Chiral linker 5: scope and limitations of arylsubstituted m-hydrobenzoins as solid supported open chain chiral auxiliaries for diastereoselective syntheses

Article abstract of DOI:10.1016/j.tetasy.2009.02.004

The applicability of five aryl substituted m-hydrobenzoin ethers already tested in the L-Selectride mediated stereoselective reduction of phenylglyoxylates as open chain chiral auxiliaries was further investigated via the α-alkylation of propionates, the addition of n-BuZnCl to phenylglyoxylates and the Diels-Alder reaction of acrylates with cyclopentadiene as model reactions. As up to 90% de could be achieved in the solution phase, two optimized auxiliary structures were immobilized on commercially available Wang-resin and applied as a reusable solid supported chiral auxiliaries in the same type of reactions.

Full text of DOI:10.1016/j.tetasy.2009.02.004

Tetrahedron: Asymmetry 20 (2009) 273–287
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral linker 5: scope and limitations of arylsubstituted m-hydrobenzoins
as solid supported open chain chiral auxiliaries for diastereoselective syntheses
*
Joachim Broeker, Max Knollmueller, Peter Gaertner
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
The applicability of five aryl substituted m-hydrobenzoin ethers already tested in the L-SelectrideÒ mediated
Article history:
Received 15 August 2008
Revised 21 January 2009
Accepted 3 February 2009
Available online 13 March 2009
stereoselectivereduction of phenylglyoxylates asopen chain chiral auxiliaries was furtherinvestigated via the
a-alkylation of propionates, the addition of n-BuZnCl to phenylglyoxylates and the Diels–Alder reaction of
acrylates with cyclopentadiene as model reactions. As up to 90% de could be achieved in the solution phase,
two optimized auxiliary structures were immobilized on commercially available Wang-resin and applied as
a reusable solid supported chiral auxiliaries in the same type of reactions.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
thetic pathway included the desymmetrization of the m-hydro-
benzoins with commercially available NOE’s anhydrolactol,3
In previous articles1 we have already presented the synthesis of
m-hydrobenzoin derived chiral auxiliaries I and II and their appli-
cation either in solution phase chemistry or, after immobilization
on solid support, as a chiral linker2 for diastereoselective reactions
on solid support.
derivatization to build up the appropriate ether moieties or
immobilization on solid support and subsequent cleavage of
the chiral protecting group.1
During the primary investigations on the potential of the aux-
iliaries without aryl substituents to induce stereoselectivities in
different model reactions, selectivities of up to 91% de (and
84% de for the solid bound auxiliary) in the L-SelectrideÒ medi-
-keto esters1b,c and 36% de (or 28% de on so-
-alkylation of the corresponding
R1
R
R1
ated reduction of
lid support) in the
a
a
propionates1a could be obtained. Apart from that it could be
shown that after cleavage of the desired products, the solid
bound auxiliaries could be reused at least three times without
the loss of the stereoinducing ability,1a,c which is a benefit com-
pared to other known chiral linkers, for example, those based on
Evans oxazolidinones.4 Finally solid bound m-hydrobenzoin, used
as a chiral linker, was applied in the addition of n-BuZnCl to an
HO
HO
O
O
O
R2
R1
R1
I
II
a
-ketoester as the stereoselective key step during the synthesis
R = Bn, i-Bu, t-Bu, C(CH3)2CH2Ph, C(CH3)2CH2OCH3,
CH2CPh2OCH3, CH2CH2N(CH3)2 , Wang-resin
R1= H, 2-CH3, 2-CF3, 2-OCH3, 4-OCH3
R2= CH3, Wang-resin
of frontalin.1e
Further investigations showed that the steric, electronic and
coordinative properties of the auxiliaries could be easily varied
not only via the ether moiety and the sublinking unit of the
solid bound auxiliaries, but also to a large extent via the aryl
substituents of the m-hydrobenzoin structure itself. Both
a
The structures could be easily obtained starting from the
corresponding m-hydrobenzoins, which were in the case of
the aryl substituted derivatives, accessible via benzoin conden-
sation of the substituted benzaldehydes or via TMS-protected
cyanohydrins as an alternative strategy.1d The following syn-
methoxyethyl ether moiety or an ethyleneglycol sublinking
unit in the case of the solid phase experiments1c and o-meth-
oxy substituents on the aryl moieties of the hydrobenzoin1d
proved to have
a positive impact on the stereoselectivities
achievable in the L-SelectrideÒ mediated reduction of
esters.
a-keto
However, as the aryl substituted structures have so far only
been tested in one model reaction, the following experiments
* Corresponding author. Tel.: +43 15880115421; fax: +43 15880115492.
E-mail address: peter.gaertner@tuwien.ac.at (P. Gaertner).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.004

274
J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
should determine their applicability in different stereoselective
reactions such as the alkylation of propionates, the addition of
Zn-organyls to phenyl glyoxylates and Diels–Alder reactions on
acrylates. The results of these recent investigations will be pre-
sented herein.
HPLC-analysis of derivatives accessible by conversion with
methyl ester (Scheme 3).10
L-valine
Table 1 shows the results of the diastereoselective alkylations of
esters 8a–8e in comparison to selected results of previous investi-
gations already published. Additionally, the coupling constants of
the two benzylic hydrobenzoin protons in the substrates 8a–8f
are shown as well, following the interpretation model stated in
case of the stereoselective reduction of the corresponding phenyl
glyoxylates.1d,11
As can be seen from Table 1 (entries 1 and 3–5), the application
of an electron poor alkylating agent had a not very significant, but
negative, effect on the achievable diastereoselectivities, a larger
degree of racemization was observed during saponification of the
obtained esters 9f–9g due to the necessity for prolonged reaction
times and higher reaction temperatures causing the nitro substi-
tuted acids 10b to be obtained in only poor enantiomeric purities.
However, especially in the case of the 2-methoxy substituted aux-
iliaries (see entries 1 and 8), satisfactory diastereomeric ratios
were observed; looking at the correlation of de-values and the cor-
responding coupling constants determined for the benzylic protons
of the substrates 8a–8e, an interpretation based on the model pro-
posed by Rosini et al.11 seems obvious (Scheme 4).
Only in case of the synclinal enolate conformations A and B,
both of which should induce a coupling constant of 2–3 Hz, is an
extensive shielding of the enolate by the ether moiety guaranteed.
The less desirable conformation C should lead to a coupling con-
stant of 10–15 Hz, therefore explaining the low diastereomeric ra-
tios obtained with auxiliaries 8b–8d and 8f. As the coupling
constants had so far only been determined for the 8, the values
of the enolate intermediates would be more useful, further depro-
tonation experiments with 8a in THF-d8 and in situ 1H NMR mea-
surements of the obtained enolates were carried out. However, a
set of numerous signals was observed in the expected ppm-range
most likely due to the different Li-enolate–diisopropylamine
aggregates. Even after additional experiments with different diiso-
propylamine-concentrations and measurement of CH-correlation
spectra, no reliable signal assignment was possible. However, since
all relevant signals had coupling constants of 2.7–3.5 Hz which
were similar to the observed values for the educt, the conformation
of the educt and the intermediate seems to be very similar.
Finally, although no difference in the diastereomeric ratios was
2. Results and discussion
2.1. Evaluation of auxiliaries via model reactions in solution
phase
As mentioned above, a set of arylsubstituted m-hydrobenzo-
ins, as in the previous investigations including 2,20-dimethyl,
2,20-bistrifluoromethyl, 2,20-dimethoxy and 4,40-dimethoxy-m-
hydrobenzoin, was accessible via benzoin-condensation5 of the
corresponding benzaldehydes or in case of the 2-trifluoromethyl-
and 4-methoxysubstituted derivatives via an alternative route
involving the corresponding TMS-protected cyanohydrins
(Scheme 1).6
For the preliminary experiments in solution the corresponding
i-butyl ethers bearing a sterically demanding moiety, as well as
the methoxyethyl ether supplying further coordination sites, were
chosen as appropriate test systems. These were, as already
described,1d easily accessible via the selective protection of the
(R)-carbon centre of the substituted meso-hydrobenzoins using
exo-anhydrolactol 4 followed by etherification using NaH and
4-toluenesulfonic acid i-butyl esters 6a–6d or via an alternative
three-step procedure 6e and cleavage of the chiral protecting
group (Scheme 2).
As the
a-alkylation of esters and amides is a reaction type
that has been applied to a large variety of chiral auxiliaries in
solution,7 as well as enantiomerically pure linkers on the solid
phase,4a,4b,8 the
a-benzylation of propanoic acid esters was
chosen as the first alternative model reaction besides the al-
ready described L-SelectrideÒ mediated reduction of phenyl
glyoxylates. The results of the preliminary experiments using
m-hydrobenzoin as a chiral linker for solid phase and using
m-hydrobenzoin benzyl ether as
a chiral auxiliary for the
model reactions in solution have already been reported.1a It
seemed obvious to apply this model reaction to the aryl
substituted systems as well.
observed during the preliminary investigations,
a significant
The auxiliary structures were esterified with propanoic acid
according to the established procedure1a using DIC and catalytic
amounts of DMAP to provide the desired test systems for the mod-
el reactions in solution. As during the preliminary investigations,
the alkylation was carried out using LDA, as well as a combination
of LDA and LiCl as a deprotonation agent followed by the addition
of benzyl bromide. Additionally the influence of the electron den-
sity at the phenyl substituent of the alkylating agent was investi-
gated using 4-nitrobenzylbromide for the alkylation step. The
stereochemical outcome of the reactions was determined via 1H
NMR of the crude reaction mixtures as well as after saponification
via specific rotation measurements of the acids obtained8c,9 and
enhancement of selectivities could be achieved for the 2-methoxy
substituted derivatives 8a and 8e by the addition of 6 equiv LiCl
before the deprotonation of the substrate (see Table 1, entries 1,
2 and 8–11). According to the literature,12 this effect could, on
the one hand be due to an enhanced polarity of the media and
the more effective coordination of the Li-cation to the coordination
sites of the substrate. On the other hand changed aggregation de-
grees of the base as well as the enolate have been published.
To gain further insight into the scope of aryl substituted auxil-
iaries, the methoxy substituted structures, which had allowed
the highest selectivities during the model reactions carried out so
R1
R1
O
2a-2b: i
2c-2d: ii
O
OH
iii
OH
OH
R1
1a-1d
R1
R1
2a-2d
3a-3d
Scheme 1. Synthesis of hydrobenzoin derivatives; R1 = 2-OCH3 (1a–3a), 2-CH3 (1b–3b), 4-OCH3 (1c–3c), 2-CF3 (1d–3d). Reagents and conditions: (i): KCN, EtOH/H2O, 4 h
reflux (2a: 50%, 2b: 31%); (ii) (1) 1.1 equiv TMS-CN, cat. ZnI2, 1 h 100 °C, (2) 1 equiv LDA, 1 equiv ArCHO, DME, ꢀ65 °C, (3) 2 N HCl, THF, 12 h rt (2c: 51%, 2d: 79%); (iii) NaBH4,
EtOH, 3 h rt (3a: 73%, 3b: 63%, 3c: 65%, 3d: 21%).

J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
275
R1
R1
R1
R1
O
O
O
OH
OH
O
4
O
ii
(
O
iii
H
H
)
i
OH
OR2
H
OH
H
OR2
R1
R1
R1
5a-5d
R1
3a-3d
6a-6g
7a-7e
R1
R2
a
b
c
d
e
f
2-OCH3
2-CH3
4-OCH3
2-CF3
2-OCH3
2-OCH3
2-OCH3
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH2OCH3
CH2COOt-Bu
CH2CH2OH
g
Scheme 2. Desymmetrization and etherification of hydrobenzoin derivatives 3a–3d. Reagents and conditions: (i) 4-toluenesulfonic acid, CH2Cl2, 12 h rt (5a: 70%, 5b: 63%, 5c:
83%, 5d: 57%); (ii) (for 5a–5d): (1) NaH, (2) 4-toluenesulfonic acid i-butyl ester, DMF, 12 h rt (6a:76%, 6b: 93%, 6c: 77%, 6d: 99%); (ii) (5a?6f): (1) NaH, (2) bromoacetic acid t-
butyl ester, HMPT, THF, 12 h rt (72%); (6f?6g): LiAlH4, Et2O, 2 h rt (73%); (6g?6e): (1) NaH, (2) CH3I, DMF, 2 h rt (74%); (iii) 4-toluenesulfonic acid, CH2Cl2/MeOH, 12 h rt (7a:
96%, 7b: 86%, 7c: 80%, 7d: 91%, 7e: 85%).
R3
R1
R1
OH
O
O
i
ii
R1
OR2
O
O
OR2
R1
R1
OR2
R1
9a-9g
7a-7e
8a-8e
O
O
iii/iv
v
O
OH
N
H
O
R3
11
10a-10b
Scheme 3. Application of the test systems on the alkylation of propionates, cleavage and derivatization; for R1, R2 and R3 (7a–9g) see Scheme 2 and Table 1, R3 = H (10a), NO2
(10b); Reagents and conditions: (i) propanoic acid, DIC, DMAP, CH2Cl2, 12 h rt; (ii) (1) 3 equiv LDA, THF, 90 min ꢀ78 °C, (2) 8 equiv BnBr (for 9a–9e) or 8 equiv 4-NO2BnBr (for
9f–9g), 1 h ꢀ78 °C; (iii) (for 9a–9e?10a) 10 equiv LiOH, THF/MeOH/H2O, 1.5 h rt; (iv) (for 9f–9g?10b): 10 equiv LiOH, THF/MeOH/H2O, 48 h rt; (v)
CH2Cl2, 12 h ꢀ30 °C?rt.
L-Val-OMe, HOBt, DIC,
far, were tested on additional model applications. As the addition
of organometallics to phenylglyoxylic acid esters is a common
method for the evaluation of chiral auxiliaries13 and good results
have been achieved with the already tested unsubstituted sys-
tems1e, the addition of organo-Zn following the experiments of
Borieau et al.14 was carried out. Therefore 12a and 12b which were
already in hand from previous investigations1d were converted into
the corresponding 2-hydroxy-2-phenylhexanoic acid esters 13
using n-BuZnCl generated in situ from n-BuMgCl and ZnCl2 at
ꢀ78 °C in diethyl ether (Scheme 5).
the measurement of the specific rotations of the obtained acids
14.14 As Table 2 shows, the stereoselectivity obtained with the
unsubstituted hydrobenzoin structure 12c1e bearing coordination
sites only at the methoxyethyl ether moiety could, however, not
be reached with the methoxysubstituted compounds 12a and
12b. A possible explanation could be the competitive coordination
of the organo-Zn with the methoxy substituents and the methoxy-
ethyl ether leading to a reduced selectivity in the case of substrate
12e. However, if coordination is only possible with the methoxy
substituents, a better steric shielding of the reacting centre by
the sterically demanding i-butyl moiety is observed.
The stereoselectivities achieved were again determined via the
1H NMR of the crude reaction mixtures as well as via HPLC- and
NMR-analysis of the derivatives 15 obtained by conversion of the
Looking closer at the stereochemical outcome of the reaction, a
mechanism based on the coordination posted in the literature13a,14
does not seem very likely, as in case of a syn-arrangement of both
cleaved acids 14 with
L-valine methyl ester following an already
established procedure. Absolute configurations were assigned after
carbonyl groups as well as in the benzylic
a-hydrogen the steric

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J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
Table 1
Diastereoselective alkylation of propionates 8a–8e compared to results from preceding investigations
Entry
Ester
R1
R2
R3
3J(benz.) 8 (Hz)
dea (S,R,S)-9 (%)
1
2b
3
4
5
6
7
8
8a
8a
8a
8b
8b
8c
8d
8e
8e
8f
2-OCH3
2-OCH3
2-OCH3
2-CH3
2-CH3
4-OCH3
2-CF3
2-OCH3
2-OCH3
H
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH2OCH3
CH2CH2OCH3
CH2Ph
H
H
NO2
H
NO2
H
H
H
H
H
3.7
3.7
3.7
6.7
6.7
6.3
7.4
3.7
3.7
6.8
6.8
59
65
57c
44
30c
44
29
63
71
36
36
9b
10d
11b,d
8f
H
CH2Ph
H
a
Diastereoisomeric ratios determined by 1H NMR integration of crude reaction mixtures 9 and HPLC analysis of
L-valine methyl ester derivatives 11 of cleaved acids 10a;
absolute configuration of the major diastereoisomers approved by specific rotations of 10.9
b
6 equiv of LiCl as additive.
C
Only 14% ee (for 8a) and 11% ee (for 8b), respectively, by specific rotation of 10b due to racemization during the course of the saponification.
Data from Ref. 1a.
d
Ar
O
R`
H
O
O
O
R`
O
Ar
H
O
R`
OLi
Ar
H
OLi
H
H
H
OLi
A
B
C
11
Scheme 4. Conformation analysis based on the model proposed by Rosini et al.
O
OH
HO
O
i
ii
O
O
O
OR2 R1
R1
OR2
R
1
R1
OR2 R1
R1
7a, 7e, 7f
12a, 12e, 12f
13a, 13e, 13f
O
O
O
iii
iv
N
OH
H
OH
OH
O
15
14
Scheme 5. Application of the test systems on the addition of n-BuZnCl to phenylgyloxylates 12a, 12e and 12f, cleavage and derivatization; R1 = 2-OCH3 (7a–13a, 7e–13e), H
(7f–13f); R2 = CH2CH(CH3)2 (7a–13a), CH2CH2OCH3 (7e–13e), CH2Ph (7f–13f). Reagents and conditions: (i) phenylglyoxylic acid, DIC, DMAP, CH2Cl2, 12 h rt; (ii) 8.8 equiv
n-BuMgCl, 8 equiv ZnCl2, Et2O, 3 h ꢀ78 °C; (iii) 5 equiv LiOH, THF/MeOH/H2O, 12 h rt; (iv) -Val-OMe, HOBt, DIC, CH2Cl2, 12 h ꢀ30 °C?rt.
L
interactions would lead to a preferred si-attack of the alkyl moiety
(see Scheme 6C). However, the substituted (S)-mandelates ob-
tained in all reactions have to be formed by a re-side attack on
the carbonyl, which could be explained either by a syn-orientation
Table 2
Diastereoselective addition of n-BuZnCl to phenylglyoxylates 12a and 12b compared
to the best result from preceding investigations
of the ester carbonyl and the a-hydrogen involving a coordination
of the Zn-atom with the reacting carbonyl and two coordination
sites of the auxiliary (see Scheme 6A) or via a coordination of the
Zn-reagent with the syn-oriented carbonyls and one methoxy sub-
stituent of the auxiliary (see Scheme 6B).
Entry
Ester
R1
R2
dea (S,R,S)-13 (%)
1
12a
12e
12f
2-OCH3
2-OCH3
H
CH2CH(CH3)2
CH2CH2OCH3
CH2CH2OCH3
90
87
94
2
3b
Finally the stereoinductive properties of the most promising
hydrobenzoin auxiliaries in the diastereoselective Diels–Alder
reactions were also investigated. As the conversion of acrylates
with cyclopentadiene on the one hand provides four diastereo-
meric norbornene esters allowing simple estimation of both the
a
Diastereoisomeric ratios determined by 1H NMR integration on crude reaction
mixtures 13 as well as by HPLC- and NMR-analysis of L-valine methyl ester deriv-
atives 15 of cleaved acids 14; absolute configuration of major diastereoisomers
approved by specific rotations of 14.14
b
Data from Ref. 1e.

J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
277
re
Cl
Zn
O
O
O
Zn
re
O
Cl
O
O
O
H
O
O
H
si
O
O
O
H
O
O
O
H
H
O
O
Zn
Cl
H
O
A
B
C
Scheme 6. Possible mechanisms for the addition of n-BuZnCl to phenylglyoxylate 12a compared to a mechanism based on a literature proposal.13a,14
endo/exo and the diastereomeric ratios, via NMR, and on the other
hand this model reaction has already been applied to a large vari-
ety of auxiliary structures15 and was chosen as a suitable test sys-
tem for the applicability of the hydrobenzoin auxiliaries. Therefore
the selected auxiliaries were esterified using acrylic acid chloride
and NEt3 in CH2Cl2, followed by conversion with cyclopentadiene
under Lewis-acidic conditions in CH2Cl2.16 The desired acids were
obtained after saponification using LiOH in refluxing DME/H2O
(Scheme 7).17
The obtained endo/exo-selectivities and the enantiomeric purity
of the endo-products were determined via 1H NMR of the crude
reaction mixtures, as well as after saponification via 1H NMR of
the obtained acids 1818 and GC analysis of the corresponding
methyl esters 19. The absolute configurations of the major prod-
ucts were assigned via the specific rotation of norbornene carbox-
ylic acids 18.19
Table 3 shows that although satisfactory endo selectivities were
observed in the model reactions, only moderate enantiomeric puri-
ties of endo-18 could be obtained even with the most suitable aux-
iliary 7a. However, considering Oppolzer’s model for the geometry
of chiral secondary alcohol acrylates20 under the influence of Lewis
acids, the fact that in almost all experiments the (1S,2S,4S)-acid
was isolated as the major product seems surprising.
Assuming the proposed syn-orientation of the carbonyl and the
hydrogen at the stereogenic centre, the anti-directed coordination
of the Lewis-acid regarding the ester oxygen and the therefore ste-
rically favoured s-trans orientation of the acrylate as depicted in
Scheme 8, the steric shielding of the re-face should cause an (R)-
selectivity of the reaction.
i-butyl ether–oxygen in 16a as depicted in Scheme 9, an altered
orientation of the carbonyl moiety seems conceivable.
Although the coordination of the Lewis acid with different oxy-
gen atoms of the auxiliary would also be possible, assuming an
acrylate geometry according to Oppolzer’s model, a changed con-
formation of the hydrobenzoin structure would prevent possible
*
pp -interactions of the aryl moieties of the auxiliary, therefore
making this coordination model less likely (see Scheme 10). Similar
conditions can be assumed for substrate 16f. Although coordina-
tion of the Lewis acid with electron donors present in the auxiliary
structure is possible, in the case of a syn orientation of the benzylic
proton and the carbonyl moiety (see Scheme 10), the reduced ex-
*
tent of possible pp -interactions could favour an altered acrylate
geometry in 16f. On the other hand, as depicted in Scheme 10, in
this case neither the ether nor the aryl substituents of the auxiliary
would ensure a sufficient shielding of the si-face of the double
bond. Therefore, the lowered selectivity observed for 16f (see Table
3, entry 6) seems plausible.
In the case of substrate 16e, a competition between coordina-
tion sites of the aryl substituents and the methoxyethyl ether could
be a reason for the lowered selectivities compared to 16a (see Ta-
ble 3, entries 2 and 4). However, an obvious reason for the collapse
and inversion of selectivity in the reaction of 16f using Me2AlCl
(see Table 3, entry 5) could not be found.
2.2. Model reactions on solid support
The polymer supported auxiliaries 7h and 7i could be obtained
by following procedures already described in previous articles1d
providing conversions of up to 83% of the available active sites of
the resin. As preliminary investigations have shown that the
However, when considering the possible coordination of the Le-
wis acid with the methoxy substituents of the aryl moiety and the
R1
R1
OH
R1
O
O
i
ii/iii
O
O
OR2
OR2
R1
OR2
R1
R1
7a 7e, 7f
,
16a, 16e, 16f
17a, 17e, 17f
iv
O
7, 16, 17
R1
R2
i-Bu
OR4
a
e
f
2-OCH3
2-OCH3
H
CH2CH2OCH3
CH2Ph
4
18
(R =H)
v
19 (R4=Me)
Scheme 7. Application of the test systems on the Diels–Alder reaction of acrylates 16a, 16e and 16f with cyclopentadiene, cleavage and methylation. Reagents and
conditions: (i) acrylic acid chloride, NEt3, CH2Cl2, 12 h rt; (ii) 1.05 equiv Me2AlCl, 10 equiv cyclopentadiene, 2 h ꢀ80 °C?ꢀ50 °C; (iii) 1.05 equiv MgBr2ꢁEt2O, 10 equiv
cyclopentadiene, 2 h ꢀ80 °C?ꢀ30 °C; (iv) 50 equiv LiOH, DME/H2O, 12–36 h rt; (v) 0.15 equiv 4toluenesulfonic acid, MeOH, 12 h rt.

278
J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
Table 3
Stereochemical outcome of the Diels–Alder reactions with acrylates 16a–16c
Entry
Ester
R1
R2
Lewis-acid
endo:exoa 18
eea (1S,2S,4S)-18 (%)
1
16a
16a
16a
16e
16f
16f
2-OCH3
2-OCH3
2-OCH3
2-OCH3
H
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH2OCH3
CH2CH2OCH3
CH2CH2OCH3
Me2AlCl
Me2AlCl
21: 1
15: 1
9: 1
18: 1
18: 1
11: 1
40
42
34
26
6c
2b
3
MgBr2ꢁEt2O
4b
5
6
Me2AlCl
Me2AlCl
MgBr2ꢁEt2O
H
25
a
endo-Selectivities and enantiomeric excesses were determined by GC analysis of methyl esters 19 and afterwards verified via comparison with values obtained from 1
H
NMR integration on crude reaction mixtures 17 as well as acids 18,18 absolute configuration of major enantiomers was approved by optical rotations of 18.19
b
Reaction quenched at ꢀ80 °C.
c
In this case (1R,2R,4R)-18 was isolated as the major product.
O
O
O
si
O
H
O
O
H
O
O
H
O
(R)
O
O
O
H
O
H
O
H
O
L.A.
re
L.A.
Scheme 8. Selectivity considerations based on the acrylate geometry proposed by Oppolzer.20
L.A.
L.A.
O
O
O
O
O
O
O
O
O
H
H
H
(S)
O
O
O
O
H
H
O
H
O
Scheme 9. Selectivity considerations based on an alternative acrylate geometry.
reaction times and higher reagent excesses to allow usual conver-
sions of 70–99%. For the benzylation of propionates on solid sup-
O
H
O
H
port,
a larger excess of reagents, compared to the model
O
reactions in solution was used as well, followed by cleavage of
the chiral product using the usual amount of base, but longer reac-
tion times to allow complete cleavage without loss of enantiomeric
purity of the product. After recovery of the resin still carrying the
chiral linker, the recyclability of the solid bound auxiliary was
investigated via a second substrate attachment, benzylation and
product cleavage cycle. The additions of n-BuZnCl to solid sup-
ported phenylglyoxylates as well as the following saponifications
were carried out under almost the same reaction conditions as
the model reactions in solution. However, in this case THF instead
of Et2O had to be used as the solvent for the selectivity reactions to
ensure sufficient swelling of the resin and as no racemization had
to be expected during the basic cleavage of the product, the
amount of LiOH as well as the reaction times was increased com-
pared to the reactions in solution phase. Although according to
the literature,4e the reaction conditions used for the Diels–Alder
reactions in solution should lead to the decomposition of the solid
support in the case of a Wang resin the same Wang resin supported
auxiliary as for the previous model reactions could be applied to
the Diels–Alder reactions of acrylate 16h0 with cyclopentadiene.
However, the solvent for the following saponification had to be
slightly varied to provide sufficient swelling of the resin.
O
O
O
O
O
H
H
O
O
L.A.
L.A.
A
16a
B
O
O
H
L.A.
O
O
H
O
O
H
O
L.A.
O
H
C
D
16f
Scheme 10. Possible coordination of Lewis acids and electron donor sites of the
auxiliary part in substrates 16a and 16f.
residual chloromethyl groups of the resin could cause a decrease in
the achievable diastereoselectivities due to the direct attachment
of the substrate acids to the resin, the remaining active sites were
removed according to the literature procedures1c,d,21 prior to the
cleavage of the chiral protecting group providing 7h0 and 7i0
(Scheme 11).
The immobilization of the substrate acids on the chiral linker
was carried out according to procedures similar to the ones used
for the experiments in solution phase, in this case using longer
Over the course of previous investigations, all conversions on
solid support could be monitored via FT-IR spectroscopy, and the
extent of the conversions was in addition estimated gravimetri-
cally. The enantiomeric purity of the products was determined
via the same methodology as used for the products obtained from
the selectivity experiments in solution. In the case of acids 10a and

J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
279
O
O
O
O
iv
HO
H
O
H
H
O
H
O
W
W
O
i
6h
7h / 7h'
iii
CH3
Cl
Cl
W
W
W
6h' / 6i'
ii
O
O
O
O
O
iv
HO
H
O
H
H
O
W
O
W
H
O
O
6i
7i / 7i'
Scheme 11. Synthesis of solid phase test systems: Reagents and conditions: (i) 5a, NaH, NaI, DMF; (ii) 6g, NaH, NaI, DMF; (iii) (1) NaI, acetone, (2) n-Bu3SnH, THF; (iv)
PPh3.HBr, MeOH, CH2Cl2.
14 via HPLC- and 1H NMR-analysis of the derivatives 11 and 15 ob-
3. Conclusion
tained after conversion with L-valine methyl ester and for acid 18
via 1H NMR- and GC-analysis of the corresponding methyl ester
19 (Scheme 12).
Encouraged by the results from our previous work on the ste-
reoinductive potential of aryl substituted meso-hydrobenzoin
ethers in the L-SelectrideÒ mediated reduction of the corre-
sponding glyoxylates,1d the effects of aryl substituents on the
As can be seen from Table 4, the correlations from the prelimin-
ary experiments in solution were confirmed; the advantages of al-
most complete conversion during the attachment step and
deactivation of remaining active sites of the resin have already
been presented in previous articles1c,1d and were again observed.
Thus, a significant enhancement in the selectivities obtained was
achieved by the application of immobilized auxiliaries showing a
large extent of linker-attachment and not bearing residual chloro-
methyl moieties (see Table 4, entries 1/2 and 6/7). Furthermore in
the case of the benzylation of propionates 8, the presence of an
ethyleneglycol sublinker unit as in 8i and 9i as well as the addition
of LiCl as an additive could again increase the enantiomeric purity
of the obtained products (see Table 4, entries 2/3 and 4/6), and the
reapplication of the solid bound chiral auxiliary 7h obtained from
the first substrate attachment-alkylation-product cleavage cycle
resulted in no significant change of stereoselective induction pro-
viding the chiral product in the same enantiomeric purity as from
the first reaction cycle. On the other hand, as already observed dur-
ing the experiments in the solution phase, additional coordination
sites provided by the ethyleneglycol sublinker in substrate 12i0 re-
a-alkylation of propionates were investigated. Thereby, after
having further outlined the benefits of 2,20-dimethoxy substi-
tuted meso-hydrobenzoin ethers, these auxiliaries could be suc-
cessfully applied to the diastereoselective addition of n-BuZnCl
to the corresponding phenylglyoxylates as well as Diels–Alder
reactions on the corresponding acrylates. After cleavage without
the loss of the enantiomeric purity, the desired products were
obtained in satisfactory yields and moderate to excellent enan-
tiomeric purity.
Furthermore, the application of the methoxy substituted meso-
hydrobenzoin auxiliary immobilized on a commercially available
Wang resin, either directly or via an ethyleneglycol sublinker unit,
even in case of a recyclization of the solid bound chiral auxiliary re-
sulted in similar results as the experiments in solution. Thereby the
applicability of the chiral linker on various types of conversions
could be proved, and although only moderate selectivities were ob-
served in this case, one of the first examples22 of a diastereoselec-
tive conversion of an acrylate to a norbornenecarboxylic acid on
solid support could be carried out.
sulted in a slight decrease in enantiomeric purity in the
a-alkylated
a
-hydroxy acid 14. However, although quite similar endo/exo- and
4. Experimental
4.1. General
enantioselectivity-results were obtained from the Diels–Alder
reactions in solution and on solid phase (see Table 3, entry 2 and
Table 4, entry 10) the transfer of the diastereoselective model reac-
tions to solid phase in all cases resulted in a drop in the achievable
selectivities. These lowered selectivities were already observed in
the L-SelectrideÒ mediated reductions of phenylglyoxylates pre-
sented in a preceeding paper1d and may be explained by the chan-
ged steric environment and the thereby hindered coordinative
interactions present in case of the resin bound auxiliaries com-
pared to the surroundings of the i-butyl/methoxyethyl ethers 8a/
8e, 12a/12e and 16a/16e in solution phase.
Commercially available reagents and solvents were used as re-
ceived from the supplier unless otherwise specified. Diethyl ether
(E), petroleum ether (PE, 60–80 °C fraction), ethyl acetate (EE)
and dichloromethane were distilled prior to use. Dry toluene, ether
and tetrahydrofuran were pre-dried over KOH and distilled from
Na/benzophenone. Dry dichloromethane was distilled from P2O5.
Dry petroleum ether and dimethylformamide were dried and

280
J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
O
OH
Cl
OH
or
or
O
O
O
i / ii
O
O
O
R5
R
R
R5
R6
HO
O
O
O
O
8, 9
CH2CH3
COPh
CH(CH3)CH2Ph
C(n-Bu)(OH)Ph
2-norbornyl
O
12, 13
16, 17
CHCH2
8h / 8h', 8i / 8i',
12h', 12i', 16h'
7h / 7h', 7i / 7i'
iii / iv / v
vi / vii / viii
O
O
ix
O
OH
or
O
O
N
R6
R
O
O
11
10a
O
O
O
O
9h / 9h', 9i / 9i',
13h', 13i', 17h'
ix
O
N
OH
or
OH
OH
O
15
14
O
O
=
(for 7h-17h)
R
W
x
O
OH
W
7i-13i
(for
)
O
19
18
Scheme 12. Application of solid phase test systems: Reagents and conditions: (i) (for 8 and 12): DIC, DMAP, CH2Cl2, 48 h rt; (ii) (for 16): Et3N, CH2Cl2, 72 h rt; (iii) (for 9): (1)
5 equiv LDA, THF, 90 min ꢀ78 °C, (2) 10 equiv BnBr, 1 h ꢀ78 °C; (iv) (for 13): 8.8 equiv n-BuMgCl, 8 equiv ZnCl2, THF, 3 h ꢀ78 °C?ꢀ30 °C; (v) (for 17h0): 1.05 equiv Me2AlCl,
10 equiv cyclopentadiene, 5 h ꢀ80 °C then 1 h ꢀ50 °C; (vi) (for 9?10a): 10 equiv LiOH, THF/MeOH/H2O, 4 d rt; (vii) (for 13?14): 10 equiv LiOH, THF/MeOH/H2O, 24 h rt; (viii)
(for 17h0?18): 40 equiv LiOH, THF/DME/H2O, 36 h rt; (ix)
L-Val-OMe, HOBt, DIC, CH2Cl2, 12 h, ꢀ30 °C?rt; (x) 0.15 equiv 4-toluenesulfonic acid, MeOH, 12 h rt.
stored over molecular sieve 4 Å. i-Pr2NH was distilled from CaH2
and stored over molecular sieve 4 Å. Cyclopentadiene was dis-
tilled directly before use. NaH was purchased from Aldrich as a
55–65% oil moistened powder and washed with dry petroleum
ether directly before use unless otherwise stated. NaI and ZnCl2
were dried by heating to 150–300 °C in high vacuo for 30 min
prior to use. Hydroxymethylated Wang-resin (200–400 mesh;
0.64 mmol/g) was purchased from Novabiochem and was thor-
oughly washed successively with DMF, methanol dichlorometh-
ane, methanol, and dried overnight in high vacuo prior to use.
All moisture sensitive reactions were carried out under a nitro-
gen atmosphere. Reactions on the solid phase were shaken on
a laboratory shaker unless otherwise stated. For TLC analysis
precoated aluminium backed plates (Silica Gel 60 F254, Merck)
were used. Compounds were visualized by spraying with 5%
phosphomolybdic acid hydrate in ethanol and heating. Vacuum
flash chromatography was carried out with Silica Gel Merck
60. All fractions of products containing NOE’s acetal protecting
group together with a free hydroxy group were concentrated
immediately after chromatography together with a few drops
of NEt3. Melting points were determined with a Kofler hot stage
apparatus. Specific rotations were measured on a Perkin–Elmer
241 polarimeter. 1H and 13C NMR spectra were recorded on a
Bruker AC 200 at 200 and 50 MHz, CH-correlation spectra on a
Bruker AC 400 at 400/100 MHz using TMS or the solvent peak
as the reference. IR spectra were recorded on a BioRad FTS 135
FT-IR-spectrometer, using KBr disks. HPLC diastereoisomeric
analysis of L-valine methyl ester derivatives 11 and 15 of acids
10a and 14 was carried out with a Shimadzu LC-10AD (Shima-
dzu SPD-10AV UV–vis detector; Nucleosil 120 S C18; H2O/MeOH
(60/40). Enantiomeric analysis of methylester 19 was carried out
via chiral GC on a HP 6890 Series Chromatograph (BGB175 30 m,
0.25 mm ID, 0.25 lm film, FID detector 230 °C, 80 °C?220 °C,
carrier He 2 mL/min). Elemental analysis was carried out at
Vienna University, Department of Physicochemistry—Laboratory
for Microanalysis, Waehringer Str. 42, A-1090 Vienna.
4.2. Synthesis of auxiliaries 7a–7e and phenylglyoxylates 12a
and 12b
For the synthesis and analytical data of auxiliaries 7a–7e and
phenylglyoxylates 12a and 12b see Ref. 1d.

J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
281
Table 4
Results of model reactions on solid support including recyclability experiments
Entry
Model reactiona
Ester
Attachment rateb (%)
eec
O
O
1
8h?9h
51
38%
O
SP
O
SP
2
8h0?9h0
8h0?9h0
8i?9i
8i?9i
8i?9i
8i0?9i0
83
83
78
78
78
75
49%
55%
49%
50%
51%
65%
3d
4
5e
6d
7d
O
O
12h0?13h0
64
62%
O
SP
8
O
SP
OH
O
O
9
12i0?13i0
75
73
57%
O
O
10
16h0?17h0
endo/exo: 13.5:1
O
SP
SP
ee ((1S,2S,4S)-18): 35%
a
SP = Solid phase.
b
c
Extent of conversion during the attachment step.
Enantiomeric excess determined by 1H NMR and HPLC analyses of
6 equiv LiCl as additive.
L
-valine methyl ester derivatives 11 and 15 and 1H NMR and GC analyses of acid 18 and methyl ester 19.
d
e
Re-application of recycled resin from entry 4.
4.3. Typical procedure for the esterification of auxiliaries 7a–7e
with propanoic acid; propanoic acid (1R,2S)-1,2-bis(2-
methoxyphenyl)-2-(2-methylpropoxy)-ethyl ester 8a
Hz, 2H, OCHPh), 3.10/2.90 (2dd, J1 = 8.8 Hz, J2 = 6.4 Hz/J1 = 8.8 Hz,
J2 = 6.2 Hz, 2H, O–CH2CH(CH3)2), 2.39/2.25 (2s, 6H, Ph-CH3), 2.21 (q,
J = 7.4 Hz, 2H, OCO–CH2CH3), 1.84/1.61 (m, J = 6.6 Hz, 1H,
OCH2CH(CH3)2), 1.01 (t, J = 7.6 Hz, 3H, OCO–CH2CH3), 0.78/0.78 (2d,
J = 6.7 Hz, 6H, OCH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) d 172.9
(O–CO), 136.9/136.8/136.6/136.5 (Ph-C-1, Ph-C–CH3), 129.7/129.4/
127.4/127.4/127.3/127.1/125.7/125.4 (Ph-C), 80.7/76.0 (OCHPh),
73.4 (OCH2CH(CH3)2), 28.5 (O–CH2CH(CH3)2), 27.5 (CO–CH2CH3),
19.1/19.0 (Ph-CH3, O–CH2CH(CH3)2), 8.7 (CO–CH2CH3); M = 354.49.
Anal. Calcd for C23H30O3: C, 77.93; H, 8.53. Found: C, 77.67; H, 8.61).
Alcohol 7a (0.80 g, 2.42 mmol), propanoic acid (0.236 g, 3.19
mmol) and N,N-dimethyl-4-aminopyridine (DMAP) (0.029 g, 0.24
mmol) were dissolved in dry dichloromethane (12 mL) under a
nitrogen
atmosphere.
N,N0-Diisopropylcarbodiimide
(DIC)
(0.403 g, 3.19 mmol) was added slowly and the mixture was stirred
for 12 h at rt. The reaction mixture was diluted with dichlorometh-
ane, washed successively with KHSO4 solution (5%), saturated
NaHCO3 solution and brine, dried, filtered and evaporated to dry-
ness yielding 0.90 g of crude product, which was purified via chro-
matography (PE/E 20:1?PE/E 5:1). Compound 8a (0.84 g, 90%) was
4.5. Propanoic acid (1R,2S)-1,2-bis(4-methoxyphenyl)-2-(2-
methylpropoxy)ethyl ester 8c
obtained as a colourless oil {½a D20
ꢂ
¼ þ38:9 (c 0.70, CH2Cl2)}; 1H
The synthesis was carried out as described above (Section 4.3)
using 7c (0.240 g, 0.73 mmol). After chromatography (PE/E
20:1?PE/E 5:1) ester 8c (0.265 g, 94%) was obtained as a colourless
NMR (CDCl3, 200 MHz) d 7.26–6.69 (m, 8H, Ph-H), 6.61/5.18 (2d,
J = 3.7 Hz, 2H, OCHPh), 3.56/3.55 (2s, 6H, Ph-OCH3), 3.21 (d, J =
6.4 Hz, 2H, O–CH2CH(CH3)2), 2.39 (q, J = 7.4 Hz, 2H, OCO–CH2CH3),
2.01–1.76 (m, J = 6.7 Hz, 1H, OCH2CH(CH3)2), 1.16 (t, J = 7.5 Hz, 3H,
OCO–CH2CH3), 0.92/0.91 (2d, J = 6.7 Hz, 6H, OCH2CH(CH3)2); 13C
NMR (CDCl3, 50 MHz) d 173.0 (O–CO), 157.2/156.6 (Ph-C–OCH3),
oil {½a 2D0
ꢂ
¼ þ14:4 (c 0.65, CH2Cl2)}; 1H NMR (CDCl3, 200 MHz) d 7.26–
6.79 (m, 8H, Ph-H), 5.79/4.40 (2d, J = 6.3 Hz, 2H, OCHPh), 3.80/3.79
(2s, 6H, Ph-OCH3), 3.08/2.91 (2dd, J1 = 8.9 Hz, J2 = 6.5 Hz, 2H, O–
CH2CH(CH3)2), 2.20 (q, J = 7.5 Hz, 2H, OCO–CH2CH3), 1.82–1.63 (m,
1H, O–CH2CH(CH3)2), 1.00 (t, J = 7.5 Hz, 3H, OCO–CH2CH3), 0.76/
0.75 (2d, J = 6.7 Hz, 6H, O–CH2CH(CH3)2); 13C NMR (CDCl3, 50
MHz) d 173.0 (O–CO), 159.2 (Ph-C–OCH3), 130.8/130.0 (Ph-C-1),
129.1/128.9/113.2/113.1 (Ph-C), 83.6/77.4 (OCHPh), 76.0 (O–CH2–
CH(CH3)2), 55.2 (Ph-OCH3), 28.5 (O–CH2–CH(CH3)2), 27.8
(CO–CH2–CH3), 19.2 (O–CH2–CH(CH3)2), 9.0 (CO–CH2–CH3);
M = 386.49. Anal. Calcd for C23H30O5: C, 71.48; H, 7.82. Found: C,
71.23; H, 7.86).
126.5/125.9
(Ph-C-1),
128.2/128.1/128.0/127.9/119.6/119.5/
109.6/109.4 (Ph-C), 76.09/75.65 (OCHPh), 70.39 (OCH2CH(CH3)2),
55.1/55.0 (Ph-OCH3), 28.6 (O–CH2CH(CH3)2), 27.8 (CO–CH2CH3),
19.3/19.2 (O–CH2CH(CH3)2), 9.0 (CO–CH2CH3); M = 386.49. Anal.
Calcd for C23H30O5: C, 71.48; H, 7.82. Found: C, 71.47; H, 7.66).
4.4. Propanoic acid (1R,2S)-1,2-bis(2-methylphenyl)-2-(2-
methylpropoxy)ethyl ester 8b
The synthesis was carried out as described above (Section 4.3)
using 7b (0.450 g, 1.51 mmol). After chromatography (PE/E
20:1?PE/E 5:1) ester 8b (0.485 g, 91%) was obtained as colourless
4.6. Propanoic acid (1R,2S)-2-(2-methylpropoxy)-1,2-bis[2-
(trifluoromethyl)phenyl]ethyl ester 8d
crystals {Fp = 47–49 °C; ½a D20
ꢂ
¼ þ53:3 (c 1.07, CH2Cl2)}; 1H NMR
The synthesis was carried out as described above (Section 4.3)
using 7d (0.300 g, 0.74 mmol). After chromatography (PE/E
(CDCl3, 200 MHz) d 7.47–7.06 (m, 8H, Ph-H), 6.19/4.84 (2d, J = 6.7

282
J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
20:1?PE/E 5:1) ester 8d (0.335 g, 98%) was obtained as colourless
4.9. 2-Methyl-3-phenylpropanoic acid (1R,2S)-1,2-bis(2-
methylphenyl)-2-(2-methylpropoxy)ethyl ester 9b
crystals {Fp = 54 °C; ½a D20
ꢂ
¼ þ13:9 (c 0.70, CH2Cl2)}; 1H NMR (CDCl3,
200 MHz) d 7.73–7.35 (m, 8H, Ph-H), 6.44/4.97 (2d, J = 7.4 Hz, 2H,
OCHPh), 2.94/2.85 (2dd, J1 = 8.8 Hz, J2 = 6.3 Hz, 2H, O–
CH2CH(CH3)2), 2.13 (q, J = 7.5 Hz, 2H, OCO–CH2CH3), 1.71–1.51
(m, 1H, O–CH2CH(CH3)2), 0.91 (t, J = 7.6 Hz, 3H, OCO–CH2CH3),
0.65/0.64 (2d, J = 6.8 Hz, 6H, O–CH2CH(CH3)2); 13C NMR (CDCl3,
50 MHz) d 172.2 (O–CO), 138.2/137.4 (q, J(C,F) = 1.4 Hz, Ph-C-1),
132.0/131.6 (q, J(C,F) = 0.9 Hz, Ph-C-4), 129.5/128.6/128.1/128.1
(Ph-C-5, Ph-C-6), 129.45/129.18 (q, J(C,F) = 30.5 Hz, Ph-C-2),
125.7/125.0 (q, J(C,F) = 5.8 Hz, Ph-C-3), 124.3/124.1 (2q,
J(C,F) = 274.1/274.5 Hz, CF3), 79.0/72.8 (q, J = 0.9/2.2 Hz, OCHPh),
75.9 (O–CH2CH(CH3)2); 28.2 (O–CH2–CH(CH3)2), 27.3 (CO–CH2–
The synthesis was carried out as described above (Section 4.8)
using 8b (0.100 g, 0.282 mmol). After chromatography (PE/E
50:1?E) 9b (0.114 g, 99%) was obtained as a yellow oil (1H NMR
(CDCl3, 200 MHz) d 7.45–6.99 (m, 13H, Ph-H), 6.17/6.16 (2d(diast.),
J = 6.8/6.5 Hz, 1H, Ph-CH–OCO), 4.85/4.81 (2d(diast.), J = 6.8/6.5 Hz,
1H, Ph-CH-O), 3.14–2.82 (m, 3H, O–CH2CH(CH3)2, CO–CH(CH3)–
CH2Ph), 2.74–2.47 (m, 2H, CO–CH(CH3)–CH2Ph), 2.42 (s, 3H, Ph-
CH3), 2.30/2.26 (2s(diast.), 3H, Ph-CH3), 1.84–1.65 (m, J = 6.6 Hz,
1H, OCH2CH(CH3)2), 1.00/0.98 (2d(diast.), J = 6.7 Hz, 3H, CO–
CH(CH3)–CH2Ph), 0.79 (d, J = 6.7 Hz, 6H, OCH2CH(CH3)2); 13C
NMR (CDCl3, 50 MHz) d 174.5/174.4 (O–CO(diast.)), 139.1/139.1
(Ph-C-1(diast.)), 137.0/136.9/136.9/136.7/136.6/136.5/136.4 (Ph-
C-1, Ph-C–CH3(diast.)), 129.8–125.4 (Ph-C), 80.8/75.9 (OCHPh),
73.7/73.6 (OCH2CH(CH3)2(diast.)), 41.4/41.1 (CO–CH(CH3)–
CH2Ph(diast.)), 39.2/39.1 (CO–CH(CH3)–CH2Ph(diast.)), 28.5 (O–
CH2CH(CH3)2), 19.2/19.1 (O–CH2CH(CH3)2), 19.1/19.2 (Ph-CH3),
16.1/15.9 (CO–CH(CH3)–CH2Ph(diast.)); M = 444.62. Anal. Calcd
for C30H36O3: C, 81.04; H, 8.16. Found: C, 80.83; H, 8.19.
CH3),
18.9/18.9
(O–CH2–CH(CH3)2),
8.7
(CO–CH2–CH3);
M = 462.44. Anal. Calcd for C23H24F6O3: C, 59.74; H, 5.23; F,
24.65. Found: C, 59.87; H, 5.05; F, 24.83).
4.7. Propanoic acid (1R,2S)-2-(2-methoxyethoxy)-1,2-bis(2-
methoxyphenyl)ethyl ester 8e
The synthesis was carried out as described above (Section 4.3)
using 7e (0.200 g, 0.60 mmol). After chromatography (PE/E
20:1?PE/E 5:1) ester 8e (0.229 g, 98%) was obtained as a colour-
4.10. 2-Methyl-3-phenylpropanoic acid (1R,2S)-1,2-bis(4-
methoxyphenyl)-2-(2-methylpropoxy)ethyl ester 9c
less oil (½a 2D0
ꢂ
¼ þ17:8 (c 1.00, CH2Cl2)};1H NMR (CDCl3, 200 MHz)
d 7.26–6.60 (m, 9H, incl. 6.61 (d, J = 3.7 Hz, 1H, OCHPh), Ph-H),
5.22 (d, J = 3.7 Hz, 2H, OCHPh), 3.64–3.33 (m, 13H, incl. 3.60/
3.47/3.35 (3s, 9H, OCH3), OCH2CH2O), 2.36 (q, J = 7.5 Hz, 2H,
OCO–CH2CH3), 1.12 (t, J = 7.6 Hz, 3H, OCO–CH2CH3); 13C NMR
The synthesis was carried out as described above (Section 4.8)
using 8c (0.100 g, 0.26 mmol). After chromatography (PE/E
50:1?E) 9c (0.098 g, 79%) was obtained as a yellow oil (1H NMR
(CDCl3, 200 MHz) d 7.24–6.78 (m, 13H, Ph-H), 5.81/4.41 (2d(diast.),
J = 6.5 Hz, 2H, OCHPh), 3.80 (s, 6H, Ph-OCH3), 3.14–2.84 (m, 3H, O–
CH2CH(CH3)2, CO–CH(CH3)–CH2–Ph), 2.71–2.45 (m, 2H, CH2–Ph),
1.85–1.65 (m, 1H, O–CH2CH(CH3)2), 1.00/0.97 (2d(diast.), J = 6.8
Hz, 3H, CO–CH(CH3)–CH2–Ph), 0.79/0.78 (2d, J = 6.7 Hz, 6H, O-
CH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) d 174.6/174.5 (CO(-
diast.)), 159.2/159.1/159.1 (Ph-C-OCH3(diast.)), 139.3/130.8/
(CDCl3, 50 MHz)
d 173.1 (O–CO), 157.2/156.6 (Ph-C–OCH3),
128.4/128.2/128.2/127.7/126.0/125.9/119.8/119.64/109.6/109.4
(Ph-C), 75.8/71.8/70.3/68.9 (OCHPh, OCH2CH2O), 58.9/55.2/54.9
(OCH3), 27.8 (CO–CH2–CH3), 9.0 (CO–CH2–CH3); M = 388.46. Anal.
Calcd for C22H28O6: C, 71.48; H, 7.82. Found: C, 71.23; H, 7.86).
4.8. Typical procedure for the a-alkylation of esters 8a–8e; 2-
methyl-3-phenylpropanoic acid (1R,2S)-1,2-bis(2-methoxy-
130.0/129.9
(Ph-C-1(diast.)),
129.1/129.0/128.9/128.2/126.1/
phenyl)-2-(2-methylpropoxy) ethyl ester 9a
113.3/113.1 (Ph-C), 83.6/77.4 (CH-Ph), 75.9 (O–CH2–CH(CH3)2),
55.1 (Ph-OCH3), 41.4/41.3 (CO–CH(CH3)–CH2-Ph(diast.)), 39.3/
39.2 (CH2-Ph(diast.)), 28.5 (O–CH2–CH(CH3)2), 19.2 (O–CH2–
CH(CH3)2), 16.4/16.2 (CO–CH(CH3)–CH2-Ph(diast.)); M = 476.62.
Anal. Calcd for C30H36O5: C, 75.60; H, 7.61. Found: C, 75.30; H, 7.56.
Under a nitrogen atmosphere, diisopropylamine (0.052 g, 0.518
mmol) was dissolved in dry THF (0.5 mL), n-BuLi (0.205 mL, 0.510
mmol) was slowly added at ꢀ30 °C and the reaction mixture was
stirred for 30 min at ꢀ5 °C. At ꢀ70 °C ester 8a (100 mg, 0.259
mmol) dissolved in THF (2.5 mL) was added and after 90 min ben-
zyl bromide (354 mg, 2.07 mmol) was added dropwise and the
mixture was stirred for 1 h at ꢀ70 °C. The mixture was allowed
to reach rt, stirred for 1 h and quenched with water. The aqueous
phase was separated, extracted with ether, and the combined ether
phases were washed with KHSO4 solution (5%) and saturated NaH-
CO3 solution, dried, filtered and evaporated to dryness. After chro-
matography (PE/E 50:1?E) 9a (119 mg, 97%) was obtained as a
colourless oil (1H NMR (CDCl3, 200 MHz) d 7.30–6.71 (m, 13H,
Ph-H), 6.57 (d, J = 3.9 Hz, 1H, Ph-CH–OCO), 5.18/5.13 (2d(diast.),
J = 3.9 Hz, 1H, OCHPh), 3.59/3.58 (2s(diast.), 3H, Ph-OCH3), 3.55/
3.57 (2s(diast.), 3H, Ph-OCH3), 3.22–3.08 (m, 3H, O–CH2CH
(CH3)2,CO–CH(CH3)–CH2Ph), 2.86–2.58 (m, 2H, CO–CH(CH3)–
CH2Ph), 1.99–1.76 (m, J = 6.6 Hz, 1H, OCH2CH(CH3)2), 1.16/1.13
4.11. 2-Methyl-3-phenylpropanoic acid (1R,2S)-2-(2-methyl-
propoxy)-1,2-bis[2-(trifluoromethyl)phenyl]ethyl ester 9d
The synthesis was carried out as described above (Section 4.8)
using 8d (0.100 g, 0.216 mmol). After chromatography (PE/E
50:1?E) 9d (0.057 g, 48%) was obtained as a colourless oil (1H
NMR (CDCl3, 200 MHz) d 7.76–6.92 (m, 13H, Ph-H), 6.42/6.140
(2d(diast.), J = 7.3/7.5 Hz, 1H, Ph-CH–OCO), 4.98 (d, J = 7.6 Hz,
1H, Ph-CH–O), 3.00–2.35 (m, 5H, O–CH2CH(CH3)2, CO–CH(CH3)–
CH2Ph, CO–CH(CH3)–CH2Ph), 1.74–1.52 (m,
OCH2CH(CH3)2), 0.90/0.86 (2d(diast.), J = 6.2/6.8 Hz, 3H, CO–
CH(CH3)–CH2Ph), 0.65/0.64 (2d(diast.), 6.8/0.7 Hz, 6H,
J = 6.6 Hz, 1H,
J
=
OCH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) d 173.9/173.8 (CO(-
diast.)), 139.0/138.9 (benzyl.Ph-C-1(diast.)), 138.4/138.2/137.3/
137.3 (q, J(C,F) = 1.3/0.9/1.4/1.4 Hz, Ph-C-1(diast.)), 132.1/131.7
(Ph-C-4), 129.4/129.3/128.8/128.7/128.5/128.4/128.3/128.29/128.1/
128.1/128.0 (benzyl. Ph-C, Ph-C-5, Ph-C-6(diast.)), 129.5/129.4 (q,
J(C,F) = 29.9/30.1 Hz, Ph-C-2), 125.6/125.0/125.0 (q, J(C,F) = 5.6/
5.7/5.9 Hz, Ph-C-3(diast.)), 124.3/124.1 (q, J(C,F) = 274.4/274.3 Hz,
CF3), 79.1/72.9/72.9 (OCHPh(diast.)), 75.9 (O–CH2CH(CH3)2), 41.3/
41.0 (CO–CH(CH3)–CH2-Ph(diast.)), 39.4/38.9 (CH2-Ph(diast.)), 28.2
(O–CH2–CH(CH3)2), 18.9/18.8 (O–CH2–CH(CH3)2), 16.1/16.0 (CO–
CH(CH3)–CH2-Ph(diast.)); M = 552.56. Anal. Calcd for C30H30F6O3:
C, 65.21; H, 5.47. Found: C, 65.04; H, 5.58.
(2d(diast.),
J = 6.6 Hz, 3H, CO–CH(CH3)–CH2Ph), 0.92/0.90
(2d(diast.), J = 6.7 Hz, 6H, OCH2CH(CH3)2); 13C NMR (CDCl3, 50
MHz) d 174.6 (O–CO), 157.3/156.7 (Ph-C–OCH3), 139.5/139.4
(Ph-C-1(diast.)), 128.9–126.0 (Ph-C), 126.0/126.0 (Ph-C-1), 119.7/
119.6/109.6/109.4
(OCH2CH(CH3)2(diast.)), 55.2/55.0 (Ph-OCH3), 41.6/41.4 (CO–CH
(CH3)–CH2Ph(diast.)), 39.4/39.3 (CO–CH(CH3)–CH2Ph(diast.)),
(Ph-C)
76.1/75.7
(OCHPh),
70.7/70.7
28.6 (O–CH2CH(CH3)2), 19.28/19.26 (O–CH2CH(CH3)2), 16.4/16.3
(CO–CH(CH3)–CH2Ph(diast.)); M = 476.62. Anal. Calcd for
C30H36O5: C, 75.60; H, 7.61. Found: C, 75.62; H, 7.73.

J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
283
4.12. 2-Methyl-3-phenylpropanoic acid (1R,2S)-2-(2-meth-
oxyethoxy)-1,2-bis(2-methoxyphenyl)ethyl ester 9e
41.3/40.7 (CO-CH(CH3)-CH2Ph(diast.)), 39.2/38.7 (CO–CH(CH3)–
CH2Ph(diast.)), 28.5/28.4 (O–CH2CH(CH3)2(diast.)), 19.1 (O–
CH2CH(CH3)2),
19.0
(Ph-CH3),
16.6/16.3
(CO–CH(CH3)–
The synthesis was carried out as described above (Section 4.8)
using 8e (0.100 g, 0.257 mmol). After chromatography (PE/E
50:1?E) 9e (0.109 g, 89%) was obtained as a yellow oil (1H NMR
(CDCl3, 200 MHz) d 7.43–6.67 (m, 13H, Ph-H), 6.57(d, J = 3.9 Hz,
1H, Ph-CH–OCO), 5.23/5.18 (2d(diast.), J = 3.9/3.8 Hz, 1H, Ph-CH–
O), 3.67–2.54 (m, 16H, incl. 3.64/3.47/3.34 (3s, OCH3), CO–
CH(CH3)–CH2Ph, OCH2CH2O, CO–CH(CH3)–CH2Ph), 1.13/1.10
(2d(diast.), J = 6.7/6.8 Hz, 3H, CO–CH(CH3)–CH2Ph); 13C NMR
(CDCl3, 50 MHz) d 174.7 (O–CO), 157.3/157.2/156.8 (Ph-C–OCH3(-
diast.)), 139.6/139.5 (Ph-C-1(diast.)), 129.1/129.0/128.6/128.5/
128.3/128.3/127.7/127.6/126.1/126.1/126.0/119.9/119.8/119.7/109.7/
109.5 (Ph-C(diast.)), 76.0/75.9/ꢀ71.8/71.8/70.7/70.6/68.9 (OCHPh,
OCH2(diast.)), 59.0/55.4/55.0(OCH3), 41.6/41.4 (CO–CH(CH3)–
CH2Ph(diast.)), 39.5/39.4 (CO–CH(CH3)–CH2Ph(diast.)), 16.5/16.4
(CO–CH(CH3)–CH2Ph(diast.)); M = 478.59. Anal. Calcd for
C29H34O6: C, 81.04; H, 8.16. Found: C, 80.83; H, 8.19.
CH2Ph(diast.)); M = 489.62. Anal. Calcd for C30H35NO5: C, 73.59;
H, 7.20; N, 2.86. Found: C, 74.14; H, 7.51; N, 2.39.
4.15. Typical procedure for the saponification of esters 9a–9g
Ester 9a (0.092 g, 0.193 mmol) and LiOH (0.046 g, 1.93 mmol)
were suspended in THF/H2O/MeOH 3:3:1 (2.5 mL) and stirred for
12 h at rt. The mixture was concentrated under reduced pressure
and the residue was diluted with saturated NaHCO3 solution,
washed with ether, acidified with 2 M HCl and extracted several
times with ether. The combined extracts were dried, filtered and
evaporated to dryness yielding 1-methyl-2-phenylpropanoic acid
10a (0.026 g, 82%) (1H NMR data according to Ref. 23).
The saponification of esters 9b–9e was carried out following the
same procedure yielding 82–97% of acid 10a.
In the case of esters 9f and 9g, the same procedure was used but
the reaction was additionally refluxed for 48 h to yield 76–81% of
acid 10b (1H NMR-data according to Ref. 8c).
4.13. 2-Methyl-3-(4-nitrophenyl)propanoic acid (1R,2S)-1,2-
bis(2-methoxyphenyl)-2-(2-methylpropoxy)ethyl ester 9f
4.16. Derivatization of acids 10a for HPLC analysis; 3-methyl-2-(2-
methyl-3-phenyl-propionylamino)butyric acid methyl ester 11
The synthesis was carried out as described above (Section 4.8)
using 8a (0.100 g, 0.259 mmol) and 4-nitrobenzylbromide
(0.447 g, 2.07 mmol) instead of benzylbromide. After chromatog-
raphy (PE/E 50:1?E) 9f (0.083 g, 61%) was obtained as a yellow
oil (1H NMR (CDCl3, 200 MHz) d 8.09/8.01 (2d(diast.), J = 8.7 Hz,
2H, CH@C-NO2), 7.31–6.64 (m, 10H, Ph-H), 6.51/6.49 (2d(diast.), J
= 4.1 Hz, 1H, Ph-CH–OCO), 5.12/5.08 (2d(diast.), J = 4.1 Hz, 1H,
Ph-CH-O), 3.58/3.52 (2s, 6H, Ph-OCH3), 3.18–3.02 (m, 3H, O–
CH2CH(CH3)2, CO–CH(CH3)–CH2Ph), 2.84–2.71 (m, 2H, CO–
CH(CH3)–CH2Ph), 1.93–1.73 (m, J = 6.7 Hz, 1H, OCH2CH(CH3)2),
1.20/1.15 (2d(diast.), J = 6.6 Hz, 3H, CO–CH(CH3)–CH2Ph), 0.87/
0.84 (2d(diast.), J = 6.7 Hz, 6H, OCH2CH(CH3)2); 13C NMR (CDCl3,
50 MHz): 173.8 (O–CO), 157.3/156.6 (Ph-C–OCH3), 147.2/147.1
(Ph-NO2(C1)(diast.)), 146.5/146.4 (Ph-NO2(C4) (diast.)), 126.3/
125.6 (Ph-C-1), 129.7–123.4 (Ph-C), 119.7/119.5/109.6/109.4
(Ph-C); 76.0/75.5 (OCHPh), 71.0/71.0(OCH2CH(CH3)2(diast.)),
55.2/54.9 (Ph-OCH3), 41.4/41.0 (CO–CH(CH3)–CH2Ph(diast.)),
Acid 10a (0.022 g, 0.134 mmol), L
-valine methyl ester10 (0.021 g,
0.161 mmol) and 1-hydroxybenzotriazole (0.020 g, 0.148 mmol)
were dissolved in dry dichloromethane (1.5 mL) under nitrogen
atmosphere. DIC (0.020 g, 0.161 mmol) dissolved in dry dichloro-
methane (0.5 mL) was added dropwise at ꢀ30 °C, the reaction
was stirred at ꢀ30 °C for 30 min and afterwards for 12 h at rt.
The mixture was filtered, diluted with dichloromethane, washed
with KHSO4 solution (5%), saturated NaHCO3 solution and brine,
dried, filtered and evaporated to dryness. The residue was dis-
solved in 0.5 mL of acetone, cooled to ꢀ10 °C, remaining diisopro-
pylurea was filtered off and the filtrate was evaporated to dryness
yielding derivative 11 (0.034 g, 92%) as a colourless oil, which
could be used for HPLC-analysis without further purification
(HPLC: Supelcosil LC-18; eluents water/methanol (45/55); flow
0.2 mL/min; sample volume
2 lL (c = 4 mg/mL); UV 214 nm,
254 nm. tR1 = 29.5 min; tR2 = 37.2 min; 1H NMR (CDCl3, 200 MHz)
d 7.28–7.02 (m, 5H, Ph-H), 5.81(major)/5.77(minor) (2d, J = 9.4
Hz, 1H, NH), 4.44 (major)/4.40(minor) (2dd, J1 = 6.6 Hz, J2 = 5.0
Hz, 1H, CH–NH), 3.63(minor)/3.60(major) (2s, 3H, OCH3), 2.97–
2.39 (m, 3H, Ph-CH2-CH), 2.10–1.82 (m, 1H, CH(CH3)2), 1.12
(minor)/1.05(major) (2d, J = 6.7/6.5 Hz, 3H, CH-CH3), 0.81/0.78
(major)/0.62/0.60(minor) (4d, J = 6.5/6.9 Hz, 6H, CH(CH3)2); 13C
NMR (CDCl3, 50 MHz) d 175.5(major)/175.2(minor)/172.5(minor)/
172.2(major) (CON, COO), 139.6(minor)/139.5(major)/128.9/128.3
(major)/128.3(minor)/126.2(major)/126.2(minor) (Ph-C), 56.7
(minor)/56.7(major) (NHCHCO), 52.0(major)/51.9 (minor) (OCH3),
39.4/39.0
(CO–CH(CH3)–CH2Ph(diast.)),
28.6/28.5
(O–
CH2CH(CH3)2(diast.)), 19.2/19.2 (O–CH2CH(CH3)2), 16.9/16.6
(CO–CH(CH3)–CH2Ph(diast.)); M = 521.62. Anal. Calcd for
C30H35NO7: C, 69.08; H, 6.76; N, 2.69. Found: C, 68.79; H, 6.82;
N, 2.90).
4.14. 2-Methyl-3-(4-nitrophenyl)propanoic acid (1R,2S)-1,2-
bis(2-methylphenyl)-2-(2-methylpropoxy)ethyl ester 9g
The synthesis was carried out as described above (Section 4.8)
using 8b (0.100 g, 0.282 mmol) and 4-nitrobenzylbromide
(0.488 g, 2.26 mmol) instead of benzylbromide. After chromatog-
raphy (PE/E 50:1?E) 9g (0.082 g, 65%) was obtained as a yellow
oil (1H NMR (CDCl3, 200 MHz) d 8.01/7.93 (2d(diast), J = 8.7 Hz,
2H, CH@C–NO2), 7.34–6.99 (m,10H, Ph-H), 6.09/6.06 (2d(diast), J
= 7.0/6.7 Hz, 1H, Ph-CH–OCO), 4.76/4.74 (2d(diast), J = 7.0/6.7
Hz, 1H, Ph-CH–O), 3.11–2.53 (m, 5H, O–CH2CH(CH3)2, CO–
CH(CH3)–CH2Ph, CO–CH(CH3)–CH2Ph), 2.37/2.35 (2s(diast), 3H,
Ph-CH3), 2.29/2.27 (2s(diast), 3H, Ph-CH3), 1.85–1.52 (m, J = 6.7
Hz, 1H, OCH2CH(CH3)2), 1.00/0.99 (2d(diast), J = 6.7 Hz, 3H, CO–
CH(CH3)–CH2Ph), 0.71 (d, J = 6.7 Hz, 6H, OCH2CH(CH3)2); 13C
NMR (CDCl3, 50 MHz) d 173.6/173.5 (O–CO(diast.)), 146.7/146.7
(Ph-NO2(C1) (diast.)), 146.4 (Ph-NO2(C4)), 136.9/136.9/136.8/
136.6/136.5/136.5/136.4 (Ph-C-1, Ph-C-CH3(diast.)), 129.8–125.4
(Ph-C), 80.8/75.9 (OCHPh), 73.9/73.8 (OCH2CH(CH3)2(diast.)),
43.8(minor)/43.3(major)
(CHCON),
40.5(minor)/39.9(major)
(PhCH2), 31.3(major)/31.0(minor) (NH–CH–COO), 18.7(major)/
18.5(minor)
(CH(CH3)2),
17.7/17.7(major)/17.7/17.6(minor)
(CH(CH3)2)).
In all other cases, the derivatization was carried out following
the same procedure to yield 92–99% of derivative 11.
4.17. Typical procedure for the addition of n-BuZnCl to
phenylglyoxylates 12a and 12e; 2-hydroxy-2-phenylhexanoic
acid (1R,2S)-1,2-bis(2-methoxyphenyl)-2-(2-methylpropoxy)
ethyl ester 13a
A freshly prepared and titrated24 solution of n-BuMgX in THF
(1.92 mL, 1.90 mmol) was slowly added to a thoroughly stirred
solution of pre-dried ZnCl2 (0.236 g, 1.73 mmol) in dry ether

284
J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
(2 mL) while cooling on an ice bath, and stirring was continued for
2 h at 0 °C. The supernatant solution of the prepared n-BuZnCl re-
agent was slowly added, by means of a syringe, over 15 min to a
solution of ester 12a (0.100 g, 0.216 mmol) in dry ether (3 mL)
which was pre-cooled to ꢀ90 °C and the resulting mixture was
stirred for 2 h at ꢀ78 °C. A 10% aqueous NH4Cl solution was added
and stirring was continued for 15 min at room temperature. The
mixture was taken up with a saturated aqueous NH4Cl solution
and extracted three times with ether. The combined ethereal ex-
tracts were successively washed with aqueous NH4Cl and brine,
dried over Na2SO4, filtered and evaporated. After chromatography
(PE/E 4:1?E) 13a (99 mg, 88%) was obtained as a yellow oil (1H
NMR (CDCl3, 200 MHz) d 7.57–6.32 (m, 14H, Ph-H, OCHPh), 5.16/
5.06 (2d(diast.), J = 4.1/3.7 Hz, 1H, OCHPh), 3.88 (s, 1H, OH),
3.61/3.46 (2s, 6H, Ph-OCH3), 3.25–3.05 (m, 2H, O–CH2CH(CH3)2),
2.36–0.81 (m, 16H, aliph. incl. 0.87 (d, J = 6.7 Hz, 6H, O–
CH2CH(CH3)2)); 13C NMR (CDCl3, 50 MHz) d 174.4 (CO), 157.3/
156.7 (Ph-C-2), 141.7/126.1/125.2 (Ph-C-1), 128.5/128.4/128.3/
127.9/127.3/127.1/125.9/120.0/119.7/109.7/109.6 (Ph-C), 78.1 (C–
OH), 76.2 (CH2O), 75.5/74.0(OCHPh), 55.3/54.9 (OCH3), 39.2
J2 = 1.8 Hz, 1H,CH@CH2), 6.08 (dd, J1 = 17.2 Hz, J2 = 10.2 Hz, 1H,
CH@CH2), 5.73 (dd, J1 = 10.2 Hz, J2 = 1.8 Hz, 1H, CH@CH2), 3.46/
3.45 (2s, 6H, OCH3), 3.12 (d, J = 6.3 Hz, 2H, O–CH2CH(CH3)2),
1.89–1.69 (m, 1H, O–CH2CH(CH3)2), 0.81 (d, J = 6.7 Hz, 6H, O–
CH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) d 165.0 (O–CO), 157.3/
156.7 (Ph-C-2), 130.3 (CH@CH2), 129.0/128.3/128.3/128.2/128.1/
119.8/119.7/109.7/109.5 (Ph-C, CH@CH2), 126.5/125.8 (Ph-C-1),
76.3 (O–CH2–CH(CH3)2), 75.8/70.9 (OCHPh), 55.3/55.1 (OCH3),
28.7 (O–CH2–CH(CH3)2), 19.4/19.3 (O–CH2–CH(CH3)2); M = 384.5.
Anal. Calcd for C23H28O5ꢁ0.2H2O: C, 71.19; H, 7.38. Found: C,
71.26; H, 7.47.
4.21. Propenoic acid (1R,2S)-2-(2-methoxyethoxy)-1,2-bis(2-
methoxyphenyl)ethyl ester 16e
The synthesis was carried out as described above (Section 4.20)
using 7e (0.118 g, 0.355 mmol). After chromatography (PE/E
10:1?E) 16e (0.102 g, 74%) was obtained as a colourless oil
{½a 2D0
ꢂ
¼ þ40:7 (c 0.95, CH2Cl2)}; 1H NMR (CDCl3, 200 MHz) d
7.18–6.57 (m, 9H, Ph-H, OCHPh), 6.35 (dd, J1 = 17.3 Hz, J2 = 1.8
Hz, 1H, CH@CH2), 6.09 (dd, J1 = 17.3 Hz, J2 = 10.3 Hz, 1H, CH@CH2),
5.74 (dd, J1 = 10.3 Hz, J2 = 1.8 Hz, 1H, CH@CH2), 5.19 (d, J = 3.5 Hz,
1H, OCHPh), 3.58–3.42 (m, 7H, incl. 3.54 (s, 3H, OCH3), OCH2CH2O),
3.39/3.28 (2s, 6H, OCH3); 13C NMR (CDCl3, 50 MHz) d 165.0 (O–CO),
157.2/156.7 (Ph-C-2), 130.4 (CH@CH2), 129.0/128.5/128.4/128.3/
127.7/119.8/119.8/109.7/109.5 (Ph-C, CH@CH2), 125.9/125.7 (Ph-
C-1), 76.0/69.1 (OCH2CH2O), 76.0/70.9 (OCHPh), 59.0/55.3/55.0
(OCH3); M = 386.45. Anal. Calcd for C22H26O6: C, 68.38; H, 6.78.
Found: C, 68.16; H, 6.83.
(CH2CH2CH2CH3),
(CH2CH2CH2CH3),
28.7
19.4/19.3
(O–CH2–CH(CH3)2),
(O–CH2–CH(CH3)2),
25.7/23.0
14.0
(CH2CH2CH2CH3); M = 520.67. Anal. Calcd for C32H40O6: C, 73.82;
H, 7.74. Found: C, 73.58; H, 7.80).
4.18. 2-Hydroxy-2-phenylhexanoic acid (1R,2S)-2-(2-
methoxyethoxy)-1,2-bis(2-methoxyphenyl)ethyl ester 13e
The synthesis was carried out as described above (Section 4.17)
using 12e (0.098 g, 0.211 mmol). After chromatography (PE/E
50:1?E) 13e (0.093 g, 84%) was obtained as a colourless oil (1H
NMR (CDCl3, 200 MHz) d 7.56–6.21 (m, 14H, Ph-H, OCHPh), 5.14/
5.06 (2d(diast.), J = 4.1/3.9 Hz, 1H, OCHPh), 3.84 (br s, 1H, OH),
3.60/3.23 (m, 13H, incl. 3.55/3.33/3.24 (3s, 9H, OCH3), OCH2CH2O),
2.26–1.86 (m, 2H, CH2CH2CH2CH3), 1.42–0.81 (m, 7H,
CH2CH2CH2CH3); 13C NMR (CDCl3, 50 MHz) d 174.3 (CO), 157.2/
156.6 (Ph-C-2), 141.8/125.6/125.1 (Ph-C-1), 128.6/128.5/128.3/
127.9/127.3/127.0/125.9/120.0/119.7/109.7/109.6 (Ph-C), 78.2 (C–
OH), 75.7/73.7 (OCHPh), 71.8/68.9 (OCH2CH2O), 59.0/55.4/54.9
(OCH3), 39.2 (CH2CH2CH2CH3), 25.6/22.9 (CH2CH2CH2CH3), 14.0
(CH2CH2CH2CH3)); M = 522.64. Anal. Calcd for C31H38O7: C, 71.24;
H, 7.33. Found: C, 71.03; H, 7.57).
4.22. Propenoic acid (1R,2S)-2-(2-methoxyethoxy)-1,2-
diphenylethyl ester 16f
The synthesis was carried out as described above (Section 4.20)
using
(1R,2S)-2-(2-methoxyethoxy)-1,2-diphenylethanol
7f1c
(0.300 g, 1.10 mmol). After chromatography (PE/E 10:1?E) 16f
(0.234 g, 65%) was obtained as a colourless oil (½a D20
¼ þ27:2 (c
ꢂ
1.00, CH2Cl2)}; 1H NMR (CDCl3, 200 MHz) d 7.28 (s, 10H, Ph-H),
6.33 (dd, J1 = 17.2 Hz, J2 = 1.6 Hz, 1H, CH@CH2), 6.06 (dd, J1 = 17.3
Hz, J2 = 10.3 Hz, 1H, CH@CH2), 6.02/4.67 (2d, J = 6.1 Hz, 2H, OCH-
Ph), 5.78 (dd, J1 = 10.3 Hz, J2 = 1.7 Hz, 1H, CH@CH2), 3.59–3.38
(m, 4H, OCH2CH2O), 3.26 (s, 3H, OCH3); 13C NMR (CDCl3, 50
MHz) d 164.7 (O–CO), 137.9/137.4 (Ph-C-1), 130.8 (CH@CH2),
128.4 (CH@CH2), 128.0/127.9/127.9/127.8/127.7 (Ph-C), 84.4/77.8
(OCHPh), 71.9/68.9 (O–CH2–CH2–O), 58.9 (OCH3); M = 326.40.
Anal. Calcd for C20H22O4: C, 73.60; H, 6.79. Found: C, 73.34; H, 7.09.
4.19. Saponification of 13a and 13e and derivatization of 2-
hydroxy-2-phenylhexanoic acid 14
The saponifications of esters 13a and 13e as well as the deriva-
tization of acids 14 with
according to Ref. 1e.
L
-valine methyl ester were carried out
4.23. Typical procedure for the Diels–Alder reaction of 16a, 16e
and 16f with cyclopentadiene; bicyclo[2.2.1]hept-5-en-2-
carboxylic acid (1R,2S)-1,2-bis(2-methoxyphenyl)-2-(2-
methylpropoxy)ethyl ester 17a
4.20. Typical procedure for the synthesis of acrylates 16a, 16e
and 16f; propenoic acid (1R,2S)-1,2-bis(2-methoxyphenyl)-2-(2-
methylpropoxy)ethyl ester 16a
To a stirred solution of Me2AlCl (0.20 mL 1 M solution in THF,
.
0.202 mmol) or MgBr2 Et2O (0.035 g, 0.133 mmol) in dry dichloro-
Alcohol 7a (0.250 g, 0.76 mmol) and triethylamine (0.154 g,
1.52 mmol) were dissolved in dry dichloromethane (10 mL) under
nitrogen atmosphere, acrylic acid chloride (0.137 g, 1.52 mmol)
was slowly added and the mixture was stirred for 12 h at rt. The
reaction mixture was diluted with dichloromethane, washed suc-
cessively with KHSO4 solution (5%), saturated NaHCO3 solution
and brine, dried, filtered and evaporated to dryness yielding
0.338 g of crude product, which was purified via chromatography
(PE/E 6:1?E). 16a (0.254 g, 87%) was obtained as colourless crys-
methane (10 mL) at ꢀ80 °C under nitrogen atmosphere 16a
(0.074 g, 0.192 mmol in the case of Me2AlCl; 0.049 g, 0.127 mmol
in case of MgBr2ꢁEt2O) dissolved in dry dichloromethane (7 mL)
was added slowly. After 1 min cyclopentadiene (0.127 g, 1.92
mmol or 0.084 g, 1.27 mmol) was added dropwise and the mixture
was stirred for 2 h at ꢀ80 °C and for 30 min at ꢀ50 °C. Afterwards
water (3 mL) was added and the mixture was allowed to reach rt.
The mixture was extracted several times with dichloromethane,
the combined extracts were washed with brine, dried, filtered
and evaporated to dryness. After chromatography (PE/E 10:1?E)
17a (0.062 g, 72% in case of Me2AlCl; 0.053 g, 93% in case of
tals {Fp = 53–55 °C; ½a D20
ꢂ
¼ þ58:3 (c 1.17, CH2Cl2)}; 1H NMR (CDCl3,
200 MHz) d 7.16–7.01 (m, 4H, Ph-H), 6.78–6.59 (m, 4H, Ph-H),
6.55/5.10 (2d, J = 3.5 Hz, 2H, OCHPh), 6.34 (dd, J1 = 17.2 Hz,
.
MgBr2 Et2O) was obtained as a colourless oil (1H NMR (CDCl3,

J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
285
200 MHz) d 7.36–6.57 (m, 8H, Ph-H), 6.40/6.37 (2d(diast.), J = 3.7/
4.5 Hz, 1H, OCHPh), 6.05/5.99 (2dd(diast.), J1 = 5.5 Hz, J2 = 2.9 Hz/
J1 = 5.6 Hz, J2 = 3.0 Hz, 1H, CH@CH), 5.72/5.66 (2dd(diast.), J1 = 5.8
Hz, J2 = 2.6 Hz/J1 = 5.7 Hz, J2 = 2.7 Hz, 1H, CH@CH), 5.05/5.03
(2d(diast.), J = 3.5 Hz, 1H, OCHPh), 3.53/3.44 (2s(diast.), 6H,
OCH3), 3.16/2.79 (2br s, 2H, CH–CH@CH–CH), 3.10/3.07 (2d(diast.),
J = 6.5 Hz/6.7 Hz, 2H, OCH2CH(CH3)2), 2.98/2.84 (m, 1H, CHCOO),
1.87–0.77 (m, 11H, incl. 0.82/0.79 (2d, J = 5.9 Hz, 6H, OCH2CH
(CH3)2), OCH2CH(CH3)2, CH2); 13C NMR (CDCl3, 50 MHz) d 173.5/
173.4 (CO(diast.)), 157.5/157.3/156.9/156.7 (Ph-C-2(diast.)), 137.4/
(5 mL) and stirred at reflux for 24 h. DME was evaporated and
the residue was diluted with saturated NaHCO3 solution, washed
with ether, acidified with concd HCl to pH 2 and extracted several
times with ee. The combined extracts were washed with brine,
dried, filtered and evaporated to dryness yielding 18 (0.009–
0.022 g, 75–97%) as a colourless oil (1H NMR (CDCl3, 200 MHz)
according to Ref. 18).
4.27. Typical procedure for the synthesis of bicyclo[2.2.1]hept-
5-en-2-carboxylic acid methyl ester 19
132.6/132.5
(CH@CH(diast.)),
128.5/128.4/128.2/.128.1/128.1/
127.8/119.9/119.8/119.7/119.5/109.8/109.7/109.6/109.5 (Ph-C
(diast.)), 126.9/126.7/126.6/126.1 (Ph-C-1), 76.2 (OCH2), 75.8/75.7/
70.9/70.6 (OCHPh(diast.)), 55.4/55.2/55.1 (OCH3(diast.)), 49.6/49.5/
29.0/28.8 (CH2(diast.)), 45.8/45.7/43.5/42.6/42.5 (aliph. CH(diast.)),
28.7 (CH(CH3)2), 19.4 (CH(CH3)2); M = 450.58. Anal. Calcd for
C28H34O5ꢁ0.3H2O: C, 73.76; H, 7.65. Found: C, 73.81; H, 7.63.
Acid 18 (0.018 g, 0.130 mmol) and 4-toluenesulfonic acid (4 mg,
0.02 mmol) were dissolved in methanol and stirred at reflux for
12 h. The mixture was concentrated, diluted with dichlorometh-
ane, washed with saturated NaHCO3 solution and brine, dried, fil-
tered and concentrated under reduced pressure (100 mbar)
yielding 19 (0.030 g, 150% because of methanol traces) as a colour-
less liquid which was used directly for GC-analysis (1H NMR
(CDCl3, 200 MHz) according to Ref. 25).
4.24. Bicyclo[2.2.1]hept-5-en-2-carboxylic acid (1R,2S)-2-(2-
methoxyethoxy)-1,2-bis(2-methoxyphenyl)ethyl ester 17e
4.28. Reactions on solid support
The synthesis was carried out as described above (Section 4.23)
using 16e (0.082 g, 0.212 mmol). After chromatography (PE/E
10:1?E) 17e (0.062 g, 65%) was obtained as a colourless oil (1H
NMR (CDCl3, 200 MHz) d 7.32–6.11 (m, 9H, Ph-H, OCHPh), 6.07/
5.97 (m, 1H, CH@CH), 5.79/5.62 (m, 1H, CH@CH), 5.13/5.11
(2d(diast.), J = 5.1/3.9 Hz, 1H, OCHPh), 3.60–3.24 (m, 13 H, incl.
3.60/3.52/3.38/3.37/3.28/3.24 (6s/(diast.), 9H, OCH3), OCH2CH2O),
3.16/2.80 (2br s, 2H, CH–CH@CH–CH), 3.00/2.85 (m, 1H, CHCOO),
1.89–1.14 (m, 4H, 2 ꢃ CH2); 13C NMR (CDCl3, 50 MHz) d 173.4/
173.4 (CO), 157.4/157.2/156.9/156.7 (Ph-C-2(diast.)), 137.4/137.3/
132.7/132.4 (CH@CH(diast.)), 128.7/128.6/128.5/128.3/128.2/
127.8/127.6/120.0/119.8/119.8/119.6/109.9/109.7/109.6/109.5
(Ph-C(diast.)), 126.5/126.2/126.3/126.01 (Ph-C-1(diast.)), 75.9/75.8/
70.7/70.5 (OCHPh(diast.)), 71.9/69.0/68.8 (OCH2CH2O(diast.)), 59.0/
59.0/55.5/55.3/55.0 (OCH3(diast.)), 49.6/49.5/29.0/28.8 (CH2 (diast.)),
45.9/45.7/43.5/42.6/42.5 (aliph. CH(diast.)); M = 452.55. Anal. Calcd
4.28.1. Synthesis of immobilized auxiliaries 7h, 7h0, 7i and 7i0
The synthesis of auxiliaries 7h, 7h0, 7i and 7i0 was carried out
following the literature procedures.1d
4.28.2. Typical procedure for the esterification of auxiliaries 7h/
7h0 and 7i/7i0 with propanoic acid 8h–8i0
At first, DIC (0.655 g, 5.2 mmol) was added dropwise to a mix-
ture of resin 7i0 (0.908 g, 0.52 mmol), propanoic acid (0.385 g, 5.2
mmol) and DMAP (0.064 g, 0.52 mmol) in dry dichloromethane
(15 mL) while cooling on an ice bath. The resulting mixture was
shaken for 48 h at rt. Then the resin was filtered off and thoroughly
washed successively with dichloromethane, methanol, dichloro-
methane, methanol, dichloromethane, methanol and dried in va-
cuo overnight at 40 °C. Therefore, 0.929 g of colourless resin 8i0
(mass increase: 0.021 g ꢄ 96%) was isolated (IR
m (KBr) =
for C H32O6ꢁ0.3H2O: C, 70.81; H, 7.18. Found: C, 70.89; H, 7.23).
3570 cmꢀ1 (OH: vanished), 1737 cmꢀ1 (COOR); no further
changes).
27
4.25. Bicyclo[2.2.1]hept-5-en-2-carboxylic acid (1R,2S)-2-(2-
methoxyethoxy)-1,2-diphenylethyl ester 17f
4.28.3. Typical procedure for the
8h–8i0 to 9h–9i0
a-alkylation of propionates
The synthesis was carried out as described above (Section 4.23)
using 16f (0.076 g, 0.234 mmol in the case of Me2AlCl; 0.077, 0.236
mmol in the case of MgBr2ꢁEt2O). After chromatography (PE/E
10:1?E) 17f (0.083 g, 90% in the case of Me2AlCl; 0.070, 76% in the
case of MgBr2ꢁEt2O) was obtained as a colourless oil (1H NMR (CDCl3,
200 MHz) d 7.25–7.19 (m, 10H, Ph-H), 5.97–5.88 (m, 1H, CH@CH),
5.79/5.62 (m, 1H, CH@CH), 5.78/5.75 (2d(diast.), J = 6.9/7.6 Hz, 1H,
OCHPh), 5.48/5.13 (2dd(diast.), J1 = 5.7 Hz, J2 = 2.7 Hz/J1 = 5.5 Hz,
J2 = 2.7 Hz, 1H, CH@CH), 4.49 (d, J = 7.0 Hz, 1H, OCHPh), 3.44–3.22
(m, 4H, OCH2CH2O), 3.14/3.10 (2s(diast.), 3H, OCH3), 3.06/2.87
(2br s, 2H, CH–CH@CH–CH), 2.78–1.07 (m, 5H, aliph.-H); 13C NMR
(CDCl3, 50 MHz) d 173.2/173.1 (CO), 138.6/138.4/138.2/137.9 (Ph-
C-1(diast.)), 137.5/137.4/132.2/132.0 (CH@CH(diast.)), 128.0/
127.9/127.8/127.8/127.8/127.7/127.7 (Ph-C(diast.)), 84.6/84.5/
77.3/77.3 (OCHPh(diast.)), 71.9/71.8/68.8/68.7 (OCH2CH2O(diast.)),
58.9/58.8 (OCH3(diast.)), 49.6/49.4/29.0/28.6 (CH2(diast.)), 46.0/
45.6/43.3/43.1/42.7 (aliph. CH(diast.)); M = 392.50. Anal. Calcd for
C25H28O4: C, 76.50; H, 7.19. Found: C, 76.29; H, 7.26).
A mixture of resin 8i0 (0.855 g, 0.38 mmol) and LiCl (0.097 g, 2.3
mmol) in dry THF (15 mL) was cooled to ꢀ85 °C and a solution of
LDA in THF (5 mL) freshly prepared from BuLi (2.35 M in THF,
0.81 mL, 1.90 mmol) and diisopropylamine (0.202 g, 2.00 mmol)
and cooled to ꢀ60 °C was added dropwise. The mixture was care-
fully stirred at ꢀ78 °C for 1.5 h, cooled to ꢀ90 °C and benzyl bro-
mide (0.650 g, 3.8 mmol) was added. After stirring for 1 h at
ꢀ78 °C the mixture was allowed to reach rt and quenched with sat-
urated NH4Cl solution. Then the resin was filtered off and thor-
oughly washed successively with dichloromethane, methanol,
water, methanol, dichloromethane, methanol, dichloromethane,
methanol and dried in vacuo overnight at 40 °C. Therefore,
0.888 g of
a
colourless resin 9i0 was obtained (IR
m
(KBr) = 1736 cmꢀ1 (COOR); no further changes).
4.28.4. Typical procedure for the saponification of esters 9h–9i0
to 10a
A mixture of resin 9i0 (0.839 g, 0.38 mmol) and LiOH (0.091 g,
3.8 mmol) in THF/methanol/water 10/4/1 (11 mL) was shaken for
96 h. After complete conversion had been indicated by IR spectros-
copy, the resin was filtered off and thoroughly washed successively
with saturated aqueous NaHCO3, water, water/THF (1/1), metha-
nol, THF, water, methanol, THF, methanol, THF, metanol and dried
in vacuo overnight at 40 °C. Therefore, 0.751 g of a colourless resin
4.26. Saponification of esters 17a, 17e and 17f; bicyclo
[2.2.1]hept-5-en-2-carboxylic acid 18
Esters 17a, 17e and 17f (0.039–0.066 g, 0.09–0.17 mmol) and
LiOH (0.179 g, 7.5 mmol) were suspended in DME/water 1:1

286
J. Broeker et al. / Tetrahedron: Asymmetry 20 (2009) 273–287
7i0 was obtained (IR
m
(KBr) = 3560 cmꢀ1 (OH), ꢅ1736 cmꢀ1 (COOR:
washed successively with dichloromethane, methanol, dichloro-
methane, methanol, dichloromethane, methanol and dried in vacuo
overnight at 40 °C. Therefore, 0.993 g of a colourless resin 16h0 (mass
vanished); no further changes). The recovered resin could be intro-
duced in the next reaction cycle without any further purification.
The combined filtrates were diluted with saturated NaHCO3
solution, and THF and methanol were evaporated. The aqueous
that remained was extracted three times with ether, acidified care-
fully with concd HCl while cooling on an ice bath and then ex-
tracted three times with ee. The combined ethyl acetate extracts
were washed with brine, dried over Na2SO4, filtered and evapo-
rated. Compound 10a (0.027 g, 49%) was obtained as a yellow oil
(1H NMR (CDCl3, 200 MHz) according to Ref. 23). The derivatization
of 10a was carried out according to the procedure described above
(Section 4.16).
increase: 0.026 g ꢄ 86%) was isolated (IR
m
(KBr) = 3567 cmꢀ1 (OH:
vanished), 1726 cmꢀ1 (COOR); no further changes.)
4.28.9. Diels–Alder reaction of immobilized acrylate 16h0 to
17h0
A suspension of resin 16h0 (0.964 g, 0.49 mmol) in dry dichloro-
methane (35 mL) was cooled to ꢀ100 °C °C and stirred for 15 min
at this temperature. Me2AlCl (1 M solution in THF, 0.51 mL, 0.51
mmol) was added dropwise followed after 1 min by cyclopentadi-
ene (0.40 mL, 4.9 mmol). The mixture was stirred for 5 h at ꢀ80 °C
and for 1 h at ꢀ50 °C and afterwards the resin was filtered off, and
thoroughly washed successively with methanol, dichloromethane,
methanol, dichloromethane, methanol, dichloromethane, metha-
nol and dried in vacuo overnight at 40 °C. Therefore, 1.00 g of a col-
4.28.5. Synthesis of immobilized phenylglyoxylic acid esters
12h0 and 12i0
The synthesis of esters 12h0 and 12i0 was carried out following
the literature procedures.1d
ourless resin 17h0 was obtained (IR
m
(KBr) = 3324 cmꢀ1 (broad
peak 3100–3700 cmꢀ1), 1727 cmꢀ1 (COOR); no further changes).
4.28.6. Typical procedure for the addition of n-BuZnCl to
phenylglyoxylates 12h0 and 12i0 to 13h0 and 13i0
4.28.10. Saponification of ester 17h0 to 18
A freshly prepared and titrated24 solution of n-BuMgCl (1.0 mL,
1.94 mmol) in THF was slowly added to a thoroughly stirred solu-
tion of pre-dried ZnCl2 (0.240 g, 1.76 mmol) in dry THF (2 mL)
while cooling on an ice bath, and stirring was continued for 2 h
at 0 °C. The solution of thus prepared n-BuZnCl was slowly added,
by means of a syringe, over 15 min to a suspension of ester 12i0
(0.594 g, 0.22 mmol) in dry THF (10 mL) which was pre-cooled to
ꢀ90 °C and the resulting mixture was stirred for 1 h at ꢀ78 °C.
Then the temperature was raised up to ꢀ30 °C over a period of
1 h, kept constant at ꢀ30 °C for 2 h and finally a 10% aqueous
NH4Cl solution (10 mL) was added and stirring was continued for
15 min at rt. The resin was filtered off and thoroughly washed suc-
cessively with aqueous NH4Cl, NH4Cl/THF (1/1), water, water/THF
(1/1), THF, methanol, dichloromethane, methanol, dichlorometh-
ane, methanol and dried in vacuo overnight at 40 °C. Therefore,
A mixture of resin 17h0 (0.946 g, 0.51 mmol) and LiOH (0.500 g,
20.8 mmol) in DME/THF/water 1/2/1 (20 mL) was refluxed for 36 h.
After complete conversion had been indicated by IR spectroscopy,
the resin was filtered off and thoroughly washed successively with
saturated aqueous NaHCO3, water, water/THF (1/1), methanol, THF,
water, methanol, THF, methanol, THF, methanol and dried in vacuo
overnight at 40 °C. Therefore, 0.927 g of a colourless resin 7h0 was
isolated (IR
ished); no further changes).
m
(KBr) = 3567 cmꢀ1 (OH), ꢅ1727 cmꢀ1 (COOR: van-
The combined filtrates were diluted with saturated aqueous
NaHCO3, and THF and DME were evaporated. The aqueous that re-
mained was extracted three times with ether, acidified carefully
with concd HCl while cooling on an ice bath and then extracted
three times with ee. The combined ethyl acetate extracts were
washed with brine, dried over Na2SO4, filtered and evaporated.
Compound 18 (0.015 g, 22%) was obtained as a colourless oil (1H
NMR (CDCl3, 200 MHz) according to the literature18). The derivati-
zation of 18 was carried out according to the procedure described
above (Section 4.27).
0.629 g of
a
colourless resin 13i0 was obtained (IR
m
(KBr) = 3505 cmꢀ1 (OH), 1728 cmꢀ1 (COOR), 1690 cmꢀ1 (C@O: van-
ished); no further changes).
4.28.7. Typical procedure for the saponification of esters 13h’
and 13i0 to 14
References
A mixture of resin 13i0 (0.611 g, 0.31 mmol) and LiOH (0.075 g,
3.1 mmol) in THF/methanol/water 10/4/1 (11 mL) was refluxed for
24 h. After complete conversion had been indicated by IR spectros-
copy, the resin was filtered off and thoroughly washed successively
with saturated aqueous NaHCO3, water, water/THF (1/1), metha-
nol, THF, water, methanol, THF, methanol, THF, methanol and dried
in vacuo overnight at 40 °C. Therefore, 0.561 g of a colourless resin
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Skarphedinsson, H.; Smith, A. D.; Vickers, R. J. Org. Biomol. Chem. 2008, 6, 1625–
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5. Sumrell, G.; Stevens, J. I.; Goheen, G. E. J. Org. Chem. 1957, 22, 39–41.
7i0 was obtained (IR
m
(KBr) = 3567 cmꢀ1 (OH), ꢅ1728 cmꢀ1 (COOR:
vanished); no further changes).
The combined filtrates were diluted with saturated aqueous
NaHCO3, and THF and methanol were evaporated. The aqueous
that remained was extracted three times with ether, acidified care-
fully with concd HCl while cooling on an ice bath and then ex-
tracted three times with ee. The combined ethyl acetate extracts
were washed with brine, dried over Na2SO4, filtered and evapo-
rated. Compound 14 (0.039 g, 85%) was obtained as a colourless so-
lid (1H NMR (acetone-d6, 200 MHz) and derivatized for HPLC-
analysis according to Ref. 1e).
4.28.8. Synthesis of immobilized acrylate 16h0
Acrylic acid chloride (0.507 g, 5.6 mmol) was added dropwise to a
mixture of resin 7h0 (0.967 g, 0.56 mmol) and Et3N (0.565 g, 5.6
mmol) in dry dichloromethane (15 mL). The resulting mixture was
shaken for 72 h at rt. Then the resin was filtered off and thoroughly

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