Synthesis of Some Selectively N-Protected (1S,2S)-p-Nitrophenylserinol-Based Diamino-1,3-dioxanes and Tripodands

Article abstract of DOI:10.1080/00397911.2015.1078360

The unconventional methodology for the non-epimerizable cycloacetalization of optically active (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (p-nitrophenylserinol) (condensed H₂SO₄ 96% as solvent and catalyst, i.e., sulfuric transacetalization) producing (2R,4S,5S) diamino-1,3-dioxanes was enlarged by the use of N-protected forms of 2,2-dimethoxyethylamine (DMEA, aminoacetaldehyde dimethylacetal). Conversely, N-protected derivatives of p-nitrophenylserinol were successfully cyclocondensed with DMEA in the same sulfuric conditions. N-Functionalization of DMEA upon treatment with trimesic acid trichloride and cyanuric chloride yielded the corresponding triple amide and melamine, respectively. Their adapted sulfuric transacetalization in triplicate in reaction with arylserinols (aryl: phenyl, p-nitrophenyl) afforded a new series of optically active tripodands.

Full text of DOI:10.1080/00397911.2015.1078360

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of Some Selectively N-Protected (1S,2S)-
p-Nitrophenylserinol–Based Diamino-1,3-dioxanes
and Tripodands
Iulia Nagy, Oana Moldovan, Flavia Popa, Pedro Lameiras, Cristina Morar,
Carmen Sacalis & Mircea Darabantu
To cite this article: Iulia Nagy, Oana Moldovan, Flavia Popa, Pedro Lameiras, Cristina Morar,
Carmen Sacalis & Mircea Darabantu (2015) Synthesis of Some Selectively N-Protected
(1S,2S)-p-Nitrophenylserinol–Based Diamino-1,3-dioxanes and Tripodands, Synthetic
Communications, 45:20, 2319-2330, DOI: 10.1080/00397911.2015.1078360
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1078360
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Date: 02 October 2015, At: 11:26

Synthetic Communications1, 45: 2319–2330, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1078360
SYNTHESIS OF SOME SELECTIVELY N-PROTECTED
(1S,2S)-p-NITROPHENYLSERINOL–BASED
DIAMINO-1,3-DIOXANES AND TRIPODANDS
Iulia Nagy,1 Oana Moldovan,1 Flavia Popa,1 Pedro Lameiras,2
Cristina Morar,1 Carmen Sacalis,1 and Mircea Darabantu1
1Department of Chemistry, Babes-Bolyai University, Cluj-Napoca, Romania
2University of Reims Champagne-Ardenne, Reims, France
GRAPHICAL ABSTRACT
Abstract The unconventional methodology for the non-epimerizable cycloacetalization of
optically active (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol (p-nitrophenylserinol)
(condensed H2SO4 96% as solvent and catalyst, i.e., sulfuric transacetalization) producing
(2R,4S,5S) diamino-1,3-dioxanes was enlarged by the use of N-protected forms of 2,2-
dimethoxyethylamine (DMEA, aminoacetaldehyde dimethylacetal). Conversely, N-
protected derivatives of p-nitrophenylserinol were successfully cyclocondensed with DMEA
in the same sulfuric conditions. N-Functionalization of DMEA upon treatment with trimesic
acid trichloride and cyanuric chloride yielded the corresponding triple amide and melamine,
respectively. Their adapted sulfuric transacetalization in triplicate in reaction with
arylserinols (aryl: phenyl, p-nitrophenyl) afforded a new series of optically active tripodands.
Keywords Protecting groups; serinols; transacetalization; tripodands
Received May 23, 2015.
Address correspondence to Oana Moldovan and Mircea Darabantu, Babes-Bolyai University,
Department of Chemistry, 11 Arany Janos st., RO-400028, Cluj-Napoca, Romania. E-mail: moldovan@
chem.ubbcluj.ro; darab@chem.ubbcluj.ro
2319

2320
I. NAGY ET AL.
INTRODUCTION
Cycloacetalization of commercial optically active l-2-amino-1-arylpropane-1,
3-diols (arylserinols) IA and IB (Scheme 1) as well as that of N-dichloroacetyl-
derivative (1R,2R)-IC of IB, the antibiotic Chloromycetin,[1,2] has been a challenging
task for organic chemists as early as 1950s,[3a] for example (1R,2R)-IC → (4R,5R)-IIC
[R2 ¼ R3 ¼ Me, (CH2)n n ¼ 4, 5 etc].
At that time, 1,3-dioxanes of type (4R,5R)-IIC were seen as prodrugs of
Chloromycetin. Their synthesis required strong dehydrating methods using P2O5,
H2SO4,[3a,3b] or concentrated HCl.[3c] Recently, conformational analysis
concepts[4a,4b] and NMR data[4c] based studies justified these experimental conditions
by the steric hindrance between the cis (gauche) positioned ligands, eq-C-4 (Ar)=ax-C-5
(HN<), in the ensuing anancomeric condensates IIA–C. This spatial arrangement ori-
ginates from (i) the l (like) configuration of the open-chain precursors IA–C and
(ii) their non-epimerizable, hence diastereospecific, cyclization. Indeed, in the absence
of the aryl moiety at C-1 in IA–C (Scheme 1), cycloacetalization of the resulting N-pro-
tected 2-aminopropane-1,3-diol (serinol), as well as that of its C-2 substituted
analogs, occurs following classical protocols.[5] We mention here the only work of
Meslard et al.[6] in 1985, claiming the synthesis of a series of Chloromycetin IC–based
1,3-dioxanes IIC in mild conditions by using various (non)symmetric carbonyl
electrophiles (Scheme 1) with yields ranging between 4 and 89%.
The same ring closure in the case of optically active free amine l-IB, p-nitrophe-
nylserinol, is much less documented. We previously demonstrated this reaction is
practicable in the so-called sulfuric (trans)acetalization conditions, for example,
starting from (1S,2S)-IB (Scheme 2).[7]
This forcing acidic medium was also mandatory to temporarily complete
blocked nucleophilicity of the primary amino group of IB, thus avoiding any
N-protection–deprotection step.[2] Our methodology was inspired by the pioneering
work of Nagawa in 1955[8] referring to the related reaction between u (unlike,
“erythro,” rac)-IB and acetone.
Taxing conditions were reported as well for cycloacetalization of N-protected
forms of (l, rac or optically active) phenylserinol IA (formyl[9a–9c] and acetyl[9d]
)
Scheme 1. Previously reported types of arylserinols and Chloromycetin-based 1,3-dioxanes.[1–4,6]

N-PROTECTED DIAMINO-1,3-DIOXANES AND TRIPODANDS
2321
Scheme 2. Previous examples for sulfuric transacetalization of p-nitrophenylserinol (1S,2S)-IB.
yielding condensates with acetone, followed by deprotection. Optically active
acetonide (4S,5S)-IIA (Scheme 1, R1 ¼ H, R2 ¼ R3 ¼ Me) is a commercial and
well-known chiral auxiliary.[10]
Based on our preceding expertise in the field of this sort of syntheses,[2,7] the aim
of the present preliminary report consists of enlarging the number of masked carbonyl
electrophiles in addition with those of N-protected forms of p-nitrophenylserinol
(1S,2S)-IB, both envisaged as suitable partners for sulfuric transacetalization
reaction. The feasibility of the latter in triplicate, providing a new family of optically
active tripodands, was also investigated. A spotlight also concerned the use of
phenylserinol IA in this purpose.
RESULTS AND DISCUSSION
Use of p-Nitrophenylserinol (1S,2S) IB in Sulfuric Transacetalization
Conditions Providing Selectively N-Protected Derivatives of
Diamino-1,3-dioxane (2R,4S,5S)-IIIB
Except for the previous use of the dimethylacetal of aminoacetaldehyde (2,2-
dimethoxyethylamine, DMEA) in the synthesis of diamino-1,3-dioxane IIIB[7c,7d]
(Scheme 2) and regardless of conditions for cycloacetalization of IA–C, so far all
tested carbonyl electrophiles were actually either oxo- or formylated hydrocarbons,
bearing no additional functional group (Scheme 1). Therefore, we primarily planned
to N-protect DMEA to access additional masked carbonyl electrophiles, envisaged
as well for sulfuric transacetalization, against arylserinols IA and IB (Scheme 3).
Compounds 1a and 1b were prepared with good or excellent yields in
unsophisticated procedures already published by other authors.[11,12] In contrast,
the N-dichloroacetyl derivative 1c of DMEA was unknown up to now. Because
crude amidoacetals 1a–c displayed clean as convincing NMR and MS spectra, they
were used as such in the next step of the syntheses.

2322
I. NAGY ET AL.
Scheme 3. Synthesis of DMEA N-protected derivatives.
With 1a–c in our hands, we first submitted p-nitrophenylserinol (1S,2S)-IB to
the title transacetalization protocol (Scheme 4).
We thus obtained the equatorially C-2 mono-N-protected forms 2b and 2c of
the diamino-1,3-dioxane (2R,4S,5S)-IIIB with satisfactory yields; meanwhile, in
the case of 1a, decomposition of this N-Boc amidoacetal was observed. This failure
motivated us to look for an alternative strategy to access a compound of type 2 based
on Boc as PG (see later discussion). Decompositions of the reaction mixture also
took place in the case of phenylserinol (1S,2S)-IA upon treatment with 1a–c. That
is, we kept in mind that Boc PG-group in 1a and IA were inapt for this type of
conditions.
To prepare regioisomers of 2b and 2c, bearing the NH-PG sequence in axial
position C-5 of the 1,3-dioxane ring, we preliminarily N-(dichloro)acetylated
(1S,2S)-IB and then successfully cyclized the resulting open-chain derivatives 3b
and 3c in the previous conditions, in reaction with DMEA (Scheme 5).
We mention the preparation of compound 3b in optically active form (1S,2S)[13a]
because, according to literature, only (rac)-3b was previously reported.[13b] The classic
procedure[1,2] for N-dichloroacetylation of (1R,2R)-IB we applied in the case of its
known (1S,2S) antipode in the synthesis of (1S,2S)-3c.
Scheme 4. Synthesis of equatorially N-protected forms of diamino-1,3-dioxane (2R,4S,5S)-IIIB.

N-PROTECTED DIAMINO-1,3-DIOXANES AND TRIPODANDS
2323
Scheme 5. Synthesis of axially N-protected forms of diamino-1,3-dioxane (2R,4S,5S)-IIIB.
Selective N-Protection of Diamino-1,3-dioxane (2R,4S,5S)-IIIB
Because we were unable to obtain a compound of type 2 having Boc as PG
(Scheme 4), in a second synthetic pathway, we decided to investigate the reactivity
of the two differently located amino functionalities of (2R,4S,5S)-IIIB against all
three PG-reagents (a–c) listed in Scheme 3 (Scheme 6).
Scheme 6. Chemoselective mono-N-protection of diamino-1,3-dioxane (2R,4S,5S)-IIIB.

2324
I. NAGY ET AL.
Thus, during the slow portionwise addition of Boc2O (a) or Ac2O (b) to IIIB in
anhydrous CHCl3 or THF, the thin-layer chromatographic (TLC) monitoring
revealed the formation of two products. To our surprise, they were identified not
as regioisomeric compounds but as mono-N-protected 2a, 2b (major) against di-N-
protected 5a, 5b (minor) derivatives of IIIB. The total conversion of the PG-reagents
(a) and (b) was nearly complete. In the case of the softest electrophile as PG-reagent
(c), the N-protection was entirely regioselective, implying the sterically less congested
aminomethyl group in equatorial position C-2 of IIIb. The quantitative results
depicted in Scheme 6 could be subjected to some incipient comments:
i. Compounds 5a and 5b originated most probably from the equatorially
N-protected precursors 2a and 2b because, in each case, no regioisomeric
compounds 4a or 4b were detected. That is, 2a and 2b were more reactive than
IIIB in reaction with PG-(a) and PG-(b), respectively.
ii. Chemoselectivity (%) as 2 > 5 was sensitive to no bulkiness (a) > (b) > (c) of
the PG reagent, to be correlated with the sterically different location of the
amino groups in IIIB. Chemoselectivity related satisfactorily with the decreasing
electrophilicity of the PG reagents as a ∼ b > c.
iii. For the PG reagents (a) and (b), chemoselectivity was slightly dependent on the
solvent polarity, CHCl3 (e ¼ 4.81) against THF (e ¼ 7.52), presumably because of
the better solvating aptitude of the latter, favoring both the SN2 polar transition
states of amidations at C-2 as well as at C-5 1,3-dioxanic positions.
Sulfuric Transacetalization in Triplicate: Synthesis of New
Tripodands, Feasibilities, and Failures
The feasibility of sulfuric transacetalization in duplicate was reported
elsewhere[7c,7d] (compound IIIC, Scheme 2). Therefore, encouraged by these results,
we decided to explore this methodology in triplicate (Scheme 7).
With this aim, we primarily prepared, in classical conditions, two meta-tri-
valent (het)aryl derivatives based on DMEA, the novel triple amide 1d (starting from
Scheme 7. Sulfuric transacetalization in triplicate producing tripodands 6d, 6e, and 7d.

N-PROTECTED DIAMINO-1,3-DIOXANES AND TRIPODANDS
2325
trimesic acid trichloride d) and the known melamine 1e[14] (starting from cyanuric
chloride e). Both N-functionalizations of DMEA gave excellent yields. Then, we
tested cycloacetalization of p-nitrophenylserinol IB upon treatment with 1d and
1e. We thus accessed the equatorially anchored trimers 6d and 6e respectively with
good results. However, as one can see, the “typical” sulfuric transacetalization
procedure used so far (10 equiv. H2SO4 : 1 equiv. IB) worked properly in the case
of the synthesis of dioxanic-melamine 6e only. In the same conditions, the reaction
between trisamide 1d and IB gave a complex as decomposed reaction mixture.
Therefore, we considered, in this latter case, a moderation of the acidity strength
of the medium by reducing the molar ratio H2SO4:IB from 10:1 to 1:1 and replacing
the excess of concentrated H2SO4 by trifluoroacetic acid, i.e., 15 equiv. TFA : 1
equiv. IB. Our option was fruitful, though limited to the reaction between 1d
and IB (→6d) then 1d and IA (→7d). In spite of this modification, cycloacetalization
involving 1e þ IA failed to afford the corresponding trimer whose formation was just
detected by MS in a multicomponent raw material.
Compounds 6d, 6e, and 7d can also be seen as the first tripodands[15] built on
arylserinol-based amino-1,3-dioxane skeleton. Except for DMF and DMSO, they
manifested low solubility in other organic solvents. Fortunately, their purification
could be accomplished simply by (i) acid-base treatment and (ii) crystallization from
boiling ethanol. All compounds 1d, 1e, 6d, 6e, and 7d provided convincing analytical
1
and spectral data. As expected, on the H NMR timescale at room temperature
in DMSO-d6, melamines 1e and 6e and trisamides 6d and 7d exhibited blocked
orientations of their acetalic arms due to the well-known restricted rotation about
the partial double bonds C(s-triazine)-NH (exocyclic)[7d,16] and >C(¼ O)-NH-↔ > C
(-O–) ¼ NHþ-.[17–19]
CONCLUSIONS
In summary, we extended the sulfuric transacetalization methodology directed to
a selectively N-protected (1S,2S)-p-nitrophenylserinol-based (2R,4S,5S)-5-amino-2-
aminomethyl-1,3-dioxane by (i) using two masked carbonyl electrophiles, as
N-protected forms of the dimethylacetal of aminoacetaldehyde in reaction with
p-nitrophenylserinol, and (ii) by using two N-protected derivatives of p-nitrophenylser-
inol in reaction with the dimethylacetal of aminoacetaldehyde. The title diamino-1,3-
dioxane can be also regioselectively N-protected with respect to the equatorial
aminomethyl group upon treatment with typical protecting group reagents. Selectivity
correlates rather with the electrophilicity strength of the protecting group reagent than
with its bulkiness or the solvent solvation capacity. Submission to (moderated) sulfuric
transacetalization conditions of two meta-trivalent (het)aryl derivatives based on
DMEA in reaction with (1S,2S)-arylserinols afforded the first series of tripondands
built on arylserinolic amino-1,3-dioxane skeleton. Their potential use in iterative
synthesis as new meta-trivalent dendritic cores will be reported in the near future.
EXPERIMENTAL
Melting points were measured on an Electrothermal instrument. NMR spectra
were recorded on Bruker AV 400, AV 500, or AV 600 instruments operating at 400,

2326
I. NAGY ET AL.
500, or 600 MHz for 1H and at 100, 125, or 150 MHz for 13C nuclei respectively. All
chemical shifts (d values) are given in parts per million (ppm); all homocoupling
patterns (nJH,H values) are given in hertz. TLC was performed by using aluminium
sheets with silica gel 60 F254 (Merck); column chromatography was conducted on sil-
ica gel 60 (40–63 µm, Merck). IR spectra were recorded on a Bruker FT-IR Vector 22
spectrometer. Microanalyses were performed on a Carlo Erba CHNOS 1160 appar-
atus. Mass spectra were carried out on a LTQ ORBITRAP XL (Thermo Scientific)
instrument, which was externally calibrated using the manufacturer's ESI(þ) cali-
bration mix. The samples were introduced into the spectrometer by direct infusion.
T
Specific rotations ½aꢀD were measured on a Polamat Karl-Zeiss Jena instrument. All
reagents and solvents were of commercial quality and used as such with no sup-
plementary purification except for methyl dichloroacetate, which was freshly distilled
prior to use. The starting (1S,2S)-2-amino-1-phenylpropane-1,3-diol (1S,2S)-IA
20
(phenylserinol, CAS No. 28143-91-1) had 99% enantiomeric purity, ½aꢀD þ 25:7
(c 1, MeOH). The starting (1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol
(1S,2S)-IB (p-nitrophenylserinol, CAS No. 2964-48-9) has a 99% enantiomeric
25
purity as ½aꢀD þ 31:0 (c 1, HCl 6 M). Synthesis and data of compound (2R,4S,5S)-
25
IIIB, ½aꢀD þ 146:2 (c 0.5, DMSO), we reported elsewhere.[7c,7d] Hereafter, p-NPh
stands for the p-nitrophenyl group. Compound 1e was previously reported;[14]
however, its complete structural characterization as well as its improved synthesis
are described in this work.
Typical Procedure for Preparation of Compounds 2b and 2c by
Sulfuric Transacetalization of p-Nitrophenylserinol (1S,2S)-IB:
Preparation of Compound 2c
At 0 °C and with vigorous stirring, fine powdered p-nitrophenylserinol (1S,2S)-
IB (1.00 g, 4.72 mmol) was slowly added to concentrated H2SO4 (96%, 2.62 mL,
4.82 g, 47.20 mmol). The resulted slurry was stirred at 0 °C for 1 h, and then crude
N-dichloroacetyl-2,2-dimethoxyethylamine 1c (1.02 g, 4.72 mmol) was rapidly injected
at this temperature. The reaction mixture was allowed to reach room temperature and
kept as such with vigorous stirring for an additional 24 h. After this period, TLC moni-
toring (eluent EtOH=CH2Cl2 3:1 v=v, visualization in UV at k ¼ 254 nm) indicated the
complete consumption of IB. At 0 °C, the reaction mixture was carefully poured into
CHCl3 (100 mL) and aqueous ammonia (25%, 20.00 mL, 19.60 g, 288.00 mmol) was
diluted 1:1 g=g with ice. The resulting pH was 10–11 and the organic layer was recov-
ered. The aqueous layer was extracted with CHCl3 (2 ꢁ 25 mL). The combined CHCl3
solution was washed with water (25 mL), dried over anhydrous Na2SO4, and then eva-
porated in vacuum to dryness to yield 1.27 g crude product 2c as brownish oil. This
was purified by column chromatography on silica gel (eluent EtOH=CH2Cl2
3:1 v=v) to give 0.9 compound 2c (58% yield with respect to IB) as an yellow solid.
(2R,4S,5S)-5-Amino-2-(N-dichloroacetyl)aminomethyl-4-(4-
nitrophenyl)-1,3-dioxane 2c
Yellow solid; mp 62–64 °C. Rf(75% EtOH=CH2Cl2) ¼ 0.60. Anal. calcd. for
C13H15Cl2N3O5: C, 42.87; H, 4.15; N, 11.54. Found: C, 43.08; H, 3.99; N, 11.28.

N-PROTECTED DIAMINO-1,3-DIOXANES AND TRIPODANDS
2327
IR (KBr) nmax 3366, 2861, 1715, 1700, 1520, 1349, 1150, 1110, 1013, 878, 812, 742,
1
1
707 cmꢂ1. H and 2D-1H, H-COSY NMR (400 MHz, CDCl3) dH 1.47 (br s, 2H,
NH2), 2.97 (s, 1H, H-5-e), 3.65 (dd, J 6.1, 3.8 Hz, 1H, CH2-NH) and 3.68 (dd, J
6.1, 4.4 Hz, 1H, CH2-NH), 4.14 (dd, J 11.9, 1.8 Hz, 1H, H-6-a), 4.18 (dd, J 11.9,
2.0 Hz, 1H, H-6-e), 4.95 (dd app. t, J 4.0 Hz, 1H, H-2-a), 5.04 (s, 1H, H-4-a), 5.99
(s, 1H, CHCl2), 6.97 (br s, 1H, NH), 7.47 (d, J 8.6 Hz, 2H, H-2, -6, p-NPh), 8.24
(d, J 8.6 Hz, 2H, H-3, -5, p-NPh) ppm. 13C NMR-Jmod (100 MHz, CDCl3) dC 43.2
(CH2-NH), 49.6 (C-5), 66.5 (CHCl2), 72.8 (C-6), 80.2 (C-4), 99.0 (C-2), 123.9 (C-2,
-6, p-NPh), 126.5 (C-3, -5, p-NPh), 145.9 (C-1, p-NPh), 147.5 (C-4, p-NPh), 164.6
(C=O) ppm. HRMS-APCI m=z (relative intensity): 364.0446 (100) [M þ H]þ. [M þ
25
H]þ calcd. for C13H16Cl2N3O5, 364.0469. ½aꢀD þ 170:6 (c 0.5, DMSO).
Typical Procedure for Regioselective N-Protection of Diamino-1,3-
dioxane (2R,4S,5S)-IIIB: Preparation of Compounds 2b and 5b
Anhydrous K2CO3 (0.54 g, 3.95 mmol) was added to a solution obtained by dis-
solving diamino-1,3-dioxane (2R,4S,5S)-IIIB (1.00 g, 3.95 mmol) in anhydrous
CHCl3 (10 mL), and the resulted suspension was cooled at 0 °C with vigorous stirring.
At this temperature, acetic anhydride (0.37 mL, 0.40 g, 3.95 mmol) was added as 10
equal portions every 2 h. After this period, TLC monitoring (eluent EtOH=CH2Cl2
3.5:1 v=v visualization in UV at k ¼ 254 nm) indicated formation of two products,
2b and 5b, and the presence of the starting material IIIB. Stirring was continued
for additional 20 h at 0 °C, then minerals were filtered off, and the product was well
washed with anhydrous CHCl3. The organic filtrate was evaporated in vacuum to give
1.20 g crude material. This was separated by column chromatography on silica gel
(eluent EtOH=CH2Cl2 3.5:1 v=v) to provide, in order, compound 5b (0.21 g, 16%
partial conversion of IIIB) and then compound 2b (0.79 g, 68% partial conversion
of IIIB).
Typical Procedure for Preparation of Compounds 6d, 6e, and 7d:
Preparation of Compound 6d
Fine powdered p-nitrophenylserinol (1S,2S)-IB (1.35 g, 6.36mmol) was added
portionwise and with vigorous stirring to cooled trifluoroacetic acid (7.40 mL,
10.88g, 95.44 mmol) in such a rhythm that temperature did not rise up to 0 °C. After
additional 2 h of stirring at 0 °C, to the resulted fine suspension H2SO4 concentrate
(96%, 0.35 mL, 0.65 g, 6.36mmol) was injected dropwise at the same temperature. Fine
powdered compound 1d (1.00 g, 2.12mmol) was then added portionwise at 0 °C and
the reaction mixture was let to reach the room temperature and was kept stirring for
24 h (TLC monitoring, eluent EtOH=NH3 25% aqueous 4:0.1 v=v, visualization in
UV at k ¼ 254 nm, one major spot). At 0 °C and with vigorous stirring, the reaction
mixture was carefully poured in aqueous ammonia (25%, 15.20 mL, 3.46g,
203.60 mmol) diluted with water (20 mL) and ice (20 g). The basic suspension (pH
¼ 10–11) was filtered off and the solid was well washed to neutrality with cooled water.
After drying, 1.80 g crude product 6d was obtained. This was taken with aqueous 10%
HCl (20 mL). The resulting fine brownish suspension (pH 0.5–1.0) was filtered off with
charcoal and the filtrate was made alkaline (pH ¼ 10–11) with anhydrous K2CO3 when

2328
I. NAGY ET AL.
6d precipitated. After filtering, washing to neutrality with water, and drying, 1.75g of
compound 6d was obtained. This material was finally taken with boiling EtOH (18 mL)
to give, after crystallization, 1.67 g pure compound 6a (86% yield with respect to 1d).
1,3,5-Tris{N-{[(2R,4S,5S)-5-amino-4-(4-nitrophenyl)-1,3-dioxan-2-yl]
methyl}aminocarbonyl}benzene 6d
Yellow solid; mp 182–184 °C (dec.). Rf(97.5% EtOH=NH3 25% aq.) ¼ 0.37.
Anal. calcd. for C42H45N9O15: C, 55.08; H, 4.95; N, 13.76. Found: C, 55.11; H,
4.75; N, 13.88. IR (KBr) nmax 3400, 3074, 2869, 1658, 1518, 1348, 1285, 1150, 1105,
1
1007, 860, 783, 742 cmꢂ1. H and 2D-1H,1H-COSY NMR (600 MHz, DMSO-d6,
298 K) dH 2.95 (br s, 3H, H-5-e), 3.57 (br s, 12H, CH2NH, NH2), 3.95 (br d, J
9.9 Hz, 3H, H-6-a), 4.08 (br d, J 9.9 Hz, 3H, H-6-e), 4.99 (br s, 3H, H-2-a), 5.13 (br
s, 3H, H-4-a), 7.61 (br d, J 7.5 Hz, 6H, H-2, -6, p-NPh), 8.21 (br d, J 7.5 Hz, 6H,
1
H-3, -5, p-NPh), 8.46 (br s, 3H, H-2, -4, -6, benzene), 8.92 (br s, 3H, NH) ppm; H
and 2D-1H,1H-COSY NMR (400 MHz, DMSO-d6, 353 K) dH 3.00 (br s, 3H, H-5-
e; 6H, NH2), 3.61 (br s, 6H, CH2NH), 3.98 (br d, J 11.2 Hz, 3H, H-6-a), 4.11 (br d,
J 11.2 Hz, 3H, H-6-e), 5.03 (br s, 3H, H-2-a), 5.12 (br s, 3H, H-4-a), 7.63 (br d, J
7.6 Hz, 6H, H-2, -6, p-NPh), 8.19 (br d, J 7.5 Hz, 6H, H-3, -5, p-NPh), 8.44 (br s,
3H, H-2, -4, -6, benzene), 8.58 (br d, J 4.8 Hz, 3H, NH) ppm. 13C NMR Jmod
(150 MHz, DMSO-d6, 298 K) dC 43.2 (CH2NH2), 48.8 (C-5), 72.6 (C-6), 79.2 (C-4),
99.1 (C-2), 123.1 (C-2, -6, p-NPh), 127.0 (C-3, -5, p-NPh), 129.0 (C-2, -4, -6, benzene),
134.7 (C-1, -3, -5, benzene), 146.6 (C-1, p-NPh), 147.6 (C-4, p-NPh), 165.9 (C=O)
ppm. HRMS-ESI(þ) (relative intensity) m=z: 916.3060 (100) [M þ H]þ. [M þ H]þ
25
calcd. for C42H46N9O15, 916.3113. ½aꢀD þ 121:0 (c 0.5, DMSO).
FUNDING
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
Babes-Bolyai University for the financial support awarded as a young researcher
(GTC 34053=2013).
SUPPORTING INFORMATION
(Typical) procedures for preparations of compounds 1a, 1b, 1c, 3b, 4b, 4c, 1d,
and 1e; full analytical data of compounds 1a, 1b, 1c, 2b, 3b, 4b, 4c, 2a, 5a, 5b, 1d, 1e,
6e, and 7d; 1H and 13C NMR spectra of compounds 1a, 1b, 1c, 2b, 4b, 4c, 3b, 2a, 5a,
5b, 1d, 1e, 6d, 6e, and 7d; and MS of compounds 6d, 6e, and 7d for this article can be
accessed on the publisher’s website.
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