Triphenylphosphine reduction of saturated endoperoxides

Article abstract of DOI:10.1021/ol901652u

(Figure Presented) Triphenylphosphine reduction of saturated endoperoxides derived from 6,6-dimethylfulvene and spiro[2.4]hepta-4,6-diene in the presence of nucleophiles results in the formation of products that mainly stem from deoxygenation followed by carbocation formation. Nucleophilic attack by solvent proceeds by an S_N1 like mechanism; allyl shifts and cyclopropylcarbinyl-cyclobutyl rearrangements also occur. With the systems lacking carbocation-stabilizing groups, the deoxygenation step is preceded by attack of H₂O at the phosphorus.

Full text of DOI:10.1021/ol901652u

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3986-3989
Triphenylphosphine Reduction of
Saturated Endoperoxides
Ihsan Erden,* Christian Ga¨rtner, and M. Saeed Azimi
San Francisco State UniVersity, Department of Chemistry and Biochemistry,
1600 Holloway AVenue, San Francisco, California 94132
ierden@sfsu.edu
Received July 20, 2009
ABSTRACT
Triphenylphosphine reduction of saturated endoperoxides derived from 6,6-dimethylfulvene and spiro[2.4]hepta-4,6-diene in the presence of
nucleophiles results in the formation of products that mainly stem from deoxygenation followed by carbocation formation. Nucleophilic attack
by solvent proceeds by an SN1 like mechanism; allyl shifts and cyclopropylcarbinyl-cyclobutyl rearrangements also occur. With the systems
lacking carbocation-stabilizing groups, the deoxygenation step is preceded by attack of H2O at the phosphorus.
The reduction of cyclic peroxides1 and ozonides2 with
triphenylphosphine has been known for a long time. In the
case of unsaturated endoperoxides, the reaction results in
deoxygenation, leading to ene epoxides,3 although a few
exceptions have been observed.4 In the case of 1,2-dioxet-
anes, the reaction with PPh3 leads to a cyclic phosphorane
that undergoes O-P cleavage followed by an intramolecular
SN2 reaction to give epoxides in a stereospecific manner.5
With bicyclic 1,2-dioxetanes, on the other hand, where
backside attack is impeded, eliminations to allylic alcohols
are observed.6 Samuelsson and co-workers reported that
prostaglandin endoperoxides PGG2 (1a) or PGH2 (1b) upon
reduction with PPh3 give the corresponding cis-1,3-diol (2),
PGF2R.7 Clennan and Heah found that saturated bicyclic
endoperoxides give with PPh3 in the presence of H2O trans-
1,n-diols;8 moreover, they were able to detect the cyclic
phosphorane intermediates by NMR and postulated for their
formation a biphilic insertion of PPh3 into the O-O linkage.
They also offered a mechanism for phosphorane decomposi-
tion involving heterolytic cleavage of the phosphorane to
give a zwitterion that reacts with water Via backside
displacement (SN2) to give the trans-diol 5 (Scheme 1). On
Scheme 1.
PPh3 Reductions of 2,3-Dioxabicyclo[2.2.1]heptanesa
(1) (a) Horner, L.; Jurgeleit, W. Annalen 1955, 591, 138–152. (b)
Pierson, G. O.; Runquist, O. R. J. Org. Chem. 1969, 34, 3654–3655. (c)
Jarvie, A. W. P.; Moore, C. G.; Skelton, D. J. Poly. Sci. Part A: Polymer
Chem 1971, 9, 3105–3114.
(2) Carles, J.; Fliszar, S. Can. J. Chem. 1969, 47, 1113.
(3) Balci, M. Chem. ReV. 1981, 81, 91–108.
(4) (a) Adam, W.; Erden, I. Tetrahedron Lett. 1979, 20, 2781–2784.
(b) Baldwin, J. E.; Lever, O. W., Jr. J. Chem. Soc., Chem. Commun. 1973,
344–345.
a Previous work by Samuelsson (1f2) and Clennan and Heah (3f5).
(5) Bartlett, P. D.; Landis, M. E.; Shapiro, M. J. J. Org. Chem. 1977,
42, 1661–1662.
(6) Kopecky, K. R.; Filby, J. E.; Mumford, C.; Lockwood, P. A.; Ding,
J.-Y. Can. J. Chem. 1975, 53, 1103–1122.
the other hand, the studies by Westheimer and co-workers,9
as well as McClelland and co-workers10 have shown, with
careful mechanistic work, that the hydrolysis of pentaary-
(7) (a) Hamberg, M.; Svensson, J.; Wakabayashi, T.; Samuelsson, B.
Proc. Natl. Acad. Sci. U.S.A. 1974, 71, 345–349. (b) Samuelsson, B. Nobel
Lectures in Physiology or Medicine 1981-1990; Lindtsen, J., Ed.; World
Scientific Publishing: Stockholm, Sweden, 1982; pp 117-138.
10.1021/ol901652u CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

loxyphosphoranes occurs by an “inner sphere” mechanism
(attack at phosphorus).
reaction was conducted in CH2Cl2 at 0 °C in the presence of a
slight excess of acetic acid. Under these conditions, a mixture
of six products was formed, four carrying the acetoxy group.
They were separated by silica gel chromatography (after treating
the mixture with cold ether/petroleum ether and removing most
of the Ph3PdO by filtration) and identified as the products
shown in Scheme 3.
The base hydrolysis appears to be an associative process
proceeding through a hexacoordinated phosphoroxanide ion,
whereas the acid-catalyzed reaction is a dissociative pathway
resembling the acetal or orthoester hydrolysis. Also contrary
to the “outer sphere” mechanism, Taylor and Greatrex
reported that a cis-1,4-diphenyl substituted 4,5-epoxy-1,2-
dioxine resulted in the hydrolysis of the phosphorane
intermediate at phosphorus rather than at the carbon center
to give a meso-1,4-diol, in addition to deoxygenation
products.11
Scheme 3. Reaction 6 with PPh3 in the Presence of AcOH
Herein we disclose our results from PPh3 reductions of
saturated endoperoxides derived from 6,6-dimethylfulvene
and spiro[2.4]hepta-4,6-diene that have unraveled new
pathways involving carbocation intermediates and rearrange-
ments. We also report that the origin of the above-mentioned
discrepancy regarding the stereochemistry of the diols 2 and
5, and hence the mechanism of phosphorane decomposition
during PPh3 reductions of saturated endoperoxides in the
[2.2.1] and [2.2.2] series in the presence of H2O is likely
just due to a misassignment of the 1,n-diol stereochemistry.
In the course of our studies on peroxides derived from
fulvenes and fulvene analogs,12 we investigated the triph-
enylphosphine reductions of 6,6-dimethylfulvene and
[2.4]spirohepta-4,6-diene since our systems promised some
unusual behavior due to the presence of the vinyl and
cyclopropyl groups adjacent to the peroxo carbons, respec-
tively.
The results presented above deserve some comment:
Oxetane 13 is most likely formed from 12 by an SN2′
reaction. Under the conditions, 13 undergoes oxetane cleav-
age to give the allenic aldehyde 8 (Scheme 4). Compound 7
After singlet oxygenation of 6,6-dimethylfulvene at -78
°C in CH2Cl2, and subsequent diazene reduction at low
temperature, as described previously,13 the saturated endop-
eroxide 6 was treated with 1.2 equivalents PPh3 at 0 °C, and
the mixture was stirred at room temperature for 10 h. The
product mixture was chromatographed on silica gel to give
one major product, 7, and a minor product, 8, a known
aldehyde.14 For characterization purposes the latter was
converted to its oxime 8a (syn and anti isomers in ca. 1:1
ratio) (Scheme 2).
Scheme 4
.
Mechanisms for the Formation of Compounds 7, 8,
10 and 11
Scheme 2
.
PPh3 Reduction of the Saturated Fulvene
Endoperoxide 6 without H2O
is formed from 14 by proton loss. Azine 9 in Scheme 3 is
formed from 8 with hydrazine, a disproportionation product
of diazene,15 in a serendipitous manner: the latter was present
in the mixture in large excess since after reduction and
(10) McClelland, R. A.; Patel, G.; Cirinna, C. J. Am. Chem. Soc. 1981,
103, 6432–6436.
(11) Greatrex, B. W.; Taylor, D. K. J. Org. Chem. 2004, 69, 2577–
2579.
We then decided to carry out the PPh3 reduction in the
presence of a nucleophile, and for reasons of easier purification/
isolation of products we chose acetic acid instead of water. The
(12) Erden, I.; Ocal, N.; Song, J.; Gleason, C.; Gaertner, C. Tetrahedron
2006, 62, 10676–10682, and references cited therein.
(13) Adam, W.; Erden, I. Angew. Chem., Int. Ed. Engl. 1978, 17, 210–
211.
(8) (a) Clennan, E. L.; Heah, P. C. J. Org. Chem. 1981, 46, 4105–4107.
(b) Clennan, E. L.; Heah, P. C. J. Org. Chem. 1982, 47, 3329–3331. (c)
Clennan, E. L.; Heah, P. C. J. Org. Chem. 1984, 49, 2284–2286.
(9) William, W. C. A., Jr.; Westheimer, F. H. J. Am. Chem. Soc. 1973,
95, 5955–5959.
(14) (a) Bertrand, M.; Cavallin, B.; Roumestant, M. L.; Sylvestre-Panthet,
P. Isrl. J. Chem. 1985, 26, 95–100. (b) Crandall, J. K.; Mualla, M.
Tetrahedron Lett. 1986, 27, 2243–2246.
(15) Wiberg, N.; Bachhuber, H.; Fischer, G. Angew. Chem., Int. Ed.
Engl. 1972, 11, 830–831.
Org. Lett., Vol. 11, No. 17, 2009
3987

filtration of KOAc, the solution was treated with PPh3
without aqueous workup.
Scheme 6. PPh3 Reduction of 21 in the Presence of AcOH
The hydroxyacetates 10a and b (cis and trans) were
isolated as mixtures, whereas 11a was obtained in pure form.
Through repeated chromatography the major isomer 10a
could be isolated free of 10b. An attractive mechanism for
the formation of 7, 8 as well as 10 and 11 would feature
oxetane 13 as the key intermediate (Scheme 4). The
assignment of the cis and trans isomers of 10 is based on
independent synthesis of an authentic sample of 10a from 6
by NaBH4 reduction in MeOH at 0 °C followed by
monoacetylation of the resulting cis-1,3-diol with acetyl
chloride in CH2Cl2 in the presence of NEt3.
bisected conformation,20 we expected a similar mechanism
as with 6 with possible carbocation rearrangement involving
the cyclopropyl group. These expectations were borne out
by the following experiments. The saturated endoperoxide
21 derived from spiro[2.4]hepta-4,6-diene, prepared as
previously described,19 reacted with PPh3 in the presence of
acetic acid at room temperature to give a mixture of three
products all of which contained an acetoxy group and which
were separated from one another by silica gel chromatog-
raphy. They were identified as 22, 23a and 23b (in order of
their Rf values with 1:1 pet.ether/EtOAc, respectively) by
means of their spectral and accurate HRMS data. The
formation of the hydroxy acetates 23a and 23b is analogous
to that of 10a and 10b from 6, and is indicative of a carbocation
intermediate derived from the initial bicyclic phosphorane by
way of Ph3PdO extrusion. In particular the formation of the
1-acetoxybicyclo[3.2.01,5]heptan-2-ol (22, a single stereoisomer)
constitutes clear-cut evidence for the intervention of a carboca-
tion intermediate of the type 26, undergoing a cyclopropyl-
carbinyl-cyclobutyl rearrangement,21 followed by capture of the
cyclobutyl cation by the acetate ion.
The intermediacy of oxetane 13 and its role as a precursor
of 8 as well as 11a/b has precedent. The diphenyl analog of
13 has been prepared by Abe and Adam et al.16 and also by
Abe et al.17 (Scheme 5). The latter group observed that 16
Scheme 5. Abe et al.’s Pathway to a
6-Oxabicyclo[3.2.0]hept-1-ene (16) and its Decomposition
Products
Both 23a and 23b were stable toward AcOH under the
reaction conditions applied to 21 and did not undergo
rearrangement to 22. The mechanism outlined in Scheme 7
satisfactorily accounts for all three products.
undergoes rearrangement to form 17, the corresponding
allene aldehyde of type 8. On the other hand, with CH3CO2H
the same oxetane was reported to give mostly the cis-acetoxy
alcohol 18 with traces of the hydroxyacetates 19 and 20. In
our case, products 10a, b and 11a, b do not have to stem
from 13 and can directly be formed from 12 by loss of
Ph3PdO, followed by capture of the allyl cation 14 by the
acetate ion. We believe that 11b is a secondary product
stemming from 11a by an intramolecular acyl transfer.18
Next, we studied the triphenylphosphine reduction of the
saturated endoperoxide 21 derived from [2.4]-spiro-4,6-
heptadiene 21.19 Considering the significant stabilizing effect
of a cyclopropyl group on adjacent carbocations when the
three-membered ring and the carbocation are fixed in a
Scheme 7. Mechanism for the PPh3 Reduction of 21
The question remained whether the parent 2,3-
dioxabicyclo[2.2.1]heptyl system 3 and its [2.2.2]octyl homo-
logue 27 lacking carbocation stabilizing groups indeed undergo
PPh3 reduction by an SN2-like attack of the nucleophile (e.g.,
H2O) at the bridgehead carbon. Our results, as presented above,
(16) (a) Abe, M.; Adam, W.; Nau, W. M. J. Am. Chem. Soc. 1998,
120, 11304–11310, 15. (b) Abe, M.; Ino, S.; Nojima, M. J. Am. Chem.
Soc. 2000, 122, 6508–6509.
(17) Abe, M.; Minamoto, T.; Ino, Y.; Kawakami, T.; Nojima, M.
Tetrahedron 2002, 58, 7043–7047.
(20) de Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 809–886,
and references cited therein. (b) Schleyer, P. v. R.; van Dine, G. W. J. Am.
Chem. Soc. 1966, 88, 2321–2322.
(18) (a) Yue, L.; Zhang, C.; Zhang, G. Lipids 2006, 41, 301–303. (b)
Hasegwa, H.; Akira, K.; Shinohara, Y.; Kasuya, Y.; Hashimoto, T. Biol.
Pharm. Bull. 2001, 24, 852–855. (c) Chu, L.; Davin, L. B.; Zajicek, J.;
Lewis, N. G.; Croteau, R. Phytochem. 1993, 34, 473–476.
(19) Adam, W.; Erden, I. J. Org. Chem. 1978, 43, 2737–2738.
(21) (a) Closson, W. D.; Kwiatkowski, G. T. Tetrahedron 1965, 21,
2779–2789. (b) Hanack, M.; Schneider, H.-J. Ann. 1965, 686, 8–18. (c)
Wiberg, K. B.; Hiatt, J. E.; Hseih, K. J. Am. Chem. Soc. 1970, 92, 544–
553.
3988
Org. Lett., Vol. 11, No. 17, 2009

Authentic samples of 28a and 28b were independently
synthesized by thiourea reduction of the respective unsatur-
ated endoperoxides 3 and 27, followed by diazene reduction
of the resulting unsaturated cis-diols in methanol (diazene
generated in situ from potassium azodicarboxylate with
AcOH in MeOH at 0 °C).
Scheme 8. Ph3P Reduction of 2,3-Dioxabicyclo[2.2.1]heptane-
and [2.2.2]octane and Independent Syntheses of the cis-Diols
In conclusion, we have shown that PPh3 reductions of
saturated endoperoxides such as 6 and 21 containing vinyl
or cyclopropyl groups R to the peroxo carbon facilitate direct
deoxygenation and carbocation formation. The initial biphilic
insertion of PPh3 into the peroxo bridge had elegantly been
demonstrated by Clennan and Heah.8 However, it is quite
likely that the deoxygenation step in the case of 28a or 28b
proceeds by heterolytic O-P cleavage of the cyclic phos-
phorane intermediate of the type 4 followed by attack of
water at the phosphonium ion before 31 collapses to Ph3PdO
and the cis-diol (Scheme 9). With a vinyl or cyclopropyl
group present at the carbon adjacent to the bridgehead
position (as in 12 and 24), facile Ph3PdO loss from
intermediate 30 occurs leading to an allyl or cyclopropyl-
carbinyl cation that undergoes SN1 substitution either directly
or after allyl shift (both cis and trans hydroxyacetates are
formed in each case), or cyclopropylcarbinyl-cyclobutyl
rearrangement, respectively.
do not support the SN2 mechanism, though it is clear that
carbocation-stabilizing groups at the R-position would dramati-
cally influence the mechanistic pathway in the deoxygenation
step. We therefore subjected the saturated endoperoxide derived
from cyclopentadiene as well as 1,3-cyclohexadiene to PPh3
reduction in the presence of water.
In our hands, the sole products formed from both reactions
were exclusively the cis-diols 28a and 28b (in 92 and 79%
yields, respectively, from the corresponding dienes) with no
traces of the trans isomers. These results confirm Samuels-
son’s earlier report on the isolation of the cis-diol 2 from
prostaglandin endoperoxide 1 with PPh3 and render the SN2
pathway less likely. We propose the mechanism shown in
Scheme 9 for PPh3 reduction of endoperoxides of the type 3
Acknowledgment. This paper is dedicated to Professor
Lawrence T. Scott on the occasion of his 65th birthday. This
work was supported by funds from the National Institutes
of Health, MBRS-SCORE Program-NIGMS (Grant No.
GM52588). We thank Professor Edward L. Clennan, Uni-
versity of Wyoming, for valuable discussions and Mr. Wee
Tam, SFSU, for recording the NMR spectra.
Scheme 9. Ph3 Reduction of 3 in the Presence of H2O
Supporting Information Available: Experimental pro-
cedures and spectral characterization data as well as 1H and
13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
and 27 lacking carbocation- stabilizing groups adjacent to
the peroxo carbons in the presence of H2O.
OL901652U
Org. Lett., Vol. 11, No. 17, 2009
3989