Chiral linker. Part 3: Synthesis and evaluation of aryl substituted m-hydrobenzoins as solid supported open chain chiral auxiliaries for the diastereoselective reduction of α-keto esters

Article abstract of DOI:10.1016/j.tetasy.2006.08.017

Five partly novel aryl substituted m-hydrobenzoins were synthesized and the corresponding desymmetrized hydrobenzoin ethers evaluated as open chain chiral auxiliaries in the L-Selectride mediated stereoselective reduction of phenylglyoxylates, resulting in de values of up to 91%. Two optimized auxiliary structures were immobilized on commercially available Wang-resin and applied as a reusable solid supported chiral auxiliary in the same type of reaction.

Full text of DOI:10.1016/j.tetasy.2006.08.017

Tetrahedron: Asymmetry 17 (2006) 2413–2429
Chiral linker. Part 3: Synthesis and evaluation of aryl substituted
m-hydrobenzoins as solid supported open chain chiral auxiliaries
for the diastereoselective reduction of a-keto esters
Joachim Broeker, Max Knollmueller and Peter Gaertner*
Department of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria
Received 15 August 2006; accepted 22 August 2006
Available online 26 September 2006
Abstract—Five partly novel aryl substituted m-hydrobenzoins were synthesized and the corresponding desymmetrized hydrobenzoin
ethers evaluated as open chain chiral auxiliaries in the L-Selectrideꢀ mediated stereoselective reduction of phenylglyoxylates, resulting
in de values of up to 91%. Two optimized auxiliary structures were immobilized on commercially available Wang-resin and applied
as a reusable solid supported chiral auxiliary in the same type of reaction.
ꢁ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
anhydrolactol,3 followed by derivatization to build up the
appropriate ether moieties or by immobilization on solid
support and subsequent cleavage of the chiral protecting
group.1 Investigations on the potential of these auxiliaries
to induce stereoselectivities in different model reactions re-
sulted in selectivities of up to 91% de (and 84% de for the
solid bound auxiliary, respectively) in the L-Selectrideꢀ
mediated reduction of a-keto esters1b,1c and 36% de (or
28% de on solid support) in the a-alkylation of the corre-
sponding propionates.1a Apart from that it could be shown
that after cleavage of the desired products, the solid bound
auxiliaries could be reused at least 3 times without the loss
of stereoinducing ability,1a,c which is a remarkable benefit
compared to other known chiral linkers for example, based
on Evans oxazolidinones.4
In previous articles,1 we have already described the benefits
of novel m-hydrobenzoin derived chiral auxiliaries I and
II, which can either be applied in solution phase chemistry
or immobilized on solid support and used as a chiral
linker.2
R
HO
HO
O
O
O
R1
Previous results indicated that the steric demand and
coordinative properties of the ether moiety and the
sublinking unit of the solid bound auxiliaries, respectively,
had a large impact on the diastereoselectivities achievable
in the different model reactions. However, the hydrobenz-
oin structure itself should allow the variation of the steric,
electronic, and coordinative properties of the whole auxil-
iary via the introduction and variation of substituents into
the hydrobenzoin aryl moieties. The results of our recent
studies on the effect of such aryl substituents on the
stereoinductive potential of m-hydrobenzoin derived
chiral auxiliaries and solid phase linkers will be presented
herein.
I
II
i-Bu, t-Bu, C(CH3)2CH2Ph, C(CH3)2CH2OCH3,
R = Bn,
CH2CPh2OCH3, CH2CH2N(CH3)2, Wang-resin
R1 = CH3, Wang-resin
These structures are easily accessible via desymmetrization
of m-hydrobenzoin with commercially available Noe’s
*
Corresponding author. Tel.: +43 15880155421; fax: +43 15880115492;
e-mail: peter.gaertner@tuwien.ac.at
0957-4166/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.08.017

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J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2. Results and discussion
meso-hydrobenzoins via selective protection of the (R)-
carbon center using exo-anhydrolactol 4 in analogy to
the literature procedures,3 the desired ethers 6a–d could
be obtained using NaH and 4-toluenesulfonic acid i-butyl-
ester. However, even after variation of the reaction condi-
tions and the base, it was not possible to convert the
desymmetrized nitro substituted compound 5e into the
corresponding i-butylether (Scheme 2).
2.1. Evaluation of auxiliaries via model reactions in the
solution phase
To gain a comprehensive insight into the possible impact of
aryl substitution on the achievable stereoinduction, a set of
five m-hydrobenzoins bearing substituents with different
steric, electronic, and coordinative properties were synthe-
sized as test systems.
Over the course of our studies, a combination of the
coordinative properties of the 2,20-dimethoxy substituted
system with the further coordination sites of the methoxy-
ethyl ether structure became attractive; compound 6g was
synthesized following a four-step procedure already de-
scribed previously.1c
The o-methoxy- and o-methyl substituted compounds 3a
and 3b could be obtained via benzoin condensation5 and
subsequent reduction with NaBH4, but as the direct con-
version of substituted benzaldehydes 1c–e to the corre-
sponding benzoins 2c–e yielded only small amounts of
the desired compounds, an alternative route6 via the
TMS-protected cyanohydrins was used for the synthesis
of derivatives 2c–e. Due to the low yield observed in the
synthesis of benzoin 2e, additional experiments for the
optimization of the meso/rac-ratio of the following reduc-
tion were carried out. Thereby the meso-selectivity of the
reaction could be improved (4.3:1 using NaBH4 compared
to 8.0:1 using BH3ÆS(CH3)2ÆTHF) allowing 89% yield for
the pure meso-product 3e (Scheme 1).
Cleavage of the chiral protecting group allowed the
recovery of the auxiliary via the corresponding methyl
acetal and yielded the desired test systems 7a–e for the
following preliminary investigations in solution phase.
As in the previous investigations, the L-Selectrideꢀ medi-
ated reduction of phenylglyoxylates was chosen as an
appropriate model reaction for the auxiliaries. Therefore,
the aryl substituted m-hydrobenzoin ethers 7a–e were con-
verted into the corresponding esters followed by reduction
according to the procedure described by Rosini et al.7
yielding mandelic acid esters 9a–e.8 The stereochemical
Due to previous investigations1b on the influence of the
ether moiety on the stereoinductive properties of m-hydro-
benzoin derived auxiliaries, the i-butylether proved to be
an easily accessible test system allowing high selectivities
in different model reactions, the aryl substituted m-hydro-
benzoins were also converted to the corresponding i-butyl
derivatives. After desymmetrization of the substituted
1
outcome of these reactions was again determined via H
NMR of the crude reaction mixtures, as well as after
saponification via the specific rotation values of the corre-
sponding acids and via HPLC of their L-valine methylester
derivatives 11,9 respectively (Scheme 3).
R1
R1
O
2a,b : i
2c-e : ii
3a-d : iii
3e : iv
O
OH
OH
OH
R1
1a-e
R1
2a-e
R1
3a-e
Scheme 1. Synthesis of hydrobenzoin derivatives; R1 = 2-OCH3 1–3a, 2-CH3 1–3b, 4-OCH3 1–3c, 2-CF3 1–3d, 2-NO2 (1–3e). 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 ꢂC, (2) 1 equiv LDA, 1 equiv ArCHO, DME, ꢀ65 ꢂC, (3)
2 M HCl, THF, 12 h rt (2c: 51%, 2d: 79%, 2e: 5%); (iii) NaBH4, EtOH, 3 h rt (3a: 73%, 3b: 63%, 3c: 65%, 3d: 21%); (iv) 1 equiv BH3ÆS(CH3)2, THF, ꢀ78 ꢂC
(89%).
R1
R1
R1
R1
O
O
O
OH
OH
O
4
O
ii
(
iii
O
H
2
)
H
i
H
H
OH
OR2
OH
OR2
R1
R1
R1
5a-e
R1
6a-d, 6g
3a-e
7a-e
Scheme 2. Desymmetrization and etherification of hydrobenzoin derivatives 3a–e. Reagents and conditions: (i) 4-toluenesulfonic acid, CH2Cl2, 12 h rt (5a:
70%, 5b: 63%, 5c: 83%, 5d: 57%, 5e: 61%); (ii) (for 5a–d) (1) NaH, (2) 4-toluenesulfonic acid i-butylester, DMF, 12 h rt (6a: 76%, 6b: 93%, 6c: 77%, 6d:
99%); (ii) (5a ! 6e) (1) NaH, (2) bromoacetic acid t-butylester, HMPT, THF, 12 h rf (72%); (6e ! 6f) LiAlH4, Et2O, 2 h rt (73%); (6f ! 6g) (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%).

J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2415
R1
O
OH
O
OH
R1
R1
i
ii
O
O
O
OR2
OR2
OR2
R1
R1
R1
7a-e
8a-e
9a-e
O
O
iv
iii
O
N
OH
H
O
OH
OH
10
11
Scheme 3. Application of the test systems on the L-Selectrideꢀ mediated reduction of phenylglyoxylates, cleavage, and derivatization. Reagents and
conditions: (i) phenylglyoxylic acid, DIC, DMAP, CH2Cl2, 12 h rt; (ii) L-Selectrideꢀ, THF, 1 h ꢀ78 ꢂC; (iii) 3 equiv LiOH, THF/MeOH/H2O, 1.5 h rt; (iv)
Val-OMe, HOBt, DIC, CH2Cl2, 12 h ꢀ30 ꢂC ! rt.
stituent or the aryl moiety is possible either in the case of
a synclinal or antiperiplanar arrangement of the benzylic
protons (see Scheme 4), on the basis of the Karplus rela-
tionship resulting in coupling constants of about 3 and
10 Hz, respectively, this does not seem surprising. Apart
from this, the preferred conformation present in the
substrate can be varied to a large extent by complexation
effects involving the Lewis acidic metal cations of the
reducing agent or an additive.
Table 1. Diastereoselective reduction of phenylglyoxylates 8a–e compared
to results from preceding investigations
Entry Ester R1
R2
3J(benzyl) dea (%)
(Hz) 8 (S,R,S)-9a
1
8a
8a
8b
8c
8d
8e
8f
2-OCH3 CH2CH(CH3)2 3.5
2-OCH3 CH2CH(CH3)2 3.5
91
72
71
74
39
80
78
77
91
2b
3
2-CH3
4-OCH3 CH2CH(CH3)2 6.8
2-CF3 CH2CH(CH3)2 6.6
2-OCH3 CH2CH2OCH3 3.9
CH2CH(CH3)2 6.1
4
5
6
7c
8c
9b,c
H
H
H
CH2CH(CH3)2 5.8
CH2CH2OCH3 6.7
CH2CH2OCH3 6.7
If coordinative interactions are considered in addition to
steric effects, an explanation of the enhanced stereoselective
induction of the o-methoxy substituted derivative 8a (see
Table 1, entries 1 and 7) based on the models depicted in
Scheme 5 is plausible: because of the possible coordination
of the Li cation with the a-carbonyl-O, the oxygen of the
ether moiety, and either one of the o-methoxy substituents
of substrate 8a (see Scheme 5A/B), the conformation of the
hydrobenzoin is fixed in a position allowing an extensive
shielding of the si-face of the a-carbonyl. As a similar coor-
dination is not possible in the case of substrates 8b and 8c,
selectivities comparable to the value of the unsubstituted
derivative 8f were expected (see Table 1, entries 3, 4, and
7). Regarding Table 1, entries 1, 2, and 6, it appears that
neither the addition of ZnCl2 as a coordination agent nor
the binding of an ether moiety bearing further coordination
sites allows further enhancement of the stereoselective
induction. In both cases, a competitive coordination model
can serve as an explanation. The complexation of a Zn cat-
ion causes a syn-arrangement of the adjacent carbonyl
groups, which leads, in case of an attack from the si-face
of the a-carbonyl, to (R)-configuration of the correspond-
ing mandelic acid ester. This anti–syn switch is only
8g
8g
a Diastereoisomeric ratios determined by 1H NMR integration on crude
reaction mixtures 9 and HPLC analysis of L-valine methyl ester deriv-
atives 11 of cleaved mandelic acids 10; absolute configuration of major
diastereoisomers approved by optical rotation of 10.
b 2 equiv of ZnCl2 as additive.
c Data from Refs. 1b and 1c, respectively.
The results of the diastereoselective reductions of esters
8a–e shown in Table 1 in comparison to the selected results
of previous investigations1b,c make it clear that the aryl
substituents allow a significant variation of the stereo-
inductive properties of the auxiliaries.
A correlation of the coupling constants of the two benzylic
hydrobenzoin protons in substrates 8a–g with the achiev-
able selectivities based on a conformation dependent steric
interaction of the ether moiety and the reacting carbonyl,
as posted by Rosini et al.7 for (R,R)-hydrobenzoin ethers,
was not observed in case of the meso-derivatives. However,
as steric shielding of the carbonyl group by the ether sub-
O
O
R'
H
O
O
O
O
Ph
Ph
R'
O
H
O
O
H
H
Ph
R'
O
H
O
O
H
A
B
C
Scheme 4. Conformation analysis based on the model proposed by Rosini et al.7 (aryl substituents omitted for clarity reasons).

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J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
O
re
Ph
re
re
H
H
H
H
O
O
H
H
O
H
O
H
O
H
O
Ph
O
O
Ph
O
O
Li+
Li+
Ar
O
si
si
X
si
O
O
O
Li+
X
O
O
O
A
B
C
Scheme 5. Proposed model for the observed selectivities caused by the preferred re-attack on the a-carbonyl.
allowed if the energy gained in the complexation is greater
than the steric repulsion and happens only in the case of
Zn2+, a stronger Lewis acid than Li+.7a For substrate 8e
the coordination depicted in Scheme 5C is conceivable, also
causing a fixed conformation of the hydrobenzoin but on
the other hand a less distinctive shielding of the si-face of
the a-carbonyl.
chloromethylated Wang-resin,10 in case of 6f providing an
ethyleneglycol spacer unit between the benzylic sublinker
moiety of the Wang-resin and the hydrobenzoin structure.
Over the course of previous investigations, presumably be-
cause of interactions of the sterically demanding auxiliary
precursor, maximum auxiliary immobilization rates of
81% were observed using commercially available Wang-
resins with about 0.6 mmol/g loading and a further drop
of attachment rates occurred when resins with higher load-
ings were used. Even with higher reagent excesses, it was
not possible to increase the conversion rate of the immobi-
lization and when an excess of NaH compared to the
amount of auxiliary precursor 5a was used for the immobi-
lization step, a surprising side reaction consuming 5a and
yielding by-product 12 was observed. After cleavage of
the chiral protecting group under acidic conditions, which
induced cyclization to [1,3,6]-trioxocan 13, the structure of
both by-products could be determined via CH-correlation
spectra (Scheme 6).
An explanation of the low selectivities obtained with auxil-
iary 8d based on the results gained so far seems difficult as
its steric and coordinative properties should be similar to
8b. However, one reason could be the reduced electron
density of the aromatic substituent of the hydrobenzoin
causing a declined pp-interaction with the carbonyl group.
This could induce a less effective shielding of the si-face by
the hydrobenzoin aryl residue compared to the model
described in Scheme 4C.
2.2. Auxiliary immobilization and evaluation via model
reactions on solid support
Although the absolute configuration of trioxocan 13 could
not be clearly determined so far, the following predictions
can be stated on the basis of the observed specific rotation
of 13, the obtained NMR data and the mechanisms to be
expected because of previous observations.
Similar to the initial experiments in the solution phase, the
o-methoxy substituted auxiliaries 7a and 7e proved to be
the most promising systems, further investigations were
carried out to determine their applicability as chiral solid
phase linkers. Therefore, the desymmetrized hydrobenzoin
derivatives 5a and 6f were immobilized on solid support via
deprotonation using NaH and subsequent conversion with
The observed specific rotation and the reduced set of sig-
nals in NMR spectra permit only C2-symmetric relative
Scheme 6. CH-correlation spectra of by-products 12 and 13.

J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2417
configurations (4R*,5R*,7R*,8R*) and (4R*,5S*,7S*,8R*),
respectively, which corresponds, presuming no change of
configuration during the attack of alkoxide 14 on the sol-
vent giving rise to 15, to the absolute configurations
(4S,5S,7S,8S) and (4S,5R,7R,8S). Therefore, retention of
the configuration has to be assumed at the second unpro-
tected carbon center during the formation of by-product
12 as well. Over the course of the following acid catalyzed
cleavage of the chiral protecting group and the ring closure,
an epimerization of both the remaining centers via the for-
mation of the corresponding carbenium ions is possible.
However, based on the fact that this reaction is an equilib-
rium reaction, the formation of the thermodynamically
more stable product is more likely and retention of config-
uration of both the remaining stereogenic centers can
be expected as well. Therefore—though not completely
proven so far, (4S,5R,7R,8S) seems to be the most likely
absolute configuration for trioxocane 13 (Scheme 7).
by the attachment of the substrate on the residual active
sites of the resin not provided with a chiral linker, the chlo-
romethyl moieties remaining after the attachment step were
converted to the corresponding iodides followed by
Bu3SnH mediated reduction to obtain a methyl residue
using literature procedures.12c,12d Resins treated according
to this deactivation procedure after the attachment of the
linker are in the following labeled as 6g0/7g0 and 6h0/7h0,
respectively. The actual influence of the incomplete linker
attachment was validated via comparison with resins not
treated following the iodination/reduction procedure. As
shown in Table 2, the achievable selectivities can be
increased by deactivating the remaining chloromethyl
residues (see entries 8 and 9). However, in the case of low
attachment rates, even after conversion of the remaining
active sites, only low stereoselectivities were achieved com-
pared to the values obtained after almost complete linker
attachment (see entries 2 and 6) (Scheme 8).
As already described,1c,12 the incomplete conversion of the
active sites of the resin can give rise to a direct attachment
of the substrate to the resin, thus providing no possibility
for the stereoselective induction from the chiral linker
and therefore lowering the achievable selectivities drasti-
cally. To prevent the limitation of stereoselectivity caused
After acid catalyzed cleavage of the chiral protecting
group, phenylglyoxylic acid was immobilized on the resin
as the substrate for the following reduction step. As during
previous investigations, model reactions were carried out
using standard procedures and the immobilized products
could be released via saponification using LiOH in
O
O
O
O
NaH
O
H
O
H
+
Cl
W
W
DMF
H
H
OH
O
W
O
O
6g
5a
O
O
O
O
O
O
O
H
+
O
H
H
N
H
H
O-
O
H
+
O
Na
O
14
15
NaH
O
O
O
H
O
1) H2O
2) 5a
O
O
H
O
p-TosOH
MeOH
O
O
H
O-
H
+
H
Na
H
O
O
O
H
H
O
O
O
16
12
O
O
O
O
H
H
H
H
O
O O
13
Scheme 7. Proposed mechanism of the formation of by-product 13 based on the lit.11

2418
J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
Table 2. Result of diastereoselective reductions of phenylglyoxylates 8g,
8g0, 8h, and 8h0 including recyclability experiments
oxyethyl 6g ethers in solution phase. This could complicate
the coordinative interactions, which were posted above as a
conceivable reason for the enhanced selectivities related to
the introduction of o-methoxy substituents onto the aryl
residues of the hydrobenzoin structure.
Entry
Ester
Attachment
rate (%)
Recycling
step
eea (%)
(S)-10
1
2
3
4
5
6
7
8
9
8g
8g
51
81
—
—
1
2
3
—
1
—
—
33
53
70
61
59
48
57
31
55
3. Conclusion
8g0
64
Herein, we have reported that conditions for the synthesis
of partly aryl substituted hydrobenzoins were found. After
desymmetrization of the obtained derivatives, the influence
of different substituents on the aryl residues of the m-
hydrobenzoin structure on the stereoselective induction
during the reduction of the corresponding phenylgloxylates
could be investigated. In the case of the o-methoxy deriva-
tive, an enhancement of the achievable stereoselectivities
up to 91% de was observed; however, neither the introduc-
tion of an altered ether residue bearing additional coordi-
native options nor the addition of ZnCl2 as a complexing
agent led to further improvements of the induction rate.
8h
8h0
76
75
a Enantiomeric excess determined by HPLC analysis of L-valine methyl
ester derivatives 11.
MeOH/THF/water yielding (S)-mandelic acids, which
were derivatized for the following determination of their
enantiomeric purity via HPLC. All conversions on solid
support were again monitored via FT-IR spectroscopy
and in addition conversion rates were estimated gravi-
metrically (Scheme 9).
Although the applicability and recyclability of the aryl
substituted m-hydrobenzoins as asymmetric solid phase
linkers could be proved, as in previous investigations, a
slight drop of the stereoselective induction was observed
when the o-methoxy substituted system was transferred
to a solid support.
As in the case of previously investigated auxiliary systems,
the results shown in Table 2 clearly prove the recyclability
of the tested hydrobenzoin derived linkers. However, the
selectivities observed in the solid phase experiments did
not reach the values of the corresponding auxiliaries in
solution with no dependence on whether the linker was
attached via ethyleneglycol spacer unit or not (see Table
1, entries 1 and 6 and Table 2, entries 2 and 8). Although
no clear explanation for this fact has been provided so
far, a possible interpretation could be the changed steric
environment present in case of the resin bound auxiliaries
compared to the surroundings of the i-butyl 6a or meth-
However, the investigations proved that the stereoselective
induction potential of m-hydrobenzoins can be varied to a
great extent via the introduction of different aryl substitu-
ents. In some cases, a significant improvement in the
obtained results was possible; however this seems to be
highly dependent on additional factors, for example, fur-
O
O
O
HO
H
iii
O
H
H
O
H
O
W
W
O
O
i
6g
7g / 7g'
ii
CH3
Cl
Cl
W
W
W
6g' / 6h'
i
O
O
O
O
iii
HO
H
O
H
H
O
W
O
H
O
W
O
O
6h
7h / 7h'
Scheme 8. Synthesis of solid phase test systems. Reagents and conditions: (i) 5a, NaH/6f, NaH; NaI, DMF; (ii) (1) NaI, acetone, (2) Bu3SnH, THF; (iii)
PPh3ÆHBr, MeOH, CH2Cl2.

J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2419
O
OH
O
i
O
O
O
O
R
R
HO
O
O
O
O
O
8g / 8g' / 8h / 8h'
7g / 7g' / 7h / 7h'
iii
ii
OH
OH
OH
O
O
O
R
10
O
O
O
iv
9g / 9g' / 9h / 9h'
OH
O
=
(for 7g-9g)
R
N
W
O
O
W
(for 7h-9h)
O
11
Scheme 9. Application of solid phase test systems. Reagents and conditions: (i) PhCOCOOH, DIC, DMAP, CH2Cl2; (ii) L-Selectrideꢀ, ꢀ78 ꢂC, THF; (iii)
LiOH, THF/MeOH/H2O; (iv) Val-OMe, HOBt, DIC, CH2Cl2, 12 h ꢀ30 ꢂC ! rt.
ther substituents and reaction conditions. Therefore, we are
encouraged to carry out further experiments to evaluate the
potential of the differentially substituted derivatives via
other model reactions as the a-alkylation of propionates,
which was already applied to similar auxiliary systems1a
in solution phase as well as on solid support.
purchased from novabiochem and was thoroughly washed
successively with DMF, methanol, dichloromethane, meth-
anol, 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 by heating. Vacuum flash chromatography was carried
out with silica gel Merck 60. All fractions of products con-
taining Noe’s acetal protecting group together with a free
hydroxy group were concentrated immediately after chro-
matography together with a few drops of NEt3. Melting
points were determined with a Kofler hot stage apparatus
and are uncorrected. 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,
respectively, CH-correlation spectra were recorded on a
Bruker AC 400 at 400/100 Hz using TMS or the solvent
peak as the reference. IR spectra were recorded on a Bio-
Rad FTS 135 FT-IR-spectrometer, using KBr disks. HPLC
diastereoisomeric analysis of L-valine methyl ester deriva-
tives 139 of mandelic acids 9 was carried out with a SHIMA-
DZU LC-10AD (SHIMADZU SPD-10AV UV/vis
detector); Nucleosil 120 S C18; H2O/MeOH (60/40).
Elemental analysis was carried out at Vienna University,
4. Experimental
4.1. General
Commercially available reagents and solvents were used as
received from the supplier unless otherwise specified.
Diethyl ether (E), petroleum ether (PE, 60–80 ꢂC 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 petro-
leum ether and dimethylformamide wereꢀdried and stored
˚
over molecular sieves (4 A). L-Selectride was purchased
from Aldrich as 1 M solutions in THF. 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 ꢂC in high vacuo for 30 min prior to use. Hydroxy-
methylated Wang-resin (200–400 mesh; 0.64 mmol/g) was

2420
J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
Department of Physicochemistry—Laboratory for Micro-
analysis, Waehringer Str. 42, A-1090, Vienna.
nitrogen atmosphere. HCl (2 M, 3 mL) was added and
the mixture was stirred at rt overnight. The solution was
evaporated to dryness under reduced pressure and nitrogen
atmosphere and the crude product was recrystallized from
95% ethanol yielding 2-hydroxy-1,2-bis-(4-methoxyphen-
yl)-ethanone 2c (9.27 g, 51%) as yellow crystals (spectral
data according to the literature14).
4.2. 2-Hydroxy-1,2-bis-(2-methoxyphenyl)-ethanone 2a
2-Methoxybenzaldehyde 1a (36.0 g, 264 mmol) was dis-
solved in ethanol (100 mL) and an aqueous solution
(20 mL) of potassium cyanide (8.6 g, 132 mmol) was
added. The mixture was refluxed for 4 h and afterwards
concentrated under reduced pressure and cooled to
ꢀ10 ꢂC. The precipitated yellow crystals were separated
and washed with small amounts of 50% ethanol and ether,
yielding 2a (18.0 g, 50%) (Fp = 96–98 ꢂC, lit.:5 108–111 ꢂC).
4.5. 2-Hydroxy-1,2-bis-(2-trifluoromethylphenyl)-ethanone
2d
The synthesis was carried out according to method ii
described above (see Section 4.4) yielding 79% of the
benzoin derivative 2d as light yellow crystals (Fp = 117–
125 ꢂC; 1H NMR d 7.72–7.35 (m, 7H, Ph–H), 6.93 (d,
J = 7.60 Hz, 1H, Ph–H), 6.11 (s, 1H, OCHPh) 4.35 (s,
1H, OH); 13C NMR d 201.67 (C@O), 135.24/134.98 (2q,
J(C,F) = 1.4 Hz/2.0 Hz, Ph–C-1), 132.34/131.18/129.26/
127.86 (4q, J(C,F) = 0.9 Hz, Ph–C-4/Ph–C-6), 130.88/
128.88 (Ph–C-5), 128.77/127.91 (2q, J(C,F) = 30.6
Hz/32.4 Hz, Ph–C-2), 126.94/126.08 (2q, J(C,F) = 5.0 Hz/
5.7 Hz, Ph–C-3), 123.66/123.17 (2q, J(C,F) = 274.2 Hz/
273.6 Hz, Ph–CF3), 74.30 (q, J(C,F) = 1.8 Hz, Ph–CH–
OH); M = 348.25. Anal. Calcd for C16H10F6O2: C, 55.18;
H, 2.89; F, 32.73. Found: C, 55.29; H, 3.09; F, 32.72).
4.3. 2-Hydroxy-1,2-bis-(2-methylphenyl)-ethanone 2b
2-Tolylaldehyde 1b (20.0 g, 166 mmol) was dissolved in
ethanol (60 mL) and an aqueous solution (10 mL) of potas-
siumcyanide (3 g, 46 mmol) was added. The mixture was
stirred at 70 ꢂC for 6 h, and afterwards concentrated under
reduced pressure and extracted with ether. The extracts
were washed with brine, dried, filtered, and evaporated
under reduced pressure. The resulting oil was purified via
vacuum flash chromatography yielding 2b (6.1 g, 31%) as
white crystals (Fp = 76–78 ꢂC, lit.:13 79 ꢂC), as well as
12.2 g (61%) of the recovered aldehyde.
4.6. 2-Hydroxy-1,2-bis-(2-nitrophenyl)-ethanone 2e
4.4. Typical procedure for the synthesis of benzoins 2c–e
(method ii)
The synthesis was carried out according to method ii
described above (see Section 4.4) yielding 5% of the benzoin
derivative 2e as orange crystals. In this case, the product
was purified via chromatography (PE/E 20:1 ! E/MeOH
3:1). (Fp = 142–144 ꢂC; 1H NMR d 8.20–7.00 (m, 8H,
Ph), 6.39 (s, 1H, CHOH), 4.19 (s, 1H, OH); 13C NMR d
200.61 (CO), 147.91/146.25 (Ph–C–NO2), 135.10/132.83
2-Hydroxy-1,2-bis-(4-methoxy-phenyl)-ethanone 2c: Zinc
iodide (0.2 g, 0.59 mmol) was added to 4-methoxybenz-
aldehyde 1c (9.0 g, 66.1 mmol) and trimethylsilylcyanide
(7.2 g, 72.5 mmol) under a nitrogen atmosphere and the
mixture was stirred for 1 h at 100 ꢂC. The reaction mixture
was cooled to rt, dissolved in PE and insoluble salts were
filtered off. The solution was evaporated to dryness yielding
14.15 g of crude a-[(trimethylsilyl)oxy]-4-methoxyphenyl-
acetonitrile, which was used in the next step without
further purification.
(Ph–C-1),
134.09/134.03/131.16/130.21/129.64/128.45/
125.05/124.23 (Ph–C), 75.41 (CHOH); M = 302.08. Anal.
Calc. for C14H10N2O6Æ0.3C2H4Æ0.1C6H15N: C, 56.91; H,
3.99; N, 9.17. Found: C, 57.15; H, 3.78; N, 9.27).
4.7. Typical procedure for the reduction of benzoins 2a–d
(method iii)
Lithiumdiisopropylamide (LDA) was prepared by adding
butyllithium-solution (2.2 M in hexane) (27.3 mL, 60.1
mmol) to a solution of diisopropylamine (6.08 g, 60.1
mmol) in dry DME at ꢀ30 ꢂC under a nitrogen atmosphere
and stirred for 30 min at ꢀ10 ꢂC. The solution was cooled
to ꢀ65 ꢂC and crude a-[(trimethylsilyl)oxy]-4-methoxyphen-
ylacetonitrile (14.15 g, 60.1 mmol) in dry DME (80 mL)
was added dropwise. After stirring for 30 min at ꢀ65 ꢂC,
4-methoxybenzaldehyde (8.18 g, 60.1 mmol) solved in
DME (30 mL) was added and the mixture stirred for 1 h.
The reaction was slowly warmed to rt and hydrolyzed with
saturated NaHCO3-solution (100 mL). The mixture was
extracted with ether, the extracts were washed with brine,
dried, filtered, and evaporated to dryness under reduced
pressure and a nitrogen atmosphere. Crude 1,2-bis-(4-meth-
oxyphenyl)-2-[(trimethylsilyl)oxy]-1-ethanone (18.22 g) was
isolated and used in the next step without further
purification.
meso-1,2-Bis-(2-methoxyphenyl)-1,2-ethanediol 3a: Sodi-
umborohydride (2.47 g, 65.31 mmol) was added to a solu-
tion of benzoin 2a (17 g, 62.3 mmol) in dry ethanol (1 L)
at 0 ꢂC. The reaction mixture was allowed to reach rt and
stirred for 2 h while the reaction was monitored via TLC.
The reaction mixture was concentrated to 300 mL, acidified
to pH 4 using concd HCl, neutralized with NaHCO3, and
extracted with CH2Cl2. The combined organic phases were
washed with water and brine, dried, filtered, and evapo-
rated under reduced pressure yielding 14.1 g of crude prod-
uct. After recrystallization from toluene/ethanol, 3a
(12.52 g, 73%) was obtained as colorless needles
1
(Fp = 146–149 ꢂC, lit.15 152–153 ꢂC, H NMR according
to the lit.15).
4.8. meso-1,2-Bis-(2-methylphenyl)-1,2-ethanediol 3b
Crude 1,2-bis(4-methoxyphenyl)-2-[(trimethylsilyl)oxy]-1-
ethanone (18.22 g) was solved in THF (150 mL) under
The synthesis was carried out according to method iii
described above (see Section 4.7) using 2-hydroxy-1,2-bis-

J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2421
(2-methylphenyl)-ethanone 2b (5.5 g, 22.89 mmol). The
crude product (6.38 g, meso/dl-ratio 8:1) was purified via
chromatography (PE/E 10:1 ! E/MeOH 5:1) yielding 3b
(3.52 g, 63%) as a colorless solid (Fp = 111–116 ꢂC, lit.15
2-yl)oxy]-ethanol 5a: Diol 3a (12.0 g, 43.75 mmol) and dil-
actol 4 (4.1 g, 10.94 mmol) were dissolved in dichlorometh-
ane (450 mL). p-Toluenesulfonic acid monohydrate (0.55 g,
2.89 mmol) was added and the mixture stirred for 2 h at rt.
Na2SO4 and after 1 h NaHCO3 were added, the mixture
was filtered and then evaporated under reduced pressure
to yield 16.6 g of crude product, which was purified via
1
104–105 ꢂC, H NMR according to the lit.15).
4.9. meso-1,2-Bis-(4-methoxyphenyl)-1,2-ethanediol 3c
chromatography (PE/E 50:1 ! E). Compound 5a (6.93 g,
20
The synthesis was carried out according to method iii
described above (see Section 4.7) using 2-hydroxy-1,2-bis-
(4-methoxy-phenyl)-ethanone 2c (1.0 g, 3.67 mmol). The
crude product (0.95 g, meso/dl-ratio 4:1) was recrystallized
from toluene yielding 3c (0.65 g, 65%) as a colorless solid
(Fp = 174 ꢂC, lit.16 169 ꢂC, 1H NMR according to the lit.17).
70%) was obtained as a colorless foam (½aꢁD ¼ ꢀ77:9 (c
1
1.49, CH2Cl2); H NMR (CDCl3, 200 MHz) d 7.22–7.13
(m, 4H, Ph), 6.93–6.76 (m, 4H, Ph), 5.51 (d, J = 6.2 Hz,
1H, OCHPh), 4.98–4.93 (m, 2H, OCHPh/OCHO), 3.71/
3.70 (2s, 6H, OCH3), 3.18 (d, J = 7.2 Hz, 1H, 7a0-H),
2.11–0.75 (m, 17H, aliph. incl. 0.91/0.86/0.75 (3s, 9H,
CH3)); 13C NMR (CDCl3, 50 MHz) d 158.13/157.73 (Ph–
4.10. meso-1,2-Bis-(2-trifluoromethylphenyl)-1,2-ethanediol
3d
C–OCH3),
130.43/129.48/128.61/128.47/120.66/120.46/
110.76/110.16 (Ph–C), 128.18/128.02 (Ph–C-1), 102.94
(OCHO), 90.95 (C-7a), 74.34/73.39 (OCHPh), 55.82/
55.68 (OCH3), 48.74 (C-4), 47.73 (C-7), 47.33 (C-8), 46.37
(C-3a), 38.91 (C-3), 32.72 (C-6), 29.33 (C-5), 23.29/20.94/
12.06 (3MBE–CH3); M = 452.60. Anal. Calcd for
C28H36O5: C, 74.31; H, 8.02. Found: C, 74.26; H, 7.64).
The synthesis was carried out according to method iii
described above (see Section 4.7) using 2-hydroxy-1,2-
bis-(2-trifluoromethylphenyl)-ethanone 2d (17.50 g, 50.3
mmol). In this case, CeCl3Æ7H2O (1.86 g, 5.0 mmol) was
added to the reaction mixture to achieve a higher meso/
dl-ratio. The crude product (15.7 g, meso/dl-ratio 4.6:1)
was purified via chromatography (PE/E 10:1 ! E/MeOH
5:1) yielding 3d (3.76 g, 21%) as yellow needles (Fp = 65–
4.13. [(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(2-methyl-
phenyl)-2-[(octahydro-7,8,8-trimethyl-4,7-methanobenzo-
furan-2-yl)oxy]-ethanol 5b
1
73 ꢂC; H NMR (CDCl3, 200 MHz) d 7.64–7.34 (m, 8H,
Ph), 5.44 (s, 2H, OCHPh), 2.39 (s, 2H, OH); 13C NMR
(CDCl3, 50 MHz) d 138.22 (Ph–C-1), 131.60/128.85/
127.97 (Ph–C-4, Ph–C-5, Ph–C-6), 128.32 (q, J(C,F) =
30.0 Hz, Ph–C-2), 125.19 (q, J(C,F) = 6.0 Hz, Ph–C-3),
123.93 (q, J(C,F) = 274.2 Hz, Ph–CF3), 71.97 (Ph–CH–
OH); M = 350.26. Anal. Calcd for C16H12F6O2: C, 54.87;
H, 3.45. Found: C, 54.72; H, 3.22) besides 6.22 g (36%)
of hydrobenzoin as a meso/dl-mixture.
The synthesis was carried out as described above (see Sec-
tion 4.12) using meso-1,2-bis-(2-methylphenyl)-ethan-1,2-
diol 3b (3.5 g, 14.44 mmol). Compound 5b (1.91 g, 63%)
20
was obtained as a colorless oil (½aꢁD ¼ ꢀ95:7 (c 0.90,
CH2Cl2); 1H NMR (CDCl3, 200 MHz) d 7.42–7.06 (m,
8H, Ph), 5.13/5.07 (2d, J = 6.8/6.7 Hz, 2H, OCHPh), 4.83
(d, J = 4.3 Hz, 1H, OCHO), 2.99 (d, J = 5.7 Hz, 1H, 7a0-
H), 2.33/2.26 (2s, 6H, Ph–CH3), 2.03–0.75 (m, 17H, aliph.
incl. 0.89/0.85/0.75 (3s, 9H, CH3)); 13C NMR (CDCl3,
4.11. meso-1,2-Bis-(2-nitrophenyl)-1,2-ethanediol 3e
50 MHz)
Ph–C-1),
d
139.92/137.62/136.68/136.05 (Ph–C–CH3/
129.90/129.38/127.81/127.46/127.03/126.45/
Borane dimethylsulfide complex (2 M solution in THF)
(0.12 mL, 0.24 mmol) was added to a solution of 2-hydr-
oxy-1,2-bis-(2-nitrophenyl)-ethanone 2e (0.10 g, 0.33 mmol)
in dry THF (5 mL) at ꢀ78 ꢂC under a nitrogen atmosphere
and the reaction stirred for 2 h at ꢀ78 ꢂC and then after-
wards for 1 h at rt while being monitored via TLC. The
mixture was hydrolyzed with 2 M HCl (5 mL), extracted
with ether, and the extracts were dried, filtered, and evap-
orated under reduced pressure yielding 0.107 g of crude
product (meso/dl-ratio 8:1). After recrystallization from
toluene, 3e (0.089 g, 89%) was obtained as light brown
crystals (Fp = 218–222 ꢂC; 1H NMR (DMSO-d6,
200 MHz) d 7.83–7.45 (m, 8H, Ph), 5.87 (s, 2H, OH),
5.19 (s, 2H, CHOH); 13C NMR (CDCl3, 50 MHz) d
149.62 (Ph–C–NO2), 137.67 (Ph–C-1), 132.83/128.60/
128.28/123.51 (Ph–C), 71.14 (PhCHOH); M = 304.08.
Anal. Calcd for C14H12N2O6: C, 55.27; H, 3.98; N, 9.21.
Found: C, 55.29; H, 3.85; N, 8.91).
125.71/125.57 (Ph–C), 101.37 (OCHO), 90.31 (C-7a),
76.04/72.87 (OCHPh), 48.14 (C-4), 47.07 (C-7), 46.70
(C-8), 45.83 (C-3a), 38.38 (C-3), 32.08 (C-6), 28.78 (C-5),
22.72/20.39/11.27
(3CH3),
19.27/19.24
(Ph–CH3);
M = 420.59. Anal. Calcd for C28H36O3Æ0.7H2O: C, 77.63;
H, 8.70. Found: C, 77.66; H, 8.68).
4.14. [(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(4-meth-
oxyphenyl)-2-[(octahydro-7,8,8-trimethyl-4,7-methano-
benzofuran-2-yl)oxy]-ethanol 5c
The synthesis was carried out as described above (see Sec-
tion 4.12) using meso-1,2-bis-(4-methoxyphenyl)-ethan-1,2-
diol 3c (1.0 g, 3.65 mmol). In this case, the reaction was
carried out under an argon atmosphere and degassed sol-
vents were used for chromatography. Compound 5c
20
(0.667 g, 83%) was obtained as a yellow oil (½aꢁD
¼
1
ꢀ72:95 (c 0.95, CH2Cl2); H NMR (CDCl3, 200 MHz) d
7.20/7.19/6.84/6.83 (4d, J = 8.7 Hz, 8H, Ph), 4.91 (d,
J = 4.3 Hz, 1H, OCHO), 4.65 (s, 2H, OCHPh), 3.79 (s,
6H, OCH3), 2.99 (d, J = 7.1 Hz, 1H, 7a0-H), 2.29 (s, 1H,
OH), 2.13–0.67 (m, 17H, aliph. incl. 0.74/0.84/0.88 (3s,
9H, CH3)); 13C NMR (CDCl3, 50 MHz) d 159.33/159.00
(Ph–C–OCH3), 133.53/130.50 (Ph–C-1), 129.30/128.44/
4.12. Typical procedure for the desymmetrization of hydro-
benzoins 3a–e
[(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(2-methoxyphe-
nyl)-2-[(octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-

2422
J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
113.55/113.06 (Ph–C), 101.80 (OCHO), 90.55 (C-7a),
80.11/76.78 (OCHPh), 55.18 (OCH3), 48.24 (C-4), 47.23
(C-7), 46.89 (C-8), 45.89 (C-3a), 38.43 (C-3), 32.25 (C-6),
28.90 (C-5), 22.81/20.43/11.52 (3MBE–CH3); M = 452.60.
Anal. Calcd for C28H36O5Æ0.3H2O: C, 73.43; H, 8.05.
Found: C, 73.38; H, 8.07).
solved in dry DMF (10 mL) was added to a suspension of
NaH (0.2 g, 8.64 mmol) in dry DMF (5 mL) and the mix-
ture stirred for 1 h at rt. p-Toluenesulfonic acid i-butylester
(1.51 g, 6.63 mmol), which was prepared according to the
literature,18 was added and the reaction mixture stirred
for 12 h at rt. The reaction was quenched with water, the
aqueous layer separated, and then extracted with ether.
The combined organic phases were washed with brine,
dried, filtered, and evaporated to dryness yielding 2.48 g
of crude product. After chromatography (PE/E 20:1 !
4.15. [(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-[(Octahydro-
7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-bis-
(2-trifluoromethylphenyl)-ethanol 5d
E), 6a (1.71 g, 76%) was obtained as a colorless oil
20
The synthesis was carried out as described above (see Sec-
tion 4.12) using meso-1,2-bis-(2-trifluoromethylphenyl)-
(½aꢁD ¼ ꢀ51:9 (c 1.08, CH2Cl2); 1H NMR (CDCl3,
200 MHz) d 7.27–6.60 (m, 8H, Ph), 5.34 (d, J = 4.7 Hz,
1H, OCHO), 4.91/4.82 (2d, J = 4.7 Hz, 2H, OCHPh),
3.57 (d, J = 5.9 Hz, 1H, 7a0-H), 3.56/3.41 (2s, 6H, Ph–
OCH3), 3.06/3.02 (2dd, J1 = 8.9 Hz, J2 = 6.3 Hz/
J1 = 9.1 Hz, J2 = 6.7 Hz, 2H, O–CH2CH(CH3)2), 2.16–
0.69 (m, 1H, OCH2CH(CH3)2, 6H, OCH2CH(CH3)2,
17H, aliph.); 13C NMR (CDCl3, 50 MHz) d 158.24/
ethan-1,2-diol 3d (3.30 g, 9.4 mmol). Compound 5d
20
(1.50 g, 57%) was obtained as a colorless oil (½aꢁD
¼
1
ꢀ85:6 (c 1.95, CH2Cl2); H NMR (CDCl3, 200 MHz) d
7.65–7.46 (m, 6H, Ph–H), d = 7.42–7.32 (m, 2H, Ph–H),
5.37–5.28 (m, 2H, OCHPh), 4.84 (d, J = 4.2 Hz, 1H,
OCHO), 3.03 (d, J = 7.1 Hz, 1H, 7a0-H), 2.65 (s, 1H,
OH), 2.10–0.65 (m, 17H, aliph. incl. 0.87/0.82/0.73 (3s,
9H, CH3)); 13C NMR (CDCl3, 50 MHz) d 139.94/137.80
(q, J(C,F) = 1.4 Hz, Ph–C-1), 131.54/131.46/129.66/
128.84 (2q, J(C,F) = 1.1 Hz, Ph–C-4/Ph–C-6), 129.58/
128.54 (q, J(C,F) = 30.0 Hz, Ph–C-2), 127.78/127.50 (Ph–
C-5), 125.10/124.90 (q, J(C,F) = 5.7 Hz/5.9 Hz, Ph–C-3),
124.06/123.89 (q, J(C,F) = 274.4 Hz, Ph–CF3), 102.13
(OCHO), 90.61 (C-7a), 72.03/71.99 (OCHPh), 48.17 (C-
4), 47.19 (C-7), 46.60 (C-8), 45.52 (C-3a), 38.35 (C-3),
32.04 (C-6), 28.69 (C-5), 22.67/20.24/11.07 (3CH3);
M = 528.54. Anal. Calcd for C28H30F6O3: C, 63.63; H,
5.72. Found: C, 63.34; H, 5.43).
157.10
(Ph–C–OCH3),
129.40/129.05/128.84/128.73/
120.30/120.12/110.18/110.05 (Ph–C), 128.08/128.03 (Ph–
C-1), 102.03 (OCHO), 90.66 (C-7a), 77.31/72.12 (OCHPh),
76.41 (OCH2CH(CH3)2), 55.72/55.71 (Ph–OCH3), 48.69
(C-4), 47.67 (C-7), 47.44 (C-8), 46.56 (C-3a), 38.93 (C-3),
32.95 (C-6), 29.51 (C-5), 29.16 (O–CH2CH(CH3)2), 23.36/
21.08/12.18 (3MBE–CH3), 19.88/19.77 (O–CH2CH-
(CH3)2); M = 508.70. Anal. Calcd for C32H44O5Æ0.5H2O:
C, 74.24; H, 8.76. Found: C, 74.17; H, 8.49).
4.18. 2-[[(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(2-meth-
ylphenyl)-2-(2-methylpropoxy)-ethoxy]-octahydro-7,8,8-tri-
methyl-4,7-methanobenzofuran 6b
4.16. [(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(2-nitro-
phenyl)-2-[(octahydro-7,8,8-trimethyl-4,7-methanobenzo-
furan-2-yl)oxy]-ethanol 5e
The synthesis was carried out as described above (see Sec-
tion 4.17) using 5b (1.77 g, 4.21 mmol). Compound 6b
20
(1.87 g, 93%) was obtained as a colorless oil (½aꢁD
¼
1
The synthesis was carried out as described above (see Sec-
tion 4.12) using meso-1,2-bis-(2-nitrophenyl)-ethan-1,2-diol
ꢀ67:4 (c 0.80, CH2Cl2); H NMR (CDCl3, 200 MHz) d
7.49–7.09 (m, 8H, Ph), 4.95/4.53 (2d, J = 8.4 Hz, 2H,
OCHPh), 4.71 (d, J = 3.9 Hz, 1H, OCHO), 3.00/2.70
(2dd, J1 = 8.7 Hz, J2 = 6.4 Hz/J1 = 8.8 Hz, J2 = 6.2 Hz,
2H, O–CH2CH(CH3)2), 2.43 (s, 6H, Ph–CH3), 2.38 (d,
J = 6.5 Hz, 1H, 7a0-H), 1.88–0.69 (m, 1H, OCH2-
CH(CH3)2, 17H, aliph.), 0.65/0.62 (2d, J = 6.8 Hz/6.7 Hz;
6H, OCH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) d
3e (0.49 g, 1.16 mmol). Compound 5e (0.241 g, 61%) was
20
obtained as colorless crystals (Fp = 140–144 ꢂC, ½aꢁD
¼
1
ꢀ16:4 (c 0.50, CH2Cl2); H NMR (CDCl3, 200 MHz) d
7.88–7.38 (m, 8H, Ph); 5.70 (dd, J1 = 7.8 Hz, J2 = 5.8 Hz,
1H, PhCHOH); 5.47 (d, J = 7.8 Hz, 1H, OCHPh); 4.76
(d, J = 4.5 Hz, 1H, OCHO); 3.09 (d, J = 5.8 Hz, 1H,
OH); 2.61 (d, J = 7.1 Hz, 1H, 7a0-H); 2.16–0.53 (m, 17H,
aliph. incl. 0.79/0.76/0.70 (3s, 9H, CH3)); 13C NMR
(CDCl3, 50 MHz) d 150.75/149.71 (Ph–C–NO2), 137.68/
134.71 (Ph–C-1), 132.79/132.69/128.89/128.67/128.35/
127.83/123.98/123.48 (Ph–C), 101.73 (OCHO), 90.74 (C-
7a), 73.86/71.17 (OCHPh), 48.17 (C-4), 47.19 (C-7), 46.69
(C-8), 45.46 (C-3a), 38.23 (C-3), 32.20 (C-6), 28.77 (C-5),
22.71/20.37/11.28 (3CH3); M = 482.54. Anal. Calcd for
C26H30N2O7Æ0.15C6H14: C, 65.21; H, 6.53; N, 5.65. Found:
C, 65.48; H, 6.20; N, 5.95).
140.02/139.26/137.93/137.42
(Ph–C-1,
Ph–C–CH3),
129.35/129.29/127.00/126.73/126.69/125.44/125.29
(Ph–
C), 100.36 (OCHO), 89.52 (C-7a), 82.29/77.06 (OCHPh),
75.82 (O–CH2CH(CH3)2), 47.99 (C-4), 46.74 (C-7), 46.64
(C-8), 45.77 (C-3a), 41.21 (C-3), 31.98 (C-6), 28.76 (C-5),
28.38 (O–CH2CH(CH3)2) 22.67/20.40/11.21 (3CH3)
19.64/19.46/18.96/18.92 (O–CH2CH(CH3)2, 2Ph–CH3);
M = 476.71. Anal. Calcd for C32H44O5Æ0.5H2O: C, 79.43;
H, 9.33. Found: C, 79.59; H, 9.36).
4.19. 2-[[(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(4-meth-
oxyphenyl)-2-(2-methylpropoxy)-ethoxy]-octahydro-7,8,8-
trimethyl-4,7-methanobenzofuran 6c
4.17. Typical procedure for the etherification of hydro-
benzoin-acetals 5a–d
2-[[(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(2-methoxy-
phenyl)-2-(2-methylpropoxy)-ethoxy]-octahydro-7,8,8-tri-
The synthesis was carried out as described above (see Sec-
tion 4.17) using 5c (1.34 g, 2.95 mmol). Compound 6c
20
methyl-4,7-methanobenzofuran 6a: Under
a
nitrogen
(1.15 g, 77%) was obtained as a colorless oil (½aꢁD ¼
1
atmosphere, hydrobenzoin acetal 5a (2.0 g, 4.42 mmol) dis-
ꢀ66:9 (c 4.70, CH2Cl2); H NMR (CDCl3, 200 MHz) d

J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2423
7.30/7.28/6.87/6.85 (4d, J = 8.7 Hz, 8H, Ph), 4.82 (d,
J = 4.2 Hz, 1H, OCHO), 4.52/4.06 (2d, J = 8.2 Hz, 2H,
OCHPh), 3.81 (s, 6H, Ph–OCH3), 3.03/2.75 (2dd,
J1 = 8.9 Hz, J2 = 6.5 Hz, 2H, O–CH2CH(CH3)2), 2.45 (d,
J = 6.5 Hz, 1H, 7a0-H), 1.96–0.51 (m, 23H, aliph. incl.
0.81/0.80/0.69 3s, 9H, CH3, 0.67/0.64 2d, J = 3.5/
J = 3.4 Hz, 6H, OCH2CH(CH3)2); 13C NMR (CDCl3,
50 MHz) d 158.95/158.86 (Ph–C–OCH3), 133.51/132.72
(Ph–C-1), 129.33/129.15/113.00/112.92 (Ph–C), 100.67
(OCHO), 89.79 (C-7a), 84.81/78.27 (OCHPh), 75.79
(OCH2CH(CH3)2), 55.21/55.13 (Ph–OCH3), 48.09 (C-4),
46.91 (C-7), 46.87 (C-8), 45.91 (C-3a), 38.29 (C-3), 32.19
(C-6), 28.95 (C-5), 28.40 (O–CH2CH(CH3)2), 22.81/20.49/
11.51 (3CH3), 19.18 (O–CH2CH(CH3)2); M = 508.70.
Anal. Calcd for C32H44O5Æ0.6C2H4: C, 75.88; H, 8.90.
Found: C, 75.81; H, 9.02).
(PE/E 100:1 ! E), 6e (2.70 g, 72%) was obtained as a col-
20
orless oil (½aꢁD ¼ ꢀ66:5 (c 1.03, CH2Cl2); 1H NMR
(CDCl3)
d 7.34–6.64 (m, 8H, Ph), 5.50/5.17 (2d,
J = 3.9 Hz, 2H, OCHPh), 4.92 (d, J = 4.5 Hz, 1H, OCHO),
4.03 (s, 3H, OCH2CO), 3.82 (d, J = 7.5 Hz, 1H, 7a-H),
3.61/3.45 (2s, 6H, OCH3), 2.33–0.75 (m, 26H, aliph. incl.
1.40/0.98/0.90/0.77 (4s, 12H, CH3)); 13C NMR (CDCl3) d
170.2 (O–CO), 157.97/157.58 (Ph–C–OCH3), 129.52/
128.93/128.32/128.27/120.33/120.24/110.03 (Ph–C), 127.74/
127.47 (Ph–C-1), 102.4 (O–CH–O), 90.99 (C-7a), 81.22
(C(CH3)3), 77.25/71.22 (CH–Ph), 67.91 (O–CH2–CO),
55.67/55.57 (O–CH3), 48.76 (C-4), 47.76 (C-7), 47.45 (C-
8), 46.42 (C-3a), 38.89 (C-3), 32.85 (C-6), 29.41 (C-5),
28.43 (C(CH3)3), 23.34/21.03/12.17 (C-9, C-10, C-11);
M = 566.74. Anal. Calcd for C34H46O7Æ0.6H2O: C, 70.71;
H, 8.24. Found: C, 70.81; H, 8.35).
4.20. 2-[[(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-(2-Methyl-
propoxy)-1,2-bis-(2-trifluoromethylphenyl)-ethoxy]-octa-
hydro-7,8,8-trimethyl-4,7-methanobenzofuran 6d
4.21.1. [[(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(2-meth-
oxyphenyl)-2-[(octahydro-7,8,8-trimethyl-4,7-methanobenzo-
furan-2-yl)-oxy]-2-ethoxy]-ethanol 6f. Compound 6e
(2.58 g, 4.55 mmol) dissolved in dry ether (70 mL) was
added to a suspension of LiAlH4 (0.518 g, 13.7 mmol) in
dry ether (100 mL) at 0 ꢂC under a nitrogen atmosphere
and the mixture stirred for 2 h at rt. The reaction was
quenched with 2 M NaOH (6 mL), diluted with brine and
extracted several times with ether. The combined organic
phases were washed with brine, dried, filtered, and evapo-
rated to dryness yielding 1.94 g of crude product. After
The synthesis was carried out as described above (see Sec-
tion 4.17) using 5d (1.00 g, 1.89 mmol). Compound 6d
20
(1.09 g, 99%) was obtained as a colorless oil (½aꢁD
¼
1
ꢀ53:7 (c 1.80, CH2Cl2); H NMR (CDCl3, 200 MHz) d
7.83–7.72 (m, 2H, Ph–H), 7.64–7.52 (m, 4H, Ph–H),
7.44–7.33 (m, 2H, Ph–H), 5.21/4.74 (2d, J = 8.0 Hz, 2H,
OCHPh), 4.70 (d, J = 4.2 Hz, 1H, OCHO), 2.89/2.73
(2dd, J1 = 8.8 Hz, J2 = 6.3 Hz/J1 = 8.7 Hz, J2 = 6.1 Hz,
2H, O–CH2CH(CH3)2), 2.29 (s, J = 7.1 Hz, 1H, 7a0-H),
1.84–0.53 (m, 18H, aliph., OCH2CH(CH3)2), 0.65/0.62
(2d, J = 6.8/6.7 Hz, 6H, OCH2CH(CH3)2); 13C NMR
chromatography (PE/E 10:1 ! E/MeOH 1:1), 6f (1.649 g,
20
73%) was obtained as a colorless oil (½aꢁD ¼ ꢀ61:9 (c
1
1.40, CH2Cl2); H NMR (CDCl3, 200 MHz) d 7.32–6.65
(m, 8H, Ph), 5.52 (d, J = 4.1 Hz, 1H, OCHO), 5.09/4.95
(2d, J = 4.4 Hz, 2H, OCHPh), 3.87–3.24 (m, 12H, incl.
3.70/3.41 (2s, 6H, OCH3) OCH2CH2OH, 7a0-H), 2.35–
0.78 (m, 17H, aliph.); 13C NMR (CDCl3, 50 MHz)
(CDCl3, 50 MHz)
d 131.69/131.47 (q, J(C,F) = 1.0/
1.3 Hz, Ph–C-1), 129.14/128.58/127.57/126.86 (Ph–C-4,
Ph–C-2, Ph–C-6), 127.27/127.22 (Ph–C-5), 124.64/124.52
1
(Ph–C-3), 124.12 (q, J(C,F) = 273.3 Hz, Ph–CF3), 100.87
157.55/157.27
126.82/119.97/119.90/109.74/109.68
(Ph–C–OCH3),
128.89/128.09/127.98/
(Ph–C/Ph–C-1),
(OCHO), 89.69 (C-7a), 80.27/74.24 (OCHPh), 75.69 (O–
CH2CH(CH3)2), 47.98 (C-4), 46.81 (C-7), 46.50 (C-8),
45.44 (C-3a), 38.16 (C-3), 31.98 (C-6), 28.69 (C-5), 28.07
(O–CH2CH(CH3)2), 22.66/20.26/11.07 (3CH3), 18.71/
18.63 (O–CH2CH(CH3)2); M = 584.65. Anal. Calcd for
C32H38F6O3: C, 65.74; H, 6.55. Found: C, 65.56; H, 6.61).
102.18 (OCHO), 90.85 (C-7a), 78.36/71.67 (OCHPh),
77.20/70.99 (OCH2CH2OH), 55.39/55.04 (Ph–OCH3),
48.33 (C-4), 47.44 (C-7), 46.99 (C-8), 45.91 (C-3a), 38.56
(C-3), 32.53 (C-6), 28.92 (C-5), 22.91/20.57/11.72 (CH3);
M = 496.65. Anal. Calcd for C30H40O6: C, 72.55; H,
8.12. Found: C, 72.33; H, 8.36).
4.21. Three-step synthesis of 2-[[(2S)-(2a(1R*,2S*),3aa,4b,
7b,7aa)]-(2-(2-methoxyethoxy)-1,2-bis-(2-methoxyphenyl)-
ethoxy)]-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran
6g
4.21.2. 2-[[(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-(2-Methoxy-
ethoxy)-1,2-bis-(2-methoxyphenyl)-ethoxy]-octahydro-7,8,8-
trimethyl-4,7-methanobenzofuran
6g. Compound
6f
(0.688 g, 1.39 mmol) dissolved in dry DMF (5 mL) was
added to a suspension of NaH (0.100 g, 4.17 mmol) in
dry DMF (5 mL) under a nitrogen atmosphere and the
mixture stirred for 1 h. MeI (1.02 g, 7.20 mmol) was added
and the solution was stirred for 2 h at rt. The reaction was
quenched with water, extracted several times with ether,
and the combined organic phases were washed with brine,
dried, filtered, and evaporated to dryness yielding 0.648 g
of crude product. After chromatography (PE/E
30:1 ! E/MeOH 5:1), 6g (0.525 g, 74%) was obtained as
[[(2S)-(2a(1R*,2S*),3aa,4b,7b,7aa)]-1,2-Bis-(2-methoxyphe-
nyl)-2-(octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-
2-yl-oxy)ethoxy]acetic acid, 1,1-dimethylethylester 6e:
Acetal 5a (3.0 g, 6,6 mmol) dissolved in dry THF (25 mL)
was added under a nitrogen atmosphere to a suspension
of NaH (0.36 g, 15 mmol) in THF (5 mL) and the mixture
stirred for 1 h at rt. Bromoacetic acid, t-butylester (2.85 g,
14.6 mmol), and HMPT (11.35 g, 63.36 mmol) dissolved in
dry THF (30 mL) were added and the mixture was heated
at reflux for 12 h. The mixture was quenched with water,
the aqueous layer was separated, and extracted several
times with ether. The combined organic phases were
washed with brine, dried, filtered, and evaporated to dry-
ness yielding 5.7 g of crude product. After chromatography
20
1
a colorless oil (½aꢁD ¼ ꢀ85:4 (c 1.05, CH2Cl2); H NMR
(CDCl3, 200 MHz) d 7.34–6.68 (m, 8H, Ph), 5.46 (d, J =
4.3 Hz, 1H, OCHO), 5.06/4.90 (2d, J = 4.5 Hz, 2H,
OCHPh), 3.72–3.46 (m, 11H, incl. 3.62/3.51 (2s, 6H,
OCH3) OCH2CH2O, 7a0-H), 3.32 (s, 3H, OCH2CH2OCH3),

2424
J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2.29–0.77 (m, 17H, aliph.); 13C NMR (CDCl3, 50 MHz)
157.77/157.47 (Ph–C–OCH3), 128.95/128.51/128.06/
4.24. (1R,2S)-1,2-Bis-(4-methoxyphenyl)-2-(2-methylprop-
oxy)-ethanol 7c
d
127.95/127.75/119.91/119.78/109.75 (Ph–C/Ph–C-1), 101.77
(OCHO), 90.40 (C-7a), 77.28/71.37 (OCHPh), 72.18/
68.88 (OCH2CH2OCH3), 58.99 (OCH2CH2OCH3) 55.30/
55.27 (Ph–OCH3), 48.32 (C-4), 47.29 (C-7), 46.99
(C-8), 46.09 (C-3a), 38.49 (C-3), 32.52 (C-6), 29.04 (C-5),
22.92/20.61/11.72 (CH3); M = 510.68. Anal. Calcd for
C31H42O6Æ0.1H2O: C, 72.66; H, 8.30. Found: C, 72.63; H,
8.20).
The synthesis was carried out as described above (see Sec-
tion 4.22) using 6c (1.15 g, 2.26 mmol). Crude product
(1.40 g) was purified via chromatography (PE/E
20:1 ! 2:1) yielding 7c (0.595 g, 80%) as a yellow oil
20
(½aꢁD ¼ þ25:4 (c 0.90, CH2Cl2); 1H NMR (CDCl3) d
7.13–6.77 (m, 8H, Ph–H), 4.75/4.29 (2d, J = 5.5 Hz, 2H,
CH–Ph), 3.79/3.78 (2s, 6H, Ph–OCH3), 3.10/2.96 (2dd,
J1 = 8.9 Hz, J2 = 6.5 Hz, 2H, O–CH2–CH(CH3)2), 1.89–
1.69 (m, 1H, O–CH2–CH(CH3)2), 0.81/0.80 (2d,
J = 6.7 Hz, 6H, O–CH2–CH(CH3)2); 13C NMR (CDCl3)
d 159.23/158.87 (Ph–C–OCH3), 132.81/130.20 (Ph–C 1),
129.02/128.26/113.28/113.08 (Ph–C), 85.62/76.76 (CH–
Ph), 75.83 (O–CH2–CH(CH3)2), 55.17 (Ph–OCH3), 28.52
(O–CH2–CH(CH3)2), 19.34/19.27 (O–CH2–CH(CH3)2);
M = 330.43. Anal. Calcd for C20H26O4: C, 72.70; H,
7.93. Found: C, 72.99; H, 8.22).
4.22. Typical procedure for the deprotection of acetals
6a–d and 6g
(1R,2S)-1,2-Bis-(2-methoxyphenyl)-2-(2-methylpropoxy)-
ethanol 7a: Acetal 6a (1.6 g, 3.15 mmol) was dissolved in
methanol (15 mL), p-toluenesulfonic acid monohydrate
(0.11 g, 0.58 mmol) was added and the reaction stirred
for 12 h. Saturated NaHCO3-solution (5 mL) was added
to the mixture, methanol evaporated under reduced pres-
sure, and the residue dissolved in water and extracted sev-
eral times with ether. The combined extracts were washed
with brine, dried, filtered, and evaporated to dryness, yield-
ing 1.56 g of crude product that was purified via chroma-
4.25. (1R,2S)-2-(2-Methylpropoxy)-1,2-bis-(2-trifluorometh-
ylphenyl)-ethanol 7d
The synthesis was carried out as described above (see Sec-
tion 4.22) using 6d (1.07 g, 1.84 mmol). Crude product
(1.08 g) was purified via chromatography (PE/E
tography (PE/E 20:1 ! E). Compound 7a (1.01 g, 96%)
20
was obtained as a colorless oil (½aꢁD ¼ þ29:8 (c 0.84,
CH2Cl2); 1H NMR (CDCl3, 200 MHz) d 7.34–6.70 (m,
8H, Ph), 5.32/5.16 (2d, J = 4.6Hz, 2H, OCHPh), 3.67/
3.54 (2s, 6H, Ph–OCH3), 3.20/3.11 (2dd, J1 = 9.0 Hz,
J2 = 6.9 Hz/J1 = 8.9 Hz, J2 = 6.4 Hz, 2H, O–CH2-
CH(CH3)2), 1.98–1.70 (m, 1H, OCH2CH(CH3)2), 0.88/
0.89 (2d, J = 6.5/6.7 Hz, 6H, OCH2CH(CH3)2); 13C
NMR (CDCl3, 50 MHz) d 157.46/156.72 (Ph–C–OCH3),
127.75/127.69 (Ph–C-1), 130.45/128.60/127.96/127.88/
50:1 ! E) yielding 7d (0.679 g, 91%) as a colorless oil
20
(½aꢁD ¼ þ34:3 (c 0.40, CH2Cl2); 1H NMR (CDCl3) d
7.60–7.30 (m, 8H, Ph–H), 5.37 (br s, 1H, Ph–CH–OH),
5.00 (d, J = 5.3 Hz, 1H, Ph–CH–OR), 3.09–2.95 (m, 2H,
O–CH2–CH(CH3)2), 2.61 (br s, 1H, OH), 1.86–1.66 (m,
J = 6.6 Hz, 1H, O–CH2–CH(CH3)2), 0.78/0.77 (2d,
J = 6.7 Hz, 6H, O–CH2–CH(CH3)2); 13C NMR (CDCl3,
50 MHz) d 139.14/137.55 (q, J(C,F) = 1.2 Hz, Ph–C-1),
131.65/131.46 (q, J(C,F) = 0.8 Hz, Ph–C-4), 129.04 (q,
J(C,F) = 29.5, Ph–C-2) 128.00/127.73 (Ph–C-5, Ph–C-6),
125.20/125.16 (q, J(C,F) = 5.9 Hz, 2 · Ph–C-3), 124.17/
124.12 (q, J(C,F) = 274.2/274.1 Hz, 2 · CF3), 79.65/72.11
(2q, J = 1.7/2.3 Hz, OCHPh), 75.88 (O–CH2CH(CH3)2);
28.40 (O–CH2CH(CH3)2), 19.19/19.04 (O–CH2CH(CH3)2);
M = 406.37. Anal. Calcd for C20H20F6O2: C, 59.11; H,
4.96. Found: C, 59.00; H, 5.22).
119.91/119.76/109.56/109.55
(Ph–C),
77.38/75.96
(OCHPh), 71.47 (OCH2CH(CH3)2), 55.07/54.94 (Ph–
OCH3), 28.53 (O–CH2CH(CH3)2), 19.29/19.20 (O–CH2-
CH(CH3)2); M = 330.42. Anal. Calcd for C21H24O4Æ
0.9C4H10O: C, 72.57; H, 8.17. Found: C, 72.47; H, 7.79).
4.23. (1R,2S)-1,2-Bis-(2-methylphenyl)-2-(2-methylprop-
oxy)-ethanol 7b
The synthesis was carried out as described above (see
Section 4.22) using 6b (1.73 g, 3.63 mmol). In this case
dichloromethane (10 mL) was added because of the poor
solubility of the educt in methanol. Crude product
4.26. (1R,2S)-2-(2-Methoxyethoxy)-1,2-bis-(2-methoxy-
phenyl)-ethanol 7e
The synthesis was carried out as described above (see Sec-
tion 4.22) using 6g (0.475 g, 0.93 mmol). Crude product
(0.422 g) was purified via chromatography (PE/E
(1.74 g) was purified via chromatography (PE/E 50:1 !
20
E) yielding 7b (0.93 g, 86%) as a colorless oil (½aꢁD
¼
1
þ37:3 (c 1.26, CH2Cl2); H NMR (CDCl3, 200 MHz) d
7.33–7.03 (m, 8H, Ph), 5.18/4.76 (2d, J = 5.6 Hz, 2H,
OCHPh), 3.10/2.96 (2dd, J1 = 8.8 Hz, J2 = 6.8 Hz/J1 =
8.8 Hz, J2 = 6.1 Hz, 2H, O–CH2CH(CH3)2), 2.37 (s, 1H,
OH), 2.21/2.17 (2s, 6H, Ph–CH3), 1.90–1.71 (m, J =
6.6 Hz, 1H, OCH2CH(CH3)2), 0.84/0.82 (2d, J = 6.6 Hz,
6H, OCH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) d
30:1 ! E/MeOH 5:1) yielding 7e (0.264 g, 85%) as a yellow
20
oil (½aꢁD ¼ þ17:3 (c 1.00, CH2Cl2); 1H NMR (CDCl3,
200 MHz) d 7.25–6.66 (m, 8H, Ph), 5.39/5.20 (2d,
J = 3.9 Hz, 2H, OCHPh), 3.72–3.46 (m, 11H, incl. 3.62/
3.47 (2s, 6H, OCH3), OCH2CH2O, Ph–CH–OH), 3.36 (s,
3H, OCH2CH2O CH3); 13C NMR (CDCl3, 50 MHz) d
157.41/156.70 (2s, Ph–C–OCH3), 128.62/126.30 (2s, Ph–
C-1), 128.17/127.97/127.86/127.77/120.02/119.90/109.59/
109.55 (8d, Ph–C), 77.81/70.85 (2d, OCHPh), 71.91/68.56
(2t, OCH2CH2OCH3), 58.91 (q, OCH2CH2OCH3) 55.16/
55.01 (2q, Ph–OCH3); M = 332.40. Anal. Calcd for
C19H24O5Æ0.1H2O: C, 68.29; H, 7.30. Found: C, 68.23; H,
7.40).
139.01/136.99/136.46/135.84
(Ph–C–CH3,
Ph–C-1),
129.91/129.51/127.44/127.11/126.58/125.78/125.58 (Ph–C),
81.62 (OCH2CH(CH3)2), 75.84/72.57 (OCHPh), 28.59
(O–CH2CH(CH3)2), 19.30/19.21/19.14/19.05 (O–CH2CH-
(CH3)2, Ph–CH3); M = 298.43. Anal. Calcd for C20H26-
O2Æ0.2H2O: C, 79.54; H, 8.81. Found: C, 79.56; H, 8.71).

J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2425
4.27. Typical procedure for the esterification of auxiliaries
7a–e
NMR (CDCl3) d 7.63–6.79 (m, 13H, Ph–H), 6.13/4.48
(2d, J = 6.8 Hz, 2H, OCHPh), 3.81/3.79 (2s, 6H, OCH3),
3.08/2.94 (2dd, J1 = 8.8 Hz, J2 = 6.5 Hz, 2H, O–
CH2CH(CH3)2), 1.85–1.64 (m, 1H, O–CH2CH(CH3)2),
0.75/0.74 (2d, J = 6.7 Hz, 6H, O–CH2CH(CH3)2); 13C
NMR (CDCl3) d 186.34 (CO), 162.99 (O–CO), 159.60/
159.48 (Ph–C-4), 134.66/128.72/128.69 (Ph–C-1), 132.25/
130.11/129.94/129.24/113.57/113.41 (Ph–C), 83.31/79.18
(OCHPh), 76.01 (O–CH2–CH(CH3)2), 55.25/55.17
(OCH3), 28.48 (O–CH2–CH(CH3)2), 19.20 (O–CH2–
CH(CH3)2); M = 462.55. Anal. Calcd for C28H30O6: C,
72.71; H, 6.54. Found: C, 73.01; H, 6.73).
Oxophenylacetic acid, (1R,2S)-1,2-bis-(2-methoxyphenyl)-
2-(2-methylpropoxy)ethyl ester 8a:
Alcohol 7a (0.50 g, 1.51 mmol), benzoylformic acid
(0.453 g, 3.02 mmol), and N,N-dimethyl-4-aminopyridine
(DMAP) (0.092 g, 0.755 mmol) were dissolved in dry
dichloromethane (12 mL) under a nitrogen atmosphere.
N,N0-Diisopropylcarbodiimide (DIC) (0.378 g, 3.02 mmol)
was slowly added and the mixture stirred for 12 h at rt.
The reaction mixture was diluted with dichloromethane,
washed successively with a KHSO4-solution (5%), satu-
rated NaHCO3-solution, and brine, dried, filtered, and
evaporated to dryness yielding 0.90 g of crude product,
which was purified via chromatography (PE/E 20:1 !
PE/E 5:1). Compound 8a (0.636 g, 91%) was obtained as
a colorless oil (½aꢁD ¼ þ51:8 (c 1.10, CH2Cl2); H NMR
(CDCl3, 200 MHz) d 7.98–6.68 (m, 13H, Ph–H), 6.90/
5.30 (2d, J = 3.9 Hz, 2H, OCHPh), 3.66/3.49 (2s, 6H,
Ph–OCH3), 3.22 (d, J = 6.5 Hz, 2H, O–CH2CH(CH3)2),
1.99–1.79 (m, J = 6.7 Hz, 1H, OCH2CH(CH3)2), 0.89 (d,
J = 6.7 Hz, 6H, OCH2CH(CH3)2); 13C NMR (CDCl3,
50 MHz) d 186.62 (CO), 163.14 (O–CO), 157.28/156.70
(Ph–C–OCH3), 134.51/125.65/124.52 (Ph–C-1), 132.45/
129.94/128.72/128.63/128.31/128.27/128.03/119.92/119.78/
109.68/109.51 (Ph–C), 76.23/75.26 (OCHPh), 72.77
(OCH2CH(CH3)2), 55.29/54.91 (Ph–OCH3), 28.61 (O–
CH2CH(CH3)2), 19.24/19.17 (O–CH2CH(CH3)2); M =
462.55. Anal. Calcd for C28H30O6: C, 72.71; H, 6.54.
Found: C, 72.58; H, 6.81).
4.30. Oxophenylacetic acid, (1R,2S)-2-(2-methylpropoxy)-
1,2-bis-(2-trifluoromethylphenyl)-ethyl ester 8d
The synthesis was carried out as described above (Section
4.27) using 7d (0.30 g, 0.74 mmol). After chromatography,
8d (0.362 g, 91%) was obtained as a colorless oil
20
20
(½aꢁD ¼ þ10:8 (c 1.15, CH2Cl2); 1H NMR (CDCl3) d
1
7.81–7.35 (m, 13H, Ph–H), 6.81/5.10 (2d, J = 6.5 Hz, 2H,
OCHPh), 2.98 (d, J = 6.4 Hz, 2H, O–CH2CH(CH3)2),
1.79–1.59 (m, 1H, O–CH2CH(CH3)2), 0.70 (d, J = 6.7 Hz,
6H, O–CH2CH(CH3)2); 13C NMR (CDCl3) d 185.42
(CO), 161.71 (O–CO), 136.85/135.06 (2q, J(C,F) =
1.4 Hz/1.5 Hz, Ph–C-1), 134.64 (Ph–C-1), 131.97/129.66/
129.63/128.88/128.61/128.53/128.25 (Ph–C), 131.69 (q,
J(C,F) = 0.8 Hz, Ph–C-4), 129.54/128.95 (2q, J(C,F) =
30.3 Hz/30.6 Hz, Ph–C-2), 125.56/125.12 (2q, J(C,F) =
5.7 Hz, Ph–C-3), 123.87/123.79 (2q, J(C,F) = 274.3 Hz,
CF3), 78.31/73.99 (2q, J(C,F) = 1.3 Hz/2.0 Hz, OCHPh),
75.94 (O–CH2CH(CH3)2), 28.16 (O–CH2–CH(CH3)2),
18.85/18.74 (O–CH2–CH(CH3)2); M = 538.49. Anal. Calcd
for C28H24F6O4: C, 62.45; H, 4.49. Found: C, 62.22; H,
4.56).
4.28. Oxophenylacetic acid, (1R,2S)-1,2-bis-(2-methylphen-
yl)-2-(2-methylpropoxy)ethyl ester 8b
4.31. Oxophenylacetic acid, (1R,2S)-2-(2-methoxyethoxy)-
1,2-bis-(2-methoxyphenyl)-ethyl ester 8e
The synthesis was carried out as described above (Section
4.27) using 7b (0.150 g, 0.50 mmol). After chromatography,
ester 8b (0.206 g, 95%) was obtained as a colorless oil
The synthesis was carried out as described above (Section
4.27) using 7e (0.43 g, 1.29 mmol). After chromatography,
20
(½aꢁD ¼ þ46:9 (c 1.13, CH2Cl2); 1H NMR (CDCl3,
200 MHz) d 7.63–7.06 (m, 13H, Ph–H), 6.48/4.90 (2d,
J = 7.1 Hz, 2H, OCHPh), 3.09/2.90 (2dd, J1 = 8.7 Hz,
J2 = 6.4 Hz/J1 = 8.7 Hz, J2 = 6.2 Hz, 2H, O–CH2CH-
(CH3)2), 2.39/2.30 (2s, 6H, Ph–CH3), 1.83/1.63 (m,
J = 6.6 Hz, 1H, OCH2CH(CH3)2), 0.75/0.74 (2d, J =
6.7 Hz, 6H, OCH2CH(CH3)2); 13C NMR (CDCl3,
50 MHz) d 186.06 (CO), 162.65 (O–CO), 136.88/136.85/
136.34/135.35/134.49 (Ph–C-1, Ph–C–CH3), 132.12/
130.10/129.73/129.66/128.61/127.98/127.66/127.08/126.00/
125.72 (Ph–C), 80.26/76.01 (OCHPh), 75.56 (OCH2-
CH(CH3)2), 28.43 (O–CH2CH(CH3)2), 19.18/19.02/18.97
(Ph–CH3, O–CH2CH(CH3)2); M = 430.55. Anal. Calcd
for C28H30O4: C, 78.11; H, 7.02. Found: C, 77.83; H, 7.17).
8e (0.593 g, 99%) was obtained as a colorless oil
20
(½aꢁD ¼ þ34:9 (c 0.80, CH2Cl2); 1H NMR (CDCl3) d
7.91–7.87 (m, 2H, Ph–H), 7.61–6.95 (m, 7H, Ph–H), 6.84/
5.29 (2d, J = 4.1 Hz, 2H, OCHPh), 6.77–6.57 (m, 4H,
Ph–H), 3.65–3.42 (m, 7H, incl. 3.61 (s, 3H, OCH3), OCH2-
CH2O), 3.36/3.26 (2s, 6H, OCH3); 13C NMR (CDCl3) d
186.61 (CO), 163.09 (O–CO), 157.20/156.66 (Ph–C-2),
134.55 (Ph–C-1), 132.42/130.01/128.77/128.65/128.46/
128.39/127.84/119.98/119.83/109.67/109.51 (Ph–C), 125.07/
124.34 (Ph–C-1), 75.40/72.58 (OCHPh), 71.71/68.82
(OCH2CH2O), 58.84/55.32/55.86 (OCH3); M = 464.52.
Anal. Calcd for C27H28O7: C, 69.81; H, 6.08. Found: C,
69.54; H, 6.09).
4.29. Oxophenylacetic acid, (1R,2S)-1,2-bis-(4-methoxy-
phenyl)-2-(2-methylpropoxy)ethyl ester 8c
4.32. Typical procedure for the reduction of esters 8a–e
Hydroxyphenylacetic acid, (1R,2S)-1,2-bis-(2-methoxyphen-
yl)-2-(2-methylpropoxy) ethylester 9a:
The synthesis was carried out as described above (Section
4.27) using 7c (0.30 g, 0.90 mmol). After chromatography,
8c (0.288 g, 89%) was obtained as a colorless solid
To a stirred solution of ester 8a (0.100 g, 0.216 mmol) at
ꢀ78 ꢂC under a nitrogen atmosphere, a 1 M solution of
20
(Fp = 102–106 ꢂC; ½aꢁ ¼ þ17:1 (c 0.55, CH2Cl2); 1H
D

2426
J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
L-Selectrideꢀ in THF (0.24 mL, 0.24 mmol) was added
dropwise and the resulting mixture stirred for 1 h at
ꢀ78 ꢂC. After TLC analysis had indicated total conversion,
the reaction was quenched by the addition of a 10% aque-
ous solution of KHSO4 and warmed to ambient tempera-
ture. The mixture was diluted with water and extracted
three times with ether. The combined ether extracts were
washed with brine, dried over Na2SO4, filtered, and evapo-
rated. After chromatography (PE/E 20:1 ! E), 9a (0.070 g,
94%, 12 mg of starting material recovered) was obtained as
a colorless oil (1H NMR (CDCl3, 200 MHz) d 7.38–6.15
(m, 13H, Ph–H), 6.51 (d, J = 3.5 Hz, 1H, Ph–CH–OCO),
5.27 (s, 1H, CH(OH)), 5.15/4.99 (2d(diast.), J = 3.5 Hz,
1H, Ph–CH–O), 3.52/3.47 (2s, 6H, Ph–OCH3), 3.18 (d,
J = 6.4 Hz, 2H, O–CH2CH(CH3)2), 1.95–1.75 (m,
J = 6.7 Hz, 1H, OCH2CH(CH3)2), 0.89 (d, J = 6.7 Hz,
6H, OCH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) d
172.39 (O–CO), 157.04/156.34 (Ph–C–OCH3), 138.10/
126.68/124.56 (Ph–C-1), 128.22–126.67 (Ph–C), 119.73/
119.40/109.40/109.34 (Ph–C) 76.13/75.23 (OCHPh), 73.20
(CH(OH)), 72.83 (OCH2CH(CH3)2), 55.08/54.85 (Ph–
OCH3), 28.53 (O–CH2CH(CH3)2), 19.22/19.20 (O–
CH2CH(CH3)2); M = 464.56. Anal. Calcd for C28H32O6:
C, 72.39; H, 6.94. Found: C, 72.14; H, 7.05).
4.35. Hydroxyphenylacetic acid, (1R,2S)-2-(2-methylprop-
oxy)-1,2-bis-(2-trifluoromethylphenyl)-ethyl ester 9d
The synthesis was carried out as described above (see Sec-
tion 4.32) using ester 8d (0.100 g, 0.186 mmol). After chro-
matography, 9d (0.094 g, 94%) was obtained as a colorless
oil (1H NMR (CDCl3, 200 MHz) d 7.67–6.60 (m, 13H, Ph–
H), 6.54/6.36 (2d(diast.), J = 6.4 Hz/6.8 Hz, 1H, OCHPh),
5.02/4.98 (2s(diast.), 1H, CH–OH), 4.91/4.84 (2d(diast.),
J = 6.5 Hz/6.9 Hz, 1H, OCHPh), 3.25 (br s, 1H, OH),
2.96–2.76 (m, 2H, O–CH2CH(CH3)2), 1.67–1.37 (m, 1H,
OCH2CH(CH3)2), 0.63/0.61 (3d(diast.), J = 6.6/6.7 Hz,
6H, OCH2CH(CH3)2); 13C NMR (CDCl3, 50 MHz) d
171.90/171.53 (O–CO(diast.)), 137.59/137.45 (Ph–C-
1(diast.)), 137.33/136.62/135.76/135.40 (4q(diast.), J(C,F) =
1.4/1.3/1.3/1.3 Hz, Ph–C-1), 131.96/131.54/131.17/129.24/
128.99/128.62/128.46/128.37/128.45/128. 02/127.88/127.51/
126.69/126.60 (Ph–C(diast.)), 129.21/128.99 (2q, J(C,F) =
30.3 Hz, Ph–C-2), 125.61/125.42/125.08/124.94 (4q(diast.),
J(C,F) = 5.7/5.6/5.7/6.1 Hz,
Ph–C-3),
123.85/123.75
(2q, J(C,F) = 274.4 Hz, CF3), 78.20 (q, J(C,F) = 0.9 Hz,
CHOH), 75.78/75.66 (O–CH2CH(CH3)2(diast.)), 74.98/
74.13 (2q(diast.), J(C,F) = 2.3 Hz/1.9 Hz, OCHPh),
73.06/72.64 (OCHPh(diast.)), 28.05 (d, O–CH2–CH-
(CH3)2), 18.79/18.70 (2q, O–CH2–CH(CH3)2); M =
574.52. Anal. Calcd for C31H26F6O4Æ1.1H2O: C, 62.65; H,
4.44. Found: C, 62.61; H, 4.76).
4.33. Hydroxyphenylacetic acid, (1R,2S)-1,2-bis-(2-methyl-
phenyl)-2-(2-methylpropoxy)ethyl ester 9b
The synthesis was carried out as described above (see Sec-
tion 4.32) using ester 8b (0.100 g, 0.231 mmol). After chro-
matography, 9b (0.082 g, 82%) was obtained as a yellow oil
(1H NMR (CDCl3, 200 MHz) d 7.33–6.54 (m, 13H, Ph–H),
6.26/6.10 (2d(diast.), J = 6.1 Hz, 1H, Ph–CH–OCO), 5.06/
5.03 (2s(diast.), 1H, CH(OH)), 4.74/4.65 (2d(diast.),
J = 6.1 Hz, 1H, Ph–CH–O), 3.06/2.85 (2dd, J1 = 8.7 Hz,
J2 = 6.3 Hz, 2H, O–CH2CH(CH3)2), 2.25/2.23 (2s, 6H,
Ph–CH3), 1.80–1.58 (m, J = 6.6 Hz, 1H, OCH2CH(CH3)2),
0.75/0.69 (2d(diast.), J = 6.7 Hz, 6H, OCH2CH(CH3)2);
13C NMR (CDCl3, 50 MHz) d 172.61/172.11 (O–CO-
4.36. Hydroxyphenylacetic acid, (1R,2S)-2-(2-methoxy-
ethoxy)-1,2-bis-(2-methoxyphenyl)-ethyl ester 9e
The synthesis was carried out as described above (see Sec-
tion 4.32) using ester 8e (0.107 g, 0.230 mmol). Crude 9e
(0.167 g) was isolated as a yellow oil and used for the fol-
lowing saponification without further purification due to
the poor stability of the product. (1H NMR (CDCl3,
200 MHz) d 7.38–5.94 (m, 13H, with 6.46 (d, J = 3.4 Hz,
1H, OCHPh), Ph–H), 5.20/5.07 (2s(diast.), 1H, CH–OH),
5.13/5.00 (2d(diast.), J = 3.4/3.8 Hz, 1H, OCHPh), 3.55–
3.22 (m, 13H, incl. 3.52/3.30/3.28 (3s, 9H, OCH3),
OCH2CH2O)).
(diast.)),
137.94/137.73/136.95/136.40/136.27/136.24/
135.74/135.32 (Ph–C-1, Ph–C–CH3(diast.)), 129.83–125.26
(Ph–C (diast.)), 80.05/79.59/75.95/75.74 (OCHPh(diast.)),
75.91/75.36
(OCH2CH(CH3)2(diast.)),
73.04/72.83
4.37. Reduction of ester 8a under addition of ZnCl2
(CH(OH)(diast.)), 28.39 (O–CH2CH(CH3)2), 19.02/19.01/
18.95/18.71 (O–CH2CH(CH3)2, Ph–CH3),; M = 432.56.
Anal. Calcd for C28H32O4Æ0.2 H2O: C, 77.11; H, 7.49.
Found: C, 77.14; H, 7.64).
A solution of ester 8a (0.100 g, 0.216 mmol) together with a
1 M ZnCl2-solution in Et2O (0.43 mL, 0.43 mmol) was stir-
red at ꢀ78 ꢂC under a nitrogen atmosphere for 10 min. A
1 M solution of L-Selectrideꢀ in THF (0.24 mL, 0.24
mmol) was added dropwise and the resulting mixture
stirred for 1 h at ꢀ78 ꢂC. After TLC analysis had indicated
total conversion, the reaction was allowed to reach ꢀ30 ꢂC
and quenched by the addition of 2 M NaOH (3 mL) and
H2O2-solution (30%) (3 mL). The mixture was diluted with
water and extracted three times with ether. The combined
ether extracts were washed with brine, dried over Na2SO4,
filtered, and evaporated. After chromatography (PE/E
20:1 ! E), pure 9a (0.079 g, 79%) was obtained.
4.34. Hydroxyphenylacetic acid, (1R,2S)-1,2-bis-(4-meth-
oxyphenyl)-2-(2-methylpropoxy)ethyl ester 9c
The synthesis was carried out as described above (see Sec-
tion 4.32) using ester 8c (0.053 g, 0.115 mmol). Crude 9c
(0.071 g) was isolated as a yellow oil and used for the fol-
lowing saponification without further purification due to
the poor stability of the product. (1H NMR (CDCl3,
200 MHz) d 7.31–6.57 (m, 13H, Ph–H), 5.69 (d, J =
6.2 Hz, 1H, OCHPh), 5.04 (s, 1H, CH–OH), 4.26 (d,
J = 5.9 Hz, 1H, OCHPh), 3.79/3.71 (2s, 6H, OCH3),
3.00/2.83 (2dd, J1 = 8.9 Hz, J2 = 6.4 Hz, 2H, O–
CH2CH(CH3)2), 1.83–1.59 (m, 1H, OCH2CH(CH3)2),
0.69/0.68 (2d, J = 6.7 Hz, 6H, OCH2CH(CH3)2)).
4.38. General procedure for the saponification of esters 9a–e
A
solution of esters 9a–e (50–150 mg) and LiOH
(3.0 equiv) in THF/methanol/water (5/4/1) (10 mL) was

J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2427
stirred for 3 h at ambient temperature. The mixture was di-
luted with a saturated aqueous NaHCO3 solution and the
organic solvents evaporated carefully (bath temperature
max 40 ꢂC). The aqueous remaining was extracted three
times with ether. For recovery of auxiliaries 6a–e, the com-
bined ether extracts were washed with brine, dried over
Na2SO4, filtered, evaporated, and the residue was purified
by vacuum flash chromatography when necessary. Thereby
all auxiliaries 6a–e could be recovered almost quantita-
tively without the loss of any enantiomeric purity. The
combined aqueous phases were carefully acidified with
concd HCl while cooling on an ice bath and extracted three
times with ethyl acetate. The combined ethyl acetate ex-
tracts were washed with brine, dried over Na2SO4, filtered,
4.40.2. Immobilization of auxiliary precursor 5a on the solid
support 6g. A solution of alcohol 5a (1.099 g, 4.39 mmol)
in dry DMF (25 mL) was added to a suspension of NaH
(60%) (0.167 g, 4.17 mmol) in dry DMF (5 mL) and the
mixture shaken for 15 min at rt. Then chloromethylated
Wang-resin (1.099 g, 0.695 mmol) and a catalytic amount
of NaI were added in one portion and the resulting suspen-
sion was shaken for 18 h at rt. Unreacted NaH was care-
fully hydrolyzed by adding portions of a mixture of
water/THF (1/1) until the reaction ceased. The resin was
filtered off and thoroughly washed successively with water,
methanol, dichloromethane, petroleum ether, methanol,
dichloromethane, methanol, dichloromethane, methanol,
and dried in vacuo overnight at 40 ꢂC.
and evaporated yielding mandelic acid 10 (77–92% yield,
20
white solid). All ½aꢁD values were (+) assigning the absolute
1.339 g of colorless resin (mass increase: 0.241 g ꢃ yield
83%). IR m (KBr) = 693 cmꢀ1 (C–Cl: shoulder vanished);
no further changes.
configurations to be (S).19 1H NMR (200 MHz, acetone-d6,
TMS) d 7.40–7.16 (m, 5H, Ph–H), 5.08 (s, 1H, Ph–CH-
(OH)-COOH), 4.71 (s, 1H, OH).
For the recovery of excess auxiliary precursor 5a, the com-
bined filtrates were diluted with brine. Dichloromethane
and methanol were evaporated and the aqueous remaining
extracted three times with ether. The combined ether ex-
tracts were washed three times with brine, dried over
Na2SO4, filtered, and evaporated. The crude oil was puri-
fied by vacuum flash chromatography on silica gel (PE/E
10:1 ! E). 1.55 g (91%) of colorless oil was obtained,
which was re-introduced in another auxiliary immobiliza-
tion step without any loss of stereoisomeric purity.
4.39. Derivatization of mandelic acids 10 and diastereoiso-
meric HPLC analysis of L-valine methyl ester derivatives 119
To a solution of mandelic acid 10 (10–30 mg) and HOBt
(10–30 mg) in dry dichloromethane (3 mL), a solution of
L-valine methyl ester (10–30 mg) in dry dichloromethane
(ꢂ1 mL) was added and the resulting mixture cooled to
ꢀ30 ꢂC. A solution of DIC (10–30 mg) in dry dichloro-
methane (ꢂ1 mL) was added and stirring continued for
1 h at ꢀ30 ꢂC and then overnight at ambient temperature.
Finally, the reaction mixture was diluted with dichloro-
methane, filtered, washed successively with 10% aqueous
KHSO4, saturated aqueous NaHCO3, and brine, dried
over Na2SO4, filtered, and evaporated. For the removal
of diisopropyl urea, the crude product was dissolved in
ꢂ1 mL of acetone, cooled for 10 min on an ice bath, fil-
tered, and evaporated. The crude product was used for dia-
stereoisomeric HPLC analysis without further purification.
The immobilization step was carried out as described
above, but in this case using 5.2 equiv of 5a (2.95 g,
6.52 mmol) and 14.4 equiv of NaH (0.438 g, 18.25 mmol)
for 2.00 g of chlorinated Wang-resin (1.26 mmol) and the
deprotonation time was increased up to 72 h. The recovery
of the auxiliary precursor followed by chromatographic
purification (PE/E 10:1 ! E) resulted in 1.01 g (42%) of
precursor 5a and 0.66 g (27%) of 2,20-[methylenebis(oxy)]-
bis-[2-((2S-(2a(1S*,2R*),3aa,4b,7b,7aa))-1,2-bis-(2-methoxy-
Nucleosil 120 S C18; eluents water/methanol (60/40); flow
0.16 mL/min; sample volume 2 lL (c = 4 mg/mL); UV 214,
230, 254 nm. tR = 17 min [R]; tR = 24 min [S].
phenyl)-ethoxy)-octahydro-7,8,8-trimethyl-4,7-methano-
20
benzofuran] 12 as a colorless oil (½aꢁD ¼ ꢀ95:5 (c 1.04,
1
CH2Cl2); H NMR (CDCl3) d 7.19–7.02 (m, 8H, Ph–H),
6.87–6.57 (m, 8H, Ph–H), 5.55/5.35 (2d, J = 4.1 Hz/
3.9 Hz, 4H, OCHPh), 4.94 (d, J = 4.5 Hz, 2H, OCHO),
4.74 (s, 2H, OCH2O), 3.72 (d, J = 7.2 Hz, 2H, 7a0-H),
3.53/3.44 (2s, 12H, OCH3), 2.32–0.80 (m, 34H, aliph., with
0.99/0.93/0.80 (3s, 18H, CH3)); 13C NMR (CDCl3) d
157.89/157.30 (2s, Ph–C-2), 129.18/129.79/127.60/127.30/
119.65/119.39/109.76/109.23 (8d, Ph–C), 127.93/127.73
(2s, Ph–C-1), 101.45 (d, OCHO), 92.43 (t, OCH2O), 90.41
(d, C-7a), 73.43/71.18 (2d, OCHPh), 55.21/54.99 (2q,
OCH3), 48.37 (d, C-4), 47.30 (s, C-7), 47.03 (s, C-8),
46.05 (d, C-3a), 38.56 (t, C-3), 32.46 (t, C-6), 29.02 (t,
C-5), 22.95/20.66/11.79 (3q, C-9, C-10, C-11); M =
917.20. Anal. Calcd for C57H72O10Æ1.2H2O: C, 72.92; H,
7.99. Found: C, 72.98; H, 7.86).
4.40. Reactions on solid support
4.40.1. Chlorination of hydroxymethylated Wang-resin.10
Hydroxymethylated Wang-resin (4.90 g, 3.14 mmol) was
suspended in dry DMF (60 mL) and cooled to ꢀ10 ꢂC.
Diisopropylethylamine (5.5 mL, 31.6 mmol) and metha-
nesulfonyl chloride (2.4 mL, 31.6 mmol) were added suc-
cessively while maintaining the temperature below
ꢀ10 ꢂC and the resulting mixture was stirred for four days
at ambient temperature. Finally the resin was filtered off
and thoroughly washed successively with DMF, dichloro-
methane, methanol, dichloromethane, methanol, dichloro-
methane, methanol, and dried in vacuo overnight at 40 ꢂC.
The whole procedure was repeated once to assert quantita-
tive chlorination.
The chiral auxiliary was cleaved by dissolving 12 (0.171 g,
0.19 mmol) together with p-toluenesulfonic acid mono-
hydrate (0.02 g, 0.10 mmol) in methanol/CH2Cl2 (1:1)
(10 mL) and stirring the resulting mixture for 2 h at rt. Sat-
urated NaHCO3-solution (4 mL) was added, MeOH was
4.984 g of colorless resin. IR m (KBr) = 693 cmꢀ1 (shoul-
der; C–Cl); no further changes. Anal. Calcd for 0.63
mmol/g Cl: Cl, 2.24. Found: Cl, 2.33; N, <0.05.

2428
J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
removed under reduced pressure, and the residue was di-
luted with water and extracted with CH2Cl2. The extracts
were washed with brine, dried over Na2SO4, and evapo-
rated to dryness yielding after recrystallization from
CH2Cl2 0.088 g (85%) of (4S)-(4R*,5R*,7R*,8R*)- or (4S)-
(4R*,5S*,7S*,8R*)-4,5,7,8-tetra(2-methoxyphenyl)-[1,3,6]-
trioxocan 20 as a colorless solid (Fp = 143–145 ꢂC;
½aꢁD ¼ þ58:1 (c 1.10, acetone); H NMR (CDCl3) d 7.11–
6.94 (m, 8H, Ph–H), 6.77–6.58 (m, 8H, Ph–H), 5.64/5.54
(2d, J = 3.5 Hz, 4H, OCHPh), 4.55 (s, 2H, OCH2O),
3.56/3.40 (2s, 12H, OCH3); 13C NMR (CDCl3) d 157.84/
157.17 (2s, Ph–C-2), 128.80/128.71/128.29/128.22/120.30/
109.96/109.91 (7d, Ph–C), 126.15 (s, Ph–C-1), 92.09 (t,
OCH2O), 75.18/71.40 (2d, OCHPh), 55.56/55.41 (2q,
OCH3); M = 542.63. Anal. Calcd for C33H34O7Æ1.0H2O:
C, 70.70; H, 6.47. Found: C, 70.62; H, 6.84).
cooling on an ice bath. The resulting mixture, which had
turned from pale yellow to orange, was shaken for 48 h
at rt. The resin was filtered off and thoroughly washed suc-
cessively with dichloromethane, methanol, dichlorometh-
ane, methanol, dichloromethane, methanol, and dried in
vacuo overnight at 40 ꢂC. 0.755 g of pale yellow resin
(mass increase: 0.041 g ꢃ 76%). IR m (KBr) = 3570 cmꢀ1
(OH: vanished), 1742 cmꢀ1 (COOR), 1690 cmꢀ1 (CO); no
further changes.
20
1
4.40.7. Typical procedure for the stereoselective reduction of
keto esters 8g–h0 (9g–h0). A suspension of resin 8h0
(0.697 g, 0.31 mmol, determined gravimetrically from the
mass increase during the esterification) in dry THF
(10 mL) was cooled to ꢀ78 ꢂC and stirred for 15 min at this
temperature. The L-Selectrideꢀ (0.34 mL, 0.34 mmol) was
then slowly added and stirring was continued for 2 h at
ꢀ78 ꢂC. After complete conversion had been detected by
IR spectroscopy (otherwise another 0.1 equiv of L-Select-
rideꢀ was added and stirring was continued for 30 min at
ꢀ78 ꢂC), the reaction mixture was allowed to warm to
0 ꢂC. The resin was filtered off, treated two times with a
solution of triphenylphosphine hydrobromide in dichloro-
methane, and thoroughly washed successively with dichlo-
romethane, THF, water, THF/water (1/1), methanol,
dichloromethane, methanol, dichloromethane, methanol,
and dried in vacuo overnight at 40 ꢂC. 0.703 g of pale yel-
4.40.3. Immobilization of auxiliary precursor 6f on the solid
support 6h. The synthesis was carried out as described
above (see Section 4.40.2) using auxiliary precursor 6f
(1.793 g, 3.61 mmol), NaH (60%) (0.14 g, 4.17 mmol),
and chlorinated Wang-resin (1.045 g, 0.700 mmol). This
gave 1.287 g of
a
colorless resin (mass increase:
0.242 g ꢃ yield 75%). IR m (KBr) = 693 cmꢀ1 (C–Cl: shoul-
der vanished); no further changes. 1.40 g (92%) of excess
auxiliary precursor 6f was recovered in analogy to Section
4.40.2.
low resin. IR
m
(KBr) = 3524 cmꢀ1(OH), 1737 cmꢀ1
4.40.4. Typical procedure for the deactivation of unreacted
chloromethyl groups in resins 6g and 6h (6g0/6h0). A mix-
ture of resin 6g (1.206 g) and NaI (0.752 g, 5.02 mmol) in
dry acetone (10 mL) was refluxed for 48 h. After cooling
to rt, the resin was filtered off and successively washed with
acetone, THF, ethanol, methanol, methanol/water (1/1),
THF, water, THF/water (1/1), methanol, dichlorometh-
ane, methanol, dichloromethane, methanol and dried in
vacuo for 12 h at 40 ꢂC. The resin was then suspended in
dry THF (10 mL), Bu3SnH (0.39 mL, 1.49 mmol) was
added and the mixture was refluxed for 48 h. After cooling
to rt, the resin was filtered off and thoroughly washed suc-
cessively with THF, ethanol, methanol, methanol/water
(2/1), water, methanol, dichloromethane, methanol, dichlo-
romethane, methanol and dried in vacuo overnight at
40 ꢂC. 1.143 g of colorless resin.
(COOR), 1690 cmꢀ1 (CO: vanished); no further changes.
4.40.8. Typical procedure for the saponification of hydroxy
esters 9g–h0 (7g–7h0). A mixture of resin 9h0 (0.679 g,
0.35 mmol) and LiOH (0.025 g, 1.05 mmol) in THF/meth-
anol/water (10/4/1) (10 mL) was shaken for 2 h at rt. After
complete conversion had been detected by IR spectro-
scopy, the resin was filtered off and thoroughly washed
successively with saturated aqueous NaHCO3, water,
methanol, THF, water, methanol, THF, methanol, THF,
methanol, and dried in vacuo overnight at 40 ꢂC. The resin
was introduced in the next reaction cycle without any
further purification.
0.649 g of pale yellow resin. IR m (KBr) = 3567 cmꢀ1(OH),
1737 cmꢀ1 (COOR: vanished); no further changes.
4.40.5. Typical procedure for the deprotection of auxiliary
precursors 6g/6g0/6h/6h0. Dry methanol (2.0 mL) and tri-
phenylphosphine hydrobromide (0.209 g, 0.61 mmol) were
added to a suspension of resin 6g0 (1.065 g, 0.554 mmol)
in dry dichloromethane (10 mL) and the mixture was
shaken for 48 h at rt. Then the resin was filtered off and
thoroughly washed successively with dichloromethane,
methanol, dichloromethane, methanol, dichloromethane,
methanol, and dried in vacuo overnight at 40 ꢂC. 0.975 g
of pale yellow resin (mass decrease: 0.090 g ꢃ 94%). IR m
(KBr) = 3566 cmꢀ1 (O–H); no further changes.
The combined filtrates were diluted with saturated aqueous
NaHCO3, and THF and methanol were evaporated (bath
temperature max 40 ꢂC). The aqueous remaining was ex-
tracted three times with ether, acidified with HCl and then
extracted three times with ethyl acetate. The combined
ethyl acetate extracts were washed with brine, dried over
Na2SO4, filtered, evaporated, and dried in high vacuo
yielding mandelic acid 10 (0.029 g, 71%), which was dried
in high vacuo and introduced directly in the derivatization
step for enantiomeric analysis (vide supra).
4.40.6. Typical procedure for the esterification of auxiliaries
7g/7g0/7h/7h0 (8g–h0). DIC (0.517 g, 4.1 mmol) was added
dropwise to a mixture of resin 7h0 (0.714 g, 0.41 mmol),
benzoylformic acid (0.616 g, 4.1 mmol), and DMAP
(0.050 g, 0.41 mmol) in dry dichloromethane (15 mL) while
References
1. (a) Gaertner, P.; Schuster, C.; Knollmueller, M. Lett. Org.
Chem. 2004, 1, 249–253; (b) Schuster, C.; Broeker, J.;
Knollmueller, M.; Gaertner, P. Tetrahedron: Asymmetry

J. Broeker et al. / Tetrahedron: Asymmetry 17 (2006) 2413–2429
2429
2005, 16, 2631–2647; (c) Schuster, C.; Knollmueller, M.;
Gaertner, P. Tetrahedron: Asymmetry 2005, 16, 3211–
3223.
8. Chromatographic purification and complete characterization
of mandelic acid esters 9c and 9e was not possible due to a
acid induced rearrangement resulting in bis(2-methoxy-
phenyl)acetaldehyde and bis(4-methoxyphenyl)acetaldehyde,
respectively, that was already described for substituted
hydrobenzoins: Karlsson, O.; Lundquist, K. Acta Chem.
Scand. 1992, 46, 283–289.
2. For a recent review on polymer supported chiral auxiliaries
see: Chung, C. W. Y.; Toy, P. H. Tetrahedron: Asymmetry
2004, 15, 387–399.
3. (a) Noe, C. R. Chem. Ber. 1982, 115, 1576–1590; (b) Noe, C.
R.; Knollmueller, M.; Wagner, E.; Voellenkle, H. Chem. Ber.
1985, 118, 1733–1745; (c) Noe, C. R.; Knollmueller, M.;
Steinbauer, G.; Voellenkle, H. Chem. Ber. 1985, 118, 4453–
4458; (d) Noe, C. R.; Knollmueller, M.; Steinbauer, G.;
Jangg, E.; Voellenkle, H. Chem. Ber. 1988, 121, 1231–1239.
4. (a) Allin, S. M.; Shuttleworth, S. J. Tetrahedron Lett. 1996,
37, 8023–8026; (b) Burgess, K.; Lim, D. Chem. Commun.
1997, 785–786; (c) Purandare, A. V.; Natarajan, S. Tetrahe-
dron Lett. 1997, 38, 8777–8780; (d) Phoon, C. W.; Abell, C.
Tetrahedron Lett. 1998, 39, 2655–2658; (e) Winkler, J. D.;
McCoull, W. Tetrahedron Lett. 1998, 39, 4935–4936; (f)
Faita, G.; Paio, A.; Quadrelli, P.; Rancati, F.; Seneci, P.
Tetrahedron Lett. 2000, 41, 1265–1269; (g) Faita, G.; Paio,
A.; Quadrelli, P.; Rancati, F.; Seneci, P. Tetrahedron 2001,
57, 8313–8322; (h) Desimoni, G.; Faita, G.; Galbiati, A.;
Pasini, D.; Quadrelli, P.; Rancati, F. Tetrahedron: Asymmetry
2002, 13, 333–337; (i) Kotake, T.; Rajesh, S.; Hayashi, Y.;
Mukai, Y.; Ueda, M.; Kimura, T.; Kiso, Y. Tetrahedron Lett.
2004, 45, 3651–3654.
9. Cavelier, F.; Gomez, S.; Jacquier, R.; Llinares, M.; Merca-
dier, J. L.; Petrus, C.; Verducci, J. Tetrahedron: Asymmetry
1993, 12, 2495–2500.
10. Nugiel, D. A.; Wacker, D. A.; Nemeth, G. A. Tetrahedron
Lett. 1997, 38, 5789–5790.
11. Hart, H.; Rajakumar, P. Tetrahedron 1995, 51, 1313–1336.
12. (a) Kawana, M.; Emoto, S. Tetrahedron Lett. 1972, 48, 4855–
4858; (b) Kawana, M.; Emoto, S. Bull. Chem. Soc. Jpn. 1974,
47, 160–165; (c) Worster, P. M.; McArthur, C. R.; Leznoff, C.
C. Angew. Chem. 1979, 91, 255; (d) McArthur, C. R.;
Worster, P. M.; Jiang, J.-L.; Leznoff, C. C. Can. J. Chem.
1982, 60, 1836–1841; (e) Enders, D.; Kirchhoff, J. H.;
Koebberling, J.; Pfeiffer, T. H. Org. Lett. 2001, 3, 1241–1244.
13. Ekecrantz, T.; Ahlqvist, A. Chem. Zentralblatt 1908, 79,
1688–1690.
14. Koikov, L. N.; Han, M.; Wellman, D. M.; Kelly, J. A.;
Smoliakova, I. P. Synth. Commun. 2000, 18, 3451–3464.
15. Wallace, T. W.; Wardell, I.; Li, K.-D.; Leeming, P.;
Redhouse, A. D.; Challand, S. R. J. Chem. Soc., Perkin
Trans. 1 1995, 2293–2304.
16. Seebach, D. et al. Chem. Ber. 1977, 110, 2316–2333.
17. Wang, L.; Zhang, Y. Synth. Commun. 1998, 28, 3991–3997.
18. Butler, C. L.; Hostler, M.; Cretcher, L. H. J. Am. Chem. Soc.
1937, 59, 2345–2355; Sekera, V. C.; Marvel, C. S. J. Am.
Chem. Soc. 1933, 55, 345–349.
19. (a) Polavarapu, P. L.; Fontana, L. P.; Smith, H. E. J. Am.
Chem. Soc. 1986, 108, 94–99; (b) Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester,
1995; Vol. 5, pp 3219–3221.
5. Sumrell, G.; Stevens, J. I.; Goheen, G. E. J. Org. Chem. 1957,
22, 39–41.
6. (a) Merz, A.; Gromann, L.; Karl, A.; Burgemeister, T.;
Kastner, F. Liebigs Ann. Org. Bioorg. Chem. 1996, 10, 1635–
1640; (b) Deuchert, K.; Hertenstein, U.; Huenig, S.; Wehner,
G. Chem. Ber. 1979, 112, 2045–2061; (c) Huenig, S.; Wehner,
G. Chem. Ber. 1979, 112, 2062–2067.
7. (a) Superchi, S.; Contursi, M.; Rosini, C. Tetrahedron 1998,
54, 11247–11254; (b) Scafato, P.; Leo, L.; Superchi, S.;
Rosini, C. Tetrahedron 2002, 58, 153–159.