Scope and limitations of the photooxidations of 2-(α-Hydroxyalkyl) furans: Synthesis of 2-hydroxy-exo -brevicomin

Article abstract of DOI:10.1021/ol200027f

Photooxygenation of 2-(α-hydroxyalkyl)furans at 5 °C in MeOH followed by in situ reduction affords, in one synthetic operation, 6-hydroxy-3(2H)-pyranones and/or 5-hydroxy-2(5H)-furanones. The relative ratio of the final products is highly dependent on the substitution of the starting furan substrate. Photooxygenation of 2-(α,β-dihydroxyalkyl)furans followed by in situ reduction and ketalization with acid rapidly provides the 6,8-dioxabicyclo[3.2.1]oct-3-en-2-one framework. This new methodology was successfully applied to the synthesis of 2-hydroxy-exo-brevicomin.(Figure Presented)

Full text of DOI:10.1021/ol200027f

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1166–1169
Scope and Limitations of the
Photooxidations of 2-(r-
Hydroxyalkyl)furans: Synthesis of
2-Hydroxy-exo-brevicomin
Dimitris Noutsias, Antonia Kouridaki, and Georgios Vassilikogiannakis*
Department of Chemistry, University of Crete, Vasilika Vouton, 71003 Iraklion, Crete,
Greece
*E-mail: vasil@chemistry.uoc.gr.
Received January 5, 2011
ABSTRACT
Photooxygenation of 2-(R-hydroxyalkyl)furans at 5 °C in MeOH followed by in situ reduction affords, in one synthetic operation, 6-hydroxy-3(2H)-
pyranones and/or 5-hydroxy-2(5H)-furanones. The relative ratio of the final products is highly dependent on the substitution of the starting
furan substrate. Photooxygenation of 2-(R,β-dihydroxyalkyl)furans followed by in situ reduction and ketalization with acid rapidly provides
the 6,8-dioxabicyclo[3.2.1]oct-3-en-2-one framework. This new methodology was successfully applied to the synthesis of 2-hydroxy-exo-
brevicomin.
8
It is well-known that with multifarious advantages and
disadvantages to each discrete method, 2-(R-hydroxyalkyl)-
furans can be oxidized to afford the corresponding 6-hy-
droxy-3(2H)-pyranones (1 f 2, Scheme 1) under a variety
of conditions, including Br2/MeOH,1 peracids (e.g., m-
CPBA,2 magnesium monoperoxypthalate3), NBS,4 dioxir-
anes (DMDO5), metal-based oxidations (PCC,6 VO(acac)2/
t-BuOOH,7 titanium(IV) silicalite 1/H2O2 ), as well as
with electrochemical oxidation.9 The proliferation of
methods available to undertake this transformation attests
to the synthetic versatility of the 6-hydroxy-3(2H)-pyra-
none unit, and yet, major problems remain to anyone wish-
ing to apply these protocols within a synthetic context
mostly arising from the lack of selectivity and/or harshness
associated with these existing oxidative methods.
With some tentative initial findings10 in mind from early
investigations in our field of interest, namely, the reactivity
of furans with singlet oxygen,11 we felt there might possibly
exist a synthetically valuableand mild method usingsinglet
oxygen as oxidant with which the 6-hydroxy-3(2H)-pyr-
anone unit could be accessed that has not yet been properly
investigated and deconvoluted.
(1) Achmatowicz, O.; Bukowski, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojsk, A. Tetrahedron 1971, 27, 1973.
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Denny, R.; Schenck, G. O.; Schulte-Elte, K. H. Tetrahedron 1967, 23,
2583. (b) For a general review of furan photooxygenation, see: Feringa,
B. L. Recl. Trav. Chim. Pays-Bas 1987, 106, 469.
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Adv. Synth. Catal. 2004, 346, 333.
r
10.1021/ol200027f
Published on Web 01/31/2011
2011 American Chemical Society

the intermediate ozonides 3 were also reduced at low
temperature by dimethyl sulfide (DMS) or PPh3, the
formation of 6-hydroxy-3(2H)-pyranone 2 was seen to
dominate (3 f 8 f 7 f 2, Scheme 2).12,13 This adapted
1O2 technology was successfully applied as one of the
key steps in the total synthesis of cryptofauronol,13a as
well as in the synthesis of secodolastanes,13b cyathin,13c and
taxane13d diterpene skeletons. In the first case, the problem
of concurrent oxidation of the disubstituted double
bond when either Br2/MeOH1 or m-CPBA2 were used
as oxidant was eliminated.13a Similarly, the highly che-
moselective singlet oxygen oxidation of a furan nucleus
to yield the corresponding intermediate 1,4-enedione, in
the presence of two trisubstituted double bonds on the
2-alkyl side chain, was achieved in the total synthesis of
litseaverticillols.14 Application of the literature proto-
cols for the direct oxidation of furans to 1,4-enediones,
involving treatment with either Br2/MeOH,1 m-CPBA,2
or magnesium monoperoxypthalate (MMPP),3 had led
to rapid bromination or epoxidation of the side chain
double bonds.
Scheme 1. Achmatowicz Rearrangement
Scheme 2. Competing Pathways
These prior investigations, however, leave an impor-
tant question unanswered: Which one of the two
possible paths (fragmentation a or intermolecular nu-
cleophilic opening b, Scheme 2) would prevail if the
reaction was run in a nucleophilic solvent such as MeOH
at temperatures much closer to the ambient ideal? In
other words, can the oxidation mechanism be manipu-
lated and diverted, by the introduction of a nucleophi-
lic solvent (MeOH), in order to promote the desired
reaction pathway. To this end, there was a need to
explore the photooxygenation of 2-(R-hydroxyalkyl)-
furans in MeOH at more user-friendly temperatures
(e.g., 5 °C), in order to understand how this adjustment
would affect the final product distribution, (5-hydroxy-
2(5H)-furanone of type 4 vs 6-hydroxy-3(2H)-pyranones
of type 2). The 6-hydroxy-3(2H)-pyranone unit is a highly
prized synthetic intermediate by virtue of the fact that it
contains at least three reactive sites for further synthetic
elaboration, so development of a mild and selective meth-
odology for its synthesis would be of great value. Finally, it
is important to note that from a practical standpoint, as
already intimated, low-temperature photooxidations are
not easy reactions to perform, and developing a method
that operates much closer to room temperature is therefore
highly desirable.
To outline the idea and place it in context with what is
known already, the mechanisms invoked for such singlet
oxygenoxidations mustfirst be examined. Itisveryreason-
able to assume that 6-hydroxy-3(2H)-pyranone 2 might
1
be the final product of the O2-oxidation of 2-(R-hydro-
xyalkyl)furans of type 1 via intermediate formation of
enedione 7 (Scheme 2). There is, however, a competing
fragmentation pathway which frequently leads to the for-
mation of the 5-hydroxy-2(5H)-furanone nucleus 4 (via
path a, Scheme 2).12 It has been observed that when the
photooxidations were performed at low temperature, and
An investigation aimed at clarifying all these issues
started with the simplest possible substrate, namely, the
completely unsubstituted 2-(R-hydroxymethyl)furan
(1a, Scheme 3). When furan 1a was subjected to a stan-
dard set of singlet oxygen (1O2) photooxygenation
conditions (catalytic quantities of rose bengal as photosen-
sitizer, oxygen bubbling through the reaction mixture with
irradiation from a visible spectrum light) for 4 min, the
formation of an equimolar mixture of hydroperoxides
(11) (a) Montagnon, T.; Tofi, M.; Vassilikogiannakis, G. Acc. Chem.
Res. 2008, 41, 1001. (b) Georgiou, T.; Tofi, M.; Montagnon, T.;
Vassilikogiannakis, G. Org. Lett. 2006, 8, 1945. (c) Tofi, M.; Koltsida,
K.; Vassilikogiannakis, G. Org. Lett. 2009, 11, 313. (d) Pavlakos, E.;
Georgiou, T.; Tofi, M.; Montagnon, T.; Vassilikogiannakis, G. Org.
Lett. 2009, 11, 4556.
(12) Lee, G. C. M.; Syage, E. T.; Harcourt, D. A.; Holmes, J. M.;
Garst, M. E. J. Org. Chem. 1991, 56, 7007.
(13) (a) Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun.
1983, 666. (b) Williams, D. R.; Benbow, J. W.; Allen, E. E. Tetrahedron
Lett. 1990, 31, 6769. (c) Magnus, P.; Shen, L. Tetrahedron 1999, 55, 3553.
(d) Bauta, W. E.; Booth, J.; Bos, M. E.; DeLuca, M.; Diorazio, L.;
Donohoe, T. J.; Frost, C.; Magnus, N.; Magnus, P.; Mendoza, J.; Pye,
P.; Tarrant, J. G.; Thom, S.; Ujjainwalla, F. Tetrahedron 1996, 52,
14081.
(14) (a) Vassilikogiannakis, G.; Stratakis, M. Angew. Chem., Int. Ed.
2003, 42, 5465. (b) Vassilikogiannakis, G.; Margaros, I.; Montagnon, T.
Org. Lett. 2004, 6, 2039. (c) Vassilikogiannakis, G.; Margaros, I.;
Montagnon, T.; Stratakis, M. Chem.;Eur. J. 2005, 11, 5899.
Org. Lett., Vol. 13, No. 5, 2011
1167

of the fragmentation product 4-hydroxybutenolide 4 was
observed; while, when R1 =methyl or phenyl formation
of 6-hydroxy-3(2H)-pyranone 2 dominated. These results
are consistent with the R1-substituent stabilizing a devel-
oping positive charge during the nucleophilic attack of
MeOH onto the intermediate ozonide (TSa). It is also
reasonable to propose that the extra intramolecular hydro-
gen bond possible only in the case of TSa makes it a more
stable when compared to its regioisomer, TSb.
Scheme 3. Photooxidation of 2-(R-Hydroxyalkyl)furans
The upshot of the stabilizing effect of the alkyl
substituent at position 5 is that nucleophilic opening
(path b, Scheme 2) is kinetically favored when com-
pared to the alternative fragmentation pathway (path a).
A similar mechanistic explanation had been invoked
previously, to explain the regioselective attack of
MeOH, EtOH, and i-PrOH onto the more sterically
hindered 2-position of a 2-alkylfuran endoperoxide.15
To a lesser extent, the substitution of the furylic posi-
tion (R2 and R3) also plays a role in determining the
product distribution. Higher order substitution at the
furylic position leads to an increase of the fragmenta-
tion pathway (e.g., 1a vs 1b vs 1d, 1e vs 1f vs 1g, and 1j
vs 1k). It is also obvious that when R3 = prenyl or
phenyl (substrates 1c, 1h, and 1i) exclusive formation
of the fragmentation products was observed. These
latter results may be rationalized by a faster elimina-
tion of a very stable conjugated aldehyde, or benzal-
dehyde, compared to the alternative attack of metha-
nol. In agreement with our previous observations,14 the
prenyl side chain of substrates 1c and 1h did not under-
go a singlet oxygen ene reaction under the reaction
conditions.
Another important finding is the predominant forma-
tion of the desired 6-hydroxy-3(2H)-pyranone 2l and 2m
when the R3 substituent contains a carbonyl at the β-
position. Once again, and in agreement with the previous
results, when R1 becames hydrogen (substrate 1n, Scheme 3)
almost exclusive formation of the fragmentation product
was observed.
With all these results in mind, exploration of the photo-
oxygenation of 2-(R,β-dihydroxyalkyl)furans seemed ap-
propriate for the following two reasons. First, it was
necessary to investigate the infuence that the extra hydrox-
yl at the β-position of the alkyl side-chain has on the
product distribution (12 vs fragmentation product 4e,
Scheme 4). Second, it was anticipated that a useful and
efficient one-pot synthesis of 6,8-dioxabicyclo[3.2.1]oct-3-
en-2-ones (13, Scheme 4) could be developed.
a Relative ratios were determined by 1H NMR of the crude photo-
oxidation mixture.
(see 5, Scheme 2) and fragmentation product 4a was
1
observed by H NMR spectra of the crude reaction
mixture. Overnight treatment of this reaction mixture
with dimethyl sulfide afforded an equimolar mixture of
6-hydroxy-3(2H)-pyranone 2a and 5-hydroxy-2(5H)-
furanone 4a. Any additional substitution at the furylic
position (see furans 1b-d, Scheme 3) resulted in almost
exclusive formation of the undesired fragmentation
product 4a.
The next modification to the photooxidation substrate
to be investigated was substitution at the 5-position of the
furan, initially focusing on replacing the hydrogen with a
methyl group (1e-g, Scheme 3). This minor change altered
completely the outcome of the reaction, favoring the
formation of 6-hydroxy-3(2H)-pyranones 2e, 2f, and 2g.
Curiously, however, this methyl-substitution, when com-
bined with the presence of a prenyl or a phenyl group at the
furylic position (1h and 1i, Scheme 3), afforded almost
exclusively 4-hydroxybutenolides 4 via the once again
dominant fragmantation pathway.
When the methyl group at the 5-position of the furan
was replaced with a phenyl (1j, Scheme 3), formation of
pyranone 2j (R2=R3=H) predominated. Pyranone 2j was
isolated as an equillibrium mixture with the open 1,4-
enedione of type 7. In contrast, almost completely domi-
nant was fragmentation when furanol 1k (R2 = H, R3 =
n-Bu) was subjected to photooxidation.
These results show clearly that the substitution pattern
at position-5 (R1) of the starting 2-(R-hydroxyalkyl) furan
1 is absolutely crucial in determining the course of the
reaction. Thus, when R1 = H, almost exclusive formation
To this end, 2-(R,β-dihydroxyalkyl)furans 11a-c were
easily prepared using Wittig reactions between different
phosphonium ylides and 5-methyl furaldehyde 9, followed
(15) Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057.
Org. Lett., Vol. 13, No. 5, 2011
1168

Scheme 4. Photooxidation of 2-(R,β-Dihydroxyalkyl)furans:
One-Pot Synthesis of 6,8-Dioxabicyclo[3.2.1]oct-3-en-2-ones
Scheme 5. Synthesis of 2-Hydroxy-exo-brevicomin
behaves similarly to furanol 1m. In other words, the
extra hydroxyl at the β-position of the side chain
does not have significant effect on the distribution of
the final products.
The synthetic potential of this new methodology was
demonstrated by a rapid and enantioselective synthesis
of 2-hydroxy-exo-brevicomin20 (14, Scheme 5). With
compound 13a already in hand, the synthesis of the
natural product was completed by diasterospecific re-
duction using NaBH4, followed by double bond hydro-
genation. The spectroscopic data of synthetic hydroxy-
exo-brevicomin were in full agreement with those of the
natural product.20d,h,i
a Relative ratios were determined by 1H NMR of the crude photo-
oxidation mixture. b Isolated yield.
The procedures developed herein, in which oxygen from
the air is excited to transiently generate singlet oxygen in
situ, are green, clean, and highly atom economic.21 Many
standard laboratory oxidants used to attain similar results,
employ toxic heavy metals, or are reagents that require their
own laborious synthesis. In contrast, when using singlet oxy-
gen there is no waste either in terms of its generation, or in its
application (wherein both oxygen atoms are transferred and
incorporated into the oxidation substrate).
For all these reasons, using singlet oxygen to access
the sought after 6-hydroxy-3(2H)-pyranone unit from
2-(R-hydroxyalkyl)furans is particularly attractive from a
synthetic standpoint. The original concept has also been
neatly extended to show how readily and effectively a
2-(R,β-dihydroxyalkyl)furan can yield the 6,8-dioxabi-
cyclo[3.2.1]oct-3-en-2-one framework from a one-pot sing-
let oxygen initiated reaction sequence.
by Sharpless asymmetric dihydroxylation (SAD)16 of the
resulting olefins. Wittig coupling ofthe phosphonium ylide
10b gave almost exclusively the trans-olefin and, as ex-
pected, the following SAD reaction afforded the threo-1,2-
diol 11b. Wittig coupling of the phosphonium ylides 10a
and 10c resulted into the formation of cis/trans mixtures of
geometrical isomers (1.3:1 in case of 10a, and 1.5:1 in case
of 10c). SAD reactions of these two mixtures of geome-
trical isomers resulted in the unexpected predominat for-
mation of the threo-1,2-diols 11a and 11c. Similar results
have been recently reported17 and were attributed to a
cis-trans isomerization, occurring during the reaction
itself, combined with the known faster dihydroxylation
of a trans double bond when compared with its cis isomer.
Furandiols 11a-c were subjected to the previously
described 1O2 photooxidation and reduction conditions.
In situ treatment with catalytic amount of p-TsOH
afforded the desired 6,8-dioxabicyclo[3.2.1]oct-3-en-2-
ones 13a-c in good overall isolated yield (Scheme 4).
Several different classes of natural products including
the pteriatoxins and pinnatoxins18 and the didemnise-
rinolipids19 contain such a motif.
Acknowledgment. We are grateful to Dr. Tamsyn Mon-
tagnon (University of Crete) for valuable discussions and
comments. This research was supported by COST action
CM0804.
Supporting Information Available. Experimental proce-
dures, full spectroscopic data, and copies of 1H and 13
The product distribution for the substrates 11a and
11c is similar to substrate 1f, while furandiol 11b
C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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