Synthesis of iminodiacetaldehyde derivatives as building blocks for pharmacologically active agents

Article abstract of DOI:10.1055/S-0029-1218622

The preparation of iminodiacetaldehyde derivatives is reported via oxidative cleavage of 3,4-dihydroxypyrrolidines with sodium periodate. High yields of iminodiacetaldehydes are obtained starting from N-acyl-protected pyrrolidines, whereas the basic N-benzyl-protected derivative does not yield the expected dialdehyde. A cis-configured dihydroxypyrrolidine, prepared from 2,5-dihydropyrrole, reacts considerably faster with sodium periodate than the corresponding trans-configured derivatives which are obtained in three steps from (R,R)-tartaric acid. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218622

PAPER
791
Synthesis of Iminodiacetaldehyde Derivatives as Building Blocks for
Pharmacologically Active Agents
S
ynthesis of Imino
v
diacetaldehy
o
de
D
erivativ
n
es ne Fricke, Nicole Kopp, Bernhard Wünsch*
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstr. 58–62, D-48149 Münster, Germany
Fax +49(251)8332144; E-mail: wuensch@uni-muenster.de
Received 8 September 2009; revised 9 November 2009
65% yield by oxidation of dihydroxy amine 3a with the
Collins reagent [CrO3(pyr)2]. In the second method, Boc-
protected Weinreb amide 4a was reduced with lithium
aluminum hydride to afford 1a in 56% yield. However,
Abstract: The preparation of iminodiacetaldehyde derivatives is
reported via oxidative cleavage of 3,4-dihydroxypyrrolidines with
sodium periodate. High yields of iminodiacetaldehydes are ob-
tained starting from N-acyl-protected pyrrolidines, whereas the ba-
sic N-benzyl-protected derivative does not yield the expected neither a detailed reaction procedure nor a work-up were
reported in this short communication,2 and only limited
dialdehyde. A cis-configured dihydroxypyrrolidine, prepared from
2,5-dihydropyrrole, reacts considerably faster with sodium perio-
spectroscopic data were provided.
date than the corresponding trans-configured derivatives which are
obtained in three steps from (R,R)-tartaric acid.
Boc
O
Boc
N
O
Key words: amino aldehydes, diol, cleavage, oxidation
N
MeO
OMe
HO
OH
N
N
3a
4a
Me
Me
This paper describes the synthesis of iminodiacetaldehyde
derivatives 1 containing various residues at the nitrogen
atom. The dialdehydes 1 represent promising building
blocks for the synthesis of N-heterocyclic diols 2 of vary-
ing ring size (n = 1, 2, 3) (Figure 1).
H
Boc
H
N
O
O
1a
R
N
Scheme 1 Reported syntheses of iminodiacetaldehyde 1a
H
R
N
H
Initially, we repeated the reported syntheses. Oxidation of
the Boc-protected diol 3a with the Collins reagent2 led to
the formation of dialdehyde 1a, as indicated by thin layer
chromatography. However, it was not possible to separate
dialdehyde 1a from the accompanying chromium salts.
Modification of the reaction conditions and the work-up
procedure did not lead to the isolation of the desired prod-
uct. Therefore, other oxidizing agents were investigated
for the oxidation of diol 3a. The chromium(VI) reagent
pyridinium dichromate (PDC),3 and the hypervalent io-
dine reagents, iodoxybenzene (IBX)4 and Dess–Martin
periodinane,5 did not provide the desired dialdehyde 1a.
Swern oxidation6of 3a with oxalyl chloride and dimethyl
sulfoxide at –78 °C gave low yields (15–20%) of the de-
sired dialdehyde 1a. However, purification of 1a proved
to be difficult; rapid hydration and decomposition were
observed during flash chromatography on silica gel.
O
HO
OH
O
n
1
2
Figure 1 General structures of dialdehydes 1 and N-heterocyclic
diols 2
Compounds containing N-heterocyclic diol units such as
2 exhibit interesting pharmacological properties and
multi-step procedures starting from natural products have
been reported for their preparation. One such example is
the synthesis of polyhydroxylated azepanes, which are po-
tent inhibitors of glucosidases, starting from quinic acid.1
The reaction of dialdehydes 1 with symmetrical dinucleo-
philes such as diethyl malonate, diethyl succinate or di-
methyl acetone-1,3-dicarboxylate should lead to six-,
seven- or eight-membered N-heterocycles, respectively,
with potentially interesting pharmacological activity.
For the synthesis of N-heterocyclic diols of type 2, a reli-
able method for the preparation of iminodiacetaldehyde
derivatives 1 is required. In 1986, Garrigues and Lazraq
described two methods for the synthesis of iminodiacetal-
dehyde 1a (Scheme 1).2 According to the first method,
Boc-protected iminodiacetaldehyde 1a was obtained in
Next, reduction of the Weinreb amide 4a was investigat-
ed. Compound 4a was prepared by condensation of N-
Boc-protected iminodiacetic acid and N,O-dimethylhy-
droxylamine in the presence of diethyl dicarbonate as the
coupling agent.2 The required Weinreb amide 4a was iso-
lated in a moderate 41% yield as a result of the formation
of several side products. After reduction of 4a with lithi-
um aluminum hydride, the dialdehyde 1a, could not be
isolated as during the work-up, its separation from alumi-
num salts proved to be problematic.
SYNTHESIS 2010, No. 5, pp 0791–0796
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Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218622; Art ID: T17509SS
© Georg Thieme Verlag Stuttgart · New York

792
Y. Fricke et al.
PAPER
Oxidative cleavage of 3,4-dihydroxypyrrolidines 7 was um aluminum hydride gave the 3,4-dihydroxypyrro-
envisaged as an alternative strategy to obtain dialdehydes lidines cis-7c and trans-7c in the ratio 67:33. Since
1 in high yields without laborious purification procedures separation of the diastereomeric mixtures of pyrrolidines
(Scheme 2). Thus, cis-configured 3,4-dihydroxypyrroli- 7 and 9 was not possible by recrystallization or by column
dine, cis-7b, was synthesized by acylation of 2,5-dihydro- chromatography on silica gel, this synthetic route was not
pyrrole (5) with benzyl chloroformate (CbzCl) and pursued any further.
subsequent oxidation of the double bond of intermediate
6 with osmium tetroxide (OsO4) and N-methylmorpholine
O
OH
N-oxide (NMO), in an overall yield of 76% (Scheme 2).7
OH
HO
OH
8a
(a)
O
(a)
Cbz
N
HN
5
6
91%
O
O
(b)
OH
OH
OH
Bn
N
Bn
N
OH
H
Cbz
N
H
(c) or (d)
OH
Cbz
N
O
O
O
O
cis-
9
63%
trans-
9
OH
dr (cis-
9
/trans-
9) = 64:36
1b (via c) 27%
cis-7b 84%
(via d) 82%
(b)
Scheme 2 Synthesis and oxidative cleavage of 3,4-dihydroxypyrro-
lidine cis-7b. Reagents and conditions: (a) CbzCl, Et3N, CH2Cl2, 24
h; (b) OsO4, t-BuOH, NMO, THF, r.t., 6 h; (c) Pb(OAc)4, CH2Cl2, r.t.,
3 h; (d) NaIO4, THF, H2O, r.t., 5 min.
OH
OH
OH
Bn
N
Bn
N
OH
trans-7c
dr (cis-7c/trans-7c) = 67:33
cis-7c
38%
Two common reagents for oxidative cleavage of diols are
lead(IV) acetate [Pb(OAc)4]8 in anhydrous solvents, and
sodium periodate (NaIO4) in aqueous solution.9 In order
to avoid the formation of aldehyde hydrates the oxidative
cleavage of cis-7b was investigated first with lead(IV)
acetate providing dialdehyde 1b in 27% yield. Since this
yield was not satisfactory, cleavage of cis-7b was per-
formed with sodium periodate in aqueous solution. After
a reaction time of five minutes, the transformation was
complete and dialdehyde 1b was isolated in 82% yield.
The high yield of 1b was obtained by careful drying of the
dialdehyde solution with magnesium sulfate in order to
shift the equilibrium between the dialdehyde and its hy-
drates (e.g. 10b or 12b, cf. Scheme 6) in favor of the dial-
dehyde.
Scheme 3 Synthesis of 3,4-dihydroxypyrrolidines starting from
meso-tartaric acid. Reagents and conditions: (a) BnNH2, o-xylene,
reflux, 7 h; (b) LiAlH4, THF, reflux, 24 h.
Since it is known that trans-configured diols can be
cleaved by sodium periodate, although longer reaction
times are required,11 the oxidative cleavage of trans-con-
figured pyrrolidine-3,4-diols was investigated. The trans-
configured diol, trans-7c, was obtained by condensation
of (R,R)-tartaric acid (8b) with benzylamine and subse-
quent reduction with lithium aluminum hydride.10 During
this transformation trans/cis epimerization was not ob-
served. The N-acyl derivatives, trans-7a and trans-7d,
were obtained in 92% and 49% yields, respectively, by
hydrogenolytic removal of the N-benzyl protecting group
of trans-7c and acylation of the resulting secondary amine
(Scheme 4).
Having successfully generated dialdehyde 1b, an im-
provement of the preparation of 3,4-dihydroxypyrro-
lidines 7 was investigated. The major drawbacks in the
synthesis of the diol cis-7b are the expensive and unstable
starting compound dihydropyrrole (5), as well as the high
toxicity of osmium tetroxide. The synthesis of trans-con-
figured 3,4-dihydroxypyrrolidines starting from (R,R)-
tartaric acid (8b) has been reported.10 Hence, to obtain the
cis-configured diol cis-7c, this synthesis was transferred
to meso-tartaric acid (8a) (Scheme 3).
Following preparation of the trans-diols 7 the oxidative
cleavage with sodium periodate was carried out
(Scheme 5) in a similar manner to that described for cis-
7b. Oxidative cleavage of the Boc- and Bz-protected di-
ols, trans-7a and trans-7d, with sodium periodate was
complete in 24 hours. Following careful drying of the so-
lutions with magnesium sulfate, the dialdehydes 1a and
1d were isolated in 88% and 77% yield, respectively. The
N-Bn-protected diol trans-7c reacted immediately with
sodium periodate, however, dialdehyde 1c was not isolat-
ed due to the rapid formation of several side products. It is
assumed that the tertiary amine group of trans-7c is re-
sponsible for its rapid decomposition.
Unexpectedly, condensation of meso-tartaric acid (8a)
with benzylamine resulted in a mixture of diastereomeric
diols, cis-9 and trans-9, in the ratio 64:36. It is thought
that, at high temperature (160 °C, 7 h), the basic benzyl-
amine is responsible for the epimerization to the thermo-
dynamically more stable diastereomer, trans-9. Reduction
of the diastereomeric mixture of cis-9/trans-9 with lithi-
Synthesis 2010, No. 5, 791–796 © Thieme Stuttgart · New York

PAPER
Synthesis of Iminodiacetaldehyde Derivatives
793
Whereas cleavage of the cis-configured diol cis-7b was
complete after five minutes, the corresponding reaction of
trans-7a and trans-7d required 24 hours. This difference
in reaction rates is based on the relative orientation of the
two adjacent hydroxy moieties.
O
O
OH
OH
OH
(a)
OH
Bn
N
HO
OH
8b
O
O
trans-9 75%
Due to their high reactivity, spectroscopic characteriza-
tion and determination of the purity of the iminodiacetal-
dehydes 1 turned out to be very difficult. The H NMR
spectrum of 1a, recorded directly after purification and
drying of the sample, is shown in Figure 2. The presence
of small amounts of water or alcohols led to the rapid for-
mation of acyclic and cyclic hydrates 10 and 12, or hemi-
acetals 11 and 13, in addition to other products
(Scheme 6).
(b)
1
OH
OH
OH
OH
(c) or (d)
R
N
Bn
N
trans-7a: R = Boc 92%
trans-7d: R = Bz 49%
trans-7c
62%
Scheme
4
Synthesis of trans-3,4-dihydroxypyrrolidines 7.
Reagents and conditions: (a) BnNH2, o-xylene, reflux, 20 h; (b)
LiAlH4, THF, reflux, 48 h; (c) H2, Pd/C, Boc2O, EtOH, r.t., 20 h
(trans-7a); (d) (1) H2, Pd/C, MeOH, r.t., 20 h; (2) BzCl, K2CO3,
CHCl3–MeOH (1:1), 0 °C, 20 h (trans-7d).
OR2
OH
OR2
O
O
R2OH
N
O
N
1
H
R1
R1
OH
H
R
N
H
OH
O
(a)
R
N
12: R2 = H
10: R2 = H
O
O
13: R2 = Me
11: R2 = Me
OH
trans-7a,c,d
1a–d
Scheme 6 Formation of hydrates and hemiacetals
1a: R = Boc 88%
1c: R = Bn 0%
1d: R = Bz 50%
In the 13C NMR spectra of 1 weak signals due to the acetal
carbon atoms of hydrates 10 and 12 were present in the
range 80–90 ppm. The mass spectrum of a sample of 1d
which had been dissolved in methanol, showed, in addi-
tion to the mass ion of 1d (m/z = 205), peaks for the hy-
drates 10d/12d (R1 = Ph, R2 = H, m/z = 246 [M + Na +
H2O]+) and the hemiacetals 11d/13d (R1 = Ph, R2 = Me,
m/z = 260 [M + Na + MeOH]+).
Scheme 5 Oxidative cleavage of trans-3,4-dihydroxypyrrolidines
7. Reagents and conditions: (a) NaIO4, THF, H2O, r.t., 24 h.
In general, the oxidative cleavage of cis- and trans-con-
figured 3,4-dihydroxypyrrolidines 7 with sodium perio-
date represents an efficient and reliable method for the
synthesis of iminodiacetaldehydes 1. The configuration of
the diols 7 had a significant influence on the reaction rate.
Figure 2 1H NMR spectrum of 1a
Synthesis 2010, No. 5, 791–796 © Thieme Stuttgart · New York

794
Y. Fricke et al.
PAPER
MS spectra were recorded using a MAT GCQ (Thermo-Finnigan)
apparatus, EI = electron impact, ESI = electrospray ionization. Ex-
act mass spectra were obtained using MicroTof (Bruker Daltronics)
or LTQ Orbitap LTQ XL (Thermo-Fisher Scientific) instruments.
The characterization data for compounds 6,12 trans-7a,13 trans-7c,10
trans-7d13 and trans-910 was comparable with reported data.
To demonstrate the suitability of the very reactive dialde-
hyde 1d in further chemistry, a Wittig reaction with
(ethoxycarbonylmethylene)triphenylphosphorane
was
carried out (Scheme 7). The resulting diene 14 was ob-
tained in 51% yield. The yield of 14 could be improved
via in situ preparation of the dialdehyde 1d and using it di-
rectly without purification in the Wittig reaction.
Iminodiacetaldehydes 1; General Procedure
A soln of NaIO4 (1.2 or 1.5 equiv) in H2O (1.5 mL) was added to a
soln of 3,4-dihydroxypyrrolidine 7 (1 equiv) in THF (3.5 mL). After
stirring the reaction mixture for 5 min (cis-7) or 24 h (trans-7), the
solvent was removed under vacuum. The aq layer was sat. with
NaCl and extracted with EtOAc (3 × 2 mL). The combined organic
layer was dried (Na2SO4), filtered, concd under vacuum and the res-
idue was dissolved in anhyd CH2Cl2. Anhyd MgSO4 was added, and
after stirring for 24 h at r.t., the suspension was filtered and concd
under vacuum.
CO2Et
H
Bz
N
H
(a)
Bz
N
O
O
CO2Et
14 51%
1d
Scheme 7 Wittig reaction of iminodiacetaldehyde 1d. Reagents and
conditions: (a) Ph3PCHCO2Et, THF, r.t., 20 h.
N-(tert-Butoxycarbonyl)iminodiacetaldehyde (1a)
Following the general procedure, oxidative cleavage of trans-7a
(102 mg, 0.50 mmol) with NaIO4 (128 mg, 0.6 mmol) was complete
In conclusion, an efficient and reproducible method for
the synthesis of N-protected iminodiacetaldehyde deriva- in 24 h.
tives 1 has been presented. Various methods for the oxi-
dation of diol 3a as well as lithium aluminum hydride
reduction of the Weinreb amide 4a did not provide the di-
aldehyde 1a. High yields of dialdehydes 1a, 1b and 1d
were obtained by oxidative cleavage of the corresponding
3,4-dihydroxypyrrolidines 7 using sodium periodate, pro-
vided that the basic nature of the N-atom was negated by
the introduction of an N-acyl moiety. Whereas the cis-
configured diol cis-7b was cleaved within five minutes,
the cleavage of the trans-configured diols trans-7a and
trans-7d required 24 hours. The diol cis-7b was prepared
from expensive and unstable 2,5-dihydropyrrole (5) using
osmium tetroxide as the oxidant. Condensation of (R,R)-
tartaric acid (8b) with benzylamine, lithium aluminum hy-
dride reduction and exchange of the N-protecting group
gave the trans-configured diols, trans-7a and trans-7d.
Colorless oil; yield: 88.6 mg (88%); Rf = 0.39 (CH2Cl2–MeOH,
10:1).
IR (film): 2978 (w, CH2), 1731 (m, C=Oaldehyde), 1690 (s, C=Ocarbamate
)
cm–1.
1H NMR (CDCl3): d = 1.44 [s, 9 H, C(CH3)3], 3.96 (s, 2 H, NCH2),
4.17 (s, 2 H, NCH2), 9.64 (s, 1 H, CHO), 9.66 (s, 1 H, CHO).
13C NMR (CDCl3): d = 28.3 [C(CH3)3], 58.4 (NCH2), 58.5 (NCH2),
82.2 [C(CH3)3], 155.3 (Ccarbamate), 198.1 (CHO), 198.5 (CHO).
HRMS–ESI (MeCN): m/z [M + Na]+ calcd for C9H15NO4Na:
224.0888; found: 224.0893; m/z [M + Na + H2O]+ calcd for
C9H15NO4Na·H2O: 242.0999; found: 242.0994.
N-(Benzyloxycarbonyl)iminodiacetaldehyde (1b)
Following the general procedure, oxidative cleavage of cis-7b (108
mg, 0.45 mmol) with NaIO4 (146 mg, 0.68 mmol) was complete in
5 min.
Colorless oil; yield: 87.0 mg (82%); Rf = 0.37 (CH2Cl2–MeOH,
10:1).
Unless otherwise noted, moisture-sensitive reactions were conduct-
ed under anhyd N2. CH2Cl2 and MeOH were distilled over CaH2.
THF was dried over Na/benzophenone and was freshly distilled be-
fore use. Thin layer chromatography (TLC) was performed using
silica gel 60 F254 plates (Merck). Flash chromatography was per-
formed using silica gel 60, 40–64 m (Merck) with the eluent speci-
fied in each case. Melting points were recorded using an SMP 3
apparatus (Stuart Scientific) and are uncorrected. HPLC data were
obtained using Merck Hitachi Equipment; UV detector: L-7400; au-
tosampler: L-7200; pump: L-7100; degasser: L-7614; column: Li-
Chrospher® 60 RP-select B (5 m); LiChroCART® 250–4 mm
cartridge; flow rate: 1.0 mL/min; injection volume: 5.0 mL; detec-
tion at l = 210 nm. Method 1: the mobile phase was composed of
(A) 100% H2O and (B) 100% MeCN. TFA (0.05%) was added to
both components. The following gradient was applied (A%): 0 min
(90%), 4 min (90%), 29 min (0%), 31 min (0%), 31.5 min (90%),
40 min (90%). Method 2: the mobile phase was composed of (A)
100% H2O and (B) 100% MeOH. TFA (0.05%) was added to both
components. The following gradient was applied (A%): 0 min
(80%), 1 min (80%), 22 min (0%), 30 min (0%), 31.5 min (80%),
40 min (80%). IR spectra were recorded on a 480 Plus FT-ATR-IR
(Jasco) spectrophotometer. 1H NMR (400 MHz) and 13C NMR (100
MHz) spectra were obtained using a Mercury-400BB spectrometer
(Varian); chemical shifts (d) are reported in ppm relative to tetra-
methylsilane; coupling constants are given with 0.5 Hz resolution.
IR (film): 2923 (w, CH2), 1738 (m, C=Oaldehyde), 1695 (s, C=Ocarbamate),
735, 696 (s, Ar out of plane) cm–1.
1H NMR (CDCl3): d = 4.10 (s, 2 H, NCH2), 4.22 (s, 2 H, NCH2),
5.15 (s, 2 H, ArCH2), 7.29–7.38 (m, 5 H, ArH), 9.62 (s, 1 H, CHO),
9.64 (s, 1 H, CHO).
13C NMR (CDCl3): d = 58.2 (NCH2), 58.7 (NCH2), 68.5 (ArCH2N),
128.3 (CAr), 128.6 (CAr), 128.8 (CAr), 135.8 (Cq,Ar), 155.9 (Ccarbamate),
197.6 (CHO), 197.7 (CHO).
HRMS–ESI (MeCN): m/z [M + H]+ calcd for C12H14NO4:
236.0917; found: 236.0911; m/z [M + Na]+ calcd for C12H13NO4Na:
258.0737; found: 258.0730; m/z [2M
C24H26N2O8Na: 493.1581; found: 493.1566.
+
Na]+ calcd for
N-Benzoyliminodiacetaldehyde (1d)
Following the general procedure, oxidative cleavage of trans-7d
(170 mg, 0.82 mmol) with NaIO4 (263 mg, 1.23 mmol) was com-
plete in 24 h.
Colorless oil; yield: 83.2 mg (50%); Rf = 0.35 (CH2Cl2–MeOH,
10:1).
IR (film): 2925 (w, CH2), 1724 (m, C=Oaldehyde), 1615 (s, C=Oamide),
789, 699 (s, Ar out of plane) cm–1.
Synthesis 2010, No. 5, 791–796 © Thieme Stuttgart · New York

PAPER
Synthesis of Iminodiacetaldehyde Derivatives
795
1H NMR (CDCl3): d = 4.30 (s, 2 H, NCH2), 4.33 (s, 2 H, NCH2),
7.35–7.53 (m, 5 H, ArH), 9.54 (s, 1 H, CHO), 9.72 (s, 1 H, CHO).
IR (neat): 3388 (m, OH), 2947 (w, CH2), 1670 (s, C=Ocarbamate), 744,
696 (s, Ar out of plane) cm–1.
13C NMR (CDCl3): d = 60.9 (2 × NCH2), 127.3 (CAr), 128.1 (CAr),
129.4 (CAr), 135.0 (Cq,Ar), 172.5 (ArC=O), 196.4 (CHO), 197.1
(CHO).
1H NMR (CDCl3): d = 2.54 (br s, 2 H, 2 × OH), 3.36–3.48 (m, 2 H,
NCH2), 3.62–3.69 (m, 2 H, NCH2), 4.26 (br s, 2 H, 2 × CHOH), 5.12
(s, 2 H, ArCH2), 7.29–7.37 (m, 5 H, ArH).
HRMS–ESI (MeOH): m/z [M + H]+ calcd for C11H12NO3:
206.0812; found: 206.0816; m/z [M + Na]+ calcd for C11H11NO3Na:
228.0631; found: 228.0630; m/z [M + Na + H2O]+ calcd for
C11H11NO3Na·H2O: 246.0737; found: 246.0736; m/z [M + Na +
MeOH]+ calcd for C11H11NO3Na·CH3OH: 260.0893; found:
260.0893: m/z [2M + Na]+ calcd for C22H22N2O6Na: 433.1370;
found: 433.1379.
MS (EI): m/z = 237 [M]+, 91 [PhCH2]+.
(3S,4S)-1-Benzylpyrrolidine-3,4-diol (trans-7c)10
LiAlH4 (1.7 g, 46 mmol) was suspended in THF (150 mL) and the
mixture was cooled to 0 °C in an ice-bath. Next, trans-9 (4.4 g, 20
mmol) was added slowly and the mixture was heated under reflux
for 48 h. After cooling to –15 °C, H2O (1.7 mL), NaOH (2 M, 1.7
mL) and H2O (5.3 mL) were added dropwise. The soln was stirred
for 1 h at –15 °C after which the resulting precipitate was removed
by filtration. The precipitate was suspended in THF (50 mL), heated
to reflux for a short time, and then filtered. This procedure was re-
peated three times. The filtrate was concd under vacuum and the
residue was purified by recrystallization from EtOAc.
Benzyl 2,5-Dihydro-1H-pyrrole-1-carboxylate (6)12
CbzCl (0.21 mL, 1.5 mmol) in toluene (1 mL) was added to a soln
of 2,5-dihydropyrrole (5) (0.11 mL, 1.5 mmol, 96%) in CH2Cl2 (4
mL). Et3N (0.28 mL, 1.5 mmol) was added dropwise and the reac-
tion was stirred for 24 h at r.t. The reaction mixture was washed
with sat. aq NH4Cl soln (2 × 10 mL) and brine (10 mL) and the aq
layer then extracted with EtOAc (3 × 10 mL). The combined organ-
ic layer was dried (Na2SO4), concd under vacuum and the residue
was purified by flash column chromatography (silica gel, cyclohex-
ane–EtOAc, 4:1).
Pale-yellow solid; yield: 2.5 g (64%); mp = 99.3 °C; purity (HPLC,
method 2): 98%, tR = 4.6 min.
IR (neat): 3311 (s, OH), 2921 (w, CH2), 722 (m, Ar out of plane),
697 (s, Ar out of plane) cm–1.
1H NMR (DMSO-d6): d = 2.29 (dd, 2 H, 2J = 9.6 Hz, 3J = 4.3 Hz,
Colorless oil; yield: 278 mg (91%); Rf = 0.31 (cyclohexane–EtOAc,
2:1); purity (HPLC, method 1): 99%, tR = 19.1 min.
NCH2CHOH), 2.74 (dd,
2
H, 2J = 9.5 Hz, 3J = 5.9 Hz,
2
NCH2CHOH), 3.46 (d, 1 H, J = 13.0 Hz, ArCH2), 3.58 (d, 1 H,
2J = 13.0 Hz, ArCH2), 3.80–3.87 (m, 2 H, 2 × CHOH), 4.83 (d, 2 H,
2 × OH), 7.19–7.34 (m, 5 H, ArH).
IR (film): 3033 (w, CH), 2953 (w, CH2), 1699 (s, C=Ocarbamate), 747,
696 (s, Ar out of plane) cm–1.
1H NMR (CDCl3): d = 4.20 (m, 4 H, 2 × NCH2), 5.17 (s, 2 H,
ArCH2), 5.76 (td, 1 H, 3J = 6.6 Hz, 3J = 1.7 Hz, CH), 5.80 (td, 1 H,
3J = 6.5 Hz, 3J = 1.7 Hz, CH) 7.29–7.40 (m, 5 H, ArH).
MS (EI): m/z = 193 [M]+, 91 [PhCH2]+.
(3R,4S)-1-Benzylpyrrolidine-3,4-diol (cis-7c) and (3S,4S)-1-
Benzylpyrrolidine-3,4-diol (trans-7c)
MS (EI): m/z = 203 [M]+, 91 [PhCH2]+.
Dione 9 (286 mg, 1.3 mmol, cis-9/trans-9 = 64:36) was added care-
fully to a suspension of LiAlH4 (154 mg, 4.1 mmol) in THF (5 mL)
at 0 °C. The reaction mixture was heated at reflux for 24 h. After
cooling to –15 °C, H2O (60 L), NaOH (2 M, 60 L) and H2O (180 L)
were added dropwise. The soln was stirred for 1 h at –15 °C after
which the resulting precipitate was removed by filtration. The pre-
cipitate was suspended in THF (5 mL), heated for a short time, and
then filtered. This procedure was repeated three times. The filtrate
was concd in vacuo and the residue was purified by flash column
tert-Butyl (3S,4S)-3,4-Dihydroxypyrrolidine-1-carboxylate
(trans-7a)13
Diol trans-7c (198 mg, 1.0 mmol) was dissolved in EtOH (7 mL)
and Boc2O (247 mg, 1.1 mmol) and Pd/C (16%, 32.7 mg) were add-
ed. The reaction mixture was stirred at r.t. under a H2 atm (1 bar,
balloon) for 20 h and then filtered through Celite®. The solvent was
removed under vacuum and the residue purified by recrystallization
from EtOAc.
chromatography
[silica
gel,
CH2Cl2→CH2Cl2–MeOH
Colorless solid; yield: 191 mg (94%); mp 162.5 °C; purity (HPLC,
method 1): 99%, tR = 14.8 min.
(10:1)→CH2Cl2–MeOH (5:1)] to afford the product as a diastereo-
meric mixture (cis-7c/trans-7c, 67:33).
IR (neat): 3386 (m, OH), 3321 (m, OH), 2979 (w, CH2), 1657 (s,
C=Ocarbamate) cm–1.
1H NMR (DMSO-d6): d = 1.39 [s, 9 H, C(CH3)3], 3.10 (dd, 2 H,
2J = 11.6 Hz, 3J = 3.0 Hz, NCH2CHOH), 3.29–3.34 (m, 2 H,
NCH2CHOH), 3.83–3.88 (m, 2 H, 2 × CHOH), 5.06 (d, 2 H, 2 ×
CHOH).
Pale-yellow oil; yield: 94.7 mg (38%); Rf = 0.1 (CH2Cl2–MeOH,
2:1).
IR (film): 3336 (s, OH), 2922 (s, CH2), 2804 (s, CH2), 751 (m, Ar
out of plane), 697 (s, Ar out of plane) cm–1.
1H NMR (DMSO-d6): d (67:33 diastereomeric mixture) = 2.28 (dd,
2
3
2 × 0.67 H, J = 9.5 Hz, J = 4.9 Hz, NCH2CHOH), 2.29 (dd, 2 ×
MS (ESI): m/z = 226 [M + Na]+, 429 [2M + Na]+.
0.33 H, 2J = 9.6 Hz, 3J = 4.3 Hz, NCH2CHOH), 2.74 (dd, 2 × 0.33
2
3
H, J = 9.5 Hz, J = 5.9 Hz, NCH2CHOH), 2.81 (dd, 2 × 0.67 H,
Benzyl cis-3,4-Dihydroxypyrrolidine-1-carboxylate (cis-7b)7
A soln of OsO4 (1.7 mg, 0.007 mmol) in t-BuOH (6 mL) was added
to a soln of 6 (156 mg, 0.77 mmol) in THF (2 mL). After addition
of NMO (90 mg, 0.77 mmol), the reaction mixture was stirred for 6
h at r.t. The solvent was removed under reduced pressure and the
residue was dissolved in EtOAc and washed with sat. aq Na2SO3
soln, sat. aq NaHCO3 soln and brine. The organic layer was dried
(Na2SO4), concd in vacuo and the residue purified by flash column
chromatography (silica gel, CH2Cl2–MeOH, 20:1). In ref.7 only the
mp and Rf value are given.
2J = 9.5 Hz, J = 6.2 Hz, NCH2CHOH), 3.46 (d, 0.33 H, J = 13.0
Hz, ArCH2), 3.54 (s, 2 × 0.67 H, ArCH2), 3.57 (d, 0.33 H, 2J = 13.0
Hz, ArCH2), 3.80–3.87 (m, 2 × 0.33 H, 2 × CHOH), 3.91–3.95 (m,
2 × 0.67 H, 2 × CHOH), 4.53 (d, 2 × 0.67 H, 2 × OH), 4.83 (d, 2 ×
0.33 H, 2 × OH), 7.19–7.36 (m, 5 × 0.33 H, 5 × 0.67 H, ArH).
3
2
MS (EI): m/z = 193 [M]+, 91 [PhCH2]+.
(3S,4S)-1-Benzoylpyrrolidine-3,4-diol (trans-7d)13
Diol trans-7c (861 mg, 4.5 mmol) was dissolved in MeOH (15 mL)
and Pd/C (15%, 470 mg) was added. After stirring for 20 h under a
H2 atm (1 bar, balloon) the mixture was filtered through Celite®.
The solvent was removed under vacuum and the residue was dis-
Colorless solid; yield: 153 mg (84%); mp 82.1 °C; Rf = 0.32
(CH2Cl2–MeOH, 10:1); purity (HPLC, method 1): 99%, tR = 12.5
min.
Synthesis 2010, No. 5, 791–796 © Thieme Stuttgart · New York

796
Y. Fricke et al.
PAPER
solved in CHCl3–MeOH (15 mL, 1:1). K2CO3 (5.5 g) was added,
the mixture cooled to 0 °C and benzoyl chloride (564 mL, 4.9 mmol)
was added dropwise. The reaction mixture was stirred for 20 h at r.t.
after which the solvent was removed under reduced pressure and the
residue was dissolved in Et2O (10 mL) and filtered. Following evap-
oration of the solvent in vacuo, the residue was purified by flash col-
umn chromatography (silica gel, CH2Cl2–MeOH, 9:1).
MS (EI): m/z = 221 [M]+, 91 [PhCH2]+.
Diethyl 4,4¢-(benzoylimino)bisbut-2-enoate (14)
(Ethoxycarbonylmethylene)triphenylphosphorane (568 mg, 1.63
mmol) was added to a soln of dialdehyde 1d (127 mg, 0.62 mmol)
in THF (5 mL) and the mixture was stirred for 20 h at r.t. Then H2O
was added, the organic solvent was removed in vacuo and the resid-
ual mixture was extracted with EtOAc (3 × 5 mL). The combined
organics were dried (Na2SO4), filtered, concd under vacuum and the
residue purified by flash column chromatography (silica gel, cyclo-
hexane–EtOAc, 2:1).
Pale-yellow oil; yield: 451 mg (49%); Rf = 0.19 (CH2Cl2–MeOH,
9:1); purity (HPLC, method 2): 97%, tR = 6.13 min.
IR (neat): 3386 (m, OH), 3321 (m, OH), 2979 (w, CH2), 1657 (s,
C=O).
Colorless resin; yield: 109 mg (51%); Rf = 0.53 (cyclohexane–
EtOAc, 1:4); purity (HPLC, method 1): 99%, tR = 19.03–19.71 min.
1H NMR (DMSO-d6): d = 3.15 (d, 1 H, 3J = 11.2 Hz, NCH2CHOH),
3
3
3.34 (d, 1 H, J = 12.7 Hz, NCH2CHOH), 3.67 (td, 2 H, J = 11.4
Hz, 3J = 3.7 Hz, 2 × CHOH), 3.89 (br s, 1 H, NCH2CHOH), 3.98 (d,
1 H,3J = 3.7 Hz, NCH2CHOH), 5.19 (br s, 2 H, 2 × OH), 7.40–7.55
(m, 5 H, ArH).
IR (film): 2981 (w, C–H), 2940 (w, CH2), 1714 (s, C=Oester), 1699
(s, C=Ocarbamate) cm–1.
1H NMR (CDCl3): d = 1.30 (t, 6 H, 3J = 7.1 Hz, 2 × CH3), 4.02 (br
s, 2 H, NCH2), 4.21 (q, 4 H, 3J = 7.2 Hz, 2 × CH2CH3), 4.25–4.34
(m, 1 H, NCH2), 4.44–4.77 (m, 1 H, NCH2), 5.94 (d, 2 H, 3J = 15.1
Hz, 2 × CH=CHCO2Et), 6.12–6.36 (m, 0.5 H, CH=CHCO2Et),
6.58–6.73 (m, 1.5 H, CH=CHCO2Et) 7.35–7.48 (m, 5 H, ArH).
13C NMR (CDCl3): d = 14.4 (2 × CH2CH3), 45.9, 49.9 (2 × NCH2),
60.9 (2 × CH2CH3), 123.4, 123.7 (2 × CH=CHC=O), 126.8 (CAr),
128.7 (CAr), 128.9 (CAr), 130.5 (CAr), 135.1 (Cq,Ar), 142.4
(CH=CHC=O), 145.2 (CH=CHC=O), 165.9 (C=Oamide), 172.1 (2 ×
CHC=Oester).
MS (EI): m/z = 206 [M – H]+, 105 [PhC=O]+, 77 [Ph]+.
(3R,4R)-1-Benzyl-3,4-dihydroxypyrrolidine-2,5-dione (trans-
9)10
A suspension of (R,R)-(+)-tartaric acid (8b) (751 mg, 5.0 mmol) and
benzylamine (0.55 mL, 5 mmol) in o-xylene (50 mL) was heated at
reflux in a Dean–Stark apparatus. After 20 h, the reaction mixture
was cooled to r.t. and the resulting precipitate was removed by fil-
tration. The product was recrystallized from EtOH.
Pale-yellow solid; yield: 905 mg (82%); mp 196.7 °C; purity
(HPLC, method 1): >99%, tR = 10.1 min.
MS (EI): m/z = 345 [M]+, 240 [M – PhC=O]+, 105 [PhC=O]+, 77
[Ph]+.
IR (neat): 3439 (w, OH), 3223 (s, OH), 2928 (m, CH2), 1705 (s,
C=O), 745, 690 (s, Ar out of plane) cm–1.
Supporting Information for this article is available online at
3
1H NMR (DMSO-d6): d = 4.38 (d, 2 H, J = 2.4 Hz, 2 × CHOH),
http://www.thieme-connect.com/ejournals/toc/synthesis.
2
2
4.53 (d, 1 H, J = 15.0 Hz, ArCH2), 4.57 (d, 1 H, J = 15.0 Hz,
ArCH2), 6.31 (br s, 2 H, 2 × OH), 7.22–7.35 (m, 5 H, ArH).
References
MS (EI): m/z = 221 [M]+, 106 [C7H8N]+, 91 [PhCH2]+.
(1) Shih, T.; Yang, R.; Li, S.; Chiang, C.; Lin, C. J. Org. Chem.
2007, 72, 4258.
(2) Garrigues, B.; Lazraq, M. Tetrahedron Lett. 1986, 27, 1685.
(3) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399.
(4) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisanoj, G.
J. Org. Chem. 1995, 60, 7272.
(5) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(6) Tidwell, T. T. Synthesis 1990, 857.
(7) Rosenberg, S. H.; Woods, K. W.; Sham, H. L.; Kleinert, H.
D.; Martin, D. L.; Stein, H.; Cohen, J.; Egan, D. A.; Bopp, B.
J. Med. Chem. 1990, 33, 1962.
(3R,4S)-1-Benzyl-3,4-dihydroxypyrrolidine-2,5-dione (cis-9)
and (3R,4R)-1-Benzyl-3,4-dihydroxypyrrolidine-2,5-dione
(trans-9)
Benzylamine (0.44 mL, 4 mmol) was added to a suspension of
meso-tartaric acid (8a) (600 mg, 4.0 mmol) in o-xylene (50 mL).
After heating for 7 h under reflux in a Dean–Stark apparatus, the re-
action mixture was cooled to r.t. The resulting precipitate was fil-
tered, washed with cold acetone and dried under high vacuum. The
product was recrystallized from EtOH as a diastereomeric mixture
(cis-9/trans-9, 64:36).
(8) Criegee, R. Chem. Ber. 1931, 64, 260.
(9) Fatiadi, A. J. Synthesis 1974, 229.
Colorless solid; yield: 561 mg (63%).
IR (neat): 3310 (m, OH), 2945 (w, CH2), 1699 (s, C=O), 749, 692
(s, Ar out of plane) cm–1.
(10) Rocha Gonsalves, M. d’A.; Serra, M. E. S.; Murtinho, D.;
Silva, V. F.; Matos Beja, A.; Paixão, J. A.; Ramos Silva, M.;
Alte da Veiga, L. J. Mol. Catal. A: Chem. 2003, 195, 1.
(11) Price, C. C.; Knell, M. J. Am. Chem. Soc. 1942, 64, 552.
(12) Chapman, T. M.; Courtney, S.; Hay, P.; Davis, B. G. Chem.
Eur. J. 2003, 9, 3397.
1H NMR (DMSO-d6): d (64:36 diastereomeric mixture) = 4.38 (d, 2
× 0.36 H, 3J = 2.4 Hz, 2 × CHOH), 4.41 (d, 2 × 0.64 H, 3J = 5.1 Hz,
2 × CHOH), 4.53 (d, 0.36 H, 2J = 15.0 Hz, ArCH2), 4.54 (s, 2 × 0.64
H, ArCH2), 4.57 (d, 0.36 H, 2J = 15.0 Hz, ArCH2), 6.02 (d, 2 × 0.64
H, 3J = 5.1 Hz, 2 × OH), 6.31 (br s, 2 × 0.36 H, 2 × OH), 7.21–7.35
(m, 5 × 0.36 H, 5 × 0.64 H, ArH).
(13) Siedlecka, R.; Wojaczynska, E.; Skarzewski, J.
Tetrahedron: Asymmetry 2004, 15, 1473.
Synthesis 2010, No. 5, 791–796 © Thieme Stuttgart · New York