Design, iterative synthesis and structure of novel optically active trispiro-dendritic melamines incorporating 'open-chain' versus 'closed-chain' serinolic peripheral units

Article abstract of DOI:10.1016/j.tetasy.2015.05.003

Abstract Starting from commercial C-2-substituted 2-aminopropane-1,3-diols (serinols, 'open-chain' peripheral units) and optically active amino-1,3-dioxanes ('closed-chain' peripheral units) as cycloacetals of (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-

Full text of DOI:10.1016/j.tetasy.2015.05.003

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Design, iterative synthesis and structure of novel optically active
trispiro-dendritic melamines incorporating ‘open-chain’ versus
‘closed-chain’ serinolic peripheral units
Oana Moldovan a, Iulia Nagy a, Pedro Lameiras b, Cyril Antheaume c, Carmen Sacalis a, Mircea Darabantu a,
⇑
a Babes-Bolyai University, Department of Chemistry, 11 Arany János St., 400028 Cluj-Napoca, Romania
b University of Reims Champagne-Ardenne, ICMR, UMR 7312, BP 1039, 51687 Reims, France
c University of Strasbourg, Faculty of Pharmacy, 74 Rhin St., BP 60024, 67401 Illkirch Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from commercial C-2-substituted 2-aminopropane-1,3-diols (serinols, ‘open-chain’ peripheral
units) and optically active amino-1,3-dioxanes (‘closed-chain’ peripheral units) as cycloacetals of
(1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (p-nitrophenylserinol) or its 2-dimethylamino ana-
logue, we herein report a new series of di- and trimeric G-1 trispiro-dendritic melamines, they were
synthesised convergently by iterative chemoselective amination of cyanuric chloride. Depending on
the number of hydroxymethyl groups in the ‘open-chain’ peripheral unit and the type of the rigid
amino-anchorage (axial or equatorial) of the ‘closed-chain’ counterpart, the classic restricted rotation
about the C(s-triazine)–N(exocyclic) partial double bonds induced, progressively, specific spatial arrange-
ments in angularly connected G-0 and G-1 dendrons, including axial chirality in G-1 dimeric or G-1
trimeric melamines.
Received 2 March 2015
Accepted 1 May 2015
Available online xxxx
Dedicated to Dr. Emil POP
Ó 2015 Elsevier Ltd. All rights reserved.
R2
NH2
1. Introduction
R1
1
2
Serinol is the trivial nomenclature for 2-aminopropane-1,3-diol,
seen as the reduced form of serine, and the parent term of a series
comprising its C-substituted commercial analogues (Scheme 1).1
The resourceful reactivity of C-2-substituted serinols A–C with
electrophiles has been a challenging task in organic synthesis
since the 1940-s.2 Optically active C-1-substituted (1R,2R)-(p-
nitro)phenylserinols are well-known key intermediates in the manu-
facturing of the classical antibiotic Chloromycetin (Chloramphenicol)
as early as 1947.3,4
OH
OH
R2
H
Trivial nomenclature
Serinol
R1
H
C-2-substituted serinols
H
H
H
C-1-substituted Serinols
Ph
Methylserinol (A)
Ethylserinol (
TRIS, THAM (C)
Me
Et
B
)
CH2OH
(1R,2R) or (1S,2S)
"Threo"-phenylserinol
(1R,2R) or (1S,2S)
H
H
In a ‘dendritic context’, it was in 1985, when Newkome et al.5
used TRIS C (Scheme 1) in the preparation of the first so-called ‘ar-
borol’, that the chemistry of dendrimers was born. Later develop-
ments of these ‘cascade syntheses’6 recommended TRIS as a very
practical building-block for such polymeric architectures, because
it could play almost all crucial roles within these innovative struc-
tures: a peripheral unit, a tetravalent branch-cell and a core.5b
Serinol itself, as well as its 5-amino-1,3-dioxane derivatives, are of
interest for iterative construction of macromolecules in
biomedicine7a–e and nanomaterials.7f,g Except for our previously
p-NPh
(p-O2N-C6H4)
p n ph
itro enylserinol
"Threo"-
-
Scheme 1.
reported results,8 no attention, however, has been paid to
methylserinol A and ethylserinol B.
Arising from the pioneering achievements of Simanek et al. in
2000,9 there has been increasing interest in melamine-based den-
drimers. Many approaches to this new class of macromolecules
have been reported first, in the domain of iterative convergent9,10
versus divergent syntheses9,10a,11 by exploiting the ‘classic’ (but
still versatile) chemoselective amination of cyanuric chloride.
⇑
Corresponding author. Tel.: +40 264 59 38 33; fax: +40 264 59 08 18.
E-mail
addresses:
darab@chem.ubbcluj.ro,
m.darabantu@upcmail.ro
(M. Darabantu).
http://dx.doi.org/10.1016/j.tetasy.2015.05.003
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
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2
O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Later on, Simanek et al. described manipulations specifically corre-
lated with the peripheral groups of dendritic melamines.12 Thus,
two major applications of these macromolecules, organic nanoma-
terials13 and vehicles for drug delivery systems,14 were highlighted
and recently reviewed.15
analogue21 upon treatment with equimolar amounts of
p-formaldehyde [?D-NH2 (ax)] or 2,2-dimethoxyethylamine
[?D-NH2 (eq)], respectively, following our ‘sulfuric’ and
non-epimerisable (trans)acetalisation methodology.1,17b,22 By
combining these two types of amino-nucleophiles, we previously
described the convergent manipulation of two tandems, SER-NH2
(A–C)/D-NH2 (ax) and SER-NH2 (A–C)/D-NH2 (eq), up to the G-0
melamine dendrons in a preliminary publication.17e Herein, a
third tandem, D-NH2 (ax)/D-NH2 (eq), is included.
Targeting bioactive N-substituted melamines, the amination of
cyanuric chloride with C-substituted (optionally O,O-‘masked’)
serinols has rarely been mentioned since 1979.16 It was our group
which reported on the developments of this new facet of serinolic
chemistry,17 that is, the convergent synthesis of the first serinolic
G-2 melamine dendrimer incorporating optically active p-nitro-
phenylserinol17a,c or C-2-substituted serinols A–C as peripheral
units.17f These macromolecular melamines manifested interesting
electrochemical properties17g and stereodynamic behaviour.8,17
They both were due to the well-documented restricted rotation
about the C(s-triazine)–N(exocyclic) partial double bonds.18 For
example, this intrinsic structural feature can promote the so-called
‘dendritic choreography’ (Moreno and Simanek in 2008)18l and the
‘open gates–closed gates frontier mechanism’ thereof containing C-
2-substituted serinols A–C (Scheme 1) as peripheral units (our data
in 2012).8 In this context, we recently described the use of mono-8
or trispiranic motifs17f (as peripheral units or linkers, respectively)
in the iterative synthesis of some G-2 and G-1 dendritic
melamines. According to the literature, very few spirane
dendrimers have been reported.19 Therefore, our aim herein con-
sists of the convergent synthesis of new trispiro-dendritic melami-
nes comprising various (O,O-protected)serinols as peripheral units
whose oriented rotamerism about the C(s-triazine)–N(exocyclic)
partial double bonds can induce distinct spatial arrangements,
including axial chirality phenomena at the dendritic scale.
Piperazine (Scheme 2) HN<(L1)>NH is a traditional linker in
dendritic melamines’ chemistry.15,17 Instead, we utilised this
diamino-nucleophile for mono-N-functionalisation, taking into
account its transannular effect13e,f and Simanek’s ‘relative reactivity
maps’,10b referring to
a large variety of monoamines- and
(non)symmetric (di)amines in reaction with cyanuric chloride.23 In
contrast, the trispirotetraacetal diamine linker HN<(L2)>NH
(Scheme 2) was not previously known to play such a role. This
compound was of special interest due to its easily improvable
preparation by double cyclocondensation of pentaerythritol with
the commercially available ‘monohydrate’ of piperidone hydrochlo-
ride (95%, our yield,17f 56%, lit. yield24). With HN<(L2)>NH in hand,
we recently demonstrated17f both its configurational and
conformational chirality using deeper approaches than those of
Dodziuk25 and, later on, of Grosu et al., which focused on spiranic
stereochemistry.26
2.1.2. Synthesis of G-0 melamine dendrons as building blocks
Scheme 3 shows the first three amination steps (i–iii) affording
G-0 melamines 4a–c, 5a–c and 7. As already reported,17e the one-
pot synthesis of G-0 chlorodendrons 2a–c and 3a–c consisted of
the use of C-2-substituted serinols, A–C, as the first amino-
nucleophiles (i) and amino-1,3-dioxanes D-NH2 (ax or eq, (ii) as
the second. In series 2, the inverted addition of reagents caused
lower yields, for example, in the case of 2c, the yields decreased
from 84% to 55%. However, targeting series 3, previous data from
us17b and from others27 supported the (non)-selective interaction
between equimolar amounts of cyanuric chloride and tertiary ami-
nes, that is, the 5-dimethylamino-1,3-dioxane D-NH2 (eq), as side
oligomerisations and demethylation occurred, both in low yield.
Therefore, primary amination with SER-NH2 (A–C), followed by
treatment with D-NH2 (eq), was advised. D-NH2 (eq) was also used
as the second amino nucleophile in the preparation of the new
compound 6. In particular, we noted that the clean aminations
2. Results and discussion
2.1. Synthesis
2.1.1. Starting materials and their designed roles
The starting materials were either commercial or prepared with
a priori designed roles (Scheme 2). SER-NH2 (A–C) were assigned
as ‘open-chain’ peripheral units, while the ‘sugar-like’ anancomeric
amino-1,3-dioxanes17b,20 D-NH2 (ax) or D-NH2 (eq) were
designated as ‘closed-chain’ peripheral units. The optically active
building-blocks are readily available by ring closure of (1S,2S)-p-
nitrophenylserinol (Scheme 1) or its (1S,2S)-N,N-dimethyl
Linkers
NH A C
- )
peripheral units SER-
(
"Open-chain "
:
2
HN
NH
R
NH2
R = Me (A)
HN<(L1)>NH
B
Et (
)
CH2OH (C)
OH
OH
18
21
O
O
peripheral units
"Closed-chain"
D-NH2 ax D-NH eq
:
3
HN15
NH
(
),
(
)
2
O
O
11
HN<(L2)>NH
7,11,18,21-Tetraoxa-3,15-diazatrispiro
[5.2.2.5.2.2] heneicosane
7
NH2
O2N
5
O
O
4
D-NH2 (ax)
(4S,5S)-5-amino-4-( p-nitrophenyl)
-1,3-dioxane
Core, Branch Cell
R
NMe2
X = N, R = Cl
2,4,6-Trichloro- s-triazine
T
O2N
5
O
Cyanuric chloride
X
X
NH2
CH2
O
2
4
X
C
R
CO-Cl
=
=
,
R
X
R
D-NH2 (eq)
Benzene-1,3,5-tricarbonyl
chloride. Trimesic acid trichloride
(2R,4S,5S)-2-aminomethyl-5-dimethyl-
amino-4-( p-nitrophenyl)-1,3-dioxane
Scheme 2.
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O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
SER-NH2 A C D-NH ax
) /
eq
)
Tandems
C3N3Cl3
(
-
(
or
1a–c ? 3a–c and 6 ? 7 were caused, most likely, by the sterically
crowded and rigid location of the axial C-5 dimethylamino group
in D-NH2 (eq).17b The chemoselective attachment of the first
linker (iii) was performed based on our earlier reported
procedures,8,17c–e that is, the portionwise addition of G-0 chloro-
dendrons 2a–c, 3a–c and 6 to a four-fold molar amount of piper-
azine at room temperature. No contamination with dimeric side
products was detected by TLC, NMR or MS in the G-0 melamine
dendrons.
2
Cl
R
N
R = Cl
D (ax): 2a-c
ii
i
D
eq 3a c
( ): -
N
N
N
N
iii
SER-NH
1a*
N
Cl
1c*
SER-NH
NH-D (ax, eq)
A
B
1b* C
;
→
;
→
→
R = piperazin-1-yl
D (ax): 4a (80%), 4b (84%), 4c (86%)
eq 5a 5b 5c
(81%)
D
(
):
(85%),
(67%),
Key
(i): 1 equiv. SER-NH2 (A-C), 1 equiv. K2CO3, THF / 0 oC → r.t. (24 h)
2.1.3. Synthesis of G-1 chloro- and melamine dendrons:
feasibilities and failures
(ii): 1 equiv. D-NH2 (ax or eq), 1 equiv. K2CO3, THF / T (oC), t (h)
iii
): 5×0.2 equiv.
2a c
3a c
- added every 2 h to 4.0 equiv. piperazine, 1.0 equiv.
(
-
or
In the next two steps of our convergent strategy (iv and v,
Scheme 4), we realised the two-fold connexion of G-0 melamines
4a–c, 5a–c and 7 to cyanuric chloride to access G-1 chlorodendrons
8a–c, 9a–c and 11 (iv), and then G-1 trispiranic melamines 10c and
12 (v). Angular dimerisations (iv) occurred in satisfactory to good
yields. Except for compound 9b, all G-1 chlorodendrons required
purification by column chromatography on silica gel (when some
loss of material due to retention, which was observed), followed
by trituration. To ensure chemoselectivity, manipulations started
at low temperatures in THF and continued at room temperature.
In the case of compounds 8a–c and 9a–c, TLC monitoring indicated
that the aminations reached completion only if THF was replaced
by 1,4-dioxane in the final stage. Overall, in the depicted condi-
tions, we avoided side nucleophilic SN2-Ar processes, such as
C-5-N-demethylation,17b,27 during transformations 5a–c ? 9a–c
and C(s-triazine)-alkoxylations.28 On the other hand, our protocols
also revealed the moderate reactivity of melamines 4a–c, 5a–c and
7 with cyanuric chloride. This fact is not quite unexpected, taking
into account their rotamerism combined with strong solvation
(see later discussion in Section 2.2.2) in hydrogen bond acceptor
solvents.18j The results of the two subsequent aminations (v),
8c ? 10c and 11 ? 12, where more forcing conditions (reflux in
1,4-dioxane) had to be applied, supported this analysis. G-1
trispiranic melamines 10c and 12 were successfully purified by
column chromatography on partially deactivated silica gel. The
excess of linker HN<(L2)>NH was easily recovered by a simple
K2CO3, THF / r.t. (24 h)
D
eq
)
Equatorial anchorage of
(
Axial anchorage of D (ax)
T (oC) / t (h)
yield (%)
ii
No.
T (oC) / t (h)
yield (%)
ii
No.
i
(
+
)
i
( +
)
65 / 16
65 / 22
65 / 12
3a
3b
3c
→
→
→
83
42
95
2a
2b
2c
80
66
84
-10
-10
-10
r.t. / 24; 65 / 14
r.t. / 24; 65 / 16
r.t. / 24; 65 / 12
Tandem D-NH2 (ax) / D-NH2 (eq)
Cl
R
R = Cl
6 (94%, i + ii)
i
ii
N
N
N
N
C3N3Cl3
ax D-NH
)
ax D-NH
)
NH-D eq
(
N
1d*
Cl
(
N
(
)
iii
7 (92%), R = piperazin-1-yl
Key
(i): 1 equiv. D-NH2 (ax), 1 equiv. K2CO3, CHCl3 / -5 oC → r.t. (24 h)
(ii): 1 equiv. D-NH2 (eq), 1 equiv. K2CO3 / r.t. (48 h) / reflux (8 h)
iii
(
): 5×0.2 equiv. 6 added every 2 h to 4.0 equiv. piperazine, 1.0 equiv. K2CO3, THF/
r.t. (14 h)
*not isolated ( for the full characterisation of these intermediates, see Ref. [17b, 17c])
Scheme 3.
D (ax)
[G-0]
[G-0]
8a (49%)
N
N
N
O
O
O
O
8b (97%)
8c (84%)
4a-c
N
N
Cl
N
N
N
NH
N
iv
v (8c)
D (eq)
9a (75%)
L2
9b
9c
(74%)
(73%)
= G-0
= G-0
5a c
-
L1
L1
N
N
N
N
10c (83%)
N
N
N
N
(ax or eq) D-NH
(ax) D-NH
NH-SER (A-C)
NH-SER (C)
[G-0]
[G-0]
N
N
N
N
O
O
O
O
iv
v
N
N
Cl
N
N
NH
11
7
(72%)
L2
N
= G-0
= G-0
12 (54%)
L1
L1
N
N
N
N
N
N
N
N
ax D-HN
)
(
(ax) D-HN
NH-D (eq)
NH-D (eq)
Key
(iv): → 8a-c, 9a-c: 0.45 equiv. C3N3Cl3, 1.00 equiv. K2CO3, THF / -15 ºC → r.t. (12 h) / reflux (12 h)
then replacement of THF by 1,4-dioxane, reflux (35 h, 8a, 8c, 9b), (30 h, 8b, 9a), (40 h, 9c)
→ 11
: 0.45 equiv. C3N3Cl3, 1.00 equiv. K2CO3, THF / -12 ºC
→
t.a. (12 h) / reflux (25 h)
10c 12 8c
HN< L2 >NH
, 1.0
(v): →
,
: 5×0.2 equiv.
(or 11) added portionwise every 2 h to 4.0 equiv.
(
)
equiv. K2CO3, 1,4-dioxane / reflux (35 h)
Scheme 4.
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O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
work-up (up to 80% yield, see Section 4.5). In this context, it should
be mentioned that Wessig et al.29 followed a protection–deprotec-
tion strategy in the synthesis of oligomeric spiranes with two
terminal 4-piperidones to prevent unwanted double reactions.
At this stage of our work, we report two failures:
(a) The triple amination of cyanuric chloride by G-1 dendron
10c was unsuccessful. This tentatively yielded a multi-component
crude reaction mixture. The formation of the targeted G-2 den-
dritic melamine could be only deduced by MS (MALDI+) as a con-
stituent of the crude material. Therefore, mono-attachment of
linker HN<(L2)>NH to G-1 chlorodendrons 8a and 8b was not
attempted.
(b) We also failed to follow step (v) based on G-1 chloroden-
drons 9a–c (Scheme 4). The envisaged G-1 melamines, having
the tandem SER-NH (A–C)/D-NH (eq) as peripheral units, appeared
unstable during their preparation and/or their isolation.
Therefore, at this point of our work, we had to keep the ensuing
interest limited to building-blocks 8a–c, 11 and 12, that is, those
mandatory for the presence of the D (ax) N-ligand as the peripheral
unit.
2.2. Structural approach on rotational asymmetry phenomena
about the C(s-triazine)–N(exocyclic) partial double bonds in
G-1, G-2 dendrons and dendrimers
2.2.1. Brief overview of the problem in the case of melamine G-0
dendrons: the syn/anti rotamerism
As we demonstrated in a previous preliminary report,17e each
compound of series 4 and 5 consisted of a four-component
mixture of exchangeable rotamers about the C(s-triazine)–
N(exocyclic) partial double bonds at room temperature. Their
number could be easily predicted following
a topologically
idealised model, which combines the ‘a’ (anti) and ‘s’ (syn) location
of each N-ligand, SER or D (ax, eq), with respect to the piperazine
ligand (Scheme 6).
The same situation was found for the new melamine 7 (not
depicted in Scheme 6) concerning its N-ligands D (ax) versus D
(eq). This is essentially in contrast with other simpler melami-
nes.18d–k In our case, rotamerism was identified by NMR as a
classically entitled ‘slow exchange status between (un)equally
populated sites’.20,30 On the 1D-1H timescale, the supporting num-
ber of broad signals D-NH (ax, eq) and SER-NH (indicative protons)
did not entirely correlate with the number of the expected environ-
ments because of partial overlapping. However, the 2D-1H,1H-COSY
charts, for example, of compounds 4c and 7, disclosed four distinct
cross-peaks as four times the NH-CH 3JH,H couplings. In conclusion,
in melamines 4, 5 and 7, there were two axes of diastereomerism
along the C(-4, -6, s-triazine)–N(exocyclic) bonds. Their discrete
existence prevented us from establishing the exact anti/syn nature
between the rotameric species revealed above using 2D-1H,1H-
NOESY experiments. Upon heating to 80–90 °C, all G-0 melamines
became single mediated structures, in a fast freely rotating status
about all C(s-triazine)–N(exocyclic) connexions.
2.1.4. Synthesis of G-1 dimeric and G-1 trimeric dendrimers
In the final steps of our iterative synthesis, we coupled G-1
chlorodendrons 8a–c and 11 through the trispiranic linker
HN<(L2)>NH (linear connexion, vi) and trimerised G-1 melamine
12 with the use of trimesic acid trichloride (angular connexion,
vii) (Scheme 5). The depicted aminations were viable, in moderate
yields, if the starting G-1 dendrons contained the D (ax) N-ligand
as the main D-NH (ax) peripheral unit. The crude products
required purification by column chromatography and trituration,
while a loss of material was observed. The same synthetic strategy
did not work using G-1 chlorodendrons 9a–c [N-ligands SER (A–
C)/D (eq)], because the targeted compounds decomposed during
preparation and/or column chromatography in the presence of
C1–C3 alcohols, as these were the only suitable solvents for TLC elu-
tion. The tentative trimerisation of 12 in reaction with cyanuric
chloride failed, as it also had been the case starting from 10c (see
Section 1.3). Therefore, a meta-trivalent aromatic partner more
electrophilic than cyanuric chloride, benzene-1,3,5-tricarbonyl
chloride, was considered instead. The G-2 dendrimer 15 was
obtained smoothly, with a satisfactory optimised yield.
2.2.2. Analysis of G-1 dendrons: The (in)/(out) global rotamerism
inducing homo- and heterotopicity of their G-0 branches
Comparative NMR-based structural analyses of G-1 dendrons
8a–c, 9a–c, 10c, 11 and 12 are shown in Table 1.
Chemical shifts and coupling patterns were similar to those of
G-0 precursors.17e Temperature gradients of the indicative NH
protons revealed major differences between the three types of
N-ligands. Although this parameter is appropriate for amide
NH-D ax
(
)
R
Yield (%)
No.
N
T-0
N
SER
A
)
13a
(
38
37
48
46
HN
R
N
N
N
13b SER (B)
SER
C
)
13c
14
(
D
eq
( )
vi
= G-0
8a-c
11
14
3'
N
1
4
[G-0]
T-1'
N
O
O
2'
15
N
3
N
N
N
9
12
T-1
N
6
O
2
N
1'
O
G-0
[
]
3
2
16
[G-0]
NH-D (ax)
N
HN
(eq) D
N
N
T-0
N
15
[G-1]
(56%)
O
N
vii
O
12
= G-0
N
N
N
O
O
[G-1]
N
T-1
N
O
O
O
[G-0]
G-1 =
Key
vii
(vi): 0.48 equiv. HN<(L2)>NH, 1.00 equiv. K2CO3, 1,4-dioxane / reflux (40 h)
): 0.33 equiv. benzene-1,3,5-tricarbonyl chloride, 1.00 equiv. K2CO3, THF / -15 ºC →
(
r.t. (12 h) / 40 ºC (72 h)
Scheme 5.
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O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
H
N
protons in melamines are more negative than ꢀ4 ppb/K in strong
hydrogen bond acceptor solvents,18j such as DMSO-d6, the NH
groups are exposed to the solvent rather than forming
intramolecular hydrogen bonds. On the other hand, a temperature
gradient value less negative than ꢀ4 ppb/K indicates that the NH
group preferentially forms intramolecular hydrogen bonds at
room temperature. In our cases (Table 1), the following order of
temperature gradient values was observed: D-NH (eq)<D-NH
(ax)<SER-NH, denoting the progressive diminishing of the
exposure to solvent in the C(s-triazine)–NH zones. Indeed, the
‘closed-chain’ equatorial anchorage D-NH-C(s-triazine) was
sterically the most permissive to solvation. Conversely, in the
‘open-chain’ N-ligands, the SER-NH protons were involved in
intramolecular hydrogen bonds with the adjacent hydroxymethyl
groups.
H
N
N
N
N
N
N
N
6
N
4
2
SER
H
SER
D (ax, eq)
N
H
N
N
H
N
N
H
D
ax eq
(
,
)
4a-c, 5a-c
(s*-s)
4a c 5a c
- ,
-
(SER-s, D-a*)
H
N
H
N
As expected, higher hydrodynamic diameters (dH) were
observed in the 2D-1H-DOSY NMR charts of compounds containing
the D (eq) N-ligand 9a–c than in dendrons involving the D (ax),
8a–c. Minor changes (12 vs 11) or no increase (10c vs 8c) in the
dH values followed attachment of the trispiranic linker.
From the point of view of restricted rotational phenomena
about the C(s-triazine)–N(exocyclic) partial double bonds, we asso-
ciated the NMR data (Table 1) with the allowance of access
towards a library of angularly built rotational species, with a
36-term theoretical diversity. Their discrimination criteria are
summarised in Scheme 7.
N
N
N
N
N
N
H
D ax eq
( , )
H
H
N
N
N
H
N
N
N
SER
SER
D (ax, eq)
4a-c, 5a-c
(SER-a, D-s)
4a c 5a c
- ,
-
(a-a)
*stereochemical descriptors s (syn) and a (anti) define location
of the N-ligand with respect to the piperazine linker as reference
Thus, the syn/anti local rotamerism comprising of four species
(Scheme 6) was multiplied by an additional one, henceforward
entitled global rotamerism. We designed the global rotational sta-
tus of G-1 dendrons, hitherto unknown in the s-triazine literature,
as of type (in)/(out) (three species) with respect to their angular
Scheme 6.
protons in peptides and proteins,31 it can also be applied to amino-s-
triazines, as established by Moreno and Simanek.18l Following this
extrapolation, if temperature gradient values of ‘amide-like’
Table 1
Relevant 1H NMR data of restricted rotation about C(s-triazine)–N(exocyclic) bonds in G-1 amino-s-triazine dendrons 8a–c, 9a–c, 10c, 11 and 12 (on 500 MHz timescale in DMSO-
d6) and their hydrodynamic diameters
No.
T (K)
dNH (ppm) of the N-ligand and multiplicity
Temperature gradientsa
dH (nm)b
[D (
m2/s)]
l
Tandem
D-NH (ax)
SER-NH (A–C)
D-NH (ax)
ꢀ4.7, ꢀ1.5
SER-NH (A–C)
8a
298
353
298
353
298
353
298
363
5.92, 5.74 (br s)
5.66 (d)c
5.94, 5.79 (br s), 5.70 (br s)
5.64 (d)
6.03, 5.97, 5.84 (br s)
5.71 (br d)
5.98, 5.90, 5.79 (br s)
5.62 (d)
5.74, 5.62 (br s)
5.57 (s)
5.65, 5.48 (br s)
5.44 (s)
5.63, 5.53 (br s)
5.50 (s)
5.59, 5.50 (br s)
5.46 (s)
ꢀ3.1, ꢀ0.9
ꢀ3.8, ꢀ0.7
ꢀ2.4, ꢀ0.5
ꢀ2.0, ꢀ0.6
2.18
[100.2]
2.17
[100.4]
2.18
[100.1]
2.17
8b
8c
ꢀ5.5, ꢀ2.7, ꢀ1.1
ꢀ5.8, ꢀ4.7, ꢀ2.4
ꢀ5.5, ꢀ4.3, ꢀ2.6
10c
[100.5]
Tandem
D-NH (eq)
SER-NH (A–C)
D-NH (eq)
ꢀ9.5, ꢀ6.2
SER-NH (A–C)
ꢀ3.1, ꢀ0.9
9a
298
353
298
353
298
353
6.93, 6.75 (br s)
6.41 (bdd app. bt)d
6.96, 6.73, 6.65 (br s)
6.44 (br s)
7.11, 7.00, 6.83, 6.78 (br s)
6.51 (br s)
5.80, 5.68 (br s)
5.63 (s)
5.68, 5.53 (br s)
5.54 (s)
5.71, 5.54 (br s)
5.60 (s)
2.40
[90.8]
2.46
[88.7]
2.55
[85.7]
9b
9c
ꢀ9.5, ꢀ5.3, ꢀ3.8
ꢀ2.5
ꢀ10.9, ꢀ8.9, ꢀ5.8, ꢀ4.9
ꢀ2.0, ꢀ1.1
Tandem
D-NH (ax)
D-NH (eq)
D-NH (ax)
D-NH (eq)
11
298
363
298
363
5.96, 5.85 (br s), 5.72 (br d)
6.83, 6.78, 6.73, 6.67 (br s)
5.62 (br d)
—
—
—
—
ꢀ5.2, ꢀ3.5, ꢀ1.5
—
—
2.23
[98.0]
ꢀ8.5, ꢀ7.7, ꢀ6.9, ꢀ6.0
6.28 (br s)
12
5.93, 5.88, 5.76, 5.68 (br d)
6.77, 6.65 (br s)
5.57 (br d)
ꢀ5.5, ꢀ4.8, ꢀ2.9, ꢀ1.7
ꢀ8.5, ꢀ6.6
2.63
[83.0]
6.22 (bt)
a
Calculated as (
D
dNH
/
D
T) ꢁ 103 (ppb/K):
D
dNH = [dNH(T) ꢀ dNH(Trt)] < 0;
D
T = (T ꢀ Trt) > 0 (K) where T = 353 (or 363) K and Trt is the room temperature, 298 K.
b
dH (hydrodynamic diameter) issued from D [diffusion coefficient observed in 2D-1H-DOSY NMR charts in 5 mM DMSO-d6
(
g
, dynamic viscosity 2.00 ꢁ 10ꢀ3 kg mꢀ1 sꢀ1) at
298 K] by applying the Stokes–Einstein equation.
c
3
(Broad) doublets with a typical JH,H(ax-NH-5-H-e) = 7.0–9.0 Hz in D (ax) N-ligand of compounds 8a–c and 10c.
Broad doublet of doublets as broad triplet with a JH,H(eq-CH2-NH) = 5.5–6.0 Hz in D (eq) N-ligand of compounds 9a–c and 12.
d
3
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6
O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
R
R = Cl
ΔG≠ = 66.72 0.19 kJ/mol
*
(out)
N
N
of the cavity
T-1**
N 6 N
H
H
N
N
4
N
N
N
N
N
N
SER D
(syn***/anti***)
(
)
SER (D)
(in)
the cavity
T-0**
N
N
N
N
N
(D) SER
D
SER
)
(
H
H
(syn / anti)
8a c 9a c 11
R = Cl ( - , - , ); R =
N< L2 >NH 10c 12
(
)
(
,
)
*Ref. [8], [17c]
**s-Triazines according to generation, 0 or 1
***stereochemical descriptors syn and anti refer to the N-ligand orientations
T-0
against piperazine about the C(s-triazine
)-NH< partial double bonds;
additional stereochemical descriptors (ax) and (eq) were omitted for
reasons of simplicity.
Scheme 7.
Table 2
Proposed criteria for assignment of the (in)/(out) global rotamerism in compounds 8a–c, 9a–c, 11 and 12
Criteria
Proposed assignments
(i) D (eq) > D (ax) > SER (A–C)a; (ii) N-ligand (out) > N-ligand (in)
C.I.P. ranking of the N-ligands
Rotameric arrangements
Non-alternant
Non-alternant
Alternant
(out–out)
D (out)-SER (in)-SER (in)-D (out)
D (eq) (out)-D (ax) (in)-D (ax) (in)-D (eq) (out)
SER (out)-D (in)-D (in)-SER (out)
D (ax) (out)-D (eq) (in)-D (eq) (in)-D (ax) (out)
D (out)-SER (in)-D (in)-SER (out)
D (eq) (out)-D (ax) (in)-D (eq) (in)-D (ax) (out)
(in–in)
(out–in ꢂ in–out)
1H NMR assignment of the indicative NH protonsb,c
In the decreasing order of structural complexity.
D N-ligand
SER N-ligand
dNH-in (in–in) > dNH-in (in–out) > dNH-out (in–out) > dNH-out (out–out)
dNH-in (in–out) > dNH-in (out–out) > dNH-out (in–out) > dNH-out (in–in)
a
b
c
Suggested by the variable vicinity of the most
The basic assignment as dNH D-NH (eq) > dNH D-NH (ax) > dNH SER-NH (A-C) is given (Table 1).
p-deficient rings, s-triazine T-1 and p-nitrophenyl, seen as deshielding factors, that is, dNH-in > dNH-out.
cavity. In Table 2, some proposed criteria for assignment of this
novel stereodynamism are presented.
as [G-01] or [G-02] in the non-alternant (out–out) or (in–in) rota-
mers, respectively, but diastereotopic, [G-01] – [G-02], in the alter-
nant (out–in) one. Moreover, as shown in Scheme 8, the (in)/(out)
rotameric distribution was non-statistical, the decreasing content
of the alternant stereoisomer (T-1)[G-01][G-02] being 8c (80%)>8b
(70%)>8a (60%). Statistics were reasonably established in the case
of the G-1 chlorodendron 11, possessing the tandem
D-NH (ax)/D-NH (eq) as peripheral units.
The same rotational syn/syn local diastereoselectivity was found
in G-1 trispiranic melamines 10c and 12. The content of the
(in)/(out) global arrangements was statistical in 12 and less stereos-
elective in 10c (60% alternant) against 8c (80% alternant).
No rotational diastereoselectivity was observed in series 9, hav-
ing the peripheral tandem SER-NH (A–C)/D-NH (eq). Thus, the
2D-1H,1H-NOESY charts of compounds 9a–c exposed no relevant
magnetic dipolar interactions of type H (piperazine)/H [D (eq)] or
H (piperazine)/H [SER (A–C)], that is, we had to presume that the
entire 36 species rotational diversity referred to compounds 9a–c
only.
Concerning G-1 chlorodendrons 8a–c and 9a–c (Scheme 7), we
previously demonstrated the frozen rotamerism, at room temper-
ature, about the C-4, -6 (s-triazine T-1)–N(piperazine) partial
double bonds with the simpler ‘model compound’, 2-chloro-4,6-
bis(4-oxopiperidin-1-yl)-s-triazine.8,17c
The
2D-1H,1H-NOESY
charts of series 8 (compound 8b, Fig. 1a), whose compounds 8a–c
had the tandem SER-NH (A–C)/D-NH (ax) as peripheral units, were
consistent with the presence of just one type of local rotamerism,
syn/syn. As shown in Scheme 8, the only three resulting (in)/(out)
global rotamers (Table 2) are slowly interchangeable by a single rota-
tion about the (s-triazine T-0)–N(piperazine) bonds/equilibrium.
In spite of inherent overlapping, the step by step integration of
the indicative NH broad singlets of 8b (Fig. 1) was in agreement
with the number of species above. In addition, the 13C NMR spec-
trum (Fig. 1b) supported not more than four distinct magnetic
environments for certain key positions, that is, C-2(6) (p-NPh,
D-ax), C-3(5) (p-NPh, D-ax), C-4, -6 (T-0) and C-4, -6 (T-1). These
key C-nuclei are isochronous in each of the C2 symmetric non-
alternant rotamers but anisochronous in the C1 alternant one.
Furthermore, because the (in)/(out) global rotamerism was
local syn/syn diastereoselective, one must observe the two homo-
morphicà branches [G-0] of compounds 8a–c becoming homotopic§
Therefore, we rationalised the discussion above as follows:
(a) The presence of the D (ax) N-ligand was mandatory for the
syn/anti local rotamerism become syn/syn selective.
(b) Only the tandem of the peripheral units SER-NH (A–C)/D-
NH (ax) can promote the non-statistical (in)/(out) global
rotamerism. The non-statistical rotamerism also depends on the
p-deficiency of the s-triazine T-1 branch-cell (see above, higher
For the use of this ‘simulation method’ in similar cases, see also Ref. 18l.
‘Ligands that are structurally (including configurationally) identical when
detached’ (Ref. 20a).
‘Homomorphic ligands in constitutionally and configurationally equivalent
positions’ (Ref. 20a).
in 8c vs 10c), that is, on the strength of the partial double bond
character of the C(s-triazine T-1)–N(piperazine) bonds.
Our attempt to explain at least the observed syn/syn local stere-
opreference in compounds 8a–c and 10c, recalled some of our
à
§
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O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
7
OH OH
H
N
δNH (ppm)
N
0.15
0.15
8b
D (out)-SER (in)-SER (in)-D (out)
%
N
∼
5.70 5.65
5.65
∼
5.70 15
T-0
N
0.15
0.15
0.70
0.15
0.15
0.70
H
N
0.15
N
SER (out)-D (in)-D (in)-SER (out)
5.48 5.94 5.94 5.48
%
0.70
0.15
0.70
5
6
O
O2N
15
Cl
N
N
O
H
T-1
2
D (out)-SER (in)-D (in)-SER (out) %
N
N
4
5.79
5.65
5.94 5.48
70
piperazine CH2OH
Et
a
p-NPh
H-5-e
↓ ↓
CH2
CH3
↓
b
↑ 2 (T-0)
p-NPh p-NPh
2 (D-ax)
↑4, 6 (T-1)
↑ 4, 6 (T-0)
p-NPh
CH2OH
piperazine
Cq SER (B)
2 (T-1)
4 (D-ax) 6 (D-ax)
5 (D-ax)
Figure 1. (a) 2D-1H,1H-NOESY Chart of compound 8b (on 500 MHz timescale in DMSO-d6 at 298 K) and the relevant magnetic dipolar interactions; (b) 13C NMR spectrum of
compound 8b (on 125 MHz timescale in DMSO-d6 at 298 K); labelling of the active nuclei as ‘C’ was omitted for reasons of simplicity.
previous similar findings showing the influence of dipole–dipole
interactions on diamino-s-triazines containing the D (ax) N-ligand
and an additional stronger electron donor N-group.17b The
examples given herein relate to the piperazine nitrogen N-1 in
G-0 melamines 4a–c versus the N-4 in G-1 chlorodendrons 8a–c
(Scheme 9).
Thus, in 8a–c, a syn-orientation of the D (ax) N-ligand should be
favoured by the dipole–dipole attraction between the two proxi-
mal aromatic rings. The latter are exposed to opposite electronic
repulsive orientation against that of the p-nitrophenyl ring. In
contrast, for the rotational syn option of the SER (A–C) N-ligand,
at the present state of our knowledge, just
a p-stacking
interaction of type –O. . .H. . . (s-triazine) could be invoked. This
p
is in line with the results of Insight II 98 calculations by Fuchs
et al. in 200219a in the case of G-1 dendritic 2,4,8,10-
tetraoxaspiro[5.5]undecanes of some aryl aldehydes. However,
the Fuchs example referred to
tricarbaldehyde as an aromatic branch-cell richer in
a
tris-O,O-protected 1,3,5-
-electrons.
p
influences, the p-deficient benzene ring by the presence of a strong
electron-attracting p-nitro group versus the s-triazine by the elec-
tron-donating ability of the N-4 ‘dialkylated’ piperazine nitrogen. A
similar stabilisation was less plausible in compounds 4a–c because
of the fast acid–base interchange involving the piperazine nitrogen
N-4. We previously discussed this detail as occurring in some G-0
serinolic melamines comprising of the piperazine motif.17e,8 This
dynamic behaviour would create a third dipole moment with a
2.2.3. Analysis of trispiranic G-1, G-2 dendrimers: the incidence
of the axial (pro)chirality promoted by the (in)/(out) global
rotamerism
The main 1H NMR data for the title dendrimers are shown in
Table 3. Except for the normal increase in the dH values, all 1H
parameters, dNH and temperature gradients, were in the range of
those of the G-1 precursors 8a–c, 11 and 12. Therefore, we focused
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8
O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Cl
N
Cl
OH
OH
R
N
N
OH
OH
R
G-02
N
=
= G-02
N
N
N
4
G-01
=
4
2
= G-01
T-1
N
O
N
N
O
O
N
N
O
O2N
N
NO2
NO2
6
N
N
N
N
6
O2N
H
H
N
N
N
N
N
H
H
2
N
N
N
N
T-0
T-1 G-01
)[
N
N
N
N
(
]
2
N
N
4
R
H
H
N
N
H
OH
HO
HO
H
(T-1)[G-02]2
R
O
O
O
O
OH
(out-out): D* (out) - SER (in) - SER (in) - D (out)
(in-in): SER (out) - D (in) - D (in) - SER (out)
Statistics 25% Found 8a
8b
8c
(15%), (10%)
:
.
:
(20%),
Statistics 25% Found 8a
8b
8c
(15%), (10%)
:
.
:
(20%),
R = Me (8a)
8b
Cl
N
Et (
)
CH2OH (8c)
N
N
OH
OH
R
= G-02
G-01
=
O
N
N
O
NO2
N
H
N
N
N
N
N
O2N
H
*the additional stereochemical
descriptor (ax) was omitted
for the sake of simplicity
N
N
N
N
R
N
N
H
OH
H
OH
T-1 G-01 G-02
( )[ ][
]
O
O
(out-in): D (out) - SER (in) - D (in) - SER (out)
Statistics 50% Found 8a
8b
8c
:
.
:
(60%),
(70%),
(80%)
Scheme 8.
our analysis on the prevailing slow-exchange global (in)/(out) rota-
tional stereodynamism in duplicate (compounds 13a–c, 14) or in
triplicate (15), and the syn/syn local stereoselectivity being
rediscovered.
OH
OH
OH
R
OH
H
H
N
8a-c
N
N
R
N
N
4a-c
When G-1 chlorodendrons 8a–c and 11 were linked thorough
N
N
N
the trispiranic linker HN<(L2)>NH, the newly created partial
1
4
0
0
double bonds, C(2)( )[s-triazine T-1( )]–N(3 or 15)(trispirane)
(Scheme 5), required the perpendicular arrangement of the planes
containing the proximal atoms C(2)/C(4)(trispirane)/N(1)/N(3)
(T-1) versus C(14)/C(16)(trispirane)/N(10)/N(30)/(T-10). Due to the
odd number of spiranic carbons in the central linker, a mediated
axis connecting the flipping positions (C-2, T-1)ꢃN(3)ꢃC(6)ꢃC(9)ꢃ
H
H
N
N
N
N
4
1
O2N
O2N
HN
N
O
O
H+
O
O
Scheme 9.
0
0
C(12)ꢃN(15)ꢃ[C-2( ),T-1( )], exists as pseudo-allenic.17f Subsequent
definitions of this axis concern six arrangements as illustrated in
Table 4: achiral (in I and II), proprochiral (in III), prochiral (in IV
and V) and chiral (in VI). Our discrimination takes into account,
once again, the homo- and/or heterotopic– relationship between
the homomorphic [G-0] branches,17f created by the (in)/(out) global
rotamerism, [G-01] and/or [G-02]. As one can see, the axially
(pro)chiral arrangements IV, V and VI are statistically favoured,
each one at 25%. Furthermore, the 1H NMR line shape of the
indicative NH protons (Fig. 2) was consistent with the expected
slow exchange status between the unequally populated sites I–VI.
The same calculations as in the case of the G-1 dendrons (Fig. 1)
provided the rotameric occurrences in 13a–c being different from
statistics although they refer to just one terminal site of the
dendrimer (Fig. 2).
(a) Since statistical calculations resulted in equal contents of
achiral I, II and proprochiral III dendritic species, 6.25% (Table 4),
which were not found experimentally, except in the case of the
peripheries of compound 13b (Fig. 2), we were unable to
predict any ‘rule’ for certain terminal stereoselective couplings
8a–c ? 13a–c. (b) By combining statistics versus experiment, we
could estimate, however, the occurrence of axially prochiral (IV
and V) and axially chiral VI arrangements as shown in Table 4. As
an example calculation in the case of compound 13b, one has the
rotameric abundance of the alternant arrangement, as one type of
one terminal site, as 87% (Fig. 2). This abundance is disseminated,
statistically, in IV (25%) (containing one alternant terminal site), V
(25%) (containing one alternant terminal site) and VI (25%) (con-
taining two alternant terminal sites) in a IV/V/VI = 1:1:1 ratio.
This follows an experimental abundance of 29:29:29%.
Therefore, the following assignments are reasonably limited:
(c) The same approach was applied in the case of compound 14
(Fig. 2, not included in Table 4) by defining its homomorphic
branches [G-0] as [G-01] = [D (eq) (out)][D (ax) (in)](T-0)(L1)-dif-
–
‘Two homomorphic ligands are heterotopic if replacement of each in turn by a
new ligand, not already present at the sites of attachment of the ligands, gives rise to
distinct products’ (Ref. 20a).
ferent from [G-02] = [D (eq) (in)][D (ax) (out)](T-0)(L1)-in
a
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O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
9
Table 3
Relevant 1H NMR data of restricted rotation about C(s-triazine)–N(exocyclic) bonds in G-1 dimeric 13a–c, 14 and G-2 trimeric 15 dendrimers (on 500 MHz timescale in DMSO-d6)
and their hydrodynamic diameters
No.
T (K)
dNH (ppm) of the N-ligand and multiplicity
Temperature gradients
SER-NH (A–C)
d (nm)
[D (
m2/s)]
l
Tandem
D-NH (ax)
SER-NH (A–C)
D-NH (ax)
ꢀ4.9, ꢀ2.5
13a
298
363
298
363
298
363
5.86, 5.70 (br s)
5.54 (d)
5.70, 5.60 (br s)
5.48 (s)
ꢀ3.4, ꢀ1.8
2.89
[75.5]
3.06
[71.4]
3.08
[70.9]
13b
13c
5.87, 5.71 (br s)
5.56 (d)
5.71, 5.59, 5.47 (br s)
5.39 (s)
ꢀ4.8, ꢀ2.3
ꢀ4.9, ꢀ3.1, ꢀ1.2
ꢀ2.0, ꢀ0.6
5.99, 5.91, 5.79 (br s)
5.62 (d)
5.59, 5.50 (br s)
5.46 (s)
ꢀ5.6, ꢀ4.5, ꢀ2.6
Tandem
D-NH (ax)
D-NH (eq)
D-NH (ax)
D-NH (eq)
14
298
363
298
363
5.92, 5.89, 5.76, 5.69 (br s)
6.76, 6.65 (br s)
5.58 (br d)
—
—
—
—
ꢀ5.2, ꢀ4.8, ꢀ2.8, ꢀ1.7
ꢀ8.3, ꢀ6.6
—
—
3.12
[70.0]
6.22 (br s)
15
5.93, 5.90, 5.77, 5.69 (br s)
6.75, 6.64 (br s)
5.57 (br d)
ꢀ5.7, ꢀ5.1, ꢀ3.1, ꢀ1.8
ꢀ8.5, ꢀ6.8
4.20
[52.0]
6.20 (bt)
spirodendritic environment. Calculations gave very similar results
as in the case of precursors 11 and 12 of 14, that is, a statistical rate
of the (in)/(out) global rotamerism.
C-6 in the same s-triazines. Our attempts to explain these differ-
ences started, again, from the statistical manner in which this den-
drimer was built. Thus, the three branches [G-1] were
homomorphic before trimerisation because the syn/syn local and
alternant (in)/(out) global orientations were simultaneously
adopted by the peripheral units. After trimerisation, a sterical
(non)-equivalence as [G-11] = [G-12] – [G-13] appeared. Indeed,
as depicted in Figure 4, following trimerisation, branches [G-11]
and [G-12] had the same orientation of the alternant [G-0] periph-
eries, D (eq) ‘front’/D (ax) ‘rear’. Meanwhile, this order was
inverted in branch [G-13] as D (ax) ‘front’/D (eq) ‘rear’. To conclude,
one has the statistical combination of three elements, [G-11],
[G-12] and [G-13], against just two oriented options, ‘front’/‘rear’.
(c) Axial chirality was present, in triplicate, because, in each
branch [G-11–3], the pseudo-allenic axis mediating positions
AC(@O, amide)ꢃN(3)ꢃC(6)ꢃC(9)ꢃC(12)ꢃN(15)ꢃ(C-2, T-1) bears
two different ligands at each terminal position. In branch [G-13],
one has {[G-11][G-12]m-C6H3} – (@O, amide) against peripheral
[G-01] – [G-02]; in branch [G-12], one has {[G-11][G-13]m-
C6H3} – (@O, amide) against peripheral [G-01] – [G-02]; in branch
[G-11], one has {[G-12][G-13]m-C6H3} – (@O, amide) against periph-
eral [G-01] – [G-02].
On the quantitative 13C NMR time scale, spectra of compounds
13a–c and 14 fully confirmed the desired structures. In continua-
tion of our previous findings with respect to the relevance of
s-triazine C-nuclei integrations disclosing skeleton asymmetries
at the dendritic level,8 the present analysis confirmed and com-
pleted the 1H NMR assignments. As shown in Figure 3, compounds
13a and 14 exhibited more than five of the expected types of s-tri-
azine carbons. Overall, the asymmetry of dendrimers 13a–c and 14
was best revealed as C-anisochrony in s-triazines T-1 branch-cells,
where between two and four dC values were displayed by the
carbon nuclei in positions 4 against 6. It follows that the steric
non-equivalence between dendritic branches, [G-01] – [G-02],
was immediate.
Finally, the most relevant features concerning dendrimer 15 are
illustrated in Figure 4. On the 1H NMR timescale (Fig. 4a), one can-
not distinguish any significant difference between 15 and its pre-
cursors 11 and 12 (Table 1) or its dimeric analogue 14 (Table 2).
The peripheral tandem D-NH (eq)/D-NH (ax) revealed the same
statistical (in)/(out) orientation with respect to the angular cavities.
The quantitative 13C NMR spectrum was much more informa-
tive (Fig. 4).
3. Conclusion
(a) First of all, in the core-region, each of the three different
types of 1,3,5-tricarbonylbenzene C-nuclei showed a unique reso-
nance as CH (123.4 ppm), Cq (148.9) and ˜C@O (168.0).
Starting from optically active amino-1,3-dioxanes of (1S,2S)-p-
nitrophenylserinol (or its dimethylamino analogue), designed as
‘closed-chain’ peripheral units D-NH2 in tandem with commercial
C-2-substituted serinols as ‘open-chain’ peripheral units SER-NH2,
we have described the iterative synthesis and structure of a new
family of G-1 dimeric and G-1 trimeric spirodendritic melamines.
In our convergent strategy, we omitted protection–deprotection
steps. The entire chemistry was feasible only if the anancomeric
amino-1,3-dioxane building-block had the amino group in an axial
C-5 position D-NH2 (ax), in partnership with SER-NH2 or an anan-
comeric amino-1,3-dioxane possessing an aminomethyl group
located in the equatorial C-2 position, D-NH2 (eq). The first use
of a trispirotetraacetal diamine linker was reported, together with
its versatile aptitude to be chemoselectively attached to elabo-
rated, N,N0-unsymmetrically substituted chlorodiamino-s-triazines
as G-1 chlorodendrons. Some (un)surmountable synthetic prob-
lems originated from the restricted rotational phenomena in
amino-s-triazines about their C(s-triazine)–N(exocyclic) partial
Therefore,
a
propeller arrangement18j of the three dendritic
branches [G-11], [G-12] and [G-13] around the proximity of the
core was deduced. However, this C3 symmetric organisation
concerned only the central part of the macromolecule.
(b) Furthermore, we followed the same postulated rules with
respect to dC values as those already listed in Figure 3. Thus, certain
unequal integrations of the s-triazine T-1 carbons (Fig. 4b) indi-
cated two unexpected situations of anisochrony. The integrals of
each of the anisochronous carbons C-4 and C-6 in s-triazines
T-1[G-11,2] (dC-4 – dC-6) were double compared with the integral
of the anisochronous carbons C-4 and C-6 (dC-4 – dC-6) in s-triazi-
nes T-1[G-13]. Next, the integral of the isochronous carbons C-2
in s-triazines T-1[G-11,2] was also double versus the integral refer-
ring to the anisochronous C-2 carbon in s-triazine T-1[G-13], that
is, dC-2, T-1[G-11] = dC-2, T-1[G-12] – dC-2, T-1[G-13]. All peripheral
C-4 carbons in branch-cells T-0[G-11–3] were isochronous, as were
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10
O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Table 4
Possible co-orientations of global rotamers (in)/(out) (alternant vs non-alternant) in dimeric G-1 dendrimers 13a–c
Nature of the pseudo-allenic axis mediating positions
Possible co-orientations of rotamers and their statistical versus experiment calculated abundances
0
0
(C-2-T-1)ꢃN(3)ꢃC(6ꢃ9ꢃ12)ꢃN(15)ꢃ[C-2( )-T-1( )
I. Achiral
]
Non-alternant versus non-alternant identical:
(out–out) versus (out–out)
in [G-01]2(T-1)-(L2)-(T-1)[G-01]2
a
Branches [G-01]: homotopic
L2
[G-01]
[G-01]
[G-01]
3
6
9
12 15
(T-1)
(L1)
N∼∼C∼∼C∼∼C∼∼N
(T-1)
= G-01
T-0
(
)
SER (in)
D (out)
Statistics: 6.25%; found: —
II. Achiral
Non-alternant versus non-alternant identical:
(in–in) versus (in–in)
in [G-02]2(T-1)-(L2)-(T-1)[G-02]2
Branches [G-02]: homotopic
[G-02]
L2
[G-02]
[G-02]
T-1
∼∼ ∼∼ ∼∼ ∼∼
C C C N
(
)
N
(T-1)
(L1)
T-0
= G-02
(
)
D (in)
SER (out)
Statistics: 6.25%; found: —
III. Proprochiral
Non-alternant versus non-alternant different:
(out–out) versus (in–in)
in [G-01]2(T-1)-(L2)-(T-1)[G-02]2
Branches [G-01]: homotopic
Branches [G-02]: homotopic
[G-01]
[G-02]
L2
(T-1)
N∼∼C∼∼C∼∼C∼∼N
(T-1)
[G-02]
[G-01]
Statistics: 12.5%; found: —
Alternant versus non-alternant:
(out–in) versus (in–in)
IV. Prochiral
in [G-01][ G-02](T-1)-(L2)-(T-1)[G-02]2
Geminal [G-02]2 branches: enantiotopic
[G-01]
[G-02]
L2
T-1
T-1
)
(
)
N∼∼C∼∼C∼∼C∼∼N
(
[G-02]
[G-02]
Statistics: 25%
Found: 13a (20%), 13b (29%), 13c (20%)
Alternant versus non-alternant:
(out–in) versus (out–out)
V. Prochiral
in [G-01][G-02](T-1)-(L2)-(T-1)[G-01]2
Geminal branches [G-01]2: enantiotopic
[G-01]
[G-01]
[G-01]
L2
T-1
T-1
)
(
)
N∼∼C∼∼C∼∼C∼∼N
(
[G-02]
Statistics: 25%
Found: 13a (20%), 13b (29%), 13c (20%)
Alternant versus alternant:
(out–in) versus (out–in)
VI. Chiral
in [G-01][G-02](T-1)-(L2)-(T-1)[G-01][G-02]
Branches [G-01]: enantiotopic
Branches [G-02]: enantiotopic
D (out)
D
out
(
)
T-0
(L1)
(
)
SER (in)
(T-0)
SER (in)
L2
∼∼ ∼∼ ∼∼ ∼∼
(L1)
T-1
T-1
(
(
)
N
C
C
C
N
)
(L1)
(T-0)
(L1)
D
(in)
D
in
( )
T-0
(
)
SER
(out)
SER (out)
Statistics: 25%
Found: 13a (20%), 13b (29%), 13c (20%)
a
Additional labelling as (ax), A–C, (‘) and (‘‘) were omitted for reasons of simplicity as well as ANHA and ˜NA bridges.
double bonds, combined with solvation effects. This classic feature
was gradually rediscovered in our chemistry. Angular dimerisation
of G-0 melamines yielded G-1 chlorodendrons as libraries with an
expected 36 rotational term topological diversity. Nevertheless, the
tandems of peripheral N-ligands SER/D(ax) and D (ax)/D (eq)
demonstrated their existence as only three global (in)/(out) non-
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O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
11
13a D-NH (ax)
SER-NH (A)
13b D-NH (ax)
SER-NH (B)
∼ 5.65
1.20
1.20
0.30
0.30
0.50
0.50
1.75
0.13
0.13
1.75
0.13
1.20
0.50
0.50
1.75
1.75
0.13
0.13
1.20
0.13
0.13
0.30
0.30
0.13
δNH (ppm): D (out)-SER (in)-SER (in)-D (out)
5.70 5.70 5.70 5.70
SER (out)-D (in)-D (in)-SER (out)
5.60 5.86 5.86 5.60
%
δNH (ppm): D (out)-SER (in)-SER (in)-D (out)
5.71 5.65 5.65 5.71
SER (out)-D (in)-D (in)-SER (out)
5.47 5.87 5.87 5.47
%
25
%
6.5
%
15
6.5
D (out)-SER (in)-D (in)-SER (out) %
D (out)-SER (in)-D (in)-SER (out) %
5.70
5.70
5.86 5.60
60
5.71
5.59
5.87 5.47
87.0
13c D-NH (ax)
SER-NH (C)
14 D-NH (eq)
D-NH (ax)
0.96
0.54
0.54
0.96
0.48
0.48
0.96
0.96
1.18
0.33
0.33
1.18
0.50
0.50
1.18
0.33
0.33
0.48
0.48
0.54
0.54
1.18
0.50
0.50
δNH (ppm):D (out)-SER (in)-SER (in)-D (out)
5.79 5.59 5.59 5.79
SER (out)-D (in)-D (in)-SER (out)
5.50 5.99 5.99 5.50
%
δNH (ppm): D (eq) (out)-D (ax) (in)-D (ax) (in)-D (eq) (out)
6.65 5.92 5.92 6.65
D (ax) (out)-D (eq) (in)-D (eq) (in)-D (ax) (out)
5.69 6.76 6.76 5.69
D (eq) (out)-D (ax) (in)-D (eq) (in)-D (ax) (out) %
6.65 5.89 6.76 5.76 49
%
16
%
24
%
27
25
D (out)-SER (in)-D (in)-SER (out) %
5.79
5.59
5.90 5.50
59
Figure 2. Rotameric (in)/(out) abundance in dendrimers 13a–c and 14 with respect to one terminal site (details from 1H NMR of the indicative protons NH zone on 500 MHz
timescale in DMSO-d6 at 298 K).
statistical arrangements with respect to the angular cavity,
because the local G-0 rotamerism became syn–syn diastereoselec-
tive. First discrimination of G-1 rotameric dendrons in terms of
homo- and heterotopicity of their [G-0] branches was discussed.
gradient intensity values were equally spaced from 2% to 95%. For
getting 2D-1H,1H-NOESY Experiments, the mixing times were from
550 to 900 ms. In the NMR descriptions, some specific abbreviations
were used: ‘br d’ (broad doublet), ‘br t’ (broad triplet), ‘bdd’ (broad
doublet of doublets), ‘brm’ (broad multiplet), Pip (Piperazine linker),
p-NPh (p-nitrophenyl), Tsp (trispirane linker), T-0, -1 (s-triazine,
branch cell), SER A–C, D-ax, D-eq (peripheral N-ligand, Scheme 2).
TLC was performed by using aluminium sheets with silica gel 60
F254 (MerckÒ); column chromatography was conducted on Silica
gel Si 60 (40–63 mm, MerckÒ). IR spectra were recorded on a
JASCOÒ FT-IR 6100 Spectrometer. Only relevant absorption maxima
are listed, throughout, in cmꢀ1: s (strong), m (medium) and w
(weak). Microanalyses were performed on a Carlo ErbaÒ CHNOS
1160 apparatus. Mass spectra were carried out as follows: ESI spec-
tra on a BrukerÒ Esquire Instrument with ions trapping in electro-
spray mode; MALDI spectra on Micromass TOF-SpecE MALDIÒ
Instrument equipped with a time of flight analyser and a nitrogen
Finally, linear connexion of G-1 chlorodendrons through
a
trispirotetraacetalic diamine linker gave G-1 dimers exhibiting
axial (pro)chirality promoted by the heterotopic nature of the
[G-0] branches. Angular trimerisation of a G-1 spirodendritic mel-
amine allowed the detection of axial chirality in triplicate, based on
the same concepts as above, in the resulting G-2 dendrimer.
4. Experimental
4.1. General
Melting points were carried out on ELECTROTHERMALÒ instru-
ment. Conventional NMR spectra were recorded on a BrukerÒ AM
300 instrument operating at 300 and 75 MHz for 1H and 13C nuclei,
respectively. VT 1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-NOESY, 2D-1H-
DOSY NMR, Quantitative and 13C-DEPT experiments were recorded
on BrukerÒ AV 400 or 500 instruments operating at 400 or 500 MHz
for 1H and at 100 or 125 MHz for 13C nuclei. All chemical shifts (d val-
ues) are given in parts per million (ppm); all homocoupling patterns
(nJH,H values) are given in Hertz. For determining 13C NMR quantita-
tive integration, all 1D-13C spectra were acquired using the inverse
gated proton decoupling pulse sequence: zgig. All 2D-1H-DOSY
spectra were performed using the ledbpgp2s pulse sequence: 2D
sequence for diffusion measurement using stimulated echo and lon-
pulsed laser (337 nm). Specific rotations [a]
20 were measured on a
D
POLAMATÒ Karl-Zeiss Jena instrument All reagents and solvents
were of commercial quality and used as such with no supplementary
purification. The starting (1S,2S)-2-amino-1-(4-nitrophenyl)-
propane-1,3-diol had a 99% enantiomeric purity. Synthesis and
data of compounds 2–5a–c are reported elsewhere.17e
4.2. 2-Chloro-4-{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-
1,3-dioxan]-2-yl}methylamino-6-[(4S,5S)-4-(4-nitrophenyl)-1,
3-dioxan-5-yl]amino-s-triazine 6
To anhydrous K2CO3 (0.80 g, 5.80 mmol) suspended in anhy-
drous CHCl3 (100 mL), freshly prepared (4S,5S)-5-amino-4-(4-ni-
trophenyl)-1,3-dioxane D-NH2 (ax) (1.30 g, 5.80 mmol) was
gitudinal eddy current delay (LED). The diffusion times (D) were
from 150 to 250 ms and the gradient pulse lengths (d) were from
1.5 to 2 ms. The size of the raw data sets were 32 ꢁ 8192. The
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12
O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
δC (ppm)
6(4)
N
s-triazine T-1
s-triazine T-0
2
N<(L2)>N-
N
T-1
C-2
C-4, -6
C-2 C-4
C-6
No.
13a
4(6)
N
164.3 164.6
164.4 164.9
164.6
165.3 165.7 165.4
N
Postulated decreasing order
>
)
of the deshielding of s-triazine
carbons (δC) according to their
substituents and π-deficiency
L1
(
<
164.6 164.6
164.9
164.5 164.5
164.9
165.3 165.6 165.4
13b
13c
N
2
N
6
N
upfield
δC C-2 (T-1)
(4)
165.3 165.6 165.3
165.4
N
H
T-0
δC C-4(6) (T-1)
4(6)
N
N
δC C-2 (T-0)
165.3
165.6
δC SER (A-C) at C-6 (T-0)
δC D (ax) at C-4(6) (T-0)
δC D (eq) at C-4 (T-0)
H
164.6 164.76
164.7 164.82
164.9
165.3 165.76 166.1
165.7 166.1
14
downfield
165.3
2 (T-0)
13b
13a
6 (T-0)
2 (T-0)
2 (T-1)
4(6) (T-1)
2 (T-1)
4(6) (T-1)
4 (T-0)
4 (T-0)
6 (T-0)
6(4) (T-1)
2 (T-1)
6(4) (T-1)
Σ = 18.002
Σ = 18.002
4(6) (T-1)
2 (T-0)
6 (T-0)
4 (T-0)
6 (T-0)
13c
14
2 (T-0)
2 (T-1)
4(6) (T-1)
4(6) (T-1)
4 (T-0)
2 (T-0)
4 (T-0)
6 (T-0)
6 (T-0)
2 (T-1)
6(4) (T-1)
Σ = 17.992
Σ = 18.00
Figure 3. Details from the quantitative 13C NMR spectra of dendrimers 13a–c and 14 in the s-triazines region (on 125 MHz time scale in DMSO-d6 at 298 K); labelling of the
active nuclei as ‘C’ as well as their discrimination with additional symbols (‘) and (‘‘) was omitted for reasons of simplicity.
3
added with vigorous stirring. The resulting suspension was cooled
at ꢀ5 °C when cyanuric chloride (1.07 g, 5.80 mmol) was added.
The reaction mixture was then allowed to gently reach room tem-
perature and was kept as such for an additional 24 h. After this
period, TLC monitoring indicated the intermediate 2,4-dichloro-
6-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-s-triazine
1d as a single spot (ligroin/acetone 1.5:1 v/v, Rf = 0.90). Freshly pre-
pared (2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-1,3-diox-
ane D-NH2 (eq) (1.60 g, 5.80 mmol) and anhydrous K2CO3 (0.80 g,
5.80 mmol) were added and the reaction mixture was stirred at
room temperature for 48 h then heated at reflux (60 °C) for addi-
tional 8 h (TLC monitoring, ligroin/acetone 1.5:1 v/v). When
D-NH2 (eq) and 1d were detected in small traces only, the reaction
mixture was cooled at room temperature. Minerals were filtered
off and washed with anhydrous CHCl3. The organic filtrate was
evaporated under reduced pressure to dryness to provide 3.80 g
of crude product. This was purified by trituration from Et2O/THF
3:1 (v/v) mixture at ꢀ20 °C to give 3.36 g pure 6 (94% yield with
respect to cyanuric chloride). Yellowish powder, mp 110–112 °C.
Found: C, 50.74; H, 5.05; N, 17.88; C26H29ClN8O8 (616.18) requires:
C, 50.61; H, 4.74; N, 18.16; Rf (60% ligroin/acetone) 0.83; IR mmax
(KBr) 3318 (m), 2936 (m), 2858 (m), 2858 (m), 2791 (m), 1575
(s), 1519 (s), 1408 (w), 1346 (s), 1153 (m), 1173 (s), 1083 (s),
2, -6, p-NPh), 7.65 (2H, d, JH,H = 9.0 Hz, H-2, -6, p-NPh), 8.11 (2H,
3
3
d, JH,H = 8.5 Hz, H-3, -5, p-NPh), 8.15 (2H, d, JH,H = 8.5 Hz, H-3,
-5, p-NPh) ppm; 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC
43.8 (NMe2), 44.16, 44.21, 44.3 (CH2NH), 49.3, 49.5, 49.6 (C-5, D-
ax), 58.5 (C-5, D-eq), 64.4, 64.5, 64.6 (C-6, D-eq), 70.0, 70.1, 70.4,
70.5 (C-6, D-ax), 78.2, 78.3, 78.5 (C-4, D-ax), 79.95, 79.98, 80.07,
80.11, 80.3 (C-4, D-eq), 93.88, 93.94 (C-2, D-ax), 98.9, 99.05,
99.13, 99.2 (C-2, D-eq), 123.18, 123.23, 123.3 (C-2, -6, p-NPh),
127.0, 127.6, 127.7, 127.8 (C-3, -5, p-NPh), 146.70, 146.74,
146.76, 146.82, 147.1, 148.7, 148.8 (C-1, -4, p-NPh), 165.4, 165.5,
165.6, 165.68, 165.74, 165.85, 165.9, 166.0 (C-4, -6, s-triazine),
168.2, 168.4, 168.6, 169.0 (C-2, s-triazine) ppm; MS (ESI+) m/z
(rel. abund.%) 617.13 (M+H) (100); [a]
20 = +160.1 (0.5% DMSO).
D
4.3. 1-{4-{[(2R,4S,5S)-5-(Dimethylamino)-4-(4-nitrophenyl)-1,3-
dioxan]-2-yl}methylamino-6-[(4S,5S)-4-(4nitrophenyl)-1,3-dio-
xan-5-yl]amino-s-triazin-2-yl}-piperazine 7
In a solution obtained by dissolving anhydrous piperazine
(1.23 g, 14.26 mmol) in anhydrous THF (125 mL), anhydrous
K2CO3 (0.49 g, 3.57 mmol) was suspended at room temperature
with vigorous stirring. To this suspension, chlorodiamino-s-triazine
6 (2.20 g, 3.57 mmol) was added portionwise (5 equal portions,
0.44 g 6/portion, every 2 h). After each addition and within 2 h,
TLC monitoring indicated the completion of reaction as follows:
total consumption of 6 (ligroin/acetone = 1.5:1 v/v, visualisation in
UV 254 nm) and formation of 7 (EtOH/aq NH3 25% = 9:1 v/v,
Rf = 0.78, double visualisation, UV 254 nm then I2 bath). Finally,
the reaction mixture was stirred at room temperature for additional
24 h. Minerals were filtered off and well-washed with anhydrous
THF. The combined THF solution was evaporated under reduced
pressure to yield 2.32 g crude material which was purified by
1030 (s), 966 (m), 846 (m), 805 (m), 748 (m), 709 (m) cmꢀ1 1H
;
NMR, 2D-1H,1H-COSY, 2D-1H,1H-NOESY (500 MHz, DMSO-d6,
363 K) dH 2.23 (6H, s, NMe2), 2.89 (1H, s, H-5-e, D-eq), 3.46 (2H,
br s, CH2NH), 3.99 (1H, br s, H-6-a, D-eq), 4.04 (1H, br s, H-6-a,
D-ax), 4.11 (1H, br s, H-6-e, D-ax), 4.45 (2H, br s, H-5-e, D-ax;
2
H-6-e, D-eq), 4.93 (1H, s, H-2-a, D-eq), 4.99 (1H, d, JH,H = 5.8 Hz,
2
H-2-a, D-ax), 5.18 (1H, s, H-4-a, D-eq), 5.22 (1H, d, JH,H = 5.8 Hz,
H-2-e, D-ax), 5.26 (1H, s, H-4-a, D-ax), 6.87, 7.05 (1H, br s, D-ax-
3
NH), 7.31, 7.53, (1H, br s, D-eq-NH), 7.63 (2H d, JH,H = 8.5 Hz, H-
Please cite this article in press as: Moldovan, O.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.05.003

O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
13
a
D-NH (eq)
D-NH (ax)
H
N
D (eq) (in)
D (ax) (in)
N
H
N
N
H
N
N
1.40
1.40
0.75
0.75
6
1.40
1.40
0.75
0.75
D (ax) (out)
= G-02
N
G-01 =
N
0.75
0.75
0.75
0.75
2
N
N
T-0
N
N
6
4
N
N
H
N T-1
N
4
N
2
D (eq) (out)
N
δNH (ppm): D (eq) (out)-D (ax) (in)-D (ax) (in)-D (eq) (out)
6.64 5.93 5.93 6.64
D (ax) (out)-D (eq) (in)-D (eq) (in)-D (ax) (out)
5.67 6.75 6.75 5.67
%
26
%
O
25
O
D (eq) (out)-D (ax) (in)-D (eq) (in)-D (ax) (out) %
6.64
5.90
6.75
5.77
49
O
H
O
D (ax) (out)
N
N
H
N
G-11
=
N
N
N
T-0
O
D (eq) (in)
N
O
= G-12
"Propeller"
T-1
arrangement
N
N
O
= G-02
= G-01
N
O
N
6
N
15
N
12
O
N
9
3
O
O
O
N
O
= G-13
N
N
N
D (ax) (in)
N
N
N
O
O
H
D (eq) (out)
H
b
N
T-1
D (ax) (out)
N
N
N
4(6) T-1[G-11,2
4(6) T-1[G-13]
2 T-1[G-13]
]
H
N
N
= G-01
N
N
2
N
N
N
T-0[G-11-3
]
G-02
D (eq) (in)
=
6
]
N
H
6(4) T-1[G-13]
6(4) T-1[G-11,2
T-0[G-11-3
]
N
D (eq) (out)
N
T-0
N
2 T-1[G-11,2
]
4
N
H
T-0[G-11-3
]
N
N
H
D (ax) (in)
Σ = 27.001
Figure 4. Deduced main structure of dendrimer 15. (a) Detail from the 1H NMR spectrum in the D-NH indicative protons region (on 500 MHz timescale in DMSO-d6 at 298 K);
(b) detail from Quantitative 13C NMR spectrum in the s-triazines region (on 125 MHz time scale in DMSO-d6 at 298 K).
trituration from a Et2O/THF 3:1 (v/v) mixture at ꢀ20 °C to give 2.19 g
pure 7 (92% yield with respect to 6). Orange-yellowish powder, mp
155–157 °C (Et2O/THF = 3:1). Found: C, 54.29; H, 6.06; N, 20.88;
127.4, 127.49, 127.51, 127.55, 127.57 (C-3, -5, p-NPh), 146.7,
146.98, 147.00, 147.04, 147.2, 149.0 (C-1, -4, p-NPh), 164.63,
164.67, 164.71 (C-2, s-triazine), 165.70, 166.1 (C-4, -6, s-triazine)
ppm. MS (ESI+) m/z (rel. abund.%) 667.27 (M+H) (100);
C30H38N10O8 (666.29) requires: C, 54.05; H, 5.75; N, 21.01; Rf (90%
EtOH/aq NH3 25% v/v) 0.78; IR mmax (KBr) 2936 (m), 2852 (m),
2791 (m), 1578 (s), 1545 (s), 1522 (s), 1444 (m), 1346 (s), 1173
(m), 1095 (m), 1028 (m), 1016 (m), 849 (w), 807 (m), 709 (m)
[a]
20 = +112.0 (0.5% DMSO).
D
4.4. Typical procedure for the synthesis of compounds 8a–c, 9a–
c and 11. Preparation of compound 8c
;
cmꢀ1 1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-NOESY (500 MHz,
DMSO-d6, 363 K) dH 2.23 (6H, s, NMe2), 2.62–2.64 (4H, m, H-3, -5,
3
Pip), 2.86 (1H, dd app. t, JH,H = 2.8 Hz, H-5-e, D-eq), 3.45 (2H, dd
Anhydrous K2CO3 (0.38 g, 2.76 mmol) was suspended, at room
temperature and with vigorous stirring, in a solution obtained by
dissolving compound 4c (1.40 g, 2.76 mmol) in anhydrous THF
(120 mL). The resulting suspension was cooled at ꢀ15 °C when
cyanuric chloride (0.23 g, 1.26 mmol) was added. The reaction
mixture was allowed to reach room temperature and was kept
as such for additional 12 h with stirring. THF was replaced by
1,4-dioxane and the reaction mixture was refluxed for additional
35 h when TLC monitoring (Toluene/EtOH = 2:1 v/v) confirmed
the formation of 8c. Minerals were filtered off and well-washed
with anhydrous 1,4-dioxane. The combined 1,4-dioxane solution
was evaporated under reduced pressure to yield 1.54 g crude
material which was purified by flash column chromatography
(eluent Toluene/EtOH = 2:1 v/v). The isolated 8c (1.50 g) was
then triturated from a Et2O/THF 4:1 (v/v) mixture at ꢀ20 °C to
give the pure product (1.18 g 8c, 84% yield with respect to
cyanuric chloride).
3
3
app. t, JH,H = 3.5 Hz, CH2NH), 3.50 (4H, t, JH,H = 5.0 Hz, H-2, -6,
Pip; 1H, H-4, Pip), 3.96 (1H, dd, JH,H = 12.5 Hz, JH,H = 3.0 Hz, H-6-
2
3
2
a, D-eq), 4.02 (1H, d, JH,H = 10.9 Hz, H-6-a, D-ax), 4.10 (1H d,
2JH,H = 10.9 Hz, H-6-e, D-ax), 4.45 (1H d, JH,H = 12.5 Hz, H-6-e, D-
2
3
eq), 4.46 (1H, d, JH,H = 8.0 Hz, H-5-e, D-ax), 4.92 (1H, dd app. t,
3JH,H = 4.8 Hz, H-2-a, D-eq), 4.99 (1H, d, 2JH,H = 5.8 Hz, H-2-a, D-ax),
5.16 (1H, d, 3JH,H = 3.5 Hz, H-4-a, D-eq), 5.22 (1H, d, 2JH,H = 5.8, H-2-
3
e, D-ax), 5.23 (1H, s, H-4-a, D-ax), 5.49 (1H, d, JH,H = 8.0 Hz, D-
ax-NH), 6.12 (1H, br s, D-eq-NH), 7.62 (2H, d, 3JH,H = 9.0 Hz, H-2, -6,
3
p-NPh), 7.63 (2H, d, JH,H = 8.5 Hz, H-2, -6, p-NPh), 8.09 (2H, d,
3JH,H = 8.5 Hz, H-3, -5, p-NPh), 8.14 (2H, d, 3JH,H = 9.0 Hz, H-3, -5, p-
NPh) ppm; 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC 43.8
(NMe2), 44.2, 44.3 (C-2, -6, Pip; CH2NH), 46.0 (C-3, -5, Pip), 48.6,
48.79, 48.84 (C-5, D-ax), 58.5 (C-5, D-eq), 64.4 (C-6, D-eq), 70.7,
70.8 (C-6, D-ax), 78.9 (C-4, D-ax), 80.1 (C-4, D-eq), 94.0 (C-2, D-ax),
99.8 (C-2, D-eq), 123.19, 123.23, 123.4 (C-2, -6, p-NPh), 127.0,
Please cite this article in press as: Moldovan, O.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.05.003

14
O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
4.4.1. 2-Chloro-4,6-bis{4-{6-{[1,3-dihydroxy-2-(methyl)prop-2-yl]-
amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-
s-triazin-2-yl}-piperazin-1-yl}-s-triazine 8a
4.4.3. 2-Chloro-4,6-bis{4-{6-{[1,3-dihydroxy-2-(hydroxymethyl)-
prop-2-yl]amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-
yl]amino}-s-triazin-2-yl}-piperazin-1-yl}-s-triazine 8c
Yield 49% (0.59 g, 0.54 mmol) 8a starting from 1.20 g
(2.45 mmol) 4a and 0.21 g (1.11 mmol) cyanuric chloride.
Yellowish powder, mp 226–229 °C (flash column chromatogra-
phy, eluent Toluene/iPrOH = 3:1 v/v). Found: C, 49.51; H, 5.51;
N, 23.99; C45H58ClN19O12 (1091.42) requires C, 49.47; H, 5.35;
N, 24.36; Rf (75% Toluene/iPrOH) 0.60; IR mmax (KBr) 3394 (m),
2862 (m), 1560 (s), 1494 (s), 1439 (s), 1346 (m), 1273 (m),
1173 (m), 1106 (w), 1083 (w), 1028 (m), 978 (m), 997 (m),
Yellowish powder, mp 278–280 °C (flash column chromatogra-
phy, eluent Toluene/EtOH = 2:1 v/v). Found C, 48.38; H, 5.15; N,
24.01; C45H58ClN19O14 (1123.41) requires C, 48.06; H, 5.20; N,
23.67; Rf (67% Toluene/EtOH) 0.85; IR mmax (KBr) 3392 (m), 2864
(m), 1565 (s), 1492 (s), 1441 (s), 1347 (s), 1274 (m), 1231 (m),
1174 (m), 1104 (m), 1026 (m), 978 (m), 874 (w), 852 (w), 809 (m),
;
743 (w), 711 (w), 584 (w) cmꢀ1 1H NMR, 2D-1H,1H-COSY,
2D-1H,1H-NOESY (500 MHz, DMSO-d6, 353 K) dH 3.64 (20H, s,
CH2OH; H-3, -5, Pip), 3.72 (8H, s, H-2, -6, Pip), 4.04 (2H, d,
852 (w), 810 (m), 745 (w), 712 (w) cmꢀ1 1H NMR, 2D-1H,1H-
;
COSY, 2D-1H,1H-NOESY (500 MHz, DMSO-d6, 353 K) dH 1.23
2JH,H = 11.5 Hz, H-6-a, D-ax), 4.13 (2H, d, JH,H = 11.5 Hz, H-6-e,
2
2
(6H, s, Me), 3.48 (4H, d, JH,H = 10.6 Hz, CH2OH), 3.58 (4H, d,
D-ax), 4.43 (2H, br s, H-5-e, D-ax), 4.54 (6H, br s, OH), 5.01 (2H, d,
2JH,H = 6.3 Hz, H-2-a, D-ax), 5.24 (2H, d, 2JH,H = 6.3 Hz, H-2-e, D-ax),
5.25 (2H, s, H-4-a, D-ax), 5.50 (2H, s, SER-NH), 5.71 (2H, bd,
3JH,H = 9.0 Hz, D-ax-NH), 7.64 (4H, d, 3JH,H = 8.5 Hz, H-2, -6, p-NPh),
3
2JH,H = 10.6 Hz, CH2OH), 3.64 (8H, t, JH,H = 4.5 Hz, H-3, -5, Pip),
3.71 (8H, d, 3JH,H = 4.5 Hz, H-2, -6, Pip), 4.03 (2H, d,
2
2JH,H = 11.3 Hz, H-6-a, D-ax), 4.13 (2H, d, JH,H = 11.3 Hz, H-6-e,
3
3
D-ax), 4.44 (2H, d, JH,H = 8.0 Hz, H-5-e, D-ax), 4.57 (4H, br s,
8.13 (4H, d, JH,H = 8.5 Hz, H-3, -5, p-NPh) ppm; 13C NMR, DEPT
2
OH), 5.01 (2H, d, JH,H = 6.3 Hz, H-2-a, D-ax), 5.24 (2H, d,
(125 MHz, DMSO-d6, 298 K) dC 42.6 (C-3, -5, Pip), 43.4 (C-2, -6,
Pip), 48.9 (C-5, D-ax), 61.2 (C-2, SER C), 61.4 (CH2OH), 70.6, 70.7,
70.8, 70.9 (C-6, D-ax), 78.36, 78.41, 78.5, 78.9, 79.0 (C-4, D-ax),
93.9, 94.0, 94.1 (C-2, D-ax), 123.3, 123.6 (C-2, -6, p-NPh), 127.3,
127.6 (C-3, -5, p-NPh), 147.0, 147.1, 147.2 (C-1, -4, p-NPh), 164.3,
164.5, 165.4 (C-2, -4, -6, T-0) 165.20, 165.23, 165.3, 165.6, 165.7
(C-4, -6, T-1), 169.3 (C-2, T-1) ppm; HRMS (ESI+) m/z (rel. abund.%)
2JH,H = 6.3 Hz, H-2-e, D-ax), 5.25 (2H, s, H-4-a, D-ax), 5.57 (2H,
3
s, SER-NH), 5.66 (2H, d, JH,H = 8.0 Hz, D-ax-NH), 7.64 (4H, d,
3
3JH,H = 8.8 Hz, H-2, -6, p-NPh), 8.12 (4 H d, JH,H = 8.8 Hz, H-3,
-5, p-NPh) ppm; 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC
19.2 (Me), 42.7, 42.6 (C-3, -5, Pip), 43.4 (C-2, -6, Pip), 48.9,
49.2 (C-5, D-ax), 57.9, 58.0, 58.4 (C-2, SER A), 64.5, 64.8
(CH2OH), 70.6, 70.7 (C-6, D-ax), 78.5, 78.6, 78.9 (C-4, D-ax),
94.0 (C-2, D-ax), 123.3, 123.5 (C-2, -6, p-NPh), 127.4, 127.6 (C-
3, -5, p-NPh), 141.07, 141.14 (C-1, -4, p-NPh), 164.2 (C-2, T-0),
164.3, 164.5 (C-4, -6, T-1), 165.4, 165.7 (C-4, -6, T-0), 169.3 (C-
2, T-1) ppm; MS (ESI+) m/z (rel. abund.%) 1130.4 (M+K) (0.45),
1126.5 (M+Cl) (1.9), 1114.4 (M+Na) (1.2), 1092.5 (M+H) (1.8),
1124.4210 (M+H) (100); [a]
20 = +98.8 (0.5% DMSO).
D
4.4.4. 2-Chloro-4,6-bis{4-{{[1,3-dihydroxy-2-(methyl)prop-2-yl]-
amino}-4-{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-1,
3-dioxan-2-yl]methylamino}-s-triazin-2-yl}-piperazin-1-yl}-s-
triazine 9a
Yield 75% (0.90 g, 0.75 mmol) 9a starting from 1.20 g
(2.19 mmol) 5a and 0.18 g (0.99 mmol) cyanuric chloride. Orange-
yellow powder, mp 220–223 °C (flash column chromatography, elu-
ent EtOH/acetone = 1:1 v/v). Found C, 51.11; H, 6.35; N, 24.22;
1090.6 (MꢀH) (0.55); [
a
]
D
20 = +72.3 (0.5% DMSO).
4.4.2. 2-Chloro-4,6-bis{4-{{[1-hydroxy-2-(hydroxymethyl)but-2-
yl]amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-
s-triazin-2-yl}-piperazin-1-yl}-s-triazine 8b
C51H72ClN21O12 (1205.54) requires C, 50.76; H, 6.01; N, 24.38; Rf
Yield 97% (1.37 g, 1.23 mmol) 8b starting from 1.40 g
(2.78 mmol) 4b and 0.23 g (1.26 mmol) cyanuric chloride.
Yellowish powder, mp 227–229 °C (flash column chromatography,
eluent Toluene/EtOH = 4:1 v/v). Found: C, 50.51; H, 5.55; N, 23;
(50% EtOH/acetone) 0.68; IR mmax (KBr) 3373 (m), 2932 (m), 2868
(m), 1567 (s), 1494 (s), 1440 (s), 1347 (m), 1276 (m), 1225 (m),
1152 (w), 1109 (w), 1048 (m), 999 (m), 974 (m), 873 (w), 852 (w),
;
810 (m). 709 (w), 575 (w) cmꢀ1 1H NMR, 2D-1H,1H-COSY,
C47H62ClN19O12 (1119.45) requires: C, 50.38, H, 5.58, N, 23.75; Rf
2D-1H,1H-NOESY (500 MHz, DMSO-d6, 353 K) dH 1.29 (6H, s, Me),
2.24 (12H, s, NMe2), 2.86 (2H, dd app. t, 3JH,H = 3.0 Hz, H-5-e, D-eq),
3.52 (2H, ddd, 2JH,H = 10.0 Hz, 3JH,H = 5.0 Hz, CH2NH), 3.53 (2H, ddd,
(80% Toluene/EtOH) 0.85; IR mmax (KBr) 3406 (m), 2862 (m), 2362
(w), 1564 (s), 1493 (s), 1441 (s), 1346 (s), 1272 (m), 1231 (m),
1174 (m), 1106 (m), 1085 (m), 1029 (m), 999 (m), 978 (m), 873
3
2
2JH,H = 10.0 Hz, JH,H = 6,0 Hz, CH2NH), 3.54 (4H, d, JH,H = 10.5 Hz,
(w), 852 (w), 810 (m), 743 (w), 710 (w), 583 (w) cmꢀ1
;
1H NMR,
CH2OH), 3.62 (4H, d, JH,H = 10.5 Hz, CH2OH), 3.74 (16H, s, Pip),
3.97 (2H, dd, JH,H = 12.5 Hz, JH,H = 2.5 Hz, H-6-a, D-eq), 4.46 (2H,
2
2D-1H,1H-COSY, 2D-1H,1H-NOESY (500 MHz, DMSO-d6, 353 K) dH
2
3
3
2
2
0.74 (6H, t, JH,H = 7.3 Hz, Me), 1.72 (2H, ddd, JH,H = 12.5 Hz,
d, JH,H = 12.5 Hz, H-6-e, D-eq), 4.68 (4H, br s, OH), 5.01 (2H, dd
3JH,H = 7.2 Hz, CH2CH3), 1.78 (2H, ddd, 2JH,H = 12.5 Hz, 3JH,H = 7.2 Hz,
app. t, 3JH,H = 4.5 Hz, H-2-a, D-eq), 5.19 (2H, d, 3JH,H = 3.0 Hz, H-4-a,
2
CH2CH3), 3.51 (4H, d, JH,H = 10.3 Hz, CH2OH), 3.57 (4H, d,
D-eq), 5.63 (2H, s, SER-NH), 6.41 (2H, bdd app. bt, 3JH,H = 5.8 Hz, D-
2JH,H = 10.3 Hz, CH2OH) 3.63 (8H, s, H-3, -5, Pip), 3.71 (8H, s, H-2,
eq-NH), 7.65 (4H, d, JH,H = 8.5 Hz, H-2, -6, p-NPh), 8.17 (4H, d,
3
2
-6, Pip), 4.03 (2H, d, JH,H = 11.3 Hz, H-6-a, D-ax), 4.13 (2H, d,
3JH,H = 8.5 Hz, H-3, -5, p-NPh) ppm; 13C NMR, DEPT (125 MHz,
DMSO-d6, 298 K) dC 19.3 (Me), 42.7, 42.8, 42.9, 43.4 (C-3, -5, Pip),
43.8 (NMe2), 44.3, 44.5 (C-2, -6, Pip), 58.0 (C-2, SER A), 58.1, 58.5,
58.6 (C-5, D-eq), 64.6, 64.8 (CH2OH), 65.4 (C-6, D-eq), 80.2, 80.4
(C-4, D-eq), 99.7, 100.06, 100.14 (C-2, D-eq), 123.2, 123.3 (C-2, -6,
p-NPh), 127.1 (C-3, -5, p-NPh), 146.7 (C-1, p-NPh), 148.9 (C-4, p-
NPh), 164.3, 164.8, 166.0 (C-2, -4, -6, T-0; C-4, -6, T-1), 169.3 (C-2,
T-1) ppm; HRMS (ESI+) m/z (rel. abund.%) 1206.5433 (M+H) (100);
2JH,H = 11.3 Hz, H-6-e, D-ax), 4.43 (2H, d, JH,H = 8.8 Hz, H-5-e, D-
3
2
ax), 4.58 (4H, br s, OH), 5.01 (2H, d, JH,H = 6.0 Hz, H-2-a, D-ax),
5.24 (2H, d, JH,H = 6.0 Hz, H-2-e, D-ax), 5.25 (2H, s, H-4-a, D-ax),
5.44 (2H, s, SER-NH), 5.64 (2H, d, JH,H = 8.8 Hz, D-ax-NH), 7.63
2
3
3
3
(4H, d, JH,H = 8.5 Hz, H-2, -6, p-NPh), 8.11 (4H, d, JH,H = 8.5 Hz, H-
3, -5, p-NPh) ppm; 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC
8.1 (Me), 23.45, 23.53 (CH2CH3), 42.56, 42.63, 42.7 (C-3, -5, Pip),
43.4 (C-2, -6, Pip), 48.9, 49.1 (C-5, D-ax), 60.3 (C-2, SER B), 62.4,
63.0, 63.3 (CH2OH), 70.7, 70.8 (C-6, D-ax), 78.6, 79.0 (C-4, D-ax),
93.9, 94.0, 94.1 (C-2, D-ax), 123.2, 123.37, 123.41, 123.6 (C-2, -6, p-
NPh), 127.4, 127.5, 127.7 (C-3, -5, p-NPh), 147.1 (C-1, -4, p-NPh),
163.3 (C-2, T-0), 164.6 (C-4, -6, T-1), 165.5, 165.6, 165.7 (C-4, -6, T-
0), 169.3 (C-2, T-1) ppm; HRMS (ESI+) m/z (rel. abund. ꢁ 106%) calcd
for C47H63ClN19O12 1120.4592; found 1120.4583 (M+H) (100);
[a]
20 = +184.5 (0.5% DMSO).
D
4.4.5. 2-Chloro-4,6-bis{4-{{[1-hydroxy-2-(hydroxymethyl)but-
2-yl]amino}-4-{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-
1,3-dioxan-2-yl]methylamino}-s-triazin-2-yl}-piperazin-1-yl}-s-
triazine 9b
Yield 74% (0.59 g, 0.48 mmol) 9b starting from 0.80 g
(1.43 mmol) 5b and 0.12 g (0.65 mmol) cyanuric chloride. Orange-
[a]
20 = +89.5 (0.5% DMSO).
D
Please cite this article in press as: Moldovan, O.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.05.003

O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
15
yellow powder, mp 170–173 °C (flash column chromatography, elu-
ent EtOH/Toluene/aq NH3 25% = 1:2.5:0.1). Found C, 51.39; H, 6.55;
N, 24.06; C53H76ClN21O12 (1233.57) requires C, 51.55; H, 6.20; N,
23.82; Rf (10% EtOH/69% Toluene/aq NH3 25%) 0.55; IR mmax (KBr)
3388 (m), 2959 (m), 2925 (m), 2862 (m), 1567 (s), 1492 (s), 1438
(s), 1346 (s), 1256 (s), 1232 (s), 1150 (m), 1106 (m), 999 (m), 972
22.63; C63H74ClN23O16 (1443.54) requires C, 52.37; H, 5.16; N
22.30; Rf (10% EtOH/55% Toluene/Et2O) 0.65; IR mmax (KBr) 3430
(m), 2857 (m), 2779 (w), 1567 (s), 1550 (s), 1517 (s), 1491 (s),
1441 (s), 1346 (s), 1271 (m), 1232 (m), 1173 (m), 1096 (m), 1028
(m), 999 (m), 980 (m), 871 (w), 851 (m), 810 (m), 741 (w), 710
(w) cmꢀ1 1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-NOESY (500 MHz,
;
(m), 852 (w), 808 (m), 708 (w) cmꢀ1
;
1H NMR, 2D-1H,1H-COSY,
DMSO-d6, 363 K) dH 2.24 (12H, s, NMe2), 2.86 (2H, dd app. t,
2D-1H,1H-NOESY (500 MHz, DMSO-d6, 353 K) dH 0.80 (6H, t,
3JH,H = 3.2 Hz, H-5-e, D-eq), 3.46 (4H, ddd, JH,H = 5.5 Hz, CH2NH),
3
3JH,H = 7.5 Hz, Me), 1.82 (4H, q, 3JH,H = 7.3 Hz, CH2CH3), 2.24 (12H, s,
3.66 (8H, t, JH,H = 5.5 Hz, H-3, -5, Pip), 3.69 (8H, t, JH,H = 5.5 Hz,
3
3
3
2
3
NMe2), 2.87 (2H, dd app. t, JH,H = 2.9 Hz, H-5-e, D-eq), 3.51 (2H,
H-2, -6, Pip), 3.97 (2H, dd, JH,H = 12.8 Hz, JH,H = 2.5 Hz, H-6-a,
dd, 3JH,H = 4.5 Hz, CH2NH), 3.56 (4H, d, 2JH,H = 10.8 Hz, CH2OH), 3.63
D-eq), 4.04 (2H, d, JH,H = 10.8 Hz, H-6-a, D-ax), 4.11 (2H, d,
2
2
2
(4H, d, JH,H = 10.8 Hz, CH2OH), 3.74 (16H, s, Pip), 3.97 (2H,
2JH,H = 10.8 Hz, H-6-e, D-ax), 4.46 (2H, d, JH,H = 12.8 Hz, H-6-e,
2
3
3
dd, JH,H = 12.4 Hz, JH,H = 2.8 Hz, H-6-a, D-eq), 4.47 (2H, d,
D-eq), 4.49 (2H, d, JH,H = 8.0 Hz, H-5-e, D-ax), 4.94 (2H, dd app. t,
2JH,H = 12.4 Hz, H-6-e, D-eq), 4.67 (4H, br s, OH), 5.01 (2H, dd app.
3JH,H = 5.0 Hz, H-2-a, D-eq), 5.01 (2H, d, 2JH,H = 6.0 Hz, H-2-a, D-ax),
3
3
3
t, JH,H = 4.5 Hz, H-2-a, D-eq), 5.19 (2H, d, JH,H = 2.9 Hz, H-4-a,
D-eq), 5.54 (2H, s, SER-NH), 6.44 (2H, br s, D-eq-NH), 7.65 (4H, d,
3JH,H = 8.5 Hz, H-2, -6, p-NPh), 8.17 (4H, d, 3JH,H = 8.5 Hz, H-3, -5, p-
NPh) ppm; 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC 8.3 (Me),
23.5, 23.6 (CH2CH3), 42.6, 43.4 (C-3, -5, Pip), 43.8 (NMe2), 44.6 (C-
2, -6, Pip), 58.6 (C-5, D-eq), 60.4 (C-2, SER B), 62.6, 64.5 (C-6, D-eq),
80.2, 80.4 (C-4, D-eq), 99.8, 100.1 (C-2, D-eq), 123.3 (C-2, -6, p-
NPh), 127.0 (C-3, -5, p-NPh), 146.7 (C-1, p-NPh), 148.9 (C-4, p-
NPh), 164.3 (C-2, T-0), 164.8 (C-4, -6, T-1), 165.9, 166.0 (C-4, -6, T-
0), 169.2 (C-2, T-1) ppm; MS (ESI+) m/z (rel. abund. ꢁ 106%) 1268.6
5.17 (2H, d, JH,H = 3.2 Hz, H-4-a, D-eq), 5.23 (2H, s, H-4-a, D-ax),
2
3
5.24 (2H, d, JH,H = 6.0, H-2-e, D-ax), 5.62 (2H, bd, JH,H = 8.0 Hz,
D-ax-NH), 6.28 (2H, bdd app. bt, 3JH,H = 5.5 Hz, D-eq-NH), 7.63 (4H,
3
3
d, JH,H = 7.0 Hz, H-2, -6, p-NPh), 7.64 (4H, d, JH,H = 8.0 Hz, H-2, -6,
p-NPh), 8.10 (4H, d, JH,H = 8.5 Hz, H-3, -5, p-NPh), 8.15 (4H, d,
3
3JH,H = 9.0 Hz, H-3, -5, p-NPh) ppm; 13C NMR, DEPT (125 MHz,
DMSO-d6, 298 K) dC 43.4 (C-3, -5, Pip), 43.8 (NMe2), 44.2 (C-2, -6,
Pip), 44.4 (CH2NH), 48.7, 48.86, 48.89, 48.90 (C-5, D-ax), 58.5 (C-5,
D-eq), 64.5 (C-6, D-eq), 70.7, 70.8 (C-6, D-ax), 78.5, 78.6, 78.9 (C-4,
D-ax), 80.1, 80.3 (C-4, D-eq), 94.0 (C-2, D-ax), 99.5, 99.6, 99.68,
99.71, 99.84, (C-2, D-eq), 123.2, 123.3, 123.4 (C-2, -6, p-NPh),
127.0, 127.34, 127.5, 127.6 (C-3, -5, p-NPh), 146.7, 147.05, 147.13
(C-1, p-NPh), 148.9 (C-4, p-NPh), 164.3, 164.6, 164.7, 164.8 (C-2,
T-0; C-4, -6, T-1), 165.8, 166.1 (C-4, -6, T-0), 169.2 (C-2, T-1) ppm;
MS (ESI+) m/z (rel.abund. ꢁ 104%) 1444.6 (M+H) (5.25), 1430.6
(M+Cl) (1.35), 1234.6 (M+H) (1.65); [a]
20 = +163.3 (0.5% DMSO).
D
4.4.6. 2-Chloro-4,6-bis{4-{{[1,3-dihydroxy-2-(hydroxymethyl)-
prop-2-yl]amino}-4-{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitro-
phenyl)-1,3-dioxan-2-yl]methylamino}-s-triazin-2-yl}-piperaz-
in-1-yl}-s-triazine 9c
(2.15); [a]
20 = +128.5 (0.5% DMSO).
D
Yield 73% (1.85 g, 1.49 mmol) 9c starting from 2.50 g
(4.44 mmol 5c) and 0.37 g (2.02 mmol) cyanuric chloride.
Orange-yellowish powder, mp 270–272 °C (flash column chro-
matography, eluent acetone/EtOH = 1:1 v/v). Found C, 49.55; H,
6.15; N, 24.11; C51H72ClN21O14 (1237.53) requires C, 49.45; H,
5.86; N, 23.75; Rf (50% acetone/EtOH) 0.40; IR mmax (KBr) 3382
(m), 2932 (m), 2866 (m), 2788 (m), 1563 (s), 1494 (s), 1436 (s),
1348 (s), 1273 (m), 1230 (m), 1152 (m), 1109 (m), 1049 (m), 998
4.5. Typical procedure for the synthesis of compounds 10c and
12. Preparation of compound 10c
In a solution obtained by dissolving the trispirotetraacetalic dia-
mine linker HN<(L2)>NH (1.06 g, 3.57 mmol) in anhydrous 1,4-
dioxane (100 mL), anhydrous K2CO3 (0.12 g, 0.89 mmol) was
added. The resulting suspension was heated at reflux with vigorous
stirring. At this temperature, compound 8c (1.00 g, 0.89 mmol) was
added in five equal portions (0.20 g/portion) every 2 h. Within 2 h,
the starting 8c was consumed (TLC monitoring, eluent
toluene/EtOH = 2:1 v/v). The formation of the desired product
10c was monitored by TLC (EtOH/aq NH3 25% = 3:1 v/v, visualisa-
tion UV-254 nm, then I2-bath). After cooling at room temperature,
the reaction mixture was evaporated under reduced pressure to
dryness. At room temperature, the solid residue was taken with
cooled water (10 mL) under vigorous stirring for 1 h, filtered off
and washed with cooled water to neutrality, to yield 1.27 g of
crude material. This was purified by flash column chromatography
(eluent EtOH/aq NH3 25% = 3:1 v/v) to afford 1.02 g of compound
10c (83% yield with respect to 8c). Linker recovery: the aqueous fil-
trate (see above) containing the excess of linker HN<(L2)>NH
(0.80 g, 2.68 mmol) was saturated with NaCl and then extracted
with chloroform (3 ꢁ 50 mL). After separation, the organic layer
was dried over anhydrous Na2SO4. After filtering off and washing
minerals with dry chloroform, the organic solution was evaporated
under reduced pressure to dryness. The resulted solid was
crystalised at ꢀ20 °C from ligroin to provide 0.64 g (80% yield) of
recovered linker HN<(L2)>NH.
(m), 977 (m), 873 (w), 852 (w), 809 (m), 753 (w), 710 (w) cmꢀ1
;
1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-NOESY (500 MHz, DMSO-d6,
3
353 K) dH 2.42 (12H, s, NMe2), 2.87 (2H, dd app. t, JH,H = 2.9 Hz,
3
H-5-e, D-eq), 3.51 (2H, d, JH,H = 5.5 Hz, CH2NH), 3.52 (2H, d,
3JH,H = 5.5 Hz, CH2NH), 3.69 (12H, s, CH2OH), 3.74 (16H, s, Pip),
2
3
3.98 (2H, dd, JH,H = 12.5 Hz, JH,H = 3.0 Hz, H-6-a, D-eq), 4.47 (2H,
2
d, JH,H = 12.5 Hz, H-6-e, D-eq), 4.64 (6H, br s, OH), 5.02 (2H, d,
3JH,H = 4.5 Hz, H-2-a, D-eq), 5.20 (2H, d, JH,H = 2.9 Hz, H-4-a, D-
3
eq), 5.60 (2H, s, SER-NH), 6.51 (2H, br s, D-eq-NH), 7.65 (4H, d,
3
3JH,H = 8.8 Hz, H-2, -6, p-NPh), 8.17 (4H, d, JH,H = 8.8 Hz, H-3, -5,
p-NPh) ppm; 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC 42.6,
42.8, 43.1, 43.4 (C-3, -5, Pip), 43.9 (NMe2), 44.3, 44.7 (C-2, -6,
Pip), 58.6 (C-5, D-eq), 61.3 (CH2OH), 61.5 (C-2, SER C), 61.7
(CH2OH), 64.5 (C-6, D-eq), 80.2, 80.4 (C-4, D-eq), 99.7, 99.8 (C-2,
D-eq), 123.3 (C-2, -6, p-NPh), 127.0, 127.1 (C-3, -5, p-NPh), 146.7
(C-1, p-NPh), 149.0 (C-4, p-NPh), 164.3 (C-2, T-0), 164.7, 165.9
(C-4, -6, T-1), 165.5, 165.8 (C-4, -6, T-0), 169.28, 169.32 (C-2, T-1)
ppm; HRMS (ESI+) m/z (rel. abund.%) 1238.5338 (M+H) (100);
[a]
20 = +183.3 (0.5% DMSO).
D
4.4.7. 2-Chloro-4,6-bis{4-{4-{[(2R,4S,5S)-5-(dimethylamino)-4-
(4-nitrophenyl)-1,3-dioxan]-2-yl}methylamino-6-[(4S,5S)-4-(4-
nitrophenyl)-1,3-dioxan-5-yl]amino-s-triazin-2-yl}-piperazin-
1-yl}-s-triazine 11
Yield 72% (1.20 g, 0.83 mmol) 11 starting from 1.70 g
(2.55 mmol) 7 and 0.21 g (1.16 mmol) cyanuric chloride. Yellow
powder, mp 212–215 °C (flash column chromatography, eluent
EtOH/Toluene/Et2O = 1:3:1.5 v/v/v). Found: C, 52.47; H, 5.42; N,
4.5.1. 3-{4,6-Bis{4-{{[1,3-dihydroxy-2-(hydroxymethyl)prop-2-
yl]amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-
s-triazin-2-yl}-piperazin-1-yl}-s-triazin-2-yl}-7,11,18,21-tetra-
oxa-3,15-diazatrispiro[5.2.2.5.2.2]heneicosane 10c
Yellowish powder, mp 238–240 °C (flash column chromatogra-
phy, eluent EtOH/aq NH3 25% = 3:1 v/v). Found C, 51.71; H, 6.15; N,
Please cite this article in press as: Moldovan, O.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.05.003

16
O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
20.91; C60H83N21O18 1386.6303 requires C, 51.98; H, 6.03; N,
21.22; Rf (75% EtOH/aq NH3 25%) 0.56; IR mmax (KBr) 3338 (s),
2964 (m), 2867 (m), 1546 (s), 1489 (s), 1438 (s), 1347 (m), 1252
(m), 1174 (s), 1098 (s), 893 (w), 808 (w), 743 (w), 711 (w), 618
80.3 (C-4, D-eq), 94.0 (C-2, D-ax), 96.9 (C-12, Tsp), 97.2 (C-6, Tsp),
99.5, 99.67, 99.70, 99.8, 99.9 (C-2, D-eq), 123.2, 123.3, 123.4 (C-2,
-6, p-NPh), 127.0, 127.3, 127.4, 127.5, 127.6 (C-3, -5, p-NPh),
146.7, 147.02, 147.04, 147.1 (C-1, p-NPh), 148.9 (C-4, p-NPh),
164.3, 164.6, 164.8 (C-2, T-0; C-4, -6, T-1), 165.8, 166.1 (C-4, -6, T-
0), 169.2 (C-2, T-1) ppm; MS (ESI+) m/z (rel. abund. ꢁ 104%)
1720.0 (M+2H+Na) (0.02), 1707.0 (M+2H) (1.1), 1430.6 (1.8);
(m) cmꢀ1
;
1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-NOESY (500 MHz,
3
DMSO-d6, 363 K) dH 1.74 (4H, t, JH,H = 5.5 Hz, H-1, -5, Tsp), 1.79
3
2
(4H, t, JH,H = 5.0 Hz, H-13, -17, Tsp), 2.73 (2H, dd, JH,H = 10.8 Hz,
3JH,H = 5.0 Hz, H-14, -16, Tsp), 2.74 (2H, dd, JH,H = 10.8 Hz,
[a]
20 = +147.0 (0.5% DMSO).
D
2
3JH,H = 5.0 Hz, H-14, -16, Tsp), 3.60 (4H, t, JH,H = 5.5 Hz, H-2, -4,
3
3
Tsp), 3.65 (13H, s, CH2OH, H-15, Tsp), 3.68 (16H, t, JH,H = 4.8 Hz,
4.6. Typical procedure for the synthesis of compounds 13a–c
and 14. Preparation of compound 13C
Pip), 3.72 (4H, s, H-8, -20, Tsp), 3.74 (4H, s, H-10, -19, Tsp), 4.04
2
2
(2H, d, JH,H = 10.8 Hz, H-6-a, D-ax), 4.13 (2H, d, JH,H = 10.8 Hz,
3
H-6-e, D-ax), 4.44 (2H, bd, JH,H = 8.5 Hz, H-5-e, D-ax), 4.51 (6H,
In a solution obtained by dissolving compound 8c (0.35 g,
0.31 mmol) and trispirotetraacetalic diamine linker HN<(L2) >
NH (0.04 g, 0.15 mmol) in anhydrous 1,4-dioxane (15 mL), anhy-
drous K2CO3 (0.04 g, 0.31 mmol) was added and the resulting sus-
pension was refluxed, with vigorous stirring, until TLC monitoring
(EtOH/CHCl3/Toluene = 1:2:0.5 v/v) indicated the presence of the
starting materials in small traces only (about 40 h). After cooling
at room temperature, the reaction mixture was evaporated under
reduced pressure to dryness. The resulting solid was taken with
water (5 mL). After stirring at room temperature for 1 h, the sus-
pension was filtered off and washed with water to yield 0.36 g of
crude material, which was purified by flash column chromatogra-
phy (eluent EtOH/CHCl3/toluene = 1:2:0.5 v/v/v). The isolated 13C
0.16 g was triturated from a Et2O/THF 4:1 (v/v) mixture at
ꢀ20 °C to give 0.14 g of pure 13C (48% yield with respect to linker
HN<(L2)>NH).
2
br s, OH), 5.02 (2H, d, JH,H = 5.8 Hz, H-2-a, D-ax), 5.24 (2H, d,
2JH,H = 5.8 Hz, H-2-e, D-ax), 5.25 (2H, s, H-4-a, D-ax), 5.46 (2H, s,
3
SER-NH), 5.62 (2H, d, JH,H = 8.5 Hz, D-ax-NH), 7.64 (4H, d,
3JH,H = 9.0 Hz, H-2, -6, p-NPh), 8.12 (4H, d, JH,H = 9.0 Hz, H-3, -5,
3
p-NPh) ppm; 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC 32.4,
32.6 (C-9, Tsp), 33.2 (C-13, -17, Tsp), 40.0 (C-1, -5, Tsp), 42.8 (C-
14, -16, Tsp), 43.0 (C-2, -4, Tsp, Pip), 48.9 (C-5, D-ax), 61.2, 61.4
(C-2, SER C, CH2OH), 62.5 (C-10, -19, Tsp), 62.8 (C-8, -20, Tsp),
70.6, 70.8 (C-6, D-ax), 78.5, 78.9 (C-4, D-ax), 94.0, (C-2, D-ax),
97.0 (C-12, Tsp), 97.3 (C-6, Tsp), 123.3, 123.6 (C-2, -6, p-NPh),
127.3, 127.6 (C-3, -5, p-NPh), 147.0 (C-1, p-NPh), 147.2 (C-4, p-
NPh), 164.6 (C-2, T-1), 164.74, 164.79 (C-4, -6, T-1), 164.82 (C-2,
T-0), 164.9, 165.3, 165.7 (C-4, -6, T-0) ppm; HRMS (ESI+) m/z (rel.
abund. ꢁ 104%) 1386.6255 (M+H) (40); [
a]
20 = +75.1 (0.5% DMSO).
D
4.5.2. 3-{4,6-Bis{4-{4-{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitro-
phenyl)-1,3-dioxan]-2-yl}methylamino-6-[(4S,5S)-4-(4-nitro-
phenyl)-1,3-dioxan-5-yl]amino-s-triazin-2-yl}-piperazin-1-yl}-
s-triazin-2-yl}-7,11,18,21-tetraoxa-3,15-diazatrispiro[5.2.2.5.2.2]
heneicosane 12
Yield 54% (0.38 g, 0.22 mmol) 12 starting from 0.55 g
(0.38 mmol) 11 and 0.45 g (1.52 mmol) HN<(L2)>NH. Orange yel-
lowish powder, mp 210–213 °C (flash column chromatography
EtOH/CH2Cl2/aq NH3 25% = 1:2.5:0.1 v/v/v). Found C, 55.03; H,
6.11; N, 20.25; C79H99N25O20 (1706.78) requires C, 54.89; H, 5.85;
4.6.1. 3,15-Bis{4,6-bis{4-{6-{[1,3-dihydroxy-2-(methyl)prop-2-yl]-
amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-
s-triazin-2-yl}-piperazin-1-yl}-s-triazin2-yl}-7,11,18,21-tetrao-
xa-3,15-diazatrispiro[5.2.2.5.2.2]heneicosane 13a
Yield 38% (0.14 g, 0.06 mmol) 13a starting from 0.35 g
(0.38 mmol) 8a and 0.05 g (0.15 mmol) HN<(L2)>NH. Yellowish
powder, mp 225–227 °C (flash column chromatography, eluent
EtOH/CHCl3/Toluene = 1:2:1 v/v/v). Found C, 51.98; H, 6.01; N,
23.15; C105H140N40O28 (2409.08) requires C, 52.32; H, 5.85; N,
23.24; Rf (10% EtOH/50% CHCl3/Toluene) 0.70; IR mmax (KBr) 3394
(m), 2931 (m), 2852 (m), 1545 (s), 1494 (s), 1436 (s), 1346 (s),
1265 (m), 1173 (m), 1081 (m), 1028 (m), 997 (m), 896 (w), 807
N, 20.52; Rf (10% EtOH/69% CH2Cl2/aq NH3 25%) 0.45; IR mmax (KBr)
3420 (w), 2930 (m), 2860 (m), 2785 (w), 1542 (s), 1525 (s), 1438
(s), 1347 (s), 1256 (m), 1174 (s), 1096 (s), 1000 (s), 851 (m), 810
(m), 740 (w), 710 (w) cmꢀ1
;
1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-
(m), 737 (w), 709 (w) cmꢀ1 1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-
;
3
NOESY (500 MHz, DMSO-d6, 363 K) dH 1.76 (4H, t, JH,H = 5.0 Hz,
3
NOESY (500 MHz, DMSO-d6, 363 K) dH 1.22 (12H, s, Me), 1.81 (8H,
t, 3JH,H = 5.3 Hz, H-1, -5, -13, -17, Tsp), 3.48 (8H, dd, 2JH,H = 10.5 Hz,
3JH,H = 5.0 Hz, CH2OH), 3.58 (8H, m, CH2OH), 3.60 (16H, t,
3JH,H = 4.7 Hz, H-2, -6, Pip), 3.68 (16H, t, 3J = 4.7 Hz, H-3, -5, Pip),
H-1, -5, Tsp), 1.77 (4H, t, JH,H = 5.0 Hz, H-13, -17, Tsp), 2.24 (12H,
3
s, NMe2), 2.74 (2H, t, JH,H = 5.0 Hz, H-14, -16, Tsp), 2.86 (2H, dd
3
3
app. t, JH,H = 2.5 Hz, H-5-e, D-eq), 3.46 (4H, ddd, JH,H = 5.0 Hz,
3
CH2NH), 3.63 (8H, t, JH,H = 5.3 Hz, H-3, -5, Pip), 3.64 (8H, t,
3
3JH,H = 5.3 Hz, H-2, -6, Pip; 1H, H-15, Tsp), 3.70 (2H,t, 3JH,H = 5.3 Hz,
3.72 (8H, t, JH,H = 5.3 Hz, H-2, -4, -14, -16, Tsp), 3.76, 3.78 (8H, s,
2
3
H-8, -10, -19, -20, Tsp), 4.04 (4H, d, JH,H = 11.3 Hz, H-6-a, D-ax),
H-2, -4, Tsp), 3.71 (2H, t, JH,H = 5.3 Hz, H-2, -4, Tsp), 3.72 (4H, s,
4.13 (4H, d, 2JH,H = 11.3 Hz, H-6-e, D-ax), 4.44 (4H, d, 3JH,H = 9.3 Hz,
H-8, -20, Tsp), 3.73 (4H, s, H-10, -19, Tsp), 3.97 (2H, dd,
3
2JH,H = 12.5 Hz, 3JH,H = 3.0 Hz, H-6-a, D-eq), 4.04 (2H, d,
H-5-e, D-ax), 4.56 (8H, dd as t, JH,H = 5.0 Hz, OH), 5.02 (4H, d,
2JH,H = 6.5 Hz, H-2-a, D-ax), 5.24 (4H, d, 2JH,H = 4.5 Hz, H-2-e, D-ax),
5.25 (4H, s, H-4-a, D-ax), 5.48 (4H, s, SER-NH), 5.54 (4H, d,
3JH,H = 9.3 Hz, D-ax-NH), 7.64 (8H, d, 3JH,H = 9.0 Hz, H-2, -6, p-NPh),
2
2JH,H = 11.3 Hz, H-6-a, D-ax), 4.11 (2H, d, JH,H = 11.3 Hz, H-6-e,
2
D-ax), 4.45 (2H, d, JH,H = 12.5 Hz, H-6-e, D-eq), 4.49 (2H, d,
3
3JH,H = 9.0 Hz, H-5-e, D-ax), 4.94 (2H, dd app. t, JH,H = 5.3 Hz, H-2-
3
8.12 (8H, d, JH,H = 9.0 Hz, H-3, -5, p-NPh) ppm; Quantitative 13C
2
a, D-eq), 5.01 (2H, d, JH,H = 6.0 Hz, H-2-a, D-ax), 5.17 (2H, d,
3JH,H = 3.5 Hz, H-4-a, D-eq), 5.23 (2H, s, H-4-a, D-ax), 5.24 (2H, d,
2JH,H = 6.0, H-2-e, D-ax), 5.57 (2H, bd, 3JH,H = 9.0 Hz, D-ax-NH), 6.22
NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC 19.2 (4C, Me), 32.5 (5C,
C-1, -5, -9, -13, -17, Tsp), 43.0 (20C: 16C, Pip; 4C, C-2, -4, -14, -16,
Tsp), 48.9 (4C, C-5, D-ax), 57.9 (4C, C-2, SER A), 62.8 (4C, C-8, -10,
-19, -20, Tsp), 64.5 (8C, CH2OH), 70.7, 70.8 (4C, C-6, D-ax), 78.6,
79.0 (4C, C-4, D-ax), 94.0 (4C, C-2, D-ax), 97.3 (2C, C-6, -9, Tsp),
123.3, 123.50, 123.53, 123.6 (8C, C-2, -6, p-NPh), 127.4, 127.6 (8C,
C-3, -5, p-NPh), 147.08, 147.14 (8C, C-1, -4, p-NPh), 164.3, 164.4,
164.6 (2C, C-2, T-1), 164.6, 164.9 (4C, C-4, -6, T-1), 165.3 (4C, C-2,
T-0), 165.4, 165.7 (8C, C-4, -6, T-0) ppm; MS (ESI+) m/z (rel.
abund. ꢁ 104%) 2448.8 (M+K) (1.4), 2432.8 (M+Na) (2.4), 2410.9
3
(2H, bt, 3JH,H = 6.0 Hz, D-eq-NH), 7.63 (4H, d, JH,H = 8.0 Hz, H-2, -6,
3
p-NPh), 7.64 (4H, d, JH,H = 9.0 Hz, H-2, -6, p-NPh), 8.10 (4H, d,
3JH,H = 9.0 Hz, H-3, -5, p-NPh), 8.15 (4H, d, 3JH,H = 9.0 Hz, H-3, -5, p-
NPh) ppm; 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC 32.4,
32.6, 33.0 (C-9, -13, -17, Tsp), 42.7, 42.8, 43.0 (C-1, -5, Tsp; C-3, -5,
Pip), 43.8 (NMe2), 44.4 (C-2, -6, Pip; C-2, -4, -14, -16, Tsp; CH2NH),
48.6, 48.8 (C-5, D-ax), 58.47, 58.52 (C-5, D-eq), 62.5, 62.6, 62.7,
62.8 (C-8, -10, -19, -20, Tsp), 64.4, 64.5 (C-6, D-eq), 70.64, 70.66,
70.69, 70.8 (C-6, D-ax), 78.52, 78.55, 78.59, 78.9 (C-4, D-ax), 80.1,
(M+H) (1.7); [a]
20 = +76.3 (0.5% DMSO).
D
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O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
17
4.6.2. 3,15-Bis{4,6-bis{4-{6-{[1-hydroxy-2-(hydroxymethyl)but-
2-yl]amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-
s-triazin-2-yl}-piperazin-1-yl}-s-triazin2-yl}-7,11,18,21-tetraoxa-3,
15-diazatrispiro[5.2.2.5.2.2]heneicosane 13b
Yield 37% (0.09 g, 0.03 mmol) 13b starting from 0.25 g
(0.22 mmol) 8b and 0.03 g (0.11 mmol) HN<(L2)>NH. Yellowish
powder, mp 221–224 °C (flash column chromatography, eluent
EtOH/CH2Cl2/Toluene = 1:3:2 v/v/v). Found C, 52.88; H, 6.21; N
22.95; C109H148N40O28 (2465.14) requires C, 53.08; H, 6.05; N,
22.71; Rf (10% EtOH/50% CH2Cl2/Toluene) 0.55; IR mmax (KBr) 3406
(m), 2970 (m), 2936 (m), 2860 (m), 1545 (s), 1491 (s), 1438 (s),
1345 (s), 1262 (s), 1174 (s), 1084 (s), 1028 (s), 1000 (m), 896 (w),
70.6, 70.8 (4C, C-6, D-ax), 78.5, 78.6, 78.9, 79.1 (4C, C-4, D-ax),
94.0 (4C, C-2, D-ax), 97.3 (2C, C-6, -9, Tsp), 123.3, 123.6 (8C, C-2,
-6, p-NPh), 127.3, 127.6 (8C, C-3, -5, p-NPh), 147.1 (8C, C-1, -4, p-
NPh), 164.5 (2C, C-2, T-1), 164.5, 164.9, 165.3 (4C, C-4, -6, T-1),
165.3 (4C, C-2, T-0), 165.3, 165.4, 165.6 (8C, C-4, -6, T-0) ppm;
MS (ESI+) m/z (rel. abund. ꢁ 104%) 2512.8 (M+K) (0.2), 2496.8
(M+Na) (4.2); [a]
20 = +81.7 (0.5% DMSO).
D
4.6.4. 3,15-Bis{4,6-bis{4-{6-{{[(2R,4S,5S)-5-(dimethylamino)-4-
(4-nitrophenyl)-1,3-dioxan]-2-yl}methylamino}-4-{[(4S,5S)-4-
(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-s-triazin-2-yl}-piper-
azin-1-yl}-s-triazin2-yl}-7,11,18,21-tetraoxa-3,15-diazatrispiro-
[5.2.2.5.2.2]heneicosane 14
810 (m), 741 (w), 712 (w) cmꢀ1
;
1H NMR, 2D-1H,1H-COSY,
2D-1H,1H-NOESY (500 MHz, DMSO-d6, 363 K) dH 0.75 (12H, t,
Yield 46% (0.15 g, 0.05 mmol) 14 starting from 0.33 g
(0.23 mmol) 11 and 0.03 g (0.11 mmol) HN<(L2)>NH. Yellowish
powder, mp 253–255 °C (flash column chromatography, eluent
EtOH/CHCl3/Toluene = 1:2:2 v/v/v). Found C, 54.69; H, 5.87; N,
21.81; C141H172N48O36 (3113.31) requires C, 52.36; H, 5.57; N,
21.58; Rf (20% EtOH/40% CHCl3/Toluene) 0.60; IR mmax (KBr) 3422
(m), 2929 (m), 2857 (m), 1545 (s), 1438 (s), 1347 (s), 1265 (s),
1174 (m), 1094 (m), 1028 (m), 1013 (m), 852 (m), 810 (m), 741
3JH,H = 7.2 Hz, Me), 1.75 (8H, dd app. q, JH,H = 7.2 Hz, CH2CH3),
3
3
1.80 (8H, dd app. q, JH,H = 5.6 Hz, H-1, -5, -13, -17, Tsp), 3.52 (8H,
d, 2J = 11.8 Hz, CH2OH), 3.58 (8H, d, JH,H = 11.8 Hz, CH2OH), 3.60
2
3
(8H, t, JH,H = 5.2 Hz, H-2, -6, Pip), 3.68 (8H, t, 3J = 5.2 Hz, H-3, -5,
3
Pip), 3.72 (8H, t, JH,H = 5.6 Hz, H-2, -4, -14, -16, Tsp), 3.77 (8H, s,
2
H-8, -10, -19, -20, Tsp), 4.04 (4H, d, JH,H = 10.8 Hz, H-6-a, D-ax),
4.13 (4H, d, 2JH,H = 10.8 Hz, H-6-e, D-ax), 4.44 (4H, d,
3JH,H = 10.0 Hz, H-5-e, D-ax), 4.55 (8H, br s, OH), 5.02 (4H, d,
2JH,H = 5.5 Hz, H-2-a, D-ax), 5.24 (4H, d, 2JH,H = 5.5 Hz, H-2-e, D-ax),
5.25 (4H, s, H-4-a, D-ax), 5.39 (4H, s, SER-NH), 5.56 (4H, d,
(w), 710 (w) cmꢀ1 1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-NOESY
;
(500 MHz, DMSO-d6, 363 K) dH 1.78 (8H, s, H-1, -5, -13, -17, Tsp),
2.24 (24H, s, NMe2), 2.87 (4H, s, H-5-e, D-eq), 3.47 (8H, dd app. t,
3JH,H = 5.5 Hz, CH2NH), 3.63 (16H, br s, H-2, -6, Pip), 3.65 (16H, br
s, H-3, -5, Pip), 3.68 (8H, s, H-2, -4, -14, -16, Tsp), 3.77 (8H, s, H-
3JH,H = 10.0 Hz, D-ax-NH), 7.64 (8H, d, JH,H = 8.8 Hz, H-2, -6, p-
3
NPh), 8.11 (8H, d, 3JH,H = 8.8 Hz, H-3, -5, p-NPh) ppm; Quantitative
13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC 8.1 (4C, Me), 23.4
(4C, CH2CH3), 32.3, 32.68, 32.70 (5C, C-1, -5, -9, -13, -17, Tsp), 43.0
(20C: 16C, Pip; 4C, C-2, -4, -14, -16, Tsp), 48.9, 49.2 (4C, C-5, D-ax),
60.3 (4C, C-2, SER B), 62.4 (8C, CH2OH), 62.9 (4C, C-8, -10, -19, -20,
Tsp), 70.6, 70.7, 70.81, 70.84 (4 C, C-6, D-ax), 78.5, 78.6, 78.97,
79.00 (4 C, C-4, D-ax), 94.0 (4 C, C-2, D-ax), 97.3 (2C, C-6, -9, Tsp),
123.2, 123.4, 123.6 (8C, C-2, -6, p-NPh), 127.3, 127.5, 127.6 (8C,
C-3, -5, p-NPh), 147.1 (8C, C-1, -4, p-NPh), 164.6 (2C, C-2, T-1),
164.6, 164.9 (4C, C-4, -6, T-1), 165.3 (4C, C-2, T-0), 165.4, 165.6
(8C, C-4, -6, T-0) ppm; MS (ESI+) m/z (rel. abund. ꢁ 104%) 2504.8
(M+K) (0.7), 2488.8 (M+Na) (2.9); isotope pattern for
2
3
8, -10, -19, -20, Tsp), 3.97 (4H, dd, JH,H = 12.4 Hz, JH,H = 2.3 Hz,
2
H-6-a, D-eq), 4.04 (4H, d, JH,H = 11.0 Hz, H-6-a, D-ax), 4.11 (4H,
d, JH,H = 11.0 Hz, H-6-e, D-ax), 4.46 (4H, d, JH,H = 12.4 Hz, H-6-e,
2
2
3
D-eq), 4.50 (4H, d, JH,H = 8.0 Hz, H-5-e, D-ax), 4.94 (4H, dd app. t,
3JH,H = 4.8 Hz, H-2-a, D-eq), 5.00 (4H, d, JH,H = 5.8 Hz, H-2-a,
2
3
D-ax), 5.17 (4H, d, JH,H = 3.5 Hz, H-4-a, D-eq), 5.23 (4H, s, H-4-a,
2
D-ax), 5.24 (4H, d, JH,H = 5.8 Hz, H-2-e, D-ax), 5.58 (4H, bd,
3JH,H = 8.0 Hz, D-ax-NH), 6.22 (4H, br s, D-eq-NH), 7.63 (8H, d,
3JH,H = 8.0 Hz, H-2, -6, p-NPh), 7.64 (8H, d, JH,H = 8.5 Hz, H-2, -6,
3
3
p-NPh), 8.09 (8H, d, JH,H = 8.5 Hz, H-3, -5, p-NPh), 8.15 (8H, d,
3JH,H = 9.0 Hz, H-3, -5, p-NPh) ppm; Quantitative 13C NMR, DEPT
(125 MHz, DMSO-d6, 298 K) dC 32.4, 32.7 (1C, C-9, Tsp), 42.8, 43.0
(12C: 4C, C-1, -5, -13, -17, Tsp; 8C, C-2, -6, Pip), 43.8 (8C, NMe2),
44.4, 44.5 (16C: 8C, C-3, -5, Pip; 14C, C-2, -4, -14, -16, Tsp; 4C,
CH2NH), 48.64, 48.67, 48.74, 48.83, 48.85, 48.88, 48.92 (4C, C-5,
D-ax), 58.49, 58.55 (4C, C-5, D-eq), 62.72, 62.78, 62.81 (4C, C-8,
-10, -19, -20, Tsp), 64.4, 64.5 (4C, C-6, D-eq), 70.7, 70.8 (4C, C-6,
D-ax), 78.52, 78.54, 78.59, 78.61, 78.62, 78.65 (4C, C-4, D-ax),
80.1, 80.3, (4C, C-4, D-eq), 94.0 (4C, C-2, D-ax), 97.3 (2C, C-6, -12,
Tsp), 99.5, 99.67, 99.72, 99.8, 99.9 (4C, C-2, D-eq), 123.2, 123.5
(16C, C-2, -6, p-NPh), 127.0, 127.4, 127.5, 127.6 (16C, C-3, -5, p-
NPh), 146.7, 147.03, 147.06, 147.2, 148.9 (16C, C-1, -4, p-NPh),
164.6, 164.7, (2C, C-2, T-1), 164.76, 164.82, 164.9, 165.3 (4C, C-4,
-6, T-1), 165.3, 165.7 (4C, C-2, T-0), 165.76, 166.1 (8C, C-4, -6, T-
0) ppm; MS (ESI+) m/z (rel. abund. ꢁ 105%) 3114.3129 (M+H)
C
109H148N40O28Na: monoisotopic Mwt 2488.128441; average Mwt
2489.664; [
a]
20 = +79.4 (0.5% DMSO).
D
4.6.3. 3,15-Bis{4,6-bis{4-{6-{[1,3-dihydroxy-2-(hydroxymethyl)-
prop-2-yl]amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-
yl]amino}-s-triazin-2-yl}-piperazin-1-yl}-s-triazin2-yl}-7,11,18,
21-tetraoxa-3,15-diazatrispiro[5.2.2.5.2.2]heneicosane 13C
Yellowish powder, mp 265–267 °C (flash column chromatogra-
phy, eluent EtOH/CHCl3/Toluene = 1:2:0.5 v/v/v). Found C, 51.28;
H, 6.01; N, 22.88; C105H140N40O32 (2473.06) requires C, 50.97; H,
5.70; Rf (10% EtOH/57% CHCl3/Toluene) 0.75; IR mmax (KBr) 3390
(m), 2931 (m), 2856 (m), 1553 (s), 1491 (s), 1436 (s), 1346 (s),
1268 (s), 1100 (m), 1026 (s), 851 (w), 809 (m), 744 (w), 710 (w)
cmꢀ1
;
1H NMR, 2D-1H,1H-COSY, 2D-1H,1H-NOESY (500 MHz,
DMSO-d6, 363 K) dH 1.81 (8H, dd app. t, JH,H = 5.6 Hz, H-1, -5,
(0.9); [a]
20 = +121.5 (0.5% DMSO).
D
3
3
-13, -17, Tsp), 3.60 (8H, t, JH,H = 5.1 Hz, H-2, -6, Pip), 3.69 (8H, t,
3J = 5.1 Hz, H-3, -5, Pip), 3.70 (24H, s, CH2OH), 3.72 (8H, t,
3JH,H = 5.6 Hz, H-2, -4, -14, -16, Tsp), 3.78 (8H, s, H-8, -10, -19,
4.6.5. 1,3,5-Tris{{15-{4,6-bis{4-{4-{[(2R,4S,5S)-5-(dimethylamino)-
4-(4-nitrophenyl)-1,3-dioxan]-2-yl}methylamino-6-[(4S,5S)-4-
(4-nitrophenyl)-1,3-dioxan-5-yl]amino-s-triazin-2-yl}-piper-
azin-1-yl}-s-triazin-2-yl}-7,11,18,21-tetraoxa-3,15-diazatrispiro-
[5.2.2.5.2.2]heneicosan-3-yl}-carbonyl}benzene 15
Compound 12 (0.26 g, 0.15 mmol) was suspended in anhydrous
THF (50 mL) after which anhydrous K2CO3 (0.02 g, 0.15 mmol) was
added with vigorous stirring. The resulting suspension was cooled
at ꢀ15 °C at which point benzene-1,3,5-tricarbonyl chloride
(0.01 g, 0.05 mmol) as clear anhydrous THF (1 mL) solution was
injected rapidly. The reaction mixture was allowed to gently reach
room temperature and was kept as such for an additional 12 h with
2
-20, Tsp), 4.04 (4H, d, JH,H = 11.3 Hz, H-6-a, D-ax), 4.13 (4H, d,
2JH,H = 11.3 Hz, H-6-e, D-ax), 4.44 (4H, d, JH,H = 9.0 Hz, H-5-e, D-
3
2
ax), 4.51 (12H, br s, OH), 5.02 (4H, d, JH,H = 5.3 Hz, H-2-a, D-ax),
5.24 (4H, d, JH,H = 5.3 Hz, H-2-e, D-ax), 5.25 (4H, s, H-4-a, D-ax),
5.46 (4H, s, SER-NH), 5.62 (4H, d, JH,H = 9.0 Hz, D-ax-NH), 7.65
(8H, d, JH,H = 8.8 Hz, H-2, -6, p-NPh), 8.13 (8H, d, JH,H = 8.8 Hz,
H-3, -5, p-NPh) ppm; Quantitative 13C NMR, DEPT (125 MHz,
DMSO-d6, 298 K) dC 32.7 (5C, C-1, -5, -9, -13, -17, Tsp), 43.0 (20C:
16C, Pip; 4C, C-2, -4, -14, -16, Tsp), 48.9 (4C, C-5, D-ax), 61.1 (4C,
C-2, SER C), 61.4 (12C, CH2OH), 62.8 (4C, C-8, -10, -19, -20, Tsp),
2
3
3
3
Please cite this article in press as: Moldovan, O.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.05.003

18
O. Moldovan et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
stirring. The formation of the desired product 15 was monitored by
TLC (eluent EtOH/CHCl3/Toluene = 1:3:1.5 v/v/v). The reaction mix-
ture was heated at 40 °C for an additional 72 h when TLC monitoring
confirmed the formation of 15. After cooling at room temperature,
the reaction mixture was evaporated under reduced pressure to
dryness. The resulting solid was taken with water (4 mL) with stir-
ring at room temperature for 1 h, then the suspension was filtered
off and washed with water to yield 0.25 g of crude material.
This was purified by flash column chromatography (eluent
EtOH/CHCl3/toluene = 1:3:1.5 v/v/v) to afford 0.11 g of compound
15 (56% yield with respect to benzene 1,3,5-tricarbonyl chloride).
Orange-yellowish powder, mp 232-234 °C (flash column chro-
matography, eluent EtOH/CHCl3/Toluene = 1:3:1.5 v/v/v). Found C,
54.98; H, 5.71; N, 20.19; C243H297N75O63 (5273.23) requires C,
55.31; H, 5.67; N, 19.91; Rf (10% EtOH/55% CHCl3/Toluene) 0.65;
IR mmax (KBr) 2964 (m), 2931 (m), 2858 (m), 1542 (s), 1441 (s),
1346 (s), 1262 (s), 1173 (m), 1095 (s), 1030 (m), 1000 (m), 851
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(w), 810 (m), 743 (w), 709 (w) cmꢀ1 1H NMR, 2D-1H,1H-COSY,
;
2D-1H,1H-NOESY (500 MHz, DMSO-d6, 363 K) dH 1.78 (12H, br s,
H-13, -17, Tsp), 1.87 (12H, br s, H-1, -5, Tsp), 2.23 (36H, s, NMe2),
3
2.86 (6H, dd app. t, JH,H = 3.0 Hz, H-5-e, D-eq), 3.47 (12H, dd app.
3
t, JH,H = 4.5 Hz, CH2NH), 3.62 (24H, br s, H-2, -6, Pip), 3.64 (24H,
br s, H-3, -5, Pip), 3.70 (24H, br s, H-2, -4, -14, -16, Tsp), 3.756-
3,763 (24H, br s, H-8, -10, -19, -20, Tsp), 3.96 (6H, dd,
2JH,H = 12.2 Hz, 3JH,H = 2.3 Hz, H-6-a, D-eq), 4.03 (6H, d,
2
2JH,H = 10.5 Hz, H-6-a, D-ax), 4.11 (6H, d, JH,H = 10.5 Hz, H-6-e, D-
2
ax), 4.45 (6H, d, JH,H = 12.2 Hz, H-6-e, D-eq), 4.49 (6H, d,
9. Zhang, W.; Simanek, E. E. Org. Lett. 2000, 2, 843–845.
3
3JH,H = 8.5 Hz, H-5-e, D-ax), 4.94 (6H, dd app. t, JH,H = 4.5 Hz, H-2-
10. (a) Steffensen, M. B.; Simanek, E. E. Angew. Chem., Int. Ed. 2004, 43, 5178–5180;
(b) Moreno, X. K.; Simanek, E. E. Tetrahedron Lett. 2008, 49, 1152–1154.
11. (a) Hollink, E.; Simanek, E. E. Org. Lett. 2006, 8, 2293–2295; (b) Lim, J.; Mintzer,
M. A.; Perez, L. M.; Simanek, E. E. Org. Lett. 2010, 12, 1148–1151.
12. (a) Umali, A. P.; Simanek, E. E. Org. Lett. 2003, 5, 1245–1247; (b) Zhang, W.;
Tichy, S. E.; Perez, L. M.; Maria, C. G.; Lindahl, P. A.; Simanek, E. E. J. Am. Chem.
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2013, 15, 3808–3811.
2
a, D-eq), 5.00 (6H, d, JH,H = 6.0 Hz, H-2-a, D-ax), 5.16 (6H, d,
3JH,H = 3.5 Hz, H-4-a, D-eq), 5.22 (6H, s, H-4-a, D-ax), 5.23 (6H, d,
3
2JH,H = 6.0 Hz, H-2-e, D-ax), 5.57 (6H, bd, JH,H = 8.5 Hz, D-ax-NH),
3
6.20 (6H, bt, JH,H = 6.3 Hz, D-eq-NH), 7.47 (3H, s, H-2, -4, -6, ben-
3
zene) 7.62 (12H, d, JH,H = 8.0 Hz, H-2, -6, p-NPh), 7.63 (12H, d,
3
3JH,H = 8.5 Hz, H-2, -6, p-NPh), 8.08 (12H, d, JH,H = 9.0 Hz, H-3, -5,
3
p-NPh), 8.14 (12H, d, JH,H = 9.0 Hz, H-3, -5, p-NPh) ppm;
Quantitative 13C NMR, DEPT (125 MHz, DMSO-d6, 298 K) dC 32.3,
32.4 (3C, C-9, Tsp), 42.8, 42.96, 43.03 (24C: 12C, C-1, -5, -13, -17,
Tsp; 12C, C-2, -6, Pip), 43.8 (12C, NMe2), 44.4 (30C: 12C, C-3, -5,
Pip; 12C, C-2, -4, -14, -16, Tsp; 6C, CH2NH), 48.8 (6C, C-5, D-ax),
58.49, 58.54 (6C, C-5, D-eq), 62.76, 62.84, 62.9 (12C, C-8, -10, -
19, -20, Tsp), 64.4, 64.5 (6C, C-6, D-eq), 70.7, 70.8 (6C, C-6, D-ax),
78.5, 78.6, 78.9 (6C, C-4, D-ax), 80.1, 80.30, 80.34 (6C, C-4, D-eq),
94.0 (6C, C-2, D-ax), 97.0, 97.3 (6C, C-6, -12, Tsp), 99.5, 99.72,
99.75, 99.9 (6C, C-2, D-eq), 123.2, 123.3, 123.4 (27C: 24C, C-2, -6,
p-NPh; 3C, C-2, -4, -6, benzene), 127.0, 127.4, 127.50, 127.53
(24C, C-3, -5, p-NPh), 146.6, 147.0, 147.1, 148.9 (27C: 24C, C-1,
-4, p-NPh; 3C, C-1, -3, -5, benzene), 164.6 (2C, C-2, T-1 [G-11,2],
164.8 (1C, C-6(4), T-1 [G-13]), 164.8 (2C, C-6(4), T-1 [G-11,2]),
164.9 (1C, C-2, T-1 [G-13]), 164.9 (1C, C-4(6), T-1 [G-13]), 164 9
(2C, C-4(6), T-1 [G-11,2]), 165.3 (6C, C-2, T-0 [G-11–3]), 165.8 (6C,
C-4, T-0, [G-11–3]), 166.0 (6C, C-6, T-0 [G-11–3]), 168.3 (3C, ˜C@O)
ppm; MS (MALDI, DHB) m/z (rel. abund. ꢁ 104%) 5123.530 (M-
3 ꢁ NO2) (2.6); MS (ESI+) m/z (rel. abund.%) 5277.0361 [M+H],
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[a]
20 = +147.0 (0.5% DMSO).
D
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The financial support from a Grant provided by the Research
Council Romania (project PN-II-ID-PCE-2011-3-0128) is gratefully
acknowledged. O.M. thanks University Babes-Bolyai for the
financial support awarded as Young Researcher (GTC 34053/2013-
2014). We wish to thank Prof. Jurgen Liebscher (Humboldt
University) for reading the Manuscript and suggesting
improvements.
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