A new synthetic route to tyromycin A and its analogue from renewable resources

Article abstract of DOI:10.1016/j.tet.2008.11.091

The synthesis of tyromycin A and that of the non-natural lower homologue, involving as featuring steps a transition metal catalyzed atom transfer radical cyclization and a functional rearrangement of the polyhalogenated 2-pyrrolidinones thus obtained, are

Full text of DOI:10.1016/j.tet.2008.11.091

Tetrahedron 65 (2009) 1481–1487
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A new synthetic route to tyromycin A and its analogue from renewable resources
,
b
,
a
b
Fabrizio Roncaglia a , Christian V. Stevens , Franco Ghelfi , Marijke Van der Steen ,
*
*
Mariella Pattarozzi a, Laurent De Buyck b
a
`
Dipartimento di Chimica, Universita degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
b Research group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of tyromycin A and that of the non-natural lower homologue, involving as featuring steps
a transition metal catalyzed atom transfer radical cyclization and a functional rearrangement of the
polyhalogenated 2-pyrrolidinones thus obtained, are described. Both routes use 10-undecenoic acid,
a renewable source from castor oil, as starting material for the preparation of the pivotal intermediates
Received 25 September 2008
Received in revised form 11 November 2008
Accepted 27 November 2008
Available online 3 December 2008
a,a, ,a
a0 0-tetrachlorodicarboxylic acids.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Undecylenic acid
Tyromycin A
Rearrangement
Radical reaction
Bio-based chemicals
1. Introduction
immunomodulating drug.5 These properties, together with the
scarce availability from natural origin, make 10 and analogous
structures precious targets to be prepared, in order to investigate
further the said biological activity. To the best of ourknowledge, only
a couple of synthetic approaches to 10 appeared in the literature.6
In this paper a new synthesis of 10, based on a known strategy,
developed by us for the attainment of mono methylmaleic anhy-
Exopeptidases are proteolytic enzymes that catalyze the hy-
drolytic removal of amino acids from the termini of peptides and
proteins. Two major classes of exopeptidases exist: aminopepti-
dases (APs), which cleave N-terminal amino acids, and carboxy-
peptidases, which cleave C-terminal ones.1 APs occur in both
soluble and membrane bound forms and mainly consist of
metalloproteins. Historically, APs were considered as a ubiquitous
set of enzymes with routinary roles in cell homeostasis, controlling
mainly the final events of the journey of a polypeptide through
a cell. Instead, in recent years, new evidence showed how APs carry
out important functions in cell growth and development, and de-
fence.2 Hence APs are emerging as novel and exciting potential
targets to treat diverse diseases, like hypertension, cancer, or
immuno-disregulation,3 among others.
Tyromycin A (10, Fig. 1) is a naturally occurring metabolite that
holds two 3-methyl maleic (citraconic) anhydride moieties,4 and
was originally isolated from cultures of the wood basidiomycete
Tyromyces lacteus (Fr.) Murr.5 At non-cytotoxic levels, 10 strongly
inhibits both leucine and cysteine mammalian APs bound to outer
surface of HeLa S3 cells, holding in such way, promising potential as
dride structures,7 is reported. The starting point is a0 0-tetra-
a,a, ,a
chlorodicarboxylic acid 6, an interesting bio-based building block
recently prepared by us through an acyloin condensation (via the
methylester) of 10-undecenoic acid (1), a renewable resource from
castor oil (Scheme 1, route a).8 An alternative manipulation of 1,
here illustrated (Scheme 1, route b), led to the one carbon atom
fewer analogue 14. From this molecule, the non-natural analogue
20 (Fig. 1) was prepared, following a modified approach we have
recently worked out for the synthesis of disubstituted maleic an-
hydrides.9 Both the syntheses of 6 and 14 were designed to be
suitable for large scale, aiming to direct some effort into the pro-
duction of bio-based chemicals.
O
O
n
O
O
O
O
10 (n=6,Tyromycin A)
20 (n=5)
* Corresponding authors. Tel.: þ39 059 2055049; fax: þ39 059 373543.
E-mail addresses: fabrizio.roncaglia@unimore.it (F. Roncaglia), chris.stevens@
ugent.be (C.V. Stevens).
Figure 1. Tyromycin A and its analogue.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.091

1482
F. Roncaglia et al. / Tetrahedron 65 (2009) 1481–1487
O
subjected to an oxidative treatment with aqueous H2O2, resulting in
the breaking of the
-oxoacid moieties.12 A convenient work-up
a
( )8
OH
was developed by the addition of Et2O and a little amount of Et3N
(10 mol % in respect to 13), after which an easily filterable crystal-
line mass was obtained. Isolation of this mass, a complex composed
by Et3N/14 1:3, permitted us to largely recover the desired product
by acidification and recrystallization from CCl4. Curiously enough,
tetrachlorodiacid 14 is almost insoluble in CCl4, CHCl3 and CH2Cl2,
but very soluble in Et2O at 20 ꢀC, whereas the triethylammonium
monocarboxylate complex is poorly soluble in cold Et2O and dis-
solves readily in CH2Cl2. This procedure, although straightforward,
gave only 28% of purified 14, while around 10% of it was still
detected in solution (by 1H NMR) together with some over-
chlorinated compounds and unreacted oxoacids. A practical way to
recover this valuable material was then successfully attempted.
Treating the mother liquors with an excess of Zn0 powder and HOAc
(for 4 h at 110 ꢀC), the crystalline non-chlorinated C19 diacid was
obtained. Subsequent reduction with LiAlH4 afforded the crystal-
lizable diol 5a, analogue of 5 (in 50% yield from 13), whose con-
version to the desired halogenated diacid 14 was possible (in 40%
yield from 5a), following the same steps used to prepare 6 from 5
(Scheme 1, route a).8
1
O
( )8
OCH3
b
2
1. NaOMe
a
(see ref. 8)
O
2. NaOH / H2O
O
( )
( )8
3
( )8 ( )8
11
8
OH
1. NH2NH2
2. KOH, Δ
( )17
( )17
12
4
1. HCOOH, H2O2
2. KOH
OH OH
( )17
13
OH
HO
OH
( )17
HO
5
(see Scheme 2)
OH
OH
OH
Cl Cl
O
( )15
Cl Cl
( )13
O
O
O
Cl Cl
14
Cl Cl
OH
6
2.2. Preparation of tyromycin A and its analogue (20)
Scheme 1. Preparation of the intermediates from 10-undecylenic acid.
The condensation of a,a-dichlorocarboxylic acids A with N-3-
chloroallyl secondary amine B1, followed by a Transition Metal
Catalyzed-Atom Transfer Radical Cyclization (TMC-ATRC) pro-
moted by the redox catalyst formed by CuCl and a polydentate
nitrogen ligand, is a convenient route towards polychloro pyrroli-
dinones D1 (Scheme 3).13 The ensuing functional rearrangement
(FR) of D1 (route I), promoted by the methoxide ion in methanol,
represents an elegant access to 5,5-dimethoxy-4-methyl-3-pyrro-
lin-2-ones E, good precursors towards the methylmaleic anhydride
framework G.7 Alternatively G can be approached from a non-
chlorinated amine B0 (route II, Scheme 3). In this case the FR of D0
2. Results and discussion
2.1. Preparation of tetrachlorodiacid 14
For the construction of 14,
a Claisen condensation/de-
carboxylation of methylester 2 was developed (Scheme 1, route b)
by which one carbon atom was lost. This coupling process fur-
nished ketone 11, isolated through crystallization in 64% yield, to-
gether with some unreacted starting material recovered as 1 from
the aqueous phase (23%). Subsequent Wolff–Kishner reduction
proceeded smoothly and gave diene 12 in 85% yield.
Dihydroxylation of 12 with formic acid/hydrogen peroxide gave
tetraol 13 directly, without isolation of the diepoxide,10 in a 50%
crystallized yield. The direct chlorination of 13, using gaseous Cl2
within the DMF/CHCl3/MgCl2 system (Scheme 2),11 gave bis-(3,3-
dichloro-2-oxoacid) 13a, which, without isolation, was further
Cln
Cl
Cl
Cln
Cl
Cl
R
O
R
+
OH
A
HN
CA
N
O
CA
Bn
Cn
TMC-
ATRC
CA = Cyclization Auxiliary
Cl
Cln
OH
OH
Cl
R
R
FR
HO
O
OH
( )17
(n=1)
OMe
13
Cl2
O
O
N
CA
N
CA
I
OMe
DMF·HCl
MgCl2
Dn
E
O
FR
(n=0)
II
HO
OH
( )13
Cl
Cl
R
Cl Cl
13a
O
O
R
H2O2
O
O
OMe
O
O
N
CA
O
G
H
O
O
+ residue
1. Zn0, HOA
( )13
OH
HO
Cl
Cl
Cl
Cl
c
14 (28%)
R
R
2. LiAlH4
O
O
(see
OH
N
CA
N
CA
( )13
5a (50%)
Scheme 2. Chlorination/oxidative breaking of tetraol 13.
scheme 1)
HO
OH
I
F
Scheme 3. Alternative routes (I or II) towards methylmaleic cores.

F. Roncaglia et al. / Tetrahedron 65 (2009) 1481–1487
1483
N
N
O
O
O
O
O
O
O
H2SO4
H2O
N
N
N
N
O
O
( )13
Cl Cl
HO
OH
( )13
( )13
Cl Cl
14
O
O
O
1. (COCl)2, DMF
2. Py, 7a (2 eq)
19 (85%)
20 (67%)
MnO2
O
O
N
N
O
N
O
N
( )13
Cl Cl
N
N
N
( )13
Cl Cl
HO
OH
15 (95%)
18 (75%)
CuCl
H2SO4
H2O
TMEDA
N
N
N
O
N
O
O
O
Na
MeOH
N
N
N
( )13
Cl
( )13
Cl
MeO
17 (62%)
OMe
Cl
Cl
16 (90%) (cis,cis isomer 81%)
Scheme 4. Preparation of the tyromycin A analogue (20) following the route II.
affords the 5-methoxy-3-pyrrolin-2-one H, an intermediate that
requires two steps to be converted into the maleimide precursor F:
(i) hydrolysis to the 5-hydroxy-3-pyrrolin-2-one I, and (ii) oxida-
tion of I to F.9
Notwithstanding route I is shorter, it is afflicted by an inefficient
preparation of the starting amine.7 On the contrary, way II, even if
longer, appears more practical, since both the preparation of the
starting material and of all the intermediates can be completed
with simple, economic and high yielding procedures.9
With the aim to compare the two approaches, we scheduled the
synthesis of 20 from 14 according to path II (Scheme 4), and that of
10 from 6 following the route I (Scheme 5), using N-allylamines 7a
and 7 (Fig. 2), respectively. The selected cyclization auxiliary, i.e.,
the 2-pyridyl group, not only helps the TMC-ATRC step, but is able
to facilitate the FR and the final hydrolytic steps.9
After the preparation of N-allyl-2-aminopyridine 7a (as de-
scribed in Ref. 9), its coupling with diacid 14 smoothly furnished
bis-amide 15 (Scheme 4). TMC-ATRC of 15, promoted by CuCl/
TMEDA in CH3CN and CH2Cl2 (as a co-solvent to improve the sol-
ubility), gave bis-2-pyrrolidinone 16. The cyclization was conducted
at 60 ꢀC for 20 h (under thermodynamic control)9 in order to obtain
16, mainly in the cis,cis configuration (81%). The cis arrangement
between the pyrrolidinones’ substituents bound at the annular
positions C(3) and C(4) is a need, since it is the only configuration
that can give the functional rearrangement with sodium methoxide
in methanol.7,9
hot ethanol, an insoluble brown impurity oiled-out during cooling.
After its removal, a clean and easy crystallization, from the same
solvent, afforded 10 in 55% yield (37% overall yield from 6).
Although path II is more appropriate for large-scale preparation,
owing to the easier preparation of the starting allylamine, it ap-
pears less efficient than route I, 23% overall yield against 37%, cal-
culated from the intermediates
a
,a
,
a0
,a
0-tetrachlorodicarboxylic
O
Cl Cl
HO
6
( )15
Cl Cl
OH
O
1. (COCl)2 , DMF
2. Py, 7 (2 eq)
Cl
O
N
Cl Cl
N
( )15
Cl Cl
N
N
O
8 (78%)
CuCl
TMEDA
Cl
Cl
Cl
Cl
O
N
N
N
( )15
N
O
Cl
Cl
9 (86%)
In fact, after subjecting 16 to the FR in MeOH and Et2O (as
a solubility enhancer), bis-5-methoxy-3-pyrrolin-2-one 17 was
isolated in 62% yield. The hydrolysis of 17 gave us 5,50 dihydroxy-
pyrrolinone 18 in 75% yield; 18 was then oxidized with MnO2
affording imide 19 in good yield (85%). Finally, the hydrolysis of 19
secured the desired tyromycin A analogue 20 in 67% yield (23%
from 14).
Cl
Na
(cis,cis isomer 86%)
MeOH
OMe
MeO
N
N
O
N
( )15
O
N
The preparation of N-(3-chloroallyl)-2-aminopyridine 7 (as de-
scribed in Ref. 7), although not particularly effective (35% yield),
gave us bis-amide 8 through its coupling with diacid 6 (prepared as
in Ref. 8), in good yield (Scheme 5). TMC-ATRC of 8, promoted by
CuCl/TMEDA in CH3CN and CH2Cl2 (to improve the solubility) at
60 ꢀC for 20 h, gave bis-pyrrolidinone 9, mainly in the cis,cis-rela-
tive configuration (86%).
9a
OMe
MeO
H2SO4
H2O
O
O
O
( )15
O
O
O
Then, subjecting 9 to the one-pot FR-hydrolysis sequence,7
crude tyromycin A (10) was obtained. For the purification of 10, we
observed that when the crude reaction residue was solubilized in
10 (55%)
Scheme 5. Tyromycin A synthesis according to route I.

1484
F. Roncaglia et al. / Tetrahedron 65 (2009) 1481–1487
Elemental analyses were performed through a Perkin Elmer CHNS/O
Cl
2400 (Series II) Analyzer, at Ghent University facility. Infrared
spectra were recorded on a Perkin Elmer 1600 Series FTIR spec-
trophotometer. Mass spectra were acquired over an Agilent 1100
Series HPLC coupled with a VS (ES, 4000 V) MS (Agilent 1100 Series)
or, alternatively, over a HP6890 GC coupled with an HP5973 MS
quadrupole detector. Melting points of crystalline compounds were
measured with a Bu¨chi 540 apparatus and are uncorrected.
HN
HN
N
N
7
7a
Figure 2. Amines used following route I (7) or II (7a).
4.2. Preparation of heneicosa-1,20-dien-11-one (11)
acids 14 and 6, respectively. Surely the main reason for this less
appealing performance of II relates to the isolation–purification of
every intermediate. This is not the case for route I where the FR and
hydrolysis stages were integrated in a one-pot process. Since the
hydrolytic steps of the intermediates 17 and 19 (path II) were car-
ried out in acidic water, the identification of an environmental
friendly oxidant able to work effectively in H2O/Hþ will give the
opportunity to integrate these three passages in a one-pot pro-
cedure with favourable effect on the process efficiency.
A solution of NaOMe was prepared by dissolving Na0 (27 g,
1.27 mol) in dry methanol (250 mL) into a 1-L two-necked flask,
fitted with a dropping funnel and a condenser connected at the top
to a CaCl2 tube. Methylester 2 (500 g, 2.52 mol) was then added to
the (still) hot solution of NaOMe, with the help of a little amount of
petroleum ether (bp 40–60 ꢀC), and heater was turned on. Through
a 40 cm Vigreux column (not insulated, to prevent the distillation of
2), petroleum ether (bp. 40–60 ꢀC) and methanol were distilled off.
After 20 h, vacuum was applied to obtain 10 mmHg with a bath
temperature of 150 ꢀC. After cooling down the mixture, a solution
of NaOH (60 g, 1.5 mol) in ethanol/water 8:2 (250 mL) was added
and the mixture was refluxed for 4 h. Then, vacuum was applied in
order to remove most of the ethanol and to ensure a complete
hydrolysis. Dilution with water (250 mL) and extraction with
CH2Cl2 (2ꢁ250 mL) gave the crude product (without much problem
of emulsification). Evaporation of the solvent and recrystallization
from petroleum ether (bp 40–60 ꢀC) (or from ethanol) at 0 ꢀC (or
less) afforded the ketone 11 (247.4 g, 64%), as white solid. Some
unreacted undecylenic acid 1 (106.8 g, 23%) was recovered from the
aqueous phase by acidifying with concentrated HCl(aq) (until pH 2)
and extracting with petroleum ether (bp. 40–60 ꢀC).
3. Conclusions
We have described the synthesis of tyromycin A (10) and that of
its non-natural lower homologue 20, comparing two different pro-
cedures for building of the maleic core. The pivotal intermediates to
these target compounds,
a,a, ,a
a0 0-tetrachlorodicarboxylic acids 6
and 14, were both obtained from undecylenic acid (1), a renewable
resource from castoroil. While the preparation of 6 was illustrated in
our previous article,8 we now also report the transformation of 1 to
get 14.
4. Experimental part
4.1. General
Found: C, 82.2; H, 12.6. C21H38O requires C, 82.29; H, 12.50. 1H
NMR (200 MHz, CDCl3): d 1.00–1.45 (20H, m, 10CH2), 1.45–1.70 (4H,
m, 2CH2), 2.04 (4H, q, J 6.6 Hz, 2CH2CH]), 2.38 (4H, t, J 7.4 Hz,
2C(O)CH2), 4.85–5.08 (4H, m, 2]CH2), 5.81 (2H, qt, J 17.0, 10.2,
Reagents and solvents were standard grade commercial prod-
ucts, purchased from: Aldrich, Acros, Fluka or RdH, and used
without further purification, except for acetonitrile and CH2Cl2 that
were dried over three batches of 3 Å sieves (5% w/v, 12 h).
2,2,19,19-Tetrachloroicosan-1,20-dioic acid (6), 10-undecylenic acid
methylester (2), N-(2-pyridyl)-3-chloro-allylamine (7) and N-(2-
pyridyl)-allylamine (7a) have been prepared according to the
literature.7–9 The silica gel used for flash chromatography was Silica
Gel 60 Merck (0.040–0.063 mm). 1H and 13C NMR were recorded on
a Jeol JNM-EX 300 NMR, a Bruker DPX 200 and a Bruker Avance 400
6.6 Hz, 2CH]). 13C NMR (50.3 MHz, CDCl3):
d 23.9 (2CH2CH2C(O)),
28.9, 29.0, 29.2, 29.3, 29.3 (10CH2), 33.8 (2CH2CH]), 42.8
(2CH2C(O)), 114.1 (2]CH2), 139.2 (2CH]), 211.7 (C]O). IR (KBr):
915 (CH]CH2), 994 (CH]CH2), 1698 (C]O) cmꢂ1. MS (EI, m/z): 306
(5%, Mþ), 249 (18), 167 (29), 149 (28), 83 (56), 69 (47), 55 (100).
Mp¼55–56 ꢀC.
4.3. Preparation of heneicosa-1,20-diene (12)
by Wolff–Kishner reduction
spectrometer. Chemical shift (d) have been reported in parts per
million (ppm) relative to the residual undeuterated solvent as an
internal reference (CDCl3: 7.26 ppm for 1H NMR and 77.0 ppm for
13C NMR; CD3OD: 4.84 ppm for 1H NMR and 49.05 ppm for 13C
NMR). Carbon spectra assignments are supported by DEPT analysis
and 1H–13C correlations where necessary. The relative stereo-
chemistry of structure 9 was assigned by comparison of its 1H NMR
spectrum with those of cis- and trans-N-(2-pyridyl)-3-chloro-4-
dichloromethyl-3-methyl-2-pyrrolidinone, which relative config-
urations between C(3) and C(4) were determined through NOE
techniques.7 Particularly, the cis diastereomer shows a multiplet for
the C(4)H proton and a doublet for the CHCl2 at 3.02 and 6.11 ppm,
respectively, while for the trans isomer, the same signals can be
found at 3.41 and 5.99 ppm, respectively. Similarly, the 1H NMR
spectra of cis- and trans-N-(2-pyridyl)-3-chloro-4-chloromethyl-3-
methyl-2-pyrrolidinone, previously analyzed through NOE tech-
niques,9 were compared with 1H NMR spectra of 16. The cis isomer
shows a multiplet for the C(4)H proton at 2.67 ppm and an ABX
system for the diastereotopic protons C(5)H2 at 3.66 and 4.50 ppm.
Instead, in the trans diastereomer the C(4)H multiplet is at
3.06 ppm, and the ABX system can be found at 4.00 and 4.38 ppm.
Ketone 11 (30.7 g, 0.10 mol) was dissolved in diethylene glycol
(DEG) (300 mL) into a 1-L two-necked flask, fitted with a dropping
funnel and a condenser. Then, hydrazine monohydrate 98% (64–
65% NH2NH2) (50.1 mL, 10 equiv) was added and the reaction
mixture was heated at 80 ꢀC for 30 min. Afterwards, KOH (14 g,
2.5 mol), dissolved in DEG (150 mL), was added and the reaction
mixture was heated at 140 ꢀC using an oil bath for 1 h. Then, the
reflux condenser was replaced by a Vigreux column (first a 20 cm
Vigreux, then a 10 cm one and, at the end of the distillation, no
Vigreux column) and water and the excess of hydrazine were dis-
tilled off. This took from 2.5 to 4 h. The temperature of the oil bath
should reach 170–190 ꢀC in order to break down the hydrazone
intermediate, but higher temperatures lead to isomerisation re-
actions. The mixture was cooled down and extracted with hexane
(200 mL). After washing three times with water, the organic layer
was dried over MgSO4, filtered and concentrated under vacuum.
Distillation at reduced pressure afforded the diene 12 (25.0 g, 85%)
(bp 145 ꢀC at 0.11 mbar) as a colourless thick oil.
Found: C, 86.4; H, 13.9. C21H40 requires C, 86.22; H, 13.78. 1H
NMR (200 MHz, CDCl3):
d 1.00–1.50 (30H, m, 15CH2), 2.05 (4H, q, J

F. Roncaglia et al. / Tetrahedron 65 (2009) 1481–1487
1485
6.8 Hz, 2CH2CH]), 4.88–5.08 (4H, m, 2]CH2), 5.82 (2H, qt, J 17.0,
10.3, 6.8 Hz, 2CH]). 13C NMR (50.3 MHz, CDCl3):
29.0, 29.2, 29.5,
29.7, 29.7 (15CH2), 33.8 (2CH2CH]), 114.1 (2]CH2), 139.2 (2CH]).
IR (film): 909 (CH]CH2) cmꢂ1; 992 (CH]CH2) cmꢂ1. MS (EI, m/z):
292 (5%, Mþ), 109 (32), 96 (83), 82 (93), 69 (68), 55 (100). Mp¼27–
29 ꢀC.
Found: C, 49.2; H, 7.0. C19H32Cl4O4 requires C, 48.94; H, 6.92. 1H
NMR (300 MHz, CDCl3): 1.00–1.50 (22H, m, 11CH2), 1.50–1.80 (4H,
m, 2CH2), 2.30–2.55 (4H, m, 2CH2CCl2), 8.56 (2H, br s, 2 OH). 13C
NMR (75.5 MHz, CD3OD): 25.4 (2CH2CH2CCl2), 28.7
(2CH2CH2CH2CCl2), 29.3, 29.4, 29.6 (9CH2), 45.2 (2CH2CCl2), 86.9
(2CCl2), 167.2 (2COOH). IR (KBr): 1740 (C]O) cmꢂ1. ESI-MS (m/z):
463.3 (MꢂH)ꢂ. Mp¼99–102 ꢀC.
d
d
d
4.4. Preparation of heneicosane-1,2,20,21-tetraol (13)
4.6. Preparation of the N1,N20-di(3-chloroallyl)-N1,N20
di(2-pyridyl)-2,2,19,19-tetrachloro-icosane-diamide (8)
-
A mixture of the diene 12 (50.0 g, 0.17 mol), formic acid 99%
(300 mL) and lauric acid (solubility enhancer) (0.6 g) was vigor-
ously stirred at 25 ꢀC in a 500-mL two-necked flask, fitted with
a dropping funnel and a reflux condenser. H2O2(aq) 50 wt % (28 g,
0.42 mol) was added and the reaction mixture was stirred for 18 h
at 40 ꢀC, then another amount of H2O2 (14 g, 0.21 mol) was care-
fully inserted and the reaction mixture was stirred again for 18 h at
40 ꢀC. After, 3 mL of 5 N aqueous H2SO4 were added and the excess
of formic acid was removed (and recovered) through distillation at
reduced pressure. The residue was refluxed for 1 h with alcoholic
KOH (3 N in EtOH, 165 mL, 0.495 mol). Most of the alcohol was then
evaporated and water (200 mL) was added in order to precipitate
the crude tetraol. After cooling to room temperature and removing
the water, the crude product was washed again (2ꢁ100 mL H2O) to
remove the residual base. Recrystallization from ethanol/water 8:2
afforded tetraol 13 (30.81 g, 50%), as white solid.
Tetrachlorodiacid
6 (8.00 g, 16.6 mmol) was weighed in
a Schlenk tube fitted with a pierceable septum (blocked by a screw
cap) and equipped with a stirring bar. CH2Cl2 (17 mL) and a catalytic
amount of dimethylformamide (56 mL) were added under nitrogen.
Then, an excess of oxalyl chloride (4.46 mL, 50 mmol) was carefully
added (evolution of CO!) and, leaving the screw cap slightly
unlocked, the mixture was stirred for 2 h at room temperature
(during this time, the complete dissolution of the chloride was
observed). The solution was concentrated under vacuum with
a membrane pump (equipped with a NaOH trap). The residual
brownish oil was then cooled down with an ice bath and re-diluted
with CH2Cl2 (8 mL). Pyridine (2.96 mL, 36.5 mmol), dissolved in
CH2Cl2 (3.3 mL), and allylamine 7 (6.2 g, 36.5 mmol), dissolved in
CH2Cl2 (5.5 mL), were slowly added under nitrogen. After locking
the Schlenk cap and stopping the gas flow, the solution was stirred
for 2.5 h at 0 ꢀC. Afterwards, Na2CO3 (1.8 g, 16.7 mmol) was added,
and the whole mixture was concentrated under vacuum. Flash
chromatography of the crude product on silica gel, using a petro-
leum ether (bp 40–60 ꢀC)/diethyl ether/CH2Cl2 gradient (from
9.5:0:0.5 to 5.5:4:0.5) as eluant, afforded 8 (10.21 g, 78%; mixture of
two E/Z stereoisomers), as a yellow oil. Rf¼0.44 (petroleum ether
(bp 40–60 ꢀC)/diethyl ether 50:50).
Found: C, 70.3; H, 12.1. C21H44O4 requires C, 69.95; H, 12.30. 1H
NMR (200 MHz, CD3OD):
10.9, 6.5 Hz, 2CHHOH), 3.47 (2H, dd, J 10.9, 4.3 Hz, 2CHHOH), 3.48–
3.65 (2H, br m, 2CHOH). 13C NMR (50.3 MHz, CD3OD):
25.3
d 1.20–1.70 (34H, m,17CH2), 3.40 (2H, dd, J
d
(2CH2CH2CHOH), 29.2, 29.3, 29.3, 29.4, 29.4 (13CH2), 33.0
(2CH2CHOH), 66.0 (2CH2OH), 71.9 (2CHOH). IR (KBr): 3398 (O–
H) cmꢂ1. ESI-MS (m/z): 361.5 (MþH)þ, 359.5 (MꢂH)ꢂ. Mp¼144–
150 ꢀC.
Found: C, 55.4; H, 6.2; N, 7.3. C36H48Cl6N4O2 requires C, 55.33; H,
4.5. Preparation of 2,2,18,18-tetrachloro-nonadecane-1,19-
dioic acid (14)
6.19; N, 7.17. 1H NMR (300 MHz, CDCl3):
d 0.78–0.95 (4H, m, 2CH2),
1.00–1.45 (20H, m, 10CH2), 1.45–1.75 (4H, m, 2CH2), 2.40–2.55 (4H,
m, 2CH2CCl2), 4.70 (4H, d, J 6.3 Hz, 2ECH2N), 4.86 (4H, dd, J 6.3,
1.4 Hz, 2ZCH2N), 5.90–6.20 (4H, m, EþZCH]CH), 7.26 (2H, ddd, J 7.7,
4.9, 0.8 Hz, 2Hpy-5), 7.40 (2H, br dd, J 7.7, 2.9 Hz, 2Hpy-3), 7.76 (2H, tt,
J 7.7, 2.0 Hz, 2Hpy-4), 8.54 (2H, br d, J 4.9 Hz, 2Hpy-6). 13C NMR
Tetraol 13 (70 g, 0.194 mol), DMF (300 mL), CHCl3 (270 mL, from
which EtOH (stabilizer) was removed by washing with concen-
trated H2SO4), CH2Cl2 (90 mL) and MgCO3 (34.2 g, 0.4 mol) were
added in a 2-L two-necked flask, equipped with a condenser con-
nected at the top to a CaCl2 tube. The mixture was stirred in the
dark and was thermostated at 50 ꢀC using an oil bath, then chlorine
gas was flushed inside at ca. 3.1 g/min. An exotherm was rapidly
detected (temperature rise to 73 ꢀC), which finished after about
40 min (temperature down to 64 ꢀC; w25 mL of CH2Cl2 was added
during this time to compensate for some evaporation). The chlorine
flow was then gradually reduced and stopped after 2 h. The heating
was stopped and the mixture was stirred overnight. The reaction
mixture was extracted with a mixture of diethyl ether/petroleum
ether (bp 40–60 ꢀC) 2:1 (350 mL) and 50% H2SO4(aq) (350 mL). The
organic phase was washed with 50% H2SO4(aq) (3ꢁ80 mL) and the
aqueous phase was washed with diethyl ether/petroleum ether (bp
40–60 ꢀC) 1:1 (2ꢁ125 mL). To the combined organic extracts, 35%
H2O2(aq) (130 mL) was added and the resulting mixture was stirred
for 24 h at 30 ꢀC, and at 40 ꢀC for another 48 h. Vacuum evaporation
of the solvent left a colourless crude product (85 g). The absence of
a brownish colour during evaporation indicates a good conversion,
otherwise re-dissolving the crude in CH2Cl2 and further treating
with aqueous H2O2 are necessary. Dilution with diethyl ether (re-
frigerated at ꢂ5 ꢀC, 500 mL) and treatment with Et3N (2.8 mL,
20 mmol, i.e., around 1:10 of 13) in Et2O resulted in a filterable
crystalline mass strongly enriched in the desired product 14
(around 90% as evidenced by 1H NMR). After acid work-up, re-
crystallization from CCl4 furnished the tetrachlorodiacid 19 as
white crystals (25.32 g, 28%).
(100.7 MHz, CDCl3): Z
(12CH2), 46.8 (2CH2CCl2), 48.2 (2CH2N), 85.4 (2CCl2), 121.1
(2]CHCl), 122.9 (2Cpy-5), 123.7 (2Cpy-3), 127.3 (2CH]), 137.9 (2Cpy
4), 149.1 (2Cpy-6), 154.2 (2Cpy-2), 165.3 (2C]O); E 25.5 (2CH2),
d 25.1 (2CH2), 29.0, 29.3, 29.4, 29.5, 29.6
-
d
29.0, 29.3, 29.4, 29.5, 29.6 (12CH2), 46.0 (2CH2CCl2), 50.6 (2CH2N),
85.5 (2CCl2), 121.5 (2]CHCl), 122.7 (2Cpy-5), 123.3 (2Cpy-3), 126.5
(2CH]), 137.8 (2Cpy-4), 149.0 (2Cpy-6), 153.8 (2Cpy-2), 165.0
(2C]O). IR (film): 1667 (C]O) cmꢂ1. ESI-MS (m/z): 779.0 (MþH)þ.
4.7. Preparation of 3,30-(hexadecane-1,16-diyl)-bis(N-
(2-pyridyl)-3-chloro-4-(dichloromethyl)-pyrrolidin-2-one) (9)
Diamide 8 (3.126 g, 4 mmol) and CuCl (79 mg, 0.8 mmol) were
weighed in a Schlenk tube fitted with a pierceable septum (blocked
by a screw cap) and equipped with a magnetic stirring bar. CH2Cl2
(4 mL), acetonitrile (6 mL) and N,N,N0,N0-tetramethylethylendi-
amine (TMEDA) (242 mL, 1.6 mmol) were then added under nitro-
gen. The mixture was stirred at 60 ꢀC for 20 h. Then it was diluted
with NaOH(aq) 4% (16 mL) and extracted with CH2Cl2 (3ꢁ15 mL) and
with toluene (3ꢁ12 mL). The combined organic layers were con-
centrated under vacuum and the crude product was purified by
flash chromatography on silica gel, using a petroleum ether (bp
40–60 ꢀC)/diethyl ether/CH2Cl2 gradient (from 9:0:1 to 7:2:1) as
eluant. The product 9 was recovered (2.70 g, 86%; mixture of cis,cis/
cis,trans/trans,trans diastereomers 86:13:1; cis/trans 92:7 from 1H

1486
F. Roncaglia et al. / Tetrahedron 65 (2009) 1481–1487
NMR spectrum) as a colourless oil. Rf¼0.60 (petroleum ether (bp
40–60 ꢀC)/diethyl ether 50:50).
4.10. Preparation of 3,30-(pentadecane-1,15-diyl)-bis(N-(2-
pyridyl)-3-chloro-4-(chloromethyl)-pyrrolidin-2-one) (16)
Found: C, 55.7; H, 6.4; N, 7.3. C36H48Cl6N4O2 requires C, 55.33; H,
6.19; N, 7.17. 1H NMR (300 MHz, CDCl3):
1.00–1.80 (24H, m, 12CH2), 2.42 (4H, m, 2C(3)CH2), 3.26 (2H, td, J
9.2, 7.5 Hz, 2cisC(4)H), 3.37 (2H, br q, J 5.0 Hz, 2transC(4)H), 3.75
d
0.75–0.97 (4H, m, 2CH2),
Following the same procedure used for the preparation of 9,
diamide 15 (5.31 g, 7.6 mmol) was transformed into the crude
product 16. Flash chromatography on silica gel, using a petroleum
ether (bp 40–60 ꢀC)/diethyl ether/CH2Cl2 gradient (from 10:0:0
to 7:2:1) as eluant, afforded 16 (4.78 g, 90%; mixture of cis,cis/
cis,trans/trans,trans diastereomers 81:18:1; cis/trans 90:10 from 1H
NMR spectrum) as a brownish-white solid. Rf¼0.28 (petroleum
ether (bp 40–60 ꢀC)/diethyl ether 60:40). It was possible to purify
16 through crystallization from diethyl ether, but the preferential
crystallization of the cis,cis isomer occurred.
(2H, dd,
J 11.5, 9.2 Hz, 2cisC(5)H), 4.40 (4H, d, J 5.5 Hz,
2transC(5)H2), 4.52 (2H, dd, J 11.5, 7.5 Hz, 2cisC(5)H), 5.99 (2H, d, J
4.1 Hz, 2transCHCl2), 6.13 (2H, d, J 9.2 Hz, 2cisCHCl2), 7.12 (2H, ddd, J
7.2, 5.2, 0.8 Hz, 2Hpy-5), 7.74 (2H, ddd, J 8.6, 7.2, 1.8 Hz, 2Hpy-4),
8.34–8.46 (4H, m, 2Hpy-3þ2Hpy-6). 13C NMR (75.5 MHz, CDCl3): cis
d
25.7, 29.3, 29.6, 29.7 (14CH2), 37.3 (2C(3)CH2), 47.2 (2C(5)H2), 48.5
(2C(4)H), 71.7 (2CHCl2), 73.4 (2C(3)), 115.2 (2Cpy-3), 120.7 (2Cpy-5),
138.1 (2Cpy-4), 147.8 (2Cpy-6), 150.8 (2Cpy-2), 169.2 (2C]O); trans
(signals not overlapped to the cis ones)
Found: C, 60.1; H, 7.0; N, 7.8. C35H48Cl4N4O2 requires C, 60.18;
d
33.1 (2C(3)CH2), 41.4
H, 6.93; N, 8.02. 1H NMR (300 MHz, CDCl3):
d 1.00–1.90 (26H, m,
(2C(5)H2), 53.3 (2C(4)H), 70.6 (2CHCl2), 72.8 (2C(3)), 115.0 (2Cpy-3),
120.5 (2Cpy-5), 138.0 (2Cpy-4). IR (film): 1723 (C]O) cmꢂ1. ESI-MS
(m/z): 779.0 (MþH)þ.
13CH2), 2.00–2.40 (4H, m, 2C(3)CH2), 2.86 (2H, m, 2cisC(4)H),
3.03 (2H, m, 2transC(4)H), 3.51 (2H, t, J 10.4 Hz, 2transCHCl), 3.70
(2H, dd, J 11.3, 9.3 Hz, 2cisC(5)H), 3.77 (2H, dd, J 11.2, 9.1 Hz,
2cisCHCl), 3.91 (2H, dd, J 11.2, 5.4 Hz, 2cisCHCl), 4.12 (2H, dd, J
4.8. One-pot preparation of 3,30-(hexadecane-1,16-diyl)-
bis(4-methyl-furan-2,5-dione) (tyromycin A) (10) from 9
11.6, 4.5 Hz, 2transC(5)H), 4.35 (2H, dd, J 11.6, 6.6 Hz, 2
transC(5)H), 4.52 (2H, dd, J 11.3, 7.3 Hz, 2cisC(5)H), 7.11 (2H, br
ddd, J 7.3, 4.9, 1.0 Hz, 2Hpy-5), 7.74 (2H, ddd, J 8.4, 7.3, 1.6 Hz,
2Hpy-4), 8.30–8.50 (4H, m, 2Hpy-3þ2Hpy-6). 13C NMR (75.5 MHz,
In a Schlenk tube, fitted with a Teflon septum (blocked by
a screw cap), bis-pyrrolidinone 3 (2.20 g, 2.82 mmol) and diethyl
ether (11.3 mL) were added, together with a stirring bar. The so-
lution was thermostated at 25 ꢀC. Apart, in a second Schlenk tube,
metallic Na (0.52 g, 22.5 mmol) was carefully dissolved in CH3OH
(11.3 mL) and the resulting solution, thermostated at 25 ꢀC, was
poured into the first Schlenk tube. The reaction mixture was then
stirred for 24 h. After aqueous H2SO4 2 M (1.4 mL) was added, the
solvent was removed under vacuum and the residue was treated
with H2SO4 2 M (4.2 mL) and water (1.4 mL). The mixture was
heated at 130 ꢀC for 3 h (under a stream of argon to remove the
CH3OH released from hydrolysis of the bis(5,5-dimethoxy 3-pyr-
rolin-2-one) intermediate 9a, Scheme 5), then it was diluted with
H2O (10 mL) and extracted with CH2Cl2 (3ꢁ10 mL). The combined
organic layers were then concentrated under reduced pressure.
Hence, a solid residue was collected (0.82 g). Recrystallization from
ethanol (after quick separation of the insoluble impurities) afforded
pure tyromycin A (1) (0.69 g, 55%), as a white solid. Characteriza-
tions were in agreement with those previously reported.6
CDCl3): cis d 25.3 (2CH2), 29.4, 29.6, 29.7 (11CH2), 37.6 (2C(3)CH2),
42.6 (2C(4)Hþ2CH2Cl), 47.8 (2C(5)H2), 74.2 (2C(3)), 115.1 (2Cpy-3),
120.5 (2Cpy-5), 138.0 (2Cpy-4), 147.8 (2Cpy-6), 151.1 (2Cpy-2), 170.1
(2C]O); trans (signals not overlapped to the cis ones)
d 24.2
(2CH2), 33.8 (2C(3)CH2), 42.2 (2CH2Cl), 46.9 (2C(5)H2), 47.5
(2C(4)H), 73.5 (2C(3)). IR (KBr): 1711 (C]O) cmꢂ1. ESI-MS (m/z):
697.0 (MþH)þ. Mp¼76–80 ꢀC.
4.11. Preparation of 3,30-(pentadecane-1,15-diyl)-bis(N-(2-
pyridyl)-5-methoxy-4-methyl-3-pyrrolin-2-one) (17)
In a Schlenk tube, fitted with a Teflon septum (blocked by
a screw cap), substrate 16 (3.97 g, 5.7 mmol) and Et2O (9 mL) were
added, together with a stirring bar. The solution was thermostated
at 25 ꢀC. Apart, in a second Schlenk tube, metallic Na (0.79 g,
34.2 mmol) was carefully dissolved in CH3OH (9 mL) and the
resulting solution, thermostated at 25 ꢀC, was poured into the first
Schlenk tube. The reaction mixture was stirred for 24 h. Then it was
diluted with water (10 mL) and extracted with CH2Cl2 (2ꢁ10 mL)
and toluene (2ꢁ10 mL). The combined organic layers were col-
lected and concentrated under vacuum. Flash chromatography of
the crude product on silica gel, using a petroleum ether (bp 40–
60 ꢀC)/diethyl ether/CH2Cl2 gradient (from 9.5:0:0.5 to 5:4.5:0.5) as
eluant, afforded 17 (2.18 g, 62%), as a pale yellow oil. Rf¼0.15 (pe-
troleum ether (bp 40–60 ꢀC)/diethyl ether 50:50).
4.9. Preparation of the N1,N19-diallyl-N1,N19-di(2-pyridyl)-
2,2,18,18-tetrachloro-nonadecane-diamide (15)
Following the same procedure used for preparation of 8, diacid
14 (4.90 g, 10.5 mmol) was coupled with allylamine 7a (3.30 g,
22 mmol) affording the crude diamide 15. Flash chromatography on
silica gel, using a petroleum ether (bp 40–60 ꢀC)/diethyl ether
gradient (from 10:0 to 6:4) as eluant, afforded 15 (6.99 g, 95%), as
a yellow oil. Recrystallization at 0 ꢀC from methanol was also pos-
sible, although the obtained white crystals of 15 melt to a yellow oil
at room temperature. Rf¼0.27 (petroleum ether (bp 40–60 ꢀC)/
diethyl ether 60:40).
Found: C, 71.9; H, 8.3; N, 8.9. C37H52N4O4 requires C, 72.05; H,
8.50; N, 9.08. 1H NMR (300 MHz, CDCl3):
d 1.00–1.40 (22H, m,
11CH2), 1.40–1.70 (4H, m, 2CH2), 2.01 (6H, s, 2C(4)CH3), 2.33 (4H, t, J
7.7 Hz, 2C(3)CH2), 3.11 (6H, s, 2OCH3), 6.27 (2H, s, 2C(5)H), 7.03 (2H,
ddd, J 7.1, 4.8, 0.9 Hz, 2Hpy-5), 7.71 (2H, ddd, J 8.7, 7.1, 1.7 Hz, 2Hpy-4),
8.16 (2H, br dt, J 7.1, 0.9 Hz, 2Hpy-3), 8.42 (2H, ddd, J 4.8, 1.7, 0.9 Hz,
Found: C, 60.2; H, 6.8; N, 7.8. C35H48Cl4N4O2 requires C, 60.18; H,
2Hpy-6). 13C NMR (75.5 MHz, CDCl3):
d 11.7 (2C(4)CH3), 23.5
6.93; N, 8.02. 1H NMR (300 MHz, CDCl3):
d
1.14–1.45 (22H, m,
(2C(3)CH2), 28.5, 29.5, 29.6, 29.7 (13CH2), 50.5 (2OCH3), 87.3
(2C(5)H), 114.9 (2Cpy-3), 119.4 (2Cpy-5), 135.3 (2C(3)), 137.9 (2Cpy-4),
147.9 (2C(4)), 148.1 (2Cpy-6), 150.5 (2Cpy-2), 170.1 (2C]O). IR (film):
1708 (C]O) cmꢂ1. ESI-MS (m/z): 617.3 (MþH)þ.
11CH2), 1.62 (4H, m, 2CH2), 2.49 (4H, m, 2CH2CCl2), 4.71 (4H, br d, J
6.0 Hz, 2CH2N), 5.00–5.20 (4H, m, 2]CH2), 4.88 (2H, qt, J 9.2,
6.0 Hz, 2–CH]), 7.23 (2H, ddd, J 7.4, 4.8, 0.9 Hz, 2Hpy-5), 7.39 (2H, br
dt, J 8.0, 0.9 Hz, 2Hpy-3), 7.74 (2H, ddd, J 8.0, 7.4, 1.9 Hz, 2Hpy-4), 8.54
(2H, ddd, J 4.8, 1.9, 0.7 Hz, 2Hpy-6). 13C NMR (75.5 MHz, CDCl3):
4.12. Preparation of 3,30-(pentadecane-1,15-diyl)-bis(N-(2-
d
25.3 (2CH2), 29.2, 29.5, 29.6, 29.7 (11CH2), 47.0 (2CH2CCl2), 53.7
pyridyl)-5-hydroxy-4-methyl-3-pyrrolin-2-one) (18)
(2CH2N), 85.6 (2CCl2), 118.7 (2]CH2), 122.8 (2Cpy-5), 123.9 (2Cpy-3),
132.3 (2CH]), 137.8 (2Cpy-4), 149.1 (2Cpy-6), 154.4 (2Cpy-2), 165.2
(2C]O). IR (film): 1668 (C]O) cmꢂ1. ESI-MS (m/z): 697.0 (MþH)þ.
Mp¼10–12 ꢀC.
In a Schlenk tube, substrate 17 (0.617 g, 1 mmol), H2SO4 2 M
(1 mL) and H2O (1 mL) were added under nitrogen. The mixture,
under vigorous stirring, was heated to 140 ꢀC for 3 h. Then it was

F. Roncaglia et al. / Tetrahedron 65 (2009) 1481–1487
1487
neutralized with NaOH(aq) (1 M) and extracted with CH2Cl2
(3ꢁ5 mL). The combined organic layers were concentrated under
vacuum. Flash chromatography of the crude product on silica gel,
using a petroleum ether (bp 40–60 ꢀC)/diethyl ether/CH2Cl2 gra-
dient (from 9.5:0:0.5 to 5:4.5:0.5) as eluant, afforded 18 (0.44 g,
75%), as a pale yellow oil. Rf¼0.19 (petroleum ether (bp 40–60 ꢀC)/
diethyl ether 50:50).
bar. The mixture, under vigorous stirring, was heated to 130 ꢀC
for 3 h. Then it was diluted with H2O (3.2 mL) and extracted with
CH2Cl2 (4ꢁ5 mL). The combined organic layers were concentrated
under vacuum. Flash chromatography of the crude product on
silica gel, using a petroleum ether (bp 40–60 ꢀC)/diethyl ether/
CH2Cl2 gradient (from 9.5:0:0.5 to 6.5:3:0.5) as eluant, afforded
20 (0.44 g, 69%) as a beige solid. Rf¼0.54 (petroleum ether (bp
40–60 ꢀC)/diethyl ether 50:50). Then, the product was recrystal-
lized from petroleum ether/diethyl ether as a white solid (0.43 g,
65%).
Found: C, 71.3; H, 8.3; N, 9.7. C35H48N4O4 requires C, 71.40; H,
8.22; N, 9.52. 1H NMR (300 MHz, CDCl3):
d 1.00–1.40 (22H, m,
11CH2), 1.40–1.70 (4H, m, 2CH2), 2.07 (6H, s, 2C(4)CH3), 2.30 (4H, t, J
7.4 Hz, 2C(3)CH2), 5.70 (2H, br s, 2 OH), 5.97 (2H, s, 2C(5)H), 7.00
(2H, br dd, J 7.0, 5.3 Hz, 2Hpy-5), 7.71 (2H, ddd, J 8.6, 7.0, 1.7 Hz,
Hpy-4), 8.26 (2H, br d, J 5.3 Hz, 2Hpy-6), 8.37 (2H, d, J 8.6 Hz, 2Hpy-3).
Found: C, 69.5; H, 8.6. C25H36O6 requires C, 69.42; H, 8.39. 1H
NMR (300 MHz, CDCl3):
m, 2CH2), 2.07 (6H, s, 2C(4)CH3), 2.45 (4H, t, J 7.6 Hz, 2C(3)CH2). 13
NMR (75.5 MHz, CDCl3): 9.6 (2C(4)CH3), 24.5 (2C(3)CH2), 27.7,
d 1.00–1.45 (22H, m, 11CH2), 1.45–1.70 (4H,
C
13C NMR (75.5 MHz, CDCl3):
d
11.6 (2C(4)CH3), 23.4 (2C(3)CH2),
d
28.4, 29.1, 29.5, 29.7, 29.8 (13CH2), 83.6 (2C(5)H), 113.1 (2Cpy-3),
118.8 (2Cpy-5), 134.5 (2C(3)), 138.7 (2Cpy-4), 147.1 (2Cpy-6), 149.5
29.3, 29.5, 29.6, 29.7 (13CH2), 140.6 (2C(3)), 144.9 (2C(4)), 166.0
(2C]O), 166.þ4 (2C]O). IR (KBr): 1766 (C]O) cmꢂ1. ESI-MS (m/z):
433.3 (MþH) . Mp¼53 ꢀC.
(2C(4)), 151.8 (2Cpy-2), 169.6 (2C]O). IR (film): 1699 (C]O) cmꢂ1
.
ESI-MS (m/z): 589.3 (MþH)þ.
4.13. Preparation of 3,30-(pentadecane-1,15-diyl)-bis(N-(2-
Acknowledgements
pyridyl)-4-methyl-3-pyrrolin-2,5-dione) (19)
`
We thank the Ministero della Universita e della Ricerca Scien-
tifica e Tecnologica (MURST) for financial assistance.
In a 100 mL round bottom flask, substrate 18 (1.93 g, 3.28 mmol),
MnO2 (13.12 g) and CH2Cl2 (65 mL) were added in sequence. The
reaction mixture was vigorously stirred at room temperature. After
24 h (GC monitoring), the mixture was filtered on paper. The MnO2
cake was washed with CH2Cl2 (3ꢁ15 mL) and the filtrate was con-
centrated under vacuum. In this way the crude product was re-
covered and further purified by recrystallization from methanol/
diethyl ether. Pure 19 was obtained (1.56 g, 85%) as needle-shaped
white crystals.
References and notes
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2. (a) Matsui, M.; Fowler, J. H.; Walling, L. L. Biol. Chem. 2006, 387, 1535–1544; (b)
Taylor, A. FASEB J. 1993, 7, 290–298.
`
3. (a) Vazeux, G.; Wang, J.; Corvol, P.; Llorens-Cortes, C. J. Biol. Chem. 1996, 271,
9069–9074; (b) Sin, N.; Meng, L.; Wang, M. Q. W.; Wen, J. J.; Bornmann, W. J.;
Crews, C. M. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 6099–6103; (c) Wu, Q.; Lahti,
J. M.; Air, G. M.; Burrows, P. D.; Cooper, M. D. Proc. Natl. Acad. Sci. U.S.A. 1990, 87,
993–997.
Found: C, 71.6; H, 7.6; N, 9.3. C35H44N4O4 requires C, 71.89; H,
7.58; N, 9.52.1H NMR (300 MHz, CDCl3):
d 1.00–1.45 (22H, m,11CH2),
1.45–1.70 (4H, m, 2CH2), 2.06 (6H, s, 2C(4)CH3), 2.47 (4H, t, J 7.6 Hz,
2C(3)CH2), 7.29 (2H, dddd, J 7.7, 4.9, 1.0 Hz, 2Hpy-5), 7.34 (2H, br dt, J
7.7 Hz, 2Hpy-3), 7.83 (2H, dt, J 7.7, 1.9 Hz, Hpy-4), 8.62 (2H, ddd, J 4.9,
4. Chen, X.; Zheng, Y.; Shen, Y. Chem. Rev. 2007, 107, 1777–1830.
5. Weber, W.; Semar, M.; Anke, T.; Bross, M.; Steglich, W. Planta Med.1992, 58, 56–59.
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1.9, 0.7 Hz, 2Hpy-6). 13C NMR (75.5 MHz, CDCl3):
d 9.0 (2C(4)CH3),
23.9 (2C(3)CH2), 28.3, 29.4, 29.6, 29.7 (13CH2), 121.2 (2Cpy-3), 122.9
(2Cpy-5), 137.8 (2C(3)), 138.2 (2Cpy-4), 141.9 (2C(4)), 146.4 (2Cpy-2),
149.5 (2Cpy-6), 170.1 (2C]O), 170.4 (2C]O). IR (KBr): 1711
(C]O) cmꢂ1. ESI-MS (m/z): 585.3 (MþH)þ. Mp¼76–77 ꢀC.
4.14. Preparation of 3,30-(pentadecane-1,15-diyl)-bis-
(4-methyl-furan-2,5-dione) (20)
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Chim. Belg. 1984, 93, 913–917.
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Libertini, E.; Pagnoni, U. M.; Schenetti, L. Tetrahedron 2003, 59, 1147–1157.
In a Schlenk tube, substrate 19 (0.89 g, 1.52 mmol), H2SO4 2 M
(1.52 mL) and H2O (1.52 mL) were added, together with a stirring