Oxidation of aryl-substituted allylic alcohols by an optically active Fe(III)(porph*) catalyst: Enantioselectivity, diastereoselectivity and chemoselectivity in the epoxide versus enone formation

Article abstract of DOI:10.1016/S0957-4166(01)00483-9

A set of aryl-substituted allylic alcohols (±)-2 was oxidized using the chiral Fe(porph*) complex 1 as the catalyst and iodosyl benzene (PhIO) as the oxygen source. Whereas one enantiomer of the allylic alcohol 2 is preferentially epoxidized to give the threo- or cis-epoxy alcohol 3 (up to 43% e.e.) as the main product (d.r. up to >95:5), the other enantiomer of 2 is enriched (up to 31% e.e.). Some non-stereoselective allylic oxidation to give the enone 4 also takes place. The observed diastereo- and enantioselectivities in the epoxidation reactions are rationalized in terms of a synergistic interplay between the hydroxy-directing effect and the steric interactions of the catalyst 1 and the substrate 2.

Full text of DOI:10.1016/S0957-4166(01)00483-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2677–2681
Oxidation of aryl-substituted allylic alcohols by an optically
active Fe(III)(porph*) catalyst: enantioselectivity,
diastereoselectivity and chemoselectivity in the epoxide versus
enone formation
Waldemar Adam, Serguei Prikhodovski, Konrad J. Roschmann* and Chantu R. Saha-Mo¨ller
Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany
Received 10 September 2001; accepted 26 October 2001
Abstract—A set of aryl-substituted allylic alcohols ( )-2 was oxidized using the chiral Fe(porph*) complex 1 as the catalyst and
iodosyl benzene (PhIO) as the oxygen source. Whereas one enantiomer of the allylic alcohol 2 is preferentially epoxidized to give
the threo- or cis-epoxy alcohol 3 (up to 43% e.e.) as the main product (d.r. up to >95:5), the other enantiomer of 2 is enriched
(up to 31% e.e.). Some non-stereoselective allylic oxidation to give the enone 4 also takes place. The observed diastereo- and
enantioselectivities in the epoxidation reactions are rationalized in terms of a synergistic interplay between the hydroxy-directing
effect and the steric interactions of the catalyst 1 and the substrate 2. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
efficiency of this kinetic resolution depends profoundly
on the structure of the allylic alcohol employed, the e.e.
values of the enriched alcohols range from 10 to >96%.2
Optically active epoxy alcohols are valuable building
blocks for the asymmetric synthesis of biologically
active molecules; for example, the b-blockers
Propanolol® and Falintolol® have been prepared from
(R)-propenol oxide.1 For such an enantioselective
transformation, the Sharpless–Katsuki epoxidation rep-
resents one of the most efficient routes to optically
active epoxy alcohols from primary allylic alcohols.2
When a racemic allylic alcohol is used as substrate,
kinetic resolution is a necessary consequence, in which
one enantiomer is epoxidized preferably to the corre-
sponding erythro epoxy alcohol, while the other enan-
tiomer of the allylic alcohol is enriched (Scheme 1). The
Recently we have reported that secondary allylic alco-
hols are epoxidized with high threo diastereoselectivity
by an achiral Fe(III)(porph) complex with iodosyl ben-
zene as oxygen source;3 with an optically active
Mn(III)-(salen*) catalyst, kinetic resolution takes
place.4 This raises the question as to whether these
racemic allylic alcohols may also be enantioselectively
epoxidized with a chiral Fe(III) (porph*) catalyst 1
(Fig. 1) through kinetic resolution. The catalyst 1 was
recently described by Collman et al.5 as a highly selec-
tive (e.e. up to 90%) and readily prepared
Fe(III)(porph*) complex for the epoxidation of unfunc-
tionalized olefins.
Although the enantioselective epoxidation by optically
active Fe(III)(porph*) catalysts has been extensively
investigated during the last decades,6 their use in the
enantioselective epoxidation of functionalized alkenes
such as allylic alcohols appears not to have been
attempted to date. Herein, we report the asymmetric
epoxidation of acyclic and cyclic racemic allylic alco-
hols 2 by the Fe(III)(porph*) catalyst 1 under condi-
tions of <50% conversion (Scheme 2). Since tri-
substituted olefins had not been investigated by Collman
et al.5 for the catalyst 1, the diastereomeric pair of
trisubstituted racemic allylic alcohols 2e and 2f was also
Scheme 1. The kinetic resolution of a chiral allylic alcohol in
the Sharpless–Katsuki epoxidation.
* Corresponding author. Fax: +49-931/888-4756; e-mail: adam@
chemie.uni-wuerzburg.de
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00483-9

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W. Adam et al. / Tetrahedron: Asymmetry 12 (2001) 2677–2681
Figure 1. Structure of the chiral Fe(III)(porph*) catalyst 1.
examined. The diastereoselectivity and particularly the
enantioselectivity, as well as the chemoselectivity
between epoxide 3 and enone 4 formation were of
interest in this study.
2. Results
Scheme 2. Enantioselective epoxidation of the racemic allylic
alcohols 2 with catalyst 1.
The chiral Fe(porph*)Cl catalyst 1 was prepared as
already described by Collman et al.5,7 The allylic alco-
Table 1. Fe-catalyzed oxidation of allylic alcohols 2

W. Adam et al. / Tetrahedron: Asymmetry 12 (2001) 2677–2681
2679
hols ( )-2a–f (for structures, see Table 1) were synthe-
sized according to literature methods.8–13 Racemic sam-
ples of diastereomers of the epoxides 3a, 3b and 3d–f
were prepared by dimethyldioxirane (DMD) epoxida-
tion of the corresponding allylic alcohols 2, while epoxy
alcohol 3c (cis:trans=67:33) was obtained by oxidation
of 2c with PhIO, catalyzed by an achiral Mn(III)(salen)
complex. The iron-catalyzed asymmetric epoxidation of
the allylic alcohols 2 was carried out with 5 mol% of
catalyst 1 and 0.8 equiv of iodosyl benzene (PhIO) as
oxygen source. The results are summarized in Table 1;
for comparison, the selectivity factors krel are also
given.14
for the (S) and 88% for the (R)-enantiomer] were
separately treated with catalyst 1 and iodosyl benzene
to assess the effect of allylic oxidation on the enantiose-
lectivity. The chemoselectivities are quite similar [the
epoxide 3c/enone 4c ratios are 42:58 for (S)-2c, 62:38
for (R)-2c and 62:38 for ( )-2c], which implies that
enone formation plays only a minor role in influencing
the enantioselectivity of this asymmetric epoxidation.
Furthermore, since both enantiomers of 2c are oxidized
to the enone 4c with about equally efficiency, CH
oxidation does not significantly contribute to the
kinetic resolution of the allylic alcohol 2c. Moreover,
the conversion of the allylic alcohol 2c is moderate
(34%) such that only low e.e. values are expected. The
combined effect of these factors may be responsible for
the lack of kinetic resolution in the reaction of the
allylic alcohol 2c.
Since it is well known15 that Fe(porph)-catalyzed epoxi-
dations work best for cis-disubstituted olefins, the sub-
strates
2a–d
were
employed
first.
The
phenyl-substituted acyclic allylic alcohol 2a (entry 1)
was epoxidized with excellent chemo- and diastereose-
lectivity (95:5) to afford the corresponding threo-
For the 1,1,2-trimethyl-1,2-dihydronaphthalen-2-ol 2d,
CH oxidation is not possible, and for this reason this
tertiary alcohol was chosen to assess the enantioselec-
tivity of the epoxidation (entry 4) without complica-
tions by competitive allylic oxidation. Whereas
excellent diastereoselectivity (>95:5) was observed, the
major epoxide cis-3d was formed as an essentially
racemic mixture (2% e.e.), but for the minor epoxide
trans-3d an e.e. of 48% was obtained. In view of these
facts, essentially no enrichment (3% e.e.) of the remain-
ing allylic alcohol 2d was found.
configured
epoxy
alcohol
3a.
Unlike
the
manganese-catalyzed epoxidation,4 no cis/trans isomer-
ization was observed. At a conversion of 33%, the
unreacted allylic alcohol 2a was obtained in 11% e.e.,
with the (R)-enantiomer as the major isomer, while the
(S) enantiomer was preferentially epoxidized to the
(2S,3R,4S)-epoxide 3a in 23% e.e.
When the indenol 2b (entry 2) was subjected to the
Fe(porph*)Cl/PhIO oxidation, no allylic CH oxidation
to the enone 4b took place (epoxide/enone >95:5) and
the cis-configured epoxide 3b was observed as the main
product (dr 90:10). At 48% conversion, the kinetic
resolution of indenol 2b gave the (1R)-cis-epoxide in
43% e.e. and the (1S)-trans-epoxide in 48% e.e., while
(R)-indenol (R)-2b was enriched to the extent of 31%
e.e.
To determine the steric effects on the various selectivi-
ties, the diastereomerically trisubstituted 4-phenyl-3-
penten-2-ols 2e and 2f were examined. The
(E)-diastereomer 2e (entry 5) was epoxidized with good
chemoselectivity (83:17) and diastereoselectivity (87:13)
to afford the corresponding threo-configured epoxy
alcohol 3e. As in the case of (Z)-4-phenyl-3-buten-2-ol
2a, no cis/trans isomerization was detected. The enan-
tioselectivity was low [3% e.e. for (2R)-3e] and, there-
fore, allylic alcohol 2e remained almost racemic (5%
e.e.). When the diastereomeric (Z)-4-phenyl-3-penten-2-
ol 2f was submitted to the iron-catalyzed oxidation
(entry 6), analogous to its (E)-diastereomer 2e (entry 5),
the threo-epoxide 3f was formed as the major
diastereomer. Although better chemoselectivity (93:7)
and diastereoselectivity (>95:5) were achieved for the
diastereomer 2f compared to 2e, essentially racemic
epoxy alcohol 3f (6% e.e.) and allylic alcohol 2f (1%
e.e.) were obtained. Due to the low e.e. values found
for these trisubstituted allylic alcohols 2e and 2f, their
enantioselectivity shall not be discussed in terms of a
mechanistic rationale.
In the oxidation of the cyclic allylic alcohol 1,1-
dimethyl-1,2-dihydronaphthalen-2-ol 2c, only moderate
chemoselectivity (62:38) and diastereoselectivity (73:27)
was obtained (entry 3). While the major diastereomer
cis-3c showed at 34% conversion an e.e. of 40% in
favor of the (2S)-enantiomer, the enantiomeric excess
of the other diastereomer (2R)-3c was rather low (9%
e.e.) and of the remaining allylic alcohol 2c none at all
(0% e.e.).
To account for the lack of resolution of the allylic
alcohol 2c, possibly the (R)-enantiomer of 2c is prefer-
entially epoxidized to the (2S)-3c epoxy alcohol,
whereas the enantiomeric (S)-2c is more readily con-
verted to the enone 4c by allylic oxidation. If these two
reaction modes were to occur to the same extent, the
remaining alcohol 2c would not be enantiomerically
enriched. Indeed, a related case of such competitive
oxidations has already been demonstrated in the man-
ganese-catalyzed epoxidation of the allylic alcohol 2c.4
While (S)-2c was converted preferentially to the enone
4c by the chiral (S,S)-Mn(III)(salen*) catalyst, the
remaining (R)-2c enantiomer was epoxidized. To test
such a possibility for the present case, the two enan-
tiomers of the allylic alcohol 2c [the e.e. values are 91%
3. Discussion
The diastereo- and enantioselectivity of this iron-cata-
lyzed epoxidation may be rationalized in terms of the
synergistic interplay between the hydroxy-directing
effect3,16 and the steric interactions between the chiral
Fe(porph*)oxo complex and the allylic alcohol 2.5 In
Scheme 3 this is illustrated for the model substrate
indenol 2b, for which the chemoselectivity is excellent
(exclusive epoxidation), the diastereoselectivity high
(d.r. 90:10), and the enantioselectivity is the best [the

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W. Adam et al. / Tetrahedron: Asymmetry 12 (2001) 2677–2681
Scheme 3. Mechanistic rationale for the kinetic resolution in the catalytic epoxidation of indenol ( )-2c by the chiral
Fe(porph*)oxo complex.
(S)-2b enantiomer is epoxidized to the cis-configured
(1R)-epoxide 3b (43% e.e.), whereas the (R)-configured
allylic alcohol 2b is enantiomerically enriched up to
31% e.e. (Table 1, entry 2)] for all the allylic alcohols 2
examined herein. Hydrogen bonding between the
hydroxyl functionality of the allylic alcohol 2b and the
Fe(porph*)oxo oxidant favors attack onto the p face of
the double bond syn to the hydroxy group, such that
the oxygen transfer leads to the cis-epoxide 3b as the
main diastereomer. Thus, the observed cis diastereose-
lectivity (Table 1, entry 2) underlies hydroxy-directive
control.16
more demanding L part of the substrate avoids interac-
tion with the upper, inwardly leaning lobe of the
binaphthyl bridge, analogous to the indenol 2b (Scheme
4), such that the type A structure is preferred over type
B. For the allylic alcohols 2a and 2b, the aryl ring
constitutes the L group and, consequently, the epoxides
(2S,3R,4S)-3a and (1R,2R,3S)-3b are formed as the
main enantiomers. In contrast, for the allylic alcohol
2c, the gem-dimethyl substituent represents the L group
and, thus, the (2S,3S,4R)-3c enantiomer is obtained
preferentially on epoxidation.
The set of allylic alcohols 2a–f, oxidized in this work by
the chiral Fe(porph*) catalyst 1, had already been
examined in the Mn(salen*)-catalyzed enantioselective
epoxidation.4 Consequently, it is pertinent to compare
the efficacy of these two catalytic oxidation systems in
terms of chemo-, diastereo- and enantioselectivity. The
To rationalize the observed enantioselectivity, the steric
interactions between catalyst 1 and the substrate 2b
need to be examined in more detail. As already pro-
posed by Collman et al.,5 the binaphthyl bridge forms a
chiral pocket around the Fe(porph*)oxo functionality.
Consequently, the two diastereomeric catalyst-substrate
complexes A and B shall be considered for the reaction
of the racemic indenol ( )-2b with the oxidant. When
the hydroxy-directed (S)-2b enantiomer approaches the
Fe(porph*)oxo functionality as shown in complex A,
the sterically more demanding aryl ring of the substrate
fits into the available space away from the upper
inwardly leaning binaphthyl lobe. In contrast, complex
B is less favored since the aryl ring of the (R)-2b
enantiomer interferes with the upper inwardly leaning
binaphthyl lobe. Thus, the (S)-2c alcohol enantiomer is
epoxidized preferentially to the (1R)-cis-3b epoxy alco-
hol, such that the (R)-2b enantiomer is enriched. Evi-
dently, the steric interactions between the substrate and
catalyst are relatively weak and, hence, the enantiose-
lectivity is only moderate, i.e. the e.e. values fall
between 40 and 50% for the allylic alcohol 2b (Table 1,
entry 2), the substrate with the best asymmetric control.
The mechanistic rationale in Scheme 3 also applies to
the substrates 2a and 2c. While the diastereoselectivity
in the epoxidation of allylic alcohols 2 implies hydroxy-
directivity control,16 the enantioselectivity is also
directed by the steric demand of the substituents on the
double bond of the substrate (Scheme 4). The sterically
Scheme 4. Substrate-directed enantioselectivity in the asym-
metric epoxidation of allylic alcohols 2a, 2c and 2d by the
chiral Fe(porph*)oxo complex (L=large, s=small).

W. Adam et al. / Tetrahedron: Asymmetry 12 (2001) 2677–2681
2681
epoxide 3/enone
4
ratios are similar for both
Analytical and spectral characterization data of the
alcohols 2, the epoxides 3 and the enones 4 can be
found in the Supporting Information of Ref. 4.
Fe(porph*) and Mn (salen*) complexes: Whereas the
allylic alcohols 2a (95:5 versus >95:5) and 2f (93:7
versus 91:9) display almost the same high chemoselec-
tivity in favor of epoxidation, more epoxide is produced
in the iron-catalyzed oxidation of the substrates 2b
(>95:5 versus 87:15) and 2c (62:38 versus 44:56); how-
ever, for the allylic alcohol 2e (83:17 versus >95:5),
epoxidation is favored by the Mn(salen*) complex. The
diastereoselectivities, which range from 73:27 to >95:5,
are about the same with both metals for all substrates
2a–f within experimental error; thus, for both metal-
oxo oxidants the hydroxy-directing effect operates with
equal efficiency. The main discrepancy between the
Fe(porph*) and Mn(salen*) catalysts concerns the
enantioselectivity: Whereas the iron complex 1 displays
only low selectivities with e.e. values from 2 to 43% (the
krel values range from 1.0 to 2.7), e.e. values up to 80%
(krel 12.9) may be obtained for the Mn(salen*) complex.
Acknowledgements
This work was financially supported by the Deutsche
Forschungsgemeinschaft (Sonderforschungsbereich 347
‘Selektive Reaktionen metallaktivierter Moleku¨le’) and
the Fonds der Chemischen Industrie, for which we are
grateful.
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A mixture of the Fe(porph*)Cl catalyst 1 (37.4 mg, 25.0
mmol, 5 mol%) and the appropriate allylic alcohol 2
(500 mmol) in CH2Cl2 (5 mL) was stirred for 2 min at rt
(ca. 20°C). PhIO (88.0 mg, 400 mmol) was then added
in small portions over 2 min and the resulting suspen-
sion was stirred for ca. 14 h until a clear purple solution
was obtained. After removal of the solvent (20°C, 400
mbar), the residue was transferred onto a short column
of silica gel (ca. 10 g) and eluted first with 100 mL of
petroleum ether to remove iodobenzene, afterwards
with 200 mL of a petroleum ether/diethyl ether mixture
(1:1) to recover the oxidation products. After removal
of the solvent (30°C, 10 mbar), the resulting colorless
1
oil was analyzed by H NMR spectroscopy and chiral
HPLC; the mass balance was determined by the weight
of the crude product and the products detected by
NMR spectroscopy. The quantitative data are summa-
rized in Table 1 (see main text).