New isosteres of (R)-2-methylhomoserine and (R)-2-methylaspartic acid by alkylation of a chiral imine leading stereoselectively to a quaternary stereogenic center

Article abstract of DOI:10.1016/j.tetasy.2009.07.005

Imines obtained from either chiral 3-amino-4-silyloxymethylpyrrolidin-2-one 5a or 5b underwent alkylation to give, in good yield and total stereoselection, the corresponding 3,3,4-trisubstituted pyrrolidin-2-ones 8a-d where both the amino and the silyloxy

Full text of DOI:10.1016/j.tetasy.2009.07.005

Tetrahedron: Asymmetry 20 (2009) 1824–1827
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Tetrahedron: Asymmetry
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New isosteres of (R)-2-methylhomoserine and (R)-2-methylaspartic acid
by alkylation of a chiral imine leading stereoselectively to a quaternary
stereogenic center
*
Emanuela Crucianelli, Gianluca Martelli , Mario Orena, Samuele Rinaldi, Federica Sgolastra
Dipartimento I.S.A.C., Università Politecnica delle Marche, Via Brecce Bianche, I-60131 Ancona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Imines obtained from either chiral 3-amino-4-silyloxymethylpyrrolidin-2-one 5a or 5b underwent alkyl-
ation to give, in good yield and total stereoselection, the corresponding 3,3,4-trisubstituted pyrrolidin-2-
ones 8a–d where both the amino and the silyloxymethyl groups lie cis to each other, as shown by 1H NMR
spectroscopic data and NOE experiments. By removal of both the imino group and the chiral inducer from
8b, the pyrrolidin-2-one 12, an isostere of (R)-2-methylhomoserine 2 and the pyrrolidin-2-one 14, an iso-
stere of (R)-2-methylaspartic acid 4 were obtained straightforwardly.
Received 10 June 2009
Accepted 1 July 2009
Available online 5 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
butyrine) 3 has been used to construct peptides with a 310 helical
structure.5 On the other hand, (R)-
a-methylaspartate 4 is an espe-
Structural modifications are often required in order to over-
come problems arising from current drug-delivery strategies of
biologically active peptides, which have a large potential for ther-
apeutical applications. In fact, the properties desired but often not
present in the native ligand include: receptor/acceptor selectivity;
high potency; stability against proteolytic breakdown; and appro-
priate biodistribution and bioavailability, so that analogues are of-
ten employed in order to circumvent these drawbacks.1 Owing to
their biological properties, both as free amino acids and as compo-
cially effective building block for engineering
a
-helical structures.6
COOH
HO
NH2
COOH
NH2
HO
1
2
OH
COOH
HOOC
COOH
NH2
nents of peptides, and to their conformational properties,
amino acids have assumed an important role in bioorganic chem-
istry in recent years. For example, (S)- -methyl-DOPA (Aldomet)
1, an inhibitor of DOPA decarboxylase, is an important commercial
antihypertensive.2 Substitution of (50)-
-methyltyrosine for tyro-
a-methyl
NH2
a
3
4
a
sine-4 in angiotensin II results in a peptide that is resistant to chy-
motrypsin degradation, but retains 93% of the pressor activity of
the parent peptide.3 In an analogue of the locust CRF-like diuretic
peptide, methionines at the 1-, 3-, and 13-positions were replaced
by isosteric methyl-homoserine residues 2. This analogue has been
tested for biological activity on Malpighian tubules in vitro, and
feeding behavior in vivo. It is highly active in the stimulation of
fluid secretion and accumulation of cAMP in tubules, and on
increasing the latency to feed and reduce meal duration.4
Eventually, incorporation of amino acids isosteres into proteins
that carry conformational restrictions due to rigidity elements such
as double bonds, carbocyclic, or heterocyclic rings is a versatile
technique for affecting or enhancing their biological activity.7
Therefore, the development of methods for the stereoselective syn-
thesis of 3,3,4-trisubstituted pyrrolidin-2-ones is of growing inter-
est directed toward the preparation of strongly conformationally
restricted analogues of naturally occurring amino acids.
For the de novo design of peptides and proteins, several chiral
a
-methyl amino acids are useful building blocks for engineering
2. Results and discussion
helical secondary structures. For instance, (S)-isovaline ( -methyl-
a
We have already reported the stereoselective synthesis of con-
formationally restricted analogues of proteinogenic amino acids
* Corresponding author. Tel.: +39 071 2204720; fax: +39 071 2204714.
E-mail address: gmartell@univpm.it (G. Martelli).
where the rigidity arises from a c
-lactam ring.8 Herein we report
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.005

E. Crucianelli et al. / Tetrahedron: Asymmetry 20 (2009) 1824–1827
1825
work directed to cyclic homoserine and aspartic acid analogues
with an quaternary carbon. In fact an additional alkyl substituent
n.O.e. 6%
n.O.e. 5.5%
a
PMP
O
H
CH3
H
was introduced via the stereoselective alkylation of the chiral
imine 7, easily prepared from the enantiomerically pure 3,4-
trans-disubstituted pyrrolidin-2-one 5, already synthesized in our
laboratory (Scheme 1). At first, the pyrrolidin-2-one 5 was treated
with benzaldehyde in dry THF, in the presence of 4 Å molecular
sieves, to afford the corresponding imine 6 in high purity, which
was not separated, but directly underwent reaction with TBDMS-
Cl to give in quantitative yield the corresponding TBDMS ether 7,
which was subsequently used without any further purification.
The alkylation of the imine 7 was carried out with LiHMDS, and
proceeded in very high yield and total stereoselection, to give
3,3,4-disubstituted pyrrolidin-2-ones 8 as the sole isomers, as evi-
denced by 1H NMR data (Scheme 1).
CH3
H
H
N
N
O
O
H3C
NH-t-Boc
PMP
O
N
H
10
11
OH
CH3
Scheme 2. Significant NOE effects for compounds 10 and 11.
O
O
CH3
H
N
t-BocNH
OH
H3C
H
O
O
N
N
H
Ph
12
10
H2N
N
OH
i
OH
PMP
ii
H
O
ii
O
iv
N
N
N
5
6
R1
CH3
N
R1
N
CH3
N
H2N
t-BocNH
OH
OH
i
iii
8b
O
O
R3
N
Ph
Ph
9
11
OR2
OR2
PMP
PMP
iv
iii
H
H
O
O
N
CH3
N
COOCH3
t-BocNH
CH3
7
COOCH3
R1
t-BocNH
O
8
R1
v
O
Scheme 1. Reagents and conditions. (i) PhCHO, MS 4 Å, dry THF, (a) R1 = C6H5, (b)
N
H
R
R
R
1 = 4-CH3OC6H4; (ii) TBDMSCl, imidazole, THF, (a) R1 = C6H5, R2 = TBDMS, 92%, (b)
1 = 4-CH3OC6H4, R2 = TBDMS, 92%; (iii) LiHMDS, THF, 0 °C, then R3CH2X, (a)
1 = C6H5, R2 = TBDMS, R3 = H, 78%, (b) R1 = 4-CH3OC6H4, R2 = TBDMS, R3 = H, 78%,
13
14
PMP
(c) R1 = C6H5, R2 = TBDMS, R3 = C6H5, 76%, (d) R1 = C6H5, R2 = TBDMS, R3 = CH=CH2,
67%.
Scheme 3. Reagents and conditions. (i) 6 M HCl, MeOH, rt, 76%; (ii) COCl2, DCM,
NaHCO3, 0 °C, 83%; (iii) Boc2O, Na2CO3,THF, 0 °C, 61%; (iv) CAN, MeCN–H2O, rt, 82%;
(v) Jones’ reagent, rt, then CH2N2, 73%.
The configuration of compounds 8 was first assigned on the ba-
sis of chemical shifts and the stereochemical outcome of the reac-
tion, leading to trisubstituted compounds 8, exclusively, where H-4
and the alkyl substituent at C-3 are cis- to each other, could be as-
cribed to the effect of the substituent at C-4 (Scheme 2). In fact, by
steric hindrance, the alkylating reagent is biased to an attack of the
planar enolate anion of 7 from only the opposite side with respect
to the trialkylsilyloxymethyl group at C-4.9 In order to confirm the
structural assignment, compound 8b was first converted into 9,
which by treatment with phosgene afforded the corresponding
1,3-oxazin-2-one 10. Next, NOE experiments were carried out on
10 in order to establish a cis-relationship between the methyl
group and H-4 of the parent 9 (Scheme 2).
The configuration was definitively confirmed when the amino
alcohol 9 was converted into the t-Boc derivative 11, where a cis-
relationship between the methyl group and H-4 was evidenced
by further NOE experiments (Scheme 2). The synthetic usefulness
of the chiral 3,3,4-trisubstituted pyrrolidin-2-one 11 was proven
by the preparation of conformationally restricted analogues of
the bioactive non-proteinogenic amino acids 2 and 4 (Scheme 3).
Thus, the chiral inducer 4-methoxyphenylethyl group was re-
moved from 11 by using CAN in MeCN–H2O,10 to give the corre-
moval of the chiral inducer 4-methoxyphenylethyl group by using
CAN in MeCN–H2O9 allowed us to obtain 14, a conformationally re-
stricted analogue of a-methylaspartic acid 4.
3. Experimental
1H and 13C NMR spectra were determined on a Varian Gemini
200 spectrometer at 200 and 50.3 MHz for 1H and 13C, respectively,
in CDCl3 unless otherwise reported. Chemical shifts are given as
ppm from tetramethylsilane and J values are given in hertz. Diaste-
reomeric purity was determined by g.l.c. analysis by using a
Chrompack 9001 gas-chromatograph equipped with a capillary
column Chrompack 7720 (50 m ꢀ 0.25 mm i.d.; stationary phase
CP-Sil-5 CB). Optical rotations, [a]D, were recorded at room tem-
perature on a Perkin–Elmer Model 241 polarimeter at the sodium
D line (concentration in g/100 mL). MS spectral analyses were ob-
tained on a Hewlett–Packard spectrometer model 5890, series II.
Column chromatography was performed using Kieselgel 60 Merck
(230–400 mesh ASTM). Tetrahydrofuran was distilled from so-
dium/benzophenone under an argon atmosphere. Compounds 5a
and 5b were obtained according to Ref. 8b.
sponding pyrrolidin-2-one 12 analogue of a-methylhomoserine 2.
On the other hand, the oxidation of 12, performed by using Jones’
reagent, gave 14 in very low yield. Thus, in order to circumvent this
result, compound 11 was first treated with the Jones’ reagent at low
temperature, to give the carboxylic acid, which was converted with-
out isolation into the methyl ester 13 by using CH2N2. Eventually, re-
3.1. General procedure for the preparation of the imines 7
In a flask under an argon atmosphere, pyrrolidin-2-ones 5
(3.0 mmol), benzaldehyde (3.0 mmol), and dried molecular sieves

1826
E. Crucianelli et al. / Tetrahedron: Asymmetry 20 (2009) 1824–1827
4 Å (0.8 g) were added to dry THF (12 mL) and the mixture was stirred
for 4 h at rt. The mixture was then filtered off onCelite, and the filtrate
was washed with ethyl ether (3 ꢀ 20 mL). Volatiles were evaporated
under reduced pressure and the imines 6 were recovered as colorless
oilswhichwereimmediatelydissolvedindryTHF(10 mL).Thenimid-
azole (3.1 mmol) and t-butyldimethylchlorosilane (3.1 mmol) were
added and the mixture was stirred at rt for 12 h. The solution
was poured in H2O (20 mL) and extracted with ethyl acetate
(2 ꢀ 50 mL). Afterdrying overNa2SO4 the solventwas removed under
reduced pressure to give analytically pure compounds 7.
3.2.2. (3R,4R,10S)-3-Benzylideneamino-4-t-butyldi-methylsilyl-
oxymethyl-1-[10-(4-methoxyphenyl)ethyl]-3-methylpyrrolidin-
2-one 8b
Starting from 7b and methyl iodide, compound 8b (0.37 g; 78%
yield) was obtained as a colorless oil. 1H NMR: ꢁ0.01 (s, 3H), 0.01
(s, 3H), 0.85 (s, 9H), 1.49 (d, 3H, J = 7.0), 1.50 (s, 3H), 2.22–2.41 (m,
1H), 3.02 (dd, 1H, J = 7.8, J = 9.4), 3.14 (dd, 1H, J = 8.6, J = 9.4), 3.69
(dd, 1H, J = 7.9, J = 11.3), 3.82 (s, 3H), 4.01 (dd, 1H, J = 6.2, J = 11.3),
5.45 (q, 1H, J = 7.0), 6.88 (d, 2 ArH, J = 8.6), 7.24 (d, 2 ArH, J = 8.6),
7.31–7.45 (m, 3 ArH) 7.71–7.77 (m, 2 ArH), 8.46 (s, 1H); 13C
NMR: ꢁ5.8, 16.0, 17.7, 21.4, 25.4, 42.3, 47.2, 48.5, 54.7, 61.2,
67.9, 113.4, 127.6, 127.8, 128.0, 128.5, 129.2, 130.3, 131.7, 136.2,
3.1.1. (3S,4R,10S)-3-Benzylideneamino-4-t-butyldi-methylsilyloxy-
methyl-1-(10-phenylethyl)pyrrolidin-2-one 7a
158.4, 159.4, 173.5; [
a]
D = ꢁ17.5 (c 1.14, CHCl3); MS (ESI): m/z
480.3 [M+], 503.3 [M+Na]+. Anal. Calcd for C28H40N2O3Si: C,
69.96; H, 8.39; N, 5.83. Found: C, 81.11; H, 7.28; N, 3.47.
Starting from 5a and benzaldehyde, compound 7a (1.2 g; 92%
yield) was obtained as a colorless oil. 1H NMR: 0.03 (s, 2 ꢀ 3H),
0.87 (s, 9H), 1.56 (d, 3H, J = 7.0), 2.56–2.73 (m, 1H), 3.14 (dd, 1H,
J = 9.2, J = 9.5), 3.24 (dd, 1H, J = 9.2, J = 9.5), 3.65 (dd, 1H, J = 1.2,
J = 10.3), 3.67 (dd, 1H, J = 1.2, J = 10.3), 4.06 (d, 1H, J = 7.8), 5.51
(q, 1H, J = 7.0), 7.22–7.44 (m, 8 ArH), 7.71–7.82 (m, 2 ArH), 8.41
(s, 1H); 13C NMR: ꢁ5.6, 16.0, 18.0. 25.6, 42.0, 42.1, 49.4, 61.3,
71.6, 126.9, 127.3, 128.2, 128.3, 128.8, 129.5, 130.8, 135.6, 139.5,
3.2.3. (3R,4R,10S)-3-Benzyl-3-benzylideneamino-4-t-butyldi-
methylsilyloxymethyl-1-(10-phenylethyl)pyrrolidin-2-one 8c
Starting from 7a and benzyl bromide, 8c (0.32 g; 76% yield) was
obtained as a colorless oil. 1H NMR: ꢁ0.01 (s, 3H), 0.01 (s, 3H), 0.86
(s, 9H), 1.47 (d, 3H, J = 7.0), 2.39–2.59 (m, 1H), 2.76 (dd, 1H, J = 7.9,
J = 9.4), 2.94 (dd, 1H, J = 9.0, J = 9.4), 3.06 (d, 1H, J = 12.9), 3.39 (d,
1H, J = 12.9), 3.66 (dd, 1H, J = 7.8, J = 10.1), 4.01 (dd, 1H, J = 6.8,
J = 10.1), 5.48 (q, 1H, J = 7.0), 6.95–7.06 (m, 2 ArH), 7.14–7.49 (m,
11 ArH) 7.73–7.82 (m, 2 ArH), 8.63 (s, 1H); 13C NMR: ꢁ5.5, 16.3,
18.2, 25.8, 41.0, 42.7, 48.9, 53.1, 61.7, 72.2, 126.3, 126.4, 126.8,
127.0, 128.0, 128.2, 128.4, 128.6, 128.8, 128.9, 129.2, 129.5,
164.6, 171.4; [
a
]
D = ꢁ218.4 (c 1.19, CHCl3). MS (ESI): m/z 436.2
[M+], 459.2 [M+Na]+. Anal. Calcd for C26H36N2O2Si: C, 71.52; H,
8.31; N, 6.42. Found: C, 71.42; H, 8.37; N, 6.51.
3.1.2. (3S,4R,10S)-3-Benzylideneamino-4-t-butyldi-methylsilyloxy-
methyl-1-[10-(4-methoxyphenyl)ethyl] pyrrolidin-2-one 7b
130.7, 131.0, 136.5, 136.9, 139.7, 159.9, 172.6; [
a
]D = ꢁ22.7 (c
1.25, CHCl3); MS (ESI): m/z 526.3 [M+], 549.3 [M+Na]+. Anal. Calcd
for C33H42N2O2Si: C, 75.24, H, 8.04; N, 5.32. Found: C, 75.30; H,
7.98; N, 5.27.
Starting from 5b and benzaldehyde, compound 7b (1.29 g; 92%
yield) was obtained as a colorless oil. 1H NMR: 0.03 (s, 2 ꢀ 3H),
0.88 (s, 9H), 1.53 (d, 3H, J = 7.0), 2.54–2.75 (m, 1H), 3.13 (dd, 1H,
J = 9.2, J = 9.5), 3.22 (dd, 1H, J = 9.2, J = 9.5), 3.64 (dd, 1H, J = 1.2,
J = 10.3), 3.68 (dd, 1H, J = 1.2, J = 10.3), 3.81 (s, 3H, OCH3), 4.05 (d,
1H, J = 7.7), 5.47 (q, 1H, J = 7.0), 6.88 (d, J = 8.8, 2 ArH), 7.28 (d,
J = 8.8, 2 ArH), 7.35–7.72 (m, 5 ArH), 8.40 (s, 1H); 13C NMR: ꢁ5.6,
16.2, 18.0. 25.6, 42.0, 42.2, 49.0, 55.1, 61.5, 71.7, 113.7, 128.1,
128.2, 128.3, 128.4, 128.9, 129.6, 130.8, 131.7, 134.3, 135.8,
3.2.4. (3R,4R,10S)-3-Allyl-3-benzylideneamino-4-t-butyldimethyl-
silyloxymethyl-1-(10-phenylethyl)pyrrolidin-2-one 8d
Starting from 7a and allyl bromide, 8d (0.32 g; 67% yield) was
obtained as a colorless oil. 1H NMR: 0.00 (s, 3H), 0.01 (s, 3H),
0.85 (s, 9H), 1.51 (d, 3H, J = 7.0), 2.51–2.68 (m, 3H), 2.62 (dd, 1H,
J = 8.2, J = 8.5), 3.05 (dd, 1H, J = 4.1, J = 8.5), 3.69 (dd, 1H, J = 8.3,
J = 10.1), 4.05 (dd, 1H, J = 6.0, J = 10.1), 5.11–5.22 (m, 2H), 5.52 (q,
1H, J = 7.0), 5.68–5.92 (m, 1H), 7.21–7.44 (m, 8 ArH), 7.68–7.75
(m, 2 ArH), 8.54 (s, 1H); 13C NMR: ꢁ5.6, 16.2, 18.1, 25.7, 40.1,
42.4, 42.9, 49.1, 61.8, 70.8, 119.0, 126.7, 126.8, 127.0, 127.2,
127.9, 128.0, 128.1, 128.3, 128.4, 128.5, 130.6, 133.4, 136.4, 139.9,
158.8, 164.6, 171.3; [
a]
D = ꢁ230.7 (c 1.04, CHCl3). MS (ESI): m/z
466.3 [M+], 489.3 [M+Na]+. Anal. Calcd for C27H38N2O3Si: C,
69.49; H, 8.21; N, 6.00. Found: C, 69.42; H, 8.13; N, 6.06.
3.2. General procedure for the alkylation of imines 7a,b
160.0, 172.7; [
a]
D = ꢁ31.7 (c 1.5, CHCl3); MS (ESI): m/z 476.3 [M+],
To a solution of imine 7a or 7b (1.0 mmol) in dry THF (8 mL),
LiHMDS (1.0 M solution in hexanes; 1.1 mL; 1.1 mmol) was added
dropwise at 0 °C. After stirring for 1 h, a solution of the appropriate
halide (1.1 mmol) dissolved in dry THF (3 mL) was added at 0 °C
and the mixture was stirred for a further 2 h. Then the reaction
mixture was poured in H2O (100 mL) and extracted with ethyl ace-
tate (3 ꢀ 100 mL). The organic layer was dried (Na2SO4) and evap-
orated to give the pure pyrrolidin-2-ones 8a–d.
499.3 [M+Na]+. Anal. Calcd for C29H40N2O2Si: C, 73.06; H, 8.46; N,
5.88. Found: C, 73.00; H, 8.38; N, 5.82.
3.3. (3R,4R,10S)-3-Amino-4-hydroxymethyl-1-[10-(4-methoxy-
phenyl)ethyl]-3-methylpyrrolidin-2-one 9
To a solution containing pyrrolidin-2-one 8b (0.48 g; 1.0 mmol)
in methanol (3.0 mL), 6 M HCl (1.0 mL) was added and the mixture
was stirred for 12 h at rt. The volatiles were removed under re-
duced pressure, after which ethyl acetate (25 mL) and 3 M NaOH
(10 mL) were added to the residue and the aqueous layer was fur-
ther extracted with ethyl acetate (2 ꢀ 25 mL). After drying over
Na2SO4, removal of the solvent gave compound 9 (0.21 g; 76%
yield) as a clear oil. 1H NMR: 1.28 (s, 3H), 1.52 (d, 3H, J = 7.1),
2.05–2.17 (m, 1H), 2.87–3.04 (m, 2H), 3.06 (br s, NH2+OH), 3.67
(d, 2H, J = 6.1), 3.78 (s, 3H), 5.39 (q, 1H, J = 7.1), 6.87 (d, 2 ArH,
J = 8.7), 7.20 (d, 2 ArH, J = 8.7); 13C NMR: 15.6, 26.2, 41.6, 43.1,
3.2.1. (3R,4R,10S)-3-Benzylideneamino-4-t-butyldimethylsilyl-
oxymethyl-3-methyl-1-(10-phenylethyl)pyrrolidin-2-one 8a
Starting from 7a and methyl iodide, compound 8a (0.35 g; 78%
yield) was obtained as a colorless oil. 1H NMR: ꢁ0.01 (s, 3H), 0.00
(s, 3H), 0.84 (s, 9H), 1.50 (s, 3H), 1.52 (d, 3H, J = 7.0), 2.27–2.42 (m,
1H), 3.04 (dd, 1H, J = 7.4, J = 9.3), 3.14 (dd, 1H, J = 8.6, J = 9.3), 3.69
(dd, 1H, J = 8.3, J = 10.4), 4.01 (dd, 1H, J = 6.2, J = 10.4), 5.49 (q, 1H,
J = 7.0), 7.18–7.43 (m, 8 ArH) 7.66–7.78 (m, 2 ArH), 8.46 (s, 1H); 13C
NMR: ꢁ5.4, 16.2, 18.0, 21.7, 25.7, 42.8, 47.5, 49.2, 61.5, 68.1, 126.7,
127.3, 128.0, 128.3, 128.4, 128.8, 129.5, 130.6, 136.4, 140.0, 159.7,
48.6, 54.9, 58.9, 62.0, 118.6, 127.8, 131.3, 158.6, 176.0; [a] =
D
ꢁ110.0 (c 0.54, CHCl3); MS (ESI): m/z 278.2 [M+], 301.2 [M+Na]+.
Anal. Calcd for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C,
64.67; H, 8.04; N, 9.98.
173.9; [
a]
D = ꢁ6.7 (c 0.74, CHCl3); MS (ESI): m/z 450.3 [M+], 473.3
[M+Na]+. Anal. Calcd for C27H38N2O2Si: C, 71.95; H, 8.50; N, 6.22.
Found: C, 71.85; H, 8.44; N, 6.29.

E. Crucianelli et al. / Tetrahedron: Asymmetry 20 (2009) 1824–1827
1827
3.4. (4aR,7aR,1’S)-6-[-1-(4-Methoxyphenyl)ethyl]-7a-methyl-
hexahydropyrrolo[3,4-d][1,3]oxazine-2,7-dione 10
and the mixture was stirred for 5 min. Then ethyl acetate
(20 mL) and then saturated aqueous Na2CO3 solution (15 mL) were
added at 0 °C. After extraction of the aqueous phase with ethyl ace-
tate (50 mL), the organics were discarded and the pH of the aque-
ous layer raised to pH 2 by the slow addition of 1 M HCl under
stirring. Then, extraction with ethyl acetate (2 ꢀ 50 mL) followed
by drying over Na2SO4 and removal of the solvent under reduced
pressure gave a residue which was dissolved in methanol (5 mL).
This solution was treated with an ethereal solution of CH2N2 until
nitrogen evolution ceased and the solvent was evaporated under
reduced pressure to give a residue which was purified by silica
gel chromatography (cyclohexane/acetate 70:30) affording the es-
ter 13 (0.9 g; 73% yield) as a colorless oil. 1H NMR: 1.41 (s, 9H), 1.49
(s, 3H), 1.56 (d, 3H, J = 7.2), 2.95 (dd, 1H, J = 7.0, J = 10.2), 3.24 (dd,
1H, J = 2.3, J = 7.2), 3.45–3.53 (m, 1H), 3.66 (s, 3H), 3.79 (s, 3H), 5.18
(s, 1H, NH), 5.42 (q, 1H, J = 7.2), 6.86 (d, 2 ArH, J = 8.4), 7.19 (d, 2
ArH, J = 8.4); 13C NMR: 15.3, 22.7, 28.2, 42.3, 48.1, 49.2, 51.9,
55.2, 59.8, 79.6, 114.0, 128.2, 131.4, 154.3, 159.0, 171.4, 172.1;
To a mixture of DCM (5 mL) containing compound 9 (0.3 g;
1.1 mmol) and saturated NaHCO3, (5 mL) phosgene (1.9 M in tolu-
ene, 0.85 mL; 1.62 mmol) was added at 0 °C. After 15 min the mix-
ture was extracted with ethyl acetate (2 ꢀ 50 mL). The organic
layer was dried over Na2SO4 and after removal of the solvent under
reduced pressure, the residue was purified by silica gel chromatog-
raphy (cyclohexane/ethyl acetate 6:4) to give 10 (0.27 g; 83% yield)
as a colorless oil. 1H NMR: 1.37 (s, 3H), 1.48 (d, 3H, J = 6.8), 2.35–
2.43 (m, 1H), 3.06 (dd, 1 H, J = 10.0, J = 14.0), 3.11 (dd, 1H, J = 6.4,
J = 14.0), 3.76 (s, 3H), 4.02 (dd, 1H, J = 9.2, J = 15.6), 4.27 (dd, 1H,
J = 5.6, J = 15.6), 5.38 (q, 1H, J = 6.8), 5.74 (s, 1H, NH), 6.84 (d, 2
ArH, J = 8.8), 7.16 (d, 2 ArH, J = 8.8); 13C NMR: 15.8, 23.7, 29.6,
35.1, 40.4, 49.0, 55.2, 59.4, 64.9, 113.8, 128.0, 130.8, 152.9, 158.9,
171.9; [
a]
D = ꢁ108.2 (c 1.04, CHCl3); MS (ESI): m/z 304.1 [M+],
327.1 [M+Na]+. Anal. Calcd for C16H20N2O4: C, 63.14; H, 6.62; N,
9.20. Found: C, 63.20; H, 6.69; N, 9.16.
[a
]
D = ꢁ104.5 (c 1.32, CHCl3); MS (EI): m/z 406.21 [M+], 429.22
[M+Na]+. Anal. Calcd for C21H30N2O6: C, 62.05; H, 7.44; N 6.89.
Found: C, 61.93; H, 7.36; N, 6.94.
3.5. (3R,4R,10S)-3-t-Butoxycarbonylamino-4-hydroxy-methyl-
1-[10-(4-methoxyphenyl)ethyl]-3-methylpyrrolidin-2-one 11
3.8. (3R,4R)-Methyl 4-t-butoxycarbonylamino-4-methyl-5-
oxopyrrolidine-3-carboxylate 14
To a solution of 9 (0.1 g; 0.36 mmol) in THF (5 mL) at 0 °C, a sat-
urated solution of Na2CO3 (2.2 mL) was added, followed by di-t-bu-
tyl dicarbonate (0.24 g; 1.08 mmol). After 12 h, the volatiles were
removed under reduced pressure, after which H2O (10 mL) was
added and the mixture was extracted with ethyl acetate
(2 ꢀ 50 mL). After drying over Na2SO4 and removal of the solvent
under reduced pressure, the residue was purified by silica gel chro-
matography (cyclohexane/ethyl acetate 1:1) to give 11 (0.08 g; 61%
yield) as a colorless oil. 1H NMR: 1.35 (s, 3H), 1.42 (s, 9H), 1.52 (d,
3H, J = 7.1), 1.55 (br s, 1H, OH), 2.33–2.49 (m, 1H), 2.87 (dd, 1H,
J = 6.6, J = 10.3), 3.30 (dd, 1H, J = 1.2, J = 10.3), 3.44 (dd, 1H, J = 7.2,
J = 11.3), 3.67 (dd, 1H, J = 5.0, J = 11.3), 3.78 (s, 3H), 5.28 (br s, 1H,
NH), 5.37 (q, 1H, J = 7.1), 6.85 (d, 2 ArH, J = 8.7), 7.17 (d, 2 ArH,
J = 8.7); 13C NMR: 15.6, 21.9, 28.2, 42.1, 44.2, 48.9, 55.1, 59.4,
To a solution of 13 (0.13 g; 0.32 mmol) in CH3CN (3 mL) and
H2O (3 mL), CAN (0.36 g; 0.65 mmol) was added and the mixture
was stirred for 15 min at rt. Then, a saturated NaHCO3 solution
(10 mL) was added and the mixture was extracted with ethyl ace-
tate (3 ꢀ 15 mL). After drying (Na2SO4) and removal of volatiles
under reduced pressure, the residue was purified by silica gel chro-
matography (cyclohexane/ethyl acetate 3:7) to give product 14
(0.12 g; 82% yield) as a colorless oil. 1H NMR: 1.39 (s, 9H), 1.55
(s, 3H), 3.31–3.54 (m, 2H), 3.68 (s, 3H), 3.70–3.79 (m, 1H), 5.11
(s, 1H, NH), 6.72 (s, 1H, NH); 13C NMR: 23.6, 28.1, 41.8, 50.0,
52.0, 58.2, 79.7, 154.3, 170.9, 176.2; [
a
]
D = ꢁ43.8 (c 0.57, CHCl3);
MS (ESI): m/z 272.14 [M+], 295.15 [M+Na]+. Anal. Calcd for
C12H20N2O5: C, 52.93; H, 7.40; N, 10.29. Found: C, 53.98; H, 7.29;
N, 10.25.
61.2, 79.7, 119.8, 128.0, 131.4, 155.3, 158.9, 173.4; [
a]D = ꢁ125.0
(c 1.16, CHCl3); MS (ESI): m/z 378.2 [M+], 401.2 [M+Na]+. Anal.
Calcd for C20H30N2O5: C, 63.47; H, 7.99; N, 7.40. Found: C, 63.55;
H, 7.92; N, 7.46.
Acknowledgments
3.6. (3R,4R)-3-t-Butoxycarbonylamino-3-methyl-4-hydroxy
methylpyrrolidin-2-one 12
We thank Nanodream s.r.l. [Iesi (Ancona), Italy] for financial
support whereas Dr. Antonella Monsignori and Dr. Stefania Tibur-
tini are acknowledged for valuable technical support.
To a solution of 11 (0.38 g; 1 mmol) in CH3CN (3 mL) and H2O
(3 mL), CAN (1.1 g; 2 mmol) was added and the mixture was stirred
for 15 min at rt. Then, a saturated NaHCO3 solution (10 mL) was
added and the mixture was extracted with ethyl acetate
(3 ꢀ 15 mL). Afterdrying over Na2SO4 and removalof volatilesunder
reduced pressure, the residue was purified by silica gel chromatog-
raphy (cyclohexane/ethyl acetate 3:7) to give product 12 (0.2 g;
82% yield) as a colorless oil. 1H NMR: 1.42 (s, 9H), 1.47 (s, 3H),
2.53–2.63 (m, 1H), 3.00 (br s, 1H, OH), 3.42 (d, 2H, J = 4.8), 3.52 (dd,
1H, J = 6.7, J = 11.1), 3.68 (dd, 1H, J = 4.9, J = 11.1), 5.27 (br s, 1H,
NH), 6.70 (br s, 1H, NH); 13C NMR: 22.5, 28.2, 42.1, 46.6, 58.2, 61.2,
References
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79.9, 155.4, 177.8; [
a]
D = ꢁ50.0 (c 0.6, CHCl3); MS (ESI): m/z 244.14
6. Altmann, K.-H.; Altmann, E.; Mutter, M. Helv. Chim. Acta 1992, 75, 1198–1210.
7. Perdih, A.; Kikelj, D. Curr. Med. Chem 2006, 13, 1525–1556.
8. See, for examples: (a) Galeazzi, R.; Martelli, G.; Orena, M.; Rinaldi, S.; Sabatino,
P. Tetrahedron 2005, 61, 5465–5473; (b) Galeazzi, R.; Martelli, G.; Natali, D.;
Orena, M.; Rinaldi, S. Tetrahedron: Asymmetry 2005, 16, 1779–1787; (c)
Galeazzi, R.; Marcucci, E.; Martelli, G.; Mobbili, G.; Natali, D.; Orena, M.;
Rinaldi, S. Eur. J. Org. Chem. 2007, 4402–4407.
[M+], 267.14 [M+Na]+. Anal. Calcd for C11H20N2O4: C, 54.08; H,
8.25; N, 11.47. Found: C, 54.98; H, 8.19; N, 11.55.
3.7. (3R,4R,10S)-Methyl 4-t-butoxycarbonylamino-1-[10-(4-
methoxyphenyl)ethyl]-4-methyl-5-oxopyrrolidine-3-
carboxylate 13
9. Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.; Panagiotaki, M. Heterocycles
2003, 60, 2485–2498.
10. For reviews on CAN catalyzed reactions: (a) Nair, V.; Panicker, S. B.; Nair, L. G.
Synlett 2003, 156–165; (b) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc.
Chem. Res. 2004, 37, 21–30.
To a solution containing compound 11 (0.23 g; 0.6 mmol) in
acetone (7 mL), the Jones’ reagent (0.92 mL) was added at ꢁ15 °C