A general synthesis of bis-α-acyloxy-1,4- and -1,5-diketones through catalytic oxidative opening of acylated THF and THP diols

Article abstract of DOI:10.1002/ejoc.201201554

The first general synthesis of bis-α-acyloxy-1,4- and -1,5-diketones has been accomplished in a catalytic oxidative opening of bis-acylated THF and THP (tetrahydropyran) diols, which were synthesised by osmium- or ruthenium-catalysed oxidative cyclisation of 1,5- and 1,6-dienes. The overall sequence corresponds to the regioselective double ketoacyloxylation of the starting diene. The synthesised bis-α-acyloxy-1,5-dicarbonyl compounds have been transformed into pyridine-based oxido pincer ligands or pyrazinedimethanol substances, leading to the discovery of unprecedented aromatisation routes. The first general synthesis of bis-α-acyloxy-1,4- and -1,5-diketones is reported. The process features the catalytic oxidative opening of bis-acylated THF and THP diols, which were synthesised by the transition-metal-mediated oxidative cyclisation of 1,5- and 1,6-dienes. The 1,5-diketone products were cyclised to give pyridinedimethanol derivatives. New aromatisation modes have been disclosed. Copyright

Full text of DOI:10.1002/ejoc.201201554

FULL PAPER
DOI: 10.1002/ejoc.201201554
A General Synthesis of Bis-α-acyloxy-1,4- and -1,5-diketones Through
Catalytic Oxidative Opening of Acylated THF and THP Diols
Vincenzo Piccialli,*[a] Stefano D’Errico,[b] Nicola Borbone,[b] Giorgia Oliviero,[b]
Roberto Centore,[a][‡] and Sabrina Zaccaria[a]
Keywords: Synthetic methods / Oxidation / Ring-opening / Cyclization / Nitrogen heterocycles / Oxygen heterocycles
The first general synthesis of bis-α-acyloxy-1,4- and -1,5-di-
ylation of the starting diene. The synthesised bis-α-acyloxy-
ketones has been accomplished in a catalytic oxidative open- 1,5-dicarbonyl compounds have been transformed into pyr-
ing of bis-acylated THF and THP (tetrahydropyran) diols,
which were synthesised by osmium- or ruthenium-catalysed
oxidative cyclisation of 1,5- and 1,6-dienes. The overall se-
quence corresponds to the regioselective double ketoacylox-
idine-based oxido pincer ligands or pyrazinedimethanol sub-
stances, leading to the discovery of unprecedented aromati-
sation routes.
chromate) and periodic acid,[5] as a powerful reagent
capable of oxidising THF-containing compounds of vary-
ing structural complexity.[6] In a single case, we observed
that the oxidative opening of 2,5-bis-benzoyloxymethyl
THF derivative 1 (Scheme 1) led to bis-α-benzoyloxy 1,4-
diketone 2 in an excellent yield.
Introduction
α-Acyloxy ketones are important intermediates in or-
ganic synthesis, and their structural motif is found in a vari-
ety of natural products (e.g., taxol) and pharmaceutical
agents. They can be seen as protected α-hydroxy ketones,
themselves structural subunits of several active natural sub-
stances and useful synthetic building blocks.[1]
The keen interest of synthetic organic chemists in α-
acyloxy ketones is demonstrated by the number of pro-
cedures that have been developed to obtain these sub-
stances.[2] Generally, their synthesis features the introduc-
tion of the acyloxy group α to the ketone functional group.
Recently, various asymmetric α-oxybenzoylation methods
have been reported.[3] A thallium-promoted preparation of
α-formyloxy ketones is also known.[2f] However, despite the
potential uses of the products in organic synthesis, to the
best of our knowledge, no general method for the synthesis
Scheme 1. Oxidative THF opening under previous conditions.[6]
This result was particularly interesting, since it suggested
of bis-α-acyloxy diketones has been developed to date, and that THF rings, and possibly other ether rings flanked by
the chemistry of these compounds and that of the corre- acylated hydroxymethyl groups, could be seen as masked
sponding free bis-ketols is still largely unexplored.[4]
bis-α-acyloxy diketones. With the above result in mind, we
Recent work in our laboratory has focussed on the cata- envisaged that 1,5- and 1,6-dienes could be transformed
lytic use of chlorochromatoperiodate (CCP, Scheme 1), gen- into bis-α-acyloxy-1,4- and -1,5-diketones through a short
erated by the condensation of PCC (pyridinium chloro- sequence consisting of transition-metal-mediated oxidative
cyclisation of the diene[7] to give THF or THP diols, fol-
lowed by hydroxyl acylation, and CCP-catalysed opening of
the ether ring (Scheme 2).
[a] Dipartimento di Scienze Chimiche, Università degli Studi di
Napoli “Federico II”,
Via Cintia 4, 80126 Napoli, Italy
Since the formation of the two ketone functionalities oc-
curs at the ether carbons, the projected sequence should
allow the bis-ketoacyloxylation of the starting diene to oc-
cur regioselectively, which is hardly achievable in a direct
way. In a previous investigation by Smith III and Scarbor-
ough,[8] the system RuO2 (cat.)/NaIO4 was used to ac-
complish the oxidation of unfunctionalised THF or THP
rings, mostly to give lactones. In a single case, a 2,5-disub-
Fax: +39-081-674393
E-mail: vinpicci@unina.it
Homepage: www.docenti.unina.it/vincenzo.piccialli
[b] Dipartimento di Chimica delle Sostanze Naturali, Università
degli Studi di Napoli “Federico II”,
Via D. Montesano 49, 80131 Napoli, Italy
[‡] Author to whom correspondence regarding the X-ray crystal
structure should be addressed
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201554.
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FULL PAPER
Table 1. CCP-catalysed oxidative opening of protected 2,5-disubsti-
tuted THF and 2,6-disubstituted THP diols.[a]
Scheme 2. Projected general synthesis of bis-α-acyloxy diketones
from dienes.
stituted THF was converted into a 1,4-diketone, but the
process required long reaction times (typically 24 h), and
there were no chiral centres adjacent to the reaction centre.
In this paper, we report the accomplishment of the above
idea and the use of some of the synthesised 1,5-diketones
to obtain six-membered nitrogen heterocycles.
Results and Discussion
To test the substrate scope of the projected transforma-
tion, a range of tetrahydrofuran and tetrahydropyran diols
were synthesised, mostly through well-established ruthe-
nium[9] or osmium[10]-catalysed oxidative cyclisation of suit-
able 1,5- and 1,6-dienes. The diols were then acylated (or in
one case tosylated) and subjected to our oxidative pro-
cedure (Table 1).
Optimisation of the oxidative protocol was carried out
with THF 1 and THP 13 as model compounds. We found
that the oxidation of 1 (entry 1, Table 1) proceeded in excel-
lent yields and short reaction times with 2 mol-% of PCC,
even when the amount of the co-oxidant was reduced to
3 equiv. However, the opening of the THP ring of 13 pro-
ceeded very slowly or the reaction was incomplete under
these conditions. A screening of the reaction conditions for
this substrate showed that the best results were obtained
with 4 mol-% of catalyst and 4 equiv. of periodic acid.
Oxidation of all the other substrates was then carried out
under the optimised conditions. As summarised in Table 1,
both THF and THP derivatives reacted well to give the ex-
pected diketones in generally good to excellent yields.[11]
The process was shown to be tolerant of various substitu-
tion patterns and of structural complexity in the substrate.
Even bicyclic THF 11 (entry 6) gave a good yield of the
corresponding diketone 12. Isomeric trans and cis[9d] THPs
15 and 17, respectively (entries 8 and 9), gave the same
product 16 in comparable yields. In an attempt to further
expand the utility of this reaction, morpholine derivative 20
(entry 11, Scheme 3) was oxidised. However, a more com-
plex reactivity pattern resulted in this case. The expected
diketone (i.e., 21) was obtained, albeit in a diminished 26%
yield (HPLC),[12] along with a non-negligible amount of by-
products 22 (18%) and 23 (12%). We believe that the Achil-
les’ heel of this substrate is the double bond character of
the benzamide group, which favours the formation of unsat-
urated morpholine intermediate 24, which is then oxidat-
[a] Reagents and conditions. THF oxidations: substrate (0.05 m in
CH3CN), PCC (2 mol-%), H5IO6 (3.2 equiv.), 30–40 min, room
temp. THP oxidations: substrate (0.05 m in CH3CN), PCC (4 mol-
%), H5IO6 (4 equiv.), 6–8 h, room temp. [b] This process required
24 h. [c] Isolated yields. [d] Isolated HPLC yield.
Scheme 3. Oxidation of a morpholine-protected substrate. Reaction
ively cleaved by CCP itself (Scheme 3).[13] Presumably, conditions as in Table 1.
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Synthesis of Bis-α-acyloxy-1,4- and -1,5-diketones
higher yields of compounds corresponding to 21 could be all incorporated the terminal unsaturated lactone function-
obtained by tuning the nitrogen-protecting group in 20. As ality (characteristic proton signals at ca. 5 and 7 ppm),
can be seen, benzoate (entry 1), acetate, tosylate (entries 2 which indicates that even this moiety is tolerant to the ox-
and 3), and amide functionalities (entry 11) were compati- idising conditions. This transformation also highlights that
ble with the ether-cleavage reaction conditions.
the method may be useful to prepare analogues of a variety
An important aspect of the process that must be ad- of biologically active natural substances, where saturated
dressed concerns the fate of the potentially epimerisable chi- ether rings of various sizes are often flanked by hydroxy
ral centers adjacent to the newly-formed ketone functionali- groups.
ties in compounds such as 8, 10, and 12. Considering the
It is well known[1b,2] that α-oxygenated carbonyl groups
oxidation of 11, NMR spectroscopic analysis of the by- are susceptible to several transformations. The presence in
products of the process ruled out the presence of stereoiso- the same molecule of two of these structural subunits fur-
mers of diketone 12. In addition, an X-ray diffraction ther increases the synthetic utility of these compounds.
analysis of this compound (Figure 1)[14] was carried out, Among the various conceivable synthetic uses of the synthe-
and the results showed that the relative stereochemistry of sised substances, we planned to probe the transformation
THF precursor 11 had been preserved in 12. This suggests of the 1,5-dicarbonyl compounds into the corresponding
that the synthesis of chiral, acyclic bis-α-acyloxy-1,4-diket- pyridinedimethanol derivatives[21,22] (Scheme 5). These sub-
ones such as 8 and 10 is feasible, given the easy access to stances have notable coordination properties, and belong to
chiral THF-dimethanol substances such as 7 or 9 according the oxido pincer ligands class.[23]
to the OsO4-catalysed protocol developed by Donohoe and
Butterworth.[15]
Figure 1. ORTEP drawing of diketone 12. Ellipsoids are drawn at
the 30% probability level.
To test our procedure on a more elaborate substrate,
acetylated and benzoylated cis-reticulatacins 25 and 26,
respectively, were oxidised (Scheme 4).[16,17] cis-Reticulata-
cin belongs to the Annonaceous acetogenins class, a group
of plant-derived metabolites having a wide array of bio-
logical properties such as antitumor, immunosuppressive,
antimicrobial, and insecticidal activities.[18] Several synthe-
Scheme 5. Pyridine and pyrazine diol synthesis from bis-α-benzo-
yloxy 1,5-diketones. a) NH4OAc (7 equiv.), AcOH (6.5 equiv.), dry
MeOH, 24 h room temp. and 48 h 55 °C; b) NH2OH·HCl
(3.5 equiv.), dry EtOH, 6–15 h, reflux; c) K2CO3 (10 mol-%),
MeOH, room temp., 30 min; d) MCPBA (1.2 equiv.), CHCl3, room
temp., 90 min.
ses of some members of this group as well as the prepara-
tion of analogues have been reported.[19] We envisaged that
our process could be used to cleave the THF ring in this
compound to obtain non-THF analogues such as recently
synthesised dihydro-coibin[20] or other derivatives thereof.
Reaction of 16 with ammonium acetate and AcOH gave,
in a reproducible manner, the expected pyridine (i.e., 29a)
together with the corresponding debenzoylated compound
(i.e., 30) in a ca 2:1 ratio. Usually, it is believed that under
these conditions, 1,4-dihydropyridine intermediates dispro-
portionate to give the pyridine compounds and products
with higher hydrogen content such as piperidines or tetra-
hydropyridines. However, our process was very clean, and
Scheme 4. Oxidation of bis-acylated cis-reticulatacin.
Indeed, the reaction of 25 and 26 under slightly modified no by-products of this type could be detected. Thus, in
conditions gave the expected reticulatacin-derived diketones agreement with Rodriguez et al.,[24] we presume that atmo-
(i.e., 27 and 28, respectively; Scheme 4) albeit in lower yields spheric oxygen could be responsible for the oxidation step
(30–40%). Although the structures of the by-products leading to aromatisation.
(HPLC separation) of this process were not thoroughly in-
vestigated, H NMR spectroscopic data showed that they an alternative approach, good yields of pyridine 31a were
Compound 14 failed to cyclise under these conditions. In
1
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obtained by the reaction of 14 with hydroxylamine hydro- the transformation of a morpholine derivative into a pyr-
chloride under classical Knoevenagel conditions. Analo- azine, may have synthetic and pharmacological value.[26]
gously, the reaction of diketone 19 under the conditions
used to cyclise 14 led to pyridine oxide 32a. Even diketo-
benzamide 21 could be cyclised to give 2,6-bis(hydroxy-
methyl)pyrazine 33a in good yield and in a short time com-
Conclusions
In conclusion, we have developed the first general pro-
cedure for the synthesis of bis-α-acyloxy-1,4- and -1,5-di-
ketones from 1,5- and 1,6-dienes, respectively, in a regiose-
lective manner. An interesting feature of our procedure is
the timing of the introduction of the acyloxy and ketone
functionalities onto the diene, which allows a variety of acy-
loxy moieties to be incorporated. In addition, it is reason-
able to assume that THF or THP substrates that lack one
or both of the neighbouring acyloxy groups could be
cleaved using our procedure, which would give a wider spec-
trum of 1,4- and 1,5-diketones. We have demonstrated that
the process can be applied to acylated cis-reticulatacin, a
representative mono-THF Annonaceous acetogenin, thus
opening the way to the preparation of new non-THF ana-
logues of these active substances to be used in biological
assays. The 1,5-diketone products have been successfully
cyclised to give pyridinedimethanol derivatives, opening a
new route to pyridine-based oxido pincer ligands, and, in
one case, to a pyrazinedimethanol derivative. The direct
conversion of a 3-benzoyloxy-1,5-diketone into a pyridine
N-oxide is also unprecedented. The synthetic utility of the
bis-α-acyloxy-diketone products is currently under investi-
gation.
pared to the pyridine cyclisations. The formation of a pyr-
azine ring through cyclisation of a diketoamide such as 21
has never been accomplished before, and it is likely that
variants of this process will be feasible. Debenzoylation of
the mixture of 29a and 30,[25] and of compounds 31a–33a
was then carried out with K2CO3 (cat.) in MeOH to give
the corresponding diols. Compounds 29b and 31b are
known. The structural relationship between 31b and 32b
was proved by MCPBA (m-chloroperbenzoic acid) oxi-
dation of the former to give the latter.
The cyclisations of 19 and 21 are particularly interesting
and deserve a comment. As for the transformation of 19
into 32a (Scheme 6), the benzoate group on C-4 acts as a
leaving group and, after formation of the intermediate N-
hydroxydihydropyridine, aromatisation occurs by elimi-
nation of benzoic acid. This is the first example of the syn-
thesis of the pyridine nucleus using a 3-benzoyloxy-1,5-di-
ketone. An interesting new feature of this reaction is the
direct formation of a pyridine oxide.
Experimental Section
General Methods: All reagents and anhydrous solvents were pur-
chased (Aldrich and Fluka) at the highest commercial quality and
were used without further purification. Reactions were monitored
by thin-layer chromatography carried out on precoated silica gel
plates (Merck 60, F254, 0.25 mm thick). Merck silica gel (Kieselgel
40, particle size 0.063–0.200 mm) was used for column chromatog-
raphy. Na2SO4 was used as a drying agent for aqueous work-up.
HPLC separations were carried out with a Varian 2510 apparatus
equipped with a Waters R403 dual cell differential refractometer
using Phenomenex 250ϫ10 mm and 250ϫ4.6 mm (both 5 μm)
Scheme 6. Plausible pathways leading to pyridine oxide 32a and
pyrazine 33a.
A pathway leading to pyrazine 33a is shown in Scheme 6. columns. NMR experiments were performed with Varian Unity In-
ova 700, Varian Unity Inova 500, Varian Mercury Plus 400, and
Gemini 200 spectrometers in CDCl3 or CD3OD. Proton chemical
shifts were referenced to the residual CHCl3 (δ = 7.26 ppm) or
CD2HOD (δ = 3.31 ppm) signals. 13C NMR chemical shifts were
referenced to the solvents CDCl3 (δ = 77.0 ppm) or CD3OD (δ =
49.0 ppm). Coupling constants, J values, are given in Hz. Abbrevi-
ations for signal coupling are as follows: s = singlet, d = doublet,
dd = double doublet, ddd = double double doublet, t = triplet, dt
= double triplet, q = quartet, quin = quintet, m = multiplet, app
= apparent, br. = broad. Optical rotations were recorded with a
Jasco P-1010 polarimeter (using the sodium D line, 589 nm) and
[α]D values are given in units of degcm3 g–1 dm–1. IR spectra were
collected with a Jasco FTIR-430 spectrometer. Melting points were
obtained with a Gallenkamp melting point apparatus. High Reso-
lution MS were recorded with a Bruker APEX II FT-ICR mass
spectrometer using the electrospray ionisation (ESI) technique in
positive mode.
In this case, the initial closure of the N-hydroxydihydropyr-
azine ring is followed by the elimination of the benzoyl por-
tion, probably through a transamidation step driven by aro-
matisation. Overall, the oxidative opening of the morph-
oline ring in 20 to give diketone 21 (Scheme 7), followed by
cyclisation of the latter compound to give pyrazine 33a, i.e.,
Scheme 7. Overall transformation of morpholine 20 into pyrazine
33a.
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Synthesis of Bis-α-acyloxy-1,4- and -1,5-diketones
Crystals of 12 were grown by slow evaporation from a CHCl3/tolu-
ene (1:1) solution. A prismatic colourless crystal of 12 was selected
for X-ray analysis. Single crystal X-ray diffraction data were col-
lected using graphite monochromated Mo-Kα radiation (λ =
(؎)-[(1R,4R,5S,7R)-4-(Benzoyloxy)-6-oxabicyclo[3.2.1]octan-7-yl]-
methyl Benzoate (11): Oil. IR: ν = 2953 (br. w), 2874 (br. w), 1716
˜
(s), 1450 (w), 1335 (w), 1313 (w), 1271 (s), 1176 (w), 1114 (w), 1098
(w), 1069 (w), 1026 (w), 941 (w), 711 (m) cm–1 1H NMR
.
0.71073 Å) with a Bruker–Nonius kappaCCD diffractometer at (200 MHz, CDCl3): δ = 8.13–8.02 (d, J = 7.3 Hz, 2 H), 7.63–7.35
room temperature. Owing to the poorly diffracting features of the
crystal, data were collected up to θmax = 25°. Unit cell parameters
were determined by least-squares refinement of the θ angles of 35
strong reflections in the range 3.785° Ͻ θ Ͻ 11.308°. Data re-
duction and semiempirical absorption correction were done using
SADABS program.[27] The structure was solved by direct methods
(SIR97 program[28]) and refined by the full-matrix least-squares
method on F2 using SHELXL-97 program.[29] All non-hydrogen
atoms were refined anisotropically. H atoms were determined ste-
reochemically and refined by the riding model with Uiso = 1.2·Ueq
of the carrier atom.
(m, 6 H), 4.94 (dd, J = 9.2, 6.7 Hz, 1 H), 4.75–4.51 (m, 3 H), 4.40
(br. dd, J = 9.6, 6.1 Hz, 1 H), 2.40 (br. s, 1 H), 2.34–1.84 (m, 4 H),
1.78 (d, J = 11.8 Hz, 1 H), 1.73–1.53 (m, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 166.5, 166.2, 133.0, 132.9, 130.3, 130.1,
129.9, 129.8, 128.3, 128.2, 80.3, 78.0, 75.0, 63.8, 37.1, 35.8, 25.3,
24.0 ppm. HRMS (ESI): calcd. for C22H22NaO5 [M + Na]+
389.1365; found 389.1362.
(؎)-[(2S,6S)-Tetrahydro-2H-pyran-2,6-diyl]bis(methylene) Dibenzo-
ate (13): Oil. IR: ν = 2940 (br. w), 1717 (s), 1601 (w), 1584 (w),
˜
1451 (w), 1315 (w), 1275 (s), 1118 (br. m), 1070 (w), 1026 (w), 710
1
(s) cm–1. H NMR (200 MHz, CDCl3): δ = 7.98 (d, J = 7.1 Hz, 4
Synthesis of Substrates: Substrates 1,[9c] 3,[9c] 5,[9c] 7,[30] 9,[31] 11,[32]
13,[9d] 15,[9d] 17,[9d] and 20[9e] were obtained by acetylation, benzo-
ylation and tosylation of the corresponding THF, THP, or morph-
oline polyols under standard conditions. The latter compounds
were synthesised according to literature procedures. Compound 1[6]
is a known compound. Compound 18 was synthesised from hepta-
1,6-dien-4-yl benzoate according to a literature procedure[9e] and
benzoylated under standard conditions.
H), 7.52 (t, J = 7.4 Hz, 2 H), 7.33 (t, J = 7.6 Hz, 4 H), 4.58 (dd, J
= 12.5, 9.0 Hz, 2 H), 4.35–4.18 (m, 4 H), 1.96–1.39 (m, 6 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 166.5, 132.8, 130.0, 129.6, 128.3,
69.6, 65.2, 26.3, 18.5 ppm. HRMS (ESI): calcd. for C21H22NaO5
[M + Na]+ 377.1365; found 377.1368.
(؎)-2-{(2S,6S)-6-[(Benzoyloxy)methyl]oxan-2-yl}propan-2-yl Benzo-
ate (15): Oil. IR: ν = 2867 (w), 2940 (br. w), 1720 (s), 1602 (w),
˜
1583 (w), 1451 (m), 1386 (w), 1366 (w), 1314 (m), 1275 (br. s), 1113
(؎)-[(2S,5R)-Tetrahydrofuran-2,5-diyl]bis(methylene) Diacetate (3): (br. m), 1070 (w), 1026 (w), 710 (s) cm–1. 1H NMR (200 MHz,
Oil. IR: ν = 1742 (s), 1372 (w), 1235 (br. s), 1041 (m) cm–1. 1H
CDCl3): δ = 8.00 (d, J = 8.1 Hz, 2 H), 7.95 (d, J = 8.1 Hz, 2 H),
˜
NMR (200 MHz, CDCl3): δ = 4.30–4.06 (m, 4 H), 3.97 (dd, J = 7.57–7.46 (m, 2 H), 7.35 (td, J = 7.9, 3.3 Hz, 4 H), 4.81 (dd, J =
12.3, 7.2 Hz, 2 H), 2.07 (s, 6 H), 2.16–1.89 (m, 2 H), 1.83–1.55 (m,
2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 170.5, 77.0, 66.1, 27.3,
20.5 ppm. HRMS (ESI): calcd. for C10H16NaO5 [M + Na]+
239.0895; found 239.0884.
10.4, 7.8 Hz, 1 H), 4.45–4.30 (m, 2 H), 4.45–4.24 (m, 2 H), 4.07 (d,
J = 10.8 Hz, 1 H), 1.97–1.36 (m, partly overlapping with methyl
signals, 6 H), 1.59 (s, 3 H), 1.57 (s, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 166.4, 165.5, 132.9, 132.4, 131.8, 130.1, 129.6, 129.4,
128.3, 128.1, 84.0, 74.5, 71.0, 62.9, 25.5, 25.0, 22.9, 21.5, 19.0 ppm.
HRMS (ESI): calcd. for C23H26NaO5 [M + Na]+ 405.1678; found
405.1676.
(؎)-[(2S,5R)-Tetrahydrofuran-2,5-diyl]bis(methylene) Bis(4-methyl-
benzenesulfonate) (5): Oil. IR: ν = 2957 (m), 2922 (m), 2855 (w),
˜
1597 (w), 1356 (m), 1260 (w), 1189 (m), 1174 (s), 1094 (m), 969
(m), 812 (m), 665 (m) cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.77 (؎)-2-{(2S,6R)-6-[(Benzoyloxy)methyl]oxan-2-yl}propan-2-yl
(d, J = 8.1 Hz, 4 H), 7.34 (d, J = 8.1 Hz, 4 H), 4.17–4.02 (m, 2 H),
3.93 (m, 4 H), 2.45 (s, 6 H), 2.03–1.85 (m, 2 H), 1.84–1.64 (m, 2
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 144.9, 132.8, 129.9,
127.9, 77.2, 71.1, 27.5, 21.6 ppm. HRMS (ESI): calcd. for
C20H24NaO7S2 [M + Na]+ 463.0861; found 463.0859.
Benzoate (17): Oil. IR: ν = 2983 (w), 2942 (br. w), 2858 (w), 1716
˜
(br. s), 1602 (w), 1583 (w), 1451 (m), 1384 (w), 1367 (w), 1314 (m),
1
1290 (s), 1274 (s), 1118 (m), 1069 (w), 1027 (w), 711 (s) cm–1. H
NMR (200 MHz, CDCl3): δ = 7.98 (m, 4 H), 7.58–7.45 (m, 2 H),
7.37 (t, J = 7.6 Hz, 4 H), 4.30 (app d, J = 5.3 Hz, 2 H), 3.91–3.71
(m, 2 H), 2.08–1.91 (m, 1 H), 1.62 (s, 3 H), 1.57 (s, 3 H), 1.80–1.21
(m, partly overlapping with methyl signals, 6 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 166.4, 165.5, 132.8, 132.4, 131.8, 130.2,
129.5, 129.4, 128.2, 128.1, 83.8, 81.4, 75.9, 67.6, 27.7, 24.9, 23.0,
21.6 ppm. HRMS (ESI): calcd. for C23H26NaO5 [M + Na]+
405.1678; found 405.1677.
(؎)-(4S)-4-(Benzoyloxy)-4-{(2S,5R)-5-[(1R)-1,4-bis(benzoyloxy)-
butyl]oxolan-2-yl}butyl Benzoate (7): Oil. IR: ν = 2956 (br. w), 2877
˜
(br. w), 1716 (br. s), 1601 (w), 1584 (w), 1451 (w), 1314 (w), 1272
1
(br. s), 1176 (w), 1112 (m), 1069 (w), 1025 (w), 710 (m), cm–1. H
NMR (200 MHz, CDCl3): δ = 8.09 (d, J = 7.6 Hz, 4 H), 8.01 (d,
J = 7.0 Hz, 4 H), 7.60–7.27 (m, 12 H), 5.49–5.24 (m, 2 H), 4.47–
4.24 (br. s, 4 H), 4.24–4.04 (m, 2 H), 2.11–1.67 (m, 12 H) ppm. 13
C
(؎)-[(2S,6S)-4-(Benzoyloxy)-tetrahydro-2H-pyran-2,6-diyl]bis-
NMR (50 MHz, CDCl3): δ = 166.3, 166.1, 132.8, 132.7, 130.1, (methylene) Dibenzoate (19): Oil. IR: ν = 2857 (br. w), 1720 (s),
˜
130.0, 129.5, 129.4, 128.2, 128.1, 79.8, 75.0, 64.4, 27.7, 27.4,
24.7 ppm. HRMS (ESI): calcd. for C40H40NaO9 [M + Na]+
687.2570; found 687.2566.
1601 (w), 1583 (w), 1451 (m), 1315 (m), 1272 (br. s), 1176 (w), 1110
(br. m), 1026 (m), 710 (m) cm–1. 1H NMR (200 MHz, CDCl3): δ =
8.13–7.94 (m, 6 H), 7.64–7.41 (m, 3 H), 7.34 (t, J = 7.6 Hz, 6 H),
5.57–5.40 (m, 1 H), 4.84 (dd, J = 11.5, 8.0 Hz, 1 H), 4.74–4.49 (m,
2 H), 4.50–4.21 (m, 3 H), 2.27 (dt, J = 13.7, 4.3 Hz, 1 H), 2.05 (t,
J = 5.5 Hz, 2 H), 1.85 (dt, J = 13.8, 7.0 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 166.3, 165.7, 133.2, 132.9, 129.9, 129.85,
129.80, 129.6, 129.5, 128.5, 128.3, 68.9, 67.6, 67.1, 65.3, 65.1, 31.6,
31.4 ppm. HRMS (ESI): calcd. for C28H26NaO7 [M + Na]+
497.1576; found 497.1573.
(؎)-(R)-1-{(2R,5S)-5-[(S)-1-(Benzoyloxy)undecyl]tetrahydrofuran-2-
yl}butane-1,4-diyl Dibenzoate (9): Oil. IR: ν = 2924 (m), 2852 (w),
˜
1
1718 (s), 1271 (s), 1112 (m), 1069 (w), 1026 (w), 710 (m) cm–1. H
NMR: (200 MHz, CDCl3): δ = 8.18–7.91 (m, 6 H), 7.60–7.31 (m,
9 H), 5.42–5.14 (m, 2 H), 4.30 (t, J = 5.6 Hz, 2 H), 4.21–4.06 (m,
2 H), 2.07–1.51 (m, 12 H), 1.46–1.05 (m, 10 H), 0.84 (t, J = 6.8 Hz,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 166.5, 166.3, 132.9,
132.81, 132.80, 130.4, 130.2, 130.1, 129.8, 129.7, 129.5, 128.35,
128.30, 80.1, 79.8, 75.9, 75.2, 64.6, 31.9, 30.9, 29.55, 29.53, 29.50,
27.8, 27.5, 25.4, 24.9, 22.6, 14.1 ppm. HRMS (ESI): calcd. for
C40H50NaO7 [M + Na]+ 665.3454; found 665.3458.
(؎)-[(2S,6S)-4-Benzoylmorpholine-2,6-diyl]bis(methylene) Dibenzo-
ate (20): Oil. IR: ν = 2955 (br. w), 1721 (s), 1639 (br. s), 1602 (w),
˜
1451 (m), 1273 (br. s), 1114 (m), 1070 (w), 1027 (w), 711 (s) cm–1.
1H NMR (200 MHz, CDCl3): δ = 8.14–7.73 (br. m, 6 H), 7.53 (t,
Eur. J. Org. Chem. 2013, 1781–1789
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1785

V. Piccialli et al.
J = 7.3 Hz, 3 H), 7.48–7.27 (m, 6 H), 4.76–4.43 (br. m, 2 H), 4.43– less solid. m.p. 138–140 °C. IR (thin film): ν = 2949 (w), 1724 (s),
FULL PAPER
˜
4.17 (br. m, 4 H), 4.17–3.75 (br. m, 2 H), 3.75–3.38 (br. m, 2 H)
1600 (w), 1451 (w), 1408 (m), 1271 (s), 1128 (w), 1101 (w), 1063
1
ppm. 13C NMR (50 MHz, CDCl3): δ = 171.1, 166.0, 134.7, 133.1,
(w), 1028 (w), 988 (w), 702 (m) cm–1. H NMR and 13C NMR see
130.0, 129.6, 129.5, 128.6, 128.3, 127.0, 68.8, 62.8, 47.8, (br) 43.4 ref.[6]
(br) ppm. HRMS (ESI): calcd. for C27H25NNaO6 [M + Na]+
2,5-Dioxohexane-1,6-diyl Diacetate (4): Acetate-protected tetra-
hydrofuran 3 (24.5 mg, 0.113 mmol) was subjected to Procedure A
(1R)-1-((2R,5S)-5-{(1S)-1-(Acetyloxy)-15-[(5S)-5-methyl-2-oxo- to give title compound 4 (20.8 mg, 0.090 mmol, 80%) as a colour-
2,5-dihydrofuran-3-yl]pentadecyl}oxolan-2-yl)tridecyl Acetate (25): less solid. m.p. 86–88 °C. IR (thin film): ν = 3004 (w), 2934 (w),
482.1580; found 482.1583.
˜
Oil. IR: ν = 2922 (br. s), 2852 (m), 1735 (br. s), 1459 (w), 1370 (w),
1763 (s), 1722 (s), 1415 (s), 1367 (m), 1304 (w), 1281 (m), 1232 (br.
s), 1102 (w), 1038 (br. m), 1034 (w), 960 (w), 841 (w), 755 (br. w),
˜
1318 (w), 1237 (s), 1073 (w), 1025 (m), 949 (w) cm–1. 1H NMR
(200 MHz, CDCl3): δ = 6.98 (br. q, J = 1.3 Hz, 1 H), 4.99 (br. q,
J = 6.7 Hz, 1 H), 4.94–4.81 (m, 3 H), 4.01–3.89 (m, 2 H), 2.26 (t,
J = 7.6 Hz, 2 H), 2.07 (s, 6 H), 2.01–1.16 (m, 48 H), 1.40 (d, J =
1
713 (w), 682 (w), 619 (w) cm–1. H NMR (200 MHz, CDCl3): δ =
4.69 (s, 4 H), 2.74 (s, 4 H), 2.15 (s, 6 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 202, 170.2, 67.9, 31.9, 20.4 ppm. HRMS (ESI): calcd.
6.8 Hz, 3 H), 0.87 (t, J = 6.1 Hz, 5 H) ppm. 13C NMR (50 MHz, for C10H14NaO6 [M + Na]+ 253.0688; found 253.0691.
CDCl3): δ = 173.8, 170.7, 148.8, 134.3, 79.8, 77.4, 75.4, 31.9, 30.8,
2,5-Dioxohexane-1,6-diyl Bis(4-methylbenzenesulfonate) (6): Tosyl-
ate-protected tetrahydrofuran 5 (15.7 mg, 0.036 mmol) was sub-
jected to Procedure A to give title compound 6 (13.8 mg,
29.6, 29.6, 29.3, 29.3, 29.2, 27.8, 27.4, 25.3, 25.2, 22.7, 21.1, 19.2,
14.1 ppm. HRMS (ESI): calcd. for C41H72NaO7 [M + Na]+
699.5176; found 699.5180.
0.030 mmol, 85%) as an oil. IR (thin film): ν = 2922 (br. w), 2852
˜
(1R)-1-[(2R,5S)-5-[(1S)-1-(Benzoyloxy)-15-[(5S)-5-methyl-2-oxo- (w), 1732 (m), 1597 (w), 1359 (m), 1189 (m), 1176 (s), 1091 (w),
2,5-dihydrofuran-3-yl]pentadecyl]oxolan-2-yl]tridecyl Benzoate (26):
1003 (br. m), 814 (m), 667 (m) cm–1. 1H NMR (200 MHz, CDCl3):
Oil. IR: ν = 2917 (m), 2850 (w), 1716 (s), 1599 (w), 1585 (w), 1451 δ = 7.81 (d, J = 8.3 Hz, 4 H), 7.37 (d, J = 8.1 Hz, 4 H), 4.52 (s, 4
˜
(m), 1361 (w), 1311 (w), 1272 (s), 1248 (m), 1121 (m), 1023 (w), H), 2.80 (s, 4 H), 2.46 (s, 6 H) ppm. 13C NMR (50 MHz, CDCl3):
1
771 (w), 714 (m) cm–1. H NMR (200 MHz, CDCl3): δ = 8.07 (d, δ = 201.7, 145.6, 132.1, 130.1, 128.1, 71.7, 32.2, 21.7 ppm. HRMS
J = 7.3 Hz, 4 H), 7.53 (t, J = 7.4 Hz, 2 H), 7.38 (t, J = 7.4 Hz, 4 (ESI): calcd. for C20H22NaO8S2 [M + Na]+ 477.0654; found
H), 6.98 (s, 1 H), 5.23 (app q, J = 5.5 Hz, 2 H), 4.99 (br. q, J =
7.3 Hz, 1 H), 4.17–4.03 (m, 2 H), 2.26 (t, J = 7.9 Hz, 2 H), 2.05–
1.09 (m, 48 H), 1.40 (d, J = 6.8 Hz, 3 H), 0.87 (t, J = 6.0 Hz, 3 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 174.5, 166.3, 166.2, 148.8,
134.3, 132.7, 130.5, 129.7, 128.3, 79.9, 77.4, 76.0, 31.9, 30.8, 29.63,
29.56, 29.50, 29.3, 29.2, 27.9, 27.4, 25.5, 25.2, 22.7, 19.2, 14.1 ppm.
HRMS (ESI): calcd. for C51H76NaO7 [M + Na]+ 823.5489; found
823.5491.
477.0658.
(؎)-(4R,9S)-5,8-Dioxododecane-1,4,9,12-tetrayl Tetrabenzoate (8):
Benzoate-protected tetrahydrofuran 7 (122.0 mg, 0.184 mmol) was
subjected to Procedure A to give title compound 8 (92.3 mg,
0.136 mmol, 74%) as a white solid. m.p. 123–125 °C. IR (thin film):
ν = 2960 (br. w), 2917 (w), 1716 (br. s), 1600 (w), 1584 (w), 1451
˜
(w), 1315 (w), 1272 (br. s), 1112 (br. m), 1070 (w), 1026 (w), 710
(m) cm–1. H NMR (200 MHz, CDCl3): δ = 8.06 (t, J = 8.3 Hz, 8
1
Procedure A for the Oxidative Cleavage of Tetrahydrofuran Sub-
strates: PCC (2 mol-% from a 0.01 m stock solution in CH3CN)
was added to a suspension of H5IO6 (3.2 equiv.) in CH3CN at room
temp. with vigorous stirring. After 5 min, a solution of the THF
compound (1 equiv.) in CH3CN was added. The overall volume of
CH3CN was such that the final concentration of the solution was
0.05 m. After complete consumption of the starting material (TLC
control, typically 30–40 min), EtOH (excess) was added, and stir-
ring was continued until the colour of the solution turned from
yellow to green (ca. 5 min). Then silica (excess) was added, and
the solvent was evaporated under reduced pressure. The resulting
powder was loaded onto a silica gel column. Flash chromatog-
raphy, eluting with CHCl3/MeOH (100:0 to 9:1), gave the desired
product.
H), 7.82–7.26 (m, 12 H), 5.36 (t, J = 5.9 Hz, 2 H), 4.39 (t, J =
5.8 Hz, 4 H), 3.15–2.62 (m, 4 H), 2.33–2.07 (m, 2 H), 2.07–1.87 (m,
2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 205.7, 166.5, 166.0,
133.5, 132.8, 130.1, 129.8, 129.5, 129.1, 128.5, 128.3, 78.3, 64.1,
31.8, 27.4, 24.5 ppm. HRMS (ESI): calcd. for C40H38NaO10 [M +
Na]+ 701.2363; found 701.2367.
(؎)-(4R,9S)-5,8-Dioxononadecane-1,4,9-triyl Tribenzoate (10):
Benzoate-protected tetrahydrofuran 9 (11.6 mg, 0.018 mmol) was
subjected to Procedure A to give title compound 10 (7.2 mg,
0.011 mmol, 61%) as an oil. IR (thin film): ν = 2923 (br. m), 2853
˜
(w), 1717 (br. s), 1602 (w), 1451 (w), 1315 (w), 1271 (br. s), 1176
(w), 1112 (m), 1070 (w), 1026 (w), 711 (m) cm–1 1H NMR
.
(500 MHz, CDCl3): δ = 8.08 (d, J = 7.6 Hz, 4 H), 8.03 (d, J =
7.7 Hz, 2 H), 7.59 (dd, J = 7.9, 5.9 Hz, 2 H), 7.54 (t, J = 7.4 Hz, 1
H), 7.46 (t, J = 7.7 Hz, 4 H), 7.42 (t, J = 7.7 Hz, 2 H), 5.35 (dd, J
= 8.0, 4.5 Hz, 1 H), 5.25 (dd, J = 6.9, 5.9 Hz, 1 H), 4.43–4.34 (m,
2 H), 2.95 (dt, J = 14.9, 6.0 Hz, 2 H), 2.85–2.75 (m, 2 H), 2.23–
2.08 (m, 2 H), 1.96 (dq, J = 13.4, 6.2 Hz, 4 H), 1.48 (s, 2 H), 1.28
(t, J = 23.1 Hz, 14 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 206.2, 205.8, 166.5, 166.2, 166.1, 133.5,
133.4, 132.9, 130.1, 129.83, 129.81, 129.6, 129.4, 129.1, 128.54,
128.49, 128.34, 79.0, 78.4, 64.2, 31.87, 31.83, 30.8, 29.7, 29.53,
29.51, 29.35, 29.29, 29.21, 27.5, 25.3, 24.6, 22.7, 14.1 ppm. HRMS
(ESI): calcd. for C40H48NaO8 [M + Na]+ 679.3247; found 679.3245.
Procedure B for the Oxidative Cleavage of Tetrahydropyran Sub-
strates: PCC (4 mol-% from a 0.01 m stock solution in CH3CN)
was added to a suspension of H5IO6 (4.0 equiv.) in CH3CN at room
temp. with vigorous stirring. After 5 min, a solution of the THP
compound (1 equiv.) in CH3CN was added. The overall volume of
CH3CN was such that the final concentration of the solution was
0.05 m. After complete consumption of the starting material (TLC
control, typically 6–8 h), EtOH (excess) was added, and stirring
was continued until the colour of the solution turned from yellow
to green (ca. 5 min). Then silica (excess) was added, and the solvent
was evaporated under reduced pressure. The resulting powder was
loaded onto a silica gel column. Flash chromatography, eluting
with chloroform/methanol (100:0 to 9:1), gave the desired product.
(؎)-2-[(1S,4R)-4-(Benzoyloxy)-3-oxocyclohexyl]-2-oxoethyl Benzo-
ate (12): Benzoate-protected tetrahydrofuran 11 (17.7 mg,
0.048 mmol) was subjected to Procedure A to give title compound
12 (13.7 mg, 0.036 mmol, 75%) as white needles. m.p. 156–157 °C.
2,5-Dioxohexane-1,6-diyl Dibenzoate (2): Benzoate-protected tetra-
hydrofuran 1 (22.0 mg, 0.065 mmol) was subjected to Procedure A
to give title compound 2 (22.3 mg, 0.063 mmol, 97%) as a colour-
IR (thin film): ν = 2934 (br. w), 1721 (br. s), 1601 (w), 1584 (w),
˜
1451 (m), 1414 (w), 1316 (m), 1274 (br. s), 1177 (w), 1114 (m), 1065
1786
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1781–1789

Synthesis of Bis-α-acyloxy-1,4- and -1,5-diketones
(m), 1026 (w), 996 (w), 710 (m) cm–1. 1H NMR (200 MHz, CDCl3): and 23 (2.3 mg, 0.005 mmol, 12%). Data for 21: Oil. IR (thin film):
δ = 8.17–8.00 (m, 4 H), 7.75–7.34 (m, 6 H), 5.38 (dd, J = 8.9,
6.2 Hz, 1 H), 5.12 (d, J = 16.8 Hz, 1 H), 4.85 (d, J = 16.8 Hz, 1
ν = 2921 (w), 2848 (w), 1725 (br. s), 1644 (m), 1601 (w), 1451 (m),
˜
1414 (w), 1315 (w), 1275 (s), 1112 (m), 1069 (m), 1027 (w), 712 (m)
1
H), 3.64–3.09 (m, 1 H), 2.85 (ddd, J = 14.5, 4.4, 1.5 Hz, 1 H), 2.58 cm–1. H NMR (200 MHz, CDCl3): δ = 8.10 (d, J = 7.6 Hz, 2 H),
(ddd, J = 14.5, 5.7, 0.6 Hz, 1 H), 2.49–2.09 (m, 4 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 204.0, 201.6, 165.9, 165.5, 133.6, 9 H), 5.04 (s, 2 H), 4.74 (s, 2 H), 4.52 (s, 2 H), 4.42 (s, 2 H) ppm.
7.99 (d, J = 7.7 Hz, 2 H), 7.60 (t, J = 7.3 Hz, 2 H), 7.54–7.31 (m,
133.3, 130.0, 129.9, 129.4, 128.9, 128.5, 128.4, 75.7, 67.0, 45.4, 40.0,
28.9, 24.5 ppm. HRMS (ESI): calcd. for C22H20NaO6 [M + Na]+
403.1158; found 403.1161. Single crystal X-ray diffraction data for
12 (Figure 1): C22H20O6, M = 380.38, monoclinic, a = 5.300(5), b
= 10.946(4), c = 32.574(9) Å, β = 97.37(3)°, V = 1874(2) Å3, T =
298 K, space group P21/c, Z = 4, μ(Mo-Kα) = 0.098 mm–1, 10511
reflections measured, 3248 unique [R(int) = 0.0690] which were
used in all calculations. Final agreement indices were R = 0.0573
[IϾ2σ(I)]. and wR(F2) = 0.1421 (all data).
13C NMR (50 MHz, CDCl3): δ = 200.0, 199.8, 172.3, 166.0, 165.7,
134.2, 133.7, 133.6, 130.5, 129.94, 129.87, 128.80, 128.5, 126.8,
67.5, 67.0, 56.8, 52.6 ppm. HRMS (ESI): calcd. for C27H23NNaO7
[M + Na]+ 496.1372; found 496.1373.
1-(Benzoyloxy)-3-(N-formyl-1-phenylformamido)propan-2-yl
2-(Benzoyloxy)acetate (22): Oil. IR (thin film): ν = 2949 (br. w),
˜
2926 (br. w), 2849 (w), 1762 (w), 1727 (s), 1673 (s), 1602 (w), 1451
(w), 1275 (br. s), 1206 (br. m), 1117 (br. m), 1071 (w) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 8.96 (s, 1 H), 8.06 (d, J = 7.7 Hz, 2
H), 8.03 (d, J = 8.4 Hz, 2 H), 7.62–7.53 (m, J = 8.1 Hz, 5 H), 7.51–
7.39 (m, 6 H), 5.72 (d, J = 3.4 Hz, 1 H), 4.85 (d, J = 16.0 Hz, A
part of an AB system, 1 H), 4.79 (d, J = 16.0 Hz, B part of an AB
system, 1 H), 4.60 (dd, J = 12.2, 3.8 Hz, 1 H), 4.54–4.43 (m, 3 H),
4.15 (dd, J = 14.0, 2.9 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3):
δ = 172.1, 167.7, 166.0, 165.8, 164.2, 133.4, 133.3, 133.0, 132.3,
129.9, 129.8, 129.4, 129.3, 129.0, 128.9, 128.5, 128.4, 70. 6, 63.6,
61.1, 40.5 ppm. HRMS (ESI): calcd. for C27H23NNaO8 [M +
Na]+ 512.1321; found 512.1320.
2,6-Dioxoheptane-1,7-diyl Dibenzoate (14): Benzoate-protected
tetrahydropyran 13 (24.1 mg, 0.068 mmol) was subjected to Pro-
cedure B to give title compound 14 (21.3 mg, 0.058 mmol, 85%) as
a white solid. m.p. 123–125 °C. IR (thin film): ν = 2949 (br. w),
˜
2918 (w), 2850 (w), 1724 (br. s), 1600 (w), 1451 (w), 1408 (m), 1271
(br. s), 1128 (w), 1101 (m), 1063 (m), 1028 (m), 988 (w), 702 (m)
1
cm–1. H NMR (200 MHz, CDCl3): δ = 8.09 (d, J = 7.0 Hz, 4 H),
7.60 (t, J = 7.3 Hz, 2 H), 7.46 (t, J = 7.4 Hz, 4 H), 4.87 (s, 4 H),
2.61 (t, J = 6.8 Hz, 4 H), 2.01 (quin, J = 6.8 Hz, 2 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 203.6, 165.9, 133.4, 129.9, 129.6,
128.5, 68.4, 37.2, 16.7 ppm. HRMS (ESI): calcd. for C21H20NaO6
[M + Na]+ 391.1158; found 391.1159.
1-(Benzoyloxy)-3-(phenylformamido)propan-2-yl 2-(Benzoyloxy)-
acetate (23): Oil. IR (thin film): ν = 3380 (br. w), 3300 (br. w), 3061
˜
(w), 2934 (w), 1726 (s), 1645 (w), 1537 (br. w), 1451 (w), 1275 (s),
1
1203 (w), 1117 (m), 709 (m) cm–1. H NMR (200 MHz, CDCl3): δ
7-Methyl-2,6-dioxooctane-1,7-diyl Dibenzoate (16): Benzoate-pro- = 8.06–7.95 (m, 4 H), 7.83 (d, J = 7.9 Hz, 2 H), 7.65–7.35 (m, 9
tected tetrahydropyrans 15 (26.4 mg, 0.068 mmol) and 17 (21.0 mg,
0.055 mmol) were subjected to Procedure B to give title compound
16 (25.7 mg, 0.065 mmol, 95% from 15; 18.2 mg, 0.046 mmol, 83%
H), 6.75 (br. t, J = 5.4 Hz, 1 H), 5.59–5.42 (m, J = 7.3 Hz, 1 H),
4.92 (d, J = 15.8 Hz, A part of an AB system, 1 H), 4.82 (d, J =
15.8 Hz, B part of an AB system, 1 H), 4.60 (dd, J = 12.2, 4.1 Hz,
1 H), 4.49 (dd, J = 12.2, 5.5 Hz, 1 H), 3.99 (ddd, J = 14.5, 6.5,
3.9 Hz, 1 H), 3.67 (ddd, J = 14.5, 7.2, 5.6 Hz, 1 H) ppm. 13C NMR
from 17) as an oil. IR (thin film): ν = 2990 (w), 2937 (br. w), 1721
˜
(br. s), 1601 (w), 1584 (w), 1451 (m), 1416 (w), 1367 (w), 1316 (m),
1
1286 (br. s), 1113 (m), 1070 (m), 1026 (m), 712 (s) cm–1. H NMR (101 MHz, CDCl3): δ = 167.7, 167.4, 166.7, 166.2, 133.8, 133.7,
(500 MHz, CDCl3): δ = 8.07 (d, J = 7.2 Hz, 2 H), 8.01 (d, J =
7.2 Hz, 2 H), 7.60–7.54 (m, 2 H), 7.45 (t, J = 7.4 Hz, 2 H), 7.43 (t,
133.3, 131.6, 129. 9, 129.7, 129.6, 129.3, 128.555, 128.548, 128.5,
127.1, 126.6, 72.2, 63.3, 61.7, 40.1 ppm. HRMS (ESI): calcd. for
J = 7.4 Hz, 2 H), 4.88 (s, 2 H), 2.66–2.50 (q, 4 H), 1.97 (quin, J = C26H23NNaO7 [M + Na]+ 484.4531; found 484.4520.
6.8 Hz, 2 H), 1.59 (s, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
(13R,18S)-18-(Acetyloxy)-32-[(5S)-5-methyl-2-oxo-2,5-dihydro-
208.4, 203.8, 165.8, 133.3, 129.9, 129.8, 129.2, 128.4, 84.1, 68.4,
furan-3-yl]-14,17-dioxodotriacontan-13-yl Acetate (27): cis-Reticula-
37.2, 33.8, 23.7, 16.9 ppm. HRMS (ESI): calcd. for C23H24NaO6
tacin diacetate 25 (5.4 mg, 0.008 mmol) was subjected to Procedure
[M + Na]+ 419.1471; found 419.1473.
B. After being stirred for 12 h, the reaction mixture was filtered
and evaporated to dryness, and the crude mixture was separated
by HPLC (hexane/EtOAc, 8:2) to give title compound 27 (1.4 mg,
2,6-Dioxoheptane-1,4,7-triyl Tribenzoate (19): Benzoate-protected
tetrahydropyran 18 (27.0 mg, 0.057 mmol) was subjected to Pro-
cedure B to give title compound 19 (21.5 mg, 0.044 mmol, 78%) as
0.002 mmol, 30%) as a colourless oil. IR (thin film): ν = 2924 (s),
˜
2853 (m), 1747 (br. s), 1374 (w), 1235 (br. m) cm–1 1H NMR
.
a white solid. m.p. 148–150 °C. IR (thin film): ν = 3068 (w), 2929
˜
(400 MHz, CDCl3): δ = 6.99 (s, 1 H), 5.04–4.92 (m, 3 H), 2.88–
2.75 (m, 2 H), 2.75–2.62 (m, 2 H), 2.26 (t, J = 7.6 Hz, 2 H), 2.14
(s, 6 H), 1.90–1.65 (m, 6 H), 1.66–1.17 (m, 38 H), 1.40 (d, J =
6.8 Hz, 3 H), 0.88 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 206.1, 173.9, 170.7, 148.8, 134.3, 78.6, 77.4, 31.9, 31.7,
30.5, 29.6, 29.5, 29.4, 29.2, 27.4, 25.21, 25.20, 22.7, 20.7, 19.2,
14.1 ppm. HRMS (ESI): calcd. for C41H70NaO8 [M + Na]+
713.4968; found 713.4966.
(w), 1720 (s), 1601 (w), 1583 (w), 1451 (w), 1406 (br. w), 1314 (w),
1
1275 (s), 1177 (w), 1112 (w), 1069 (w), 1026 (w), 711 (m) cm–1. H
NMR (200 MHz, CDCl3): δ = 8.18–7.91 (m, 6 H), 7.67–7.52 (m, 3
H), 7.50–7.34 (m, 6 H), 5.86 (quin, J = 6.0 Hz, 1 H), 4.96 (d, J =
16.9 Hz, A part of an AB system, 2 H), 4.87 (d, J = 16.9 Hz, B
part of an AB system, 2 H), 3.23–2.97 (m, 4 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 201.0, 165.8, 165.6, 133.5, 133.3, 129.9,
129.7, 129.6, 129.0, 128.5, 68.7, 66.5, 41.9 ppm. HRMS (ESI):
calcd. for C28H24NaO8 [M + Na]+ 511.1369; found 511.1366.
(13R,18S)-18-(Benzoyloxy)-32-[(5S)-5-methyl-2-oxo-2,5-dihydro-
furan-3-yl]-14,17-dioxodotriacontan-13-yl Benzoate (28): cis-Reticu-
3,3Ј-Benzamidobis(2-oxopropane-3,1-diyl) Dibenzoate (21): latacin dibenzoate 26 (3.6 mg, 0.004 mmol) was subjected to Pro-
Benzoate-protected morpholine 20 (20.0 mg, 0.044 mmol) was sub-
jected to Procedure B. The reaction mixture was filtered and evapo-
rated to dryness, and the crude material was separated by HPLC
(hexane/EtOAc, 6:4) to give title compound 21 (5.2 mg,
0.011 mmol, 26%), and compounds 22 (3.9 mg, 0.008 mmol, 18%)
cedure B. After being stirred for 8 h, the reaction mixture was fil-
tered and taken to dryness, and the crude mixture was separated by
HPLC (hexane/EtOAc, 85:15) to give title compound 28 (1.6 mg,
0.002 mmol, 40%) as a colourless oil. [α]3D0 = –23.3 (c = 0.03,
CHCl ). IR (thin film): ν = 2924 (s), 2853 (m), 1756 (m), 1720 (s),
˜
3
Eur. J. Org. Chem. 2013, 1781–1789
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1787

V. Piccialli et al.
FULL PAPER
1453 (w), 1316 (w), 1271 (m), 1112 (br. w), 1028 (w), 712 (m) cm–1.
1H NMR (200 MHz, CDCl3): δ = 8.08 (d, J = 7.1 Hz, 4 H), 7.60
(t, J = 7.3 Hz, 2 H), 7.46 (t, J = 7.4 Hz, 4 H), 6.98 (br. q, J =
1.7 Hz, 1 H), 5.24 (t, J = 6.4 Hz, 2 H), 4.99 (br. q, J = 6.8 Hz, 1
H), 3.05–2.67 (m, 4 H), 2.26 (t, J = 7.6 Hz, 2 H), 1.94 (app q, J =
6.5 Hz, 4 H), 1.64–1.15 (m, 40 H), 1.40 (d, J = 6.8 Hz, 3 H), 0.87
(t, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 206.2,
173.9, 166.9, 166.2, 148.9, 134.3, 133.4, 129.8, 129.3, 128.5, 79.0,
77.4, 31.9, 31.8, 30.7, 29.7, 29.6, 29.5, 29.3, 29.2, 27.4, 25.3, 25.1,
22.7, 19.2, 14.1 ppm. HRMS (ESI): calcd. for C51H74NaO8 [M +
Na]+ 837.5281; found 837.5284.
were consistent with those previously reported for this com-
pound.[33]
2,6-Bis(hydroxymethyl)-1λ4-pyridin-1-olate (32b): NH2OH·HCl
(5.1 mg, 0.0073 mmol) was added to a solution of diketone 19
(10.5 mg, 0.021 mmol) in dry EtOH (500 μL). After being stirred
for 32 h at room temp. and 15 h at reflux, NaHCO3 (sat. aq.) was
added until neutrality was reached, and then the mixture was con-
centrated under reduced pressure and filtered through a short pad
of silica gel (CHCl3/MeOH, 8:2). Purification by preparative TLC
(hexane/EtOAc, 1:1) gave 32a (5.3 mg, 0.014 mmol, 68 %) as a
colourless oil. Data for 32a: IR (thin film): ν = 2924 (br. m), 2852
˜
(w), 1717 (s), 1601 (w), 1449 (w), 1368 (w), 1264 (s), 1174 (m), 1115
2-[6-(Hydroxymethyl)pyridin-2-yl]propan-2-ol (29b): NH4OAc
(4.0 mg, 0.052 mmol) and AcOH (3 μL) were added to a solution
of diketone 16 (12.0 mg, 0.030 mmol) in dry MeOH (300 μL). After
being stirred for 24 h at room temp. and 48 h at 55 °C, the reaction
mixture was diluted with EtOAc (2 mL) and washed with NaHCO3
(sat. aq.) and water. The organic phase was dried, filtered and con-
centrated under reduced pressure. Separation by preparative TLC
(hexane/EtOAc, 3:7) gave 29a (6.3 mg, 55%) and 30 (2.1 mg, 25%)
1
(s), 1071 (m), 1027 (w), 845 (m), 769 (w), 709 (s) cm–1. H NMR
(500 MHz, CDCl3): δ = 8.15 (d, J = 7.5 Hz, 4 H), 7.62 (t, J =
7.2 Hz, 2 H), 7.50 (t, J = 7.7 Hz, 4 H), 7.46 (d, J = 7.6 Hz, 2 H),
7.34 (t, J = 8.0 Hz, 1 H), 5.71 (s, J = 32.9 Hz, 4 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 165.7, 147.3, 133.5, 129.8, 129.3, 128.6,
125.5, 122.2, 60.8 ppm. HRMS (ESI): calcd. for C21H17NNaO5 [M
+ Na]+ 386.1010; found 370.1012.
as colourless oils. Data for 29a: oil. IR (thin film): ν = 2923 (br.
˜
Debenzoylation of 32a (3.8 mg, 0.010 mmol) with K2CO3 in
MeOH as described for 30 gave diol 32b (1.2 mg, 0.008 mmol,
w), 2849 (w), 1716 (s), 1594 (w), 1450 (w), 1314 (w), 1265 (br. s),
1151 (w), 1108 (s), 1070 (w), 1026 (w), 709 (s) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 8.11 (d, J = 7.2 Hz, 2 H), 8.06 (d, J =
7.2 Hz, 2 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.60–7.54 (m, 2 H), 7.48–
7.42 (m, 4 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.32 (d, J = 7.6 Hz, 1 H),
5.52 (s, 2 H), 1.94 (s, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
166.3, 165.3, 155.3 154.9, 137.2, 133.1, 132.7, 129.7, 129.6, 128.4,
128.3, 119.3, 117.9, 83.3, 67.2, 27.6 ppm. HRMS (ESI): calcd. for
C23H21NNaO4 [M + Na]+ 398.1368; found 398.1367.
78%) as an oil. Data for 32b: IR (thin film): ν = 3418 (br. m), 2918
˜
(w), 2849 (w), 1644 (br. m), 1416 (w), 1358 (w), 1212 (w), 1166 (w),
1085 (w), 1031 (w) cm–1. 1H NMR (200 MHz, CDCl3): δ = 7.36
(br. s, 3 H), 4.84 (br. s, 4 H) ppm. 13C NMR (175 MHz, CD3OD):
δ = 157.6, 130.1, 122.4, 59.7 ppm. HRMS (ESI): calcd. for
C7H9NNaO3 [M + Na]+ 178.0480; found 178.0481.
Converson of 31b to 32b: MCPBA (1.2 equiv., 0.030 mmol, 500 μL)
from a stock solution (0.060 mm) in CHCl3 was added to a solution
of pyridine diol 31b (3.5 mg, 0.025 mmol) in CHCl3 (500 μL). The
mixture was stirred for 90 min at room temp. and then it was con-
centrated under reduced pressure. Separation by preparative TLC
(CHCl3/MeOH, 8:2) gave 32b (1.4 mg, 0.009 mmol, 36%) as a
colourless oil.
K2CO3 (1.0 mg, 10 mol-%) was added to a solution of 30 (2.1 mg,
0.008 mmol) in MeOH. After being stirred for 30 min at room
temp., AcOH was added until neutrality was reached, and then the
mixture was evaporated under reduced pressure. The residue was
redissolved in CHCl3 and filtered to give pyridine diol 29b (1.2 mg,
0.007 mmol, 85%) as an oil. Data for 29b: IR (thin film): ν = 3420
˜
(br. m), 2920 (br. m), 2853 (m), 1736 (br. m), 1462 (br. w), 1376
(br. w), 1260 (br. w), 1169 (br. w), 1099 (br. w), 1022 (br. w), 802
[6-(Hydroxymethyl)pyrazin-2-yl]methanol
(33b):
NH2OH·HCl
(4.8 mg, 0.069 mmol) was added to a solution of diketone 21
(10.8 mg, 0.023 mmol) in dry EtOH (500 μL). After being stirred
for 6 h at room temp., NaHCO3 (sat. aq.) was added until neu-
trality was reached, and then the mixture was concentrated under
reduced pressure and filtered through a short pad of silica gel
(CHCl3/MeOH, 8:2). Purification by HPLC (hexane/EtOAc, 6:4)
gave 33a (5.6 mg, 0.016 mmol, 68%) as a colourless oil. Data for
1
(w) cm–1. H NMR (200 MHz, CDCl3): δ = 7.72 (t, J = 7.7 Hz, 1
H), 7.32 (d, J = 7.8 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 4.79 (s, 2
H), 1.57 (s, 6 H) ppm. HRMS (ESI): calcd. for C9H13NNaO2 [M
+ Na]+ 190.0844; found 190.0842.
[6-(Hydroxymethyl)pyridin-2-yl]methanol (31b): NH2OH·HCl
(5.8 mg, 0.084 mmol) was added to a solution of diketone 14
(9.4 mg, 0.024 mmol) in dry EtOH (1 mL). After being stirred for
16 h at room temp. and 8 h at reflux, NaHCO3 (sat. aq.) was added
until neutrality was reached, and then the mixture was concen-
trated under reduced pressure and filtered through a short pad of
silica gel (CHCl3/MeOH, 8:2). Purification by preparative TLC
(hexane/EtOAc, 3:7) gave 31a (5.4 mg, 0.016 mmol, 65 %) as a
33a: IR: ν = 2917 (m), 2849 (w), 1719 (s), 1601 (w), 1451 (w), 1315
˜
(w), 1266 (s), 1176 (w), 1110 (m), 1071 (w), 1025 (w), 709 (s) cm–1.
1H NMR (200 MHz, CDCl3): δ = 8.74 (s, 2 H), 8.11 (d, J = 7.0 Hz,
4 H), 7.61 (t, J = 7.3 Hz, 2 H), 7.47 (t, J = 7.3 Hz, 4 H), 5.54 (s, 4
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 166.1, 150.9, 142.6,
133.5, 129.8, 129.4, 128.6, 65.1 ppm. HRMS (ESI): calcd. for
C20H16N2NaO4 [M + Na]+ 371.3418; found 371.3419.
colourless oil. Data for 31a: IR (thin film): ν = 2917 (br. m), 2850
˜
(m), 1716 (m), 1600 (w), 1585 (w), 1451 (w), 1361 (w), 1311 (w),
1272 (s), 1248 (m), 1173 (w), 1121 (m), 1023 (w), 771 (w), 714 (m)
Debenzoylation of 33a (6.5 mg, 0.019 mmol) with K2CO3 in
MeOH as described for 30 gave diol 33b (1.7 mg, 0.012 mmol,
1
cm–1. H NMR (200 MHz, CDCl3): δ = 8.16–8.08 (m, 4 H), 7.76
66%) as an oil. Data for 33b: IR (thin film): ν = 3364 (br. m), 2924
˜
(t, J = 7.7 Hz, 1 H), 7.65–7.54 (m, 2 H), 7.52–7.43 (m 4 H), 7.41 (d,
J = 7.2 Hz, 2 H), 5.51 (s, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 166.2, 155.9, 137.6, 132.2, 129.8, 128.6, 128.5, 120.7, 67.0 ppm.
HRMS (ESI): calcd. for C21H17NNaO4 [M + Na]+ 370.1055; found
370.1053.
(s), 2854 (m), 1723 (br. m), 1641 (br. m), 1576 (w), 1539 (w), 1490
(w), 1456 (w), 1418 (br. w), 1275 (br. m), 1160 (br. w), 1083 (br.
m), 1022 (w), 713 (m) cm–1. 1H NMR (200 MHz, CDCl3): δ = 8.58
(br. s, 2 H), 4.86 (br. s, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 153.6, 141.5, 62.9 ppm. HRMS (ESI): calcd. for C6H8N2NaO2
[M + Na]+ 163.0483; found 163.0485.
Debenzoylation of 31a (4.5 mg, 0.013 mmol) with K2CO3 in
MeOH as described for 30 gave pyridine-2,6-diyldimethanol 31b
(1.5 mg, 0.011 mmol, 82%) as an oil. Spectroscopic data for 31b
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C spectra of all new compounds.
1788
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1781–1789

Synthesis of Bis-α-acyloxy-1,4- and -1,5-diketones
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range of THF compounds (see ref.[6]).
Acknowledgments
[14] CCDC-892952 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
This work was supported by the Ministero dell’Istruzione, dell’Uni-
versità e della Ricerca (MIUR) (PRIN 2009).
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˘
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Received: November 19, 2012
[11] For a mechanistic hypothesis, see ref.[6]
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Published Online: February 4, 2013
Eur. J. Org. Chem. 2013, 1781–1789
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1789