nu
Ar
Nu
Ar
O
N
O
I
N
N
N
O
N
O
O
N
O
F3C
CF3
Nu
Nu
5
Ar
Ar
12-30
,
, -Major isomer
Z Z Z
Z,Z,E-Minor isomer
Scheme 2. Seven component cascades. TFP
furylphosphine)
=
tri(2-
5
6
7
8
21
20
16
17
>99:1
>99:1
60d
Initially, we investigated the cascades with the
pharmaceutically important α-amino acid esters (S)-tryptophan 7
and (S)-serine 8. The former reacted with iodobenzene in
acetonitrile at 80 °C over 6 h in the presence of Pd2(dba)3 (7.5
mol%) and TFP (30 mol%) to give the Z,Z,Z-cascade product 12
in 74% yield (Table 1, entry 1). Repeating the reaction with
reduced amount of Pd2(dba)3 (2.5 mol%) and TFP (10 mol%)
over 18 h gave an improved yield of 12 (82%). The significant
reduction in the amount of Pd2(dba)3 and TFP prompted us to use
4e
4e
60d

ACCEPTED MANUSCRIPT
3
cAllene (1 equiv), aryl iodide (3.6 equiv), nucleophile (3.6 equiv), Pd2(dba)3
(7.5 mol%), TFP (30 mol%), K2CO3 (9 equiv), MeCN (5 mL/ mmol) at 80 °C.
dPd2(dba)3 (2.5 mol%), TFP (10 mol%) and K2CO3 (6 equiv) was used.
eIsomeric ratio was determined after column chromatography (One single
isomer).
7
2
18
87:13
72c
9
9
4c
fIsomeric ratio was determined after column chromatography.
8
9
2
19
20
87:13
87:13
63c
57c
3. Conclusion
4a
In conclusion, we have demonstrated that the hitherto
unknown planar 1,3,5-tri(buta-2,3-dien-1-yl)-1,3,5-triazinane-
I
2,4,6-trione
3 participates in seven component palladium
9
9
2.5
F3C
CF3
catalyzed stereoselective cascade reactions with a combination of
aryl/heteroaryl iodides and primary and secondary amines,
including α-amino acid esters. The latter are highly selective for
Z,Z,Z-isomers. Thus, the novel planar 1,3,5-triazinane-2,4,6-
trione provides a compact planar core particularly suitable for
cascades employing amino acid ester nucleophiles.
5
10
2
21
87:13
72c
4b
4. Experimental section
11
12
9
9
1.5
2
22
23
76:24
87:13
91c
66c
The crystallographic data for the trisalkyne 2 has been
deposited with the Cambridge Crystallographic Data Center as
CCDC 996268. Thin layer chromatography (TLC) was carried
out on aluminium plates pre-coated with silica gel 60 F254
(Merck), and were visualised using ultraviolet light and/or
aqueous KMnO4/I2. Flash column chromatography employed
silica gel 60 (Merck, 230-400 mesh). Melting points were
4d
6
determined on
a Reichert hot-stage microscope and are
uncorrected. Microanalyses were performed on a Carlo Erba
1108 elemental analyser and optical rotations were measured on a
Polartronic H 532 (Schmidt + Haensch) instrument. Infrared
spectra were recorded on a Perkin-Elmer Spectrum FT-IR
spectrometer either as thin films on sodium chloride discs or as
solids using a golden gate apparatus. The former were created by
dissolving the compound in CHCl3 and transfering the solution to
a sodium chloride disc and allowing the solvent to evaporate.
Proton nuclear magnetic resonance spectra were recorded on 500
MHz Avance and 300 MHz DPX300 Bruker instruments.
Chemical shifts (δ) are reported in parts per million relative to
tetramethylsilane (δ = 0.00) and coupling constants are given in
hertz (Hz). The following abbreviations are used: s = singlet, br =
broad, d = doublet, dd = doublet of doublets, ddd = doublet of
double doublets, dt = doublet of triplets, m = multiplet, t = triplet,
td = triplet of doublets. 13C-NMR spectra were recorded at 125
MHz Avance and 75 MHz DPX300 Bruker instruments and
13
9
2
24
n.de
85c
4e
14
15
2
25
26
87:13
87:13
82c
64c
4a
10
10
I
2.5
F3C
CF3
5
16
10
2
27
87:13
73c
1
chemical shifts are reported in parts per million (ppm). H-NMR
peak assignments are mainly based on DEPT135, COSY, HMQC
and HMBC spectral data. Accurate masses were obtained using a
Bruker Daltonics micrOTOF spectrometer. The m/z data
mentioned in the case of 7-component cascade products are the
result of two runs: one using the auto sampler technique and the
other by injecting the sample directly into the machine using a
syringe pump. All compounds are named according to the
IUPAC system using the ACD/ILAB (ACD/IUPAC v.12.0
programme) web service (http:/www.acdlabs.com). Microwave
reactions employed the CEM Discovery Explorer SP. Cyanuric
acid (Aldrich, 98%), propargyl bromide (Alfa aesar, 80% wt/wt
in toluene) and acetonitrile (VWR, BDH) are commercially
available and were used as received.
4e
6
17
18
10
10
2
2
28
29
86:14
79:21f
70c
78c
4c
6
19
3
30
62:38
69c
4.1. 1,3,5-Tri(prop-2-yn-1-yl)-1,3,5-triazinane-2,4,6-trione (2).
11
Cyanuric acid 1 (5.0 g, 38.76 mmol) and K2CO3 (20.86 g,
151.16 mmol) were added to a mixture of DMF (90 mL), and
propargyl bromide (15.5 mL, 139.50 mmol) at room temperature
aIsomeric ratio was determined by 1H-NMR of the crude material.
bIsolated yield after column chromatography.

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4
Tetrahedron
and the mixture was heated and stirred at 50 °C for 24 h. The
A mixture of trisallene 3 (0.25 mmol), aryl/hetereoaryl iodides
(0.90 mmol), nucleophiles (0.90 mmol), Pd2(dba)3 (2.5 mol%),
TFP (tri-(2-furyl)phosphine) (10 mol%), and K2CO3 (1.5 mmol)
in MeCN (5 mL) was stirred and heated at 80 °C (oil bath
temperature) until the starting material was completely consumed
as monitored by tlc (see Table 1). The mixture was worked up as
mentioned in general procedure A.
solution was then cooled, filtered and the filtrate evaporated. The
resultant residue was dissolved in CHCl3 (200 mL) and washed
with 10% NH4Cl solution (3 × 100 mL) and finally with water
(100 mL). The organic layer was dried over anhydrous MgSO4,
filtered and the filtrate evaporated under vacuum. The resulted
solid was crystallised from 1:1 v/v MeOH/CHCl3 to give the
pure trisalkyne 2 (4.5 g, 48%) as colourless plates, mp 164-166
°C; δH (300 MHz, CDCl3); 4.70 (6H, d, J 2.4, 3 × CH2), 2.31 (3H,
t, J 2.4, 3 × CH); δC (500 MHz, CDCl3); 147.3, 76.7, 72.7, 32.6;
δC (75 MHz, CDCl3); 147.2, 76.6, 72.4, 32.5; Anal. Calcd for
C12H9N3O3: C, 59.26; H, 3.73; N, 17.28. Found: C, 59.30; H,
3.60; N, 17.40; υmax/cm-1 (film); 3277, 3011, 2128, 1693, 1461,
1414, 1356, 1310; m/z (ESI+) 266.1 (100%, MNa+); (Found
MNa+, 266.0540. C12H9N3NaO3 requires 266.0536).
4.5. Trimethyl (2S,2'S,2''S)-2,2',2''-[(2,4,6-trioxo-1,3,5-
triazinane-1,3,5-triyl)tris{[(2Z)-2-phenylbut-2-ene-4,1-
diyl]imino}]tris[3-(1H-indol-3-yl)propanoate] (12).
Prepared by general procedure B from trisallene 3 in CH3CN
and heating for 18 h. Flash chromatography eluting with EtOAc
gave Z,Z,Z-product 12 (82%) as a pale yellow froth; [α]D
27
+
23.0 (c, 10 mg/1 mL CHCl3); mp 87-88 oC; δH (300 MHz,
CDCl3); 8.25 (3H, br s, 3 × indolyl-NH), 7.52 (3H, d, J 7.6, 3 ×
indolyl-H), 7.28-7.31 (6H, m, 3 × phenyl-H), 7.23-7.25 (3H, m, 3
× indolyl-H), 7.17-7.21 (9H, m, 3 × phenyl-H), 7.07 (3H, t, J 7.0,
3 × indolyl-H), 7.04 (3H, t, J 7.0, 3 × indolyl-H), 6.85 (3H, d, J
2.1 3 × indolyl-H), 5.70 (3H, t, J 6.6, 3 × NCH2CH=), 4.60-4.45
(6H, m, 3 × NCH2CH=), 3.84 (3H, d, J 12.6, 3 × =CCH2N), 3.59-
3.71 (3H, m, 3 × CHCO2Me), 3.66 (9H, s, 3 × CO2Me), 3.61 (3H,
d, J 13.1, 3 × =CCH2N), 3.18 (3H, dd, J 5.4 and 14.2, 3 ×
4.2. 1,3,5-Tri(buta-2,3-dien-1-yl)-1,3,5-triazinane-2,4,6-trione
(3).
A
mixture of trisalkyne
2
(1.0 g, 4.2 mmol),
paraformaldehyde (0.92 g, 30.7 mmol), dicyclohexylamine (4.4
mL, 22.1 mmol) and CuI (1.17 g, 6.15 mmol) in dry dioxane (6
mL) was refluxed for 3 h then cooled, filtered and the filtrate
evaporated under vacuum. The residue was dissolved in EtOAc
(100 mL) and the organic layer washed with 10% ammonium
hydroxide solution (2 × 60 mL), water (60 mL) and 3 M HCl (2 ×
30 mL) (during extraction some yellow precipitate of
dicyclohexylamine hydrochloride was formed between two
phase). The water layer was extracted again with EtOAc (2 × 30
mL). All the organic layers combined, filtered to remove yellow
precipitate and the precipitate washed two times with EtOAc (2 ×
10 mL). The organic layer was dried over anhydrous MgSO4 and
the residue was purified by flash column chromatography eluting
with 90:10 v/v hexane/EtOAc to give the pure trisallene 3 (0.68,
59%) as a pale yellow viscous oil; δH (300 MHz, CDCl3); 5.26
(3H, m, 3 × CH), 4.85 (6H, dt, J 2.9 and 6.4, 3 × CH2), 4.50 (6H,
dt, J 2.9 and 6.4, 3 × CH2); δC (75 MHz, CDCl3); 208.9, 148.3,
85.5, 77.6, 41.1; υmax/cm-1 (film); 3384, 3066, 2991, 2959, 1957,
1685, 1458, 1361, 1317; Anal. Calcd for C15H15N3O3: C, 63.15;
H, 5.30; N, 14.73. Found: C, 63.20; H, 5.40; N, 14.60; m/z (ESI+)
308.1 (100%, MNa+); (Found MNa+, 308.1003. C15H15N3NaO3
requires 308.1006).
CHACHCO2Me), 3.03 (3H, dd,
J 8.2 and 14.2, 3 ×
CHBCHCO2Me), 1.86 (3H, br, 3 × NH); δC (75 MHz, CDCl3);
175.1, 148.5, 141.6, 140.6, 136.1, 128.3, 127.5, 127.2, 126.2,
124.1, 123.2, 121.8, 119.2, 118.6, 111.1, 110.8, 61.4, 51.8, 46.8,
41.2, 29.2; υmax/cm-1 (film); 3407, 3015, 2951, 1751, 1690, 1456,
1357, 1216, 1011; m/z (ESI+) 1190.5 (100% MNa+), (Found
MNa+, 1190.5132 C69H69N9NaO9 requires 1190.5110). NOE data
(CDCl3) for 12:
% Enhancement
Irradiated
proton
phenyl-
H
Indolyl-
CH2
1-H
2-H
4-H
Indolyl-H
1-H
2-H
4-H
2.51 2.84
-
-
-
-
-
7.36
(δ 7.3)
1.88
-
-
1.12
1.01
0.42 (δ 6.8),
0.89 (δ 7.5)
-
(δ 7.2)
(δ 3.0-3.2)
4.3. General Procedure A: Pd catalysed 7-component cascades.
4.6. Trimethyl (2S,2'S,2''S)-2,2',2''-[(2,4,6-trioxo-1,3,5-
triazinane-1,3,5-triyl)tris{[(2Z)-2-(4-methoxyphenyl)but-2-ene-
4,1-diyl]imino}]tris[3-(1H-indol-3-yl)propanoate] (13).
A mixture of trisallene 3 (0.25 mmol), aryl/heteroaryl iodides
(0.90 mmol), nucleophiles (0.90 mmol), Pd2(dba)3 (7.5 mol%),
TFP (tri-(2-furyl)phosphine) (30 mol%), and K2CO3 (2.25 mmol)
in MeCN (5 mL) was stirred and heated at 80 °C (oil bath
temperature) until the starting material was completely consumed
as monitored by tlc (see Table 1). The mixture was cooled and
solvent removed under vacuo. The residue was dissolved in
CHCl3 (25 mL) and extracted with H2O (20 mL) three times. The
organic layer was dried over anhydrous MgSO4 and evaporated
under rotatory evaporator to give the crude product which
purified by flash chromatography.
Prepared by general procedure B from trisallene 3 in CH3CN
and heating for 24 h. Flash chromatography eluting with EtOAc
gave Z,Z,Z-isomer 13 (73%) as a pale yellow froth; [α]D27 + 96.0
o
(c, 10 mg/1 mL CHCl3); mp 95-96 C; δH (500 MHz, CDCl3);
8.29 (3H, br s, indolyl-NH), 7.50-7.52 (3H, m, 3 × indolyl-H),
7.20-7.22 (3H, m, 3 × indolyl-H), 7.21 (6H, d, J 8.7, 3 × phenyl-
H), 7.10 (3H, t, J 7.3, 3 × indolyl-H), 7.04 (3H, t, J 7.3, 3 ×
indolyl-H), 6.87 (3H, br s, 3 × indolyl-H), 6.69 (6H, d, J 8.7, 3 ×
phenyl-H), 5.64 (3H, t, J 6.6, 3 × NCH2CH=), 5.62-4.52 (6H, m,
3 × NCH2CH=), 3.80 (3H, d, J 12.8, 3 × =CCH2N), 3.76 (9H, s, 3
× OMe), 3.64-3.74 (3H, m, 3 × CHCO2Me), 3.66 (9H, s, 3 ×
CO2Me), 3.60 (3H, d, J 12.8, 3 × =CCH2N), 3.17 (3H, dd, J 5.4
and 14.5, 3 × CHACHCO2Me), 3.03 (3H, dd, J 7.7 and 14.5, 3 ×
CHBCHCO2Me), 1.91 (3H, br, 3 × NH); δC (75 MHz, CDCl3);
175.1, 159.0, 148.5, 140.8, 136.1, 132.7, 127.3, 123.3, 121.7,
119.2, 118.6, 113.6, 111.1, 110.6, 109.8, 61.4, 55.2, 51.9, 46.6,
41.2, 29.1; υmax/cm-1 (film); 3404, 2951, 1731, 1689, 1511, 1457,
1248, 1217; m/z (ESI+) 1258.5 (32%, MH+), (Found MH+,
1258.5611. C72H76N9O12 requires 1258.5608).
4.4. General Procedure B: Pd catalysed 7-component cascades.

ACCEPTED MANUSCRIPT
5
4.7. Trimethyl (2S,2'S,2''S)-2,2',2''-[(2,4,6-trioxo-1,3,5-
CHBCHCO2Me), 1.89 (3H, br s, 3 × NH); δC (75 MHz, CDCl3);
triazinane-1,3,5-triyl)tris({(2Z)-2-[4-(trifluoromethyl)phenyl]but-
2-ene-4,1-diyl}imino)]tris[3-(1H-indol-3-yl)propanoate] (14).
175.1, 148.5, 140.7, 139.7, 137.4, 136.2, 127.3, 123.7, 123.3,
121.9, 119.7, 119.3, 119.0, 118.6, 111.2, 110.7, 110.5, 61.3, 51.9,
46.5, 41.2, 29.2; υmax/cm-1 (film); 3403, 2950, 1731, 1689, 1521,
1456, 1330, 1215, 1070; m/z (ESI+) 1385.5 (100%, MNa+);
(Found MNa+, 1385.5909. C81H78N12NaO9 requires 1385.5907).
Prepared by general procedure B from trisallene 3 in CH3CN
and heating for 19 h. Flash chromatography eluting with 95:5 v/v
CHCl3/MeOH gave Z,Z,Z-product 14 (79%) as a pale yellow
froth; [α]D27 + 7.5 (c, 10 mg/1 mL CHCl3); mp 86-87 oC; δH (500
MHz, CDCl3); 8.26 (3H, br, 3 × indolyl-NH), 7.51 (3H, d, J 7.8,
3 × indolyl-H), 7.33 (6H, d, J 8.2, 3 × phenyl-H), 7.29 (6H, d, J
8.2, 3 × phenyl-H), 7.22 (3H, d, J 6.8, 3 × indolyl-H), 7.12 (3H, t,
J 7.3, 3 × indolyl-H), 7.04 (3H, t, J 7.3, 3 × indolyl-H), 6.81 (3H,
br s, 3 × indolyl-H), 5.71 (3H, t, J 6.8, 3 × NCH2CH=), 4.52-4.6
(6H, m, 3 × NCH2CH=), 3.83 (3H, d, J 12.8, 3 × =CCH2N), 3.70-
3.63 (3H, m, 3 × CHCO2Me), 3.68 (9H, s, 3 × CO2Me), 3.58 (3H,
d, J 13.2, 3 × =CCH2N), 3.18 (3H, dd, J 5.0 and 14.6, 3 ×
4.10. Trimethyl (2S,2'S,2''S)-2,2',2''-[(2,4,6-trioxo-1,3,5-
triazinane-1,3,5-triyl)tris({(2Z)-2-[4-(1H-pyrrol-1-yl)phenyl]but-
2-ene-4,1-diyl}imino)]tris(3-hydroxypropanoate) (17).
Prepared by general procedure B from trisallene 3 in CH3CN
and heating for 20 h. Flash chromatography eluting with EtOAc
then 1:1 v/v EtOAc:MeOH gave Z,Z,Z-isomer 17 (60%) as a pale
yellow froth; [α]D27 + 75.0 (c, 10 mg/1 mL CHCl3); mp 89-91 oC;
δH (500 MHz, CDCl3); 7.50 (6H, d, J 8.5, phenyl-H), 7.34 (6H, d,
J 8.5, phenyl-H), 7.07 (6H, br s, pyrol-H), 6.33 (6H, br s, pyrol-
H), 5.89 (3H, t, J 7.0, 3 × NCH2CH=), 4.88-4.77 (6H, m, 3 ×
NCH2CH=), 3.93 (3H, d, J 11.8, =CCH2N), 3.81 (3H, dd, J 4.1
and 11.4, CHCO2Me), 3.74 (3H, d, J 11.8, =CCH2N), 3.71 (9H,
s, CO2Me), 3.60 (3H, dd, J 6.4 and 10.5, CHAOH), 3.43-3.45
(3H, m, CHBOH), 2.0 (3H, br, 3 x NH); δC (75 MHz, CDCl3);
173.2, 148.8, 141.2, 140.1, 137.7, 127.6, 123.6, 120.1, 119.1,
110.6, 62.9, 62.7, 52.1, 46.5, 41.4; υmax/cm-1 (film); 3324, 2952,
1735, 1687, 1522, 1458, 1330, 1200, 1069; m/z (ESI+) 1088.4
(100%, MNa+), (Found MNa+, 1088.4501. C57H63N9NaO12
requires 1088.4488).NOE data (CDCl3) for 17:
CHACHCO2Me), 2.99 (3H, dd,
J 8.2 and 14.6, 3 ×
CHBCHCO2Me), 1.87 (3H, br, 3 × NH); δC (125 MHz, CDCl3);
175.1, 148.4, 144.0 (br s), 140.0, 136.2, 129.5 (J 31.1), 127.7,
126.5 (br s), 125. 7, 125.1 (J 10.9), 124.1 (J 271.2), 123.1, 121.9,
119.3, 118.6, 111.3 (br s), 110.8, 61.3, 51.9, 46.6, 41.1, 29.2;
υmax/cm-1 (film); 3405, 2952, 1732, 1692, 1456, 1325, 1215,
1165, 1119, 1068; m/z (ESI+) 1394.4 (100%, MNa+), (Found
MNa+, 1394.4668. C72H66F9N9NaO9 requires 1394.4737).
4.8. Trimethyl (2S,2'S,2''S)-2,2',2''-[(2,4,6-trioxo-1,3,5-
triazinane-1,3,5-triyl)tris({(2Z)-2-[3,5-
bis(trifluoromethyl)phenyl]but-2-ene-4,1-diyl}imino)]tris[3-(1H-
indol-3-yl)propanoate] (15).
% Enhancement
Irradiated proton 1-H
2-H
4-H
phenyl-H
Prepared by general procedure B from trisallene 3 in CH3CN
and heating for 19 h. Flash chromatography eluting with 9:1 v/v
CHCl3/MeOH gave Z,Z,Z-product 15 (79%) as a pale yellow
froth; [α]D27 + 8.0 (c, 10 mg/1 mL CHCl3); mp 90-91 oC; δH (300
MHz, CDCl3); 8.21 (3H, br s, 3 × indolyl-NH), 7.86 (6H, br s, 3
× phenyl-H), 7.70 (3H, br s, 3 × phenyl-H), 7.49 (3H, d, J 7.6, 3
× indolyl-H), 7.23 (3H, br s, 3 × indolyl-H), 7.10 (3H, dt, J 1.0
and 8.2, 3 × indolyl-H), 7.02 (3H, t, J 7.6, 3 × indolyl-H), 6.93
(3H, d, J 2.1, 3 × indolyl-H), 5.79 (3H, t, J 6.6, 3 × NCH2CH=),
4.60 (6H, d, J 6.6 3 × NCH2CH=), 3.84 (3H, d, J 12.6, 3 ×
=CCH2N), 3.62-3.73 (3H, m, 3 × CHCO2Me), 3.7 (9H, s, 3 ×
CO2CH3), 3.57 (3H, d, J 12.6, 3 × =CCH2N), 3.19 (3H, dd, J 4.9
and 14.2, 3 × CHACHCO2Me), 3.04 (3H, dd, J 7.6 and 14.2, 3 ×
CHBCHCO2Me), 1.86 (3H, br s, 3 × NH); δC (125 MHz, CDCl3);
175.1, 148.4, 142.8, 139.5, 136.0, 131.4 (J 33.1), 128.7, 127.2,
126.4 (J 2.2), 123.3 (J 273), 121.4 (J 3.3), 122.9, 121.9, 119.3,
118.4, 111.1, 110.9, 61.5, 51.9, 46.7, 41.1, 29.2; υmax/cm-1 (film);
3408, 3016, 2953, 1731, 1693, 1457, 1381, 1279, 1179, 1133;
m/z (ESI+) 1598.4 (100% MNa+), (Found MNa+ 1598.4330
C75H63F18N9NaO9 requires 1598.4354).
1-H
2-H
-
2.55 0.77
-
1.08
-
-
5.82 (δ 7.5)
4.11. 1,3,5-Tris[(2Z)-3-(4-methoxyphenyl)-4-
(tricyclo[3.3.1.13,7]dec-1-ylamino)but-2-en-1-yl]-1,3,5-
triazinane-2,4,6-trione (18).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with EtOAc
then 19:1 v/v EtOAc/MeOH gave Z,Z,Z-isomer 18 (72%) as a
o
pale yellow froth; mp 103-105 C; δH (500 MHz, CDCl3); 7.42
(6H, d, J 8.7, 3 × phenyl-H), 6.83 (6H, d, J 8.7, 3 × phenyl-H),
5.74 (3H, t, J 7.1, 3 × NCH2CH=), 4.72 (6H, d, J 7.1, 3 ×
NCH2CH=), 3.79 (9H, s, 3 × OCH3), 3.75 (6H, s, 3 × =CCH2N),
2.07 (9H, br s, 9 × adamantyl-CH), 1.70 (18H, br s, 9 ×
adamantyl-CH2), 1.65 (18H, br q, J 11.9, 9 × adamantyl-CH2),
1.23 (3H, br s, 3 × NH), δC (75 MHz, CDCl3); 159.1, 148.8,
142.7, 133.4, 127.5, 121.0, 113.7, 55.2, 50.8, 42.5, 41.5, 39.1,
36.8, 29.6; υmax/cm-1 (film); 2904, 2847, 1688, 1607, 1510, 1455,
1309, 1246, 1179; m/z (ESI+) 1057.6 (100%, MH+); (Found MH+,
1057.6495. C66H85N6O6 requires 1057.6525). NOE data (CDCl3)
for 18:
4.9. Trimethyl (2S,2'S,2''S)-2,2',2''-[(2,4,6-trioxo-1,3,5-
triazinane-1,3,5-triyl)tris({(2Z)-2-[4-(1H-pyrrol-1-yl)phenyl]but-
2-ene-4,1-diyl}imino)]tris[3-(1H-indol-3-yl)propanoate] (16).
Prepared by general procedure B from trisallene 3 in CH3CN
% Enhancement
Irradiated
and heating for 21 h. Flash chromatography eluting with EtOAc
27
gave Z,Z,Z-product 16 (60%) as a pale yellow froth; [α]D
–
1-H
2-H
4-H
phenyl-H
adamantyl-CH2
proton
o
10.0 (c, 10 mg/1 mL CHCl3); mp 100-101 C; δH (300 MHz,
CDCl3); 8.27 (3H, br, 3 × indolyl-NH), 7.53 (3H, d, J 7.6, 3 ×
indolyl-H), 7.26 (6H, d, J 8.5, 3 × phenyl-H), 7.12-7.23 (9H, m, 3
× indolyl-H), 7.10 (6H, d, J 8.5, 3 × phenyl-H), 7.03 (6H, t, J 2.1,
3 × pyrol-H), 6.84 (3H, d, J 2.1, 3 × indolyl-H), 6.34 (6H, t, J
2.1, 3 × pyrol-H), 5.71 (3H, t, J 6.8, 3 × NCH2CH=), 4.63-4.56
(6H, m, 3 × NCH2CH=), 3.84 (3H, d, J 13.1, 3 × =CCH2N), 3.80
(3H, d, J 13.1, 3 × =CCH2N), 3.67 (3H, m, 3 × CHCO2Me), 3.69
(9H, br s, 3 × CO2Me), 3.20 (3H, dd, J 4.3 and 14.2, 3 ×
1-H
2.22 2.15
-
-
2-H
1.87
2.25
-
7.90 (δ 7.4)
4.38 (δ 7.4)
-
4-H
-
5.41 (δ 1.7)
4.12. 1,3,5-Tris[(2Z)-3-phenyl-4-(tricyclo[3.3.1.13,7]dec-1-
ylamino)but-2-en-1-yl]-1,3,5-triazinane-2,4,6-trione (19).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with EtOAc
CHACHCO2Me), 3.01 (3H, dd,
J 8.2 and 14.2, 3 ×

ACCEPTED MANUSCRIPT
6
Tetrahedron
then 7:3 v/v EtOAc/MeOH gave Z,Z,Z-product 19 (63%) as a
4-H
2.44
-
5.14 (δ 7.3)
5.79 (δ 1.6)
o
colourless froth, mp 108-110 C; δH (500 MHz, CDCl3); 7.48
(6H, d, J 7.8, 3 × phenyl-H), 7.22-7.30 (9H, m, 3 × phenyl-H),
5.80 (3H, t, J 7.1, 3 × NCH2CH=), 4.74 (6H, d, J 7.1, 3 ×
NCH2CH=), 3.77 (6H, s, 3 × =CCH2N), 2.07 (9H, br s, 9 ×
adamantyl-CH), 1.71 (18H, br s, 9 × adamantyl-CH2), 1.64 (18H,
br q, J 11.4, 9 × adamantyl-CH2), 1.26 (3H, br s, 3 × NH), δC
(125 MHz, CDCl3); 148.7, 143.4, 141.1, 128.3, 127.5, 126.4,
122.7, 50.8, 42.6, 41.5, 39.3, 36.8, 29.6; υmax/cm-1 (film); 3428,
2904, 2847, 1688, 1567, 1455, 1309, 1215, 1097; m/z (ESI+)
967.6 (18%, MH+); (Found MH+, 967.6190. C63H79N6O3 requires
967.6208); 484.3 (100%, [M+2H]2+, (Found [M+2H]2+, 484.3158
C63H80N6O3 requires 484.3140); 323.2 (26%, [M+3H]3+, (Found
[M+3H]3+, 323.2118 C63H81N6O3 requires 323.2128). NOE data
(CDCl3) for 19:
4.15. 1,3,5-Tris{(2Z)-4-(tricyclo[3.3.1.13,7]dec-1-ylamino)-3-[4-
(trifluoromethyl)phenyl]but-2-en-1-yl}-1,3,5-triazinane-2,4,6-
trione (22).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 1.5 h. Flash chromatography eluting with 98:2
v/v CHCl3/MeOH gave the product 22 as a 71:29 mixture of
Z,Z,Z- and Z,Z,E-isomers (91%) as a colourless froth. Major
Z,Z,Z-isomer: δH (500 MHz, CDCl3); 7.61 (6H, d, J 8.2, 3 ×
phenyl-H), 7.54 (6H, d, J 8.2, 3 × phenyl-H), 5.85 (3H, t, J 7.1, 3
× NCH2CH=), 4.77 (6H, d, J 7.1, 3 × NCH2CH=), 3.75 (6H, s, 3
× =CCH2N), 2.08 (9H, br s, 9 × adamantyl-CH), 1.70 (18H, br s,
9 × adamantyl-CH2), 1.57-1.68 (18H, m, 9 × adamantyl-CH2),
1.3 (3H, br s, 3 × NH), δC (75 MHz, CDCl3); 148.8, 144.8 (br s),
142.5, 129.5 (J 33), 129.0 (J 272), 126.6 (br s), 124.3, 111.1 (J
9.9), 50.9, 42.5, 41.4, 39.3, 36.7, 29.6; υmax/cm-1 (film); 2905,
2848, 1690, 1457, 1325, 1164, 1124, 1068; m/z (ESI+) 1170.5
(39%, MH+); (Found MH+, 1171.5813. C66H76F9N6O3 requires
1171.5835).
% Enhancement
Irradiated
proton
1-H
2-H
4-H
phenyl-H
adamantyl-CH2
1-H
4.08 3.06
-
-
2-H
2.59
3.18
-
9.75 (δ 7.4)
5.95 (δ 7.4)
-
4-H
-
7.02 (δ 1.6)
4.16. 1,3,5-Tris[(2Z)-4-(adamantan-1-ylamino)-3-(pyridin-3-
yl)but-2-en-1-yl]-1,3,5-triazinane-2,4,6-trione (23).
4.13. 1,3,5-Tris[(2Z)-3-[3,5-bis(trifluoromethyl)phenyl]-4-
(tricyclo[3.3.1.13,7]dec-1-ylamino)but-2-en-1-yl]-1,3,5-
triazinane-2,4,6-trione (20).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with EtOAc
then 10:3 v/v EtOAc/MeOH gave the product 23 (66%) as a
single Z,Z,Z-isomer which crystallized from CHCl3 as a
colourless fine needles, mp 111-113 °C; δH (300 MHz, CDCl3);
8.75 (3H, d, J 1.9, 3 × pyridyl-H), 8.49 (3H, dd, J 1.9 and 4.8, 3 ×
pyridyl-H), 7.85 (3H, td, J 1.9, 8.1, 3 × pyridyl-H), 7.22 (3H, dd,
J 4.8 and 8.1, 3 × pyridinyl-H), 5.85 (3H, t, J 7.2, 3 ×
NCH2CH=), 4.78 (6H, d, J 7.2, 3 × NCH2CH=), 3.76 (6H, s, 3 ×
=CCH2N), 2.08 (9H, br s, 9 × adamantyl-CH), 1.71 (18H, br d, J
1.9, 9 × adamantyl-CH2), 1.65 (18H, br q, J 10.5, 9 × adamantyl-
CH2); δC (75 MHz, CDCl3); 148.7, 148.69, 147.7, 140.8, 136.8,
133.7, 123.9, 123.1, 50.9, 42.6, 41.4, 39.3, 36.8, 29.6; υmax/cm-1
(film); 3318, 2905, 2848, 1693, 1567, 1455, 1357, 1310, 1215;
m/z (ESI+) 970.6 (33%, MH+); (Found MH+, 970.6069.
C60H76N9O3 requires 970.6066).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2.5 h. Flash chromatography eluting with CHCl3
then 9:1 v/v CHCl3/MeOH gave the product 20 as a 87:13
mixture of Z,Z,Z- and Z,Z,E-isomers (57%) as a colourless froth.
Major Z,Z,Z isomer δH (500 MHz, CDCl3); 8.0 (6H, br s, 3 ×
phenyl-H), 7.70 (3H, br s, 3 × phenyl-H), 5.85 (3H, t, J 6.8, 3 ×
NCH2CH=), 4.75 (6H, d, J 6.8, 3 × NCH2CH=), 3.7 (6H, s, 3 ×
=CCH2N), 2.0 (9H, br s, 3 × adamantyl-CH), 1.5-1.8 (36H, m, 3
× adamantyl-CH2), 1.26 (3H, br s, 3 × NH).; δC (125 MHz,
CDCl3); 148.6, 143.5, 141.3, 131.3 (J 34), 126.6 (br s), 123.4 (J
271), 121.2 (J 3.6), 50.9, 42.7, 41.4, 39.5, 36.7, 29.6; υmax/cm-1
(film); 2909, 2850, 1693, 1456, 1383, 1310, 1278, 1179, 1235;
m/z (ESI+) 1375.5 (72%, MH+); (Found MH+, 1375.5472.
C69H73F18N6O3 requires 1375.5451).
4.17. 1,3,5-Tris[(2Z)-3-[4-(1H-pyrrol-1-yl)phenyl]-4-
(tricyclo[3.3.1.13,7]dec-1-ylamino)but-2-en-1-yl]-1,3,5-
triazinane-2,4,6-trione (24).
4.14. 1,3,5-Tris[(2Z)-3-(4-methylphenyl)-4-
(tricyclo[3.3.1.13,7]dec-1-ylamino)but-2-en-1-yl]-1,3,5-
triazinane-2,4,6-trione (21).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with CHCl3
then 9:1 v/v CHCl3/MeOH gave the product 24 as a single Z,Z,Z-
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with EtOAc
gave 21 as a single Z,Z,Z-isomer (72%) as a colourless froth. mp
o
isomer (85%) as a pale yellow froth. mp 134-137 C.; δH (500
o
97-99 C; δH (500 MHz, CDCl3); 7.35 (6H, d, J 7.8, 3 × phenyl-
MHz, CDCl3); 7.56 (6H, d, J 8.7, 3 × phenyl-H), 7.32 (6H, d, J
8.7, 3 × phenyl-H), 7.07 (6H, t, d, J 2.2, 3 × pyrol-H), 6.33 (6H, t,
J 2.2, 3 × pyrol-H), 5.84 (3H, t, J 6.8, 3 × NCH2CH=), 4.77 (6H,
d, J 6.8, 3 × NCH2CH=), 3.77 (6H, s, 3 × =CCH2N), 2.09 (9H, br
s, 9 × adamantyl-CH), 1.73 (18H, br s, 9 × adamantyl-CH2), 1.66
(18H, br q, J 11.4, 9 × adamantyl-CH2), 1.26 (3H, br s, 3 × NH);
δC (125 MHz, CDCl3); 148.8, 142.5, 140.0, 138.4, 127.5, 122.4,
120.1, 119.1, 110.5, 50.9, 42.6, 41.5, 39.3, 36.8, 29.7; υmax/cm-1
(film); 2904, 2848, 1689, 1608, 1520, 1455, 1330, 1215, 1069;
m/z (ESI+) 1162.6 (100%, MH+); (Found MH+, 1162.6960.
C75H88N9O3 requires 1162.7005).
H), 7.10 (6H, d, J 7.8, 3 × phenyl-H), 5.79 (3H, t, J 7.1, 3 ×
NCH2CH=), 4.73 (6H, d, J 7.1, 3 × NCH2CH=), 3.81 (6H, s, 3 ×
=CCH2N), 2.32 (9H, s, 3 × Me) 2.08 (9H, br s, 9 × adamantyl-
CH), 1.64 (18H, br q, J 12.3, 9 × adamantyl-CH2), 1.25 (3H, br s,
3 × NH); δC (125 MHz, CDCl3); 148.8, 143.2, 138.1, 137.2,
129.0, 126.3, 121.9, 110.8, 50.8, 42.6, 41.5, 39.2, 36.8, 29.7,
21.1; υmax/cm-1 (film); 2904, 2847, 1687, 1454, 1309, 1096; m/z
(ESI+) 1009.6 (100%, MH+); (Found MH+, 1009.6728.
C66H85N6O3 requires 1009.6678). NOE data (CDCl3) for 21:
% Enhancement
Irradiated
proton
4.18. 1,3,5-Tris[(2Z)-4-(8-fluoro-1,3,4,5-tetrahydro-2H-
pyrido[4,3-b]indol-2-yl)-3-phenylbut-2-en-1-yl]-1,3,5-triazinane-
2,4,6-trione (25).
1-H
2-H
4-H
phenyl-H
adamantyl-CH2
1-H
2.54 2.06
-
-
-
-
2-H
1.64
7.95 (δ 7.3)
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with CHCl3

ACCEPTED MANUSCRIPT
7
4.21. 1,3,5-Tris[(2Z)-4-(8-fluoro-1,3,4,5-tetrahydro-2H-
pyrido[4,3-b]indol-2-yl)-3-(pyridin-3-yl)but-2-en-1-yl]-1,3,5-
triazinane-2,4,6-trione (28).
then 9:1 v/v CHCl3/MeOH gave the product 25 as a 87:13
mixture of Z,Z,Z- and Z,Z,E-isomers (82%) as a colourless froth.
Major Z,Z,Z-isomer: δH (500 MHz, CDCl3); 7.72 (3H, br s, 3 ×
pyridoindolyl-NH), 7.43 (6H, td, J 1.6 and 7.6, 3 × phenyl-H),
7.25-7.17 (9H, m, 3 × phenyl-H), 7.05 (3H, dd J, 4.3 and 8.7, 3 ×
pyridoindolyl-H), 7.0 (3H, dd J, 2.1 and 9.3, 3 × pyridoindolyl-
H), 6.78 (3H, dt, J 2.1 and 11.5, 3 × pyridoindolyl-H), 5.89 (3H,
t, J 6.6, 3 × NCH2CH=), 4.75 (6H, d, J 6.6, 3 × NCH2CH=), 3.75
(6H, br s, 3 × =CCH2N), 3.64 (6H, br s, 3 × pyridoindolyl-CH2),
2.79 (6H, br s, 3 × pyridoindolyl-CH2), 2.58 (6H, br s, 3 ×
pyridoindolyl-CH2); δC (125 MHz, CDCl3); 156.7 (J 237.7),
148.9, 141.9, 134.3, 132.3, 128.2, 127.4, 126.6 (J 9.1), 125.9,
111.6 (J 9.1), 109.1 (J 23.4), 108.8 (J 3.66), 102.7 (J 23.4), 56.2,
49.6, 49.3, 41.5, 23.6; υmax/cm-1 (film); 3415, 2918, 1686, 1595,
1458, 1365, 1323, 1232, 1181, 1147, 1085; m/z (ESI+) 1084.4
(100%, MH+); (Found MH+, 1084.4811. C66H61F3N9O3 requires
1084.4844).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with EtOAc
then 5:1 v/v EtOAc/MeOH gave the product 28 as a 86:14
mixture of Z,Z,Z-and Z,Z,E-isomers (70%) as a colourless froth.
Major Z,Z,Z isomer: δH (300 MHz, DMSO); 10.86 (3H, s, 3 ×
NH), 8.71 (3H, d, J 1.4, 3 × pyridyl-H), 8.41 (3H, dd, J 1.4 and
4.8, 3 × pyridyl-H), 7.89 (3H, td, J 1.4 and 8.1, 3 × pyridyl-H),
7.30 (3H, dd, J 4.8 and 8.1, 3 × pyridyl-H), 7.21 (3H, dd, J 4.5
and 9.1, 3 × pyridoindolyl-H), 7.07 (3H, dd, J 2.5 and 10.0, 3 ×
pyridoindolyl-H), 6.79 (3H, dt, J 2.5 and 9.1, 3 × pyridoindolyl-
H), 6.07 (4H, t, J 5.7, 3 × NCH2CH=), 4.77 (6H, d, J 5.7, 3 ×
NCH2CH=), 3.76 (6H, br s, 3 × =CCH2N), 3.63 (6H, br s, 3 ×
pyridoindolyl 1-CH2), 2.84 (6H, br s, 3 × pyridoindolyl-CH2),
2.68 (6H, br s, 3 × pyridoindolyl-CH2); δC (75 MHz, DMSO);
156.6 (J 231.6), 149.0, 148.1, 147.5, 136.5, 136.0, 134.9, 133.7,
132.4, 128.1, 125.7 (J 9.9), 123.1, 111.4 (J 9.9), 107.8 (J 24.2),
107.5 (J 4.4), 101.9 (J 24.2), 54.9, 49.5, 48.9, 40.8, 23.5; υmax/cm-
1 (solid); 3183, 2923, 2385, 1688, 1634, 1588, 1455, 1369, 1324,
1286, 1234; m/z (ESI+) 1087.5 (52%, MH+); (Found MH+,
1087.4675. C63H58F3N12O3 requires 1087.4701). NOE data
(DMSO) for 28:
4.19. 1,3,5-Tris[(2Z)-3-[3,5-bis(trifluoromethyl)phenyl]-4-(8-
fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)but-2-en-1-
yl]-1,3,5-triazinane-2,4,6-trione (26).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2.5 h. Flash chromatography eluting with 19:1
then 9:1 v/v CHCl3/MeOH gave the product 26 as a 87:13
mixture of Z,Z,Z- and Z,Z,E-isomers (64%) as a colourless froth.
Major Z,Z,Z-isomer: δH (300 MHz, CDCl3); 7.92 (6H, br s, 3 ×
pyridoindolyl-NH and 3 × phenyl-H), 7.75 (6H, d, J 13.1,
phenyl-H), 7.11 (3H, dd, J 4.3 and 8.7, 3 × pyridoindolyl-H),
7.02 (3H, dd, J 2.1 and 9.3, 3 × pyridoindolyl-H), 6.80 (6H, dt, J
2.1 and 11.5, 3 × pyridoindolyl-H), 6.0 (3H, t, J 6.4, 3 ×
NCH2CH=), 4.84 (6H, d, J 6.4, 3 × NCH2CH=), 3.80 (6H, br s, 3
× =CCH2N), 3.70 (6H, br s, 3 × pyridoindolyl-CH2), 2.92 (6H, br
s, 3 × pyridoindolyl-CH2), 2.74 (6H, br s, 3 × pyridoindolyl-
CH2); δC (75 MHz, CDCl3); 157.7 (J 233.3), 148.7, 143.4, 138.9,
134.0, 132.3, 131.8 (J 33.1), 128.4, 126.8 (J 3.3), 126.3 (J 9.9),
123.3 (J 273.1), 121.2 (J 3.3), 111.0 (J 9.9), 109.1 (J 26.5), 108.7
(J 4.4), 102.7 (J 24.3), 55.7, 49.9, 48.8, 41.4, 23.5; υmax/cm-1
(film); 3468, 3413, 3022, 2927, 2837, 1695, 1597, 1456, 1382,
1278, 1181, 1134; m/z (ESI+) 1492.4 (100%, MH+); (Found MH+,
1492.4094. C72H55F21N9O3 requires 1492.4087).
% Enhancement
Irradiated
proton
1-H
2-H
4-H
Pyridyl-H
pyridoindolyl-CH2
1-H
-10.6 -5.8
-
-
-
-
-3.0 (δ 8.71)
-1.9 (δ 7.89)
2-H
4-H
-11.2
-4.7
-4.2 (δ 3.63),
4.8 (δ 2.84),
3.1 (δ 2.68)
-
-
4.22. 1,3,5-Tris[(2Z)-4-(8-fluoro-1,3,4,5-tetrahydro-2H-
pyrido[4,3-b]indol-2-yl)-3-(4-methoxyphenyl)but-2-en-1-yl]-
1,3,5-triazinane-2,4,6-trione (29).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with EtOAc
gave the product 29 as a 79:21 mixture of Z,Z,Z- and Z,Z,E-
isomers (78%) as a colourless froth. Major Z,Z,Z-isomer: δH (500
MHz, CDCl3); 7.75 (3H, br s, 3 × pyridoindolyl-NH), 7.39 (6H,
d, J 8.7, 3 × phenyl-H), 7.09 (3H, dd, J 4.1 and 8.4, 3 ×
pyridoindolyl-H), 7.01 (3H, d, J 9.1, 3 × pyridoindolyl-H), 6.78
(6H, d, J 8.7, 3 × phenyl-H), 6.78 (3H, m, 3 × pyridoindolyl-H),
5.85 (3H, t, J 6.6, 3 × NCH2CH=), 4.74 (6H, d, J 6.6, 3 ×
NCH2CH=), 3.74 (15H, br s, 3 × =CCH2N and OCH3), 3.66 (6H,
br s, 3 × pyridoindolyl-CH2), 2.82 (6H, br s, 3 × pyridoindolyl-
CH2), 2.64 (6H, br s, 3 × pyridoindolyl-CH2); δC (125 MHz,
CDCl3); 159.0, 157.6 (J 232.3), 148.8, 140.4, 134.3, 132.3, 127.7,
126.4 (J 9.1), 113.6 (J 9.1), 110.9 (J 23.8), 108.9 (J 3.6), 102.6
(J 23.8), 56.1, 55.2, 49.5, 49.3, 41.5, 23.7; υmax/cm-1 (film); 3405,
2932, 2836, 1690, 1606, 1511, 1458, 1323, 1247, 1181, 1147,
1084, 1035; m/z (ESI+) 1174.5 (100%, MH+); (Found MH+,
1174.5184. C69H67F3N9O6. requires 1174.5161). NOE data
(CDCl3) for 29:
4.20. 1,3,5-Tris{(2Z)-4-(8-fluoro-1,3,4,5-tetrahydro-2H-
pyrido[4,3-b]indol-2-yl)-3-[4-(1H-pyrrol-1-yl)phenyl]but-2-en-
1-yl}-1,3,5-triazinane-2,4,6-trione (27).
Prepared by general procedure A from trisallene 3 in CH3CN
and heating for 2 h. Flash chromatography eluting with CHCl3
then 9:1 v/v CHCl3/MeOH gave the product 27 as a 87:13
mixture of Z,Z,Z-and Z,Z,E-isomers (73%) as a pale yellow
froth. Major Z,Z,Z isomer: δH (500 MHz, CDCl3); 7.73 (3H, br s,
3 × pyridoindolyl-NH), 7.50 (6H, d, J 8.2, 3 × phenyl-H), 7.24
(6H, d, J 8.2, 3 × phenyl-H), 7.09 (3H, dd, J 4.1 and 8.7, 3 ×
pyridoindolyl-H), 7.04 (6H, t,
J 1.8, pyrol-H and 3 ×
pyridoindolyl-H), 6.82 (3H, dt, J 2.2 and 11.6, 3 × pyridoindolyl-
H), 6.32 (6H, t, J 1.8, pyrol-H), 5.94 (3H, t, J 6.4, 3 ×
NCH2CH=), 4.79 (6H, d, J 6.4, 3 × NCH2CH=), 3.78 (6H, br s, 3
× =CCH2N), 3.69 (6H, br s, pyridoindolyl-CH2), 2.84 (6H, br s,
pyridoindolyl-CH2), 2.66 (6H, br s, pyridoindolyl-CH2); δC (75
MHz, CDCl3); 157.7 (J 233.3), 148.7, 140.2, 139.8, 138.8, 134.2,
132.3, 127.7, 126.3 (J 9.9), 125.5, 119.9, 119.1, 111.6, 111.3 (J
9.9), 110.4, 108.8 (J 4.4), 102.7 (J 24.3), 55.9, 49.6, 49.2, 41.5,
23.6. υmax/cm-1 (film); 3395, 1691, 1520, 1455, 1328, 1183, 1070;
m/z (ESI+) 1279.5 (100%, MH+); (Found MH+, 1279.5662.
C78H70F3N12O6 requires 1279.5640).
% Enhancement
Irradiated proton
1-H
1-H
-
2-H
4-H
-
phenyl-H
-4.67
-
-1.80 (δ 6.78),
-1.57 (δ 7.39)
-2.58 (δ 6.78 )
2-H
4-H
-3.33
-
-
-
-1.89 -0.75

ACCEPTED MANUSCRIPT
8
Tetrahedron
4.23. 1,3,5-Tris[(2Z)-4-[3-(3-isopropyl-5-methyl-4H-1,2,4-
Med. Res. Rev. 2005, 25, 21-48; (d) Duque, M. D.; Ma, C.; Torres,
E.; Wang, J.; Naesens, L.; Juarez-Jimenez, J.; Camps, P.; Luque,
F. J.; DeGrado, W. F.; Lamb, R. A.; Pinto, L. H.; Vazquez, S. J.
Med. Chem. 2011, 54, 2646-2657; (e) Foster, T. L.; Verow, M.;
Wozniak, A. L.; Bentham, M. J.; Thompson, J.; Atkins, E.;
Weinman, S. A.; Fishwick, C.; Foster, R.; Harris, M.; Griffin, S.
Hepatology 2011, 54, 79-90; (f) Tran, L.; Choi, S. B.; Al-Najjar,
B. O.; Yusuf, M.; Wahab, H. A.; Le, L. Molecules 2011, 16,
10227-10255; (g) Kolocouris, N.; Zoidis, G.; Foscolos, G. B.;
Fytas, G.; Prathalingham, S. R.; Kelly, J. M.; Naesens, L.; De
Clercq, E. Bioorg. Med. Chem. Lett. 2007, 17, 4358-4362.
triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-3-(pyridin-3-yl)but-2-
en-1-yl]-1,3,5-triazinane-2,4,6-trione (30).
Prepared by general procedure A from 3 in CH3CN and
heating for 3 h. Flash chromatography eluting with 10:7 v/v
EtOAc/MeOH and then 1:1 v/v EtOAc/MeOH gave 30 as a 62:38
mixture of Z,Z,Z and Z,Z,E-isomers (69%) as a colourless froth;
Major Z,Z,Z isomer: δH (300 MHz, CDCl3); 8.86 (3H, d, J 2.4, 3
× pyridyl-H), 8.51 (3H, dd, J 1.4 and 4.8, 3 × pyridyl-H), 7.78
(3H, td, J 1.4 and 9.5, 3 × pyridyl-H), 7.26 (3H, dd, J 4.8 and 9.5,
3 × pyridyl-H), 5.91 (3H, t, J 6.7, 3 × NCH2CH=), 4.82 (6H, d, J
6.7, 3 × NCH2CH=), 4.28-4.15 (3H, m, 3 × azabicyclooctyl-H),
3.64 (6H, s, 3 × =CCH2N), 3.36 (6H, br s, 6 × azabicyclooctyl-
H), 2.94-2.84 (3H, m, 3 × triazolyl 3-CH(CH3)2), 2.34 (9H, s, 3 ×
triazolyl 5-CH3), 2.23-2.13 (6H, m, 6 × azabicyclooctyl-H), 2.03-
1.92 (6H, m, 6 × azbicyclooctyl-H), 1.69-1.59 (12H, m, 12 ×
azabicyclooctyl-H), 1.32 (18H, d, J 7.2, 3 × triazolyl 3-
CH(CH3)2); υmax/cm-1 (film) (isomeric mixture); 3383, 2965,
2878, 1693, 1567, 1514, 1462, 1417, 1345, 1315, 1286, 1251,
1215; m/z (ESI+) (isomeric mixture) 1219.8 (50%, MH+); (Found
MH+, 1219.7538. C69H91N18O3 requires 1219.7516).
NOE data (DMSO) for 30:
% Enhancement
Irradiated
proton
pyridoindolyl-
CH2
1-H
2-H
4-H
-5.8
-
Pyridyl-H
-
1-H
2-H
-10.6
-
-
-3.0 (δ 8.71),
-1.9 (δ 7.89)
-11.2
-4.7
-4.2 (δ 3.63),
4.8 (δ 2.84),
3.1 (δ 2.68)
4-H
-
2.5 (δ 8.41)
Acknowledgments
We acknowledge financial support from the Egyptian
Government, South Valley University, Çankırı Karatekin
University, the Turkish council of higher education (YÖK) and
Leeds University.
References and notes
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