Preparation of dendritic and non-dendritic styryl-substituted Salens for cross-linking suspension copolymerization with styrene and multiple use of the corresponding Mn and Cr complexes in enantioselective epoxidations and Hetero-Diels - Alder reactions

Article abstract of DOI:10.1002/1521-3765(20010702)7:13<2873::AID-CHEM2873>3.0.CO;2-C

Following work with TAD-DOLs and BINOLs, we have now prepared Salen derivatives (2, 3, 14, 15, 18, 19, 20, 21) carrying two to eight styryl groups for cross-linking copolymerization with styrene. The Salen cores are either derived from (R,R)-diphenyl ethylene diamine (3, 15, 19, 21) or from (R,R)-cyclohexane diamine (2, 14, 18, 20). The styryl groups are attached to the salicylic aldehyde moieties, using Suzuki (cf. 1) or Sonogashira cross-coupling (cf. 11), and/or phenolic etherification (cf. 5, 7) with dendritic styryl-substituted Frechet-type benzylic branch bromides. Subsequent condensation with the diamines provides the chiral Salens. Corresponding Salens lacking the peripheral vinyl groups (cf. 12, 13, 16, 17) were also prepared for comparison of catalytic activities in homogeneous solution with those in polystyrene. Cross-linking radical suspension copolymerization of styrene and the styryl Salens, following a procedure by Itsuno and Frechet, gave beads (ca. 400 μm diameter) which were loaded with Mn or Cr (ca. 0.2 mmol of complex per g of polymer), with more than 95 % of the Salen incorporated being actually accessible for complexation (by elemental analysis). The polymer-bound Mn and Cr complexes were used as catalysts for epoxidations of six phenyl-substituted olefins (m-CPBA/NMO; products 22 a-f), and for dihydropyranone formation from the Danishefsky diene and aldehydes (PhCHO, C₅H₁₁CHO, C₆H₁₁CHO, products 23a-c). There are several remarkable features of the novel immobilized Salens: i) The dendritic branches do not slow down the catalytic activity of the complexes in solution; ii) the reactions with Salen catalysts incorporated in polystyrene give products of essentially the same enantiopurity as those observed in homogeneous solution with the dendritically substituted or with the original Jacobsen-Katsuki complexes; iii) some Mn-loaded beads have been stored for a year, without loss of activity; iv) especially the biphenyl- and the acetylene-linked Salen polymers (p-2, -3, -20, -21, Figure 2, 3) give Mn complexes of excellent performance: after ten uses (without re-charging with Mn!) there is no loss of enantioselectivity or degree of conversion under the standard conditions. Wiley-VCH Verlag GmbH, 2001.

Full text of DOI:10.1002/1521-3765(20010702)7:13<2873::AID-CHEM2873>3.0.CO;2-C

FULL PAPER
Preparation of Dendritic and Non-Dendritic Styryl-Substituted Salens for
Cross-Linking Suspension Copolymerization with Styrene and Multiple Use of
the Corresponding Mn and Cr Complexes in Enantioselective Epoxidations
and Hetero-Diels ± Alder Reactions
Holger Sellner,[a] Jaana K. Karjalainen,[b] and Dieter Seebach*[a]
Dedicated to Professor K. Barry Sharpless on the occasion of his 60th birthday
Abstract: Following work with TAD-
DOLs and BINOLs, we have now pre-
pared Salen derivatives (2, 3, 14, 15, 18,
19, 20, 21) carrying two to eight styryl
groups for cross-linking copolymeriza-
tion with styrene. The Salen cores are
either derived from (R,R)-diphenyl eth-
ylene diamine (3, 15, 19, 21) or from
(R,R)-cyclohexane diamine (2, 14, 18,
20). The styryl groups are attached to
the salicylic aldehyde moieties, using
Suzuki (cf. 1) or Sonogashira cross-
coupling (cf. 11), and/or phenolic ether-
ification (cf. 5, 7) with dendritic styryl-
polystyrene. Cross-linking radical sus-
pension copolymerization of styrene and
the styryl Salens, following a procedure
C6H11CHO, products 23a ± c). There
are several remarkable features of the
novel immobilized Salens: i) The den-
dritic branches do not slow down the
catalytic activity of the complexes in
solution; ii) the reactions with Salen
catalysts incorporated in polystyrene
give products of essentially the same
enantiopurity as those observed in ho-
mogeneous solution with the dendriti-
cally substituted or with the original
Jacobsen ± Katsuki complexes; iii) some
Mn-loaded beads have been stored for a
year, without loss of activity; iv) espe-
cially the biphenyl- and the acetylene-
linked Salen polymers (p-2, -3, -20, -21,
Figure 2, 3) give Mn complexes of ex-
cellent performance: after ten uses
(without re-charging with Mn!) there is
no loss of enantioselectivity or degree of
conversion under the standard condi-
tions.
Â
by Itsuno and Frechet, gave beads (ca.
400 mm diameter) which were loaded
with Mn or Cr (ca. 0.2 mmol of complex
per g of polymer), with more than 95%
of the Salen incorporated being actually
accessible for complexation (by elemen-
tal analysis). The polymer-bound Mn
and Cr complexes were used as catalysts
for epoxidations of six phenyl-substitut-
ed olefins (m-CPBA/NMO; products
22a ± f), and for dihydropyranone for-
mation from the Danishefsky diene and
Â
substituted
Frechet-type
benzylic
branch bromides. Subsequent condensa-
tion with the diamines provides the
chiral Salens. Corresponding Salens
lacking the peripheral vinyl groups (cf.
12, 13, 16, 17) were also prepared for
comparison of catalytic activities in
homogeneous solution with those in
aldehydes
(PhCHO,
C5H11CHO,
Keywords: asymmetric catalysis
´
cycloadditions ´ dendritic cross-link-
ers ´ epoxidations ´ polymer-bound
Salen
progress in this area.[1±3] Simultaneously, the importance of
enantioselective synthesis has increased during the last
decades, due to development of a great variety of highly
effective catalysts for all kinds of enantioselective trans-
formations.[4±6] Unfortunately, such catalysts are often very
expensive and, in addition, have to be separated from the
reaction mixture after use so that their application for the
industrial production of chemicals is rather limited. In order
to overcome these drawbacks, it is favorable to bind such
catalysts to a polymer support which allows easy separation
from the reaction mixture and reuse in many consecutive
catalytic cycles.[7±14] In this way, even chemically sophisticated
and expensive catalytic systems might become attractive for
large-scale production. Also, chiral ligands or catalysts can be
Introduction
The preparation and application of polymer-supported re-
agents and catalysts is a rapidly growing field in modern
synthetic chemistry. Solid-phase methodology plays a crucial
role in combinatorial chemistry and led to a tremendous
[a] Prof. Dr. D. Seebach, Dr. H. Sellner
Laboratorium für Organische Chemie
der Eidgenössischen Technischen Hochschule Zürich
ETH Zentrum, Universitätstrasse 16, 8092 Zürich (Switzerland)
Fax : (‡41)1-632-1144
E-mail: seebach@org.chem.ethz.ch
[b] Dr. J. K. Karjalainen
Postdoctoral fellow at ETH Zürich (1998 ± 1999)
Chem. Eur. J. 2001, 7, No. 13
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D. Seebach et al.
FULL PAPER
bound to a soluble support. In this case, the catalytic process
can be performed under homogeneous conditions with the
advantage that the desired micro-environment around the
catalytic sites is generated, due to the very ªflexible natureº of
the supported catalyst; the major disadvantage is the recovery
of the soluble catalyst from the reaction mixture. In contrast,
immobilization of catalysts on heterogeneous supports allows
easy separation from the reaction mixture by simple filtration
and thus facilitates the handling of such catalysts tremen-
dously. Unfortunately, heterogeneous catalysts prepared in
this way are often less active than their homogeneous
counterparts due to the fact that diffusion of substrates and
products to and from the catalytic centers on the support is
hindered. It should, however, also be pointed out that
sometimes aggregation of several complexes leads to the
actual catalytically most active species (in solution, cf. non-
linear effects[15]), and such aggregation is of course prevented
on a very rigid polymer support, and especially with low
degree of loading.
Several years ago, we have immobilized the TADDOL
(TADDOL ˆ a,a,a',a'-tetraaryl-1,3-dioxolane-4,5-dimethanol)
on polystyrene, a versatile ligand for many enantioselective
transformations,[16, 17] developed in our laboratory.[18] For prac-
tical reasons, suspension copolymerization of suitable TAD-
DOL precursors with styrene and divinyl benzene (DVB) to
give polymer beads, which are easy to handle, was our preferred
way of immobilization at the time.[19] In 1997 we began to use
dendritically modified TADDOLs with styryl groups at the
periphery as cross-linkers in polystyrene, without the use of an
additional cross-linker, as for example DVB.[20] This was in
fact the first application of dendrimers as polymer cross-
linkers. Having shown that TADDOLs, immobilized in this
way, have an excellent catalytic activity,[21] we turned to the
immobilization of 1,1'-bi-2-naphthol (BINOL) in the same way,
confirming the high potential of this new way of immobilization
in various Lewis acid mediated test reactions.[22] As already
stated, we consider suspension copolymerization as a very useful
way of binding a chiral ligand to a solid polymer support.
Grafting of the desired ligand onto a commercially available
polymer, as for example a Merrifield resin, or copolymeriza-
tion of a mono-styryl substituted ligand with styrene/DVB
requires a smaller synthetic effort, but immobilization ªin our
wayº (i.e., copolymerization of a chiral cross-linking ligand
with styrene) offers certain advantages: The polymers gen-
erated this way contain cavities around the catalytic sites
within the polymer matrix that are likely to be chiral. Similar
to the method of molecular imprinting in highly cross-linked
polymer resins (developed by Wulff and his group[23, 24]) chiral
cavities could leadÐin an enzyme-like wayÐto an increase in
catalytic performance of a polymer-bound catalyst in our case.
In fact, a polymer-bound TADDOL, prepared by copolymer-
ization of a cross-linking TADDOL dendrimer with styrene,
showed a rate increase with respect to the homogeneous
reaction in the Ti-TADDOLate mediated addition of Et2Zn
to PhCHO.[21] This was not the case with polymers prepared
by copolymerization of a mono-styryl TADDOL with styrene/
DVB. Furthermore, the C2-symmetrical cross-linkers might
serve as chiral templates for the polymerization of styrene to
generate chiral polystyrene.[25]
In order to further extend this new and promising approach
and motivated by the success with our TADDOLs and
BINOLs, we have now immobilized Salen in the same way.
There have already been quite a number of attempts of
immobilizing Salen on inorganic supports,[26] as for example
on zeolites, within a polysiloxane membrane[27] and on organic
polymer supports, for use in Mn-Salen mediated enantiose-
lective epoxidation of olefins[28±31] and kinetic resolution of
terminal epoxides.[32] However, Salens immobilized on organ-
ic polymer supports have often given rather disappointing
results in heterogeneous enantioselective epoxidations.[28±30]
Quite recently, Sherrington reported for the first time on a
polymer-bound Mn-Salen with a catalytic activity comparable
to that of the homogeneous catalyst (epoxidation of 1-phenyl
cyclohexene).[31]
In order to compare our approach of immobilization in a
cross-linking fashion with other existing methods special focus
was put on the use of dendritically modified Salen cross-
linkers, especially in multiple use. Preparation of the Salen
cross-linkers, copolymerization with styrene and application
of the polymer-bound catalysts in various test reactions are
the subjects of the present paper.
Results and Discussion
Preparation of Salen cross-linkers 2 and 3: The simplest way
of generating a Salen cross-linker for styrene copolymeriza-
tion is to introduce styryl groups at both aromatic units of the
Salen core. Thus, the linear biphenyl branch 1 was generated
by Suzuki cross-coupling of 3-tert-butyl-5-bromo salicylic
aldehyde[33] and styrene boronic acid[34] (Scheme 1).[35] Very
O
OH
Br
H
+
B
H
HO
OH
O
OH
1
R
R
N
H
H
N
OH HO
2
3
(R R = -(CH2)4-)
(R = Ph)
Scheme 1. Preparation of the biphenyl arm
Conditions: [Pd(PPh3)4], 2m Na2CO3, THF, 708C, 77%. The Salen
monomers and were prepared by condensation of with the
corresponding diamines.
1 by Suzuki coupling.
2
3
1
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Enantioselective Epoxidation
2873±2887
remarkably, no protection of the aldehyde or OH functions of
the aldehyde was necessary. Condensation of 1 with (R,R)-1,2-
cyclohexane diamine or (R,R)-1,2-diphenyl ethylene diamine
under standard conditions afforded 2 and 3 in 83 and 91%
yield, respectively.[28b, 29b] In contrast to this procedure, Suzuki
cross-coupling of the Salen, prepared by condensation of
3-tert-butyl-5-bromo salicylic aldehyde with the diamine, and
styrene boronic acid was not successful due to very slow
conversion.
hyde derivatives 5a and 5b without and with vinyl groups in
yields of 53 and 60%, respectively (Scheme 2).
Analogously, second-generation salicylic aldehyde branch-
es 7a and 7b were prepared by mono-etherification of 3-tert-
butyl-5-hydroxy-salicylic aldehyde with benzylic bromides
6a[36] and 6b[22] (Scheme 3).
One of the main applications of chiral Salen ligands is the
manganese-mediated epoxidation of olefins.[37] We anticipat-
ed that Salen systems prepared from salicylic aldehyde
branches 5a,b and 7a,b might be sensitive to oxidation under
the reaction conditions due to the fact that they are hydro-
quinone derivatives. Therefore, we prepared the dendritic
branch compound 11 with an acetylene linkage between the
dendritic subunit and the salicylic aldehyde part which was
expected to be much more stable under oxidative conditions
than the branch compounds described above. The acetylene
spacer moiety was introduced by Sonogashira cross-cou-
pling[38] of 3-tert-butyl-5-bromo salicylic aldehyde[33] with
Preparation of first- and second-generation dendritic salicylic
aldehyde branches: The main focus of this work was put on
the investigation of dendritically cross-linked Salen copoly-
mers. In order to compare the catalytic activity of the
polymers to be prepared with the corresponding Salen
dendrimers under homogeneous reaction conditions we also
synthesized the analogous compounds lacking the vinyl
groups. We decided to assemble the Salen cross-linkers by
condensation of the corre-
sponding dendritic salicylic al-
dehyde branches with the de-
R
R
sired diamine. As described for
R
R
the preparation of 2 and 3, the
O
OH
OH
O
O
strategy of first preparing the
desired salicylic aldehyde de-
rivative followed by condensa-
tion with the diamine appeared
to be more promising than
coupling of branches to a pre-
formed Salen core structure.
Thus, etherification of 3-tert-
butyl-5-hydroxy-salicylic alde-
hyde[28d] with first-generation
dendritic branches 4a[36] and
4b[22] afforded salicylic alde-
H
O
O
+
O
Br
H
4a (R = H)
4b (R = vinyl)
O
OH
5a (R = H)
5b (R = vinyl)
Scheme 2. Preparation of dendritic branches 5a and 5b by etherification reaction of 3-tert-butyl-5-hydroxy
salicylic aldehyde with the benzyl bromides 4a and 4b. Conditions: K2CO3, KI, acetone, 708C, 6 h.
R
R
O
R
O
O
R
O
OH
OH
O
H
O
O
O
H
Br
O
O
+
HO
O
O
R
O
O
R
O
R
R
7a (R = H)
6a (R = H)
6b (R = vinyl)
7b (R = vinyl)
Scheme 3. Preparation of second-generation dendritic salicylic aldehyde branches 7a and 7b. Conditions: K2CO3, KI, acetone, 708C, 4 h.
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D. Seebach et al.
FULL PAPER
ethinyl trimethyl silane to give the alkinyl derivative 8 in
quantitative yield (Scheme 4). Again, no protection of func-
tional groups was necessary. The desilylation of 8 caused
problems: addition of TBAF to its solution in THF gave the
deprotected product 9 in only 27% yield, due to oligomeriza-
tion. The acetylene moiety reacts with the aldehyde group
under these reaction conditions. Therefore, the deprotection
was performed with TBAF in THF in the presence of 1n HCl,
giving 9 in 82% yield after 20 h. Subsequent Sonogashira
coupling with the dendritic aryl iodide branch compound 10,
prepared by etherification of 4b[22] with commercial 4-iodo
phenol, afforded the desired dendritically modified salicylic
aldehyde derivative 11 (63%, Scheme 4).[38, 39]
Salen and Mn(OAc)2 ´ 4H2O for several hours in EtOH/
toluene, while air was bubbled through the reaction mixture,
followed by stirring at room temperature for a further 12 h in
the presence of LiCl (following published procedur-
es[28, 29b, 33]). The epoxidation reactions were generally run
with 20 mol% of Mn-Salen,[40] two equivalents of m-chloro-
perbenzoic acid (m-CPBA) as oxidant and five equivalents of
4-methylmorpholine-N-oxide (NMO) as additive in CH2Cl2 at
208C (Scheme 6).[41]
As shown in Scheme 6, we used several different phenyl
substituted olefins as test substrates. The results are collected
in Table 1. The selectivities and conversions obtained in the
epoxidation of styrene (! 22a) with Salens 12 and 16 were
comparable to those obtained with the corresponding (and
commercially available) Jacobsen catalyst under identical
conditions (er 75:25, conversion complete after 1 h). 3-Methyl
styrene (! 22b) was oxidized in very similar selectivities and
conversions. For both substrates, the enantiomer ratios in the
epoxides formed using the diphenyl-ethylenediamine-derived
Salens 13 or 17 were higher than those achieved with the
cyclohexane diamine-derived Salens 12 and 16 (Table 1). The
epoxidation of (E)-phenylpropene (! 22c) proceeded with
lower enantioselectivities, in accordance with literature da-
ta.[37a] In contrast, enantiomerically highly enriched products
and high degrees of conversions were observed with dendriti-
cally modified Salens 12, 13, 16, and 17 in the epoxidation of
1-phenyl cyclohexene (! 22d), again comparable with the
results obtained with the simple unsubstituted Jacobsen
catalyst.[31, 42] Also, epoxidation of dihydronaphthalene (!
22e) gave rise to high enantioselectivities, again similar to the
results obtained with unsubstituted Jacobsen catalyst under
the same conditions (er 91:9, conversion complete after
15 minutes), whereas in the
Preparation of Salen dendrimers: The dendrimers 12 ± 21 with
and without peripheral vinyl groups were prepared by heating
a solution of dendritic branches 5a,b, 7a,b or 11 and the
desired diamine in EtOH for several hours (Scheme 5).[28b, 29b]
In most cases, the dendrimers were obtained in yields between
75 and 95% after purification by flash column chromatog-
raphy, and they were fully characterized by 1H NMR,
13C NMR, and IR spectroscopy, by MALDI-TOF or Hi-Res-
MALDI spectrometry, and by elemental analysis.
Epoxidation of olefins under homogenous conditions using
dendritic Salen ligands 12, 13, 16, and 17: Before immobilizing
dendritically substituted Salens in polystyrene and investigat-
ing the catalytic properties of their manganese complexes we
had to check whether the dendritic modification gives rise to
any change in the catalytic activity in solution. Thus, Salens 12,
13, 16, and 17 were loaded with Mn by heating a solution of
O
OH
case of trans-stilbene (! 22 f)
the enantiomer ratios were
H
O
OH
Br
poor. In summary, modification
of Salen ligands with dendritic
branches up to the second gen-
eration does not affect the cat-
a)
H
R
alytic performance in a nega-
tive way. The selectivities ob-
8: R = TMS
9: R = H
b)
tained
in
homogeneous
solution using Salens 12, 13,
16, and 17 are similar to those
reported for the classical Jacob-
sen catalyst under comparable
conditions. Furthermore, there
seems to be no dependence of
the catalytic activity from the
size of the dendritic branches
attached to the Salen core ±
second-generation Salens 16
and 17 gave, in most cases,
similar results as the first-gen-
eration Salens 12 and 13, in
contrast to the observations
made during our work on poly-
mer-bound TADDOL[20] and
O
O
O
OH
O
O
c)
d)
O
I
H
I
O
OH
10
11
Scheme 4. Preparation of dendritic salicylic aldehyde branch 11. Conditions: a) ethinyl trimethyl silane,
[PdCl2(PPh3)2], CuI, THF, NEt3, 708C, 12 h, quant.; b) TBAF ´ 3H2O, THF/1n HCl, 20 h, 82%; c) 4b, K2CO3, 18-
crown-6, acetone, 708C, 5 h, 92%; d) 9, [PdCl2(PPh3)2], CuI, THF, NEt3, 708C, 12 h, 63%.
BINOL[22]
!
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Enantioselective Epoxidation
2873±2887
'R
R'
12 (R–R = -(CH2)4-, R' = H)
13 (R = Ph, R' = H)
R
N
R
N
O
H
H
O
O
14 (R–R = -(CH2)4-, R' =vinyl)
O
OH HO
O
O
15 (R = Ph, R' = vinyl)
R'
'R
R'
'R
O
O
'R
R'
O
O
O
R
R
N
O
O
H
H
O
N
O
OH HO
O
O
O
O
'R
R'
O
16 (R–R = -(CH2)4-, R' = H)
17 (R = Ph, R' = H)
'R
R'
18 (R–R = -(CH2)4-, R' =vinyl)
19 (R = Ph, R' = vinyl)
R
N
R
N
O
O
H
H
O
O
OH HO
O
O
20 (R–R = -(CH2)4-)
21 (R = Ph)
Scheme 5. Dendrimers 12 ± 21 prepared by condensation of branches 5a, 5b, 7a, 7b, and 11 with the corresponding diamines.
Copolymerization of Salen cross-linkers with styrene to give
polymer-bound Salen ligands and complexes thereof: Having
shown that Salen ligands with attached dendritic branches are
catalytically highly active, we have immobilized the styryl
derivatives 2, 3, 14, 15, and 18 ± 21 in polystyrene by
suspension copolymerization using a procedure by Itsuno
process spherical beads of cross-linked polystyrene were
formed, with an average diameter of 500 mm and swelling
factors between 2.5 and 4 in solvents such as toluene, CH2Cl2
or THF. After extensive washing with various solvents the
polymer beads were collected by size, using a set of sieves with
different mesh widths. In most cases the polymers were
obtained in quantitative yield so that the loading (mmol Salen
per g polymer) was directly calculated from the stoichiometric
amounts of monomers used. Having experienced in our
previous work[22] with the copolymerization of non-protected
BINOL and styrene that the free phenolic OH groups
and Frechet.[43] A solution of cross-linkers 2, 3, 14, 15, or 18 ±
Â
21, styrene and azoisobutyronitrile (AIBN) in benzene and
THF was mixed with an aqueous solution of poly(vinyl
alcohol) (PVA) under constant stirring and heating at 858C
for 24 h (Scheme 7). During this radical polymerization
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D. Seebach et al.
FULL PAPER
0.2 equiv Mn(Cl)-Salen
2 equiv m-CPBA
R1
R4
R2
R3
R1
R4
R2
R3
O
Cross linker
2, 3, 14, 15, 18 - 21
+
5 equiv NMO
CH2Cl2, -20°C
(36 - 60 equiv)
22a-f
Suspension Copolymerisation
benzene, THF/H2O, PVA
AIBN, 90°C, 20h
O
O
O
a
b
c
Salen-Copolymers
p-2, p-3, p-14, p-15, p-18 - p-21
Scheme 7. Suspension copolymerization of cross-linkers 2, 3, 14, 15, 18 ± 21
with styrene to give Salen/styrene copolymers p-2, p-3, p-14, p-15, p-18 ±
p-21. Conversions were complete in most cases so that ligand loadings
O
O
O
were calculated by the relative amounts of monomers used. Loadings:
d
f
1
e
0.13 ± 0.20 mmolg
.
Scheme 6. Epoxidation of various olefins mediated by Mn-Salens 12 ´ ,
13 ´ , 16 ´ and 17 ´ Mn(Cl) in homogeneous solution to give epoxides 22a ± f.
The corresponding Mn-Salens were prepared according to literature
procedures.[28, 29b, 33]
the residues of the washing fractions no unpolymerized Salen
derivatives or decomposition products were detected.
Epoxidation reactions of olefins catalyzed by polymer-bound
Mn-Salens: For loading with Mn the beads were suspended in
DMF/EtOH, in the presence of ten equivalents of Mn-
(OAc)2 ´ 4H2O; the beads changed color from yellow to black,
immediately (Figure 1). Heating of the suspension under
Table 1. Selectivities and conversions obtained in the epoxidation of
various olefins, mediated by Mn complexes of Salens 12, 13, 16, and 17 in
homogeneous solution to give epoxides 22a ± f under the conditions
outlined in Scheme 6. With the Jacobsen catalyst the following selectivities
and conversions were obtained under the same conditions (conversion in
both cases complete after 30 minutes): 22a: er 75:25; 22e: er 91:9.
Epoxide 22
Salen
Conversion [%][a]
er
a
a
a
a
b
b
b
c
c
c
d
d
d
d
e
e
e
e
f
12
13
16
17
12
13
16
12
13
16
12
13
16
17
12
13
16
17
12
13
16
87
80
79
82
94
83
92
90
58
80
90
75
83
76
94
97
93
98
12
7
73:27
83:17
72:28
84:16
76:24
84:16
76:24
53:47
55:45
53:47
96:4
92:8
95:5
89:11
89:11
90:10
91:9
89:11
57:43
52:48
59:41
f
f
8
Figure 1. Polymer beads of p-14 before (yellow) and after (black) loading
with manganese.
[a] After 30 min, determined by capillary gas chromatography (CGC).
suppressed the polymerization, we were surprised to see that
in the case of the Salen derivatives (bearing a tert-butyl group
at each phenolic moiety) no problems during copolymeriza-
tion were encountered. After all, 2,6-di-tert-butyl-phenols are
widely used as antioxidants (radical traps) in plastic materi-
als.[44] Nevertheless, in order to make sure that all cross-
linking Salen moieties were covalently incorporated into the
resin and that no decomposition products from cross-linkers
remained, the beads were extensively washed with THF, a
solvent in which they swell well: by NMR measurements with
reflux for 3 h, with air bubbling through the mixture, was
followed by addition of 20 equivalents of LiCl and stirring at
room temperature for 12 h, to give polymer-bound Mn-Salens
p-2 ´ , p-3 ´ , p-14 ´ , p-15 ´ , p-18 ´ , p-19 ´ , p-20 ´ and p-21 ´
Mn(Cl).[28b, 31, 45] After the loading process, it was very
important to wash the beads extensively with THF (to remove
excess Mn salts and LiCl). The resulting supported Mn-Salens
were stable to air, and even after storage for one year
catalytically as active as directly after loading. Elemental
analysis showed that in most charges the experimentally
2878
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Chem. Eur. J. 2001, 7, No. 13

Enantioselective Epoxidation
2873±2887
determined loading of the beads with manganese correspon-
ded to the theoretical values, as shown in the following
examples: p-14 ´ Mn(Cl) (loading 0.2 mmolg ), theoretical
heterogeneous conditions that gives rise to very poor enan-
tioselectivities in solution was to check whether immobiliza-
tion of Salen (site isolation of catalytic centers) has a positive
effect on the catalytic performance (i.e., by change of the
mechanism of epoxidation on solid support). This seemed not
to be the case for 22c. In contrast, ver good results were
obtained for the epoxidations of 1-phenyl cyclohexene (!
22d) and dihydronaphthalene (! 22e). For 22d almost the
same enantiomer ratios (er up to 92:8) as in solution (er up to
96:4, Table 1) were observed whereas the enantioselectivities
for 22e (es up to 81%) were slightly reduced with respect to
the homogeneous reaction (es up to 91%, Table 1). In both
cases the best results were obtained with polymers p-14 ´ and
p-18 ´ Mn(Cl) containing cyclohexane diamine derived Salen
cross-linkers. However, trans-stilbene gave rise to very poor
enantiomer ratios and very low conversions. Again, as in the
case of (E)-phenylpropene, it was not possible to increase the
catalytic performance by binding of Salen to a solid support.
In summary, the performance of Salen cross-linked poly-
mers in epoxidation reactions was in all cases comparable to
that observed under homogeneous conditions. According to
our knowledge, the present work represents the first example
of a Salen system immobilized on an organic support that
exhibits a good catalytic activity towards a broad range of
substrates. Placing the catalytic moiety at the cross-link of the
polymer within a dendritic environment generates polymers
that are catalytically highly active.
1
Mn content 1.08%, found 1.03%; p-15 ´ Mn(Cl) (loading
1
0.2 mmolg ), theoretical Mn content 1.08%, found 1.12%.
The epoxidation reactions were generally carried out by
suspending the beads in CH2Cl2, adding an olefin and NMO,
cooling to 208C and finally adding m-CPBA (Scheme 8).
R1
R4
R2
R3
0.2 equiv
p-2•, p-3•, p-14•, p-15•, p-18•, p-19•, p-20•, p-21•Mn(Cl)
2 equiv m-CPBA, 5 equiv NMO
CH2Cl2, - 20°C, 30 min
• filtering of the reaction mixture
• washing of the polymers with CH2Cl2
• workup of the reaction solution and GC analysis
• reuse of the supported catalyst
R1
R4
R2
R3
O
22a-f
Scheme 8. Multiple application of polymer supported Mn-Salens in the
epoxidation of olefins to give epoxides 22a ± f (see Scheme 6).
Multiple application of polymer-bound Mn-Salens in enan-
tioselective epoxidations of olefins: Having shown that a
variety of olefins can be epoxidized in very good enantiose-
After 30 minutes, the reaction solution was withdrawn by
syringe and the polymer beads were washed several times
with CH2Cl2. Basic workup of the organic phases afforded the
crude product which was analyzed by capillary gas chroma-
tography (CGC) on a chiral column to provide the ratio of
enantiomeric epoxides 22 as well as the content of unreacted
olefin.[46]
Table 2. Selectivities and conversions obtained in the epoxidation of
various olefins, mediated by Mn complexes of polymer-bound Salens p-2,
p-3, p-14, p-15, p-18 ± p-21 to give epoxides 22a ± f (see Scheme 6) under the
conditions shown in Scheme 8. The loading of the polymers was
0.20 mmolg 1 unless otherwise stated.
Epoxide 22
Salen-polymer
Conversion [%][b]
er
The catalytic performance of the polymer-bound Mn-
Salens was tested using the same substrates as in the
homogeneous reaction (Scheme 6). The results are collected
in Table 2. In the epoxidation of styrene and 3-methyl styrene
to the epoxides 22a and 22b almost the same enantioselec-
tivities were observed as in solution (see Table 1). As in the
homogeneous reaction the complexes derived from Salens
with a diphenyl ethylene diimine moiety (p-3´, p-15´, p-19 ´
and p-21 ´ Mn(Cl)) gave rise to higher enantioselectivities
than the polymers containing cyclohexane diamine derived
Salen cross-linkers (p-2´, p-14´, p-18 ´ and p-20 ´ Mn(Cl)).
Furthermore, polymers p-2 ´ and p-3 ´ Mn(Cl), with the styryl
groups directly attached to the Salen core, as well as p-20 ´ and
p-21 ´ Mn(Cl), containing an acetylene spacer between Salen
core and dendritic branches, showed complete conversion
after a reaction time of 30 minutes. The results for the
epoxidation of styrene are by far the best reported up until
now for Mn-Salen complexes immobilized on organic sup-
ports. The epoxidation of (E)-phenylpropene (! 22c),
mediated by p-15 ´ Mn(Cl), proceeded with very low enan-
tiomer ratios and with low conversions, as in homogeneous
solution (Table 1). The reason for testing a substrate under
a
a
a
a
a
a
a
a
b
b
b
b
c
d
d
d
d
e
e
e
e
f
p-2
p-3
quant.
quant.
74
61
88
71:29
81:19
73:27
78:22
70:30
77:23
72:28
80:20
71:29
77:23
74:26
75:25
52:48
92:8
84:16
90:10
79:21
81:19
75:25
79:21
69:31
61:39
51:49
p-14
p-15
p-18
p-19
p-20[a]
p-21[a]
p-2
56
quant.
quant.
quant.
quant.
75
42
35
75
49
72
49
88
74
90
80
9
8
p-3
p-14
p-15
p-15
p-14
p-15
p-18
p-19
p-14
p-15
p-18
p-19
p-14
p-15
f
[a] Loading: 0.13 mmol Salen per g polymer. [b] After 30 min, determined
by CGC.
Chem. Eur. J. 2001, 7, No. 13
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2879

D. Seebach et al.
FULL PAPER
lectivities and conversions we turned to the reusability of our
catalysts. Due to the big synthetic effort of preparing a
polymer-bound catalyst (first the synthesis of suitable poly-
merizable precursors, then the immobilization) it is of utmost
importance to demonstrate its reusability in many catalytic
cycles. Polymers p-2 ´ and p-3 ´ Mn(Cl) each were recycled ten
times in the enantioselective epoxidation of styrene and
3-methyl styrene (Figure 2). The epoxides 22a and 22b were
and the conversion decreased even further. This means that in
repeated uses of manganese complexes of polymers p-14 and
p-15 irreversible inactivation occurs. Probably the Salen units
within these polymers are readily oxidized under the reaction
conditions, due to the hydroquinone structure of the Salen
cores. Very recently, Sherrington reported that recycling of a
supported Mn-Salen, anchored to the resin via a benzyl ether
linkage, failed.[31b] Furthermore, reloading of Sherringtonꢁs
supported ligand with manganese did not reinstall the original
performance of the catalyst, in accordance with our observa-
tions.[31b] Leaching of Salen from the polymer, a further
possible reason for the decline in catalytic performance, could
be excluded in our case as Salen or Salen-derived decom-
position products were never detected by NMR spectroscopy
of the crude reaction mixtures.
As we had not encountered recycling problems with
polymers p-2 ´ and p-3 ´ Mn(Cl), bearing the original styryl
groups directly attached to the Salen core, we concluded that
it would probably be favorable to introduce an acetylene
spacer between the dendritic branches and the Salen core in
order to diminish the sensitivity to oxidation (as discussed
above). It turned out that this approach was in fact very
successful. Polymers p-20 ´ and p-21 ´ Mn(Cl) could be recy-
cled ten times without significant loss in enantioselectivity and
conversion (Figure 3). These results prove that loss in catalytic
performance of polymers p-14 ´ and p-15 ´ Mn(Cl) is very
likely due to oxidation of the Salen moieties under the
reaction conditions.
Figure 2. Multiple use of supported Mn-Salens p-2 ´ and p-3 ´ Mn(Cl) in
the enantioselective epoxidation of a) styrene (!22a) and b) 3-methyl
styrene (!22b), cf. Scheme 8.
obtained without any drop in enantioselectivity and conver-
sion (always quantitative after a reaction time of 30 minutes)
over ten cycles. This was the first time that a polymer-bound
Salen could be recycled effectively without any loss in
performance.
Encouraged by this fact, we also tried to reuse the
dendritically cross-linked polymers p-14 ´ and p-15 ´ Mn(Cl),
as often as possible, in the epoxidation of styrene (!22a)
(Figure 3). Unfortunately the drop in selectivity and con-
version was very pronounced in both cases, especially with
polymer p-15 ´ Mn(Cl), containing a diphenyl ethylene di-
amine derived Salen cross-linker, which, after ten cycles, gave
rise to almost racemic product 22a. Our first assumption was
that loss in activity was due to leaching of manganese from the
polymers. However, reloading of, for example, polymer p-15 ´
Mn(Cl) with manganese after ten cycles, as described above,
did not reinstall the original activity: 22a was obtained with an
enantiomer ratio of 52:48 instead of 51:49 before reloading,
Figure 3. Comparison of polymer-bound Mn-Salens p-14 ´ and p-20 ´
Mn(Cl) (a) as well as p-15 ´ and p-21 ´ Mn(Cl) (b) during multiple use in
the enantioselective epoxidation of styrene (!22a), cf. Scheme 8.
2880
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Chem. Eur. J. 2001, 7, No. 13

Enantioselective Epoxidation
2873±2887
Hetero-Diels ± Alder reaction of Danishefskyꢀs diene with
various aldehydes mediated by polymer-bound Salens: The
growing importance of asymmetric hetero-Diels ± Alder re-
actions can be attributed to the development of a number of
very effective catalysts.[47] In 1998 Jacobsen demonstrated that
Cr-Salen complexes can be employed for asymmetric hetero-
Diels ± Alder reactions of Danishefskyꢁs diene with aldehydes
to give dihydropyranones in good enantioselectivities.[48] We
decided to test this reaction using polymers p-2, p-14, and p-20
containing a cyclohexane diamine-derived Salen. For loading
of the catalysts with chromium, the polymer beads were
suspended in THF and CrCl2 was added. The beads immedi-
ately changed color from yellow to brown. Stirring under Ar
for 3 h and with contact to air for 12 h, followed by extensive
washing with THF, afforded p-2 ´ , p-14´, and p-20 ´ Cr(Cl).
The hetero-Diels ± Alder reactions were generally performed
using 0.02 equivalents of polymer-bound Cr(Cl)-Salen and
one equivalent of diene and aldehyde, respectively (on the
1 mmol scale), in tert-butyl methyl ether (TBME) at room
temperature (Scheme 9). After a reaction time of 24 h a
sample was withdrawn from the reaction mixture for deter-
mination of the conversion by CGC. The reaction solution was
filtered off and the beads were washed with Et2O. After
treatment of the combined organic fractions with trifluoro
acetic acid (TFA) and purification by flash column chroma-
tography the enantiomer ratios of cycloadducts 23a ± c were
determined by CGC using a chiral column (Scheme 9).
had given rise to the best results during multiple use in the
epoxidation of styrene. Furthermore, the cycloadditions
proceeded very slowly in the case of cyclohexane carbox-
aldehyde. Jacobsen had shown that the best enantioselectiv-
ities and conversions were obtained using a Salen-Cr(BF4)
complex.[48] This complex is prepared in solution by treatment
of the corresponding Salen-Cr(Cl) complex with AgBF4 to
give a heterogeneous reaction mixture.[48] Generation of the
polymer-bound Cr(BF4)-Salen complex by exchange of the
counterion in the supported Cr(Cl)-Salen was, thus, not
possible. In order to circumvent this problem, p-2 ´ Cr(BF4)
was generated by preforming 2 ´ Cr(BF4) in solution, followed
by copolymerization. The complex p-2 ´ Cr(F) was prepared
by addition of NaF to a suspension of p-2 ´ Cr(BF4) in
acetonitrile/THF.[48] Unfortunately, p-2 ´ Cr(BF4) and p-2 ´
Cr(F) did not give rise to better enantiomer ratios and
conversions in the cycloaddition of capronaldehyde with
Danishefskyꢁs diene (Table 3).
Table 3. Hetero-Diels ± Alder reaction of Danishefskyꢁs diene with alde-
hydes, catalyzed by polymer-bound Cr-Salens, according to Scheme 9. The
selectivities obtained with simple unsubstituted Cr(Cl)-Salen are the
following: 23a: erˆ 80:20; 23b: erˆ 89:11; 23c: erˆ 87:13.
Catalyst
Loading
[mmolg
Cycloadduct 23 er (23) Conversion[a] [%]
1
]
p-2 ´ Cr(Cl)
p-14 ´ Cr(Cl) 0.13
p-20 ´ Cr(Cl) 0.13
p-2 ´ Cr(Cl)
p-2 ´ Cr(F)
p-2 ´ Cr(BF4) 0.20
p-14 ´ Cr(Cl) 0.13
p-20 ´ Cr(Cl) 0.13
0.20
a
a
a
b
b
b
b
b
c
78:22
79:21
75:25
85:15
85:15
85:15
86:14
85:15
85:15
86:14
82:18
74
67
82
79
58
27
70
73
60
41
36
TMSO
0.20
0.20
O
+
H
R
OMe
p-2 ´ Cr(Cl)
p-14 ´ Cr(Cl) 0.13
p-20 ´ Cr(Cl) 0.13
0.20
0.02 equiv. p-2•, p-14• and p-20• Cr(Cl)
c
c
TBME, RT, 20h
• filtering of the reaction mixture
[a] After a reaction time of 24 h.
• washing of the polymers with Et2O
• addition of TFA to the reaction solution and workup
• GC analysis of the pure cycloadduct
• reuse of the supported catalyst
Again, we turned our attention to the reusability of the
catalysts. Figure 4 shows the enantioselectivities in the
formation of cycloadducts 23a and b by reaction of Dani-
shefskyꢁs diene with PhCHO or capronaldehyde in five
consecutive catalytic cycles. Very surprisingly, in the case of
p-2 ´ and p-14 ´ Cr(Cl), the enantioselectivity with which the
dihydropyranones 23 were formed, steadily increased during
multiple use to reach the values of the homogeneous reaction
(Table 3) while the conversion gradually dropped. In contrast,
p-20 ´ Cr(Cl) could be recycled up to ten times without loss of
conversion (only the first five cycles are shown in Figure 4)
and with essentially constant enantioselectivity. Thus, also in
case of the hetero-Diels ± Alder reaction, the polymer p-20 ´
Cr(Cl) prepared from a Salen cross-linker containing acety-
lene spacers between dendritic branches and Salen core
exhibits a superior performance with respect to recycling
compared with the corresponding polymer p-14 ´ Cr(Cl), built
from a Salen cross-linker with the dendritic branches directly
attached to the core by etherification.
O
O
R
23a-c
a: R = C6H5; b: R = pentyl, c: R = cyclohexyl
Scheme 9. Multiple application of polymer supported Cr-Salens p-2 ´ ,
p-14 ´ and p-20 ´ Cr(Cl) in the hetero-Diels ± Alder reaction of Danishef-
skyꢁs diene with various aldehydes to give cycloadducts 23.
The results for benzaldehyde, capronaldehyde and cyclo-
hexane carboxaldehyde are summarized in Table 3. In all
cases selectivities were achieved that were only slightly lower
than in homogeneous solution under identical conditions.[49]
For all three aldehydes tested, the lowest selectivities were
obtained with p-20 ´ Cr(Cl), the manganese analogue of which
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2881

D. Seebach et al.
FULL PAPER
(60 mL), H2O (940 mL)). Flash column chromatography: SiO2 60 (0.040 ±
0.063 mm, Fluka), pressure 0.2 ± 0.3 bar. M.p.: open glass capillaries, Büchi
510 (Tottoli apparatus), 508C range Anschütz thermometers, uncorrected.
[a]D at RT (ca. 208C) Perkin ± Elmer 241 polarimeter (p.a. solvents, Fluka).
Capillary gas chromatography (CGC): Carlo Erba GC 8000; column:
Supelco b-Dex (30 m  0.25 mm); injector temperature 2008C, detector
temperature 2258C (FID); carrier gas: H2. 1H and 13C NMR spectra:
Bruker AMX-300, AMX-400, AMX-II-500, Varian XL-300, Gemini-200 or
Gemini-300; d in ppm downfield of TMS (d ˆ 0). IR: CHCl3 solutions;
Perkin ± Elmer FT-IR 1600; (s ˆ strong, m ˆ medium, w ˆ weak). MS:
Hitachi-Perkin ± Elmer RMU-6M (EI), Ion Spec Ultima 4.7 FT Ion
Cyclotron Resonance (ICR) mass spectrometer (Hi-Res-MALDI), matrix:
2,5-dihydroxy benzoic acid (2,5-DHB), fragment ions in m/z with relative
intensities (%) in parentheses; MALDI-TOF-spectra: Bruker Reflex
Spectrometer (N2 laser, 337 nm), matrix: 2,5-dihydroxy benzoic acid (2,5-
DHB). Elemental analyses were performed by the Microanalytical
Laboratory of the Laboratorium für Organische Chemie (ETH Zürich).
Etherification reaction of 3-tert-butyl-5-hydroxy salicylic aldehyde with
dendritic branch bromides to give dendritic salicylic aldehyde derivatives.
General procedure I (GP I): K2CO3 (1 equiv) and KI (0.01 equiv) were
subsequently added to
a solution of 3-tert-butyl-5-hydroxy salicylic
aldehyde[28d] (1 equiv) and dendritic branch bromide (1 equiv) in acetone
and the suspension was heated under reflux for several hours. After cooling
to room temperature, CH2Cl2, and H2O were added, the layers were
separated and the aqueous layer was extracted (2 Â CH2Cl2). After drying
over MgSO4 the solvent was evaporated under vacuum and the resulting
residue was purified by flash column chromatography.
Preparation of dendritic Salens by condensation of diamines with dendritic
salicylic aldehyde derivatives. General procedure II (GP II): Dendritic
salicylic aldehyde derivative (2 equiv) and diamine (1 equiv) were heated
in EtOH under reflux for several hours.[28b, 29b] The solvent was evaporated
and the residue redissolved in Et2O. After the organic layer was washed
with H2O and brine and dried over MgSO4, the solvent was evaporated and
the residue was purified by flash column chromatography.
Figure 4. Multiple use of Cr-Salen polymers p-2 ´ , p-14 ´ and p-20 ´ Cr(Cl)
in the hetero-Diels ± Alder reaction of Danishefskyꢁs diene with
a) benzaldehyde (!23a) and b) capronaldehyde (!23b), cf. Scheme 9.
Compound 1: Under Ar
a solution of 3-tert-butyl-5-bromo salicylic
Conclusion
aldehyde[33] (2.15 g, 8.4 mmol), 4-styrene boronic acid[34] (1.61 g, 10.9 mmol),
[Pd(PPh3)4] (290 mg, 0.25 mmol), Na2CO3 (2m, 11.0 mL, 22.0 mmol) in
THF (40 mL) was heated under reflux for 3 h.[35] The organic phase was
separated and the aqueous layer was extracted with Et2O (50 mL). After
the combined organic phases were dried over MgSO4 and evaporation of
the solvent, the residue was redissolved in a minimum of Et2O, the Pd salts
were allowed to precipitate and were filtered off over Celite. Flash column
chromatography (hexane/Et2O 8:1) afforded 1 (1.80 g, 77%) as a yellow
solid. M.p. 109.0 ± 110.08C; Rf (hexane/Et2O 5:1): 0.37; 1H NMR (400 MHz,
CDCl3, 258C, TMS): d ˆ 11.80 (s, 1H; CHO), 9.96 (s, 1H, OH), 7.77 ± 7.48
(m, 8H; 8arom. H), 6.76 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 1H; CHCH2), 5.79
(dd, J(H,H) ˆ 17.6, 0.9 Hz, 1H; 1vinyl. H), 5.28 (dd, J(H,H) ˆ 10.9, 0.9 Hz,
1H; 1vinyl. H), 1.47 (s, 9H; 3CH3); 13C NMR (100 MHz, CDCl3, 258C):
d ˆ 197.21, 160.66, 139.44, 138.80, 136.54, 136.26, 132.95, 131.98, 129.85,
126.78, 126.74, 120.75, 114.01, 35.04, 29.23; IR (CHCl3): nÄ ˆ 2963 (m), 1650
(s), 1514 (w), 1441 (m), 1416 (w), 1394 (m), 1363 (w), 1332 (m), 1270 (m),
1164 (m), 1074 (w), 989 (w), 912 (w), 842 cm 1; MS (EI): m/z (%): 281.2
In the present paper we have demonstrated that Salen ligands
can be successfully immobilized on polystyrene by copoly-
merization of suitable cross-linking styryl derivatives with
styrene. Polymer-bound manganese complexes were employed
for the enantioselective epoxidation of various olefins giving
rise to selectivities that were comparable with the results in
solution. Furthermore, we have demonstrated for the first
time that immobilized Salens can be recycled up to ten times
without loss of activity in Mn-Salen mediated epoxidations.
The high catalytic activity of the Salen copolymers was also
shown in the Cr-Salen catalyzed hetero-Diels ± Alder reaction
of Danishefskyꢁs diene with aldehydes. For the first time we
have shown that this reaction can be performed using a
polymer-bound Salen complex affording the corresponding
cycloadducts in the same selectivities as under homogeneous
conditions. In addition, multiple use of the supported Cr-Salen
complexes in consecutive catalytic cycles is possible.
‡
(10), 280.2 (47) [M] , 266.2 (9), 265.2 (46), 237.2 (7), 179.2 (4), 178.2 (4),
165.1 (5), 118.6 (8), 32.0 (30), 28.1 (100); elemental analysis calcd (%) for
C19H20O2 (280.36): C 81.40, H 7.19; found: C 81.41, H 7.31.
Compound 2: A solution of 1 (1.64 g, 5.9 mmol) and (R,R)-cyclohexane
diamine (334 mg, 2.9 mmol) in EtOH (20 mL) was heated under reflux for
4 h, according to GP II.[28b, 29b] After workup of the reaction mixture,
following GP II, and flash column chromatography (pentane/CH2Cl2 2:1),
2 (1.55 g, 83%) was obtained as a yellow foam. Rf (pentane/CH2Cl2 2:1):
0.28; [a]RDT ˆ ‡101.9 (c ˆ 0.54 in CHCl3); 1H NMR (500 MHz, CDCl3,
258C, TMS): d ˆ 13.9 (s, 2H; 2OH), 8.34 (s, 2H; 2imine H), 7.46 (d,
J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 7.42 ± 7.38 (m, 8H; 8arom. H), 7.19 (d,
J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.76 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 2H;
2CHCH2), 5.75 (dd, J(H,H) ˆ 17.6, 0.9 Hz, 2H; 2vinyl. H), 5.23 (dd,
J(H,H) ˆ 10.9, 0.9 Hz, 2H; 2vinyl. H), 3.38 ± 3.36 (m, 2H; 2CH2CHN),
2.04 ± 2.01 (m, 2H; 2cyclohexyl H), 1.90 ± 1.89 (m, 2H; 2cyclohexyl H),
1.79 ± 1.77 (m, 2H; 2cyclohexyl H), 1.57 ± 1.50 (m, 2H; 2cyclohexyl H), 1.44
(s, 18H; 6CH3); 13C NMR (125 MHz, CDCl3, 258C): d ˆ 165.72, 160.02,
140.47, 137.59, 136.49, 135.82, 130.39, 128.24, 127.99, 126.65, 126.53, 118.69,
113.43, 72.41, 34.94, 33.05, 29.36, 24.32; IR (CHCl3): nÄ ˆ 3008 (w), 2939 (m),
Experimental Section
General: Starting materials and reagents: The solvents used in the reactions
were of p.a. quality or purified and dried according to standard methods.
4-Methylmorpholine-N-oxide monohydrate (NMO) was heated at 1108C
under reduced pressure for 24 h to remove water. tert-Butyl methyl ether
(TBME), capron aldehyde (C5H11CHO) and benzaldehyde were distilled
prior to use. All other chemicals were used as commercially available.
Equipment: TLC: precoated silica gel 25 Durasil UV254 plates (Macherey ±
Nagel); visualization by UV254 light, development using phosphomolybdic
acid solution (phosphomolybdic acid (25 g), Ce(SO4)2 ´ 4H2O (10 g), H2SO4
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Enantioselective Epoxidation
2873±2887
2862 (w), 1630 (s), 1513 (w), 1442 (s), 1392 (m), 1272 (m), 1170 (m), 1072
(400 MHz, CDCl3, 258C, TMS): d ˆ 11.52 (s, 1H; CHO), 9.77 (s, 1H; OH),
7.42 ± 7.30 (m, 20H; 20arom. H), 7.24 (d, J(H,H) ˆ 2.7 Hz, 1H; 1arom. H),
6.83 (d, J(H,H) ˆ 3.1 Hz, 1H; 1arom. H), 6.68 ± 6.66 (m, 6H; 6arom. H),
6.57 (t, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.56 (t, J(H,H) ˆ 2.3 Hz, 1H;
1arom. H), 5.03 (s, 8H; 4OCH2), 4.98 (s, 4H; 2OCH2), 4.96 (s, 2H; OCH2),
1.40 (s, 9H; 3CH3); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 196.66, 160.20,
160.15, 159.95, 156.39, 151.08, 140.22, 139.16, 136.74, 128.61, 128.05, 127.58,
124.56, 119.81, 113.27, 106.48, 106.42, 101.62, 101.55, 70.71, 70.14, 70.03,
35.04, 29.13; IR (CHCl3): nÄ ˆ 3006 (w), 2984 (w), 2871 (w) 1651 (m), 1595
(s), 1497 (w), 1451 (s), 1374 (m), 1323 (m), 1297 (w), 1154 (s), 1051 (s),
(w), 1000 (w), 910 cm 1; Hi-Res-MALDI: m/z (%): 662.3833 (6), 661.3801
‡
‡
(12) [M‡Na] , 641.4026 (11), 640.3984 (47), 639.3947 (100) [M‡H] , 638.3862
‡
((5) [M] , calcd 638.3872), 525.2801 (14); elemental analysis calcd (%) for
C44H50N2O2 (638.88): C 82.72, H 7.89, N 4.38; found: C 82.73, H 7.93, N 4.22.
Compound 3: According to GP II, a solution of 1 (1.53 g, 5.5 mmol) and
(R,R)-diphenyl ethylene diamine (580 mg, 2.7 mmol) in EtOH (20 mL) was
heated under reflux for 3 h.[28b, 29b] After workup and flash column chroma-
tography (pentane/CH2Cl2 5:1 ! 3:1), 3 (1.84 g, 91%) was obtained as a
yellow foam. Rf (pentane/CH2Cl2 2:1): 0.70; [a]RDT ˆ ‡34.7 (c ˆ 0.87 in
CHCl3); 1H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ 13.85 (s, 2H; 2OH),
8.41 (s, 2H; 2imine H), 7.46 (d, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 7.42 ± 7.36
(m, 8H, 8arom. H), 7.25 ± 7.17 (m, 12H, 12arom. H), 6.73 (dd, J(H,H) ˆ
17.6, 10.9 Hz, 2H; 2CHCH2), 5.75 (dd, J(H,H) ˆ 17.6, 0.9 Hz, 2H; 2 vinyl.
H), 5.23 (dd, J(H,H) ˆ 10.9, 0.9 Hz, 2H; 2vinyl. H), 4.76 (s, 2H; 2PhCHN),
1.44 (s, 18H; 6CH3); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 167.10,
159.89, 140.39, 139.29, 137.65, 136.47, 135.84, 130.52, 128.61, 128.41, 128.25,
128.02, 127.64, 126.65, 126.52, 118.69, 113.45, 80.18, 34.97, 29.33; IR (CHCl3):
nÄ ˆ 3008 (m), 2960 (m), 1628 (s), 1514 (w), 1441 (s), 1393 (m), 1330 (w),
1268 (m), 1170 (m), 1048 (w), 1028 (w), 989 (w), 910 (m), 842 cm 1; Hi-Res-
‡
836 cm 1; MALDI-TOF-MS (2,5-DHB): 923.5 [M‡2] ; elemental analysis
calcd (%) for C60H56O9 (921.08): C 78.24, H 6.13; found: C 78.21, H 6.32.
Compound 7b: A mixture of 3-tert-butyl-5-hydroxy salicylic aldehyde[28d]
(1.50 g, 7.7 mmol), 6b[22] (7.04 g, 7.7 mmol), K2CO3 (1.07 g, 7.7 mmol), and
KI (19 mg, 0.07 mmol) in acetone (50 mL) was heated under reflux for 4 h,
following GP I. After workup and flash column chromatography (pentane/
CH2Cl2 1:2) 7b (1.72 g, 22%) was obtained as a yellow solid. M.p. 55.0 ±
1
56.08C; Rf (pentane/CH2Cl2 1:2): 0.57; H NMR (400 MHz, CDCl3, 258C,
TMS): d ˆ 11.51 (s, 1H; CHO), 9.76 (s, 1H; OH), 7.37 (dd, J(H,H) ˆ 25.06,
8.2 Hz, 16H; 16arom. H), 7.24 (d, J(H,H) ˆ 3.1 Hz, 1H; 1arom. H), 6.82 (d,
J(H,H) ˆ 3.1 Hz, 1H; 1arom. H), 6.70 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 4H;
4CHCH2), 6.66 (d, J(H,H) ˆ 2.3 Hz, 6H; 6arom. H), 6.55 (t, J(H,H) ˆ
2.3 Hz, 3H; 3arom. H), 5.74 (dd, J(H,H) ˆ 17.6, 0.9 Hz, 4H; 4vinyl. H),
5.24 (dd, J(H,H) ˆ 10.9, 0.8 Hz, 4H; 4vinyl. H), 5.01 (s, 8H; 4OCH2), 4.97
(s, 4H; 2OCH2), 4.95 (s, 2H; OCH2), 1.41 (s, 9H; 3CH3); 13C NMR
(100 MHz, CDCl3, 258C): d ˆ 196.63, 160.15, 156.38, 151.09, 140.22, 139.20,
137.40, 136.43, 136.27, 127.75, 126.43, 126.39, 126.34, 124.55, 119.82, 114.14,
113.30, 106.50, 106.43, 101.64, 101.59, 70.72, 70.01, 69.89, 35.04, 29.14; IR
(CHCl3): nÄ ˆ 3005 (w), 2964 (w), 2872 (w), 1646 (m), 1595 (s), 1508 (m),
1451 (s), 1436 (m), 1405 (w), 1369 (m), 1323 (m), 1297 (w), 1154 (s), 1046
(s), 1015 (w), 990 (w), 913 (m), 831 cm 1; MALDI-TOF-MS (2,5-DHB):
‡
MALDI: m/z (%): 760.3968 (6), 759.3918 (10) [M‡Na] , 737.4099 ((10)
‡
[M‡H] , calcd 737.4107), 654.3353 (13), 633.3551 (8), 632.3511 (16), 528.2975
(12), 527.2936 (28), 471.2318 (23), 415.1681 (11), 371.2197 (13), 370.2163 (45),
369.2041 (23), 368.2000 (86), 354.1845 (12), 313.1409 (22), 312.1376 (100),
302.1510 (19), 280.1688 (27), 106.0654 (31); elemental analysis calcd (%)
for C52H52N2O2 (736.98): C 84.75, H 7.11, N 3.80; found: C 84.84, H 7.24, N 3.85.
Compound 5a: According to GP I, a suspension of 3-tert-butyl-5-hydroxy
salicylic aldehyde[28d] (3.00 g, 15.4 mmol), 4a[36] (5.92 g, 15.4 mmol), K2CO3
(2.13 g, 15.4 mmol), and KI (24 mg, 0.14 mmol) in acetone (60 mL) was
heated under reflux for 6 h. Workup according to GP I and flash column
chromatography (hexane/CH2Cl2 1:2) afforded 5a (4.06 g, 53%) as a
‡
1
1048.3 [M‡Na] ; elemental analysis calcd (%) for C68H64O9 (1025.23): C
yellow solid. M.p. 117.0 ± 118.08C; Rf (hexane/CH2Cl2 1:2): 0.58; H NMR
79.66, H 6.29; found: C 79.55, H 6.38.
(400 MHz, CDCl3, 258C, TMS): d ˆ 11.52 (s, 1H; CHO), 9.77 (s, 1H; OH),
7.42 ± 7.32 (m, 10H; 10arom. H), 7.24 (dd, J(H,H) ˆ 3.1, 0.4 Hz, 1H; 1arom.
H), 6.81 (d, J(H,H) ˆ 3.1 Hz, 1H; 1arom. H), 6.68 (d, J(H,H) ˆ 2.3 Hz, 2H;
2arom. H), 6.59 (t, J(H,H) ˆ 2.3 Hz, 1H; 1arom. H), 5.25 (s, 4H; 2OCH2),
4.97 (s, 2H; OCH2), 1.41 (s, 9H; 3CH3); 13C NMR (100 MHz, CDCl3,
258C): d ˆ 196.65, 160.24, 156.39, 151.06, 140.21, 139.18, 136.72, 128.63,
128.07, 127.54, 124.60, 119.81, 113.23, 106.41, 101.62, 70.66, 70.15, 35.04,
29.13; IR (CHCl3): nÄ ˆ 3015 (w), 2964 (m), 2872 (w), 1651 (s), 1595 (s), 1492
(w), 1446 (s), 1430 (s), 1374 (m), 1318 (s), 1154 (s), 1041 (s), 836 cm 1; MS
Compound 8: [PdCl2(PPh3)2] (493 mg, 0.7 mmol) and CuI (272 mg,
1.4 mmol) were added to a solution of 3-tert-butyl-5-bromo salicylic
aldehyde[33] (9.03 g, 35.3 mmol) in THF (20 mL)/NEt3 (20 mL). To this
suspension a solution of ethinyl trimethyl silane (5.13 mL, 37.0 mmol) in
THF (7 mL) was slowly added over a period of 1 h, the reaction mixture
thereby turning black.[38] After heating under reflux for 24 h, Et2O
(100 mL) and H2O (50 mL) were added, the phases were separated and
the aqueous phase was extracted with Et2O (100 mL). Drying over MgSO4
and purification by flash column chromatography (hexane/Et2O 9:1)
afforded 8 (9.60 g, 99%) as a yellow oil. Rf (hexane/Et2O 4:1): 0.52;
1H NMR (300 MHz, CDCl3, 258C, TMS): d ˆ 11.90 (s, 1H; CHO), 9.83 (s,
1H; OH), 7.59 (d, J(H,H) ˆ 2.2 Hz 1H; 1arom. H), 7.56 (d, J(H,H) ˆ 2.2 Hz
1H; 1arom. H), 1.41 (s, 9H; 3CH3), 0.26 (s, 9H; Si(CH3)3); 13C NMR
(75 MHz, CDCl3, 258C): d ˆ 196.64, 161.35, 138.75, 137.35, 135.67, 120.32,
114.19, 104.01, 93.03, 34.94, 29.07, 29.00; IR (CHCl3): nÄ ˆ 3007 (w), 2965
(m), 2151 (m), 1653 (s), 1605 (w), 1442 (m), 1414 (m), 1320 (m), 1268 (w),
1153 (m), 1030 (w), 981 (w), 930 (w), 888 (w), 857 cm 1; MS (EI): m/z (%):
‡
(EI): m/z (%): 496.2 (3) [M] , 304.2 (8), 303.2 (35), 179.1 (5), 105.1 (5), 92.1
(8), 91.0 (100); elemental analysis calcd (%) for C32H32O5 (496.59): C 77.40,
H 6.49; found: C 77.29, H 6.56.
Compound 5b: A mixture of 3-tert-butyl-5-hydroxy salicylic aldehyde[28d]
(2.00 g, 10.3 mmol), 4b[22] (4.48 g, 10.3 mmol), K2CO3 (1.42 g, 10.3 mmol),
and KI (16 mg, 0.10 mmol) in acetone (40 mL) was heated under reflux for
12 h, according to GP I. After workup and flash column chromatography
(pentane/CH2Cl2 1:1), 5b (3.37 g, 60%) was obtained as a yellow solid. M.p.
1
109.0 ± 110.08C; Rf (pentane/Et2O 4:1): 0.51; H NMR (400 MHz, CDCl3,
‡
274.0 (16) [M] , 137.0 (35), 77.4 (10), 72.2 (15).
258C, TMS): d ˆ 11.52 (s, 1H; CHO), 9.77 (s, 1H; OH), 7.40 (dd, J(H,H) ˆ
21.3, 8.2 Hz, 8H; 8arom. H), 7.24 (dd, J(H,H) ˆ 3.1, 0.4 Hz, 1H; 1arom. H),
6.81 (d, J(H,H) ˆ 3.1 Hz, 1H; 1arom. H), 6.71 (dd, J(H,H) ˆ 17.6, 10.9 Hz,
2H; 2CHCH2), 6.67 (d, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.57 (t, J(H,H) ˆ
2.3 Hz, 1H; 1arom. H), 5.75 (dd, J(H,H) ˆ 17.6, 0.9 Hz, 2H; 2vinyl. H),
5.26 (dd, J(H,H) ˆ 10.9, 0.9 Hz, 2H; 2vinyl. H), 5.03 (s, 4H; 2OCH2), 4.96
(s, 2H; OCH2), 1.41 (s, 9H; 3CH3); 13C NMR (100 MHz, CDCl3, 258C):
d ˆ 196.62, 160.18, 156.38, 151.05, 140.20, 139.18, 137.42, 136.39, 136.23,
127.73, 126.44, 124.56, 119.81, 114.19, 113.25, 106.42, 101.63, 70.65, 69.89,
35.03, 29.13; IR (CHCl3): nÄ ˆ 2994 (w), 2954 (m), 2872 (w), 1651 (s), 1595
(s), 1508 (w), 1456 (m), 1430 (s), 1369 (m), 1323 (s), 1154 (s), 1035 (s), 1015
Compound 9: TBAF ´ 3H2O (1.41 g, 4.5 mmol) was added to a solution of 8
(1.02 g, 3.7 mmol) in THF (10 mL)/1n HCl (3.7 mL, 3.7 mmol). After
stirring at room temperature for 20 h, Et2O (50 mL) and H2O (50 mL) were
added, the phases were separated and the aqueous phase was extracted
with CH2Cl2 (2 Â 50 mL). Drying of the combined organic phases over
MgSO4 and evaporation of the solvent gave the crude product which was
purified by flash column chromatography (hexane/Et2O 20:1) to afford 9
(620 mg, 82%) as a yellow solid. M.p. 58.0 ± 59.08C; Rf (hexane/Et2O 1:2):
0.53; 1H NMR (300 MHz, CDCl3, 258C, TMS): d ˆ 11.94 (s, 1H; CHO),
9.84 (s, 1H; OH), 7.62 (d, J(H,H) ˆ 1.9 Hz, 1H; 1arom. H), 7.58 (d,
J(H,H) ˆ 2.2 Hz, 1H; 1arom. H), 3.02 (s, 1H; 1acetylene H), 1.41 (s, 9H;
3CH3); 13C NMR (75 MHz, CDCl3, 258C): d ˆ 196.58, 161.57, 138.97,
137.44, 135.75, 120.35, 113.07, 82.68, 76.17, 34.95, 29.03; IR (CHCl3): nÄ ˆ
‡
(w), 990 (w), 913 (m), 831 cm 1; MS (EI): m/z (%): 549.3 (19) [M] , 548.3
(55), 356.3 (8), 355.2(26), 239.1 (6), 233.2 (10), 207.2 (6), 194.1 (8), 179.1
(11), 118.1 (11), 117.1 (100), 115.1 (9), 91.1 (6); elemental analysis calcd (%)
for C36H36O5 (548.67): C 78.81, H 6.61; found: C 78.69, H 6.61.
3304 (m), 2964 (m), 1654 (s), 1608 (w), 1441 (m), 1413 (m), 1394 (w), 1382
1
(w), 1364 (w), 1317 (m), 1270 (w), 1148 (m), 1029 (w), 970 (w), 889 cm
;
Compound 7a: According to GP I, a suspension of 3-tert-butyl-5-hydroxy
salicylic aldehyde[28d] (0.72 g, 3.7 mmol), 6a[36] (3.00 g, 3.7 mmol), K2CO3
(0.51 g, 3.7 mmol), and KI (6 mg, 0.04 mmol) in acetone (40 mL) was
heated under reflux for 4 h. Workup according to GP I and flash column
chromatography (pentane/CH2Cl2 1:1) afforded 7a (1.65 g, 50%) as a
yellow solid. M.p. 60.0 ± 61.08C; Rf (hexane/CH2Cl2 1:1): 0.38; 1H NMR
‡
MS (EI): m/z (%): 201.0 (4) [M H] , 199.0 (14), 198.0 (7), 187.0 (5), 137.0
(34), 136.5 (5), 91.0 (7), 72.2 (4); elemental analysis calcd (%) for C13H14O2
(202.25): C 77.20, H 6.98; found: C 77.27, H 6.91.
Compound 10: A suspension of 4b[22] (4.95 g, 11.4 mmol), 4-iodo phenol
(2.50 g, 11.4 mmol), K2CO3 (3.20 g, 22.8 mmol) and 18-crown-6 (0.60 g,
Chem. Eur. J. 2001, 7, No. 13
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0713-2883 $ 17.50+.50/0
2883

D. Seebach et al.
FULL PAPER
2.3 mmol) in acetone (150 mL) was heated under reflux for 5 h. After
cooling to room temperature, K2CO3 was filtered off and acetone was
evaporated. The residue was redissolved in Et2O (100 mL), H2O (50 mL)
was added and the phases were separated. After the organic phase was
dried over MgSO4 and evaporation of the solvent, purification of the
residue by flash column chromatography (hexane/CH2Cl2 1:1) afforded 10
(6.00 g, 92%) as a colorless oil. Rf (hexane/CH2Cl2 1:1): 0.53; 1H NMR
(400 MHz, CDCl3, 258C, TMS): d ˆ 7.54 ± 7.52 (m, 2H; 2arom. H), 7.38 (dd,
J(H,H) ˆ 23.8, 8.1 Hz, 8H; 8arom. H), 6.72 (dd, J(H,H) ˆ 17.6, 10.9 Hz,
2H; 2vinyl. H), 6.69 (d, J(H,H) ˆ 9.1 Hz, 2H; 2arom. H), 6.62 (d,
J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.54 (t, J(H,H) ˆ 2.3 Hz, 1H; 1arom.
H), 5.75 (dd, J(H,H) ˆ 17.6, 0.9 Hz, 2H; 2vinyl. H), 5.26 (dd, J(H,H) ˆ 10.9,
0.9 Hz; 2H; 2vinyl. H), 5.01 (s, 4H; 2CH2O), 4.95 (s, 2H; CH2O); 13C NMR
(100 MHz, CDCl3, 258C): d ˆ 160.13, 158.48, 138.99, 138.22, 137.38, 136.40,
136.23, 127.71, 126.41, 117.31, 114.14, 106.28, 101.65, 83.10, 69.91, 69.86; IR
(CHCl3): nÄ ˆ 3008 (w), 1597 (s), 1514 (w), 1485 (s), 1458 (m), 1405 (w), 1373
(m), 1292 (m), 1154 (s), 1059 (w), 1046 (w), 1024 (w), 913 (m), 830 cm 1; Hi-
heated under reflux for 12 h.[28b, 29b] Workup and purification of the crude
product by flash column chromatography (pentane/CH2Cl2 1:2) afforded 13
(1.79 g, 76%) as a yellow foam. Rf (pentane/CH2Cl2 1:1): 0.67; [a]DRT
ˆ
1
27.5 (c ˆ 0.56 in CHCl3); H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ
13.39 (s, 2H; 2OH), 8.28 (s, 2H; 2imine H), 7.41 ± 7.17 (m, 30H; 30arom.
H), 6.98 (d, J(H,H) ˆ 3.0 Hz, 2H; 2arom. H), 6.65 (d, J(H,H) ˆ 2.3 Hz, 4H;
4arom. H), 6.55 (t, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.50 (d, J(H,H) ˆ
3.0 Hz, 2H; 2arom. H), 5.01 (s, 8H; 4OCH2), 4.81 (s, 4H; 2OCH2), 4.70 (s,
2H; 2PhCHN), 1.41 (s, 18H; 6CH3); 13C NMR (100 MHz, CDCl3, 258C):
d ˆ 166.75, 160.14, 155.07, 150.38, 139.65, 139.42, 138.81, 136.80, 128.62,
128.58, 128.35, 128.02, 127.99, 127.55, 119.49, 117.83, 112.87, 106.38, 101.61,
80.18, 70.63, 10.09, 35.00, 29.29; IR (CHCl3): nÄ ˆ 3067 (w), 3005 (m), 2954
(m), 2872 (m), 1631 (m), 1595 (s), 1497 (w), 1451 (s), 1435 (s), 1374 (s), 1328
(s), 1297 (w), 1272 (w), 1154 (s), 1046 (s), 836 cm 1; MALDI-TOF-MS (2,5-
‡
DHB): 1170.5 [M‡H] ; elemental analysis calcd (%) for C78H76N2O8
(1169.45): C 80.11, H 6.55, N 2.40; found: C 78.75, H 6.80, N 2.24.
Compound 14: According to GP II, a solution of 5b (1.72 g, 3.1 mmol) and
(R,R)-cyclohexane diamine (333 mg, 1.6 mmol) in EtOH (80 mL) was
heated under reflux for 12 h.[28b, 29b] Workup and purification of the crude
product by flash column chromatography (pentane/CH2Cl2 7:3) afforded 14
‡
Res-MALDI: m/z (%): 598.0921 (5), 597.0898 ((15) [M‡Na] , calcd
597.0903), 573.0922 (4), 563.3732 (4), 505.3360 (6), 470.1861 (6), 457.2933
(5), 456.2895 (16), 447.2931 (8), 274.0430 (14), 243.2877 (8), 242.2845 (42),
137.0240 (25), 91.0153 (8), 72.1908 (9); elemental analysis calcd (%) for
C31H27O3I (574.45): C 64.82, H 4.74; found: C 64.80, H 4.88.
(1.46 g, 73%) as a yellow foam. Rf (pentane/CH2Cl2 1:2): 0.78; [a]DRT
ˆ
110.7 (c ˆ 1.00 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ
13.50 (s, 2H; 2OH), 8.19 (s, 2H; 2imine H), 7.42 ± 7.34 (m, 16H; 16arom.
H), 6.97 (d, J(H,H) ˆ 3.0 Hz, 2H; 2arom. H), 6.71 (dd, J(H,H) ˆ 17.6,
10.9 Hz, 4H; 4CHCH2), 6.64 (d, J(H,H) ˆ 2.3 Hz, 4H; 4arom. H), 6.53 (t,
J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.50 (d, J(H,H) ˆ 3.0 Hz, 2H; 2arom. H),
5.75 (dd, J(H,H) ˆ 17.6, 0.9 Hz, 4H; 4vinyl. H), 5.24 (dd, J(H,H) ˆ 10.9,
0.8 Hz, 4H; 4vinyl. H), 4.99 (s, 8H, 4OCH2), 4.81 (s, 2H; OCH2), 4.80 (s,
2H; OCH2), 3.31 ± 3.29 (m, 2H; 2CH2CHN), 2.00 ± 1.97 (m, 2H; 2cyclo-
hexyl H), 1.89 ± 1.87 (m, 2H; 2cyclohexyl H), 1.76 ± 1.74 (m, 2H; 2cyclo-
hexyl H), 1.49 ± 1.45 (m, 2H; 2cyclohexyl H), 1.39 (s, 18H; 6CH3); 13C NMR
(100 MHz, CDCl3, 258C): d ˆ 196.62, 165.43, 160.10, 155.07, 150.34, 139.69,
138.73, 137.36, 136.46, 136.40, 136.35, 127.75, 127.73, 126.44, 126.41, 119.03,
117.88, 114.19, 114.10, 112.75, 106.46, 101.64, 70.67, 69.90, 69.85, 34.95, 29.31,
29.13; IR (CHCl3): nÄ ˆ 3005 (w), 2944 (m), 2862 (w), 1631 (m), 1595 (s),
1436 (s), 1374 (m), 1328 (m), 1154 (s), 1046 (s), 1015 (m), 984 (w), 913 (m),
Compound 11: [PdCl2(PPh3)2] (100 mg, 0.14 mmol) and CuI (55 mg,
0.29 mmol) were added to a solution of 10 (4.10 g, 7.1 mmol) in THF
(4 mL)/NEt3 (4 mL) under Ar. To the resulting orange suspension a
solution of 9 (1.52 g, 7.5 mmol) in THF (3 mL) was slowly added over a
period of 1 h whereupon the reaction mixture immediately turned black.[38]
After heating under reflux for 12 h Et2O (100 mL) and H2O (50 mL) were
added, the phases were separated and the aqueous phase was extracted
with Et2O (100 mL). Drying of the combined organic phases over MgSO4
and evaporation of the solvent afforded the crude product which was
purified by flash column chromatography (hexane/CH2Cl2 1:1) to give 11
(2.90 g, 63%) as a yellow foam. Rf (hexane/CH2Cl2 1:1): 0.39; 1H NMR
(400 MHz, CDCl3, 258C, TMS): d ˆ 11.89 (s, 1H; CHO), 9.86 (s, 1H; OH),
7.65 (d, J(H,H) ˆ 0.4 Hz, 1H; 1arom. H), 7.58 (d, J(H,H) ˆ 2.1 Hz, 1H;
1arom. H), 7.45 ± 7.35 (m, 10H; 10arom. H), 6.91 (d, J(H,H) ˆ 9.0 Hz, 2H;
2arom. H), 6.72 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 2H; 2CHCH2), 6.66 (d,
J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.56 (t, J(H,H) ˆ 2.3 Hz, 1H; 1arom. H),
5.75 (dd, J(H,H) ˆ 17.6, 0.9 Hz, 2H; 2vinyl. H), 5.25 (dd, J(H,H) ˆ 10.9,
0.9 Hz, 2H; 2vinyl. H), 5.02 (s, 4H; 2CH2O), 5.01 (s, 2H; CH2O), 1.40 (s,
9H; 3CH3); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 196.73, 161.02, 160.16,
158.70, 139.06, 138.85, 137.41, 137.01, 136.43, 136.26, 134.91, 132.99, 127.74,
126.44, 120.51, 115.52, 115.01, 114.66, 114.15, 106.35, 101.67, 88.23, 87.10,
69.90, 34.98, 29.12; IR (CHCl3): nÄ ˆ 3008 (m), 2964 (m), 2867 (w), 1653 (s),
1599 (s), 1508 (s), 1456 (s), 1409 (m), 1373 (m), 1332 (w), 1294 (m), 1157 (s),
1017 (w), 991 (w), 914 (w), 833 cm 1; Hi-Res-MALDI: m/z (%): 671.2778
‡
831 cm 1; MALDI-TOF-MS (2,5-DHB): 1176.7 [M‡H] ; elemental anal-
ysis calcd (%) for C78H82N2O8 (1175.53): C 79.70, H 7.03, N 2.38; found: C
79.83, H 7.03, N 1.81.
Compound 15: A solution of 5b (1.72 g, 3.1 mmol) and (R,R)-diphenyl
ethylene diamine (333 mg, 1.6 mmol) in EtOH (80 mL) was heated under
reflux for 12 h, according to GP II.[28b, 29b] Workup and flash column
chromatography (pentane/CH2Cl2 1:1) yielded 15 (1.46 g, 73%) as a yellow
foam. Rf (hexane/CH2Cl2 1:2): 0.57; [a]DRT
ˆ
30.7 (c ˆ 0.98 in CHCl3);
1H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ 13.50 (s, 2H; 2OH), 8.28 (s,
2H; 2imine H), 7.41 ± 7.17 (m, 26H; 26arom. H), 6.98 (d, J(H,H) ˆ 3.0 Hz,
2H; 2arom. H), 6.70 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 4H; 4CHCH2), 6.64 (d,
J(H,H) ˆ 2.3 Hz, 4H; 4arom. H), 6.53 (t, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H),
6.50 (d, J(H,H) ˆ 3.0 Hz, 2H; 2arom. H), 5.74 (dd, J(H,H) ˆ 17.6, 0.9 Hz,
4H; 4vinyl. H), 5.24 (dd, J(H,H) ˆ 10.9, 0.9 Hz, 4H; 4vinyl. H), 4.99 (s, 8H,
4OCH2), 4.80 (s, 4H; 2OCH2), 4.69 (s, 2H; 2PhCHN), 1.41 (s, 18H;
6CH3); 13C NMR (100 MHz, CDCl3, 258C): d ˆ 166.77, 160.09, 155.07,
150.39, 139.63, 139.38, 138.82, 137.35, 136.44, 136.32, 128.35, 128.03, 127.75,
127.56, 126.41, 119.47, 117.84, 114.10, 112.87, 106.44, 101.61, 80.18, 70.63,
69.84, 35.00, 29.29; IR (CHCl3): nÄ ˆ 3087 (w), 3005 (w), 2953 (m), 2861 (w),
‡
((3) [M‡Na] , calcd 671.2773), 274.0428 (13), 137.0237 (21), 136.5219 (6),
91.0151 (9); elemental analysis calcd (%) for C44H40O5 (648.79): C 81.46,
H 6.21; found: C 81.44, H 6.36.
Compound 12: A solution of 5a (2.0 g, 4.0 mmol) and (R,R)- cyclohexane
diamine (230 mg, 2.0 mmol) in EtOH (40 mL) was heated under reflux for
5 h, according to GP II.[28b, 29b] Workup and purification by flash column
chromatography (pentane/CH2Cl2 1:1) yielded 12 (1.63 g, 75%) as a yellow
foam. Rf (pentane/CH2Cl2 1:1): 0.62; [a]DRT
ˆ
125.9 (c ˆ 0.53 in CHCl3);
1H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ 13.50 (s, 2H; 2OH), 8.21 (s,
2H; 2imine H), 7.42 ± 7.30 (m, 20H; 20arom. H), 6.98 (d, J(H,H) ˆ 3.0 Hz,
2H; 2arom. H), 6.65 (d, J(H,H) ˆ 2.3 Hz, 4H; 4arom. H), 6.56 (t, J(H,H) ˆ
2.3 Hz, 2H; 2arom. H), 6.52 (d, J(H,H) ˆ 3.0 Hz, 2H; 2arom. H), 5.02 (s,
8H, 4OCH2), 4.83 (s, 2H; OCH2), 4.82 (s, 2H; OCH2), 3.35 ± 3.28 (m, 2H;
2CH2CHN), 2.01 ± 1.98 (m, 2H; 2cyclohexyl H), 1.91 ± 1.88 (m, 2H;
2cyclohexyl H), 1.77 ± 1.75 (m, 2H; 2cyclohexyl H), 1.50 ± 1.45 (m, 2H;
2cyclohexyl H), 1.40 (s, 18H; 6CH3); 13C NMR (100 MHz, CDCl3, 258C):
d ˆ 165.40, 160.14, 150.32, 139.68, 138.71, 136.81, 128.58, 127.99, 127.55,
155.05, 119.03, 117.87, 112.69, 106.40, 101.60, 72.36, 70.65, 70.09, 34.95, 33.06,
29.30, 24.29; IR (CHCl3): nÄ ˆ 3036 (w), 2944 (m), 2862 (m), 1631 (m), 1595
(s), 1446 (s), 1380 (m), 1328 (s), 1297 (w), 1277 (w), 1164 (s), 1046 (s),
1631 (m), 1594 (s), 1513 (m), 1451 (s), 1436 (s), 1405 (w), 1369 (m), 1328 (s),
1297 (w), 1277 (w), 1154 (s), 1046 (s), 1020 (m), 990 (w), 913 (m), 831 cm
MALDI-TOF-MS (2,5-DHB): 1296.5 [M‡Na] , 1274.5 [M‡H] ; elemen-
tal analysis calcd (%) for C86H84N2O8 (1273.60): C 81.10, H 6.65, N 2.20;
found: C 81.08, H 6.84, N 2.16.
1
;
‡
‡
Compound 16: A solution of 7a (1.50 g, 1.6 mmol) and (R,R)-cyclohexane
diamine (93 mg, 0.8 mmol) in EtOH (40 mL) was heated under reflux for
12 h, following GP II.[28b, 29b] Workup and purification by flash column
chromatography (pentane/CH2Cl2 1:2) afforded 16 (1.18 g, 75%) as a
yellow foam. Rf (hexane/CH2Cl2 1:2): 0.31; [a]DRT
ˆ
60.1 (c ˆ 0.97 in
CHCl3); 1H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ 13.50 (s, 2H; 2OH),
8.20 (s, 2H; 2imine H), 7.43 ± 7.28 (m, 40H; 40arom. H), 6.98 (d, J(H,H) ˆ
3.0 Hz, 2H; 2arom. H), 6.66 (d, J(H,H) ˆ 2.3 Hz, 8H; 8arom. H), 6.64 (d,
J(H,H) ˆ 2.3 Hz, 4H; 4arom. H), 6.56 (t, J(H,H) ˆ 2.3 Hz, 4H; 4arom. H),
6.52 (t, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.50 (d, J(H,H) ˆ 2.9 Hz, 2H;
2arom. H), 5.01 (s, 16H, 8OCH2), 4.94 (s, 8H, 4OCH2), 4.81 (s, 2H;
836 cm 1; MALDI-TOF-MS (2,5-DHB): 1094.3 [M‡Na] , 1072.4 [M‡H] ;
elemental analysis calcd (%) for C70H74N2O8 (1071.38): C 78.48, H 6.96, N
2.61; found: C 78.40, H 7.04, N 2.66.
‡
‡
Compound 13: According to GP II, a solution of 5a (2.0 g, 4.0 mmol) and
(R,R)-diphenyl ethylene diamine (428 mg, 2.0 mmol) in EtOH (40 mL) was
2884
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0947-6539/01/0713-2884 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 13

Enantioselective Epoxidation
2873±2887
OCH2), 4.80 (s, 2H; OCH2), 3.31 ± 3.28 (m, 2H; 2CH2CHN), 2.00 ± 1.96 (m,
2H; 2cyclohexyl H), 1.89 ± 1.87 (m, 2H; 2cyclohexyl H), 1.74 ± 1.72 (m, 2H;
2cyclohexyl H), 1.49 ± 1.46 (m, 2H; 2cyclohexyl H), 1.39 (s, 18H; 6CH3);
13C NMR (100 MHz, CDCl3, 258C): d ˆ 196.65, 160.20, 160.16, 160.06,
155.07, 139.67, 139.22, 138.74, 136.78, 136.74, 128.61, 128.58, 128.04, 128.00,
127.57, 127.52, 106.47, 106.41, 101.61, 101.54, 70.13, 70.10, 70.02, 69.98, 34.95,
29.30, 29.13; IR (CHCl3): nÄ ˆ 3067 (w), 3005 (w), 2933 (m), 2872 (m), 1595
(s), 1492 (w), 1451 (s), 1374 (m), 1328 (m), 1297 (m), 1154 (s), 1051 (s),
136.43, 136.29, 128.58, 128.33, 128.03, 127.75, 127.56, 126.41, 119.45, 117.83,
114.09, 106.48, 106.39, 101.61, 101.56, 80.13, 70.67, 69.95, 69.83, 35.00, 29.29;
IR (CHCl3): nÄ ˆ 3682 (w), 3005 (m), 2954 (w), 2872 (w), 1595 (s), 1513 (w),
1451 (s), 1374 (m), 1328 (m), 1292 (w), 1154 (s), 1051 (s), 990 (w), 913 (w),
‡
831 cm 1; MALDI-TOF-MS (2,5-DHB): 2227.4 [M] ; elemental analysis
calcd (%) for C150H140N2O16 (2226.72): C 80.91, H 6.34, N 1.26; found: C
80.89, H 6.52, N 1.07.
Compound 20: A solution of 11 (1.40 g, 2.2 mmol) and (R,R)-cyclohexane
diamine (123 mg, 1.1 mmol) in EtOH (25 mL) was heated under reflux for
2 h, following GP II.[28b, 29b] After workup and purification of the residue by
flash column chromatography (pentane/CH2Cl2 1:1 ! 1:2) 20 (1.25 g, 84%)
‡
836 cm 1; MALDI-TOF-MS (2,5-DHB): 1922.5 [M‡2] ; elemental anal-
ysis calcd (%) for C126H122N2O16 (1920.32): C 78.81, H 6.40, N 1.46; found: C
78.69, H 6.50, N 1.43.
Compound 17: A solution of 7a (1.00 g, 1.1 mmol) and (R,R)-diphenyl
ethylene diamine (212 mg, 0.5 mmol) in EtOH (40 mL) was heated under
reflux for 12 h, according to GP II.[28b, 29b] Workup and purification by flash
column chromatography (pentane/CH2Cl2 1:2) afforded 17 (0.80 g, 73%) as
was obtained as a yellow foam. Rf (pentane/CH2Cl2 1:1): 0.28; [a]DRT
ˆ
‡151.3 (c ˆ 0.68 in CHCl3); 1H NMR (500 MHz, CDCl3, 258C, TMS): d ˆ
14.10 (s, 2H; 2OH), 8.24 (s, 2H; 2imine H), 7.42 ± 7.34 (m, 22H; 22arom.
H), 7.17 (d, J(H,H) ˆ 2.0 Hz, 2H; 2arom. H), 6.89 ± 6.88 (m, 4H; 4arom.
H), 6.72 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 4H; 4CHCH2), 6.65 (d, J(H,H) ˆ
2.3 Hz, 4H; 4arom. H), 6.55 (t, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 5.75 (dd,
J(H,H) ˆ 17.6, 0.8 Hz, 4H; 4vinyl. H), 5.24 (dd, J(H,H) ˆ 10.9, 0.8 Hz, 4H;
4vinyl. H), 5.02 (s, 8H; 4OCH2), 5.00 (s, 4H, 2OCH2), 3.35 ± 3.33 (m, 2H;
2CH2CHN), 2.02 ± 1.99 (m, 2H; 2cyclohexyl H), 1.91 ± 1.89 (m, 2H;
2cyclohexyl H), 1.77 ± 1.75 (m, 2H; 2cyclohexyl H), 1.50 ± 1.47 (m, 2H;
2cyclohexyl H), 1.42 (s, 18H; 6CH3); 13C NMR (125 MHz, CDCl3, 258C):
d ˆ 165.08, 160.69, 160.15, 158.37, 139.18, 137.74, 137.40, 136.45, 136.30,
132.98, 132.85, 132.67, 127.74, 126.44, 118.38, 116.17, 114.90, 114.13, 112.73,
106.34, 101.71, 88.28, 87.11, 72.21, 69.90, 34.88, 32.89, 29.26, 24.23; IR
(CHCl3): nÄ ˆ 3008 (w), 2942 (m), 2867 (m), 1630 (s), 1597 (s), 1508 (s), a443
(s), 1406 (w), 1373 (m), 1293 (m), 1157 (s), 1065 (m), 1016 (m), 990 (w), 914
(m), 832 cm 1; Hi-Res-MALDI: m/z (%): 1377.6791 (17), 1376.6740 (32),
a yellow foam. Rf (hexane/CH2Cl2 1:2): 0.33; [a]DRT
ˆ
13.1 (c ˆ 0.97 in
CHCl3); 1H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ 13.40 (s, 2H; 2OH),
8.26 (s, 2H; 2imine H), 7.42 ± 7.28 (m, 50H; 50arom. H), 6.99 (d, J(H,H) ˆ
3.0 Hz, 2H; 2arom. H), 6.66 (d, J(H,H) ˆ 2.3 Hz, 8H; 8arom. H), 6.64 (d,
J(H,H) ˆ 2.3 Hz, 4H; 4arom. H), 6.55 (t, J(H,H) ˆ 2.3 Hz, 4H; 4arom. H),
6.52 (t, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 6.50 (d, J(H,H) ˆ 3.0 Hz, 2H;
2arom. H), 5.00 (s, 16H, 8OCH2), 4.93 (s, 8H, 4OCH2), 4.80 (s, 4H;
2OCH2), 4.68 (s, 2H; 2PhCHN), 1.40 (s, 18H; 6CH3); 13C NMR (100 MHz,
CDCl3, 258C): d ˆ 166.78, 160.20, 160.15, 160.06, 155.09, 139.63, 139.38,
139.21, 136.77, 136.73, 128.60, 128.58, 128.34, 128.04, 128.00, 127.57, 106.46,
106.40, 101.60, 101.55, 76.70, 70.67, 70.13, 70.10, 70.02, 70.70, 35.60, 29.29,
29.13; IR (CHCl3): nÄ ˆ 3067 (w), 3015 (m), 2964 (w), 2871 (m), 1595 (s),
1
1497 (w), 1451 (s), 1374 (s), 1328 (s), 1292 (m), 1154 (s), 1051 (s), 836 cm
;
‡
‡
‡
MALDI-TOF-MS (2,5-DHB): 2041.2 [M‡Na] , 2019.3 [M‡H] ; elemen-
tal analysis calcd (%) for C134H124N2O16 (2018.42): C 79.74, H 6.19, N 1.39;
found: C 79.69, H 5.98, N 1.22.
1375.6769 ((34) [M‡H] , calcd 1375.6775), 1164.5344 (15), 1163.5267 (17),
1022.5306 (14), 1021.5225 (27), 1020.5157 (35), 1019.5102 (36), 903.4442
(32), 847.3792 (31), 667.3534 (44), 666.3447 (66), 665.3405 (100), 117.0702
(99); elemental analysis calcd (%) for C94H90N2O8 (1375.73): C 82.07,
H 6.59, N 2.04; found: C 82.06, H 6.66, N 2.06.
Compund 18: According to GP II, a solution of 7b (0.84 g, 0.8 mmol) and
(R,R)-cyclohexane diamine (47 mg, 0.4 mmol) in EtOH (40 mL) was
heated under reflux for 4 h.[28b, 29b] Workup and purification of the crude
product by flash column chromatography (CH2Cl2/pentane 2:1 ! CH2Cl2)
afforded 18 (0.61 g, 70%) as a yellow foam. Rf (pentane/CH2Cl2 1:2): 0.41;
Compound 21: A solution of 11 (1.11 g, 1.72 mmol) and (R,R)-diphenyl
ethylene diamine (182 mg, 0.86 mmol) in EtOH (40 mL) was heated under
reflux for 3 h, according to GP II.[28b, 29b] Workup and flash column
chromatography (pentane/CH2Cl2 1:1 ! 1:2) of the residue yielded 21
[a]RDT
ˆ
58.8 (c ˆ 0.34 in CHCl3); 1H NMR (400 MHz, CDCl3, 258C,
TMS): d ˆ 13.48 (s, 2H; 2OH), 8.17 (s, 2H; 2imine H), 7.36 (dd, J(H,H) ˆ
20.6, 8.3 Hz, 32H; 32arom. H), 6.97 (d, J(H,H) ˆ 3.0 Hz, 2H; 2arom. H),
6.69 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 8H; 8CHCH2), 6.65 ± 6.63 (m, 12H;
12arom. H), 6.53 (t, J(H,H) ˆ 2.3 Hz, 4H; 4arom. H), 6.51 (t, J(H,H) ˆ
2.3 Hz, 2H; 2arom. H), 6.49 (d, J(H,H) ˆ 3.0 Hz, 2H; 2arom. H), 5.73 (d,
J(H,H) ˆ 17.6, 0.9 Hz, 8H; 8vinyl. H), 5.23 (d, J(H,H) ˆ 10.9, 0.9 Hz, 8H;
8vinyl. H), 4.98 (s, 16H, 8OCH2), 4.92 (s, 8H, 4OCH2), 4.79 (s, 2H; OCH2),
4.78 (s, 2H; OCH2), 3.29 ± 3.27 (m, 2H; 2CH2CHN), 2.00 ± 1.96 (m, 2H;
2cyclohexyl H), 1.87 ± 1.85 (m, 2H; 2cyclohexyl H), 1.73 ± 1.70 (m, 2H;
2cyclohexyl H), 1.47 ± 1.45 (m, 2H; 2cyclohexyl H), 1.38 (s, 18H; 6CH3);
13C NMR (100 MHz, CDCl3, 258C): d ˆ 165.47, 160.10, 160.05, 155.08,
150.35, 139.66, 139.25, 138.74, 137.34, 136.44, 136.30, 127.83, 127.76, 127.68,
126.41, 126.30, 119.00, 117.87, 114.09, 112.70, 106.50, 106.40, 101.63, 101.56,
72.30, 70.69, 69.96, 69.84, 34.95, 32.98, 29.30; IR (CHCl3): nÄ ˆ 3005 (w), 2933
(m), 2872 (w), 1595 (s), 1513 (w), 1451 (m), 1410 (w), 1374 (m), 1333 (m),
1297 (w), 1154 (s), 1051 (m), 1015 (w), 990 (m), 913 (m), 831 cm 1; MALDI-
(1.18 g, 94%) as a yellow foam. Rf (pentane/CH2Cl2 1:1): 0.24; [a]DRT
ˆ
1
‡67.9 (c ˆ 0.69 in CHCl3); H NMR (500 MHz, CDCl3, 258C, TMS): d ˆ
14.03 (s, 2H; 2OH), 8.27 (s, 2H; 2imine H), 7.42 ± 7.22 (m, 32H; 32arom.
H), 7.16 (d, J(H,H) ˆ 2.0 Hz, 2H; 2arom. H), 6.90 ± 6.88 (m, 4H; 4arom.
H), 6.71 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 4H; 4CHCH2), 6.65 (d, J(H,H) ˆ
2.3 Hz, 4H; 4arom. H), 6.55 (t, J(H,H) ˆ 2.3 Hz, 2H; 2arom. H), 5.75 (dd,
J(H,H) ˆ 17.6, 0.8 Hz, 4H; 4vinyl. H), 5.24 (dd, J(H,H) ˆ 10.9, 0.8 Hz, 4H;
4vinyl. H), 5.02 (s, 8H; 4OCH2), 5.00 (s, 4H, 2OCH2), 4.73 (s, 2H;
2CH2CHN), 1.44 (s, 18H; 6CH3); 13C NMR (125 MHz, CDCl3, 258C): d ˆ
166.44, 160.50, 160.15, 158.40, 139.18, 139.03, 137.82, 137.41, 136.45, 136.29,
133.24, 133.03, 132.85, 128.47, 127.98, 127.75, 126.44, 118.39, 116.14, 114.92,
114.14, 112.92, 106.35, 101.71, 88.22, 87.18, 80.05, 69.90, 34.95, 29.26; IR
(CHCl3): nÄ ˆ 3007 (w), 2999 (w), 2872 (w), 1628 (s), 1597 (s), 1508 (s), 1453
(s), 1375 (m), 1293 (m), 1157 (s), 1050 (w), 1029 (w), 1016 (w), 990 (w),
913(w), 832 cm 1; Hi-Res-MALDI: m/z (%): 1497.6843 (35), 1496.6777
‡
(54), 1495.6748 ((48) [M‡Na] , calcd 1495.6751), 1475.6987 (17), 1474.6972
‡
‡
TOF-MS (2,5-DHB): 2129.1 [M] ; elemental analysis calcd (%) for
(26), 1473.6933 ((25) [M‡H] , calcd 1473.6932), 1391.6180 (34), 1390.6216
C142H138N2O16 (2128.62): C 80.12, H 6.53, N 1.32; found: C 79.99, H 6.60,
N 1.17.
(39), 1369.6408 (44), 1368.6357 (36), 759.3336 (37), 758.3270 (39), 743.3156
(37), 739.3635 (49), 738.3609 (83), 737.3484 (56), 736.3456 (100); elemental
analysis calcd (%) for C102H92N2O8 (1473.83): C 83.12, H 6.29, N 1.90;
found: C 82.94, H 6.38, N 1.99.
Compound 19: A solution of 7b (0.88 g, 0.9 mmol) and (R,R)-diphenyl
ethylene diamine (91 mg, 0.45 mmol) in EtOH (40 mL) was heated under
reflux for 4 h, following GP II.[28b, 29b] Workup and purification by flash
column chromatography (CH2Cl2/pentane 2:1 ! CH2Cl2) yielded 19
Loading of Salens 12, 13, 16, and 17 with Mn. General procedure III
(GP III): Detailed example for the preparation of 16 ´ Mn(Cl).[28, 29b, 33]
A
(0.32 g, 34%) as a yellow foam. Rf (pentane/CH2Cl2 1:2): 0.39; [a]DRT
ˆ
solution of 16 (500 mg, 0.26 mmol) in EtOH (15 mL)/toluene (15 mL) was
treated with Mn(OAc)2 ´ 4H2O (638 mg, 2.6 mmol, 10 equiv) and heated
under reflux for 6 h while air was bubbled through the reaction solution.
Then LiCl (221 mg, 5.2 mmol, 20 equiv) was added and the mixture was
stirred at room temperature for a further 12 h. Toluene (20 mL) and H2O
(20 mL) were added, the phases were separated and the organic layer was
washed with H2O (20 mL) again. After the organic phases were dried over
MgSO4, the solvent was evaporated and the crude product was purified by
flash column chromatography (hexane/CH2Cl2 1:2) to give 16 ´ Mn(Cl)
(78%) as a dark brown foam. IR (CHCl3): nÄ ˆ 3067 (w), 3035 (w), 3005 (w),
2944 (w), 3872 (w), 1595 (s), 1544 (m), 1497 (w), 1444 (s), 1415 (w), 1369
1
16.2 (c ˆ 0.85 in CHCl3); H NMR (400 MHz, CDCl3, 258C, TMS): d ˆ
13.41 (s, 2H; 2OH), 8.25 (s, 2H; 2imine H), 7.35 (dd, J(H,H) ˆ 21.1, 8.2 Hz,
32H; 32arom. H), 7.21 ± 7.15 (m, 10H; 10arom. H), 6.99 (d, J(H,H) ˆ
3.0 Hz, 2H; 2arom. H), 6.69 (dd, J(H,H) ˆ 17.6, 10.9 Hz, 8H; 8CHCH2),
6.64 ± 6.63 (m, 12H; 12arom. H), 6.53 ± 6.51 (m, 6H; 6arom. H), 6.49 (d,
J(H,H) ˆ 3.0 Hz, 2H; 2arom. H), 5.73 (dd, J(H,H) ˆ 17.6, 0.9 Hz, 8H;
8vinyl. H), 5.23 (dd, J(H,H) ˆ 10.9, 0.9 Hz, 8H; 8vinyl. H), 4.98 (s, 16H,
8OCH2), 4.92 (s, 8H, 4OCH2), 4.78 (s, 4H; 2OCH2), 4.67 (s, 2H;
2PhCHN), 1.40 (s, 18H; 6CH3); 13C NMR (100 MHz, CDCl3, 258C): d ˆ
166.81, 160.09, 160.04, 155.08, 150.41, 139.63, 139.35, 139.23, 138.84, 137.33,
Chem. Eur. J. 2001, 7, No. 13
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2885

D. Seebach et al.
FULL PAPER
(m), 1338 (m), 1287 (m), 1154 (s), 1051 (m), 1036 (m), 831 cm 1; MALDI-
TOF-MS (2,5-DHB): 1974.2 [M-(HCl)] , 1944.3, 1922.1; elemental analysis
calcd (%) for C126H120N2O16ClMn (2008.70): C 75.34, H 6.02, N 1.39, Cl
1.76; found: C 75.35, H 6.07, N 1.28, Cl 1.92.
Epoxidation of olefins mediated by polymer-bound Mn-Salens p-2 ´ , p-3´,
p-14 ´ , p-15 ´ and p-18 ´ ± p-21 ´ Mn(Cl) under heterogeneous conditions to
give epoxides 22. General procedure VII (GP VII): Detailed example for
the epoxidation of styrene using polymer p-21 ´ Mn(Cl) to give styrene
oxide (22a). Polymer beads of p-21 ´ Mn(Cl) (404 mg, 0.052 mmol,
0.2 equiv, loading: 0.128 mmolg 1) were suspended in CH2Cl2 (4.4 mL).
After addition of styrene (30 mL, 0.26 mmol, 1 equiv) and NMO (151 mg,
1.29 mmol, 5 equiv) the reaction mixture was cooled to 208C and m-
CPBA (89 mg, 0.52 mmol, 2 equiv) was added. After stirring at this
temperature for 30 min, a sample was taken from the reaction mixture,
Et2O and 1n KOH were added and the organic layer was analyzed by CGC:
er (22a): 80:20, conversion: quantitative. The reaction solution was
withdrawn by syringe and the polymer beads were washed with CH2Cl2
(3 Â 5 mL). Et2O (50 mL) and 1n KOH (50 mL) were added to the
combined organic phases, the aqueous phase was separated and the organic
layer was extracted with H2O (50 mL). After drying of the combined
organic layers over MgSO4 and evaporation of the solvent, pure 22a was
obtained as a colorless oil. For multiple use of the catalyst p-21 ´ Mn(Cl),
the washed polymer beads were dried under high vacuum, resuspended in
CH2Cl2 and the substrates were added as described above.
‡
Epoxidation of olefins mediated by Mn-Salens 12 ´ , 13 ´ , 16 ´ and 17 ´
Mn(Cl) under homogeneous conditions to give epoxides 22. General
procedure IV (GP IV): Detailed example for the epoxidation of styrene
using 12 ´ Mn(Cl) to give styrene oxide (22a).[41] NMO (87 mg, 0.75 mmol,
5 equiv) was added to
a solution of 12 ´ Mn(Cl) (36 mg, 0.03 mmol,
0.2 equiv) and styrene (17 mL, 0.15 mmol, 1 equiv) in CH2Cl2 (2.5 mL).
After the reaction mixture was cooled to 208C, m-CPBA (51 mg, 0.3 mmol,
2 equiv) was added and the suspension was stirred at this temperature for
30 min. Et2O (50 mL) and 1n KOH (50 mL) were added, the phases were
separated and the organic phase was extracted with H2O (50 mL). Drying
of the organic phase over MgSO4 and evaporation of the solvent gave the
crude product mixture. The enantioselectivity of 22a and the conversion
were determined by CGC (b-CD; heating 908C/isothermal; pressure 1.0 bar
H2; tR (styrene) ca. 3.2 min, tR (first enantiomer (22a)) ca. 12.3 min,
tR (second enantiomer (22a)) ca. 12.8 min): er (22a): 73:27, conversion:
91%.
Loading of Salen polymers p-2, p-14, and p-20 with Cr to generate Cr-Salen
polymers p-2 ´ , p-14 ´ , and p-20 ´ Cr(Cl). General procedure VIII (GP
VIII): Detailed example for the loading of polymer p-20 with CrCl2 to give
polymer-bound Cr-Salen p-20´ Cr(Cl). CrCl2 (17 mg, 0.138 mmol, 1.1 equiv)
was added under Ar to a suspension of polymer beads p-20 (958 mg,
0.126 mmol, loading: 0.131 mmolg 1) in THF (7 mL), the beads thereby
immediately turning brown. After stirring under Ar for 3 h, the flask was
opened and the suspension was stirred with contact to air for a further
12 h.[48] Washing of the beads with THF (600 mL) and toluene (100 mL)
CGC methods for epoxides 22b ± f: 22b: b-CD; heating 808C/isothermal;
pressure 1.0 bar H2; tR (3-methyl styrene) ca. 7.1 min, tR (first enantiomer
(22b)) ca. 34.3 min, tR (second enantiomer (22b)) ca. 35.7 min; 22c: b-CD;
heating 908C/isothermal; pressure 1.0 bar H2; tR ((E)-phenylpropene) ca.
4.6 min, tR (first enantiomer (22c)) ca. 8.3 min, tR (second enantiomer
(22c)) ca. 8.7 min; 22d: b-CD; heating: 1208C/isothermal/10 min, 1.58C/
min, 1408C/isothermal/10 min; pressure 1.0 bar H2; tR (1-phenyl cyclo-
hexene) ca. 18.3 min, tR (first enantiomer (22d)) ca. 24.2 min, tR (second
enantiomer (22d)) ca. 24.5 min; 22e: b-CD; heating 1408C/isothermal;
pressure 1.0 bar H2; tR (dihydronaphthalene) ca. 3.7 min, tR (first enan-
tiomer (22e)) ca. 10.2 min, tR (second enantiomer (22e)) ca. 10.6 min; 22 f: b-
CD; heating 1608C/isothermal; pressure 1.0 bar H2; tR (trans-stilbene) ca.
21.1 min, tR (first enantiomer (22 f)) ca. 23.5 min, tR (second enantiomer
(22 f)) ca. 24.8 min.
and drying under high vacuum afforded polymer p-20 ´ Cr(Cl) (916 mg,
1
95%) as brown beads with a new theoretical loading of 0.130 mmolg
.
Hetero-Diels ± Alder reaction of Danishefskyꢀs diene with aldehydes to
give cycloadducts 23, mediated by polymer-bound p-2 ´ , p-14 ´ , and p-20 ´
Cr(Cl). General procedure IX (GP IX): Detailed example for the cyclo-
addition of Danishefskyꢁs diene to capronaldehyde (!23b), catalyzed by
p-14 ´ Cr(Cl).[48] A suspension of polymer beads p-14 ´ Cr(Cl) (150 mg,
0.02 mmol, 0.02 equiv, loading: 0.133 mmolg 1), Danishefskyꢁs diene (195 mL,
1.0 mmol, 1 equiv) and capronaldehyde (123 mL, 1.0 mmol, 1 equiv) in tert-
butyl methyl ether (TBME) (1 mL) was stirred at room temperature under
Ar for 24 h. The reaction solution was withdrawn by syringe and the
polymer beads were washed with Et2O (3 Â 5 mL). TFA (two drops) was
added to the combined organic fractions and the solvent was evaporated.
Purification of the crude product by flash column chromatography
(hexane/ethyl acetate 4:1) afforded 23b (97 mg, 58%). The enantiomeric
purity of 23b was analyzed by CGC (b-CD; heating 1208C/isothermal;
pressure 1.0 bar H2; tR (S)-23b ca. 25.0 min, tR (R)-23b ca. 25.7 min): (R)/
(S)-23b: 86:14. In order to determine the conversion of the reaction a
sample was taken from the reaction mixture prior to workup, diluted with
Et2O and treated with TFA (one drop). CGC analysis thereof (b-CD; heating
1208C/isothermal; pressure 1.0 bar H2; tR (capronaldehyde) ca. 1.4 min, tR
(23b) as described above) showed a conversion of 70%. For multiple use of
the polymer-bound catalyst, the beads were dried under high vacuum,
resuspended in TBME and substrates were added as described above.
Suspension copolymerization of Salen cross-linkers 2, 3, 14, 15, and 18 ± 21
with styrene to give polymers p-2, p-3, p-14, p-15, and p-18 ± p-21. General
procedure V (GP V): Detailed example for the preparation of Salen/
styrene copolymer p-15.[43] In a three-necked flask, equipped with a
condenser and an overhead stirrer, a warm solution of poly(vinyl alcohol)
(115 mg, degree of polymerization 100000, 86 ± 89% hydrolyzed) in H2O
(10 mL), which was prepared by violent stirring at 40 ± 508C and
subsequent filtering to remove insoluble residues, was added to a solution
of 15 (599 mg, 0.47 mmol), styrene (2.94 g, 28.2 mmol), and AIBN (130 mg)
in THF (0.6 mL) and benzene (4.5 mL). After stirring at room temperature
for 5 min to generate a homogeneous emulsion, the temperature was raised
to 80 ± 858C during one hour. Having stirred at this temperature for 20 h,
the suspension was filtered over a glass filter (G2) and the resulting
polymer beads were extensively washed with hot H2O (400 mL), H2O/
MeOH 1:1 (200 mL), MeOH (200 mL), THF (300 mL), MeOH (200 mL)
and pentane (200 mL). The beads were then dried under high vacuum for
several hours to give polymer p-15 (3.51 g, 99%, theoretical loading:
0.133 mmolg 1). The beads were sieved through a sieve (mesh widths: 1000,
800, 630, 500, 400, 250, 160, 100) to give fractions of uniform size.
The reactions with benzaldehyde and cyclohexane carboxaldehyde were
analogously performed. The enantiomer ratios of the corresponding
cycloadducts 23a and 23c were determined according to literature.[48]
According to this general procedure, all polymers were prepared by
stoichiometrically adjusting the amounts of organic solvents, AIBN, H2O
and poly(vinyl alcohol) to the amount of monomers used.
Loading of Salen polymers p-2, p-3, p-14, p-15, and p-18 ± p-21 with Mn to
generate Mn-Salen polymers p-2 ´ , p-3 ´ , p-14 ´ , p-15 ´ and p-18 ´ ± p-21 ´
Mn(Cl). General procedure VI (GP VI): Detailed example for the
generation of polymer p-15 ´ Mn(Cl).[28b, 31] Mn(OAc)2 ´ 4H2O (192 mg,
Acknowledgements
We gratefully acknowledge a postdoctoral stipend for J.K.K. from Neste
Oyꢀs Foundation (Finland), funding by the Swiss National Science
Foundation (project no. 2027-048157 and 20-50674.97) and continuing
financial support of our research from Novartis Pharma AG (Basel).
0.79 mmol, 10 equiv) was added to
a suspension of p-15 (590 mg,
0.079 mmol, loading: 0.133 mmolg 1) in DMF (11 mL)/EtOH (5 mL)
whereupon the polymer beads immediately turned black. The suspension
was heated under reflux for 3 h while air was bubbled through the
suspension, then LiCl (68 mg, 1.57 mmol, 20 equiv) was added. After
stirring at room temperature for 12 h, the suspension was filtered over a
glass filter (G2) and the polymer beads were extensively washed with THF
(400 mL), MeOH (100 mL) and pentane (100 mL). After drying under high
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1
98%) were obtained with a new theoretical loading of 0.131 mmolg
.
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0947-6539/01/0713-2886 $ 17.50+.50/0
Chem. Eur. J. 2001, 7, No. 13

Enantioselective Epoxidation
2873±2887
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dendritic acetylene branch to 3-tert-butyl-5-bromo salicylic aldehyde
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dendritic acetylene moieties occurred under the coupling conditions,
with 11 being formed in only minor amounts.
[40] In solution generally less than 5 mol% of Mn-Salen are used for the
epoxidation reactions. We decided to use 20 mol% of catalyst both for
homogeneous and heterogeneous reactions. With the heterogeneous
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[46] For determination of the degree of conversion, a sample was taken
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Ê
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Â
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Received: January 8, 2001 [F2992]
Chem. Eur. J. 2001, 7, No. 13
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