Synthesis of novel chiral hydrobenzoin mono-tert-butyl ethers derived from m-hydrobenzoin and their application as chiral auxiliaries in the diastereoselective reduction of α-keto esters

Article abstract of DOI:10.1016/j.tetasy.2005.06.033

Three m-hydrobenzoin derived chiral hydrobenzoin mono-tert-butyl ethers were synthesized by a new reaction pathway and tested as chiral auxiliaries in the L-selectride mediated stereoselective reduction of their corresponding phenyl glyoxylates. As a result, improved stereoselectivities of up to a ratio of 92:8 compared to 84:16 with the initially examined analogous benzyl ether were achieved.

Full text of DOI:10.1016/j.tetasy.2005.06.033

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2631–2647
Synthesis of novel chiral hydrobenzoin mono-tert-butyl
ethers derived from m-hydrobenzoin and their application as
chiral auxiliaries in the diastereoselective reduction of a-keto esters
Christian Schuster, Joachim Broeker, Max Knollmueller and Peter Gaertner*
Department of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria
Received 4 June 2005; accepted 24 June 2005
Dedicated to Prof. Dr. Fritz Sauter on the occasion of his 75th birthday
Abstract—Three m-hydrobenzoin derived chiral hydrobenzoin mono-tert-butyl ethers were synthesized by a new reaction pathway
and tested as chiral auxiliaries in the L-selectrideꢀ mediated stereoselective reduction of their corresponding phenyl glyoxylates. As a
result, improved stereoselectivities of up to a ratio of 92:8 compared to 84:16 with the initially examined analogous benzyl ether were
achieved.
ꢁ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
uration on the transformed stereocentre could be
achieved (Scheme 2, Table 1).
Over the course of our recent studies on novel chiral
auxiliaries, which could be attached onto a solid support
to serve at the same time as polymer bound enantio-
merically pure linkers and chiral auxiliaries,1 we synthe-
sized chiral hydrobenzoin mono-benzyl ethers 5a and b
as test systems.2 These compounds were easily accessible
by the desymmetrization of m-hydrobenzoin 1 with
commercially available anhydro lactols 2a and b as chi-
ral protecting groups,3 which finally lead to both (R)-
and (S)-substituted hydrobenzoin auxiliaries 5a and b
with the benzyl ether moiety symbolizing the linkage
of the auxiliary to a polystyrene resin such as Merrifield
or Wang (Scheme 1).
On the one hand, in the case of Rosiniꢀs (R,R)-auxiliary
the resulting stereoselectivities were interpreted to be the
result of intramolecular p,p-interactions which force
the open chain auxiliary into a conformation where the
benzyl ether moiety effectively shields away the si-face of
the keto carbonyl from the attack of the reducing
agent.4 Thus, by strengthening these p,p-interactions
by introducing various substituents into the benzyl ether
moiety, Rosini was able to improve the resulting diaste-
reo selectivities significantly5 (Table 1). On the other
hand, we surprisingly found that replacement of the
benzyl ether moiety in our m-hydrobenzoin derived aux-
iliary 5a by the sterically demanding, p,p-non-interac-
ting i-butyl group leading to auxiliary 5c increased the
resulting stereoselectivity as well (Table 1). This fact
suggested a different mechanistic influence on the auxil-
iary conformation and prompted us to look out for other
sterically more demanding ether moieties such as tert-
butyl ethers, which might lead to further improvements.
Whereas these auxiliaries were only able to induce mod-
erate diastereoselectivities up to 36% de in the alkylation
of carboxylic esters,2 we were surprised to find that
when applying auxiliary 5a in the L-selectrideꢀ mediated
reduction of phenylglyoxylic acid to mandelic acid, in
comparison with the analogous auxiliary derived from
(R,R)-hydrobenzoin, which was reported by Rosini
et al. to induce stereoselectivities up to 56% de in this
type of reaction,4 even a slightly increased diastereo-
selectivity of 68% de with the same (S)-absolute config-
Herein, we report the synthesis of three novel m-hydro-
benzoin derived chiral hydrobenzoin mono-tert-butyl
ethers 5d–f (Scheme 3) via a new synthetic pathway
using exclusively basic reaction conditions in the key
steps and their application as chiral auxiliaries in the
diastereoselective reduction of benzoylformic acid.
*
Corresponding author. Tel.: +43 1 5880155421; fax: +43 1 5880115492;
e-mail: peter.gaertner@tuwien.ac.at
0957-4166/$ - see front matter ꢁ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.06.033

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C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
OH
OH
1
i
ii
HO
HO
O
O
O
O
O
OH
OH
O
5a
5b
3b
3a
HO
O
HO
O
Noe´s anhydro lactols:
O
O
O
2a
O
O
O
... Solid support
2b
Scheme 1. Reagents and conditions: (i) exo-anhydro lactol 2a, p-TsOH, CH2Cl2; (ii) endo-anhydro lactol 2b, p-TsOH, CH2Cl2.
O
OH
i
ii
R
X
X
X
O
O
HO
O
O
O
S
R
O
O
X ... H, 4-CF3, 4-OMe, 4-i-Pr, 4-Ph
O
O
OH
iii, iv
i
ii
S
O
R
O
R
O
HO
R
O
O
OH
O
S
R
O
O
7a, c
6a, c
3a
5a, c
R ... Bn, i-Bu
Scheme 2. Reagents and conditions: (i) PhCOCOOH, DIC, DMAP, CH2Cl2; (ii) L-selectrideꢀ, ꢀ78 ꢂC, THF; (iii) NaH; BnBr or i-BuOTs, DMF;
(iv) p-TsOH, MeOH.
2. Results and discussion
refluxing the resulting alkoxide with bromoacetic acid,
tert-butyl ester in THF in the presence of HMPA. Then
ester 8 was methylated with 92% yield by deprotonation
with LDA in THF and quenching of the enolate with
CH3I at ꢀ20 ꢂC (Scheme 5).
Bearing in mind that different kinds of analogous hydro-
benzoin mono-tert-butyl ethers 5d–f can be synthesized,
we decided to derive these compounds from protected
alkoxyacetic acid, tert-butyl ester 8 (Scheme 4), which
was easily prepared in 98% yield by deprotonating pro-
tected, desymmetrized hydrobenzoin 3a with NaH and
The resulting ester 9 was an approximately 2:1 mixture
of diastereoisomers. Trying to increase the stereoinduc-

C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
2633
Table 1. Diastereoisomeric ratio of mandelates from the reduction of phenylglyoxylates using (R,R)-hydrobenzoin mono-benzyl ether auxiliaries and
(S,R)-hydrobenzoin mono-benzyl/mono-i-butyl ether auxiliaries, respectively
Auxiliary
X
Ratioa (R,R,S)/(R,R,R)
Auxiliary
R
Ratioa (S,R,S)/(S,R,R)
(R,R)
(R,R)
(R,R)
(R,R)
(R,R)
H
78:22b
87:13c
70:30c
83:17c
80:20c
(S,R)
5a
Bn
84:16
4-CF3
4-OMe
4-i-Pr
4-Ph
(S,R)
5c
i-Bu
89:11
a Directly determined on crude by 1H NMR spectroscopic analysis.
b Data from Ref. 4.
c Data from Ref. 5.
HO
O
HO
HO
O
O
O
5d
5e
5f
Scheme 3.
R
R
R
O
HO
O
O
O
OH
O
O
PG
PG
PG
O
O
O
O
R''
R''
R'
O
5
11
PG ... Protective Group / Noe's Lactol
10
8
R ... CH3, Bn, ...
R' ... H, O-CH3, ...
R'' ... t-Bu
Scheme 4.
O
O
O
i
ii
O
O
O
O
O
OH
O
O
O
O
3a
8
9
Scheme 5. Reagents and conditions: (i) NaH; BrCH2COO-t-Bu, HMPA, THF; (ii) LDA; MeI, ꢀ20 ꢂC, THF.
tion in this step by conducting the reaction at ꢀ78 ꢂC
resulted in no conversion and total recovery of ester 8,
which was interpreted as a dominance of the ꢁsecondary
amine effectꢀ (vide infra) at lower temperatures.
2.1. Second alkylation step
Over the course of this strategy, it was surprising that
subsequent methylation of ester 9 even when applying
a higher excess of 2 equiv of LDA yielded only 15% of
the desired ester 10a while 63% of 9 were recovered.
Therefore, we decided to try out some additives which
are well known for this type of reaction. Whereas the
use of HMPA6 as a co-solvent resulted in almost total
recovery of the starting ester 9, employing LiCl7 as depro-
tonation accelerating additive increased the yield of the
second methylation step up to 57% (Table 2, entry 5).
In following another alkylation of mono-methylated
ester 9 with different electrophiles, it should provide
access to various a-di-alkylated alkoxyacetic acid esters
10. After reduction to the corresponding alcohols 11,
these were thought to subsequently yield various tert-
butyl ether derivatives 5 by further alkoxylation and
reduction steps (Scheme 4).

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C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
Table 2. Second methylation stepa—addition of additives
O
O
O
O
O
O
O
O
O
O
9
10a
Entry
Additivea
Yieldb (%)
1
2
3
4
5
6
/
15c
00d
26
56
57
6 equiv HMPA
1 equiv LiCl
2 equiv LiCl
2.3 equiv LiCl
4 equiv LiCl
51
a Reaction conditions: LDA + 9 + additive, ꢀ15 ꢂC, 20 min; +MeI, ꢀ15 ꢂC ! rt; solvent: THF.
b Isolated yields by vacuum flash chromatography.
c 63% of 9 recovered.
d 90% of 9 recovered.
Alternatively, we tried the addition of 1 equiv of BuLi
after the deprotonation step, which is recommended to
overcome the so-called ꢁsecondary amine effectꢀ, that is
known to be responsible for the reformation of the start-
ing ester by a rapid, electrophile initiated proton transfer
from di-i-propyl amine (DIPA), which is generated from
LDA during the deprotonation, to the enolate.8 Thereby,
we achieved an increased methylation yield of 59%
(Table 3, entry 1). Combining the deprotonation accel-
erating effect of adding LiCl to the reaction mixture
Table 3. Second alkylation stepa—addition of BuLi
O
O
O
O
O
O
O
O
O
O
O
+
10a
O
10c
9
O
O
O
OH
O
O
O
O
O
10b
10d
Yieldb
Entry
LDA (2 equiv)
Add.
BuLi (1 equiv)
Temperature for
BuLi addition
Electrophile
deprot. time (min)
deprot. time (min)
1
2
3
4
5
6
7
60
90
90
90
90
30
60
/
/
20
60
60
40
40
20
30
ꢀ20 ꢂC
MeI
MeI
MeI
MeI
MeI
MeI
BnBr
10a (59%)
/
/
10a (60%)
10a (73%)
10a (86%)
10b (60%)
10c (13%)
/
/
10c (21%)
10c (21%)
10c (2%)
10c (24%)
/
ꢀ60 ꢂC
10d (26%)c
10d (9%)d
/
LiCl
LiCl
LiCl
LiCl
LiCl
ꢀ60 ꢂC
ꢀ20 ꢂC
ꢀ30 ! ꢀ20 ꢂC
ꢀ60 ! ꢀ20 ꢂC
ꢀ20 ꢂC
10d (3%)
10d (10%)
10d (6%)
a Reaction conditions: LDA + 9 + LiCl, ꢀ15 ꢂC; +BuLi; +Electrophile, ꢀ20 ꢂC ! rt; solvent: THF.
b Isolated yields by vacuum flash chromatography.
c 68% 9 recovered.
d 84% 9 recovered.

C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
2635
and destroying the enolate–DIPA complex by adding
BuLi resulted in 86% of di-methylated ester 10a in the
best run (Table 3, entry 6). Benzylation of ester 9 simi-
larly yielded 60% of ester 10b (Table 3, entry 7). It is
noteworthy, that on the one hand, deprotonation with
LDA/LiCl needed to be carried out for a long enough
time, otherwise the amount of by-product 10d increased
by addition of BuLi to unreacted ester 9 (Table 3, entry
6). On the other hand, an appropriate temperature was
required for the decomposition of the enolate–DIPA
complex. Thus, adding BuLi at too high a temperature
caused the formation of by-product 10c (Table 3, entries
4 and 5), which was thought to be generated by a
Grignard-reduction type hydride attack on the ether
bond of the enolate. Quenching with the electro-
phile at a too low temperature on the other side did
not effect decomposition of the complex and resulted
mainly in the recovery of ester 9 (Table 3, entries 2
and 3).
dard conditions. Methylation of 11a was then carried
out by deprotonation with NaH and quenching of the
alkoxide with CH3I (Scheme 6). Finally, methyl ether
12a was deprotected under acid catalyzed methanolysis
affording auxiliary 5d in 71% yield from 10a. Noeꢀs chi-
ral protecting group3 was isolated as its methyl acetal
for recycling.
For the synthesis of tert-butyl ether 5e, alcohol 11a was
first converted to tosylate 13a, which we then tried to
reduce with LiAlH4 according to the procedure described
by Collins and Jacobs.9 This disappointingly yielded
only 2% of the desired ether 12b. Reduction of sulfo-
nates 13a and b with LiBEt3H (superhydride) instead
of LiAlH4, which was first recommended by Krishna-
murthy,10 resulted in an evident improvement of up to
21% yield. Nevertheless, the main product in all of these
experiments was alcohol 11a, a problem that is fre-
quently reported to occur in the reduction of sterically
hindered n-alkyl sulfonates11 (Table 4).
2.2. Transformation of alcohols 11a,b to tert-butyl ethers
5d–f
Alternatively, we tried to reduce iodide 14a with
LiAlH4, which unfortunately resulted only in traces of
ether 12b with alcohol 3a as the main product. Taking
into account, that Ashby has proved a single electron
Di-alkylated esters 10a and b were reduced to the corre-
sponding alcohols 11a and b with LiAlH4 using stan-
O
O
O
O
O
O
O
OH
O
i
ii
iii
O
O
O
5d
O
10a
11a
12a
Scheme 6. Reagents and conditions: (i) LiAlH4, THF; (ii) NaH; MeI, HMPA, DMF; (iii) p-TsOH, MeOH.
Table 4. Reduction of sulfonates 13a,ba
O
O
O
i
O
O
S
R ... 4-Tol, Me
R
O
13a, b
O
O
ii
O
OH
O
O
O
11a
12b
Entry
R
Reducing agent
Yield 12bb (%)
Yield 11ab (%)
1
2
3
4-Tol 13a
4-Tol 13a
CH3 13b
LiAlH4
LiBEt3H
LiBEt3H
2
21
19
75
65
72
a Reagents and conditions: (i) TsCl, Py/MsCl, Et3N, CH2Cl2; (ii) LiAlH4/LiBEt3H, THF.
b Isolated yields by vacuum flash chromatography.

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C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
Table 5. Reduction of iodides 14a,ba
O
O
OH
ii
R
R
O
O
3a
O
O
O
OH
I
i
O
iii
R
O
11a, b
14a, b
O
O
R ... H, Ph
12b, c
Entry
Solvent
Reducing agent
Temp.
Reaction time (h)
Yield 11b
1
2
3
4
5
THF
THF
THF
THF/HMPA 4:1
THF/HMPA 4:1
LiAlH4
rt
rt
67 ꢂC
67 ꢂC
67 ꢂC
12
48
16
16
16
12b (4%)c
12b (0%)d
12b (63%)e
12b (>98%)
12c (90%)
LiBEt3H
LiBEt3H
LiBEt3H
LiBEt3H
a Reagents and conditions: (i) I2, PPh3, imidazole, toluene; (ii) LiAlH4, THF; (iii) LiBEt3H, THF/HMPA 4:1.
b Isolated yields by vacuum flash chromatography.
c Total conversion of educt 14a; 67% alcohol 3a isolated.
d 98% 14a recovered.
e 35% 14a recovered.
mechanism (SET) for the reduction of sterically hin-
dered alkyl iodides with numerous publications,12 an
SET seemed also to be responsible for the formation
of 3a due to the elimination of i-butene in our experi-
ment. Consequently, we proposed superhydride as a
solution for this problem as Ashby had found superhy-
dride to be the only exception with a proposed ionic
mechanism in the reduction of sterically hindered iod-
ides.12a Therefore, when using HMPA as a co-solvent,
iodide 14a could be transformed to tert-butyl ether
12b, quantitatively. Similarly, iodide 14b was reduced
to 12c in 90% yield (Table 5).
The diastereoisomeric ratios of the resulting a-hydroxy
esters 7d–f were directly analyzed by H NMR analysis
1
of the crude reaction mixtures by integration of the
sufficiently resolved benzylic protons Ha in the two dia-
stereoisomers (Fig. 1). The absolute configurations of
the major diastereoisomers were determined by sapon-
ification of the hydroxy ester mixtures 7d–f with LiOH
in MeOH/THF/H2O 5:4:1 at room temperature and
comparing the specific rotations of the recovered man-
delic acids with the literature values.13 This, on the one
hand, allowed us to assign all the major products as
(S)-mandelic acid esters while on the other hand, to
recover the auxiliaries quantitatively without any loss
of enantiomeric purity. For further diastereoisomeric
analysis, the mandelic acids were transformed into their
L-valine methyl ester derivatives and analyzed by
HPLC,14 which resulted in diastereoisomeric ratios
consistent with those obtained from the previous
1H NMR spectroscopic analyses and therefore
showed the ester saponifications to be free from
racemization.
Finally, tert-butyl ethers 12b and c were deprotected
under acid catalyzed methanolysis to afford auxiliaries
5e and f with 82–84% yield. Noeꢀs chiral protecting
group3 was isolated as its methyl acetal for recycling
as mentioned above.
2.3. Selectivity test
Auxiliaries 5d–f were esterified under mild conditions
with benzoylformic acid and diisopropylcarbodiimide
(DIC) in the presence of catalytic amounts of 4-(N,N-
dimethylamino)pyridine (DMAP). The resulting esters
6d–f were then reduced with L-selectrideꢀ in THF at
ꢀ78 ꢂC following the procedure described by Rosini
and co-workers4 (Table 6).
Rosini et al. proposed a conformational explanation in
their work on the basis of the well-documented fact that
in alkyl esters of secondary alcohols the hydrogen nor-
mally lies coplanar and syn to the ester carbonyl.15
Therefore, conformation A was suggested to be predom-
inant and responsible for the observed facial selectivity

C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
Table 6. Diastereoisomeric ratio of 7d–f from reduction of a-keto esters 6d–fa
2637
R
R
R
O
OH
i
ii
S
O
O
HO
O
O
O
S
R
O
O
7d-f
6d-f
5d-f
R ... OMe, H, Ph
Entry
Ester
R
Additive
/
2 equiv ZnCl2
/
2 equiv ZnCl2
/
Ratiob (S,R,S)/(S,R,R)
Yield 7d–fc (%)
1
2
3
4
5
6d
6d
6e
6e
6f
OMe
OMe
H
H
Ph
86:14
88:12
92:8
92:8
92:8
80
80
87
88
92
a Reagents and conditions: (i) PhCOCOOH, DIC, DMAP, CH2Cl2; (ii) L-selectrideꢀ, ꢀ78 ꢂC, THF.
b Diastereoisomeric ratios determined by 1H NMR integration on crude reaction mixtures and HPLC analysis of L-valine methyl ester derivatives of
cleaved mandelic acids; absolute configuration of major diastereoisomers approved by specific rotation of cleaved mandelic acids.
c Isolated yields by vacuum flash chromatography.
OH
Ha
O
O
O
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
(ppm)
Figure 1. 1H NMR spectrum of the mixture of diastereoisomers of mandelic acid ester 7e.
with the (R,R)-hydrobenzoin derived benzyl ether auxil-
iaries (Scheme 7).4,5 Therein the benzyl ether moiety had
interacted via p–p stacking with the keto ester moiety
and had consequently on the one hand forced the flexi-
ble molecule into conformation A, while on the other
hand shielded away the si-face of the carbonyl from
the hydride attack.4
face of the keto carbonyl. The fact that some addi-
tional p–p interactions between the two hydrobenzoin
aryls might have forced the molecule out of the
staggered into the more eclipsed conformation B0 result-
ing in a more efficient covering of the keto carbonyl
by the benzyl ether moiety, may therefore be an
explanation for the slightly increased stereoinduction
with our auxiliary compared to Rosiniꢀs (R,R)-auxiliary
(Table 1). In contrast, the same effect might have
moved the benzylether moiety away from the keto car-
bonyl A0.
Accordingly, our benzyl ether auxiliary test system
6a might have adopted a conformation B, again
with the benzyl ether moiety shielding away the si-

2638
C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
H
O
H
O
O
O
O
O
H
H
O
O
re attack
re attack
H-
H-
A
A'
H
O
H
O
H
H
O
O
O
O
O
O
re attack
re attack
H-
H-
B'
B
H-
H-
H
O
H
O
O
re-attack
re-attack
H
H
O
O
H
O
O
H
O
O
O
O
O
M
O
M
re attack
H-
E
C
D
Scheme 7. A: supposed mechanism for the stereoinduction with (R,R)-hydrobenzoin mono-benzyl ether auxiliaries from Refs. 4 and 5; B, C, D and E:
adoptions from model A for the observed stereochemical outcomes with m-hydrobenzoin derived benzyl ether auxiliary 5a and tert-butyl ether
auxiliaries 5d–f.
Consequently, conformation C with the sterically
demanding tert-butyl ether moiety more effectively
shielding away the si-face from the hydride attack might
be responsible for the further improved stereoinduction
with our tert-butyl ether auxiliary systems 5e and f,
although no p–p interactions between the ether moiety
and the keto carbonyl are possible in the so far adopted
model. At the moment, we have neither theoretical nor
experimental evidence if this suggestion is correct or if
other parameters are responsible for our unexpectedly
good results. Though it is remarkable that use of the
Lewis acidic additive ZnCl2, which is well known to
force the carbonyls of a-ketoesters from the normally
known dipole–dipole interactions reducing anti16 into a
syn conformation by chelation,17 did not have any effect
at all, either on the diastereoisomeric excess or on the
absolute configuration of hydroxy ester 7e (Table 6,
entry 4). Thus, another conformation D with the
carbonyls syn oriented mediated by chelation even
with the Li-cation of L-selectridereg seemed to be
possible.
explanation for this result may be that in the case of 6d
the two conformers C and D exhibit different stereose-
lectivities with D being more selective than C. With
the addition of Zn2+, the equilibrium between C and
D is then shifted towards D which is stabilized by coor-
dination to the O-atom (see E) and the selectivity is
improved.
3. Conclusion
In conclusion, we have confirmed the findings of Rosini
et al. that an open chain chiral auxiliary derived from
hydrobenzoin can be used satisfactorily in the diastereo-
selective reduction of a-keto esters.4,5 Thereby it turned
out that our benzylether auxiliary 5a derived from
m-hydrobenzoin was slightly superior to the one derived
from (R,R)-hydrobenzoin.4 Furthermore, it can be sug-
gested that not only ether substituents, which are able to
undergo p–p interactions, but also sterically demanding
tert-alkyl substituents and alkyl substituents with addi-
tional chelating atoms, respectively, can force the flexi-
ble auxiliary into a conformation, so that one of the
faces of the keto carbonyl is effectively shielded away
from the hydride attack. Initial diastereoselectivities of
about 56–68% de with benzyl ethers have thereby been
improved up to 84% de with tert-alkyl ethers. Over the
course of this work, we have developed a convenient
However, in the case of ester 6d wherein the additional
Lewis basic O-atom offers the possibility of further che-
lation a loss of stereofacial selectivity was observed (Ta-
ble 6, entry 1) compared to 6e and f (Table 6, entries 3
and 5) which could be slightly compensated by the addi-
tion of the more Lewis acidic Zn2+ (Table 6, entry 2). An

C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
2639
synthetic route towards tert-butyl ethers and analogous
tert-alkyl ethers of chiral secondary alcohols exclusively
under basic conditions. We have shown that homochiral
tert-butyl ether 12b can be synthesized from chiral alco-
hol 3a in six steps with an overall yield of 58% by this
method. This can be a useful alternative when acid sen-
sitive functionalities make commonly used acid cata-
lyzed methods for tert-butyl ether syntheses not
applicable, for example, when applying the method
described by Armstrong et al. using tert-butyl trichloro-
acetimidate under BF3ÆEt2O catalysis18 had yielded only
5% of the desired ether 12b from alcohol 3a.
trated immediately after chromatography together with
a few drops of Et3N. 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 in CDCl3 at 200 and
50 MHz, respectively, using TMS or the solvent peak
as the reference. HPLC diastereoisomeric analysis of
L-valine methyl ester derivatives of mandelic acids14
was carried out with a SHIMADZU LC-10AD (SHI-
MADZU SPD-10AV UV/vis detector; Nucleosil 120 5
C18; H2O/MeOH 60:40; 0.16 mL/min; tR1 = 17 min.
[R], tR2 = 24 min. [S]). Elemental analysis was carried
out at Vienna University, Department of Physicochem-
istry, Laboratory for Microanalysis, Wa¨hringer Str. 42,
A-1090 Vienna.
We have been encouraged by our present results to
undertake further investigations on m-hydrobenzoin
mono-ethers as chiral auxiliaries, especially by varying
the ether substituent to such an extent, that it can not
only serve as the stereoinduction optimizing moiety
but also as a sublinking unit between the hydrobenzoin
auxiliary and a polymer support. Additional introduc-
tion of substituents in the hydrobenzoin aryls could also
be a possibility of changing steric and electronic proper-
ties of the auxiliary and thereby increase stereoselectivi-
ties as well.
4.2. Desymmetrization of m-hydrobenzoin
4.2.1. [2S-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-[(Octahydro-
7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-di-
phenylethanol, 3a. m-Hydrobenzoin 1 was desymmet-
rized by a modification of the method described in the
literature—a 2-fold excess of 1 was used for achieving
better selectivities.3 A typical run was as follows: 1
(166 mmol/35.4 g) was dissolved in dry dichloromethane
(1000 mL) with gentle heating. Then exo-anhydro lactol
2a (42 mmol/15.5 g), p-toluenesulfonic acid (0.60 g) and
triphenylphosphine hydrobromide (0.10 g) were added
and the mixture stirred at ambient temperature until
complete equilibration was monitored by TLC analysis.
Then, a portion of Na2SO4 was added and stirring was
continued for 15 min. Finally, NaHCO3 was added
and the solids were filtered off after additional 15 min
stirring. The filtrate was evaporated and the crude prod-
uct was taken up with diethyl ether (500 mL) and stirred
thoroughly for 2 h at ambient temperature. The precip-
itated 1 was filtered off, washed with little portions of
cold ether and recovered for the next desymmetrization
batch. The filtrate was evaporated and the residue puri-
fied by vacuum flash chromatography on silica gel, elut-
ing with petroleum ether/ether (20:1!0:100). As a
result, 19.3 g (yield 59%) of the desired enantiopure
(R)-monoacetal 3a could be isolated. Further, enantio-
pure material could also be isolated by recrystallization
of a mixed fraction containing only small amounts of
undesired (S)-mono-acetal from petroleum ether/ether.
All other fractions containing di-acetal, mixtures of
(R)- and (S)-mono-acetal and unreacted 1 were com-
bined and could be re-equilibrated by taking them up
with dichloromethane and adding a catalytic amount
of acid as described above.
4. Experimental
4.1. General
Commercially available reagents and solvents were used
as received from the supplier unless otherwise specified.
Diethyl ether, petroleum ether (60–80 ꢂC fraction), ethyl
acetate and dichloromethane were distilled prior to use.
Dry toluene, ether and tetrahydrofuran were predried
over KOH and distilled from Na/benzophenone. Dry
dichloromethane was distilled from P2O5. Dry petro-
leum ether and dimethylformamide were dried and
˚
stored over molecular sieves (4 A). Diisopropylamine
was distilled from CaH2 and kept over molecular sieves
˚
(4 A). Lithium diisopropyl amide was prepared accord-
ing to procedures described in the literature.19 n-Butyl
lithium was purchased from Aldrich as a ꢁ2.5 M solu-
tion in hexane and titrated following the literature pro-
cedures.20 L-Selectrideꢀ and superhydride were
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. Benzyl bro-
mide was distilled prior to use. NaI, LiCl and ZnCl2
were dried by heating to 150–300 ꢂC in high vacuo for
30 min prior to use. m-Hydrobenzoin was prepared by
meso-selective reduction of rac-benzoin with NaBH4 or
LiAlH4 according to the literature procedures.21 All
moisture sensitive reactions were carried out under a
nitrogen atmosphere. For TLC-analysis precoated alu-
minium-backed plates (Silica gel 60 F254, Merck) were
used. Compounds were visualized by spraying with 5%
phosphomolybdic acid hydrate in ethanol and heating.
Column chromatography and vacuum flash chromato-
graphy were carried out with silica gel Merck 60. All
fractions of products containing Noeꢀs acetal protecting
group together with a free hydroxy group were concen-
4.3. Preparation of benzyl and isobutyl ethers
4.3.1. [2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-(2-Benzyloxy-
1,2-diphenylethoxy)octahydro-7,8,8-trimethyl-4,7-metha-
nobenzofuran, 4a.
(12.74 mmol/5.00 g) in dry DMF (10 mL) was added
slowly to suspension of freshly washed NaH
A
solution of alcohol 3a
a
(21.60 mmol/0.52 g) in dry DMF (2 mL) and the mix-
ture stirred for 1 h at room temperature. Then a cata-
lytic amount of NaI and BnBr (19.11 mmol/2.3 mL)

2640
C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
were added slowly and stirring continued overnight.
Unreacted NaH was carefully then hydrolyzed by add-
ing portions of a mixture of water/THF (1:1) while cool-
ing on an ice bath, until the reaction ceased. The
resulting mixture was diluted with brine and extracted
three times with ether. The combined ethereal extracts
were washed three times with brine, dried over Na2SO4,
filtered and evaporated. The crude product was used in
the next step without further purification. For product
characterization a small amount was purified by vacuum
flash chromatography on silica gel, eluting with petro-
leum ether/ether (20:1!5:1). White solid, mp 124–
(2q, O–CH2–CH(CH3)2). Anal. Calcd for C30H40O3
· 0.5 H2O: C, 78.73; H, 9.03. Found: C, 78.81; H,
8.81.
4.4. Preparation of tert-butyl ethers
4.4.1. [2S-(2a(1R*,2S*),3aa,4b,7b,7aa)]-[2-[(Octahydro-
7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-di-
phenylethoxy]acetic acid, 1,1-dimethylethyl ester, 8.
A
solution of alcohol 3a (10.22 mmol/4.01 g) in dry THF
(250 mL) was slowly added to a suspension of 60%
NaH (21.5 mmol/0.86 g) in dry THF (50 mL). Then
HMPA (61.296 mmol/10.8 mL) and bromoacetic acid,
tert-butyl ester (15.32 mmol/2.3 mL) were added succes-
sively and the mixture refluxed overnight. After cooling
to ambient temperature, unreacted NaH was carefully
hydrolyzed by adding portions of a mixture of water/
THF (1:1) until the reaction ceased. The resulting mix-
ture was diluted with brine and extracted three times
with ether. The combined ethereal extracts were washed
with brine, dried over Na2SO4, filtered and evaporated.
The remaining HMPA, bromoacetic acid and tert-butyl
ester were evaporated in high vacuo overnight. The
crude product was purified by vacuum flash chromato-
graphy on silica gel, eluting with petroleum ether/ether
127 ꢂC, Rf = 0.68 (PE/E 9:1), 0.78 (PE/E 3:1),
20
½aꢂD ¼ ꢀ54.0 (c 1.10, CH2Cl2). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.40–6.85 (m, 15H, aromatic),
4.83 (d, 1H, 2-H, J = 3.9 Hz), 4.70:4.28 (2d, 2H, Ph–
CH–O, JAB = 8.0 Hz), 4.41:4.10 (2d, 2H, O–CH2–Ph,
JAB = 12.0 Hz), 2.40 (d, 1H, 7a-H, J = 6.1 Hz), 1.94–
0.48 [m, 17H, 17MBE-aliphatic, therein 0.84:0.82:0.72
(3s, 9H, 3MBE-CH3)]. 13C NMR (50 MHz, CDCl3):
dC = 140.7:140.2:138.3 (3s, Ph–C-1), 128.4–127.0 (m,
Ph–C), 100.8 (d, C-2), 89.9 (d, C-7a), 84.0:78.6 (2d,
Ph–CH–O), 70.3 (t, O–CH2–Ph), 48.1 (d, C-4), 46.9 (s,
C-7), 46.8 (s, C-8), 45.8 (d, C-3a), 38.3 (t, C-3), 32.2 (t,
C-6), 28.8 (t, C-5), 22.8:20.5:11.5 (3q, 3MBE-CH3).
Anal. Calcd for C33H38O3 · 0.5 H2O: C, 80.62; H,
8.00. Found: C, 80.51; H, 8.02.
(100:1 ! 10:1). 5.10 g (yield 98%) colourless oil,
20
Rf = 0.85 (PE/E 3:1), ½aꢂD ¼ ꢀ59.9 (c 0.96, CH2Cl2).
1H NMR (200 MHz, CDCl3, TMS): dH = 7.44–7.26
(m, 10H, aromatic), 4.83 (d, 1H, 2-H, J = 3.9 Hz),
4.74:4.41 (2d, 2H, Ph–CH–O, J = 7.7 Hz), 3.76/3.63
(2d, 2H, O–CH2–CO, JAB = 15.7 Hz), 2.55 (d, 1H, 7a-
H, J = 4.6 Hz), 1.97–0.57 [m, 26H, 17MBE-aliphatic,
therein 0.81:0.80:0.70 (3s, 9H, 3MBE-CH3), 1.34 (s,
9H, O–C(CH3)3)]. 13C NMR (50 MHz, CDCl3):
dC = 169.1 (s, CO), 139.7:139.6 (2s, Ph–C-1), 128.4–
127.8 (m, Ph–C), 100.9 (d, C-2), 90.0 (d, C-7a), 85.2/
78.4 (2d, Ph–CH–O), 67.3 (t, O–CH2–CO), 48.1 (d,
C-4), 47.0 (s, C-7), 46.9 (s, C-8), 45.8 (d, C-3a), 38.3 (t,
C-3), 32.2 (t, C-6), 28.8 (t, C-5), 28.0 (q, O–C(CH3)3),
22.8:20.5:11.5 (3q, 3MBE-CH3). Anal. Calcd for
C32H42O5: C, 75.86; H, 8.36. Found: C, 75.56; H, 8.58.
4.3.2. [2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-[2-(2-Methyl-
propoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimethyl-
4,7-methanobenzofuran, 4c. A solution of alcohol 3a
(1.019 mmol/0.40 g) in dry DMF (2 mL) was added
slowly to
a suspension of freshly washed NaH
(4.076 mmol/0.10 g) in dry DMF (1 mL) and the mix-
ture stirred for 1 h at room temperature. Then, a solu-
tion of i-BuOTs (4.076 mmol/0.94 g), which had been
prepared by reaction of i-butyl alcohol with p-tosyl chlo-
ride and pyridine using standard conditions,22 in DMF
(2 mL) was added slowly and stirring continued over-
night. Unreacted NaH was then carefully hydrolyzed
by adding portions of a mixture of water/THF (1:1)
until the reaction ceased. The resulting mixture was
diluted with brine and extracted three times with ether.
The combined ethereal extracts were washed three times
with brine, dried over Na2SO4, filtered and evaporated.
The crude product was purified by vacuum flash chro-
matography on silica gel, eluting with petroleum ether/
4.4.2. [2S-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-[2-[(Octahy-
dro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,
2-diphenylethoxy]propionic acid, 1,1-dimethylethyl ester,
9. A solution of ester 8 (5.613 mmol, 2.844 g) in dry
THF (30 mL) was slowly added to a solution of freshly
prepared LDA (8.420 mmol) in THF (30 mL), precooled
to ꢀ40 ꢂC. After stirring for 20 min at ꢀ15 ꢂC, CH3I
(28.065 mmol, 1.75 mL) was added and stirring contin-
ued for 20 min at ꢀ15 ꢂC. Finally, the mixture was
warmed to room temperature, poured into a saturated
NH4Cl solution and extracted three times with ether.
The combined ethereal extracts were washed with brine,
dried over Na2SO4, filtered and evaporated. The crude
product was purified by vacuum flash chromatography
on silica gel, eluting with petroleum ether/ether
(50:1 ! 20:1). 2.689 g (yield 92%) colourless oil with
ether (100:1 ! 10:1). 0.323 g (yield 78%) colourless oil,
20
Rf = 0.85 (PE/E 3:1), ½aꢂD ¼ ꢀ66.9 (c 0.98, CH2Cl2).
1H NMR (200 MHz, CDCl3, TMS): dH = 7.46–7.26
(m, 10H, aromatic), 4.86 (d, 1H, 2-H, J = 4.1 Hz),
4.65:4.16 (2d, 2H, Ph–CH–O, J = 8.3 Hz), 3.08:2.77
(2dd, 2H, O–CH2–CH(CH3)2, J1AB = 9.0 Hz, J2 =
6.4 Hz), 2.42 (d, 1H, 7a-H, J = 6.4 Hz), 1.95–0.62 [m,
24H, 17MBE-aliphatic, therein 0.82:0.82:0.72 (3s, 9H,
3MBE-CH3); 7 aliphatic, therein 0.68:0.66 (2d, 6H, O–
CH2–CH(CH3)2, J = 6.6 Hz)]. 13C NMR (50 MHz,
CDCl3): dC = 141.4:1140.5 (2s, Ph–C-1), 128.3–127.3
(m, Ph–C), 100.8 (d, C-2), 89.8 (d, C-7a), 85.3:78.6
(2d, Ph–CH–O), 76.0 (t, O–CH2–CH(CH3)2), 48.1 (d,
C-4), 46.9 (s, C-7), 46.9 (s, C-8), 45.9 (d, C-3a), 38.3 (t,
C-3), 32.2 (t, C-6), 28.9 (t, C-5), 28.4 (d, O–CH2–
CH(CH3)2), 22.8:20.5:11.5 (3q, 3MBE-CH3), 19.1:19.1
1
diastereomeric ratio ꢁ1.5:1, Rf = 0.79 (PE/E 4:1). H
NMR (200 MHz, CDCl3, TMS): dH = 7.42–7.23 (m,
10H, aromatic), 4.81 (m, 1H, 2-H), 4.70:4.43 (2d, 2H,
Ph–CH–O, J = 7.9 Hz), 4.63*/4.22* (2d, 2H, Ph–CH–
O, J = 8.2 Hz), 3.60 (q, 1H, O–CH(CH3)–CO,

C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
2641
J = 6.6 Hz),
3.47*
(q,
1H,
O–CH(CH3)–CO,
pared LDA (2.265 mmol) in THF (15 mL), precooled
to ꢀ40 ꢂC. After stirring for 60 min at ꢀ15 ꢂC the
bright yellow solution was cooled to ꢀ30 ꢂC and
2.14 M n-BuLi (0.793 mmol, 0.32 mL) slowly added.
The mixture was warmed to ꢀ20 ꢂC over a period of
20 min. Then BnBr (3.775 mmol, 0.45 mL) was added
and stirring continued for 30 min at ꢀ15 ꢂC. Finally,
the mixture was warmed to room temperature, poured
into a saturated NH4Cl solution and extracted three
times with ether. The combined ethereal extracts were
washed with brine, dried over Na2SO4, filtered and
evaporated. The crude product was purified by vacuum
flash chromatography on silica gel, eluting with petro-
leum ether/ether (50:1 ! 20:1). 0.278 g (yield 60%) col-
ourless oil with diastereomeric ratio ꢁ2:1, Rf = 0.81
(PE/E 4:1). 1H NMR (200 MHz, CDCl3, TMS):
dH = 7.32–7.01 (m, 15H, aromatic), 4.79* (d, 1H, 2-H,
J = 4.8 Hz), 4.70 (d, 1H, 2-H, J = 4.7 Hz), 4.79*:4.53*
(2d, 2H, Ph–CH–O, J = 6.4 Hz), 4.45:4.40 (2d, 2H,
Ph–CH–O, JAB = 7.6 Hz), 2.94–2.88* (m, 2H, Ph–
CH2), 2.79:2.72 (2d, 2H, Ph–CH2, JAB = 13.5 Hz), 2.42
(d, 1H, 7a-H, J = 6.9 Hz), 2.39* (d, 1H, 7a-H,
J = 8.1 Hz), 1.97–0.62 [m; 29H, 17MBE-aliphatic, there-
in 0.70:0.64:0.62 (3s; 9H, 3MBE-CH3), 1.19* (s, 9H,
O–C(CH3)3), 0.89 (s, 9H, O–C(CH3)3), 0.74 (s; 3H,
O–C(Bn)(CH3)–CO)]. 13C NMR (50 MHz, CDCl3):
dC = 171.9*:171.8 (s, CO), 142.1:142.0*:139.8*:139.6:
136.8*:136.6 (3s, Ph–C-1), 131.0–126.3 (m; Ph–C),
101.0*:100.9 (d, C-2), 90.1*:89.9 (d, C-7a), 81.4*:81.0
(s, O–C(Bn)(CH3)–CO), 80.9*:80.8 (s, O–C(CH3)3),
80.0*:79.3:79.3:78.8* (2d, Ph–CH–O), 48.2*:48.1 (d,
C-4), 47.1*:47.0 (s, C-7), 47.0*:46.9 (s, C-8), 46.0*:45.9
(d, C-3a), 45.9:44.6* (t, CH2–Ph), 38.4*:38.3 (t,
C-3), 32.3*:32.2 (t, C-6), 29.0*:28.9 (t, C-5), 27.7*:27.2
(q, O–C(CH3)3), 19.3:19.2* (q, O–C(Bn)(CH3)–CO),
22.8*: 22.7:20.5*:20.4:11.6*:11.5 (3q, 3MBE-CH3). Anal.
Calcd for C40H50O5 · 1.4 H2O: C, 75.53; H, 8.37.
J = 6.6 Hz), 2.49 (d, 1H, 7a-H, J = 6.6 Hz), 2.42* (d,
1H, 7a-H, J = 6.6 Hz), 1.92–0.58 [m; 29H, 17MBE-ali-
phatic, therein 0.80:0.78:0.68 (3s, 9H, 3MBE-CH3),
1.26 (s, 9H, O–C(CH3)3), 1.18* (s, 9H, O–C(CH3)3),
1.14 (d, 3H, O–CH(CH3)–CO, J = 6.8 Hz), 0.96* (d,
3H, O–CH(CH3)–CO, J = 6.8 Hz)]. 13C NMR (50
MHz, CDCl3): dC = 172.2*:171.8 (s, CO), 141.0*:
140.2*:139.9:139.9 (2s, Ph–C-1), 128.5–127.2 (m, Ph–
C), 100.9*:100.8 (d, C-2), 89.9*:89.8 (d, C-7a), 85.6*:
83.8:78.6:78.4* (2d, Ph–CH–O), 80.6*:80.5 (s, O–
C(CH3)3), 76.2*:72.7 (d, O–CH(CH3)–CO), 48.1 (d; C-
4), 47.0 (s; C-7), 46.9*:46.8 (s, C-8), 45.8 (d, C-3a),
38.3*:38.2 (t, C-3), 32.2*:32.1 (t, C-6), 28.8 (t, C-5),
27.8:27.6* (q, O–C(CH3)3), 22.8:20.5 (2q, 2MBE-CH3),
18.5:17.7* (q, O–CH(CH3)–CO), 11.5:11.4* (q, 1MBE-
CH3). Anal. calcd for C33H44O5: C, 76.12; H, 8.52.
*
Found: C, 75.83; H, 8.51. (Values marked with refer
to the minor diastereomer.)
4.4.3. [2S-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-[2-[(Octahy-
dro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,
2-diphenylethoxy]-2-methylpropionic acid, 1,1-dimethyl-
ethyl ester, 10a. A solution of ester 9 (6.068 mmol,
3.160 g) and LiCl (24.28 mmol, 1.029 g) in dry THF
(70 mL) was slowly added to a solution of freshly pre-
pared LDA (12.10 mmol) in THF (30 mL), precooled
to ꢀ40 ꢂC. After stirring for 30 min at ꢀ15 ꢂC, the
bright yellow solution was cooled to ꢀ60 ꢂC and
2.14 M n-BuLi (6.068 mmol, 2.84 mL) slowly added.
The mixture was warmed to ꢀ20 ꢂC over a period of
20 min. Then CH3I (30.34 mmol, 1.89 mL) was added
and stirring continued for 30 min at ꢀ15 ꢂC. Finally,
the mixture was warmed to room temperature, poured
into a saturated NH4Cl solution and extracted three
times with ether. The combined ethereal extracts were
washed with brine, dried over Na2SO4, filtered and
evaporated. The crude product was purified by vacuum
flash chromatography on silica gel, eluting with petro-
*
Found: C, 75.44; H, 8.95. (Values marked with refer
to the minor diastereomer.)
leum ether/ether (50:1 ! 20:1). 2.806 g (yield 86%) col-
20
ourless oil, Rf = 0.81 (PE/E 4:1), ½aꢂ ¼ ꢀ57.6 (c 1.66,
CH2Cl2). 1H NMR (200 MHz,D CDCl3, TMS):
dH = 7.37–7.22 (m, 10H, aromatic), 4.82 (d, 1H, 2-H,
J = 4.1 Hz), 4.63:4.43 (2d, 2H, Ph–CH–O, J = 7.5 Hz),
2.58 (d, 1H, 7a-H, J = 6.5 Hz), 2.00–0.64 [m, 32H,
17MBE-aliphatic, therein 0.82:0.80:0.70 (3s, 9H,
3MBE-CH3), 1.14 (s, 9H, O–C(CH3)3), 1.04:0.89 (2s,
6H, O–C(CH3)2–CO)]. 13C NMR (50 MHz, CDCl3):
dC = 172.7 (s, CO), 142.4:140.0 (2s, Ph–C-1), 128.5–
126.8 (m, Ph–C), 100.8 (d, C-2), 89.8 (d, C-7a), 80.3 (s,
O–C(CH3)2–CO), 79.1:78.9 (2d, Ph–CH–O), 77.9 (s,
O–C(CH3)3), 48.1 (d, C-4), 46.9 (s, C-7), 46.8 (s, C-8),
45.9 (d, C-3a), 38.3 (t, C-3), 32.2 (t, C-6), 28.9 (t, C-5),
27.4 (q, O–C(CH3)3), 25.6:23.1 (2q, O–C(CH3)2–CO),
22.8:20.5:11.5 (3q, 3MBE-CH3). Anal. Calcd for
C34H46O5: C, 76.37; H, 8.67. Found: C, 76.06; H, 8.90.
4.4.5. General procedure for the reduction of tert-
butylesters 10a and b. To an ice cooled solution of
LiAlH4 (1.286 mmol/48 mg) in dry ether (20 mL) was
added a solution of the appropriate ester (0.643 mmol)
10a or b in dry ether (10 mL) and the reaction mixture
stirred for 1 h at ambient temperature. Water (0.5 mL)
and 40% NaOH (0.1 mL) were added while cooling in
an ice bath and the mixture stirred at ambient tempera-
ture until a white solid had precipitated. A small portion
of Na2SO4 was added and the mixture filtered over a
pad of Hyflo. Finally, the solvent was evaporated and
the crude product was purified by vacuum flash chroma-
tography on silica gel treated with Et3N, eluting with
petroleum ether/ether (20:1 ! 5:1).
4.4.5.1. [2S-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-[2-[(Octa-
hydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-
1,2-diphenylethoxy]-2-methylpropan-1-ol, 11a. 0.281 g
4.4.4.
[2S-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-[2-[(Octah-
ydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-1,
2-diphenylethoxy]-2-benzylpropionic acid, 1,1-dimethyl-
ethyl ester, 10b. A solution of ester 9 (0.755 mmol,
0.393 g) and LiCl (3.02 mmol, 0.128 g) in dry THF
(40 mL) was slowly added to a solution of freshly pre-
(yield 94%) white solid, mp 44–46 ꢂC, Rf = 0.47 (PE/E
20
4:1), ½aꢂD ¼ ꢀ49.4 (c 2.28, CH2Cl2,). 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.24 (m, 10H, aro-
matic), 4.87 (d, 1H, 2-H, J = 4.6 Hz), 4.62:4.57 (2d,
2H, Ph–CH–O, JAB = 6.3 Hz), 3.41 (dd, 1H, CH2–OH,

2642
C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
J1 = 11.7 Hz, J2 = 5.4 Hz), 3.14 (dd, 1H, CH2–OH,
J1 = 11.7 Hz, J2 = 8.0 Hz), 2.98 (m, 1H, 7a-H), 2.62
(dd, 1H, OH, J1 = 8.0 Hz, J2 = 5.4 Hz), 2.14–0.64 [m,
23H, 17MBE-aliphatic, therein 0.87:0.75:0.72 (3s, 9H,
3MBE-CH3), 0.97:0.80 (2s, 6H, O–C(CH3)2–CH2–
OH)]. 13C NMR (50 MHz, CDCl3): dC = 142.9:138.5
(2s, Ph–C-1), 128.8–127.1 (m, Ph–C), 101.5 (d, C-2),
90.6 (d, C-7a), 79.9:76.8 (2d, Ph–CH–O), 76.9 (s, O–
C(CH3)2–CH2–OH), 68.3 (t, O–C(CH3)2–CH2–OH),
48.2 (d, C-4), 47.2 (s, C-7), 46.9 (s, C-8), 45.8 (d, C-
3a), 38.4 (t, C-3), 32.3 (t, C-6), 28.8 (t, C-5), 24.5:22.0
(2q, O–C(CH3)2–CH2–OH), 22.8:20.5:11.6 (3q, 3MBE-
CH3). Anal. Calcd for C30H40O4: C, 77.55; H, 8.86.
Found: C, 77.26; H, 8.84.
3H, CH2–O–CH3), 2.82 (s, 2H, CH2–O–CH3), 2.23 (d,
1H, 7a-H, J = 6.1 Hz), 1.92–0.55 [m, 23H, 17MBE-ali-
phatic, therein 0.73:0.72:0.68 (3s, 9H, 3MBE-CH3),
0.78:0.76 (2s, 6H, O–C(CH3)2–CH2)]. 13C NMR
(50 MHz, CDCl3): dC = 144.3:140.6 (2s, Ph–C-1),
128.5–126.5 (m, Ph–C), 100.6 (d, C-2), 89.5 (d, C-7a),
79.9:77.6 (2d, Ph–CH–O), 78.9 (s, O–C(CH3)2–CH2),
75.8 (q, CH2–O–CH3), 58.8 (t, CH2–O–CH3), 47.9 (d,
C-4), 47.5 (s, C-7), 46.7 (s, C-8), 45.7 (d, C-3a), 38.2 (t,
C-3), 32.0 (t, C-6), 28.7 (t, C-5), 23.4:23.3 (2q, O–
C(CH3)2–CH2), 22.6:20.3:11.3 (3q, 3MBE-CH3). Anal.
Calcd for C31H42O4: C, 77.79; H, 8.84. Found: C,
77.57; H, 8.98.
4.4.7.
4-Methylbenzene-1-sulfonic
acid,
[2S-
(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-[2-[(octahydro-7,8,8-tri-
methyl-4,7-methanobenzofuran-2-yl)oxy]-1,2-diphenyleth-
oxy]-2-methylpropyl ester, 13a. A solution of p-tosyl
chloride (0.462 mmol/0.088 g) in pyridine (2 mL) was
4.4.5.2. [2S-(2a(1R*,2S*),3aa,4b,7b,7aa)]-2-[2-[(Octa-
hydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)oxy]-
1,2-diphenylethoxy]-2-benzylpropan-1-ol, 11b. 0.350 g
(yield 73%) colourless oil with diastereomeric ratio
ꢁ2:1, Rf = 0.36 (PE/E 3:1). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.42–6.88 (m; 15H, aromatic),
4.97* (d, 1H, 2-H, J = 4.6 Hz), 4.83 (d, 1H, 2-H, J =
4.1 Hz), 4.81*:4.71* (2d, 2H, Ph–CH–O, J = 4.4 Hz),
4.63:4.61 (2d, 2H, Ph–CH–O, JAB = 4.8Hz), 3.74–0.57
[m, 26H, 18MBE-aliphatic, therein 0.80:0.72:0.62 (3s,
9H, 3MBE-CH3); OH; 7 aliphatic, therein 0.85 (s, 3H,
O–C-CH3)]. 13C NMR (50 MHz, CDCl3): dC =
143.2:141.8*:139.1:137.7*: 137.6:136.8* (3s, Ph–C-1),
131.1–126.0 (m, Ph–C), 102.0*:101.3 (d, C-2), 91.3*:
90.3 (d, C-7a), 80.4*:79.7: 77.0:76.6* (2d, Ph–CH–O),
79.6:79.3* (s, O–C(CH3)- (CH2Ph)–CH2–OH), 65.8:
64.4* (t, O–C(CH3)(CH2Ph)–CH2–OH), 48.3*:48.1 (d,
C-4), 47.5*:47.1 (s, C-7), 46.9 (s, C-8), 45.8 (d, C-3a),
43.7*:42.2 (t, O–C(CH3)- (CH2Ph)–CH2–OH), 38.5*:
38.3 (t, C-3), 32.4*:32.2 (t, C-6), 28.8 (t, C-5), 22.8*:
22.7:20.5*:20.4:11.6*:11.5 (3q, 3MBE-CH3), 19.9:19.4*
(O–C(CH3)(CH2Ph)–CH2–OH). Anal. Calcd for
C36H44O4: C, 79.96; H, 8.20. Found: C, 79.72; H, 8.35.
(Values marked with * refer to the minor diastereomer.)
added dropwise to
a
solution of alcohol 11a
(0.308 mmol/0.143 g) in pyridine (4 mL) while cooling
on an ice bath. After stirring for 4 days at room temper-
ature the mixture was taken up with a 10% aqueous
solution of KHSO4 and extracted three times with ether.
The combined ethereal extracts were washed twice with
KHSO4 solution and with brine, dried over Na2SO4, fil-
tered and evaporated. The crude product was purified
by vacuum flash chromatography on silica gel, eluting
with petroleum ether/ether (20:1 ! 5:1). 0.151 g (yield
79%) white solid, mp 121–123 ꢂC, Rf = 0.50 (PE/E
20
2:1), ½aꢂD ¼ ꢀ66.2 (c 0.84, CH2Cl2). 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.63:7.28 (2d, 4H, Ts-
aromatic, J = 8.3 Hz), 7.31–7.26 (m, 10H, aromatic),
4.77 (d, 1H, 2-H, J = 3.8 Hz), 4.41:4.27 (2d, 2H, Ph–
CH–O, J = 8.4 Hz), 3.44:3.36 (2d, 2H, CH2–OTs,
JAB = 9.4 Hz), 2.46 (s, 3H, Ph–CH3), 2.21 (d, 1H, 7a-
H, J = 6.4 Hz), 1.91–0.48 [m, 23H, 17MBE-aliphatic,
therein 0.73:0.67:0.63 (3s, 9H, 3MBE-CH3), 0.76 (2s,
6H, O–C(CH3)2–CH2–OTs)]. 13C NMR (50 MHz,
CDCl3): dC = 144.5 (s, Ts-C-1), 143.6:140.2 (2s, Ph–C-
1), 132.9 (s, Ts-C-4), 129.7–127.0 (m, Ph–C), 100.8 (d,
C-2), 89.7 (d, C-7a), 78.8:77.9 (2d, Ph–CH–O), 75.6 (t,
O–C(CH3)2–CH2–OTs), 48.1 (d, C-4), 46.9 (s, C-7),
46.9 (s, C-8), 45.8 (d, C-3a), 38.3 (t, C-3), 32.1 (t, C-6),
28.8 (t, C-5), 23.3:21.6 (2q, O–C(CH3)2–CH2–OTs),
22.4 (q, Ph–CH3), 22.8:20.5:11.4 (3q, 3MBE-CH3).
Anal. Calcd for C37H46O6S · 0.3 hexane: C, 72.29; H,
7.85; S, 4.97. Found: C, 71.99; H, 8.02; S, 4.77. 0.015 g
(yield 10%) of alcohol 11a were recovered.
4.4.6.
oxy-1,1-dimethylethoxy)-1,2-diphenyl-ethoxy]octahydro-
7,8,8-trimethyl-4,7-methanobenzofuran, 12a. solu-
[2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-[2-(2-Meth-
A
tion of alcohol 11a (0.777 mmol/0.361 g) and HMPA
(4.76 mmol/0.83 mL) in dry DMF (10 mL) was added
slowly to a suspension of 60% NaH (1.583 mmol/
0.063 g) in dry DMF (2 mL) and the mixture stirred
for 1 h at room temperature. Then, CH3I
(1.583 mmol/0.1 mL) was added and stirring continued
overnight. Unreacted NaH was carefully hydrolyzed
by adding portions of a mixture of water/THF (1:1)
until the reaction ceased. The resulting mixture was
diluted with brine and extracted three times with ether.
The combined ethereal extracts were washed with brine,
dried over Na2SO4, filtered and evaporated. The crude
product was purified by vacuum flash chromatography
on silica gel, eluting with petroleum ether/ether
4.4.8. Methanesulfonic acid, [2S-(2a(1R*,2S*),3aa,4b,7-
b,7aa)]-2-[2-[(octahydro-7,8,8-trimethyl-4,7-methanoben-
zofuran-2-yl)oxy]-1,2-diphenylethoxy]-2-methylpropyles-
ter, 13b. Methanesulfonyl chloride (1.661 mmol/
0.13 mL) was added dropwise to a solution of alcohol
11a (0.923 mmol/0.429 g) in dichloromethane (20 mL)
while cooling on an ice bath. After stirring for 3 h at
room temperature the mixture was extracted succes-
sively with a 10% aqueous KHSO4 solution, a saturated
aqueous NaHCO3 solution and brine, dried over
Na2SO4, filtered and evaporated. The crude product
was purified by vacuum flash chromatography on silica
gel, eluting with petroleum ether/ether (10:1 ! 5:1).
(20:1 ! 5:1). 0.314 g (yield 84%) colourless oil,
20
Rf = 0.72 (PE/E 3:1), ½aꢂD ¼ ꢀ77.4 (c 1.26, CH2Cl2).
1H NMR (200 MHz, CDCl3, TMS): dH = 7.46–7.22
(m, 10H, aromatic), 4.80 (d, 1H, 2-H, J = 3.9 Hz),
4.49:4.44 (2d, 2H, Ph–CH–O, JAB = 8.7 Hz), 3.04 (s,

C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
2643
0.492 g (yield 98%) colourless oil, Rf = 0.24 (PE/E 3:1),
(d, 1H, 2-H, J = 3.9 Hz), 4.56:4.52*:4.41:4.35* (2d, 2H,
Ph–CH–O, J = 8.2 Hz), 2.92–2.41 (m, 4H, CH2–I,
CH2–Ph), 2.28*:2.26 (d, 1H, 7a-H, J = 6.2 Hz), 1.95–
0.48 [m, 20H, 17MBE-aliphatic, therein 0.80:0.80:0.70
(3s, 9H, 3MBE-CH3), 0.80 (s, 3H, O–C(CH2Ph)-
(CH2I)–CH3)]. 13C NMR (50 MHz, CDCl3): dC =
143.7:143.5*:140.1:139.9*:137.2:137.1* (3s, Ph–C-1),
133.9–126.3 (m, Ph–C), 100.9 (d, C-2), 89.8 (d, C-7a),
79.1:79.0*:78.2*:78.1 (2d, Ph–CH–O), 77.1:76.7* (s, O–
C(CH2Ph)(CH2I)-CH3), 48.1 (d, C-4), 46.9 (s, C-7),
46.8 (s, C-8), 45.8 (d, C-3a), 45.6*:44.9 (t, CH2-I),
39.0*:38.3 (t, C-3), 32.1:31.9* (t, C-6), 29.5*:29.9 (t, C-
5), 22.3 (q, O–C(CH2Ph)(CH2I)–CH3), 22.9:20.1:11.5
(3q, 3MBE-CH3), 16.4:14.1* (2t, CH2–Ph). (Values
20
½aꢂD ¼ ꢀ68.9 (c 1.15, CH2Cl2). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.45–7.20 (m, 10H, aromatic),
4.79 (d, 1H, 2-H, J = 3.9 Hz), 4.49:4.37 (2d, 2H, Ph–
CH–O, J = 8.3 Hz), 3.66:3.59 (2d, 2H, O–C(CH3)2–
CH2–OMs, JAB = 9.6 Hz), 2.71 (s, 3H, O–SO2–CH3),
2.23 (d, 1H, 7a-H, J = 6.6 Hz), 1.93–0.45 [m, 23H,
17MBE-aliphatic, therein 0.77:0.76:0.68 (3s, 9H,
3MBE-CH3), 0.77:0.76 (2s, 6H, O–C(CH3)2–CH2–
OMs)]. 13C NMR (50 MHz, CDCl3): dC = 143.6:140.2
(2s, Ph–C-1), 128.6–127.1 (m, Ph–C), 100.8 (d, C-2),
89.8 (d, C-7a), 78.9:78.0 (2d, Ph–CH–O), 75.12 (t, O–
C(CH3)2–CH2–OMs), 74.7 (s, O–C(CH3)2–CH2–OMs),
48.0 (d, C-4), 46.9 (s, C-7), 46.8 (s, C-8), 45.8 (d, C-
3a), 38.3 (t, C-3), 36.6 (q, O–SO2–CH3), 32.1 (t, C-6),
28.8 (t, C-5), 22.9:22.6 (2q, O–C(CH3)2–CH2–OMs),
22.7:20.4:11.4 (3q, 3MBE-CH3). Anal. Calcd for
C31H42O6S · 1.1 H2O: C, 66.19; H, 7.92; S, 5.70. Found:
C, 66.44; H, 7.92; S, 5.53.
*
marked with refer to the minor diastereomer.)
4.4.10. General procedure for the reduction of sulfonates
13a,b. A 1 M solution of LiBEt3H in THF (10 equiv)
was added to a solution of sulfonate 13a and b
(1 equiv/ꢁ0.100 g) in dry THF (10 mL) and the resulting
mixture refluxed overnight. 5 mL of water, 5 mL of 2 M
NaOH and 5 mL of 35% H2O2 were added successively
while cooling on an ice bath and stirring continued at
ambient temperature until gas evolution had ceased. Fi-
nally, the mixture was diluted with brine and extracted
three times with ether. The combined ethereal extracts
were washed with an aqueous FeSO4 solution and with
brine, dried over Na2SO4, filtered and evaporated. The
crude product was purified by vacuum flash chromatog-
raphy on silica gel, eluting with petroleum ether/ether
(20:1 ! 5:1).
4.4.9. General procedure for the preparation of iodides
14a and b. Iodine (0.994 mmol/0.250 g) was added to a
solution of alcohols 11a and b (0.497 mmol), PPh3
(0.994 mmol/0.260 g) and imidazole (1.989 mmol/
0.140 g) in dry toluene (40 mL) and the resulting mixture
was refluxed overnight. After cooling to ambient tem-
perature, the residue was filtered off and the filtrate ex-
tracted successively twice with a 10% aqueous KHSO4
solution, once with a 10% aqueous Na2S2O3 solution
and then with brine, dried over Na2SO4, filtered and
evaporated. The crude product was purified by column
chromatography on silica gel, eluting with petroleum
ether/ether (100:1). Since iodides 14a and b turned out
to be rather unstable when being stored for more than
48 h at room temperature, they were reacted in the next
step almost immediately.
Starting with tosylate 13a, 21% of the desired tert-butyl
ether 12b, as well as 65% of alcohol 11a, were isolated.
Reduction of mesylate 13b yielded 19% of tert-butyl
ether 12b and 72% of alcohol 11a.
4.4.9.1.
Iodo-1,1-dimethylethoxy)-1,2-diphenyl-ethoxy]octahydro-
7,8,8-trimethyl-4,7-methanobenzofuran, 14a. 0.232 g
[2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-[2-(2-
4.4.11. General procedure for the reduction of iodides
14a,b.
A
1 M solution of LiBEt3H in THF
(7.64 mmol/7.6 mL) was added to a solution of iodide
14a (0.764 mmol/0.439 g) in dry THF (33 mL) and
HMPA (10 mL) and the resulting mixture refluxed for
16 h. After cooling to ambient temperature, 2 M NaOH
(30 mL) was added in portions and stirring continued
until the gas evolution had ceased. 35% of H2O2
(30 mL) was added and stirring continued again until
gas evolution had ceased. Finally, the mixture was
diluted with brine and extracted three times with ether.
The combined ethereal extracts were washed with an
aqueous FeSO4 solution and two times with brine, dried
over Na2SO4, filtered and evaporated. The crude prod-
uct was purified by vacuum flash chromatography on
silica gel, eluting with petroleum ether/ether (100:1).
(yield 81%) colourless oil, Rf = 0.67 (PE/E 10:1),
20
½aꢂD ¼ ꢀ54.6 (c 1.00, CH2Cl2). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.47–7.22 (m, 10H, aromatic),
4.81 (d, 1H, 2-H, J = 3.8 Hz), 4.53:4.32 (2d, 2H, Ph–
CH–O, J = 8.3 Hz), 2.92:2.85 (2d, 2H, O–C(CH3)2–
CH2–I, JAB = 10.0 Hz), 2.27 (d, 1H, 7a-H, J = 6.6 Hz),
2.00–0.47 [m, 23H, 17MBE-aliphatic, therein
0.78:0.78:0.69 (3s, 9H, 3MBE-CH3), 0.91:0.82 (2s, 6H,
O–C(CH3)2–CH2–I)]. 13C NMR (50 MHz, CDCl3):
dC = 143.7:140.3 (2s, Ph–C-1), 128.6:127.8:127.5:127.5:
127.4:127.0 (6d, Ph–C), 100.8 (d, C-2), 89.7 (d, C-7a),
78.9:78.3 (2d, Ph–CH–O), 74.7 (s, O–C(CH3)2–CH2–I),
48.1 (d, C-4), 46.9 (s, C-7), 46.8 (s, C-8), 45.8 (d, C-
3a), 38.3 (t, C-3), 32.1 (t, C-6), 28.8 (t, C-5), 25.8:24.7
(2q, O–C(CH3)2–CH2–I), 22.8:20.5:11.4 (3q, 3MBE-
CH3), 18.6 (t, O–C(CH3)2–CH2–I).
4.4.11.1. [2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-[2-(1,1-
Dimethylethoxy)-1,2-diphenylethoxy]octahydro-7,8,8-tri-
methyl-4,7-methanobenzofuran, 12b. 0.335 g (yield
98%) colourless oil, Rf = 0.84 (PE/E 4:1), Rf = 0.70
4.4.9.2. [2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-[2-(1-Ben-
zyl-2-iodo-1-methylethoxy)-1,2-diphenyl-ethoxy]octahy-
dro-7,8,8-trimethyl-4,7-methanobenzofuran, 14b. 0.302 g
(yield 93%) yellowish oil with diastereomeric ratio ꢁ2:1,
Rf = 0.65 (PE/E 10:1). 1H NMR (200 MHz, CDCl3,
TMS): dH = 7.43–7.17 (m; 15H, aromatic), 4.83:4.80*
20
1
(PE/E 10:1), ½aꢂD ¼ ꢀ80.5 (c 1.10, CH2Cl2). H NMR
(200 MHz, CDCl3, TMS): dH = 7.46–7.18 (m, 10H,
aromatic), 4.80 (d, 1H, 2-H, J = 4.1 Hz), 4.47:4.28
(2d, 2H, Ph–CH–O, J = 8.6 Hz), 2.22 (d, 1H, 7a-H,

2644
C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
J = 6.6 Hz), 1.92–0.67 [m, 26H, 17MBE-aliphatic,
therein 0.77:0.75:0.67 (3s 9H, 3MBE-CH3), 0.73 (s,
9H, O–C(CH3)3)]. 13C NMR (50 MHz, CDCl3): dC =
144.9:140.8 (2s, Ph–C-1), 128.6:127.8:127.3:127.2:
127.1:126.6 (6d, Ph–C), 100.7 (d, C-2), 89.6 (d, C-7a),
79.0:77.6 (2d, Ph–CH–O), 74.1 (s, O–C(CH3)3), 48.1
(d, C-4), 46.8 (s, C-7), 46.8 (s, C-8), 45.9 (d, C-3a),
38.3 (t, C-3), 32.1 (t, C-6), 29.0 (t, C-5), 28.1 (q, O–
C(CH3)3), 22.8:20.5:11.4 (3q, 3MBE-CH3). Anal. Calcd
for C30H40O3 · 0.1 H2O: C, 79.99; H, 9.00. Found: C,
80.02; H, 9.19.
(t, O–CH2–Ph). Anal. Calcd for C21H20O2: C, 82.86;
H, 6.62. Found: C, 82.86; H, 6.89.
4.5.1.2. (1R,2S)-2-(2-Methylpropoxy)-1,2-diphenyleth-
anol, 5c. 0.22 g (yield 77% over two steps from 3a)
white solid, mp 57–60 ꢂC, Rf = 0.51 (PE/E 3:1),
20
½aꢂD ¼ þ43.7 (c 0.90, CH2Cl2). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.33–7.14 (m, 10H, aromatic),
4.86 (dd, 1H, Ph–CH–O, J1 = 5.6 Hz, J2 = 4.1 Hz),
4.41 (d, 1H, Ph–CH–O, J = 5.6 Hz), 3.17:3.02 (2dd,
2H, O–CH2–CH(CH3)2, J1AB = 9.0 Hz, J2 = 6.7 Hz),
2.54 (d, 1H, OH, J = 4.1 Hz), 1.84 (m, 1H, O–CH2–
CH(CH3)2), 0.85:0.84 (2d, 6H, O–CH2–CH(CH3)2,
J = 6.7 Hz). 13C NMR (50 MHz, CDCl3): dC =
140.4:138.1 (2s, Ph–C-1), 127.9:127.8:127.7:127.6:
127.3:127.1 (6d, Ph–C), 86.0:77.1 (2d, Ph–CH–O), 76.0
(t, O–CH2–CH(CH3)2), 28.5 (d, O–CH2-CH(CH3)2),
19.3:19.2 (2q, O–CH2–CH(CH3)2). Anal. Calcd for
C18H22O2: C, 79.96; H, 8.20. Found: C, 79.37; H, 8.48.
4.4.11.2. [2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-[2-(1,1-
Dimethyl-2-phenylethoxy)-1,2-diphenyl-ethoxy]octahydro-
7,8,8-trimethyl-4,7-methanobenzofuran,
12c. 0.240 g
(yield 90%) colourless oil, Rf = 0.69 (PE/E 10:1),
20
½aꢂD ¼ ꢀ65.8 (c 1.00, CH2Cl2). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.44–7.12 (m, 15H, aromatic),
4.85 (d, 1H, 2-H, J = 3.7 Hz), 4.52:4.38 (2d, 2H, Ph–
CH–O, J = 8.3 Hz), 2.56:2.47 (2d, 2H, O–C(CH3)2–
CH2–Ph, JAB = 18.6 Hz), 2.24 (d, 1H, 7a-H,
J = 6.6 Hz), 1.97–0.87 (m, 14H, MBE-aliphatic), 0.82
(s, 6H, O–C(CH3)2–CH2–Ph), 0.73 (s, 6H, 2MBE-
CH3), 0.56 (s, 3H, 1MBE-CH3). 13C NMR (50 MHz,
CDCl3): dC = 144.8:140.6:138.4 (3s, Ph–C-1), 130.9–
125.8 (m, Ph–C), 100.9 (d, C-2), 89.7 (d, C-7a),
79.2:77.5 (2d, Ph–CH–O), 76.5 (s, O–C(CH3)2–CH2–
Ph), 49.2 (t, O–C(CH3)2–CH2–Ph), 48.1 (d, C-4), 46.9
(s, C-8), 45.9 (d, C-3a), 38.3 (t, C-3), 32.1 (t, C-6), 28.9
(t, C-5), 25.9:24.2 (2q, O–C(CH3)2–CH2–Ph),
22.8:20.5:11.5 (3q, 3MBE-CH3). Anal. Calcd for
C36H44O3 · 0.1 H2O: C, 82.12; H, 8.46. Found: C,
82.26; H, 8.60.
4.5.1.3. (1R,2S)-2-(2-Methoxy-1,1-dimethylethoxy)-
1,2-diphenylethanol, 5d. 0.171 g (yield 91%) colourless
20
oil, Rf = 0.18 (PE/E 4:1), ½aꢂD ¼ þ123.2 (c 0.56, CH2Cl2).
1H NMR (200 MHz, CDCl3, TMS): dH = 7.19–7.04 (m,
10H, aromatic), 4.86:4.68 (2d, 2H, Ph–CH–O, J =
4.6 Hz), 3.82 (s, 1H, OH), 3.34 (s, 3H, O–CH3),
3.42:3.09 (2d, 2H, CH2–O–CH3, J = 9.8 Hz), 1.15:0.94
(2s, 6H, O–C(CH3)2–CH2–OH). 13C NMR (50 MHz,
CDCl3): dC = 141.1:140.1 (2s, Ph–C-1), 127.5–126.9
(m, Ph–C), 78.0 (t, CH2–O), 78.0 (s, O–C(CH3)2),
77.9:75.8 (2d, Ph–CH–O), 58.9 (q, O–CH3), 25.0:23.0
(2q, O–C(CH3)2). Anal. Calcd for C19H24O3 · 0.2 H2O:
C, 75.07; H, 8.09. Found: C, 75.06; H, 8.13.
4.5. Deprotection of auxiliary precursors 4a,c, 12a–c
4.5.1.4. (1R,2S)-2-(1,1-Dimethylethoxy)-1,2-diphenyl-
ethanol, 5e. 0.152 g (yield 84%) white solid, mp 73–
4.5.1. General procedure. Ethers 4a,c, 12a–c (1 equiv)
and a catalytic amount of p-TsOH were dissolved in a
10-fold amount of a mixture of methanol/dichlorometh-
ane (1:1) and stirred overnight at room temperature.
After TLC analysis had shown total conversion, a satu-
rated aqueous NaHCO3 solution was added and stirring
continued for 10 min. The organic solvents were evapo-
rated and the aqueous remains diluted with water and
extracted three times with ether. The combined ether
extracts were washed with brine, dried over Na2SO4, fil-
tered and evaporated. The crude product was purified
by vacuum flash chromatography on silica gel, eluting
with petroleum ether/ether (20:1 ! 1:1). Methyl acetal
was recovered as an additional product fraction for
recyclation of Noeꢀs chiral protecting group.3
20
75 ꢂC, Rf = 0.43 (PE/E 3:1), ½aꢂD ¼ þ55.8 (c 0.64,
CH2Cl2). 1H NMR (200 MHz, CDCl3, TMS):
dH = 7.32–7.10 (m, 10H, aromatic), 4.70 (dd, 1H, Ph–
CH–O, J1 = 6.0 Hz, J2 = 3.7 Hz), 4.54 (d, 1H, Ph–
CH–O, J = 6.0 Hz), 2.36 (d, 1H, OH, J = 3.7 Hz), 0.99
(s, 9H, O–C(CH3)3). 13C NMR (50 MHz, CDCl3):
dC = 141.5:140.9 (2s, Ph–C-1), 127.7:127.5:127.5:127.3:
127.3:127.2 (6d, Ph–C), 78.3:78.0 (2d, Ph–CH–O), 74.9
(s, O–C(CH3)3), 28.4 (q, O–C(CH3)3). Anal. Calcd for
C18H22O2 · 0.1 H2O: C, 79.43; H, 8.22. Found: C,
79.67; H, 8.23.
4.5.1.5. (1R,2S)-2-(1,1-Dimethyl-2-phenylethoxy)-1,2-
diphenylethanol, 5f. 0.125 g (yield 82%) colourless oil,
20
1
Rf = 0.39 (PE/E 3:1), ½aꢂD ¼ þ1.4 (c 1.00, CH2Cl2). H
NMR (200 MHz, CDCl3, TMS): dH = 7.37–7.13
(m, 15H, aromatic), 4.71 (dd, 1H, Ph–CH–O, J1 =
5.8 Hz, J2 = 3.4 Hz), 4.63 (d, 1H, Ph–CH–O, J =
5.8 Hz), 2.77:2.69 (2d, 2H, O–C(CH3)2–CH2–Ph,
J = 13.2 Hz), 2.39 (d, 1H, OH, J = 3.4 Hz), 0.96:0.89
(2s, 6H, O–C(CH3)2–CH2–Ph). 13C NMR (50 MHz,
CDCl3): dC = 141.3:140.6:138.1 (3s, Ph–C-1), 130.8–
126.1 (m, Ph–C), 78.2:77.9 (2d, Ph–CH–O), 77.1 (s,
O–C(CH3)2–CH2–Ph), 49.2 (t, O–C(CH3)2–CH2–Ph),
26.1:24.7 (2q, O–C(CH3)2–CH2–Ph). Anal. Calcd for
4.5.1.1.
(1R,2S)-2-Benzyloxy-1,2-diphenylethanol,
5a. 3.43 g (yield 88% over two steps from 3a) white
20
solid, mp 77–79 ꢂC, Rf = 0.30 (PE/E 3:1), ½aꢂD ¼ þ31.1
1
(c 1.00, CH2Cl2). H NMR (200 MHz, CDCl3, TMS):
dH = 7.38–7.07 (m, 15H, aromatic), 4.91 (dd, 1H, Ph–
CH–O, J1 = 4.0 Hz, J2 = 4.0 Hz), 4.51:4.24 (2d, 2H,
O–CH2–Ph, J = 12.0 Hz), 4.49 (d, 1H, Ph–CH–O,
J = 4.0 Hz), 2.32 (d, 1H, OH, J = 4.0 Hz). 13C NMR
(50 MHz, CDCl3): dC = 140.4:137.9:137.6 (3s, Ph–C-1),
128.3–127.1 (m, Ph–C), 85.0:77.0 (2d, Ph–CH–O), 70.6

C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
2645
C24H26O2 · 0.05 H2O: C, 82.98; H, 7.57. Found: C,
83.01; H, 7.73.
4.6.1.4. Oxophenylacetic acid, (1R,2S)-2-(1,1-dimethy-
lethoxy)-1,2-diphenylethyl ester, 6e. 0.206 g (yield 99%)
white solid, mp 53–55 ꢂC, Rf = 0.53 (PE/E 3:1),
20
4.6. Preparation of benzoylformic acid esters 6a, c–f
½aꢂD ¼ þ14.1 (c 0.71, CH2Cl2). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.58–7.14 (m, 15H, aromatic),
5.98:4.66 (2d, 2H, Ph–CH–O, J = 6.9 Hz), 0.85 (s,
9H, O–C(CH3)3). 13C NMR (50 MHz, CDCl3):
dC = 186.2 (s, CO), 162.8 (s, O–CO), 141.3:136.8:132.2
(3s, Ph–C-1), 134.6:130.0:128.7:128.2:127.9:127.9:127.8:
127.7:127.5 (9d, Ph–C), 80.2:76.3 (2d, Ph–CH–O), 75.1
(s, O–C(CH3)3), 28.2 (q, O–C(CH3)3). Anal. Calcd for
C26H26O4 · 0.3 H2O: C, 76.56; H, 6.57. Found: C,
76.47; H, 6.52.
4.6.1. General procedure. DIC (1.1 equiv) was added
dropwise to a solution of auxiliary 5a, c–f (1.0 equiv),
benzoylformic acid (1.1 equiv) and DMAP (0.2 equiv)
in dry dichloromethane while cooling on an ice bath.
The mixture was stirred for 1–20 h at room temperature
until TLC control indicated total conversion. Then the
white precipitate was filtered off and the filtrate diluted
with dichloromethane and washed successively with a
saturated aqueous NaHCO3 solution, 5% KHSO4 solu-
tion and then brine. The organic layer was dried over
Na2SO4, filtered and evaporated. The crude product
was purified by vacuum flash chromatography on silica
gel, eluting with petroleum ether/ether (20:1 ! 5:1).
4.6.1.5. Oxophenylacetic acid, (1R,2S)-2-(1,1-
dimethyl-2-phenylethoxy)-1,2-diphenylethyl ester, 6f.
0.159 g (yield 75%) white solid, mp 85–88 ꢂC,
20
1
Rf = 0.47 (PE/E 3:1), ½aꢂ ¼ þ9.8 (c 1.00, CH2Cl2). H
NMR (200 MHz, CDCDl3, TMS): dH = 7.64–7.05 (m,
15H, aromatic), 6.01:4.77 (2d, 2H, Ph–CH–O,
J = 6.9 Hz), 2.60 (s, 2H, O–C(CH3)2–CH2–Ph), 0.77 (s,
6H, O–C(CH3)2–CH2–Ph). 13C NMR (50 MHz,
CDCl3): dC = 186.1 (s, CO), 162.7 (s, O–CO),
141.3:138.0:136.7:132.2 (4s, Ph–C-1), 134.6–126.0 (m,
Ph–C), 80.2:76.2 (2d, Ph–CH–O), 77.3 (s, O–C(CH3)2–
CH2–Ph), 49.1 (t, O–C(CH3)2–CH2–Ph), 25.9:24.6 (2q,
O–C(CH3)2–CH2–Ph). Anal. Calcd for C32H30O4 · 0.3
H2O: C, 79.41; H, 6.37. Found: C, 79.40; H, 6.51.
4.6.1.1. Oxophenylacetic acid, (1R,2S)-2-benzyloxy-
1,2-diphenylethyl ester, 6a. 0.217 g (yield 79%) white
solid, mp 130–134 ꢂC, Rf = 0.41 (PE/E 3:1),
20
½aꢂD ¼ þ28.9 (c 1.04, CH2Cl2). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.62–7.02 (m, 20H, aromatic),
6.30:4.68 (2d, 2H, Ph–CH–O, J = 7.0 Hz), 4.50:
4.24 (2d, 2H, O–CH2–Ph, JAB = 12.0 Hz). 13C NMR
(50 MHz, CDCl3): dC = 186.0 (s, CO), 162.7 (s, O–
CO), 137.6:137.3:136.3:134.7 (4s, Ph–C-1), 132.2:129.9:
128.7:128.5:128.4:128.4:128.3:128.2:128.1:127.9:127.5:
126.1 (12d, Ph–C), 82.4:79.1 (2d, Ph–CH–O), 70.7 (t, O–
CH2–Ph). Anal. Calcd for C29H24O4: C, 79.80; H, 5.54.
Found: C, 79.60; H, 5.84.
4.7. Selectivity tests
4.7.1. General procedure for the reduction of keto esters
6a, c–f. A solution of ester 6a, c–f (1 equiv/ꢁ100 mg)
in dry THF (10 mL) and (optionally) ZnCl2 was stirred
for 10 min at ꢀ78 ꢂC. A 1 M solution of L-selectrideꢀ in
THF (1.1 equiv) 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% aqueous solution
of KHSO4 and warmed to ambient temperature. The
mixture was diluted with water and extracted three times
with ether. The combined ethereal extracts were washed
with brine, dried over Na2SO4, filtered and evaporated.
The crude product was purified by vacuum flash chro-
matography on silica gel, eluting with petroleum ether/
ether (5:1 ! 1:5).
4.6.1.2. Oxophenylacetic acid, (1R,2S)-2-(2-methyl-
propoxy)-1,2-diphenylethyl ester, 6c. 0.726 g (yield
98%) white solid, mp 70–73 ꢂC, Rf = 0.62 (PE/E 3:1),
20
½aꢂD ¼ þ26.0 (c 1.05, CH2Cl2,). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.68–7.32 (m, 15H, aromatic),
6.27:4.61 (2d, 2H, Ph–CH–O, J = 6.8 Hz), 3.16:3.00
(2dd, 2H, O–CH2–CH(CH3)2, J1 = 8.8 Hz, J2 = 6.5),
1.88–1.68 (m, 1H, O–CH2–CH(CH3)2), 0.79:0.78 (2d,
6H, O–CH2–CH(CH3)2, J = 6.7 Hz). 13C NMR
(50 MHz, CDCl3): dC = 186.1 (s, CO), 162.7 (s, O–
CO), 137.9:136.4:134.6 (3s, Ph–C-1), 132.1–127.7 (m,
Ph–C), 83.7:79.2 (2d, Ph–CH–O), 76.1 (t, O–CH2–
CH(CH3)2), 28.4 (d, O–CH2–CH(CH3)2), 19.1:19.0 (2q,
O–CH2–CH(CH3)2). Anal. Calcd for C26H26O4 · 0.3
H2O: C, 76.56; H, 6.57. Found: C, 76.96; H, 6.56.
The diastereoisomeric ratios were determined by inte-
1
gration of appropriate signals of the H NMR spectra
4.6.1.3. Oxophenylacetic acid, [1R,2S]-2-(2-methoxy-
1,1-dimethylethoxy)-1,2-diphenylethyl ester, 6d. 0.187 g
of the crude reaction mixtures as well as after saponifi-
cation with LiOH by measuring the optical rotation of
the resulting mandelic acids13 and finally by HPLC-
analysis of their L-valine methyl ester derivatives.14 In
the data, NMR values are given only for the main (S)-
diastereoisomers; yields are given for the mixtures of
diastereoisomers.
(yield 81%) white solid, mp 58–61 ꢂC, Rf = 0.56 (PE/E
20
4:1), ½aꢂD ¼ þ12.9 (c 1.06, CH2Cl2). 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.67–7.22 (m, 15H, aro-
matic), 6.10:4.98 (2d, 2H, Ph–CH–O, J = 6.8 Hz), 3.08
(s, 3H, O–CH3), 3.03:2.97 (2d, 2H, O–C(CH3)2–CH2–
O, JAB = 9.7 Hz), 0.95:0.91 (2s, 6H, O–C(CH3)2–CH2–
O). 13C NMR (50 MHz, CDCl3): dC = 186.2 (s, CO),
162.8 (s, O–CO), 140.9:136.8:134.6 (3s, Ph–C-1),
132.2–127.5 (m, Ph–C), 80.1:76.7 (2d, Ph–CH–O), 80.0
(t, CH2–O), 76.6 (s, O–C(CH3)2), 58.9 (q, O–CH3),
23.7:23.6 (2q, O–C(CH3)2). Anal. Calcd for C27H28O5:
C, 74.98; H, 6.53. Found: C, 74.83; H, 6.48.
4.7.1.1. (S)-Hydroxyphenylacetic acid, (1R,2S)-2-ben-
zyloxy-1,2-diphenylethyl ester, 7a. (Yield 88%) white
solid, Rf = 0.20 (PE/E 3:1). 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.37–6.79 (m, 20H, aromatic),
5.95:4.54 (2d, 2H, Ph–CH–O, J = 6.2 Hz), 5.05 (s, 1H,
Ph–CH(OH)–CO), 4.50:4.21 (2d, 2H, O–CH2–Ph,

2646
C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
JAB = 12.3 Hz). 13C NMR (50 MHz, CDCl3):
dC = 172.1 (s, CO), 137.8:137.2:136.8:136.4 (4s, Ph–C-
1), 128.5–126.8 (m, Ph–C), 82.4:79.5 (2d, Ph–CH–O),
72.9 (d, Ph–CH(OH)–CO), 70.6 (t, O–CH2–Ph). Anal.
Calcd for C29H26O4: C, 79.43; H, 5.98. Found: C,
79.14; H, 6.26.
C(CH3)2–CH2–Ph), 72.9 (d, Ph–CH(OH)–CO), 49.1 (t,
O–C(CH3)2–CH2–Ph), 25.8:24.5 (2q, O–C(CH3)2–
CH2–Ph).
4.8. Saponification of (S)-mandelic acid esters 7a, c–f
4.8.1. General procedure. A solution of ester 7a, c–f
(50–100 mg) and LiOH (3.0 equiv) in THF/methanol/
water (5:4:1) (10 mL) was stirred for 3 h at ambient tem-
perature. The mixture was diluted with a saturated
aqueous NaHCO3 solution and the organic solvents
were evaporated carefully (bath temperature max.
40 ꢂC). The aqueous remaining was extracted three
times with ether. For recovery of the auxiliaries 5a, c–f
the combined ethereal extracts were washed with brine,
dried over Na2SO4, filtered, evaporated and the residue
purified by vacuum flash chromatography (if necessary).
Thereby all auxiliaries 5a, c–f could be recovered almost
quantitatively without any loss of enantiomeric purity.
The combined aqueous phases were carefully acidified
with HCl conc. while cooling on an ice bath and
extracted three times with ethyl acetate. The combined
organic extracts were washed with brine, dried over
Na2SO4, filtered and evaporated, to yield the free man-
delic acids.
4.7.1.2. (S)-Hydroxyphenylacetic acid, (1R,2S)-2-(2-
methylpropoxy)-1,2-diphenylethyl ester, 7c. (Yield
73%) yellowish oil, Rf = 0.27 (PE/E 3:1). 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.37–6.80 (m, 15H, aro-
matic), 5.88:4.43 (2d, 2H, Ph–CH–O, J = 5.8 Hz), 5.08
(s, 1H, Ph–CH(OH)–CO), 3.13:2.94 (2dd, 2H, O–CH2–
CH(CH3)2, J1 = 8.8 Hz, J2 = 6.3 Hz), 1.86–1.66 (m,
1H, O–CH2–CH(CH3)2), 0.90:0.79 (2d, 6H, O–CH2–
CH(CH3)2, J = 6.7 Hz). 13C NMR (50 MHz, CDCl3):
dC = 172.1 (s, CO), 137.8:137.3:136.4 (3s, Ph–C-1),
128.4–126.7 (m, Ph–C), 83.4:79.6 (2d, Ph–CH–O), 76.1
(t, O–CH2–CH(CH3)2), 73.0 (d, Ph–CH(OH)–CO),
28.4 (d, O–CH2-CH(CH3)2), 19.1 (q, O–CH2–
CH(CH3)2). Anal. Calcd for C26H28O4: C, 77.20; H,
6.98. Found: C, 77.00; H, 7.24.
4.7.1.3. (S)-Hydroxyphenylacetic acid, (1R,2S)-2-(2-
methoxy-1,1-dimethylethoxy)-1,2-diphenylethyl ester, 7d.
(Yield 80%) white solid, Rf = 0.15 (PE/E 3:1). 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.25–6.71 (m, 15H, aro-
matic), 5.60:4.70 (2d, 2H, Ph–CH–O, J = 6.4 Hz), 4.92
(s, 1H, Ph–CH(OH)–CO), 3.30 (s, 1H, OH), 3.14–2.65
[m, 5H, C(CH3)2–CH2–O–CH3, O–CH3, therein 2.97
(s, 3H, O–CH3)], 0.82:0.77 (2s, 6H, C(CH3)2–CH2).
13C NMR (50 MHz, CDCl3): dC = 172.1 (s, CO),
141.0:138.0:137.0 (3s, Ph–C-1), 128.4–126.8 (m, Ph–C),
80.5:76.6 (2d, Ph–CH–O), 80.0 (t, CH2–O), 76.5 (s, O–
C(CH3)2), 73.0 (d, Ph–CH(OH)–CO), 58.9 (q, O–
CH3), 23.6 (q, O–C(CH3)2).
20
(Yield 90–98%) white solid. All ½aꢂD values were (+)
assigning the absolute configurations to be [S].13 1H
NMR (200 MHz, d6-acetone, TMS): dH = 7.40–7.16
(m, 5H, aromatic), 5.08 (s, 1H, Ph–CH(OH)–COOH),
4.71 (s, 1H, OH).
References
1. For a recent review on polymer supported chiral auxilia-
ries see: Chung, C. W. Y.; Toy, P. H. Tetrahedron:
Asymmetry 2004, 15, 387–399.
4.7.1.4. (S)-Hydroxyphenylacetic acid, (1R,2S)-2-(1,1-
dimethylethoxy)-1,2-diphenylethyl ester, 7e. (Yield 87–
88%) white solid, Rf = 0.40 (PE/E 2:1), 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.26–6.71 (m, 15H,
aromatic), 5.58:4.49 (2d, 2H, Ph–CH–O, J = 6.1 Hz),
4.91 (d, 1H, Ph–CH(OH)–CO, J = 5.0 Hz), 3.23
(d, 1H, OH, J = 5.0 Hz), 0.80 (s, 9H, O–C(CH3)3).
13C NMR (50 MHz, CDCl3): dC = 172.2 (s, O–CO),
141.5:138.0:137.0 (3s, Ph–C-1), 128.4–126.8 (m, Ph–C),
80.6:76.3 (2d, Ph–CH–O), 74.8 (s, O–C(CH3)3), 72.9
(d, Ph–CH(OH)–CO), 28.1 (q, O–C(CH3)3). Anal. Calcd
for C26H28O4 · 0.4 H2O: C, 75.85; H, 7.05. Found: C,
75.90; H, 7.26.
2. Gaertner, P.; Schuster, C.; Knollmueller, M. Lett. Org.
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4.7.1.5. (S)-Hydroxyphenylacetic acid, (1R,2S)-2-(1,1-
dimethyl-2-phenylethoxy)-1,2-diphenylethyl ester, 7f.
(Yield 92%) white solid, Rf = 0.10 (PE/E 3:1). 1H
NMR (200 MHz, CDCl3, TMS): dH = 7.24–6.60 (m,
20H, aromatic), 5.57:4.55 (2d, 1H, Ph–CH–O,
J = 6.4 Hz), 4.91 (s, 1H, Ph–CH(OH)–CO), 3.27 (s,
1H, OH), 2.55:2.48 (2d, 2H, O–C(CH3)2–CH2–Ph,
J = 13.5 Hz), 0.70:0.68 (2s, 6H, O–C(CH3)2–CH2–Ph).
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141.2:137.9:137.9:136.6 (4s, Ph–C-1), 130.9:128.4–126.0
(m, Ph–C), 80.5:76.1 (2d, Ph–CH–O), 77.0 (s, O–
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C. Schuster et al. / Tetrahedron: Asymmetry 16 (2005) 2631–2647
2647
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