Remarkable Change of the Diastereoselection in the Dye-Sensitized Ene Hydroperoxidation of Chiral Alkenes by Zeolite Confinement

Article abstract of DOI:10.1021/ol0352660

(Equation presented) The ene reaction of singlet oxygen with chiral trisubstituted alkenes bearing an alkyl and a phenyl group at the stereogenic center is erythro diastereoselective in solution and threo diastereoselective if carried out within zeolite Na-Y. The change of the diastereoselection trend by zeolite confinement is attributed to a synergism of steric effects and cation-π interactions.

Full text of DOI:10.1021/ol0352660

ORGANIC
LETTERS
2003
Vol. 5, No. 19
3471-3474
Remarkable Change of the
Diastereoselection in the Dye-Sensitized
Ene Hydroperoxidation of Chiral
Alkenes by Zeolite Confinement
Manolis Stratakis,* Dimitris Kalaitzakis, Dimitris Stavroulakis,
Giannis Kosmas, and Constantinos Tsangarakis
Department of Chemistry, UniVersity of Crete, 71409 Iraklion, Greece
stratakis@chemistry.uoc.gr
Received July 9, 2003
ABSTRACT
The ene reaction of singlet oxygen with chiral trisubstituted alkenes bearing an alkyl and a phenyl group at the stereogenic center is erythro
diastereoselective in solution and threo diastereoselective if carried out within zeolite Na−Y. The change of the diastereoselection trend by
zeolite confinement is attributed to a synergism of steric effects and cation−π interactions.
Dye-exchanged zeolite Na-Y is a unique medium for
carrying out large-scale singlet oxygen (1O2) ene reactions,1
with significant enhancement of product regioselectivity2 and
chemoselectivity.3 The diastereoselectivity for the intrazeolite
photooxygenation of chiral alkenes has received little atten-
tion so far. We have reported that 2-methyl-5-phenyl-2-
hexene,4 a chiral alkene that bears a stereogenic center at
the â-position with respect to the double bond, gives
enhanced regioselectivity and diastereoselectivity, for the
secondary allylic hydroperoxides, by zeolite confinement.
In addition, intrazeolite photooxygenation of (R)-(-)-R-
phellandrene5 affords enhanced regioselectivity and diaste-
reoselectivity among the ene products, with predominant
formation of (1S,5R)-5-(1-methylethyl)-2-methylidene-3-
cyclohexen-1-yl hydroperoxide, a precursor of the naturally
occurring trans-yabunikkeol.
The reaction of 1O2 with chiral alkenes, bearing a
sterogenic center at the R-position with respect to the double
bond, has been extensively studied in solution.6 For the
majority of the chiral alkenes, the reaction is erythro
diastereoselective. This trend was attributed to steric and
electronic repulsions between the incoming oxygen and the
substituents on the stereogenic carbon atom and to a
preferable conformational arrangement to minimize the 1,3-
allylic strain as well. Only the photooxygenation of chiral
allylic alcohols and amines6 is threo diastereoselective due
to an oxygen-hydroxy/amine steering effect.
In this paper, we present our results on the regioselectivity
and diastereoselectivity in the photooxygenation of chiral
alkenes 1-3, in solution and by confinement within zeolite
Na-Y. Alkenes 1-3 possess a phenyl group and an alkyl
group that may vary in size on the stereogenic carbon atom
(1) Pace, A.; Clennan, E. L. J. Am. Chem. Soc. 2002, 124, 11236-11237.
(2) (a) Ramamurthy, V.; Lakshminarasimhan, P.; Grey, C. P.; Johnston,
L. J. J. Chem. Soc., Chem. Commun. 1998, 2411-2418. (b) Stratakis, M.;
Nencka, R.; Rabalakos, C.; Adam, W.; Krebs, O. J. Org. Chem. 2002, 67,
8758-8763. (c) Clennan, E. L.; Sram, J. P. Tetrahedron 2000, 56, 6945-
6950.
(3) Stratakis, M.; Rabalakos, C.; Mpourmpakis, G.; Froudakis, G. E. J.
Org. Chem. 2003, 68, 2839-43.
(4) Stratakis, M.; Kosmas, G. Tetrahedron Lett. 2001, 42, 6007-6009.
(5) Stratakis, M.; Sofikiti, N. J. Chem. Res., Synop. 2002, 374-375.
(6) (a) Adam, W.; Bru¨nker, H.-G.; Kumar, A. S.; Peters, E.-M.; Peters,
K.; Schneider, U.; von Schnering, H. G. J. Am. Chem. Soc. 1996, 118,
1899-1905. (b) Prein, M.; Adam, W. Angew. Chem., Int. Ed. Engl. 1996,
35, 519-538.
10.1021/ol0352660 CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/22/2003

(methyl, 1; ethyl, 2; and cyclohexyl, 3). The reaction of 1O2
with 1-37 in dichloromethane (methylene blue as a sensi-
tizer) is regioselective with preferential formation of the
secondary allylic hydroperoxides. Among the secondary
hydroperoxides, the erythro isomer prevails (Scheme 1).
considering the approach of singlet oxygen to the double
bond as shown in transition state TS1 of Scheme 2.9 The
Scheme 2. Possible Transition States for the
Photooxygenation of Alkenes 1-3 in Solution
Scheme 1. Photooxygenation of Chiral Alkenes 1-3 in
Solution
phenyl group is placed to the opposite plane of the double
bond with respect to the attacking oxygen, due to unfavorable
oxygen-arene electronic repulsions. In addition, for TS1, a
minimum 1,3-allylic strain between the tertiary allylic
hydrogen and the twix allylic methyl group is in operation.
For this conformation, singlet oxygen interacts to the tertiary
allylic hydrogen, whose abstraction can lead to the formation
of the (Z)-allylic hydroperoxides 1a-3a. Transition state TS1
can also nicely explain the high degree of erythro diaste-
reoselection in the photooxygenation of alkene 3 (erythro/
threo ) 82/18), where the substituents on the stereogenic
carbon atom (phenyl and cyclohexyl) have similar steric
demands. It is worth mentioning here that for the case of
2,4,5,5-tetramethyl-2-hexene,6a where the diastereoselection
in the 1O2 ene reaction arises from the size difference between
a methyl and a tert-butyl group, the selectivity is lower
(erythro/threo ) 71/29). Transition states TS2 and TS3
(Scheme 2) which lead to the threo diastereomer are expected
to be less stable compared to TS1, due to substantial 1,3-
allylic strain between the R group and the twix allylic methyl
group for TS2 and to unfavorable oxygen-phenyl electronic
repulsion for the case of TS3.
The (Z)-stereochemistry for the minor tertiary allylic
hydroperoxides 1a-3a was established by NOE experiments.
Upon irradiation of the olefinic hydrogen absorption, the
allylic hydrogen(s) of the R chain exhibited signal enhance-
ment, indicative of a cis arrangement between the olefinic
H and the R group. The predominant formation of the erythro
isomers among the secondary allylic hydroperoxides (b >
c) was confirmed as follows. The hydroperoxides were
reduced in situ to the corresponding allylic alcohols by PPh3,
1
and their H NMR spectra were compared to the diastere-
omeric addition products from the reaction of 2-propenyl-
magnesium bromide with the chiral R-alkyl-substituted
phenylacetaldehydes. It is well-known8 that the addition of
organolithium or Grignard reagents to R-alkyl-substituted
phenylacetaldehydes is erythro diastereoselective. For ex-
ample, in our case, reaction of 2-propenylmagnesium bro-
mide with 2-phenylpropionaldehyde gave 2-methyl-4-phenyl-
pent-1-en-3-ol in a ratio of erythro/threo ) 4.6/1, while in
the addition of the same Grignard reagent to R-cyclohexyl
phenylacetaldehyde, 2-methyl-4-cyclohexyl-4-phenyl-but-1-
en-3-ol was formed in a ratio of erythro/threo ) 1.4/1.
The preferential formation of the erythro isomer in the
photooxygenation of 1-3 in solution can be explained
The thionin-sensitized photooxygenation of 1-3 adsorbed
within zeolite Na-Y is highly regioselective, since only the
secondary allylic hydroperoxides are formed, however, with
an inverse diastereoselection trend (Scheme 3). The threo
(9) For the singlet oxygen ene reactions, apart from the classical stepwise
mechanism involving formation of a perepoxide intermediate,13 Singleton
and co-workers recently proposed a two-step no-intermediate mechanism
(Singleton, D. A.; Hang, C.; Szymanski, M. J.; Meyer, M. P.; Leach, A.
G.; Kuwata, K. T.; Chen, J. S.; Greer, A.; Foote, C. S.; Houk, K. N. J. Am.
Chem. Soc. 2003, 125, 1319-1328). For both mechanisms, however, a rate-
limiting transition state such as TS1-TS3 is in operation.
(7) Photooxygenation of 1 in solution gave results similar to those
reported in the literature: (a) Adam, W.; Nestler, B. Liebigs Ann. Chem.
1990, 1051-1053. (b) Kropf, H.; Reichwaldt, R. J. Chem. Res., Synop.
1987, 412-413.
(8) Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367-1371 and
references therein.
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Org. Lett., Vol. 5, No. 19, 2003

Scheme 3. Diastereoselectivity for the Intrazeolite
Photooxygenation of 1-3
Scheme 4. Possible Phenyl-Na+ Coordination within Na-Y
1
Directing O2 Attack
diastereomer is now predominant, and the ratio of threo/
erythro increases by increasing the size of the R group. For
example, while the photooxygenation of 3 in solution gives
a ratio of erythro/threo ) 82/18, by zeolite confinement, the
ratio of erythro/threo ) 09/91. The intrazeolite photooxy-
genation experiments were accomplished as described in ref
2b. Control experiments revealed that the phenyl-substituted
alkenes were completely adsorbed within Na-Y after 2-3
min of mixing, in accordance with the observation of
Ramamurthy and co-workers10 for the higher adsorption
ability of arylalkenes relative to simple alkenes. The ratio
of the ene products was very reproducible (the error of three
measurements for each substrate was (3%), and the mass
balance for all reactions was always higher than 80%. To
ensure the accuracy of our intrazeolite results, the mixtures
of the allylic hydroperoxides obtained from the photooxy-
genation of each alkene 1-3 in solution were adsorbed
within the thionin/Na-Y and then irradiated under a constant
flow of O2 gas for 3 min. After extraction with moistened
tetrahydrofuran, it was found that the ratio of the hydro-
peroxides was almost the same (before and after the zeolite
treatment).
either from the more (twix CH3) or the less (twin CH3)
substituted side of the double bond, we prepared stereose-
lectively the chiral alkenes 1d3-3d3 labeled with deuterium
at the twin position. The synthesis of the labeled alkenes
was accomplished in >95% geometrical purity for the (E)-
isomer following a procedure reported2b earlier by our group
(see Supporting Information). The ratio of H-threo/H-erythro
allylic hydroperoxides (Scheme 5) formed by abstraction of
Scheme 5. Products from the Photooxygenation of 1d3-3d3
within Zeolite Na-Y
The remarkable change of the diastereoselection on going
from the solution to the confined environment of the zeolite
can be explained by considering the electrostatic interaction
of the phenyl ring to the Na+ present within the supercages.11
Most probably, due to the strong cation-phenyl interaction,12
the alkene adopts the conformation shown in Scheme 4. In
that conformation, preferential attack of singlet oxygen from
the less hindered top phase leads to the formation of the threo
allylic hydroperoxide as the major adduct. As the size of
the R group increases, the energy difference between the
threo- and erythro-forming transition states is expected to
increase, in favor of the threo isomer. A possible singlet
oxygen-cation coordination leading preferably to the threo
allylic hydroperoxide, as shown in TS4, which has a
minimum 1,3-allylic strain, cannot be excluded.
To determine the ratio of the threo/erythro diastereo-
selection induced by abstraction of an allylic hydrogen atom
an allylic hydrogen atom from the twix methyl group can be
assessed by integration the terminal olefinic hydrogen atoms
in the region of 5 ppm. On the other hand, the D-threo/D-
erythro ratio formed by abstraction of an allylic deuterium
atom from the twin methyl group (CD3 in our case) can be
assessed by integration of the diastereotopic allylic methyls
(10) Kaanumalle, L. S.; Shailaja, J.; Robbins, R. J.; Ramamurthy, V. J.
Photochem. Photobiol., A: Chem. 2002, 153, 55-65.
(11) For a recent review on the role of cation-π interactions in
intrazeolite reactions, see: Sivaguru, J.; Natarajan, A.; Kaanumalle, L. S.;
Shailaja, J.; Uppili, S.; Joy, A.; Ramamurthy, V. Acc. Chem. Res. 2003,
36, 509-521.
(12) Interaction of Na+ to benzene in the gas phase is exothermic by
∼25 kcal/mol. Feller, D. Chem. Phys. Lett. 2000, 322, 543-548.
Org. Lett., Vol. 5, No. 19, 2003
3473

or extrapolated, taking into account the total ratio of threo/
erythro hydroperoxides and the ratio H-threo/H-erythro as
well.
Na-Y. A similar change in the π facial photoreduction of
steroids14 has been observed on going from a homogeneous
environment to the zeolite Na-Y confinement and has been
postulated to be the result of Na+-π interactions. Intrazeolite
photooxygenation studies of other chiral alkenes are in
progress to explore novel and selective oxyfunctionalization
pathways.
While photooxygenation of 1d3-3d3 in solution gave the
typical twin/twix ratio of approximately 5/95 (“cis effect”
selectivity13), by zeolite confinement, the twin/twix regiose-
lectivity changes to approximately 60/40. The substantial
increase in the reactivity of the twin methyl group is in
accordance with earlier observations in the intrazeolite
photooxygenation of trisubstituted alkenes.2b,c Also, the threo/
erythro ratio either from H or from D abstraction is very
similar within experimental error. This result indicates that
Acknowledgment. This work was supported by the Greek
Ministry of Education (B’ ΕΠΕΑΕΚ Graduate Program).
We thank Dr. O. Krebs for taking the HRMS spectra.
1
Supporting Information Available: Full experimental
details for the synthesis of 1d3-3d3 and 1H NMR spectra of
1d3-3d3 and their photooxygenation reactions in solution or
within Na-Y. This material is available free of charge via
the Internet at http://pubs.acs.org.
within Na-Y, O2 forms preferentially a threo-perepoxide
intermediate oriented either toward the more or the less
substituted side of the double bond.
In conclusion, we have shown that the erythro diastereo-
selectivity trend in the photooxygenation of chiral alkenes
bearing a phenyl and an alkyl group at the stereogenic center
can be reversed to threo by confinement within zeolite
OL0352660
(14) Rao, V. J.; Uppili, S. R.; Corbin, D. R.; Schwarz, S.; Lustig, S. R.;
Ramamurthy, V. J. Am. Chem. Soc. 1998, 120, 2480-2481.
(13) Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 1595-1615.
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