Insight into pyridinium chlorochromate chemistry: Catalytic oxidation of tetrahydrofuran compounds and synthesis of umbelactone

Article abstract of DOI:10.1002/ejoc.201200069

The catalytic system PCC (cat.)/H₅IO₆ has been used to oxidise mono- and polytetrahydrofuran compounds. New oxidative pathways are disclosed. 2,2,5-Trisubstituted THF rings are converted into dicarbonyl compounds through oxidative cleavage of the C2-C3 bond. Cyclic enol ethers appear to be intermediate species in this process. Oxidation of 2,2,5-trisubstituted α-keto-THF compounds proceeds with the oxidative cleavage of the C2(THF)-C=O bond to give 1,4-diketones with degraded carbon backbones. Attack of the oxidant on 2,5-disubstituted THF rings leads to 1,4-diketones containing intact THF carbon frameworks. Oxidation of complex poly-THF substrates, containing up to five THF rings, allows access to new poly-THF compounds through regioselective THF oxidation along the poly-THF backbones. A mechanistic explanation of the new processes consistent with the reported reactivity of PCC and the isolation of some minor products of the process is provided. The synthesis of racemic umbelactone, an antiviral natural butenolide metabolite, has been carried out by use of the developed chemistry. The catalytic oxidation of mono- and polytetrahydrofuran compounds has been carried out with chlorochromatoperiodate (CCP), generated by the combination of PCC and H₅IO₆. New synthetically useful oxidative transformations are disclosed. Umbelactone, an antiviral natural butenolide metabolite, has been synthesized by use of the developed chemistry. Copyright

Full text of DOI:10.1002/ejoc.201200069

Job/Unit: O20069
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Date: 13-06-12 16:23:18
Pages: 14
FULL PAPER
DOI: 10.1002/ejoc.201200069
Insight into Pyridinium Chlorochromate Chemistry: Catalytic Oxidation of
Tetrahydrofuran Compounds and Synthesis of Umbelactone
Vincenzo Piccialli,*[a] Sabrina Zaccaria,[a] Giorgia Oliviero,[b] Stefano D’Errico,[b]
Valentina D’Atri,[b] and Nicola Borbone[b]
Keywords: Oxidation / Oxygen heterocycles / Reaction mechanisms
The catalytic system PCC (cat.)/H5IO6 has been used to oxi-
containing intact THF carbon frameworks. Oxidation of com-
dise mono- and polytetrahydrofuran compounds. New oxi- plex poly-THF substrates, containing up to five THF rings,
dative pathways are disclosed. 2,2,5-Trisubstituted THF rings
are converted into dicarbonyl compounds through oxidative
cleavage of the C2–C3 bond. Cyclic enol ethers appear to
be intermediate species in this process. Oxidation of 2,2,5-
trisubstituted α-keto-THF compounds proceeds with the oxi-
dative cleavage of the C2(THF)–C=O bond to give 1,4-di-
allows access to new poly-THF compounds through regiose-
lective THF oxidation along the poly-THF backbones. A
mechanistic explanation of the new processes consistent with
the reported reactivity of PCC and the isolation of some
minor products of the process is provided. The synthesis of
racemic umbelactone, an antiviral natural butenolide metab-
ketones with degraded carbon backbones. Attack of the oxi- olite, has been carried out by use of the developed chemistry.
dant on 2,5-disubstituted THF rings leads to 1,4-diketones
Introduction
Results and Discussion
Oxidation of Poly-THF Compounds – Preliminary Results
Pyridinium chlorochromate (PCC) is a well-known rea-
gent employed in an array of oxidising processes.[1] This oxi-
dant is usually used either in stoichiometric or in excess
amounts to oxidise a variety of functional groups. In con-
trast, the use of PCC in catalytic amounts has received little
attention to date[2,3] even though chromium(VI) species are
known to be carcinogenic and environmentally hazardous
and the use of substoichiometric amounts of such a reagent
would therefore be highly desirable. In this respect, the cata-
lytic system PCC (cat.)/H5IO6 is particularly appealing, al-
though it has been employed in only a few cases.[2,3] As a
part of our ongoing interest in oxidative processes mediated
by transition metal oxo species[4] and in particular in the
synthesis of new THF-containing compounds,[5] we report
here on the oxidation of mono- and poly-THF compounds
with the PCC (cat.)/H5IO6 (chlorochromatoperiodate,
CCP) system, which has led to the discovery of new types
of useful oxidative transformations involving THF ring sys-
tems. A similarity between the oxidative behaviour of PCC
and that of RuO4, which further supported our recent find-
ings in the chemistry of these oxo species, has also
emerged.[5a,5b]
In a preliminary experiment devised to test the reactivi-
ties of tetrahydrofuran-containing substances with PCC,
penta-THF dibenzoate 2 (Scheme 1), containing five dif-
ferently substituted and configured THF rings, was investi-
gated. The synthesis of 2 was accomplished by a RuO4-cata-
lysed oxidative polycyclization protocol starting from squal-
ene, previously developed in our laboratory,[5i,5f] followed
by benzoylation of the tertiary hydroxy groups in the ini-
tially formed penta-THF diol 1 under standard conditions
(BzCl, DMAP, CH2Cl2).
Treatment of 2 with PCC under classical oxidising condi-
tions (excess PCC/AcOH, CH2Cl2, Scheme 2)[5b] gave the
two isomeric tetra-THF compounds 3 and 4 (overall 32%
yield), originating from the oxidative cleavage of the C2–C3
bonds in either the D or the B THF rings of 2, respectively.
The rest of the material for mass balance was made up of
polar substances possibly derived by side- or over-oxidation
processes due to the presence of various THF rings prone
to attack by the oxidant. The structures of 3 and 4 were
determined by a full set of 2D NMR experiments recorded
at high fields. Although the process proceeded with a rather
low yield and could not be forced to completion under these
conditions, the ability of PCC to oxidise the THF ring had
been confirmed.
[a] Dipartimento di Scienze Chimiche, Università degli Studi di
Napoli “Federico II”,
Via Cintia, 80126 Napoli, Italy
Our next goal was to test the reactivity of 2 in the pres-
ence of the catalytic system PCC (cat.)/H5IO6 (Scheme 3).
From previous studies[6] it is thought that the combination
of PCC and H5IO6 generates chlorochromatoperiodate
Fax: +39-081-674393
E-mail: vinpicci@unina.it
[b] Dipartimento di Chimica delle Sostanze Naturali, Università
degli Studi di Napoli “Federico II”,
Via D. Montesano 49, 80131 Napoli, Italy
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Scheme 1. Synthesis of penta-THF dibenzoate 2.
4, in the reaction mixture (NMR, HPLC and MS analyses).
Smaller amounts of these side products were also formed
under conditions A.
Scheme 2. Cleavage products from the oxidation of penta-THF di-
benzoate 2 with PCC/AcOH.
Scheme 3. Oxidation of penta-THF dibenzoate 2 with PCC (cat.)/
H5IO6.
(CCP, Scheme 3), an oxidising agent more powerful than
PCC itself. It was hoped that the use of a more reactive
reagent such as this might possibly reduce reaction times
To test the above oxidising system further, the oxidation
and force the process to completion. The oxidation was ini- of tris-THF tetrabenzoate 5 (Scheme 4), a structurally “sim-
tially carried out in CH3CN at 0 °C with 1 mol-% of PCC plified” substrate related to 2, was then carried out. Com-
and 4 equiv. of periodic acid (Scheme 3, conditions A). The pound 5 was obtained by benzoylation of the corresponding
process was indeed much cleaner under these conditions tetrol (prepared in turn from penta-THF 1 through a short
and overall improved yields of acids 3 and 4 (3: 40%; 4: degradative sequence developed in a previous study con-
4%) were obtained in a shorter time (3 h). Importantly, the ducted by our group[5f]). Interestingly, in this case the three
two isomers were now obtained in a ca. 10:1 ratio in favour major products 6–8, two of them – acids 6 and 7 – structur-
of 3. With regard to the attack of the oxidant at the D ally related to 3 and 4 and all originating from attack of
ring of the poly-THF system of 2, the observed enhanced the oxidant at the central THF ring, were obtained. In this
regioselectivity was probably due both to the increased case 4 equiv. of H5IO6 were sufficient to drive the process
steric demand of the CCP and to the different configura- to completion. 2D NMR experiments were carried out to
tions of the involved rings (ring B: cis; ring D: trans). Under determine the stereostructures of 6–8. A new feature of this
these conditions the process was still incomplete and process was the formation of the 1,4-diketone 8 through a
stopped at 80% conversion. Addition of a further 1 mol-% different oxidative route featuring the oxidation of both the
PCC and 1 equiv. of H5IO6 (conditions B) forced the pro- angular carbons of the central THF ring in 5, not observed
cess to completion at the expense of a slight reduction in in the oxidation of penta-THF 2. 1,4-Diketones are easily
the overall yield (3 + 4 38%; 3/4 10:1) presumably due to transformed into five-membered heterocycles, so substances
the over-oxidation of 3 and 4 themselves, as indicated by such as 8 might be synthetically useful to access new types
the presence of polar products, probably related to 3 and/or of rare mixed poly-THF/heterocycle compounds.
2
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Catalytic Oxidation of Tetrahydrofuran Compounds
Scheme 6. Oxidation of THF-dilactone 9.
The above results indicated that the oxidation of complex
poly-THF compounds containing both di- and trisubsti-
tuted THF rings proceeds through two main routes. Oxidat-
ive cleavage of the C2–C3 bond is preferred when a 2,2,5-
trisubstituted THF ring is involved, as in the oxidation of
2. A second route leads to 1,4-diketones, such as 8 and 10,
through the attack of the oxidant at a 2,5-disubstituted
THF ring and oxidation of both its angular carbon atoms,
as in the oxidations of 5 and 9.
Oxidation of Mono-THF Compounds
With the aim of making the above process synthetically
useful, the oxidation of some mono-THF compounds,
based on the di- and trisubstituted THF motifs present in
previously studied poly-THF compounds, was tested. cis-
THF 11 (Table 1), obtained by benzoylation of the corre-
sponding diol, in turn synthesized by RuO4-catalyzed oxi-
dative cyclization of geranyl benzoate,[8] was initially chosen
as a model compound to find the best conditions for the
Scheme 4. Oxidation of tris-THF tetrabenzoate 5.
The parent penta-THF 2 can be obtained in a single step oxidative process. Oxidation of 11 under previously em-
in multi-gram amounts from cheap and commercially avail- ployed conditions [PCC (2 mol-%), H5IO6 (4 equiv.), 0 °C]
able squalene, so the oxidative degradation of its penta- gave acid 12, analogous to compounds 3/4 and 6/7 obtained
THF backbone can allow facile access to stereochemically from more complex substrates, in a 54% yield (Table 1, En-
definite and functionalised cis-cis-trans and trans-trans- try 1), although longer reaction times were required. The
trans tris-THF compounds by hydrolysis of the inter-THF process was then carried out at room temp. with the same
ester functions in either 3 or 4 (Scheme 5). Likewise, new amounts of catalysts and co-oxidant, leading to 12 in a sim-
functionalised cis or trans mono-THF systems can be ob- ilar 55% yield in only 3 h (Entry 2). Improved yields (80%)
tained from 6 and 7 by hydrolysis (Scheme 5). Given litera- and further reduced reaction times (45 min) were achieved
ture precedents, it can be presumed that at least some of by increasing the catalyst amount to 5% (Entry 3). Increas-
these substances should be useful for further cytotoxic ac- ing of the catalyst amount to 10% resulted in a similar yield
tivity studies and also for synthetic purposes.[7]
and further reduced times (78%, 30 min, Entry 4). Further
increasing of the catalyst up to stoichiometric amounts (50–
Table 1. Optimization of the process on a model 2,2,5-trisubstituted
THF compound.
Scheme 5. Functionalised new all-threo mono- and tris-THF sys-
tems accessible through hydrolysis of poly-THF compounds 3, 4,
6 and 7.
Entry
PCC
[mol-%]
H5IO6
[equiv.]
Time
Yield of
12[a] [%]
A further simplification of the poly-THF substrate was
achieved by conversion of the tetrol corresponding to 5 into
bis-lactone 9 (Scheme 6) through a previously developed
degradative sequence.[5f] Interestingly, oxidation of this
compound under the same conditions as used for 5 led to
1,4-diketone 10 (45% yield) through the oxidative opening
of the THF ring, whereas no acid corresponding to com-
pounds 6/7 was observed.
1[b]
2
3
4
5
6
2
2
5
10
50
100
4
4
4
4
4
4
19 h
3 h
45 min
30 min
30 min
30 min
54
55
80[c]
78
62
37
[a] Estimated by 1H NMR examination of the crude mixture.
[b] Carried out at 0 °C. [c] Isolated yield.
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100%) only resulted in diminished yields (Entries 5 and 6). derived from the oxidative removal of the dimethylated left-
Finally, the effect of addition of water to the process was hand side chain. This side process is unusual but is reminis-
tested. Although the related system CrO3(cat.)/H5IO6 has cent of the oxidative cleavage of a similar substrate.[3] This
been successfully used to oxidise alcohols cleanly in wet type of lactone is also the main side product of the process
CH3CN (0.75 vol.-% water)[9] in our case we have observed carried out on all the other substrates. Similarly, the THF
that addition of water (2–5 vol.-%) is detrimental, causing derivative 20 gave acid 21 in 65% yield.
the process to stop at 10–20% conversion.
In another experiment, α-keto THF 22 was oxidised. In
Oxidation of mono-THF compounds structurally related this case the presence of a keto group adjacent to the THF
to 11 under the optimized conditions was then carried out ring induced removal of the side chain through the oxidat-
(Scheme 7). cis-THF compounds 14, 16 and 24 were syn- ive cleavage of the C(THF)2–C=O bond to give 1,4-diket-
thesized by benzoylation of the corresponding THF diols, one 23 in good yields.
in turn obtained by RuO4-catalysed oxidative cyclization of
Finally, the reactivity of the 2,5-disubstituted cis-mono-
trans,trans-2,6-dimethyl-2,6-octadiene-1,8-diol diacetate,[5j] THF 24 was tested. Pleasingly, 1,4-diketone 25 was ob-
methyl geranate[5j] and hexa-1,5-diene,[8] respectively, as re- tained in a nearly quantitative yield (98%) even when the
ported. trans-THF 19 was obtained by benzoylation of the amount of PCC was reduced to 2 mol-%, This process is
corresponding THF diol, a minor product from the oxidat- particularly appealing because it allows, when coupled with
ive cyclization of geranyl benzoate.[10] THF 20 was synthe- the oxidative cyclization of 1,5-dienes, the transformation
sized from 11 through a short sequence. In particular, selec- of the latter into bis-ketols in a regioselective manner. This
tive removal of both the primary and secondary benzoates experiment and the oxidation of the more complex disubsti-
in 11 with K2CO3 in MeOH proceeded cleanly to give the tuted mono-THF 9 demonstrated that for substrates con-
corresponding diol. Oxidative cleavage of the diol system taining only a 2,5-disubstituted THF ring the preferred
by treatment with silica-supported NaIO4[11] in CH2Cl2, fol- route is the one leading to 1,4-diketones.
lowed by borohydride reduction and benzoylation, afforded
dibenzoate 20 in 43% yield (over four steps). Ketone 22 was
obtained by TPAP-catalysed oxidative cyclization of geranyl
Isolation of Minor Products and Mechanistic
Considerations
acetate[5g] followed by benzoylation.
A plausible mechanistic route based on the known reac-
[5a]
tivity of PCC and related oxo species such as RuO4 was
hypothesised to explain the formation of the above com-
pounds. In particular, a pathway leading to compound 12
is shown in Scheme 8, but it also applies to the formation
of the analogous compounds 3/4, 6/7, 15, 17 and 21. It is
likely that the process begins with the attack of CCP,
formed by elimination of water from PCC and periodic
acid, at the angular C–H bond of the THF ring to give the
mixed chromium ester intermediate 26. This step is conceiv-
ably a [3+2] addition of the O=Cr=O portion of the oxidant
to the angular C–H bond of the THF ring, as also hypoth-
esised for the RuO4 oxidation of neoisocedrane oxide,[12]
a
sesquiterpene containing a THF ring. It is reported that the
oxidation of the THF ring in this substance proceeds
through the intramolecular insertion of an oxoruthenium
bond into the angular C–H bond of the THF ring. In ad-
dition, it has been suggested that attack of transition metal
oxo species such as OsO4 and RuO4 to C–H bonds of al-
kanes also proceeds through a [3+2] addition of a C–H
bond across an O=M=O unit,[13] through a mechanism
analogous to the one now widely accepted for alkene bishy-
droxylation. In the next step, chromium ester 26 would give
rise to cyclic enol ether 27 through an elimination step de-
livering a low-valent chromium species that would then be
reoxidised to CCP by H5IO6. However, it cannot be ex-
Scheme 7. Oxidation of functionalised 2,5-disubstituted and 2,2,5-
trisubstituted THF compounds. i) PCC (5 mol-%), H5IO6
(4 equiv.), CH3CN, room temp., 1 h; ii) PCC (2 mol-%), H5IO6
(4 equiv.), CH3CN, room temp., 40 min.
CCP oxidation of cis-THF diacetate 14 and trans-THF cluded that the first step of the process could proceed
19 gave acids 15 and 12, respectively, in 65–70% yields. The through hydride abstraction from the angular C–H bond
methoxycarbonyl derivative 16 unexpectedly afforded the (not shown) by the same O=Cr=O portion of CCP to give
corresponding acid in a diminished 30% yield, the major an intermediate carbocation (actually an oxonium ion)
product of the process being lactone 18, analogous to 13, which could then collapse to form enol ether 27. This would
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Catalytic Oxidation of Tetrahydrofuran Compounds
Scheme 8. A plausible catalytic cycle explaining the formation of acid 12.
be consistent with the mechanism proposed by Lee and
To support the mechanistic path shown in Scheme 8, a
van den Engh for the RuO4 oxidation of tetrahydrofuran to careful examination of the minor products formed during
γ-butyrolactone,[14] in which the initially formed carbonium the oxidation of penta-THF 2, both with PCC/AcOH and
ion and RuVI oxo species recombine to give an intermediate with CCP, was undertaken. HPLC analyses (direct and re-
ester similar to 26.
versed-phase modes) led to the identification of the three
Whereas PCC is unable to cleave isolated (unactivated) side-products 30–32 (Figure 1) in both processes. Their
carbon-carbon double bonds, oxidative cleavages of both structures give strong support for the proposed mechanism
cyclic and acyclic enol ethers to esters with PCC have been and their formation could be interpreted through routes
reported.[15] In particular, the conversion of 27 to the final consistent with those given for the main oxidation products.
dicarbonyl compound 12 is thought to proceed through the
formation of the chromium diester intermediate 28, by a
second [3+2] addition step. Oxidative cleavage to afford al-
dehyde 29, followed by oxidation, eventually generates acid
12. The conversion of 27 to 29 agrees well with the pre-
viously observed oxidative cleavage of cyclic enol ethers
lacking α-hydrogen atoms.[15a,15c] Finally, formation of lact-
one 13, the main side-product of the oxidation of 11
(Table 1), can be seen to originate from the oxidative re-
moval of the dimethyl benzoate side chain. It has previously
been observed that THF rings bearing a tertiary (free)
Figure 1. Minor products obtained from the oxidation of penta-
THF dibenzoate 2.
alcohol functions undergo similar oxidative cleavage with
CCP to give γ-lactones[3] such as 13, via C-2 chromium es-
ter intermediates. It is conceivable that a similar route could
be responsible for the C2–C3 oxidative cleavage in a chro-
mium ester intermediate possibly formed by further evol-
ution of 26 (Scheme 9). This interaction is supported by the
complete absence of hydrolysis of the primary and second-
ary benzoate functions present in the same molecule.
In particular, the presence of the oxidised B ring in 30
strongly suggested that it is formed on the pathway leading
to acid 4, as shown in Scheme 10. On this pathway, acid 4
and ketol 30 would be formed by attack of CCP at the
angular C7–H bond in the THF ring B of 2 via intermedi-
ates 33, 34 and 35 as seen for the oxidation of 11. Com-
pound 35 would follow route a to give acid 4 through the
oxidative cleavage of the C7–C8 bond. Alternatively, its oxi-
dative opening would give ketol 30 through route b. The
isolation of 30 furnishes the first indirect support for the
previously hypothesised[16] formation of chromium diester
intermediates, such as 35, during the oxidative cleavage of
enol ethers with PCC, and strongly supports the involve-
ment of enol ether 34.
Scheme 9. Formation of lactone 13 by side-chain removal in inter-
mediate 26.
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Scheme 11. A mechanistic explanation for the formation of com-
pounds 31 and 32.
Scheme 10. Formation of compounds 4 and 30.
Acid 3 (see Scheme 3) would in turn originate in a similar
way by attack of CCP at the C18–H of the THF ring D in
2 whereas acids 6 and 7 (see Scheme 4) would be formed by
attack of the oxidant at the central C ring in the tris-THF
5.
With regard to the minor compounds 31 and 32 (Fig-
ure 1), it seems likely that they could originate from 2 in
the same route leading to 3 or 4 (Scheme 11). In particular,
the oxidative cleavage of the C6–C7 bond in 2 could occur
in the chromium ester intermediate 33 through an elimi-
Scheme 12. A catalytic cycle for the formation of diketone 23.
nation step now involving both the A and the B rings. This mium species, the oxidation of which would regenerate
step accounts well for the formation of the C-7 lactone CCP, closing the catalytic cycle. CCP oxidation of the
function in 31 with generation once again of an enol ether alcohol function in 41[2a] would eventually give 1,4-diketone
species, compound 36, that is then oxidatively cleaved to 25. Formation of the related 1,4-diketones 8 (Scheme 4) and
the dicarbonyl compound 32 via chromium diester 37, as 10 (Scheme 6) can be explained in a similar manner. It
previously seen. The configuration of 31 has not been deter- should be noted that the possible competing path giving
mined, so its formation might follow either the depicted rise to an enol ether species (compound 42, Scheme 13,
route, through attack of the oxidant at the C7-H and oxi- route b) from 40 is completely suppressed in this case. It is
dation of ring B, or an analogous pathway in which the worth noting that the chemical behaviour of PCC in this
D ring is oxidised by attack at the C18–H bond (pathway
not shown) and cleavage of the C18–C19 bond connecting
rings D and E.
By the same line of reasoning, the formation of diketone
23 from 22 (Scheme 12) can be explained by the assumption
that the initially formed chromium ester 38 collapses to the
dicarbonyl species 39, the α-ketol portion of which un-
dergoes oxidative cleavage to give 23 through a known pro-
cess.
The formation of 1,4-diketone 25 from 24 is shown in
Scheme 13. In particular, CCP could attack one of the
angular C–H bonds in 24 in the usual way to give chro-
mium ester 40. Opening of this would then follow to give
ketol 41 (route a) with simultaneous production of a chro- Scheme 13. A catalytic cycle for the formation of 1,4-diketone 25.
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Catalytic Oxidation of Tetrahydrofuran Compounds
Scheme 14. Synthesis of umbelactone.
transformation parallels that displayed by RuO4. In fact,
in a similar transformation, 2,5-dimethyl-tetrahydrofuran is
reported to undergo oxidative opening by the RuO2(cat.)/
NaIO4 system to afford hexane-2,5-dione.[17]
Conclusions
In summary, we have examined the oxidative behaviour
of some mono- and poly-THF compounds with the cata-
lytic system PCC (cat.)/H5IO6. Novel oxidative pathways
leading to the modification/degradation of the THF ring,
as well as of the poly-THF backbone, have been disclosed.
Plausible hypotheses, consistent with the known reactivity
of PCC, have been put forward to explain the new oxidative
routes. In particular, attack of the oxidant at the angular C–
H bond of the target THF ring with formation of a mixed
chromium ester is thought to be the first event. Two main
routes then follow. Oxidative carbon-carbon bond cleavage,
to give dicarbonyl products, occurs when 2,2,5-trisubsti-
tuted THFs are oxidised. The isolation of some minor side
products of the process strongly supports the formation of
cyclic enol ether intermediates in this transformation. With
2,5-disubstituted mono-THFs, THF ring opening, with no
C–C bond cleavage, is observed. 1,4-Diketones, useful
building blocks in organic synthesis,[22] are obtained in this
case. The latter transformation proceeds with a remarkable,
nearly quantitative yield. A third route, leading to the oxi-
dative cleavage of a C-2 side-chain, operates when the THF
ring is flanked by a ketone function. Finally, the above re-
sults provide further support for the previously observed
similarity of the chemical oxidative behaviour of PCC and
of RuO4 toward THF-containing substances.[5a] Further de-
velopment of the chemistry presented here is currently on-
going.
Synthesis of Umbelactone
As an application of the developed oxidative procedure,
a short synthesis of racemic umbelactone was carried out.
Umbelactone is a γ-butenolide natural product, isolated
from ethanolic extracts of Memecylon umbellatum Brum,[18]
that exhibited antiviral activity against the Ranikhet disease
virus as well as spasmolytic and antiamphetamine activity.
This substance has been the subject of various syntheses
both in racemic and in enantiopure form.[19]
Our oxidation of trisubstituted THFs such as 11 de-
scribed above allows access to elaborated 3,4,5-trioxygen-
ated acids. In particular, compound 12 derived from 11 was
seen as a good starting product for the synthesis of umbel-
actone (Scheme 14). Tribenzoate 12 was converted into tri-
hydroxyacid 43 in high yield by treatment with K2CO3 in
MeOH. Successive treatment of crude 43 with CH2N2 gave
transient methyl ester 44, which spontaneously cyclised to
the γ-lactone 45 in 90% yield (81% from 12). The primary
hydroxy group in 45 was then protected as the TBS ether
(compound 46) by treatment with TBSCl/imidazole in
DMF (96% yield).[20] Dehydration of 46 was accomplished
with SOCl2/pyridine to give silylated umbelactone 47 in
95% yield. Lastly, desilylation of 47 with Et3N·3HF in
THF cleanly gave umbelactone 48 (92% yield).
Our synthetic route to umbelactone is short and highly
efficient and does not require carbon-carbon bond-forming
steps. In addition, it can be made enantioselective to give
both the umbelactone enantiomers because mono-THF tri-
benzoate 11 (Table 1), the immediate precursor of 12, can
be obtained in both enantiomeric forms from commercially
available geraniol in high yields and enantiomeric purity.[21]
Studies directed towards this goal, as well as exploitation
of the above chemistry for the preparation of further func-
tionalised butenolides, are ongoing.
Experimental Section
General: All reagents were purchased in the highest commercial
quality and used without further purification. Petroleum ether had
a boiling range of 40–70 °C. 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 workup.
HPLC separations were carried out with a Varian 2510 apparatus
fitted with a Waters R403 dual cell differential refractometer with
use of Phenomenex 250ϫ10 mm and 250ϫ4.6 mm (both 5 μ) and
Eur. J. Org. Chem. 0000, 0–0
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V. Piccialli et al.
FULL PAPER
LiChrosorb RP-18 250ϫ4.0 mm columns. NMR experiments were
dried and concentrated in vacuo to give a yellow oil. Filtration on
performed with Varian Unity Inova 700, Varian Unity Inova 500, a silica gel pad (eluent CHCl3/MeOH 9:1) afforded an oily product
Varian Mercury Plus 400, and Gemini 200 spectrometers in CDCl3.
Proton chemical shifts were referenced to the residual CHCl3 signal
(δ =7.26 ppm). 13C NMR chemical shifts were referenced to the
solvent (δ =77.0 ppm). Abbreviations for signal coupling are as fol-
lows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet, br,
broad. IR spectra were recorded with a Jasco FT-IR 430 spectro-
photometer. High-resolution MS was recorded with a Bruker
APEX II FT-ICR mass spectrometer with use of ESI. For com-
pounds 2–4, 30 and 31 the numbering previously given[5f] for penta-
THF 1 is used.
(350 mg). Further elution with CHCl3/MeOH (8:2) gave a complex
mixture of polar products (57 mg) that was not studied further. The
first eluted fraction was separated by HPLC (250ϫ10 mm column;
flow: 2.5 mLmin–1; eluent: hexane/EtOAc 75:25) to give unreacted
2 (128 mg) and slightly impure compounds 3 and 4. Analytical
HPLC (250ϫ4.6 mm column; flow: 1.0 mLmin–1; 3 mg/injection,
hexane/EtOAc 75:25) afforded major acid 3 (58.4 mg, 25%, tR
11.5 min) and minor acid 4 (16.3 mg, 7%, tR = 10.0 min).
=
Acid 3 (Major Isomer): Oil. 1H NMR (700 MHz, CDCl3): δ = 7.95
(br. d, J = 7.6 Hz, 4 H), 7.52 (br. t, J = 7.4 Hz, 2 H), 7.41 (br. t, J
= 7.7 Hz, 4 H), 4.38 (dd, J = 7.3, 7.3 Hz, 1 H), 4.25 (dd, J = 7.4,
7.4 Hz, 1 H), 4.13 (br. dd, J = 7.4, 7.4 Hz, 1 H), 4.01 (dd, J = 10.0,
5.3 Hz, 1 H), 3.94 (dd, J = 9.0, 6.3 Hz, 1 H), 3.25 (d, J = 14.9 Hz,
1 H), 2.97 (d, J = 14.9 Hz, 1 H), 2.36 (ddd, J = 13.0, 8.4, 5.5 Hz,
1 H), 2.07–1.81 (14 H, overlapped multiplets), 1.69 (m, 1 H), 1.62,
1.61, 1.59, 1.56, 1.54, 1.50, 1.20, 1.13 (3 H each, singlets, 8ϫ
Me) ppm. 13C NMR (175 MHz, CDCl3): δ = 174.4, 171.9, 165.7,
165.6, 132.6, 132.5, 131.85, 131. 78, 129.42, 129.37, 128.25, 128.20,
86.4, 85.5, 85.3, 84.6, 84.5, 83.9, 83.6, 83.2, 82.8, 81.9, 42.2, 36.5,
34.5, 32.9, 27.9, 27.2, 26.7, 26.6, 26.0, 24.3, 23.14, 23.09, 22.8, 22.3,
Syntheses of Poly-THFs 2, 5 and 9: Penta-THF 1, the tetrol precur-
sor of 5 and dilactone 9 were synthesized as described previously.[5f]
Compound
1 was benzoylated as follows. Benzoyl chloride
(15 equiv., 6.75 mmol, 785 μL) and DMAP (30 equiv., 3.5 mmol,
11.6 g) were added to 1 (236 mg, 0.45 mmol) dissolved in CH2Cl2
(10 mL) and the mixture was stirred at room temp. for 30 h. Water
(2 mL) was added and the mixture was stirred for 15 min in a water
bath and then taken to dryness. The residue was taken up in
CH2Cl2 and washed with a sat. NaHCO3 solution and water. The
organic phase was dried, filtered and concentrated in vacuo to give
an oily product that was chromatographed on silica gel with elution
with petroleum ether/Et2O (8:2) to give dibenzoyl penta-THF 2
(264 mg, 80%). Further purification of 2 was carried out by HPLC
(250ϫ10 mm column; flow: 2.5 mLmin–1, hexane/EtOAc 75:25).
Penta-THF Dibenzoate 2: Oil. 1H NMR (200 MHz, CDCl3): δ =
8.05–7.92 (m, 4 H), 7.58–7.35 (m, 6 H), 4.25–4.15 (m, 2 H), 4.02–
3.75 (4 H, overlapped multiplets), 2.33–1.49 (20 H, partly over-
lapped to some methyl protons), 1.64 (s, 3 H), 1.60 (s, 6 H), 1.58,
1.23, 1.16, 1.15, 1.11 (3 H each, singlets, 5ϫ Me) ppm. 13C NMR
(50 MHz, CDCl3): δ = 165.54, 165.45, 132.3, 132.2, 131.9, 131.7,
129.2, 128.0, 86.1, 85.7, 85.1, 84.9, 84.4, 84.3, 83.83, 83.78, 83.5,
83.3, 82.5, 34.4, 34.3, 34.1, 32.5, 27.6, 26.9, 26.8, 26.7, 26.5, 24.7,
21.5, 21.41, 21.38 ppm. IR (neat): ν
= 3600–2400 (OH), 1714
˜
max
(C=O of benzoates, ester and acid), 1288, 712 cm–1. HRMS (ESI):
calcd. for C44H58NaO12 [M + Na]+ 801.3826; found 801.3819.
1
Acid 4 (Minor Isomer): Oil. H NMR (400 MHz, CDCl3): δ = 7.9
(br. d, J = 7.4 Hz, 4 H), 7.51 (br. t, J = 7.3 Hz, 2 H), 7.40 (br. t, J
= 7.4 Hz, 4 H), 4.35 (dd, J = 7.2, 7.2 Hz, 1 H), 4.24 (dd, J = 9.3,
5.9 Hz, 1 H), 4.07–3.99 (m, 2 H), 3.55 (dd, J = 7.2, 7.2 Hz, 1 H),
3.31 (d, J = 15.0 Hz, 1 H), 2.98 (d, J = 15.0 Hz, 1 H), 2.61–2.53
(m, 1 H), 2.19–2.10 (m, 1 H), 2.05–1.76 (14 H, overlapped mul-
tiplets), 1.64, 1.63, 1.60, 1.59, 1.48, 1.47, 1.15, 1.12 (3 H each, sing-
lets, 8ϫ Me) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.8, 172.9,
165.8, 165.7, 132.6, 132.4, 132.0, 131.7, 129.5, 129.4, 128.19,
128.16, 86.3, 86.0, 85.8, 85.5, 85.1, 84.3, 83.9, 83.8, 83.7, 83.4, 81.5,
43.0, 36.4, 34.7, 34.4, 26.95, 26.88, 26.82, 25.2, 24.1, 23.0, 22.7,
24.0, 23.4, 23.2, 23.0, 22.6, 21.3, 21.1 ppm. IR (neat): ν
= 1712
˜
max
(C=O benzoates), 1285, 710 cm–1. HRMS (ESI): calcd. for
C44H60NaO9 [M + Na]+ 755.4135; found 755.4144.
21.7 ppm. IR (neat): νmax = 3600–2400 (OH), 1712 (C=O of benzo-
˜
ates, ester and acid), 1287, 712 cm–1. HRMS (ESI): calcd. for
C44H58NaO12 [M + Na]+ 801.3826; found 801.3835.
The tris-THF tetrol corresponding to 5 was benzoylated as de-
scribed for 1. Benzoyl chloride (15 equiv., 2.6 mmol, 305 μL) and
DMAP (60 equiv., 10.4 mmol, 1.3 g) were added to the tetrol
(77.0 mg, 0.173 mmol) dissolved in CH2Cl2 (2.0 mL) and the mix-
ture was heated at reflux for 10 h. The mixture was worked up as
for 1 to give an oily product. Column chromatography on silica gel
with elution with petroleum ether/Et2O (8:2) gave tetrabenzoyl tris-
THF 5 (108 mg, 73%).
Oxidation of 2 with PCC (cat.)/H5IO6: PCC (2 mol-%, 700 μL of a
0.01 m stock solution in acetonitrile) was added at 0 °C with vigor-
ous stirring to
a suspension of H5IO6 (4 equiv., 78.8 mg,
0.35 mmol) in acetonitrile (1.5 mL). After 5 min, compound 2
(61 mg, 0.083 mmol) dissolved in acetonitrile (650 μL) was added.
After 3 h, CH2Cl2 (1.5 mL) was added followed by ethanol (40 μL)
and the mixture was taken to dryness. Filtration through a short
pad of sodium thiosulfate adsorbed on silica[3] (CHCl3/MeOH 9:1)
gave an oily product (50 mg). Further elution with CHCl3/MeOH
(8:2) gave a mixture of polar products (14 mg) that was not studied
further. The first eluted fraction was separated as described above
for the analogous process with PCC/AcOH to give compounds 3
(20.6 mg, 40%) and 4 (2.2 mg, 4%), along with slightly impure
1
Tris-THF Tetrabenzoate 5: Oil. H NMR (400 MHz, CDCl3): δ =
8.16–7.95 (m, 8 H), 7.64–7.45 (m, 4 H), 7.45–7.32 (m, 8 H), 4.54
(dd, J = 6.6, 6.6 Hz, 1 H), 4.32 (m, 5 H), 3.89–3.74 (m, 2 H),
2.33–2.07 (7 H, overlapped multiplets), 2.01–1.73 (13 H, overlapped
multiplets) 1.63, 1.57, 1.12, 1.08 (3 H each, singlets, 4ϫ Me) ppm.
13C NMR (100 MHz, CDCl3): δ = 166.50, 166.46, 165.6, 132.80,
132.78, 132.50, 132.46, 131.7, 131.6, 130.26, 130.24, 129.5, 129.4,
128.26, 128.24, 128.16, 128.15, 85.9, 85.3, 85.2, 84.7, 84.4, 83.9,
83.7, 81.4, 65.2, 65.1, 34.6, 34.4, 31.9, 31.5, 27.5, 27.2, 26.92, 26.86,
ketol 30 (tR = 5.0 min), lactone 31 (tR = 13.5 min) and 32 (tR
=
16.5 min). A further reversed-phase HPLC run (250ϫ4.0 mm col-
umn; flow: 1.0 mLmin–1; 2 mg/injection) was required to obtain
pure 30 (MeCN/H2O 9:1, 4.6 mg, 2%, tR = 14.0 min), 31 (MeCN/
H2O 85:15, 3.0 mg, 2%, tR = 5.2 min) and 32 (MeCN/H2O 8:2,
1.0 mg, 1%, tR = 2.0 min).
24.3, 23.7, 23.5, 23.1, 20.4, 20.0 ppm. IR (neat): νmax = 1714 (C=O
˜
benzoates), 1275, 710 cm–1. HRMS (ESI): calcd. for C52H60NaO11
[M + Na]+ 883.4033; found 883.4028.
Oxidation of 2 with PCC/AcOH: PCC (5 equiv., 2.5 mmol, 537 mg)
and AcOH (70 equiv., 35 mmol, 2 mL) were added to a solution of
2 (365 mg, 0.50 mmol) in CH2Cl2 (16 mL) and the resulting mix-
ture was heated at reflux for 16 h. A saturated aqueous NaHCO3
solution was added and the organic phase was washed with water,
Ketol 30: Oil. 1H NMR (700 MHz, CDCl3): δ = 7.99 (d, J = 6.9 Hz,
2 H), 7.98 (d, J = 6.5 Hz, 2 H), 7.52 (t, J = 7.3 Hz, 2 H), 7.43 (t,
J = 7.7 Hz, 2 H), 7.40 (t, J = 7.6 Hz, 2 H), 4.33 (br. s, 1 H, OH),
4.16 (dd, J = 9.2, 6.0 Hz, 1 H), 4.10 (dd, J = 8.2, 7.0 Hz, 1 H), 3.89
8
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Catalytic Oxidation of Tetrahydrofuran Compounds
(m, 1 H), 3.72 (m, 2 H), 2.66 (ddd, J = 12.7, 10.5, 5.4 Hz, 1 H), (ESI): calcd. for C52H58NaO14 [M + Na]+ 929.3724; found
2.55 (d, J = 16.9 Hz, 1 H), 2.44 (d, J = 16.9 Hz, 1 H), 2.18 (ddd, 929.3736.
J = 12.3, 9.3, 8.2 Hz, 1 H), 2.03–1.83 (12 H, overlapped multiplets),
Acid 7 (Minor Isomer): Oil. 1H NMR (400 MHz, CDCl3): δ = 8.04
1.71–1.61 (m, 2 H), 1.60 (s, 6 H, 2ϫ Me),1.58, 1.55, 1.36, 1.29,
(br. d, J = 7.0 Hz, 2 H), 8.02 (br. d, J = 5.5 Hz, 2 H), 7.98 (br. d,
1.14, 1.07 (3 H each, singlets, 6ϫ Me) ppm. 13C NMR (175 MHz,
J = 8.0 Hz, 4 H), 7.53 (m, 4 H), 7.41 (m, 8 H), 5.41 (dd, J = 6.1,
CDCl3): δ = 212.7, 165.8, 165.7, 132.6, 132.4, 132.0, 131.6, 129.6,
6.1 Hz, 1 H), 4.64 (dd, J = 7.4, 7.4 Hz, 1 H), 4.49–4.44 (m, 5 H),
129.4, 128.2, 128.1, 101.7, 86.4, 85.9, 85.70, 85.68, 85.65, 84.3,
2.63 (dd, J = 15.7, 7.3 Hz, 1 H), 2.56 (dd, J = 15.8, 5.9 Hz, 1 H),
83.51, 83.46, 83.2, 82.9, 77.8, 48.4, 35.1, 34.4, 31.8, 27.0, 26.86,
2.44 (br. ddd, J = 12.5, 5.5, 5.5 Hz, 1 H), 2.23–1.70 (16 H, over-
26.83, 26.81, 26.0, 24.6, 24.4, 22.82, 22.79, 22.74, 22.2, 21.6,
lapped multiplets), 1.64, 1.53, 1.44, 1.28 (3 H each, singlets, 4ϫ
20.1 ppm. IR (neat): νmax = 3301 (broad, OH), 1712 (C=O of ben-
˜
Me) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9, 171.3, 167.2,
167.0, 165.8, 165.7, 133.03, 132.98, 132.7, 132.6, 131.6, 131.4,
130.1, 129.64, 129.57, 129.4, 128.34, 128.29, 85.3, 84.6, 84.3, 84.1,
83.9, 83.5, 74.9, 65.5, 65.3, 36.5, 35.0, 33.4, 32.0, 31.1, 26.9, 26.3,
zoates and ketone), 1287, 712 cm–1. HRMS (ESI): calcd. for
C44H58NaO11 [M + Na]+ 785.3877; found 785.3884.
1
Lactone 31: Oil. H NMR (500 MHz, CDCl3): δ = 7.96 (br. d, J =
7.0 Hz, 2 H), 7.53 (br. t, J = 7.4 Hz, 1 H), 7.41 (br. t, J = 7.5 Hz, 24.8, 24.4, 23.6, 23.2, 20.8, 20.6 ppm. IR (neat): ν
= 3600–2400
˜
max
2 H), 4.25 (dd, J = 7.0, 7.0 Hz, 1 H), 3.94 (dd, J = 9.0, 6.2 Hz, 1
H), 3.88 (dd, J = 7.2, 7.2 Hz, 1 H), 3.78 (dd, J = 9.4, 5.1 Hz, 1 H),
2.80 (ddd, J = 17.4, 10.1, 10.2 Hz, 1 H), 2.47 (ddd, J = 17.4, 10.6,
3.5 Hz, 1 H), 2.39 (ddd, J = 13.9, 10.7, 3.5 Hz, 1 H), 2.09–1.65 (13
H, overlapped multiplets), 1.63, 1.58, 1.31, 1.22, 1.11 (3 H each,
singlets, 5ϫ Me) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.6,
165.7, 132.5, 131.9, 129.4, 128.2, 86.5, 85.7, 85.2, 84.6, 84.0, 83.6,
83.4, 82.7, 35.0, 32.7, 29.8, 27.8, 27.3, 26.8, 26.6, 23.5, 23.3, 23.2,
(OH), 1714 (C=O benzoates, ester and acid), 1277, 1113, 711 cm–1.
HRMS (ESI): calcd. for C52H58NaO14 [M + Na]+ 929.3724; found
929.3742.
1
Diketone 8: Oil. H NMR (200 MHz, CDCl3): δ = 8.10–7.91 (m, 8
H), 7.62–7.32 (m, 12 H), 4.54–4.24 (6 H, overlapped multiplets),
3.17–2.94 (m, 1 H), 2.94–1.68 (19 H, overlapped multiplets), 1.63
(s, 6 H), 1.37 (s, 3 H), 1.34 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 214.0, 212.7, 166.5, 165.7, 132.8, 132.7, 131.6, 131.4,
130.35, 130.31, 129.55, 129.53, 129.48, 129.43, 128.35, 128.31, 88.9,
88.7, 84.93, 84.92, 84.2, 83.4, 65.0, 35.2, 34.8, 32.3, 31.8, 30.8, 29.9,
23.0, 22.9, 21.3 ppm. IR (neat): ν
= 1773 (C=O lactone), 1711
˜
max
(C=O benzoate), 1288, 1071, 713 cm–1. HRMS (ESI): calcd. for
C29H40NaO7 [M + Na]+ 523.2672; found 523.2668.
26.3, 24.2, 23.7, 23.55, 23.51, 20.6, 20.4 ppm. IR (neat): ν
=
˜
max
Acid 32: Oil. 1H NMR (500 MHz, CDCl3): δ = 7.97 (br. d, J =
7.3 Hz, 2 H), 7.55 (br. t, 1 H, J = 7.3 Hz), 7.44 (br. t, 2 H, J =
7.7 Hz), 5.62 (dd, 1 H, J = 9.3, 3.1 Hz), 2.86 (dd, 1 H, J = 16.1,
3.2 Hz), 2.74 (dd, 1 H, J = 16.1, 9.4 Hz), 2.11 (s, 3 H), 1.66, 1.65
(3 H each, singlets, 2ϫ Me) ppm. 13C NMR (100 MHz, CDCl3): δ
= 175.2, 170.1, 165.1, 133.0, 131.1, 129.5, 128.4, 82.4, 73.9, 34.9,
1710 (C=O benzoates and ketones), 1274, 1111, 710 cm–1. HRMS
(ESI): calcd. for C52H58NaO12 [M + Na]+ 897.3826; found
897.3815.
Oxidation of 9: PCC (2 mol-% , 80 μL of a 0.01 m stock solution
in acetonitrile) was added at 0 °C with vigorous stirring to a sus-
pension of H5IO6 (4 equiv., 0.15 mmol, 35.4 mg) in acetonitrile
(600 μL). After 5 min, compound 9 (10.4 mg, 0.039 mmol) dis-
solved in acetonitrile (150 μL) was added. After 3.5 h, CH2Cl2
(750 μL) was added followed by ethanol (40 μL) and the mixture
was taken to dryness. Filtration through a short pad of sodium
thiosulfate adsorbed on silica (CHCl3/MeOH 9:1) gave almost pure
10 as an oil. Further purification by HPLC (250ϫ4.6 mm column;
flow: 1.0 mLmin–1; CHCL3/MeOH 98:2, tr = 4.0 min) gave pure
10 (4.3 mg, 45%).
22.4, 21.7, 20.9 ppm. IR (neat): ν
= 3600–2400 (OH), 1744
˜
max
(C=O acetate), 1715 (C=O benzoate and acid), 1283, 712 cm–1.
HRMS (ESI): calcd. for C15H18NaO6 [M + Na]+ 317.1001; found
317.1009.
Oxidation of 5 with PCC (cat.)/H5IO6: PCC (1 mol-%, 38 μL of a
0.01 m stock solution in acetonitrile) was added at 0 °C with vigor-
ous stirring to a suspension of H5IO6 (4 equiv., 0.15 mmol,
34.2 mg) in acetonitrile (600 μL). After 5 min, compound
5
(32.3 mg, 0.037 mmol) dissolved in acetonitrile (150 μL) was added.
After 2 h, a further 1 mol-% PCC was added and the mixture was
kept at 0 °C for an additional 1 h. CH2Cl2 (700 μL) was then added
followed by ethanol (40 μL) and the mixture was taken to dryness.
Filtration through a short pad of sodium thiosulfate adsorbed on
silica (CHCl3/MeOH 9:1) gave an oily product (19 mg). Separation
by HPLC (250ϫ4.6 mm column; flow: 1.0 mLmin–1; 1 mg/injec-
tion, hexane/EtOAc 75:25) gave compounds 6 (10.0 mg, 30%), 7
(2.0 mg, 6%) and 8 (2.9 mg, 9%).
Compound 10: Oil. 1H NMR (500 MHz, CDCl3): δ = 3.01–2.92 (m,
2 H), 2.92–2.82 (m, 2 H), 2.65–2.53 (m, 6 H), 2.12–2.04 (m, 2 H),
1.55 (s, 6 H, 2ϫ Me) ppm. 13C NMR (125 MHz, CDCl3): δ = 209.2
(2 C), 175.9 (2 C), 89.2 (2 C), 31.3 (2 C), 31.0 (2 C), 28.2 (2 C),
23.6 (2 C) ppm. IR (neat): νmax = 1774 (C=O lactones), 1717 (C=O
˜
ketones) cm–1. HRMS (ESI): calcd. for C14H18NaO6 [M + Na]+
305.1001; found 305.1008.
Synthesis of Mono-THFs 11, 14, 16, 19, 22 and 24: The title com-
pounds were obtained by benzoylation of the corresponding THF
diols (synthesized as described previously[5g,5j,8,10]). Purification of
these compounds was achieved by column chromatography with
the following eluents: 11 (petroleum ether/diethyl ether 9:1), 14 (pe-
troleum ether/diethyl ether 1:1), 16 (petroleum ether/diethyl ether
6:4), 19 (petroleum ether/diethyl ether 1:1), 22 (40:70 petroleum
ether/diethyl ether 8:2), 24 (hexane/EtOAc 8:2).
Acid 6 (Major Isomer): Oil. 1H NMR (400 MHz, CDCl3): δ = 8.02
(d, J = 8.2 Hz, 4 H), 7.96 (d, J = 8.0 Hz, 4 H), 7.55–7.45 (m, 4 H),
7.44–7.38 (m, 8 H), 5.40 (dd, J = 9.7, 3.1 Hz, 1 H), 4.49 (dd, J =
8.5, 6.2 Hz, 1 H), 4.44 (dd, J = 7.4, 7.4 Hz, 1 H), 4.40–4.28 (4 H,
overlapped multiplets), 2.73 (dd, J = 15.8, 3.0 Hz, 1 H), 2.64 (dd,
J = 15.8, 9.8 Hz, 1 H), 2.37 (ddd, J = 12.6, 7.9, 6.0 Hz, 1 H), 2.29–
2.19 (m, 2 H), 2.17–2.00 (m, 2 H), 1.98–1.58 (12 H, overlapped
multiplets), 1.57, 1.55, 1.45, 1.19 (3 H each, singlets, 4ϫ Me) ppm.
Compound 11: Oil. 1H NMR: (200 MHz, CDCl3): δ = 8.13–7.88
13C NMR (100 MHz, CDCl3): δ = 174.2, 173.4, 166.8, 166.6, 165.8, (m, 6 H), 7.68–7.28 (m, 9 H), 5.65 (dd, J = 8.8, 2.9 Hz, 1 H), 4.80
165.6, 132.93, 132. 87, 132.7, 131.5, 131.4, 130.26, 130.21, 129.6, (dd, J = 12.2, 2.9 Hz, 1 H), 4.59 (dd, J = 12.2, 8.8 Hz, 1 H), 4.33
129.55, 129.50, 128.32, 128.27, 85.2, 85.0, 83.9, 83.5, 83.3, 81.3,
75.0, 65.3, 65.0, 36.1, 35.7, 33.7, 31.6, 31.5, 26.9, 25.9, 24.1, 23.5,
(dd, J = 6.3 Hz, 1 H), 2.27–1.74 (m, 4 H), 1.67 (s, 3 H), 1.64 (s, 3
H), 1.43 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 166.4,
23.2, 22.7, 20.4, 20.2 ppm. IR (neat): νmax = 3600–2400 (OH), 1717 166.0, 165.6, 133.0, 132.9, 132.5, 131.6, 129.8, 129.65 (2 C), 129.63,
˜
(C=O benzoates, ester and acid), 1279, 1119, 710 cm–1. HRMS
129.5 (2 C), 129.3 (2 C), 128.4 (2 C), 128.3 (2 C), 128.2 (2 C), 83.5,
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Job/Unit: O20069
/KAP1
Date: 13-06-12 16:23:18
Pages: 14
V. Piccialli et al.
FULL PAPER
83.0, 82.8, 76.2, 63.9, 34.6, 26.9, 23.6, 23.2, 21.3 ppm. IR (neat):
solved in CH2Cl2 (5 mL), and the mixture was stirred for 30 min
at room temp. The reaction mixture was filtered, the solid was thor-
oughly washed with CH2Cl2, and the filtrate was taken to dryness
to give an oily product.
ν
max = 1719 (C=O benzoates), 1281, 1111, 709 cm–1. HRMS (ESI):
˜
calcd. for C31H32NaO7 [M + Na]+ 539.2046; found 539.2038.
Compound 14: Oil. 1H NMR (200 MHz, CDCl3): δ = 8.00 (m, 4
H), 7.66–7.30 (m, 6 H), 5.46 (dd, J = 8.8, 2.6 Hz, 1 H), 4.78–4.20
(5 H, overlapped multiplets), 2.15–1.88 (10 H, including two acetate
singlets at 2.02 and 1.96), 1.67 (s, 3 H), 1.36 (s, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 170.9, 170.5, 166.1, 165.6, 133.1,
132.8, 131.0, 129.7 (2 C), 129.6 (3 C), 128.5 (2 C), 128.3 (2 C), 83.2,
83.0, 80.4, 76.1, 65.2, 63.3, 34.5, 26.8, 23.5, 20.80 (2 C), 18.9 ppm.
Sodium borohydride (two spatula tips) was added to the above oil
(55.1 mg), dissolved in EtOH (4 mL). After 30 min, acetic acid was
added dropwise until no gas evolution was observed. The mixture
was filtered and the filtrate was taken to dryness to give an oily
product.
The above oil (33.0 mg, 0.12 mmol) was dissolved in pyridine
(500 μL) and benzoyl chloride (1.1 equiv., 0.13 mmol, 15 μL) was
added. After 1 h, water (100 μL) was added and the mixture was
taken to dryness. Purification by preparative TLC (hexane/EtOAc
1:1) yielded pure 20 (33.0 mg, 43% over four steps).
IR (neat): ν
= 1740 (C=O acetates), 1721 (C=O benzoates),
˜
max
1275, 712 cm–1. HRMS (ESI): calcd. for C28H32NaO9 [M + Na]+
535.1944; found 535.1963.
1
Compound 16: Oil. H NMR (200 MHz, CDCl3): δ = 8.07 (d, J =
8.5 Hz, 2 H), 7.96 (d, J = 7.1 Hz, 2 H), 7.64–7.29 (m, 6 H), 5.20
(s, 1 H), 4.33 (dd, J = 7.7, 6.9 Hz, 1 H), 3.72 (s, 3 H), 2.56–2.38
(m, 1 H), 2.19–1.75 (m, 3 H), 1.61 (s, 3 H), 1.59 (s, 3 H), 1.46 (s, 3
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 168.6, 166.0, 165.7,
133.3, 132.5, 131.6, 129.8 (3 C), 129.4 (2 C), 128.4 (2 C), 128.2 (2
C), 83.5, 83.3, 82.8, 78.0, 52.2, 34.3, 26.5, 23.4, 23.0, 21.3 ppm.
1
Compound 20: Oil. H NMR (200 MHz, CDCl3): δ = 8.06 (d, J =
7.0 Hz, 2 H), 7.98 (d, J = 6.9 Hz, 2 H), 7.61–7.33 (6 H, overlapped
multiplets), 4.38 (d, J = 11.1 Hz, 1 H), 4.31 (m, 1 H), 4.20 (d, J =
11.1 Hz, 1 H), 2.20–1.73 (m, 4 H), 1.64 (s, 3 H), 1.61 (s, 3 H), 1.38
(s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 166.4, 165.7, 133.0,
132.5, 131.7, 130.1, 129.5 (2 C), 129.4 (2 C), 128.3 (2 C), 128.2 (2
C), 83.8, 83.4, 81.8, 69.7, 34.5, 26.8, 24.1, 23.0, 21.4 ppm. IR (neat):
IR (neat): ν
= 1713 (C=O benzoates and CO2Me), 1285, 1113,
˜
max
710 cm–1. HRMS (ESI): calcd. for C25H28NaO7 [M + Na]+
ν
˜
max = 1712 (C=O benzoates), 1277, 1112, 709 cm–1. HRMS (ESI):
463.1733; found 463.1717.
calcd. for C23H26NaO5 [M + Na]+ 405.1678; found 405.1670.
1
Compound 19: Oil. H NMR (200 MHz, CDCl3): δ = 8.07 (d, J =
General Reaction Procedure for the Oxidation of Mono-THF Com-
pounds 11, 14, 16, 19, 20, 22 and 24: PCC (5 mol-%, from a 0.01 m
stock solution in acetonitrile) was added at room temp. with vigor-
ous stirring to a suspension of H5IO6 (4 equiv.) in acetonitrile. Af-
ter 5 min the mono-THF compound (1 equiv.) dissolved in acetoni-
trile was added. The overall volume of acetonitrile was such that
the final concentration of the solution was 0.05 m. After complete
consumption of the starting material (TLC monitoring, usually 45–
60 min), ethanol (excess) was added and stirring was continued un-
til the colour of the solution had turned from yellow to green. Silica
(excess) was then added and the solvent was evaporated in vacuo
to give a fine powder that was loaded on the top of a silica gel
column. Elution with CHCl3/MeOH (9:1) allowed recovery of the
acid that proved to be pure enough for successive spectral studies
and/or synthetic steps.
7.7 Hz, 2 H), 7.96 (d, J = 8.2 Hz, 4 H), 7.64–7.30 (m, 9 H), 5.65
(dd, J = 8.6, 2.7 Hz, 1 H), 4.75 (dd, J = 11.9, 2.8 Hz, 1 H), 4.55
(dd, J = 11.9, 8.6 Hz, 1 H), 4.32 (dd, J = 8.1, 6.6 Hz, 1 H), 2.27–
1.68 (m, 4 H), 1.60 (s, 6 H), 1.45 (s, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 166.5, 166.0, 165.7, 133.04, 133.02, 132.4, 131.9, 130.1,
129.72 (2 C), 129.70, 129.6 (2 C), 129.4 (2 C), 128.4 (2 C), 128.3 (2
C), 128.2 (2 C), 85.5, 83.03, 83.01, 76.1, 64.0, 34.8, 26.7, 24.1, 22.6,
21.5 ppm. IR (neat): ν
= 1712 (C=O benzoates), 1278, 1109,
˜
max
708 cm–1. HRMS (ESI): calcd. for C31H32NaO7 [M + Na]+
539.2046; found 539.2055.
Compound 22: Oil. 1H NMR (200 MHz, CDCl3): δ = 7.96–7.87 (d,
J = 6.9 Hz, 2 H), 7.59–7.35 (m, 3 H), 5.04 (AB system, J = 17.8 Hz,
2 H), 4.20 (dd, J = 7.2 Hz, 1 H), 2.54–2.39 (m, 1 H), 2.13–1.77 (6
H, overlapped multiplets including the acetate singlet at 2.08), 1.71
(s, 3 H), 1.61 (s, 3 H), 1.41 (s, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 206.5, 170.2, 165.7, 132.7, 131.4, 129.3 (2 C), 128.4 (2
C), 88.5, 85.9, 82.7, 65.7, 35.4, 26.0, 23.6, 22.8, 22.6, 20.4 ppm. IR
Compound 11 (112.0 mg, 0.22 mmol) was subjected to the stan-
dard oxidative procedure to give the crude acid as a yellow oil. It
was purified by column chromatography (CH2Cl2/MeOH 95:5) to
yield 12 (99 mg, 80%) and lactone 13 (8.0 mg, 10%) as oils.
(neat): ν
= 1735 (C=O acetate), 1716 (C=O benzoate and
˜
max
ketone), 1289, 712 cm–1. HRMS (ESI): calcd. for C19H24NaO6 [M
+ Na]+ 371.1471; found 371.1489.
1
Compound 12: Oil. H NMR: (200 MHz, CDCl3): δ = 8.00 (d, J =
Compound 24: Oil. 1H NMR (500 MHz, CDCl3): δ = 8.05 (br. d, J
= 8.4 Hz, 4 H), 7.55 (br. t, J = 7.4 Hz, 2 H), 7.42 (br. t, J = 7.8 Hz,
4 H), 4.42 (2 H, overlapped multiplets), 4.39–4.32 (4 H, overlapped
multiplets), 2.12 (m, 2 H), 1.89 (m, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 166.4 (2 C), 132.9 (2 C), 130.0 (2 C), 129.6 (4 C), 128.3
7.7 Hz, 2 H), 7.87 (m, 4 H), 7.57–7.28 (m, 9 H), 5.89 (dd, J = 7.8,
3.1 Hz, 1 H), 4.74 (dd, J = 12.2, 3.1 Hz, 1 H), 4.45 (dd, J = 12.2,
7.8 Hz, 1 H), 3.24 (AB system, J = 15.6 Hz, 2 H), 1.86 (s, 3 H),
1.71 (s, 6 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 174.1, 171.1,
166.0, 165.5, 165.2, 133.15, 133.12, 133.0, 129.8, 129.6 (6 C), 129.5,
129.3, 128.35 (4 C), 128.28 (2 C), 82.0, 79.0, 74.6, 62.8, 39.2, 24.55,
(4 C), 77.5 (2 C), 66.6 (2 C), 27.8 (2 C) ppm. IR (neat): ν
=
˜
max
1715 (C=O benzoates), 1268, 709 cm–1. HRMS (ESI): calcd. for
C20H20NaO5 [M + Na]+ 363.1208; found 363.1220.
24.46, 21.3 ppm. IR (neat): ν
= 3600–2400 (OH), 1717 (C=O
˜
max
benzoates, ester and acid), 1282, 1107, 709 cm–1. HRMS (ESI):
calcd. for C31H30NaO10 [M + Na]+ 585.1737; found 585.1723.
Synthesis of 20: K2CO3 (2 equiv., 0.4 mmol, 55 mg) was added to
compound 11 (106 mg, 0.20 mmol) dissolved in MeOH (5 mL) and
the mixture was stirred at room temp. for 1.5 h. Water (1 mL) was
added followed by acetic acid up to neutrality. The mixture was
taken to dryness in vacuo and the solid was partitioned between a
sat. NaHCO3 solution and EtOAc. The organic phase was washed
with water, dried and concentrated to give an oily product
(65.9 mg).
1
Compound 13: Oil. H NMR (200 MHz, CDCl3): δ = 8.04 (d, J =
7.9 Hz, 2 H), 7.92 (d, J = 8.0 Hz, 2 H), 7.67–7.31 (m, 6 H), 5.66
(dd, J = 8.3, 3.2 Hz, 1 H), 4.85 (dd, J = 12.1, 3.2 Hz, 1 H), 4.52
(dd, J = 12.1, 8.3 Hz, 1 H), 2.61 (t, J = 7.6 Hz, 2 H), 2.37 (ddd, J
= 13.1, 7.6, 7.6 Hz, 1 H), 2.08 (ddd, J = 13.1, 9.5, 9.5 Hz, 1 H),
1.66 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 176.2, 166.2,
165.5, 133.7, 133.2, 129.9 (2 C), 129.6 (2 C), 129.4, 128.9, 128.7 (2
C), 128.4 (2 C), 85.2, 75.6, 62.8, 31.5, 28.9, 24.2 ppm. IR (neat):
NaIO4 supported on wet silica (2.4 equiv., 0.47 mmol, 746 mg;
0.64 mmolg–1) was added to the crude product obtained above, dis-
ν
˜
max = 1778 (C=O lactone), 1721 (C=O benzoates), 1259, 709 cm–1.
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20069
/KAP1
Date: 13-06-12 16:23:18
Pages: 14
Catalytic Oxidation of Tetrahydrofuran Compounds
HRMS (ESI): calcd. for C21H20NaO6 [M + Na]+ 391.1158; found
391.1167.
Compound 23: Oil. H NMR (200 MHz, CDCl3): δ = 8.04 (d, J =
8.3 Hz, 2 H), 7.59 (t, J = 7.2 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 2 H),
2.78 (m, 4 H), 2.19 (s, 3 H), 1.65 (s, 6 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 207.8, 207.3, 165.9, 133.4, 129.8 (2 C), 129.4, 128.4 (2
1
Compound 14 (13.5 mg, 0.026 mmol) was subjected to the stan-
dard oxidative procedure to give the crude acid as an oil. This was
purified by column chromatography (CH2Cl2/MeOH 95:5) to yield
15 (9.4 mg, 65%) as an oil.
Compound 15: Oil. 1H NMR (200 MHz, CDCl3): δ = 8.0 (m, 4 H),
7.65–7.29 (m, 6 H), 5.75 (dd, J = 7.8, 2.9 Hz, 1 H), 4.67–4.49 (m,
3 H), 4.21 (dd, J = 12.1, 7.8 Hz, 1 H), 3.20 (AB system, J =
15.7 Hz, 2 H), 2.09 (s, 3 H, acetate), 1.94 (s, 3 H, acetate), 1.85 (s,
3 H), 1.73 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 172.4,
172.3, 170.5, 170.3, 165.24, 165.17, 133.4, 133.3, 130.1, 129.8 (2 C),
129.7 (2 C), 129.6, 128.5 (4 C), 82.8, 79.4, 74.3, 66.0, 62.2, 38.9,
C), 84.2, 37.0, 30.1, 30.0, 23.8 (2 C) ppm. IR (neat): ν
= 1715
˜
max
(C=O benzoate and ketones), 1287, 714 cm–1. HRMS (ESI): calcd.
for C15H18NaO4 [M + Na]+ 285.1103; found 285.1109.
Compound 24 (107.0 mg, 0.31 mmol) was subjected to the stan-
dard oxidative procedure with PCC (2 mol-%) to give 1,4-diketone
25 (109 mg, 98%).
1
Compound 25: Amorphous solid. H NMR (200 MHz, CDCl3): δ
= 8.09 (d, J = 7.2 Hz, 4 H), 7.58 (t, J = 7.5 Hz, 2 H), 7.45 (t, J =
7.7 Hz, 4 H), 4.95 (s, 4 H), 2.87 (s, 4 H) ppm. 13C NMR (50 MHz,
21.1, 20.71, 20.68, 19.7 ppm. IR (neat): ν
= 3600–2400 (OH), CDCl3): δ = 202.7 (2 C), 165.8 (2 C), 133.5 (2 C), 129.9 (4 C), 129.0
˜
max
1740 (shoulder, C=O acetates) 1721 (C=O benzoates, ester and
(2 C), 128.4 (4 C), 68.3 (2 C), 32.0 (2 C) ppm. IR (neat): ν
=
˜
max
acid), 1273, 1226, 711 cm–1. HRMS (ESI): calcd. for C28H30NaO12 1713 (C=O benzoates and ketones), 1275, 715 cm–1. HRMS (ESI):
[M + Na]+ 581.1635; found 581.1651.
calcd. for C20H18NaO6 [M + Na]+ 377.1001; found 377.1015.
Compound 16 (23.8 mg, 0.050 mmol) was subjected to the stan-
dard oxidative procedure to give an oil, which was separated by
column chromatography (CH2Cl2 to CH2Cl2/MeOH 95:5) to yield
acid 17 (7.3 mg, 30%) and lactone 18 (6.4 mg, 45%) as oils.
Synthesis of Umbelactone
Trihydroxy Acid 43: K2CO3 (2.0 equiv. 58 mg, 0.42 mmol) was
added to acid 12 (118.1 mg, 0.21 mmol), dissolved in MeOH
(5 mL), and the mixture was stirred at room temp. for 2.5 h. Water
Compound 17: Oil. 1H NMR (400 MHz, CDCl3): δ = 8.02–7.89 (m, (1 mL) was added followed by acetic acid up to neutrality. The
4 H), 7.61–7.44 (m, 2 H), 7.44–7.29 (m, 4 H), 5.69 (s, 1 H), 3.64 (s, mixture was taken to dryness in vacuo and the solid was parti-
3 H), 3.42 (d, J = 16.2 Hz, 1 H), 3.27 (d, J = 16.2 Hz, 1 H), 1.91
(s, 3 H), 1.65 (s, 3 H), 1.63 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.4, 171.0, 167.4, 165.4, 165.2, 133.4, 133.1, 130.2,
129.85, 129.84 (2 C), 129.6 (2 C), 128.4 (2 C)128.2 (2 C), 81.1, 78.8,
tioned between a sat. NaHCO3 solution and EtOAc. The organic
phase was washed with water, dried and concentrated to give 43
(31.2 mg, 90%), which was used in the next step without further
purification.
75.8, 52.4, 39.0, 24.6, 24.1, 20.7 ppm. IR (neat): ν
= 3600–2400
˜
max
Compound 43: 1H NMR (500 MHz, CD3OD): δ = 3.78 (dd, J =
10.9, 2.5 Hz, 1 H), 3.58 (dd, J = 10.9, 7.9 Hz, 1 H), 3.53 (dd, J =
7.9, 2.5 Hz, 1 H), 2.49 (d, J = 14.9 Hz, 1 H), 2.35 (d, J = 14.9 Hz,
1 H), 1.36 (s, 3 H) ppm. 13C NMR (125 MHz, CD3OD): δ = 180.6,
79.0, 73.5, 63.9, 45.6, 24.7 ppm. HRMS (ESI): calcd. for
C6H12NaO5 [M + Na]+ 187.0582; found 187.0590.
(OH), 1719 (C=O benzoates, esters and acid), 1287, 1110, 712 cm–1.
HRMS (ESI): calcd. for C25H26NaO10 [M + Na]+ 509.1424; found
509.1418.
1
Compound 18: Oil. H NMR (200 MHz, CDCl3): δ = 8.06, (d, J =
7.0 Hz, 2 H), 7.63 (t, J = 6.5 Hz, 1 H), 7.48 (t, J = 7.7 Hz, 2 H),
5.26 (s, 1 H), 3.80 (s, 3 H), 2.76–2.52 (m, 3 H), 2.20–2.01 (m, 1 H),
1.65 (s, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 175.6, 167.3,
165.5, 133.8, 129.9 c, 128.6 (3 C), 84.3, 77.2, 52.9, 30.9, 28.7,
Dihydroxylactone 45: Excess CH2N2 in Et2O was added to tri-
hydroxy acid 43 (30.0 mg, 0.18 mmol), dissolved in MeOH (4 mL),
until a yellow colour persisted. The mixture was stirred for a fur-
ther 10 min and the excess of CH2N2 was then destroyed by drop-
wise addition of acetic acid until the solution became colourless.
The mixture was taken to dryness to give an oil, which was purified
by column chromatography (CH2Cl2/MeOH 9:1) to yield lactone
45 (23.5 mg, 90%) as a clear oil.
Compound 45: Oil. 1H NMR (200 MHz, CDCl3): δ = 4.30 (dd, J =
6.0, 4.4 Hz, 1 H), 3.86 (m, 2 H), 2.77 (d, J = 17.2 Hz, 1 H), 2.50
(d, J = 17.2 Hz, 1 H), 1.44 (s, 3 H) ppm. 13C NMR (50 MHz,
23.8 ppm. IR (neat): νmax = 1781 (C=O lactone), 1726 (C=O benz-
˜
oate and CO2Me), 1271, 1112, 714 cm–1. HRMS (ESI): calcd. for
C15H16NaO6 [M + Na]+ 315.0845; found 315.0853.
Compound 19 (9.7 mg, 0.019 mmol) was subjected to the standard
oxidative procedure to give the crude acid as an oil. This was puri-
fied by column chromatography (CH2Cl2/MeOH 95:5) to yield 12
(7.3 mg, 70%).
Compound 20 (31.0 mg, 0.081 mmol) was subjected to the stan-
dard oxidative procedure to give the crude acid as an oil. This was
purified by column chromatography (CH2Cl2/MeOH 95:5) to yield
21 (21.5 mg, 65%) as an oil.
CDCl ): δ = 177.9, 90.1, 75.7, 61.0, 45.6, 24.5 ppm. IR (neat): ν
˜
3
max
= 3408 (broad, OHs), 1771 (C=O lactone) cm–1. HRMS (ESI):
calcd. for C6H10NaO4 [M + Na]+ 169.0477; found 169.0472.
Compound 21: Oil. 1H NMR (200 MHz, CDCl3): δ = 7.94 (m, 4
H), 7.60–7.44 (m, 2 H), 7.42–7.28 (m, 4 H), 4.60 (AB system, J =
11.7 Hz, 2 H), 3.12 (br. s, 2 H), 1.71 (s, 3 H), 1.64 (s, 6 H) ppm.
Silylated Lactone 46: Imidazole (3.0 equiv., 28.6 mg, 0.42 mmol)
and tert-butyldimethylsilyl chloride (1.5 equiv., 31.5 mg,
0.21 mmol) were added to lactone 45 (21.3 mg, 0.14 mmol), dis-
13C NMR (50 MHz, CDCl3): δ = 174.9, 171.3, 165.8, 165.4, 133.05, solved in DMF (300 μL), and the mixture was stirred for 2.5 h at
133.02, 129.8, 129.65, 129.6 (2 C), 129.5 (2 C), 128.35 (2 C), 128.30 room temp. MeOH (500 μL) was then added and stirring was con-
(2 C), 80.4, 78.9, 67.5, 39.9, 24.5 (2 C), 21.0 ppm. IR (neat): ν
tinued for 30 min. The reaction mixture was concentrated on silica
and purified by column chromatography (hexane/EtOAc 1:1) to
yield compound 46 (34.9 mg, 96%) as a clear oil.
Compound 46: Oil. 1H NMR (200 MHz, CDCl3): δ = 4.19 (dd, J =
3.8, 2.8 Hz, 1 H), 4.12 (dd, J = 11.8, 2.8 Hz, 1 H), 4.02 (dd, J =
11.8, 3.8 Hz, 1 H), 3.66 (br. s, 1 H), 2.73 (d, J = 17.6 Hz, 1 H),
2.57 (d, J = 17.6 Hz, 1 H), 1.49 (s, 3 H), 0.90 (s, 9 H), 0.12 (s, 6
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 174.7, 85.5, 75.4, 61.8,
˜
max
= 3600–2400 (OH), 1716 (C=O benzoates, ester and acid), 1284,
1109, 710 cm–1. HRMS (ESI): calcd. for C23H24NaO8 [M + Na]+
451.1369; found 451.1360.
Compound 22 (10.1 mg, 0.029 mmol) was subjected to the stan-
dard oxidative procedure to give an oil, which was purified by
HPLC (hexane/EtOAc 7:3) to yield 1,4-diketone 23 (5.3 mg, 70%),
as an oil.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O20069
/KAP1
Date: 13-06-12 16:23:18
Pages: 14
V. Piccialli et al.
FULL PAPER
ero, N. Borbone, A. Tuzi, R. Centore, A. Hemminki, M. Ugol-
ini, V. Cerullo, Org. Biomol. Chem. 2009, 7, 3036–3039; c) V.
Piccialli, N. Borbone, G. Oliviero, Tetrahedron 2008, 64, 11185–
11192; d) V. Piccialli, Synthesis 2007, 17, 2585–2607; e) V. Picci-
alli, T. Caserta, L. Caruso, L. Gomez-Paloma, G. Bifulco, Tet-
rahedron 2006, 62, 10989–11007; f) T. Caserta, V. Piccialli, L.
Gomez-Paloma, G. Bifulco, Tetrahedron 2005, 61, 927–939; g)
V. Piccialli, T. Caserta, Tetrahedron Lett. 2004, 45, 303–308; h)
G. Bifulco, T. Caserta, L. Gomez-Paloma, V. Piccialli, Tetrahe-
dron Lett. 2003, 44, 5499–5503; i) G. Bifulco, T. Caserta, L.
Gomez-Paloma, V. Piccialli, Tetrahedron Lett. 2002, 43, 9265–
9269; corrigendum: Tetrahedron Lett. 2003, 44, 3429; j) V. Pic-
cialli, N. Cavallo, Tetrahedron Lett. 2001, 42, 4695–4699; k)
M. de Champdorè, M. La Salvia, V. Piccialli, Tetrahedron Lett.
1998, 39, 9781–9784.
44.9, 26.7, 25.7 (3 C), 18.1, –5.6, –5.7 ppm. IR (neat): ν
= 3447
˜
max
(broad, OH), 1782 (C=O lactone) cm–1. HRMS (ESI): calcd. for
C12H24NaO4Si [M + Na]+ 283.1342; found 283.1339.
Unsaturated Lactone 47: Thionyl chloride (5 equiv., 0.55 mmol,
40 μL) was added to lactone 46 (30.0 mg, 0.11 mmol), dissolved in
pyridine (500 μL), and the mixture was stirred at 0 °C for 30 min.
Water (500 μL) was added and the reaction mixture was evaporated
in vacuo to give an oily product. Column chromatography (hexane/
EtOAc 8:2) yielded compound 47 (25.3 mg, 95%) as a clear oil.
1
Compound 47: Oil. H NMR (500 MHz, CDCl3): δ = 5.83 (br. s, 1
H), 4.82 (br. s, 1 H), 3.94 (dd, J = 11.3, 3.7 Hz, 1 H), 3.90 (dd, J
= 11.3, 3.5 Hz, 1 H), 2.10 (s, 3 H), 0.85 (s, 9 H), 0.06 (s, 3 H), 0.05
(s, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 173.2, 166.7,
118.1, 84.7, 61.7, 25.7 (3 C), 18.1, 14.1, –5.5, –5.6 ppm. IR (neat):
[6]
[7]
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ν
= 1759 (C=O α,β-unsaturated lactone), 1132, 837, 778 cm–1.
˜
max
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HRMS (ESI): calcd. for C12H22NaO3Si [M + Na]+ 265.1236; found
265.1244.
Umbelactone (48): Et3N·3HF (20 equiv., 270 μL) was added to lac-
tone 47 (20.2 mg, 0.083 mmol), dissolved in dry THF (1 mL), and
the mixture was stirred for 2.5 h at room temp. Et3N (500 μL) was
then added and the mixture was taken to dryness. The residue was
co-evaporated with Et3N (2ϫ500 μL) and MeOH (3ϫ500 μL) and
concentrated to give an oil, which was purified by column
chromatography (EtOAc) to yield umbelactone 48 (9.8 mg, 92%)
as a clear oil.
1
Compound 48: Oil. H NMR (200 MHz, CDCl3): δ = 5.89 (br. s, 1
H), 4.91 (br. s, 1 H), 4.07 (dd, J = 12.7, 2.9 Hz, 1 H), 3.77 (dd, J
= 12.7, 3.9 Hz, 1 H), 2.11 (s, 3 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 172.8, 165.8, 118.3, 85.0, 61.5, 14.0 ppm. IR (neat):
ν
max = 3404 (broad OH), 2921, 2851, 1731 (broad, C=O α,β-unsat-
˜
urated lactone), 1647, 1050 cm–1. HRMS (ESI): calcd. for
C6H8NaO3 [M + Na]+ 151.0371; found 151.0375.
Supporting Information (see footnote on the first page of this arti-
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1
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We are grateful to the Italian Ministero dell’Università e della
Ricerca Scientifica e Tecnologica (MURST) (PRIN 2007) for fin-
ancial support of this investigation. We are also grateful to the
Centro di Metodologie Chimico-Fisiche and the Centro di Servizio
Interdipartimentale di Analisi Strumentale (CSIAS) of the Univer-
sity of Napoli “Federico II” for NMR facilities, to Dr. Luisa
Cuorvo for technical assistance and to Dr. Vincenzo Perino for
NMR assistance.
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12
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/KAP1
Date: 13-06-12 16:23:18
Pages: 14
Catalytic Oxidation of Tetrahydrofuran Compounds
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Received: January 19, 2012
Published Online: ᭿
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Date: 13-06-12 16:23:18
Pages: 14
V. Piccialli et al.
FULL PAPER
Catalytic Oxidation
The catalytic oxidation of mono- and poly-
tetrahydrofuran compounds has been car-
ried out with chlorochromatoperiodate
(CCP), generated by the combination of
PCC and H5IO6. New synthetically useful
oxidative transformations are disclosed.
Umbelactone, an antiviral natural butenol-
ide metabolite, has been synthesized by use
of the developed chemistry.
V. Piccialli,* S. Zaccaria, G. Oliviero,
S. D’Errico, V. D’Atri,
N. Borbone ...................................... 1–14
Insight into Pyridinium Chlorochromate
Chemistry: Catalytic Oxidation of Tetra-
hydrofuran Compounds and Synthesis of
Umbelactone
Keywords: Oxidation
/ Oxygen hetero-
cycles / Reaction mechanisms
14
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