Chiral linker. Part 2: Synthesis and evaluation of a novel, reusable solid-supported open chain chiral auxiliary derived from m-hydrobenzoin for the diastereoselective reduction of α-keto esters

Article abstract of DOI:10.1016/j.tetasy.2005.08.030

Three novel m-hydrobenzoin derived chiral hydrobenzoin mono-alkyl ethers were synthesized and evaluated as open chain chiral auxiliaries in the L-selectride^R/ZnCl₂ mediated stereoselective reduction of their corresponding phenyl glyoxylates, resulting in des of up to 91%. The optimized auxiliary structure was immobilized on commercially available Wang-resin by using the ether substituent as a sublinking unit and applied as a reusable solid-supported chiral auxiliary in the same type of reaction with only little loss of stereofacial selectivity.

Full text of DOI:10.1016/j.tetasy.2005.08.030

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3211–3223
Chiral linker. Part 2: Synthesis and evaluation of a novel,
reusable solid-supported open chain chiral auxiliary derived from
m-hydrobenzoin for the diastereoselective reduction of a-keto esters
Christian Schuster, Max Knollmueller and Peter Gaertner*
Department of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria
Received 26 July 2005;accepted 17 August 2005
Abstract—Three novel m-hydrobenzoin derived chiral hydrobenzoin mono-alkyl ethers were synthesized and evaluated as open
chain chiral auxiliaries in the L-selectrideR/ZnCl2 mediated stereoselective reduction of their corresponding phenyl glyoxylates,
resulting in des of up to 91%. The optimized auxiliary structure was immobilized on commercially available Wang-resin by using
the ether substituent as a sublinking unit and applied as a reusable solid-supported chiral auxiliary in the same type of reaction with
only little loss of stereofacial selectivity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we have found that replacing the benzyl ether
moiety of auxiliaries I and II by sterically demanding t-
alkyl ethers effected a substantial improvement in the
stereoinducing ability of m-hydrobenzoin derived auxil-
iaries III in the L-selectrideR mediated reduction of phe-
nyl glyoxylates up to 84% de5 (Table 1, entries 1 and 2).
These results were considerably superior to those previ-
ously reported with (R,R)-hydrobenzoin derived benzyl
ether auxiliaries in this type of reaction.6
Stereoselective solid phase synthesis methods employ-
ing solid-supported chiral reagents or catalysts have
become a commonly used tool for combinatorial and
parallel synthesis, and in recent years also a number
of supported chiral auxiliaries have been developed,1
mainly serine and tyrosine derived Evans oxazolidi-
nones.2 Such immobilized auxiliaries offer some advan-
tages over their application in liquid phase, including
an easy workup, simple separation, recovery and, thus,
the possibility to recycle the expensive chiral material
by simple filtration after cleavage of desired reaction
products.
Herein, we report the synthesis and evaluation of a fur-
ther modified m-hydrobenzoin derived chiral auxiliary
for the stereoselective reduction of a-keto carboxylic
acid esters and its immobilization and application on a
solid support.
We have previously reported the synthesis and applica-
tion of novel, m-hydrobenzoin derived chiral auxiliaries
I and II, which are very similar to benzyl alcohol type
linkers commonly used in solid phase organic synthesis
(Scheme 1). These new auxiliaries were easily accessible
by desymmetrization of m-hydrobenzoin 1 with Noeꢀs
commercially available chiral anhydro lactol protecting
groups3 and subsequent derivatization,4 and induced
moderate diastereoselectivities of up to 36% de in the
a-alkylation of carboxylic acid esters in solution phase
as well as on a solid support.4
2. Results and discussion
2.1. Auxiliary evaluation using appropriate test systems
in solution
In our preliminary studies, we had intended to modify the
t-butyl moiety of auxiliary III 6a (Table 1, entries 1 and 2)
such that it might serve as a sublinking unit between the
auxiliary core and a polymer support by linking them to-
gether via a stable ether bond. However, disappointingly,
it had turned out that introduction of the second oxygen
in the t-alkyl moiety of III 6b decreased the diastereo-
selectivity significantly (Table 1, entries 3 and 4). This
*
Corresponding author. Tel.: +43 15880155421;fax: +43
15880115492;e-mail: peter.gaertner@tuwien.ac.at
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.030

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C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
HO
HO
HO
R
O
O
O
I
II
III
... Solid support
R ... H, Ph, OMe
Scheme 1.
Table 1. Diastereoisomeric ratio of 8a–e from reduction of a-keto esters 7a–ea
O
OH
O
S
i
HO
R
O
R
ii
R
O
O
O
R
S
O
O
8a-e
6a-e
7a-e
Entry
Ester
R
Additive
Ratioc (S,R,S)/(S,R,R)
Yield 8a–ed (%)
1
2
7ab
7ab
t-Bu
—
92:8b
92:8b
87
88
2 equiv ZnCl2
3
4
7bb
7bb
—
86:14b
88:12b
80
80
O
O
2 equiv ZnCl2
5
6
7c
7c
—
88.5:11.5
95.5:4.5
80
99
2 equiv ZnCl2
O
7
8
7d
7d
—
75:25
95.5:4.5
85
86
2 equiv ZnCl2
9
10
7e
7e
—
90.5:9.5
89.5:10.5
80
80
N
2 equiv ZnCl2
a Reagents and conditions: (i) PhCOCOOH, DIC, DMAP, CH2Cl2;(ii) L-selectride R, ꢀ78 ꢁC, THF.
b Data from Ref. 5.
c Diastereoisomeric ratios determined by 1H NMR integration on crude reaction mixtures 8 and HPLC analysis of L-valine methyl ester derivatives
13 of cleaved mandelic acids 9;absolute configuration of major diastereoisomers approved by optical rotation of 9.
d Isolated yields by vacuum flash chromatography.
prompted us to assume that the oxygen having an addi-
tional—presumably coordinative—and therefore coun-
terproductive influence on the preferred conformation
of the open chain auxiliary.5 Thus, as the t-butyl moiety
had proved to be a residue only feasibly capable of steri-
cal interactions, which had led to an optimum diastereo-
selectivity, one might have assumed that a sterically less
demanding residue mainly capable for coordinating
interactions might have also effected an optimization.
Consequently, we decided to skip the two methyl groups
and try out other ethylene glycol ether type sublinkers.
with good overall yields using standard reaction condi-
tions (Scheme 2). Phenyl glyoxylates 7c–e, which were
prepared by DIC/DMAP mediated esterification under
mild conditions, were finally reduced to mandelates 8c–
e according to the procedure described by Rosini et al.6
(Table 1). The stereochemical outcomes of these reduc-
tions were analyzed by 1H NMR integration on the mix-
tures of product diastereomers as well as after ester
saponification by determination of the specific rotation
of cleaved mandelic acids 97 and by further derivatiza-
tion with L-valine methyl ester and HPLC-analysis of
resulting 138 as described in our previous work.5
Therefore, desymmetrized hydrobenzoin 23,5 was con-
verted to alkoxyacetic acid ester 35 and amine 4e, respec-
tively, which were further transformed to auxiliaries 6c–e
Thus, diastereoselectivities of 50–81% de were achieved
employing auxiliaries 7c–e (Table 1, entries 5, 7 and 9),

C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
3213
O
iii, iv
O
HO
OH
O
O
O
ii
O
4c
6c
O
O
O
O
v
O
iii, iv
O
HO
OH
O
3
O
O
i
4d
6d
O
O
vi
iv
O
HO
O
N
N
OH
O
O
2
6e
4e
Scheme 2. Reagents and conditions: (i) NaH, BrCH2COO–t-Bu, HMPA, THF;(ii) LiAlH 4, THF;(iii) NaH, MeI, DMF;(iv) p-TsOH, MeOH;(v)
PhMgBr, THF;(vi) NaH, ClCH 2CH2N(CH3)2, DMF.
which had no further improvement compared to our pre-
vious results.5 However, when ZnCl2 was used as an
additive, diastereomeric excesses could be raised substan-
tially up to 91% de with both ꢁmethoxyꢀ auxiliaries 7c and
7d (Table 1, entries 6 and 8). This was in accordance with
our previous observation, that addition of the Lewis acid
ZnCl2 had improved the stereofacial selectivity of our
hydrobenzoin derived chiral auxiliary 7b, if an additional
Lewis basic O-atom had been present in the ether residue
(Table 1, entries 3 and 4). Therefore, we had suggested,
that in this particular case the predominant auxiliary
conformation had been stabilized by an additional coor-
dination of the Lewis acidic Zn2+ to the O-atom of the
ether residue, which thereby had shielded away the
si-face of the keto carbonyl from the hydride attack5
(Scheme 3). Further experiments with superhydrideR as
reducing agent in the reduction of ester 7c gave consistent
results, whereas des were slightly decreased with this ste-
rically less demanding reducing agent (Table 2, entries 3
and 4). By now, we still do not have neither theoretical
nor experimental evidence to verify if our model is cor-
rect, but the complete loss of any stereoinduction in the
reduction of ester 7c (Table 2, entry 5) on addition of
strongly coordinating HMPA as a co-solvent at least
could support the suggestion of a coordination depen-
dent explanation for the remarkable improvements with
auxiliaries 7c and 7d on addition of ZnCl2.
Furthermore, it is noteworthy, that our model could
also be applied to predict correctly the stereochemical
outcome of the analogous reduction of a b-keto acid
attached to auxiliary 6c (Scheme 3; Table 2, entry 6),
although the diastereoisomeric excess was fairly moder-
ate in this experiment, which might have been due to less
favoured chelation as a matter of inappropriate molecu-
lar dimensions. The low yield of 11 was a result of b-
keto estersꢀ general tendency to easily enolize in the pres-
ence of any basic reagent and was consistent with known
examples.9
H-
H-
re-attack
H
H
si-attack
O
O
H
H
O
2.2. Auxiliary immobilization and application on solid
support
O
O
O
O
O
O
O
Zn
Zn
We finally chose auxiliary 6c for the attachment onto a
solid support, with regard to the above results and the
expected ease of its immobilization. The latter was
Scheme 3. Proposed model for the observed ZnCl2 enhanced diastereo-
selection with auxiliary 7c.

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C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
Table 2. Diastereoisomeric ratio of 8c and11 from reduction of a-keto esters 7c and 10a
O
OH
ii
O
7c
O
O
O
O
O
O
O
O
i
HO
O
8c
O
iii
ii
6c
O
O
O
O
O
O
O
OH
O
11
10
Entry
Ester
Red.
Additive
Ratiob (S,R,S)/(S,R,R)
Yield 8c, 11c (%)
1
2
3
4
5
6
7c
7c
7c
7c
7c
10
L-Sel.
L-Sel.
LiBEt3H
LiBEt3H
L-Sel.
—
88.5:11.5
95.5:4.5
87.5:12.5
90:10
50:50
23:77
80
99
85
93
90
33
2 equiv ZnCl2
—
2 equiv ZnCl2
2 equiv HMPA
2 equiv ZnCl2
L-Sel.
a Reagents and conditions: (i) PhCOCOOH, DIC, DMAP, CH2Cl2;(ii) L-selectride R, ꢀ78 ꢁC, THF;(iii) PhCOCH 2COOEt, DMAP, toluene, reflux.
b Diastereoisomeric ratios determined by 1H NMR integration on crude reaction mixtures 8c and 11 and HPLC analysis of L-valine methyl ester
derivatives 13 of cleaved mandelic acids 9;absolute configuration of major diastereoisomers approved by specific rotation of cleaved hydroxy acids
9 and 12.
c Isolated yields by vacuum flash chromatography.
accomplished by attaching auxiliary precursor 4c, which
had easily been synthesized from desymmetrized hydro-
benzoin 25 in two steps with almost quantitative yield on
a gram scale, onto a polymer support via a stable ether
bond, thus using the ethylene glycol ether residue as a
sublinking unit. Therefore an excess of alcohol 4c was
deprotonated with NaH and reacted with chloromethy-
lated polystyrene/divinylbenzene type Wang-resin10
employing analogous reaction conditions as for the
methylation of 4c. Commercially available Wang-resin
(200–400 mesh, novabiochem) with an approx.
0.6 mmol/g loading was found to be best for a maximum
auxiliary immobilization of up to 80%, whereas higher
loaded resins of 1.0–1.5 mmol/g turned out to result in
incomplete auxiliary attachment of only 30–60%. Nei-
ther employment of higher precursor excesses nor varia-
tion of solvent with regard to resin swelling abilities nor
variation of base nor rerun of the auxiliary binding step
could effect any further auxiliary binding, so that the
auxiliary precursor was suggested to be sterically too
demanding to achieve quantitative reaction especially
with higher loaded resins. Kawana,11 Worster12 and
Enders13 have already reported the problem of incomplete
transformation of all resinꢀs active sites when attaching a
chiral auxiliary onto a solid support, and especially in
Worsterꢀs case dramatically decreased stereoselectivities
had resulted. Therefore, Worster had deactivated any
remaining active chloromethyl groups by a simple iodin-
ation/reduction protocol prior to substrate binding. As
we had calculated only an 80% yield in the optimized
auxiliary attachment step by gravimetric analysis and
had further detected the presence of unreacted chloro-
methyl groups on our functionalized resin 5f colorimet-
rically,14 we also decided to inactivate those groups by a
subsequent methoxylation 5f0 or reduction step12 5f00,
respectively.
Release of Noeꢀs chiral protecting group by acid cata-
lyzed methanolysis then yielded resin bound hydrobenz-
oin auxiliaries 6f–f00, which were to be tested in the
reduction of their phenyl glyoxylates 7f–f00 according
to the analogous experiments in solution (Scheme 4).
Therefore, auxiliaries 6f–f00 were esterified with benzoyl-
formic acid as described above, and the resulting poly-
mer bound phenyl glyoxylates 7f–f00 were reduced
according to our pre-optimized L-selectrideR/ZnCl2
protocol. All reactions on solid support were monitored
qualitatively by FT-IR spectroscopy, employing KBr
disks, as well as yields were estimated gravimetrically
(Scheme 5).
As to date, we do not have an on-bead methodology15
for the direct determination of diastereoisomeric ratios
of the resulting polymer bound a-hydroxy esters 8f–f00,
this was accomplished only after saponification of 8f–
f00 with LiOH in methanol/THF/water (5/4/1) at room
temperature and recovery of the (S)-mandelic acids 9,7
which were then transformed to their L-valine methyl
ester derivatives 13 and analyzed by HPLC.8 This meth-

C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
3215
O
O
O
O
Cl
O
vii
iv
i, ii, iii
HO
HO
O
O
OH
O
OH
5f
O
v
6f-f''
1
4c
O
5f'
Cl
... Wang resin
vi
5f''
Scheme 4. Reagents and conditions: (i) Noeꢀs exo-anhydro lactol, p-TsOH, CH2Cl2;(ii) NaH, BrCH 2COO–t-Bu, HMPA, THF;(iii) LiAlH 4, THF;
(iv) NaH, NaI, Wang-Cl, DMF;(v) NaOMe, NaI, DMF;(vi) NaI, acetone;Bu 3SnH, THF;(vii) PPh 3ÆHBr, MeOH, CH2Cl2.
Scheme 5. Monitoring of selectivity test reactions on solid phase by FT-IR spectroscopy.
odology had resulted in diastereoisomeric ratios consis-
tent with those obtained from the previous H NMR
in the stereoselective reduction of phenyl glyoxylate
on a solid support with only little loss of stereofacial
selectivity compared to the analogous system in
solution.
1
spectroscopic analyses in all preceding solution phase
experiments and had therefore proved the ester saponi-
fications to be racemization free, and has thus given us
a reliable tool for enantiomeric analysis in our solid
phase experiments.
Despite the fact that simple and efficient recyclability is
the main goal for attaching chiral auxiliaries onto a solid
support, this feature is still left undescribed for many of
the so far published polymer bound chiral auxiliaries.1
Therefore, we next decided to have a closer look at
auxiliary recycling. As we had been able to recover
auxiliaries almost quantitatively without any loss of
enantiomeric purity by ester saponification in our
previous solution phase experiments, we analogously
Diastereoselectivities of 80–86% de were obtained with
solid-supported chiral auxiliaries 6f–f00, depending on
whether unreacted chloromethyl groups had been
deactivated after the auxiliary attachment or not. This
indicated, that our open chain chiral hydrobenzoin
auxiliary was also suitable for a practicable application

3216
C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
Table 3. Auxiliary application and recycling on solid supporta
O
OH
O
i
O
HO
O
O
O
O
O
O
6f-f''
7f-f''
iii
ii
OH
OH
O
OH
9
O
O
O
O
iv
... Wang resin
OH
O
8f-f''
H
N
O
O
13
Entry
Ester
Run
Ratiob (S,R,S)/(S,R,R)
Yield 9c
1
2
3
4
5
6
7
7f0
7f00
7f
7f00
7f00
7f00
7f00
1
1
1
2
3
4
5
90:10
92:8
93:7
91:9
93:7
94:6
90:10
73
75
69
98
76
52
77
a Reagents and conditions: (i) PhCOCOOH, DIC, DMAP, CH2Cl2;(ii) L-selectride R, ꢀ78 ꢁC, THF;(iii) LiOH, THF/MeOH/H 2O;(iv) L-valine
methyl ester, DIC, HOBt, CH2Cl2.
b Diastereoisomeric ratios determined by HPLC analysis of L-valine methyl ester derivatives 13 of cleaved mandelic acids 9.
c Yields based on gravimetrically estimated amount of ketoacid bound in the esterification step.
recovered polymer bound auxiliary 6f00 by simple filtra-
tion and subsequent washing and drying steps and intro-
duced the resin in the next esterification/reduction/
saponification cycle immediately. Thus, auxiliary 6f00
could be reused at least three times without any loss of
stereofacial selectivity (Table 3, entries 4–7).
capable of coordinating interactions with the keto
acid to be reduced. By promoting these interactions
through addition of the Lewis acid, ZnCl2 diastereose-
lectivities could satisfactorily be raised up to 91% de
with methoxyethyl ether auxiliaries 6c and 6d, which
was a remarkable improvement compared to the results
with our previously investigated hydrobenzoin t-butyl
ethers 6a and 6b.5 We were further able to immobilize
our novel chiral auxiliary on commercially available
Wang-resin by a simple modification of the ether
substituent, so that it could serve as a sublinking unit
between the auxiliary core and the polymer support.
Thus, by applying the same ꢁZnCl2 trickꢀ we were
able to induce almost equal stereoselectivities of 86%
de with polymer bound, 6f00, which could further be
reused three times without any loss of its stereoinducing
ability.
3. Conclusion
Based on the suggestion of Rosini et al., that an open
chain chiral auxiliary derived from hydrobenzoin can
be satisfactorily used in the diastereoselective reduction
of a-keto esters,6 we have synthesized and evaluated a
new class of m-hydrobenzoin derived chiral auxiliaries
6. These were optimized by introducing an ether substi-
tuent bearing an additional heteroatom, which was

C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
3217
Thus, we have developed a simple, easily accessible and
reusable polymer bound open chain chiral auxiliary,
which seems to be a viable tool for stereoselective solid
phase organic synthesis, especially when bearing in mind
that by desymmetrization of m-hydrobenzoin with
both of Noeꢀs chiral anhydro lactols3 both possible
enantiomers of polymer bound 6f00 can easily be
synthesized.
recorded on a Bruker AC 200 in CDCl3 at 200 and
50 MHz, respectively, using TMS or the solvent peak
as the reference. IR spectra were recorded on a BioRad
FTS 135 FT-IR-spectrometer, using KBr disks. HPLC
diastereoisomeric analysis of L-valine methyl ester deriv-
atives 138 of mandelic acids 9 was carried out with a
SHIMADZU LC-10AD (SHIMADZU SPD-10AV
UV/VIS detector;Nucleosil 120 S C18;H 2O/MeOH
60/40). Elemental analysis was carried out at Vienna
University, Department of Physicochemistry—Labora-
tory for Microanalysis, Wa¨hringer Str. 42, A-1090
Vienna.
Further investigations are underway to evaluate applica-
tions of our novel, polymer bound chiral auxiliary 6f00,
especially in reactions involving Lewis acidic reagents
and additives, which can be supposed to result in chela-
tion mediated enhancements of stereoselectivities as
described above. We are also encouraged to undertake
additional investigations on further auxiliary improve-
ments, on the one hand by trying out other polymer sup-
ports with regard to minimize differences between the
solution phase and solid phase auxiliary, and on the
other hand, for example, by introducing substituents
in the hydrobenzoin aryls, which by changing steric
and electronic properties of the auxiliary could probably
increase stereoselectivities as well.
4.2. Preparation of auxiliary precursors
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-
phenylethoxy]acetic acid, 1,1-dimethylethyl ester, 3.
A
solution of alcohol 2 (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,
t-butyl ester (15.32 mmol/2.3 mL) were added succes-
sively and the mixture was refluxed overnight. After
cooling to ambient temperature unreacted NaH was
carefully hydrolized by adding portions of a mixture
of water/THF (1/1) until the reaction ceased. The result-
ing 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. Remainings of HMPA and bromoacetic
acid, t-butyl ester were evaporated in high vacuo over-
night. The crude product was purified by vacuum flash
chromatography on silica gel, eluting with petroleum
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 ꢁC
fraction), ethyl acetate (EE) and dichloromethane were
distilled prior to use. Dry toluene, ether and tetrahydro-
furan were predried over KOH and distilled from Na/
benzophenone. Dry dichloromethane was distilled from
P2O5. Dry petroleum ether and dimethylformamide
ether/ether (100/1!10/1). A colourless oil (5.10 g, yield
20
98%), Rf = 0.85 (PE/E 3/1), ½aŠ ¼ ꢀ59:9 (c 0.96,
D
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.
R
˚
were dried and stored over mole sieve 4 A. L-Selectride
and superhydrideR 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 sta-
ted. NaI and ZnCl2 were dried by heating to 150–300 ꢁC
in high vacuo for 30 min prior to use. Hydroxymethyl-
ated Wang-resin (200–400 mesh;0.64 mmol/g) was pur-
chased from novabiochem and was thoroughly washed
successively with DMF, methanol, dichloromethane,
methanol, and dried overnight in high vacuo prior to
use. All moisture sensitive reactions were carried out
under a nitrogen atmosphere. Reactions on solid phase
were shaken on a laboratory shaker unless otherwise
stated. For TLC-analysis, precoated aluminium-backed
plates (silica gel 60 F254, Merck) were used. Compounds
were visualized by spraying with 5% phosphomolybdic
acid hydrate in ethanol and heating. Vacuum flash chro-
matography was carried out with silica gel Merck 60. All
fractions of products containing Noeꢀs acetal protecting
group together with a free hydroxy group were concen-
trated immediately after chromatography 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
4.2.2.
[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]ethanol, 4c. To an ice cooled solu-
tion of LiAlH4 (13.4 mmol/0.500 g) in dry ether
(40 mL), a solution of ester (6.7 mmol/3.395 g) 3 in
dry ether (100 mL) was added, and the reaction mixture
was stirred for 1 h at ambient temperature. Water
(5 mL) and 40% NaOH (3 mL) were added while cool-
ing on an ice bath and the mixture was stirred at ambi-
ent temperature until a white solid had precipitated. A
small portion of Na2SO4 was added and the mixture
was filtered over a pad of hyflo. Finally the solvent

3218
C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
was evaporated and the crude product was purified by
vacuum flash chromatography on silica gel pretreated
with NEt3, eluting with petroleum ether/ether (20/
The combined ether 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 (20/
1!5/1).
A colourless oil (2.920 g, yield 99.6%),
20
Rf = 0.45 (PE/E 1/1), ½aŠ ¼ ꢀ73:1 (c 1.08, CH2Cl2).
1!5/1).
A
colourless oil (2.574 g, yield 86%),
D
20
1H NMR (200 MHz, CDCl3, TMS): dH = 7.35–7.19
(m, 10H, aromatic), 4.78 (d, 1H, 2-H, J = 4.3 Hz),
4.59/4.20 (2d, 2H, Ph–CH–O, J = 7.9 Hz), 3.47–3.02
(m, 4H, O–CH2–CH2–OH), 2.46 (d, 1H, 7a-H, J =
6.7 Hz), 1.93–0.42 [m, 17H, 17MBE-aliphatic, therein
0.74/0.72/0.63 (3s, 9H, 3MBE–CH3)]. 13C NMR
(50 MHz, CDCl3): dC = 140.3/139.9 (2s, Ph–C-1),
128.1–127.7 (m, Ph–C), 101.1 (d, C-2), 90.2 (d, C-7a),
85.4/78.8 (2d, Ph–CH–O), 70.6/61.5 (2t, O–CH2–CH2–
OH), 48.1 (d, C-4), 47.0 (s, C-7), 46.9 (s, C-8), 45.8 (d,
C-3a), 38.4 (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
C28H36O4 · 0.7H2O: C, 74.87;H, 8.39. Found: C,
74.79;H, 8.49.
Rf = 0.54 (PE/E 1/1), ½aŠ ¼ ꢀ67:8 (c 0.90, CH2Cl2).
D
1H NMR (200 MHz, CDCl3, TMS): dH = 7.43–7.22
(m, 10H, aromatic), 4.81 (d, 1H, 2-H, J = 4.1 Hz),
4.64/4.25 (2d, 2H, Ph–CH–O, J = 8.2 Hz), 3.50–3.17
(m, 4H, O–CH2–CH2–O), 3.13 (s, 3H, O–CH3), 2.43
(d, 1H, 7a-H, J = 6.4 Hz), 1.98–0.48 [m, 17H, 17MBE-
aliphatic, therein 0.79/0.79/0.69 (3s, 9H, 3MBE–CH3)].
13C NMR (50 MHz, CDCl3): dC = 140.8/140.3
(2s, Ph–C-1), 128.3/128.2/127.7/127.6/127.4/127.3 (6d,
Ph–C), 100.8 (d, C-2), 89.9 (d, C-7a), 85.7/78.3 (2d,
Ph–CH–O), 71.7/68.7 (2t, O–CH2–CH2–O), 58.7 (q,
O–CH3), 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), 22.8/20.5/11.4 (3q, 3MBE–CH3). Anal. Calcd
for C29H38O4: C, 77.30;H, 8.50. Found: C, 77.10;H,
8.68.
4.2.3.
[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]-1,1-diphenylethanol, 4d. A freshly
prepared 0.7 M solution of PhMgBr (18.0 mmol/
25.7 mL) in THF was added to a solution of ester 3
(4.5 mmol/2.281 g) in dry THF (80 mL) and the result-
ing mixture was refluxed for 24 h. After cooling to ambi-
ent temperature, the mixture was poured into a
saturated solution of NH4Cl (200 mL) and extracted
four times with ether. The combined ethereal extracts
were washed with brine, dried over Na2SO4, filtered
and evaporated. The crude product was purified by vac-
uum flash chromatography on silica gel, eluting with
petroleum ether/ether (50/1!10/1). A white solid
4.2.5. [2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-[2-(2-Meth-
oxy-2,2-diphenylethoxy)-1,2-diphenylethoxy]octahydro-
7,8,8-trimethyl-4,7-methanobenzofuran, 5d. Alcohol 4d
was methylated analogously. Ten equivalents of 18-
crown-6 was added to the reaction mixture for yield
optimization. A white solid (yield 91%), mp 52–54 ꢁC,
20
Rf = 0.75 (PE/E 3/1), ½aŠ ¼ ꢀ42:6 (c 1.23, CH2Cl2).
D
1H NMR (200 MHz, CDCl3, TMS): dH = 7.29–7.03
(m, 20H, aromatic), 4.79 (d, 1H, 2-H, J = 4.1 Hz),
4.53/4.22 (2d, 2H, Ph–CH–O, J = 8.1 Hz), 3.78 (s, 2H,
O–CH2–C(Ph)2–O), 2.92 (s, 3H, O–CH3), 2.34 (d, 1H,
7a-H, J = 6.4 Hz), 1.97–0.38 [m, 17H, 17MBE-aliphatic,
therein 0.78/0.77/0.69 (3s, 9H, 3MBE–CH3)]. 13C NMR
(50 MHz, CDCl3): dC = 143.4/143.3/140.0/140.0 (4s,
Ph–C-1), 128.4–126.7 (m, Ph–C), 100.9 (d, C-2), 89.8
(d, C-7a), 86.0/78.7 (2d, Ph–CH–O), 82.2 (s, O–CH2–
C(Ph)2–O), 72.9 (t, O–CH2–C(Ph)2–O), 51.5 (q, O–
CH3), 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),
22.6/20.4/11.5 (3q, 3MBE–CH3). Anal. Calcd for
C41H46O4: C, 81.69;H, 7.69. Found: C, 81.53;H, 7.89.
(1.97 g, yield 74%), mp 63–65 ꢁC, Rf = 0.62 (PE/E 3/1),
20
½aŠ ¼ ꢀ77:2 (c 1.00, CH2Cl2). 1H NMR (200 MHz,
D
CDCl3, TMS): dH = 7.38–7.16 (m, 20H, aromatic),
4.83 (d, 1H, 2-H, J = 4.2 Hz), 4.62/4.37 (2d, 2H, Ph–
CH–O, J = 7.6 Hz), 4.12/3.45 (2d, 2H, O–CH2–
C(Ph)2–OH, J = 10.0 Hz), 3.22 (s, 1H, OH), 2.54 (d,
1H, 7a-H, J = 6.5 Hz), 2.02–0.56 [m, 17H, 17MBE-
aliphatic, therein 0.81/0.79/0.71 (3s, 9H, 3MBE–CH3)].
13C NMR (50 MHz, CDCl3): dC = 144.8/144.0/139.9/
139.4 (4s, Ph–C-1), 128.2–126.1 (m, Ph–C), 101.1 (d,
C-2), 90.1 (d, C-7a), 86.5/78.8 (2d, Ph–CH–O), 77.9 (s,
O–CH2–C(Ph)2–OH), 76.1 (t, O–CH2–C(Ph)2–OH),
48.1 (d, C-4), 47.0 (s, C-7), 46.8 (s, C-8), 45.7 (d, C-
3a), 38.3 (t, C-3), 32.2 (t, C-6), 28.8 (t, C-5), 22.8/20.4/
11.5 (3q, 3MBE–CH3). Anal. Calcd for C40H44O4 ·
0.3H2O: C, 80.86;H, 7.57. Found: C, 80.96;H, 7.77.
4.2.6. [2S-(2a(1R*,2S*),3aa,4b,7b,7aa)]-Dimethyl-N-[(2-
(octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)-
oxy-1,2-diphenylethoxy)ethyl]amine, 4e. A solution of
alcohol 2 (2.548 mmol/1.006 g) in dry DMF (20 mL)
was added slowly to
a
suspension of NaH
(5.095 mmol/0.122 g) in dry DMF (3 mL) and the mix-
ture was stirred for 1 h at room temperature. Then a
solution of (2-chloroethyl)-dimethylamine (3.932
mmol/0.423 g) and a catalytic amount of NaI in DMF
(4 mL) was added and stirring was continued for 2 h
at room temperature. Unreacted NaH was carefully
hydrolized then 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 ether 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/
ethyl acetate (20/1!EE). A colourless oil (0.376 g, yield
4.2.4. [2S-(2a(1S*,2R*),3aa,4b,7b,7aa)]-2-[2-(2-Meth-
oxyethoxy)-1,2-diphenylethoxy]octahydro-7,8,8-trimeth-
yl-4,7-methanobenzofuran, 5c. A solution of alcohol 4c
(6.642 mmol/2.900 g) in dry DMF (40 mL) was added
slowly to a suspension of 60% NaH (13.284 mmol/
0.319 g) in dry DMF (5 mL) and the mixture was stirred
for 1 h at room temperature. Then CH3I (13.284 mmol/
0.84 mL) was added and stirring was continued over-
night. Unreacted NaH was carefully hydrolized then
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.

C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
3219
32%), Rf = 0.63 (CHCl3/MeOH 9/1 + 2 drops NH3(aq)),
4.3.2. (1R,2S)-2-(2-Dimethylaminoethoxy)-1,2-diphenyl-
ethanol, 6e. Aminoether 4e (0.727 mmol/0.337 g) and
p-TsOH (1.454 mmol/0.250 g) were dissolved in a mix-
ture of methanol/dichloromethane (1/1) (20 mL) and
stirred for 2 h at room temperature. After TLC analysis
had shown total conversion, an equal amount of a satu-
rated aqueous NaHCO3 solution was added and stirring
was continued for 10 min. The organic solvents were
evaporated and the aqueous remainings were extracted
three times with ether. The combined ethereal extracts
were extracted three times with 2 N HCl. The combined
acidic aqueous extracts were washed with ether and all
combined ethereal extracts were dried over Na2SO4, fil-
tered and evaporated to yield Noeꢀs chiral protecting
group as methyl acetal for recycling.3 The acidic aque-
ous phase was carefully made basic by addition of a sat-
urated aqueous NaHCO3 solution and extracted three
times with ether. The combined ethereal extracts were
dried over Na2SO4, filtered and evaporated. A white
20
½aŠ ¼ ꢀ82:5 (c 0.79, CH2Cl2). 1H NMR (200 MHz,
D
CDCl3, TMS): dH = 7.33–7.19 (m, 10H, aromatic),
4.73 (d, 1H, 2-H, J = 4.0 Hz), 4.56/4.14 (2d, 2H, Ph–
CH–O, J = 8.2 Hz), 3.31/3.06 (2td, 2H, O–CH2–CH2–
N(CH3)2, J1 = 10.0 Hz, J2 = 5.7 Hz), 2.36 (d, 1H, 7a-
H, J = 6.7 Hz), 2.20 (dt, 2H, O–CH2–CH2–N(CH3)2,
J1 = 5.7 Hz, J2 = 1.3 Hz), 1.96 (s, 6H, N(CH3)2), 1.85–
0.45 [m, 17H, 17MBE-aliphatic, therein 0.71/0.71/0.61
(3s, 9H, 3MBE–CH3)]. 13C NMR (50 MHz, CDCl3):
dC = 140.9/140.2 (2s, Ph–C-1), 128.4/128.2/127.7/
127.6/127.4/127.3 (6d, Ph–C), 100.8 (d, C-2), 89.9 (d,
C-7a), 85.7/78.4 (2d, Ph–CH–O), 68.0/58.6 (2t, O–
CH2–CH2–N), 48.1 (d, C-4), 46.9 (s, C-7), 46.8 (s, C-
8), 45.8 (d, C-3a), 45.7 (q, N(CH3)2), 38.3 (t, C-3),
32.2 (t, C-6), 28.8 (t, C-5), 22.8/20.5/11.4 (3q, 3MBE–
CH3). Anal. Calcd for C30H41NO3 · 0.3H2O: C,
76.82;H, 8.94;N, 2.99. Found: C, 76.77;H, 9.05;N,
2.66.
solid (0.184 g, yield 89%), mp 48–50 ꢁC, Rf = 0.50
20
4.3. Deprotection of auxiliary precursors 4e, 5c,d
(CHCl3/MeOH 9/1 + 2 drops NH3(aq)), ½aŠ ¼ 134:7
D
1
(c 0.49, CH2Cl2). H NMR (200 MHz, CDCl3, TMS):
dH = 7.19–6.92 (m, 10H, aromatic), 4.82/4.59 (2d, 2H,
Ph–CH–O, J = 3.9 Hz), 3.64 (ddd, 1H, O–CH2–CH2–
N(CH3)2, J1 = 11.6 Hz, J2 = 7.3 Hz, J3 = 4.3 Hz), 3.36
(ddd, 1H, O–CH2–CH2–N(CH3)2, J1 = 11.6 Hz, J2 =
5.9 Hz, J3 = 4.4 Hz), 2.63 (ddd, 1H, O–CH2–CH2–
N(CH3)2, J1 = 13.0 Hz, J2 = 7.4 Hz, J3 = 4.4 Hz), 2.37
(ddd, 1H, O–CH2–CH2–N(CH3)2, J1 = 13.1 Hz, J2 =
5.8 Hz, J3 = 4.5 Hz), 2.26 (s, 6H, N(CH3)2). 13C NMR
(50 MHz, CDCl3): dC = 140.1/138.5 (2s, Ph–C-1),
127.8/127.5/127.3/127.3/127.2/127.0 (6d, Ph–C), 85.6/
77.4 (2d, Ph–CH–O), 66.1/58.4 (2t, O–CH2–CH2–N),
45.1 (q, N(CH3)2). Anal. Calcd for C18H23NO2 ·
0.9H2O: C, 71.68;H, 8.29;N, 4.64. Found: C, 71.65;
H, 8.30;N, 4.64.
4.3.1. General procedure. Ether 5c,d (1 equiv) and a
catalytic amount of p-TsOH were dissolved in a 10-fold
amount of a mixture of methanol/dichloromethane (1/1)
and stirred overnight at room temperature. After TLC
analysis had shown total conversion, a saturated aque-
ous NaHCO3 solution was added and stirring was con-
tinued for 10 min. The organic solvents were evaporated
and the aqueous remainings were diluted with water and
extracted three times with ether. The combined ethereal
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
4.4. Preparation of ketoacid esters 7c–e, 10
4.3.1.1. (1R,2S)-2-(2-Methoxyethoxy)-1,2-diphenyl-
ethanol, 6c. A colourless oil (yield 93%), Rf = 0.29
4.4.1. General procedure for the preparation of benzoyl-
formic acid esters 7c–e. DIC (1.1 equiv) was added
dropwise to a solution of auxiliary 6c–e (1.0 equiv), ben-
zoylformic acid (1.1 equiv) and DMAP (0.2 equiv) in
dichloromethane while cooling on an ice bath. The mix-
ture was stirred for 1–20 h at room temperature until
TLC control had indicated total conversion. Then the
white precipitate was filtered off and the filtrate was
diluted with dichloromethane and washed successively
with a saturated aqueous NaHCO3 solution, 5% KHSO4
solution and 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).
20
(PE/E 1/1), ½aŠ ¼ 22:9 (c 1.04, CH2Cl2). 1H NMR
D
(200 MHz, CDCl3, TMS): dH = 7.27–7.10 (m, 10H, aro-
matic), 4.94/4.53 (2d, 2H, Ph–CH–O, J = 4.8 Hz), 3.67–
3.31 (m, 4H, O–CH2–CH2–O), 3.31 (s, 3H, O–CH3),
3.04 (s, 1H, OH). 13C NMR (50 MHz, CDCl3): dC =
140.1/137.5 (2s, Ph–C-1), 127.8–127.0 (m, Ph–C), 86.3/
76.7 (2d, Ph–CH–O), 71.8/68.5 (2t, O–CH2–CH2–O),
58.8 (q, O–CH3). Anal. Calcd for C17H20O3 · 0.1H2O:
C, 74.48;H, 7.43. Found: C, 74.67;H, 7.70.
4.3.1.2. (1R,2S)-2-(2-Methoxy-2,2-diphenylethoxy)-
1,2-diphenylethanol, 6d. A colourless oil (yield 99%),
20
D
1
Rf = 0.38 (PE/E 2/1), ½aŠ ¼ 42:6 (c 1.00, CH2Cl2). H
NMR (200 MHz, CDCl3, TMS): dH = 7.39–6.82 (m,
20H, aromatic), 4.68/4.44 (2d, 2H, Ph–CH–O,
J = 5.4 Hz), 4.05/3.95 (2d, 2H, O–CH2–C(Ph)2O,
JAB = 9.9 Hz), 3.09 (s, 3H, O–CH3), 2.46 (s, 1H,
–OH). 13C NMR (50 MHz, CDCl3): dC = 143.0/142.9/
139.8/137.3 (4s, Ph–C-1), 128.0–127.1 (m, Ph–C), 86.8/
82.6 (2d, Ph–CH–O), 77.2 (s, CH2–C(Ph)2O), 72.4 (t,
O–CH2–C(Ph)2O), 51.4 (q, O–CH3). Anal. Calcd for
C29H28O3 · 0.2H2O: C, 81.36;H, 6.69. Found: C,
81.43;H, 6.93.
4.4.1.1. Oxophenylacetic acid, (1R,2S)-2-(2-methoxy-
ethoxy)-1,2-diphenylethyl ester, 7c. A white solid (yield
20
91%), mp 79–81 ꢁC, Rf = 0.65 (PE/E 4/1), ½aŠ ¼ 18:6 (c
D
0.71, CH2Cl2). 1H NMR (200 MHz, CDCl3, TMS):
dH = 7.67–7.26 (m, 15H, aromatic), 6.29/4.70 (2d, 2H,
Ph–CH–O, J = 6.7 Hz), 3.59–3.38 (m, 4H, O–CH2–
CH2–O), 3.23 (s, 3H, O–CH3). 13C NMR (50 MHz,
CDCl3): dC = 186.1 (s, CO), 162.7 (s, O–CO), 137.4/
136.3/132.2 (3s, Ph–C-1), 134.7/129.9–127.7 (m,

3220
C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
Ph–C), 84.0/78.9 (2d, Ph–CH–O), 71.8/68.7 (2t, O–
CH2–CH2–O), 58.8 (q, O–CH3). Anal. Calcd for
C25H24O5 · 0.4H2O: C, 72.94;H, 6.07. Found: C,
72.99;H, 5.87.
1), 133.5/128.7–126.1 (m, Ph–C), 84.0/78.8 (2d, Ph–
CH–O), 71.8/68.8 (2t, O–CH2–CH2–O), 58.8 (q, O–
CH3), 45.9 (t, Ph–CO–CH2–COO). Enol form: dC =
171.7 (s, O–CO), 137.8/137.3/133.3 (3s, Ph–C-1),
131.2/128.7–127.7 (m, Ph–C, Ph–C(OH)@CH–COO),
87.3 (d, Ph–C(OH)@CH–COO), 84.3/77.7 (2d, Ph–
CH–O), 71.9/68.9 (2t, O–CH2–CH2–O), 58.9 (q, O–
CH3). Anal. Calcd for C26H26O5 · 0.1H2O: C, 74.30;
H, 6.28. Found: C, 74.39;H, 6.54.
4.4.1.2. Oxophenylacetic acid, (1R,2S)-2-(2-methoxy-
2,2-diphenylethoxy)-1,2-diphenylethyl ester, 7d. A col-
ourless oil (yield 91%), Rf = 0.37 (PE/E 4/1),
20
½aŠ ¼ 19:3 (c 1.21, CH2Cl2). 1H NMR (200 MHz,
D
CDCl3, TMS): dH = 7.48–6.84 (m, 25H, aromatic),
5.95/4.51 (2d, 2H, Ph–CH–O, J = 6.8 Hz), 3.86/3.76
(2d, 2H, O–CH2–C(Ph)2O, JAB = 9.7 Hz), 2.88 (s, 3H,
O–CH3). 13C NMR (50 MHz, CDCl3): dC = 186.0 (s,
CO), 162.6 (s, O–CO), 143.0/142.9/137.0/136.0/132.1
(5s, Ph–C-1), 134.7/133.7/130.2–126.9 (m, Ph–C), 84.3/
79.3 (2d, Ph–CH–O), 82.3 (s, O–CH2–C(Ph)2–O), 72.8
(t, O–CH2–C(Ph)2–O), 51.5 (q, O–CH3). Anal. Calcd
for C37H32O5 · 1.4H2O: C, 76.37;H, 6.03. Found: C,
76.45;H, 6.35.
4.5. Selectivity tests
4.5.1. General procedure for the reduction of keto esters
7c–e, 10. A solution of ester 6c–e, 10 (1 equiv/
ꢁ100 mg) in dry THF (10 mL) and ZnCl2 was stirred
for 10 min at ꢀ78 ꢁC. A 1 M solution of L-selectrideR
in THF (1.1 equiv) was added dropwise and the result-
ing mixture was stirred for 1 h at ꢀ78 ꢁC. After TLC
analysis had indicated total conversion (otherwise an-
other 1.1 equiv of L-selectrideR was added and stirring
was continued for 15 min at ꢀ78 ꢁC) the reaction was
quenched by addition of a 10% aqueous solution of
KHSO4 and warmed to ambient temperature. The mix-
ture 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).
4.4.1.3. Oxophenylacetic acid, (1R,2S)-2-(2-dimethyl-
aminoethoxy)-1,2-diphenylethyl ester, 7e. The crude
product was purified by vacuum flash chromatography
on silica gel, eluting with chloroform/methanol (100/
1!1/1). A white solid (yield 80%), mp 96–98 ꢁC,
Rf = 0.61 (CHCl3/MeOH 9/1 + 2 drops NH3(aq)),
20
½aŠ ¼ ꢀ2:4 (c 0.95, CH2Cl2). 1H NMR (200 MHz,
D
CDCl3, TMS): dH = 7.54–7.17 (m, 15H, aromatic),
6.17/4.55 (2d, 2H, Ph–CH–O, J = 6.9 Hz), 3.43–3.18
(m, 2H, O–CH2–CH2–N), 2.33–2.25 (m, 2H, O–CH2–
CH2–N), 2.02 (s, 6H, N(CH3)2). 13C NMR (50 MHz,
CDCl3): dC = 186.0 (s, CO), 162.6 (s, O–CO), 137.5/
136.4/132.1 (3s, Ph–C-1), 134.6/129.8/128.7/128.4/
128.3/128.2/128.0/128.0/127.8 (9d, Ph–C), 84.0/78.9
(2d, Ph–CH–O), 67.9/58.5 (2t, O–CH2–CH2–N), 45.6
(q, N(CH3)2). Anal. Calcd for C26H27NO4 · 1.57H2O:
C, 70.05;H, 6.81;N, 3.14. Found: C, 70.05;H, 7.11;
N, 3.41.
The diastereoisomeric ratios were determined by inte-
1
gration of appropriate signals of the H NMR spectra
of the crude reaction mixtures as well as after saponifi-
cation with LiOH by measuring the optical rotation of
the resulting mandelic acids7 and finally by HPLC-anal-
ysis of their L-valine methyl ester derivatives.8 The fol-
lowing NMR-values are given only for the main
diastereoisomers;yields are given for the mixtures of
diastereoisomers.
4.4.2. 3-Oxo-3-phenylpropionic acid, (1R,2S)-2-(2-meth-
oxyethoxy)-1,2-diphenylethyl ester, 10. A solution of
auxiliary 6c (1.131 mmol/0.308 g), 3-oxo-3-phenylprop-
ionic acid, ethyl ester (3.393 mmol/0.652 g) and DMAP
(0.566 mmol/0.069 g) in toluene (20 mL) was refluxed
for 48 h. After cooling to ambient temperature, the mix-
ture was poured into a saturated aqueous solution of
NH4Cl and extracted two times with ether. The com-
bined ethereal extracts were washed with brine, dried
over Na2SO4, filtered and evaporated. The crude prod-
uct was purified by vacuum flash chromatography on sil-
ica gel, eluting with petroleum ether/ether (20/1!1/1). A
4.5.1.1. (S)-Hydroxyphenylacetic acid, (1R,2S)-2-(2-
methoxyethoxy)-1,2-diphenylethyl ester, 8c. A white
solid (yield 99%), Rf = 0.35 (PE/E 1/1). 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.25–6.66 (m, 15H, aro-
matic), 5.85/4.43 (2d, 2H, Ph–CH–O, J = 5.6 Hz), 4.98
(s, 1H, Ph–CH(OH)–CO), 3.45–3.24 (m, 5H, O–CH2–
CH2–O, OH), 3.15 (s, 3H, O–CH3). 13C NMR
(50 MHz, CDCl3): dC = 172.1 (s, O–CO), 137.9/137.2/
136.5 (3s, Ph–C-1), 128.3–126.7 (m, Ph–C), 84.3/79.3
(2d, Ph–CH–O), 72.9 (d, Ph–CH(OH)–CO), 71.8/68.8
(2t, O–CH2–CH2–O), 58.8 (q, O–CH3). Anal. Calcd
for C25H26O5: C, 73.87;H, 6.45. Found: C, 73.63;H,
6.68.
white solid (0.402 g, yield 85%), mp 70–78 ꢁC, Rf = 0.41
20
(PE/E 1/1), ½aŠ ¼ 31:7 (c 0.73, CH2Cl2). 1H NMR
D
(200 MHz, CDCl3, TMS): Keto form: dH = 7.75–7.05
(m, 15H, aromatic), 5.87/4.49 (2d, 2H, Ph–CH–O,
J = 5.9 Hz), 3.82/3.73 (2d, 2H, Ph–CO–CH2–COO,
JAB = 15.4 Hz), 3.47–3.23 (m, 4H, O–CH2–CH2–O),
3.13 (s, 3H, O–CH3). Enol form: dH = 7.68–7.05 (m,
15H, aromatic), 5.97/4.61 (2d, 2H, Ph–CH–O,
J = 5.8 Hz), 5.57 (s, 1H, Ph–C(OH)@CH–COO), 3.47–
3.23 (m, 4H, O–CH2–CH2–O), 3.17 (s, 3H, O–CH3).
13C NMR (50 MHz, CDCl3): Keto form: dC = 191.8
(s, CO), 166.0 (s, O–CO), 137.7/136.7/136.0 (3s, Ph–C-
4.5.1.2. (S)-Hydroxyphenylacetic acid, (1R,2S)-2-(2-
methoxy-2,2-diphenylethoxy)-1,2-diphenylethyl
ester,
8d. A white solid (yield 86%), Rf = 0.54 (PE/E 1/1).
1H NMR (200 MHz, CDCl3, TMS): dH = 7.20–6.60
(m, 25H, aromatic), 5.65/4.36 (2d, 2H, Ph–CH–O,
J = 6.0 Hz), 4.88 (s, 1H, Ph–CH(OH)–CO), 3.82/3.76
(2d, 2H, O–CH2–C(Ph)2–O, JAB = 9.7 Hz), 3.22 (s,
1H, OH), 2.91 (s, 3H, O–CH3). 13C NMR (50 MHz,
CDCl3): dC = 172.0 (s, O–CO), 142.9/142.9/137.8/

C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
3221
136.8/136.0 (5s, Ph–C-1), 128.4–126.7 (m, Ph–C), 84.4/
79.5 (2d, Ph–CH–O), 82.2 (s, O–CH2–C(Ph)2–O), 72.8
(d, Ph–CH(OH)–CO), 72.5 (t, O–CH2–C(PH)2–O),
51.4 (q, O–CH3). Anal. Calcd for C37H34O5 · 0.4H2O:
C, 78.53;H, 6.20. Found: C, 78.45;H, 6.45.
acidified with HCl conc. while cooling on an ice bath
and extracted three times with ethyl acetate. The com-
bined ethyl acetate extracts were washed with brine,
dried over Na2SO4, filtered and evaporated yielding
the free hydroxy acids 9, 12.
4.6.1.1. (S)-Mandelic acid, 9. A white solid (yield
4.5.1.3. (S)-Hydroxyphenylacetic acid, (1R,2S)-2-(2-
dimethylaminoethoxy)-1,2-diphenylethyl ester, 8e. After
quenching with 10% aqueous KHSO4, the mixture was
further diluted with a 10% aqueous solution of KHSO4
and extracted three times with ether. The aqueous phase
was made basic with a saturated aqueous solution of
NaHCO3 and extracted three times with dichlorometh-
ane. The combined dichloromethane extracts were dried
over Na2SO4, filtered and evaporated. A white solid
(yield 85%), Rf = 0.24 (CHCl3/MeOH 9/1 + 2 drops
20
90–98%). All ½aŠ values were (+) assigning the absolute
configurations tDo be (S).7 1H NMR (200 MHz, d6-ace-
tone, TMS): dH = 7.40–7.16 (m, 5H, aromatic), 5.08 (s,
1H, Ph–CH(OH)–COOH), 4.71 (s, 1H, OH).
4.6.1.2. (R)-3-Hydroxy-3-phenylpropionic acid, 12.
A
22
pale yellow solid (yield 97%), ½aŠ ¼ ꢀ9:7 (c
D
1.34, EtOH).16 1H NMR (200 MHz, d6-acetone, TMS):
dH = 7.30–7.17 (m, 5H, aromatic), 5.07 (dd, 1H, Ph–
CH(OH)–CH2–COOH, J1 = 4.1 Hz, J2 = 8.5 Hz), 2.77
(dd, 1H, Ph–CH(OH)–CH2–COOH, J1 = 16.4 Hz,
J2 = 8.5 Hz), 2.66 (dd, 1H, Ph–CH(OH)–CH2–COOH,
J1 = 16.4 Hz, J2 = 4.1 Hz).
1
NH3). H NMR (200 MHz, CDCl3, TMS): dH = 7.23–
6.69 (m, 15H, aromatic), 5.82/4.36 (2d, 2H, Ph–CH–O,
J = 6.0 Hz), 4.96 (s, 1H, Ph–CH(OH)–CO), 3.97 (s,
1H, OH), 3.34/3.18 (2td, 2H, O–CH2–CH2–N,
J1 = 10.1 Hz, J2 = 5.7 Hz), 2.28 (dd, 2H, O–CH2–
CH2–N, J1 = 5.7 Hz, J2 = 5.7 Hz), 2.01 (s, 6H,
N(CH3)2). 13C NMR (50 MHz, CDCl3): dC = 172.0
(s, O–CO), 138.1/137.4/136.5 (3s, Ph–C-1), 128.3/
4.7. Derivatization of mandelic acids 9 with L-valine
methyl ester and HPLC analysis of these derivatives 138
for determination of enantiomeric excess
128.2/128.1/127.9/127.8/127.8/127.6/127.0/126.8
(9d,
4.7.1. General procedure. To a solution of mandelic
acid 9 (10–30 mg) and HOBt (10–30 mg) in dry dichlo-
romethane (3 mL), a solution of L-valine methyl ester
(10–30 mg) in dry dichloromethane (ꢁ1 mL) was added
and the resulting mixture was cooled to ꢀ30 ꢁC. Then a
solution of DIC (10–30 mg) in dry dichloromethane
(ꢁ1 mL) was added and stirring was continued for 1 h
at ꢀ30 ꢁC and then overnight at ambient temperature.
Finally the reaction mixture was diluted with dichloro-
methane, filtered, successively washed with 10% aqueous
KHSO4, saturated aqueous NaHCO3 and brine, dried
over Na2SO4, filtered and evaporated. For removal of
diisopropyl urea, the crude product was taken up with
ꢁ1 mL of acetone, cooled for 10 min on an ice bath,
filtered and evaporated. The crude product was used
for HPLC analysis without further purification. Nucleo-
sil 120 S C18 (4);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].
Ph–C), 84.3/79.0 (2d, Ph–CH–O), 73.0 (d, Ph–
CH(OH)–CO), 67.8/58.5 (2t, O–CH2–CH2–N), 45.6 (q,
N(CH3)2).
4.5.1.4. (R)-3-Hydroxy-3-phenylpropionic
(1R,2S)-2-(2-methoxyethoxy)-1,2-diphenylethyl
acid,
ester,
11. A white solid (yield 33%), Rf = 0.29 (PE/E 1/1).
1H NMR (200 MHz, CDCl3, TMS): dH = 7.26–7.09
(m, 15H, aromatic), 5.96/4.92 (2d, 2H, Ph–CH–O,
J = 5.9 Hz), 4.92 (dd, 1H, Ph–CH(OH)–CH2–COO,
J1 = 7.1 Hz, J2 = 5.6 Hz), 3.47–3.28 (m, 5H, O–CH2–
CH2–O, OH), 3.17 (s, 3H, O–CH3), 2.59–2.55 (m, 2H,
Ph–CH(OH)–CH2–COO). 13C NMR (50 MHz, CDCl3):
dC = 171.0 (s, O–CO), 142.4/137.5/136.9 (3s, Ph–C-1),
128.4–127.6/125.6 (m, Ph–C), 84.2/77.9 (2d, Ph–CH–
O), 71.8/68.7 (2t, O–CH2–CH2–O), 70.1 (d, Ph–
CH(OH)–CH2–COO), 58.8 (q, O–CH3), 43.7 (t, Ph–
CH(OH)-CH2–COO). Anal. Calcd for C26H28O5: C,
74.26;H, 6.71. Found: C, 74.00;H, 6.92. 49% of educt
ester 10 were recovered.
4.8. Reactions on solid support
4.6. Saponification of hydroxy esters 8c–e, 11
4.8.1. Chlorination of hydroxymethylated Wang-
resin.10 Hydroxymethylated Wang-resin (3.14 mmol/
4.90 g) was suspended in dry DMF (60 mL) and cooled
to ꢀ10 ꢁC. Diisopropylethylamine (31.6 mmol/5.5 mL)
and methanesulfonyl chloride (31.1 mmol/2.4 mL) were
added successively while maintaining the temperature
below ꢀ10 ꢁC and the resulting mixture was stirred
for 4 days at ambient temperature. Finally the resin
was filtered off and thoroughly washed successively
with DMF, dichloromethane, methanol, dichloro-
methane, methanol, dichloromethane, methanol, and
dried in vacuo overnight at 40 ꢁC. The whole proce-
dure was once repeated to assert quantitative chlorina-
tion. A colourless resin (4.984 g). IR m (KBr) =
693 cmꢀ1 (shoulder;C–Cl);no further changes. Anal.
4.6.1. General procedure. A solution of ester 8c–e, 11
(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 ꢁC). The aqueous remaining was extracted three
times with ether. For recovery of the auxiliaries 6c–e,
the combined ethereal extracts were washed with brine,
dried over Na2SO4, filtered, evaporated and the residue
was purified by vacuum flash chromatography if neces-
sary. Thereby all auxiliaries 6c–e could be recovered
almost quantitatively without any loss of enantiomeric
purity. The combined aqueous phases were carefully

3222
C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
Calcd for 0.63 mmol/g Cl: Cl, 2.24. Found: Cl, 2.33;N,
<0.05.
anol/water (2/1), water, methanol, dichloromethane,
methanol, dichloromethane, methanol and dried in
vacuo overnight at 40 ꢁC. A colourless resin (1.694 g).
4.8.2. Immobilization of auxiliary precursor 4c on the
solid support 5f. A solution of alcohol 4c (9.375 mmol/
4.093 g) in dry DMF (25 mL) was added slowly to a sus-
pension of 55% NaH (8.457 mmol/0.369 g) in dry DMF
(5 mL) and the mixture was shaken for 1.5 h at room
temperature. Then chloromethylated Wang resin10
(1.875 mmol/2.702 g) and a catalytic amount of NaI
were added in one portion and the resulting suspension
was shaken for 24 h at room temperature. Unreacted
NaH was carefully hydrolized by adding portions of a
mixture of water/THF (1/1) until the reaction ceased.
The resin was filtered off and thoroughly washed succes-
sively with water, methanol, dichloromethane, petro-
leum ether, methanol, dichloromethane, methanol,
dichloromethane, methanol, and dried in vacuo over-
night at 40 ꢁC. A colourless resin (3.283 g, mass
increase: 0.581 g ꢂ yield 80%). IR m (KBr) = 693 cmꢀ1
(C–Cl: shoulder vanished);no further changes.
4.8.4. Deprotection of auxiliary precursors 5f–f00.
4.8.4.1. General procedure. Dry methanol (51.8
mmol/2.1 mL) and triphenylphosphine hydrobromide
(0.968 mmol/0.332 g) were added to a suspension of
resin 5f (ꢁ0.880 mmol/1.601 g) in dry dichloromethane
and the mixture was shaken for 24 h at room temper-
ature. Then the resin was filtered off and thoroughly
washed successively with dichloromethane, methanol,
dichloromethane, methanol, dichloromethane, metha-
nol, and dried in vacuo overnight at 40 ꢁC. A pale yellow
resin (1.367 g, mass decrease: 0.234 g ꢂ 0.679 mmol
auxiliary loading). IR m (KBr) = 3576 cmꢀ1 (O–H);no
further changes.
4.8.5. Esterification of auxiliaries 6f–f00.
4.8.5.1. General procedure. DIC (7.21 mmol/1.13
mL) was added dropwise to a mixture of resin 6f00 (ꢁ0.721
mmol/1.452 g), benzoylformic acid (7.21 mmol/1.08 g)
and DMAP (0.721 mmol/0.088 g) in dry dichlorometh-
ane (15 mL) while cooling on an ice bath. The result-
ing mixture, which had turned from pale yellow to
orange, was shaken for 48 h at room temperature. Then
the resin was filtered off and thoroughly washed succes-
sively with dichloromethane, methanol, dichlorometh-
ane, methanol, dichloromethane, methanol, and dried
in vacuo overnight at 40 ꢁC. A pale yellow resin
(1.542 g, mass increase: 0.090 g = 0.681 mmol). IR m
(KBr) = 3576 cmꢀ1 (OH: vanished), 1739 cmꢀ1 (COOR),
1689 cmꢀ1 (CO);no further changes.
For recovery of excess auxiliary precursor 4c, the com-
bined filtrates were diluted with brine. Dichloromethane
and methanol were evaporated and the aqueous remain-
ing was extracted three times with ether. The combined
ethereal extracts were washed three times with brine,
dried over Na2SO4, filtered and evaporated. The crude
oil was purified by vacuum flash chromatography on sil-
ica gel, eluting with petroleum ether/ether (4/1!2/1). A
colourless oil (3.276 g), which was re-introduced in
another auxiliary immobilization step without any loss
of stereoisomeric purity.
4.8.3. Deactivation of unreacted chloromethyl groups.
4.8.3.1. Method A: methoxylation 5f0. Dry methanol
(0.44 mL) was added slowly to a suspension of 55% NaH
(10.96 mmol/0.48 g) in dry DMF (20 mL) and the mix-
ture was shaken for 30 min. at room temperature. Then
resin 5f (1.636 g) and a catalytic amount of NaI were
added in one portion and the resulting suspension was
shaken for 48 h at room temperature. Unreacted NaH
was carefully hydrolized 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, dichlorometh-
ane, methanol, and dried in vacuo overnight at 40 ꢁC.
A colourless resin (1.617 g).
4.8.6. Stereoselective reduction of keto esters 7f–f00.
4.8.6.1. General procedure. A mixture of resin 7f–f00
(ꢁ1 g) and ZnCl2 (2 equiv) in dry THF (10 mL) was stir-
red for 5 min. at room temperature and subsequently
cooled to ꢀ78 ꢁC and stirred for another 15 min. at this
temperature. Then L-selectrideR (1.15 equiv;calculated
on the mass increase in the esterification step) was
slowly added and stirring was continued for 3 h at
ꢀ78 ꢁC. After complete conversion had been detected
by IR spectroscopy (otherwise another 0.1 equiv of L-
selectrideR were added and stirring was continued for
30 min. at ꢀ78 ꢁC), the reaction was quenched by addi-
tion of an equal volume of 10% aqueous KHSO4 and the
resulting mixture was allowed to warm to room temper-
ature. The resin was filtered off, treated two times with a
solution of triphenylphosphine hydrobromide in dichlo-
romethane and thoroughly washed successively with
dichloromethane, THF, water, THF/water (1/1), metha-
nol, dichloromethane, methanol, dichloromethane,
methanol, and dried in vacuo overnight at 40 ꢁC. A pale
yellow resin. IR m (KBr) = 3528 cmꢀ1 (OH), 1739 cmꢀ1
(COOR), 1689 cmꢀ1 (CO: vanished);no further
changes.
4.8.3.2. Method B: iodination/reduction12 5f00. A mix-
ture of resin 5f (1.732 g) and NaI (6.5 mmol/0.97 g) in
dry acetone (20 mL) were refluxed for 48 h. After cooling
to room temperature, the resin was filtered off and suc-
cessively washed with acetone, THF, ethanol, methanol,
methanol/water (1/1), THF, water, THF/water (1/1),
methanol, dichloromethane, methanol, dichlorometh-
ane, methanol and dried in high vacuo for 3 h at room
temperature. Then the resin was suspended in dry THF
(25 mL). Bu3SnH (0.67 mmol/0.18 mL) was added and
the mixture was refluxed for 48 h. After cooling to room
temperature, the resin was filtered off and thoroughly
washed successively with THF, ethanol, methanol, meth-
4.8.7. Saponification of hydroxy esters 8f–f00.
4.8.7.1. General procedure. A mixture of resin 8f–f00
and LiOH (5 equiv) in THF/methanol/water (10/4/1)
was shaken for 3 h at room temperature. After complete
conversion had been detected by IR spectroscopy, the

C. Schuster et al. / Tetrahedron: Asymmetry 16(2005) 3211–3223
3223
Hayashi, Y.;Mukai, Y.;Ueda, M.;Kimura, T.;Kiso, Y.
Tetrahedron Lett. 2004, 45, 3651–3654.
resin was filtered off and thoroughly washed successively
with saturated aqueous NaHCO3, water, methanol,
THF, water, methanol, THF, methanol, THF, metha-
nol, and dried in vacuo overnight at 40 ꢁC. The resin
was introduced in the next reaction cycle without any
further purification. A pale yellow resin. IR m (KBr) =
3528 cmꢀ1 (OH), 1739 cmꢀ1 (COOR: vanished);no fur-
ther changes.
3. (a) Noe, C. R. Chem. Ber. 1982, 115, 1576–1590;(b) Noe,
C. R.;Knollmueller, M.;Wagner, E.;Vo ¨llenkle, H. Chem.
Ber. 1985, 118, 1733–1745;(c) Noe, C. R.;Knollmueller,
M.;Steinbauer, G.;Vo ¨llenkle, H. Chem. Ber. 1985, 118,
4453–4458;(d) Noe, C. R.;Knollmueller, M.;Steinbauer,
G.;Jangg, E.;Vo ¨llenkle, H. Chem. Ber. 1988, 121, 1231–
1239.
4. Gaertner, P.;Schuster, C.;Knollmueller, M. Lett. Org.
Chem. 2004, 1, 249–253.
5. Schuster, C.;Broeker, J.;Knollmueller, M.;Gaertner, P.
Tetrahedron: Asymmetry 2005, 16.
The combined filtrates were diluted with saturated aque-
ous NaHCO3, and THF and methanol were evaporated
(bath temperature max. 40 ꢁC). The aqueous remaining
was extracted 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 and evaporated. To obtain
mandelic acids 9 with appropriate purities the extractive
purification step was repeated once or twice if necessary.
Mandelic acids 9 were dried in high vacuo and intro-
duced directly in the derivatization step for enantiomeric
analysis (vide supra). Yield 52–98%-based on gravimet-
rically estimated amounts of acid bound in the esterifica-
tion steps;white solid.
6. (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.
7. (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:
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8. Cavelier, F.;Gomez, S.;Jacquier, R.;Llinares, M.;
Mereadier, J.-L.;Petrus, C.;Verducci, J.
Tetrahedron:
Asymmetry 1993, 4, 2495–2500.
9. Taber, D. F.;Deker, P. B.;Gaul, M. D. J. Am. Chem. Soc.
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10. Nugiel, D. A.;Wacker, D. A.;Nemeth, G. A. Tetrahedron
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11. (a) Kawana, M.;Emoto, S. Tetrahedron Lett. 1972, 48,
4855–4858;(b) Kawana, M.;Emoto, S. Bull. Chem. Soc.
Jpn. 1974, 47, 160–165.
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