Application of meso-hydrobenzoin-derived chiral auxiliaries for the stereoselective synthesis of highly substituted pyrrolidines by 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.tetasy.2010.04.010

The metal-catalyzed stereoselective 1,3-dipolar cycloaddition of azomethine ylides and acrylates using recyclable meso-hydrobenzoin-derived chiral auxiliaries is described. Cleavage of the auxiliary leads to highly substituted pyrrolidines in up to 87% en

Full text of DOI:10.1016/j.tetasy.2010.04.010

Tetrahedron: Asymmetry 21 (2010) 641–646
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Application of meso-hydrobenzoin-derived chiral auxiliaries
for the stereoselective synthesis of highly substituted pyrrolidines
by 1,3-dipolar cycloaddition of azomethine ylides
*
Katharina Bica, Peter Gaertner
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163, A-1060 Vienna, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
The metal-catalyzed stereoselective 1,3-dipolar cycloaddition of azomethine ylides and acrylates using
recyclable meso-hydrobenzoin-derived chiral auxiliaries is described. Cleavage of the auxiliary leads to
highly substituted pyrrolidines in up to 87% enantiomeric excess.
Received 5 January 2010
Accepted 1 April 2010
Available online 17 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Dr. Peter Stanetty on
the occasion of his 65th birthday
1. Introduction
Enantiopure substituted pyrrolidines are widely found as build-
ing blocks in alkaloids and have recently attracted considerable
interest as therapeutically interesting compounds, for example, po-
tent inhibitors of glucosidase1 and angiotensin-converting enzyme
(ACE) inhibitors.2 The possibility to form up to four new stereogen-
ic centers in a single step makes the 1,3-dipolar cycloaddition of
HO
HO
O
O
O
O
sublinking unit
azomethine ylides and
a,b-unsaturated carbonyl compounds one
chiral auxiliary
... polystyrene resin
chiral auxiliary
for solution phase
of the most potent methods for the stereoselective synthesis of
substituted pyrrolidines and some syntheses using chiral auxilia-
ries have been published so far.3
Scheme 1. meso-Hydrobenzoin derivatives as chiral auxiliaries for solid-phase
Hydrobenzoins and similar structures containing a 1,2-diol
synthesis.
moiety are already known as chiral auxiliaries for the
a-alkylation
of esters,4 reduction of -ketoesters,5 aldol addition reactions,6
a
ring-opening reactions of oxirans,7 and oxidation reactions of sul-
fides,8 respectively. In our recent studies we have designed novel
chiral hydrobenzoin ethers derived from meso-hydrobenzoin
which have been successfully applied as recyclable dual chiral aux-
iliaries and linkers for solid-phase organic synthesis (Scheme 1).4a,9
Herein, we report the highly regio- and stereoselective 1,3-
dipolar cycloaddition of a N-lithiated azomethine ylide and an aux-
iliary-bound acrylic ester for the preparation of highly substituted
pyrrolidines with the possibility for stereoselective solid-phase
synthesis.
(R)- and (S)-substituted form via desymmetrization of meso-hydro-
benzoin with either exo- or endo-anhydro lactol 2 or 20 has already
been described earlier and was performed analogously.10,11 The
reaction with acrylic acid chloride in the presence of triethylamine
and a catalytic amount of hydroquinone to prevent polymerization
led to the chiral acrylic ester 5a in 86% yield (Scheme 2).12,13
The in situ preparation of the N-lithiated azomethine ylide 7
was achieved by deprotonation of the Schiff base 6 with DBU in
the presence of a stoichiometric amount of anhydrous LiBr as a Le-
wis acid (Scheme 3).
The resulting 1,3-dipole reacted with the auxiliary-bound
acrylic ester 5a at room temperature using CH3CN/CH2Cl2 as sol-
vent and yielded the pyrrolidine 8a as a single regioisomer in a
yield of 67%, but low endo/exo selectivity and negligible diastereo-
facial selectivity were observed (Table 1).
2. Results and discussion
Our synthesis of the auxiliary-bound dipolarophile started from
the meso-hydrobenzoin derivative 4a whose preparation in both
Nevertheless, a change of the solvent to anhydrous THF led to
complete endo/exo selectivity and enhanced the yield to 85%. Var-
iation of the Lewis acid was unsuccessful: the use of AgOAc
* Corresponding author. Tel.: +4315880115421; fax: +4315880115492.
E-mail address: peter.gaertner@tuwien.ac.at (P. Gaertner).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.010

642
K. Bica, P. Gaertner / Tetrahedron: Asymmetry 21 (2010) 641–646
OH
X
OH
X
O
1a, 1c
O
O
O
O
O
i
2
2'
O
X
R
X
R
X
X
HO
O
O
HO
O
X
OH
X
OH
O
X
O
X
ent-4
3a, 3c
4a-4c
ii, iii
iv
O
X ... H
a : R ...
*
X
R
X
R
*
O
b : R ...
c : R ...
X ... H
O
O
X
O
X
O
O
O
X ... OMe
*
ent-5
5a-5c
Scheme 2. Reagents and conditions: (i) p-TsOH, CH2Cl2; (ii) for 4a: (a) (1) 3a, NaH, (2) BrCH2COO-t-Bu, HMPA, THF; (b) LiAlH4, THF; (c) (1) NaH, (2) CH3I, DMF; for 4b: (1) 3a,
NaH, (2) NaI (cat.), BrCH2PhOMe, DMF; for 4c: (1) 3c, NaH, (2) 4-toluenesulfonic acid i-butylester, DMF; (iii) p-TsOH, MeOH, CH2Cl2; (iv) acrylic acid chloride, Et3N,
hydroquinone monomethyl ether, CH2Cl2.
O
N
O
6
DBU
THF
LiBr
X
X
RO
RO
O
X
O
H
C+
O
X
O
C-
O
O
+
N
Li
O
N
O
7
E,E-dipole
8a-8c
5a-5c
Scheme 3.
resulted in a complete loss of diastereofacial selectivity, while no
cycloaddition was observed in the presence of Ti(OiPr)3Cl. The best
results were achieved at low temperature: by running the cycload-
dition with LiBr as a Lewis acid at ꢀ80 °C, the product was isolated
in 78% yield as a single regioisomer with complete endo/exo selec-
tivity and a diastereofacial selectivity of 87% de.
stacking between the electron-rich p-methoxybenzyl ether and
the acrylate in auxiliary 5b to force a conformation with an effec-
tive shielding of the acrylate si face and thus improve the selectiv-
ity. On the other hand, we introduced onto auxiliary 5c the non-
p–
p-stacking but sterically demanding sec-butyl group as well as
increasing the electron density in the aromatic rings of the hydro-
For further studies in selectivity, we synthesized different meso-
hydrobenzoin-derived auxiliaries with a p-methoxybenzyl ether
moiety 5b as well as a substituted hydrobenzoin system with a
benzoin by introduction of methoxy substituents to achieve stron-
ger
p–p-interactions in the hydrobenzoin skeleton. A significant
decrease in the diastereoselectivity and, in the case of auxiliary
5b, the yield occurred. This led us to the conclusion that coordina-
bulky sec-butyl ether moiety 5c.12,13 We expected additional
p
–p

K. Bica, P. Gaertner / Tetrahedron: Asymmetry 21 (2010) 641–646
643
Table 1
Results of cycloaddition
Entry
1d
Product
Substrate
Lewis acid Temperature (°C)
endo:exoa
Diastereofacial selectivityb (%ee)
6e
Yieldc (%)
8a
Xꢁ ꢁ ꢁH
LiBr
rt
LiBr
rt
AgOAc
rt
Ti(OiPr)3Cl
rt
LiBr
ꢀ80
LiBr
rt
LiBr
ꢀ80
3.9:1
67
85
73
0
Rꢁ ꢁ ꢁCH2CH2OCH3
Xꢁ ꢁ ꢁH
2
3
4
5
6
7
8a
8a
8a
8a
8b
8c
>99:1
>99:1
—
53
<1
—
Rꢁ ꢁ ꢁCH2CH2OCH3
Xꢁ ꢁ ꢁH
Rꢁ ꢁ ꢁCH2CH2OCH3
Xꢁ ꢁ ꢁH
Rꢁ ꢁ ꢁCH2CH2OCH3
Xꢁ ꢁ ꢁH
>99:1
>99:1
>99:1
87
35e
25
78
46
80
Rꢁ ꢁ ꢁCH2CH2OCH3
Xꢁ ꢁ ꢁH
Rꢁ ꢁ ꢁCH2Ph-4-OCH3
Xꢁ ꢁ ꢁOMe
Rꢁ ꢁ ꢁCH2CH(CH3)2
a
endo:exo ratios were determined by 13C NMR integration on crude reaction mixtures.
b
Diastereofacial selectivity was determined by HPLC analyses (ChiralcelÒ OD-H) of the pyrrolidines after reductive cleavage. It was ensured that no enrichment of any
diastereomer occurred during this process.
c
Isolated yield after flash column chromatography.
d
In this case, CH3CN/CH2Cl2 was used as a solvent.
e
In these cases, the diastereofacial selectivity was determined by 13C NMR integration on crude reaction mixtures of diastereomeric 8a and 8b.
Men+
O
tion of the oxygens in the ethylene glycol–ether chain in auxiliary
1a is necessary to obtain satisfactory selectivity. Complete endo/
exo-selectivity can be explained by the preferable endo transition
state B, in which coordination of the dipolarophile oxygen with
the Li+ cation of the dipole occurs, which is not possible in the
exo transition state A (Scheme 4).
chelation
si attack
O
H
H
O
O
preferred re attack
of the dipolarophile
π−π-stacking
O
O
O
O
O
O
O
Aux
O
O
O
Li
O
O
O
O
O
O
O
Li
N
H
N
H
4
O
O
H
N
O
5
N
2
O
Li
H
A
B
B
additional coordination in
the endo-transition state
exo/re
endo/re
2R-(2α,4α,5α)
Scheme 5. Diastereofacial selectivity.
endo/re
Scheme 4. endo/exo-Transition state.
We assumed that additional coordination to both the oxygens
of the carbonyl and the ethylene glycol moiety thus resulting in
an effective shielding of the acrylates’ si side: the favored attack oc-
curs via an endo/re transition state to form the [2R-(2a,4a,5b)] pyr-
rolidine (Scheme 5).
The cleavage of the pyrrolidine 8a and recovery of the auxiliary
were best achieved under reductive conditions, since basic LiOH-
mediated saponification at room temperature cleaved only the
methyl ester whereas harsher reaction conditions could lead to
racemization. Reductive cleavage of the auxiliary-bound pyrroli-
dine 8a with LiAlH4 in THF proceeded instantaneously to afford
the pyrrolidinediol 9 after extractive work-up in an excellent yield
of 98% (Scheme 6).
2- and 4-positions. Together with the syn-conformation of H-4
and H-5, these results are in accordance with the E,E-structure of
the N-lithiated azomethine ylide suggested by Grigg which yields
an anti-relationship between both phenyl substituents in product
8a (Scheme 8).3
Consequently, NOE measurements confirm the (2a,4a,5b) rela-
tive configuration of 8a which was proposed based on theoretical
considerations about the most likely endo/re-transition state and
thus support our model.
3. Conclusion
Isolation of the hydrobenzoin auxiliary could be achieved by
simple extraction of the acidic phase and gave pure 4a according
to 1H NMR in 96% yield.
To confirm the configuration of the pyrrolidine diol 9 NOE cor-
relations were carried out: a strong NOE between H-4 and H-5 was
observed proving the suspected syn-conformation of the protons at
C-4 and C-5 (Scheme 7).
In conclusion, we have proved the efficiency of novel meso-
hydrobenzoin-derived chiral auxiliaries for the facile stereoselec-
tive synthesis of highly substituted pyrrolidines, as well as the easy
cleavage of the heterocycle and recovery of the auxiliary. Further-
more, the ability to use an analogous meso-hydrobenzoin system
attached to a solid support4a,9 may make our method a useful tool
for the stereoselective preparation of heterocyclic compound
assemblies for drug development programs.
Additional NOE signals between Ha-3 and H-6 and H-7 indi-
cated a syn-orientation of the hydroxylmethyl substituents at the

644
K. Bica, P. Gaertner / Tetrahedron: Asymmetry 21 (2010) 641–646
O
O
O
O
O
HO
O
OH
NH
8a
N
H
LiAlH4
THF
9
+
LiOH, rt
THF:MeOH:H2O
O
O
O
HO
OH
O
OH
N
4a
H
Scheme 6. Cleavage of the auxiliary.
Merck) were used. Compounds were visualized by spraying with
5% phosphomolybdic acid hydrate in ethanol and heating. Column
chromatography was carried out with Silica Gel Merck 60. All frac-
tions of products containing NOE’s acetal-protecting group to-
gether with a free hydroxy group were concentrated immediately
after chromatography together with a few drops of NEt3. Melting
points were determined with a Kofler hot-stage apparatus. Specific
rotations were measured on a Perkin–Elmer 241 polarimeter. 1H
and 13C NMR spectra were recorded on a Bruker AC 200 in CDCl3
at 200 and 50 MHz, respectively, using TMS or the solvent peak
as the reference. HPLC analysis of pyrrolidines was carried out with
a SHIMADZU LC-10AD (SHIMADZU SPD-10AV UV/VIS detector;
NOE
HO
OH
Ha
6
4
7
5
2
N
H
Hb
H
Scheme 7. NOE-spectroscopy
ChiralcelÒ
OD-H;
n-hexane/i-PrOH
80:20;
0.80 mL/min;
4. Experimental
4.1. General
tR1 = 36.3 min, tR2 = 39.6 min). Elemental analysis was carried out
at Vienna University, Department of Physicochemistry—Laboratory
for Microanalysis, Währinger Str. 42, A-1090 Vienna.
Commercially available reagents and solvents were used as re-
ceived from the supplier unless otherwise specified. Diethyl ether
(E), petroleum ether (PE; 60–80 °C fraction), ethyl acetate (EE),
and dichloromethane (DCM) were distilled prior to use. Dry diethyl
ether and tetrahydrofuran (THF) were predried over KOH and dis-
tilled from Na/benzophenone. Dry dichloromethane was distilled
from P2O5. Compounds LiBr and AgOAc were dried by heating to
150–300 °C in high vacuo for 60 min prior to use. All moisture-sen-
sitive reactions were carried out under a nitrogen atmosphere. For
4.2. (R)-(1R*,2S*)-2-(4-Methoxybenzyloxy)-1,2-diphenylethanol
4b
A solution of alcohol 3a11 (1.46 g, 3.72 mmol) in dry DMF (5 mL)
was added slowly to a suspension of freshly washed NaH (0.18 g,
7.5 mmol) in dry DMF (5 mL) and the mixture was stirred for 2 h
at room temperature. Then a catalytic amount of NaI and 4-MeO-
BnCl (1.02 g, 6.54 mmol) was added and stirring was continued
for 30 min at room temperature. Unreacted NaH was then carefully
TLC-analysis precoated aluminum-backed plates (Silica Gel 60 F254
,
C-
O
C+
C-
O
O
N+
Li
N
N
Li
O
Li
O
O
E,E-dipole
C+
O
O
C-
H
N
Li
Scheme 8. Conformation of the 1,3-dipole.

K. Bica, P. Gaertner / Tetrahedron: Asymmetry 21 (2010) 641–646
645
hydrolyzed by adding water (60 mL) while cooling on an ice bath,
until the reaction ceased. The resulting mixture was extracted six
times with ether. The combined ether extracts were washed four
times with brine, dried over Na2SO4, filtered, and evaporated. Short
column chromatography on silica gel (100 g, PE/E 15:1) yielded
1.68 g of a colorless oil (88%), Rf = 0.64 (PE/E 3:1); 1H NMR
(200 MHz, CDCl3, TMS): dH = 7.47–7.28 (m, 10H, H-aromatic),
6.79 (d, J = 8.80 Hz, 2H, H-aromatic), 6.70 (d, J = 8.80 Hz, 2H, H-aro-
matic), 4.82 (d, 2H, J = 3.91 Hz, 1H, H-2), 4.68/4.25 (2d, J = 8.41 Hz,
2H, Ph–CH–O), 4.34/4.02 (2d, J = 11.93 Hz, 2H, Ph–CH2–), 2.37 (d,
J = 6.65 Hz, 1H, H-7a), 1.94–0.46 (m, 17H, MBE-aliph.-H, therein
0.78 (2s, 6H, 2 MBE-CH3), 0.69 (s, 3H, MBE-CH3)) ppm; 13C NMR
(50 MHz, CDCl3): dC = 158.8 (s, C-17), 140.8/140.3 (2s, C-11, C-
12), 130.4 (s, C-14), 128.9–127.4 (m, 10-Ph–C), 100.8 (d, C-2),
89.9 (d, C-7a), 83.6/78.6 (2d, C-9, C-10), 70.0 (t, C-13), 55.21 (q,
C-18), 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), 22.8/20.5/11.4 (3q, 3 MBE-CH3)
ppm. Anal. Calcd for C35H42O3ꢂ0.9H2O: C, 79.78; H, 8.38. Found:
C, 79.64; H, 8.02.
This oil (1.66 g, 3.25 mmol) was dissolved in methanol (25 mL),
p-toluenesulfonic acid monohydrate (0.11 g, 0.58 mmol) was added,
and the reaction mixture was stirred for 12 h. Then saturated NaH-
CO3 solution (50 mL) was added to the mixture, and the aqueous
phase was extracted several times with CH2Cl2. The combined ex-
tracts were dried with Na2SO4, filtered, and evaporated to dryness,
yielding 1.75 g of a colorless oil which was purified via chromatog-
raphy (PE/E 10:1 ? 4:1) to give 0.92 g 4b (85%) and 0.68 g octahy-
4.47/4.18 (2d, 2H, –OCH2–Ph), 3.81 (s, 3H, CH3O–) ppm; 13C NMR
(50 MHz, CDCl3): dC = 164.6 (s, CO), 159.0 (s, CH3O–C), 137.9/137.4
(s, Ph–C-1), 130.7 (d, –CH@CH2–), 130.0 (s, CH3O–Ph–C1), 130.8 (d,
–CH@CH2–) 129.0–127.6 (d, Ph–C and –CH@CH2–), 82.3/77.9 (2d,
Ph–CH–O), 70.2 (t, Ph–CH2–O), 55.2 (q, CH3O–) ppm. Anal. Calcd
for C29H24O4: C, 77.30; H, 6.23. Found C, 77.18; H, 6.46.
4.5. Preparation of the Schiff base phenyl[(1-phenylmethyliden)-
amino]acetic acid, methyl ester 6
rac-Phenylglycine, methylester hydrochloride, and triethyl-
amine were dissolved in 250 mL of dry DCM and stirred in the
presence of MgSO4 for 60 min. Freshly distilled benzaldehyde
was added and the mixture was refluxed for 42 h. After cooling
to room temperature, the resulting suspension was filtered and
washed twice with brine. The organic layer was dried with Na2SO4,
filtered, and evaporated. The crude product was purified by bulb to
bulb distillation (100 °C/ 0.02 mm Hg) to obtain 8.49 g (yield 81%)
of a yellow oil, Rf = 0.24 (PE/E 4:1). 1H NMR (200 MHz, CDCl3, TMS):
dH = 8.36 (s, 1H, –CH@N), 7.90–7.78 (m, 2H, aromatic), 7.60–7.31
(m, 8H, aromatic), 5.23 (s, 1H, CHNH2), 3.76 (s, 3H, CH3O) ppm.14
4.6. General procedure for the cycloaddition
A solution of the Schiff base 6 (1.0 equiv) in dry THF was added
to a solution of acrylic acid esters 5a–5c followed by a solution of
freshly dried LiBr in THF. After cooling to ꢀ80 °C DBU was added
dropwise and stirred for 2 h. Additional Schiff base and DBU were
added and stirred for 1 h at ꢀ80 °C until TLC control indicated total
conversion. The solution was allowed to reach room temperature,
diluted with 10% NH4Cl solution, and extracted with DCM. The or-
ganic phases were washed twice with brine, dried with Na2SO4, fil-
tered, and evaporated. The crude product was purified by flash
column chromatography on silica gel, eluting with PE/E (10:1).
By quantitative comparison of NMR spectra before and after flash
chromatography it was verified that no separation of the diastereo-
mers had occurred during this process. Only the NMR signals of
major diastereomers are given below.
dro-2-methoxy-7,8,8-trimethyl-4,7-methanobenzofuran
(88%)
which was used for the recyclization of NOE’s chiral protecting
group.10
Compound 4b: Rf = 0.39 (PE/E 3:1); 1H NMR (200 MHz, CDCl3,
TMS): dH = 7.43–7.20 (m, 4H, Ar–H), 7.09 (d, J = 8.6 Hz, 2H,), 6.87
(d, J = 8.6 Hz, Ar-), 4.93 (d, J = 5.7 Hz, 1H, Ph–CH–O), 4.52 (d,
5.7 Hz, 1H, Ph–CH–O), 4.49 (d, J = 11.4 Hz, 1H, Ph–CH2–O), 4.21
(d, J = 11.5 Hz, 1H, Ph–CH2–O), 3.83 (s, 3H, OCH3), 2.53 (s, 1H,
OH) ppm; 13C NMR (50 MHz, CDCl3): dC = 159.0 (s, Ph–C–OCH3),
140.5/137.7 (2s, 2Ph–C-1), 129.9 (s, CH3O–Ph–C-1), 129.2–127.0
(9d, 9Ph–C), 113.6 (d, Ph–C), 84.6/76.9 (2d, Ph–CH–O), 70.2 (t,
Ph–CH2–O), 55.1 (q, OCH3) ppm. Anal. Calcd for C22H22O3: C,
79.02; H, 6.63. Found: C, 78.74; H, 6.77.
4.7. [(2R)-(2a,4a a)]-2,5-Diphenylpyrrolidine-2,4-
(10R*,20S*),5
dicarboxylic acid, 4-[2-(2-methoxyethoxy)-1,2-diphenylethyl]-
4.3. General procedure for the preparation of acrylic acid esters
5a–5c
ester, 2-methylester 8a (contains as minor component [2S-
(2
a a a)])
(10S*,20R*),5
,4
Acrylic acid chloride (2.0 equiv) was added dropwise to a solu-
tion of auxiliary 4a–4c (1.0 equiv) and triethylamine (2.0 equiv) in
dry DCM while cooling on a NaCl/ice bath. The mixture was stirred
for 2 h at room temperature until TLC control indicated complete
conversion. Then the suspension was diluted with H2O and ex-
tracted with DCM. The organic phases were washed successively
with 5% KHSO4 solution, a saturated aqueous NaHCO3 solution,
and brine. The organic layer was dried over Na2SO4, filtered, a cat-
alytic amount of hydroquinone monomethyl ether added, and
evaporated. The crude product was purified by flash column chro-
matography on silica gel, eluting with PE/E (15:1).
Yield 67–85%, yellowoil, Rf = 0.21 (PE/EE 5:1); 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.90–6.92 (m, 20H, aromatic), 5.53/4.64 (2d, 2H,
Ph–CH–O, J = 7.4 Hz), 5.30 (br s, 1H, NH), 4.52 (d, 1H, PhCH–N,
J = 6.3 Hz), 3.80 (s, 3H, CH3OCO–), 3.55–3.40 (m, 5H, O–CH2–CH2–
O– and –CHCOO–), 3.38 (s, 3H, CH3OCH2–), 3.11/2.75 (2dd, 2H, –
COCH–CH2–CPh, J1 = 13.5 Hz, J2 = 6.3 Hz/J1 = 13.3 Hz, J2 = 7.4 Hz)
ppm; 13C NMR (50 MHz, CDCl3): dC = 174.2 (s, –COOCH3), 171.1 (s,
–CH–COO–), 142.8/139.3/137.9/137.3 (4s, Ph–C-1), 128.3–126.4
(20d, Ph–C), 83.4/78.6 (2d, Ph–CH–O), 71.6/68.8 (2t, O–CH2–CH2–
O–), 71.5 (s, N–C–Ph), 64.5 (d, PhCH–N), 58.8 (q, CH3OCH2–), 52.7
(q, CH3OCO–), 50.0 (d, –CH–COO–), 40.8 (t, –CH–CH2–CPh) ppm.
Anal. Calcd for C36H37NO6ꢂ1H2O: C, 72.34; H, 6.58; N, 2.34. Found:
C, 72.35; H, 6.54; N, 2.33.
Acrylic acid esters 5a and 5c were identical to the material de-
scribed in the literature.13
4.4. Propenoic acid, R-(1R*,2S*)-[2-(4-methoxybenzyloxy)-1,2-
4.8. [(2R)-(2a,4a a)]-2,5-Diphenylpyrrolidine-2,4-
(10R*,20S*),5
diphenylethyl]ester 5b
dicarboxylic acid, 4-[2-(4-methoxybenzyloxy)-1,2-diphenyl-
ethyl]ester, 2-methylester 8b (contains as minor component
Yield 76%, viscous oil, Rf = 0.45 (PE/EE 4:1); 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.37–7.04 (m, 10H, aromatic), 7.00/6.80 (2d, 4H,
p-Ph–H, J = 8.6 Hz), 6.31 (dd, 1H, –CH@CH2, J1 = 17.2 Hz, J2 =
1.6 Hz), 6.03/5.75 (2dd, 2H, –CH@CH2, J1 = 16.9 Hz, J2 = 10.7 Hz/
J1 = 10.2 Hz, J2 = 1.6 Hz), 6.00/4.64 (2d, 2H, Ph–CH–O, J = 6.4 Hz),
[2S-(2a,4a a)])
(10S*,20R*),5
Yield 46%, yellow oil, Rf = 0.32 (PE/EE 5:1); 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.68–6.62 (m, 24H, aromatic), 5.50 (d, 1H, Ph–
CH–O, J = 5.1 Hz), 5.30 (br s, 1H, NH), 4.44–4.15 (m, 2H, Ph–CH–O

646
K. Bica, P. Gaertner / Tetrahedron: Asymmetry 21 (2010) 641–646
and OCH2–Ph), 4.07–3.90 (m, 2H, PhCH–N and OCH2–Ph), 3.70 (s,
3H, CH3OCO–), 3.57 (s, 3H, CH3O–), 3.10 (m, 1H, –CHCOO–), 2.86/
2.46 (2dd, 2H, –COCH–CH2–CPh, J1 = 13.5 Hz, J2 = 6.5 Hz/
J1 = 13.5 Hz, J2 = 7.4 Hz) ppm; 13C NMR (50 MHz, CDCl3):
dC = 174.3 (s, –COOCH3), 171.0 (s, –CH–COO–), 159.0 (s, CHO3–C–
), 142.8/139.3/137.9/136.3 (4s, Ph–C-1), 130.3 (s, CH3O–Ph–C1),
129.0–113.5 (22d, Ph–C), 82.0/78.3 (2d, Ph–CH–O), 71.5 (s, N–C–
Ph), 70.2 (t, Ph–CH2–O), 64.4 (d, PhCH–N), 55.2 (q, CH3OPh–),
52.7 (q, CH3OCO–), 50.0 (d, –CH–COO–), 40.8 (t, –CH–CH2–CPh)
ppm. Anal. Calcd for C41H39NO6ꢂ1.4H2O: C, 73.83; H, 6.32; N,
2.10. Found: C, 73.88; H, 6.19; N, 1.95.
and, if necessary purified via flash column chromatography. There-
by all auxiliaries 5a–5c could be recovered almost quantitatively
without any loss of enantiomeric purity. To the acidic aqueous
phase was carefully added 40% NaOH while cooling on an ice bath.
The basic aqueous phase was extracted four times with CH2Cl2,
washed with brine, dried over Na2SO4, filtered, and evaporated to
yield 56 mg of pyrrolidinediol 9 (98%) as a colorless oil, Rf = 0.31
(CHCl3/MeOH 20/1); 1H NMR (200 MHz, CDCl3, TMS): dH = 7.47–
7.25 (m, 10H, aromatic), 4.52 (d, 1H, Ph–CH–N, J = 8.2 Hz), 3.77/
3.56 (2d, 2H, HO–CH2–CH–, J = 11.0 Hz), 3.32/3.25 (2dd, 2H, HO–
CH2–C–, J1 = 11.1 Hz, J2 = 6.0 Hz), 2.66–2.44 (br s, 4H, Ph–CH–CH–
CH2–, NH and 2OH), 2.39/2.31 (2dd, 2H, –CH–CH2–C–Ph,
J1 = 12.9 Hz, J2 = 8.2 Hz/J1 = 13.0 Hz, J2 = 7.2 Hz) ppm; 13C NMR
(50 MHz, CDCl3): dC = 144.7/140.5 (2s, Ph–C-1), 128.7–125.2 (d,
Ph–C), 68.6 (s, N–C–Ph), 68.0 (t, HO–CH2–CH), 66.8 (t, HO–CH2–
C), 62.0 (d, N–CH–Ph), 44,1 (d, CH2OH–CH–CH2) ppm. Anal. Calcd
for C18H21NO2ꢂ0.5H2O: C, 73.94; H, 7.58; N, 4.79. Found: C,
73.98; H, 7.27; N, 4.72.
4.9. [(2R)-(2a,4a a)]-2,5-Diphenylpyrrolidine-2,4-
(10R*,20S*),5
dicarboxylic acid, 4-[1,2-di(2-methoxyphenyl)-2-(2-
methylpropoxy)ethyl]ester, 2-methylester 8c (contains as
minor component [2S-(2a,4a a)])
(10S*,20R*),5
Yield 80%, yellow oil, Rf = 0.17 (PE/EE 4:1); 1H NMR (200 MHz,
CDCl3, TMS): dH = 7.84–6.43 (m, 18H, aromatic), 6.14 (d,
J = 3.1 Hz, 1H, OCHPh), 4.63–4.49 (m, 2H, OCHPh and PhCH–N),
4.15–3.12 (m, 10H, 3 ꢂ CH3O– and –CHCOO–), 3.19–2.94 (m, 3H,
O–CH2CH(CH3)2 and –CH–CH2–CPh), 2.71 (dd, 1H, J1 = 13.4 Hz,
J2 = 6.2 Hz, –CH–CH2–CPh) 1.96–1.71 (m, 1H, O–CH2CH(CH3)2),
0.92/0.91 (2d, J = 6.6 Hz, 6H, O–CH2CH(CH3)2) ppm; 13C NMR
(50 MHz, CDCl3): dC = 174.2 (s, –COOCH3), 171.4 (s, –CH–COO–),
157.1/156.4 (2s, Ph–C-2), 142.9/139.5 (4s, Ph–C-1), 128.7–109.3
(18d, Ph–C), 126.3/125.0 (2s, CH3O–Ph–C1), 76.1 (t, O–CH2–
CH(CH3)2), 75.9/75.6 (2d, Ph–CH–O), 71.5 (s, N–C–Ph), 64.5 (d,
PhCH–N), 55.0/54.9 (2q, Ph–OCH3), 52.6 (q, CH3OCO–), 50.0 (d, –
CH–COO–), 41.1 (t, –CH–CH2–CPh) 28.6 (d, O–CH2–CH(CH3)2),
19.4/19.3 (2q, O–CH2–CH(CH3)2) ppm. Anal. Calcd for C39H43NO7:
C, 73.45; H, 6.80; N, 2.20. Found: C, 73.21; H, 6.88; N, 2.15.
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To an ice-cooled solution of LiAlH4 (1.286 mmol/48 mg) in dry
THF (20 mL) was added a solution of ester 8a (0.643 mmol) in
dry THF (10 mL) and the reaction mixture was stirred for 1 h at
ambient temperature. Next, H2O (0.5 mL) and 40% NaOH (0.1 mL)
were added while cooling on an ice bath and the mixture was stir-
red at ambient temperature until a white solid had precipitated. A
small portion of Mg2SO4 was added and the mixture was filtered
over a pad of silica. The solvent was evaporated and the crude
product was dissolved in 10 mL CH2Cl2 and extracted five times
with 2 N HCl. For recovery of the auxiliary 5a the organic phase
was washed with brine, dried with Na2SO4, filtered, evaporated,
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