Synthesis of a cyclic isostere of α-methyl homoserine by a stereoselective acylation-alkylation sequence of a chiral γ-lactam

Article abstract of DOI:10.1007/s00726-014-1671-9

Starting from a chiral 4-hydroxymethyl pyrrolidin-2-one, an isostere of α-methyl homoserine tethered on a γ-lactam ring was prepared exploiting a stereoselective acylation-methylation sequence, followed by Curtius rearrangement, and structural assignment was confirmed by n.O.e. experiments. By reverting the sequence, the 3-carboxy-3-methyl derivative having the opposite configuration at C-3 was obtained with total stereoselection, but Curtius rearrangement invariably afforded only inseparable mixtures of decomposition products.

Full text of DOI:10.1007/s00726-014-1671-9

Amino Acids
DOI 10.1007/s00726-014-1671-9
ORIGINAL ARTICLE
Synthesis of a cyclic isostere of a-methyl homoserine
by a stereoselective acylation–alkylation sequence
of a chiral c-lactam
•
Annafelicia Civitavecchia Gianluca Martelli
•
•
Mario Orena Samuele Rinaldi
Received: 16 September 2013 / Accepted: 9 January 2014
Ó Springer-Verlag Wien 2014
Abstract Starting from a chiral 4-hydroxymethyl pyrr-
olidin-2-one, an isostere of a-methyl homoserine tethered
on a c-lactam ring was prepared exploiting a stereoselec-
tive acylation–methylation sequence, followed by Curtius
rearrangement, and structural assignment was confirmed by
n.O.e. experiments. By reverting the sequence, the 3-car-
boxy-3-methyl derivative having the opposite configuration
at C-3 was obtained with total stereoselection, but Curtius
rearrangement invariably afforded only inseparable mix-
tures of decomposition products.
Crisma et al. 2006; Feng et al. 2007; Storcken et al. 2007;
Calaza and Cativiela 2008; Cativiela and Ordon˜ez 2009;
Balducci et al. 2010; Nguyen et al. 2010; Iosub et al. 2010;
Lu and Lin 2011; Ilies et al. 2011; Weber et al. 2012;
Hugelshofer et al. 2013) represents one of the promising
strategies to preferentially stabilize an ensemble of closely
related bioactive conformations. Such modifications may
lead to enhanced potency, better selectivity, and improve-
ment on many of the above-mentioned shortcomings and,
therefore, are largely employed within development of
peptide-based therapeutics.
Keywords Conformational constriction ꢀ Amino acids ꢀ
Lactams ꢀ Alkylation ꢀ Stereoselection
Within this topic, we already reported about the stere-
oselective synthesis of isosteres of proteinogenic amino
acids, and the chiral pyrrolidin-2-one 1 was the key inter-
mediate for preparation of 2, a cyclic isostere of b-homo-
serine (Galeazzi et al. 2005). Moreover, alkylation of
pyrrolidin-2-one 1 allowed to obtain in good yield and total
stereoselection compounds 3 and 4, the isosteres of (R)-2-
methyl-b-homoserine (Martelli et al. 2010) and (R)-2-
methylaspartic acid (Crucianelli et al. 2010), respectively
(Scheme 1).
Introduction
Biologically active peptides are molecules endowed with
high therapeutic potential. However, they are scarcely used
as drugs owing to their conformational flexibility that
contributes to their promiscuous selectivity, high proteo-
lytic susceptibility, limited cellular permeability, low bio-
availability, and fast clearance (Hanessian and Auzzas
2008). Structural rigidification through lactam ring (Frei-
dinger 2003; Perdih and Kikelj 2006; Dolbeare et al. 2003;
Galaud and Lubell 2005; Broadrup et al. 2005; Seufert
et al. 2006; Otvos et al. 2007; Jamieson et al. 2009; Lesma
et al. 2009; Virlouvet and Podlech 2010; St-Cyr et al. 2010;
Boy et al. 2011) or quaternary carbon introduction
(Benedetti 1996; Toniolo et al. 2001; Sagan et al. 2004;
Results and discussion
We disclose here a novel approach to ent-3, already pre-
pared in our laboratory (Galeazzi et al. 2003), exploiting a
stereoselective acylation–alkylation sequence starting from
the hydroxymethyl derivative 5 (Scheme 2).
Thus, the TIPS-derivative 6 was treated with LiTMP,
followed by methyl chloroformate, to give in good yield
and nearly total stereoselection the acylated product 7. We
were delighted to observe that the TIPS group was essential
for trans stereoselection, since when less sterically
demanding groups such as Bn or TBDMS were employed,
A. Civitavecchia ꢀ G. Martelli ꢀ M. Orena (&) ꢀ S. Rinaldi
`
Dipartimento Di.S.V.A., Universita Politecnica delle Marche,
Via Brecce Bianche, 60131 Ancona, Italy
e-mail: m.orena@univpm.it
123

A. Civitavecchia et al.
Scheme 1 Isosteres prepared
from lactam 1
BocHN
O
H
O
R1 = Ph
N
H
H2N
H
COO
2
O
N
1
R1
R1= PMP
BocHN
O
BocHN
COOMe
H
O
an
d
O
N
H
N
3
4
H
Scheme 2 Reagents and
conditions: i TIPSCl, imidazole,
DCM, 72 %; ii LiTMP, THF,
0 °C, then MeOOCCl, THF,
0 °C, 86 %; iii n-BuLi, THF,
0 °C, then MeI, 72 %; iv 2 M
NaOH, MeOH, 50 °C, then
0.2 M HCl, 95 %; v DPPA, t-
BuOH, Et3N, 70 °C, 46 %; vi
3 M HCl, MeOH, 50 °C, then
2 M NaOH, quantitative yield;
vii Li, NH3, -78 °C, 82 %
conversion into the corresponding lactone 12, where the
cis-relationship between the hydrogen at C-4 and the
methyl group at C-3, expected from mechanistic consid-
erations, was confirmed on the basis of n.O.e. experiments
(Scheme 3).
Having compound 8 in hands, hydrolysis under basic
conditions gave the carboxylic acid 9 that by reaction with
DPPA in t-BuOH was converted into the carbamate 10 in
moderate yield. Since prolonged treatment of 10 with
fluoride anion was not effective for removal of the silyl
ether, cleavage was carried out under acidic conditions, to
give compound 11 where N-Boc group remained unaf-
fected, probably owing to steric congestion at the quater-
nary center. Eventually, by treatment with Li in NH3, the
chiral inducer phenylethyl group was easily removed, and
the isostere ent-3 was recovered in good yield.
Scheme 3 Reagents and conditions: i LiOHꢀH2O at reflux, MeOH,
then 0.1 M HCl, 64 %
the acylation reaction afforded mixtures in 60:40 and 90:10
trans:cis dr, respectively (Orena unpublished observa-
tions). Then, metalation of 7 with n-BuLi, followed by
addition of methyl iodide, allowed to introduce the methyl
group at C-3 in moderate yield but with total stereoselec-
tion. In fact, compound 8 was isolated as the sole isomer,
and its configuration was unambiguously ascertained after
With the aim of preparing also the 3,4-trans-3,3,4-tri-
substituted compound 18, again displaying (3S) configu-
ration, we envisaged a synthetic strategy starting from
hydroxymethyl derivative 13 (Galeazzi et al. 2003),
exploiting reversal of the above-reported acylation–meth-
ylation sequence (Scheme 4).
123

Synthesis of a cyclic isostere of a-methyl homoserine
Scheme 4 Reagents and
conditions: i TIPSCl, imidazole,
DCM, 85 %; ii n-BuLi, THF,
-15 °C, then MeI, THF,
-15 °C, 71 %; iii n-BuLi, THF,
-15 °C, then MeOOCCl, THF,
-15 °C, 46 %; iv 2 M NaOH,
MeOH, 50 °C, then 0.2 M HCl,
98 %; v DPPA, t-BuOH, Et3N,
70 °C, complex inseparable
mixture, product 18 was missing
In fact, the silyl derivative 14, after conversion into its
lithium enolate was treated with methyl iodide to afford
product 15 in good yield and with total trans stereoselec-
tion. Metalation at C-3 followed by addition of methyl
chloroformate afforded the ester 16 in low yield, albeit
with total trans stereoselection. After basic hydrolysis, the
acid 17 was isolated in excellent yield but, in spite of many
attempts carried out under different reaction conditions,
and in contrast to the favorable results obtained starting
from 9, all rearrangement reactions mediated by DPPA led
to complex mixtures of products, from which no identifi-
able material could be isolated. Thus, since both the
starting acid 17 and the acylazide intermediate, initially
generated by the reaction with DPPA, were missing,
extended decomposition was reasonably attributed to side
reactions of either the acylnitrene or the subsequent iso-
cyanate intermediate.
were recorded at room temperature on a Perkin-Elmer
Model 241 polarimeter at the sodium D line (concentration
in g/100 mL). LC electrospray ionization mass spectra
were obtained with an Agilent Technologies MSD1100
single-quadrupole mass spectrometer, eluting samples in
MeOH. Elemental analyses were performed with a Carlo
Erba CHN Elemental Analyzer. Column chromatography
was performed using Kieselgel 60 Merck (230–400 mesh
ASTM). Tetrahydrofuran and dichloromethane were dis-
tilled from sodium-benzophenone and CaH2, respectively,
under an argon atmosphere. Compounds 5 and 13 were
obtained according to Galeazzi et al. (2003).
Synthesis of silyl ethers 6 and 14: general procedure
To a solution of 4-hydroxymethyl pyrrolidin-2-ones 5 or 13
(1.25 g, 5.73 mmol) dissolved in dry DCM (6 mL) at rt
under inert atmosphere, imidazole (430 mg, 6.3 mmol) and
TIPSCl (1.3 mL, 6.3 mmol) were added. After 8 h, the
reaction mixture was poured into H2O-ice and extracted
with ethyl acetate (3 9 50 mL). The organic layer was
dried (Na2SO4) and volatiles removed under reduced
pressure. The residue was then purified on silica gel
(cyclohexane:ethyl acetate 80:20) to give the correspond-
ing silyl ethers 6 and 14 as colorless oils.
Conclusions
In summary, the 2-methylhomoserine constrained isostere
ent-3 was prepared exploiting a totally stereoselective
acylation–alkylation sequence. Although we planned to
synthesize also lactam 18, key intermediate to a diaste-
reomer of 3, we were not able to achieve this goal owing to
the unexpected behavior of compound 17 that decomposed
under the reaction conditions. Thus, to make available all
four stereoisomers of 3 a totally different approach was
envisaged, and synthetic procedures currently underway
will be reported in due course.
(R)-1-((S)-1-Phenylethyl)-4-(((triisopropylsilyl)oxy)
methyl)pyrrolidin-2-one, 6
1
Compound 6 (1.55 g, 72 % yield): H NMR (200 MHz,
CDCl3): d 0.96 (m, 21H), 1.52 (d, J = 7.4, 3H), 2.18–2.33
(m, 1H), 2.44–2.59 (m, 2H), 2.89 (dd, J = 4.8, J = 10.0,
1H), 3.36 (dd, J = 7.6, J = 10.0, 1H), 3.40–3.57 (m, 2H),
5.50 (q, J = 7.4, 1H), 7.18–7.27 (m, 5 ArH). 13C NMR
(50 MHz, CDCl3): d 11.7, 16.0, 17.8, 33.5, 34.0, 44.4,
48.8, 64.5, 127.0, 127.3, 128.4, 140.0, 173.6. [a]D 81.8 (c
1.1, CHCl3). MS (ESI): m/z 375.4 [M]?, 398.4 [M ? Na]?.
Anal. calcd for C22H37NO2Si: C 70.35; H 9.93; N 3.73.
Found: C, 70.25; H, 9.84; N, 3.69.
Experimental
1H and 13C NMR spectra were determined on a Varian
1
Gemini 200 spectrometer at 200 and 50 MHz for H and
13C, respectively, in CDCl3 unless otherwise reported.
Chemical shifts are given as ppm from tetramethylsilane
and J values are given in Hertz. Optical rotations, [a]D,
123

A. Civitavecchia et al.
(3R,4R)-Methyl 2-oxo-1-((S)-1-phenylethyl)-4-
(((triisopropylsilyl)oxy)methyl)pyrrolidine-3-carbo-
xylate, 7
126.7, 127.3, 128.0, 128.5, 138.7, 173.2, 173.9. [a]D -70.8
(c 1, CHCl3). MS (ESI): m/z 447.3 [M]?, 470.4
[M ? Na]?. Anal. calcd for C25H41NO4Si: C, 67.07; H,
9.23; N, 3.13. Found: C, 66.98; H, 9.10; N, 3.19.
Compound 6 (1.02 g, 2.7 mmol) was dissolved in dry THF
(10 mL) under inert atmosphere at 0 °C and tetramethyl-
piperidine (0.5 mL, 2.9 mmol) and n-BuLi (5.2 mmol,
5.2 mL of a 1 M solution in hexane) were sequentially
added. After 15 min methyl chloroformate (0.22 mL,
2.9 mmol) was slowly added and the mixture was stirred
for 15 min at 0 °C. After quick sequential addition of H2O
(100 mL) and ethyl acetate (100 mL), the organic phase
was separated, and then the aqueous phase was extracted
with additional ethyl acetate (2 9 100 mL). The organic
layers were dried (Na2SO4) and volatiles were removed
under reduced pressure. The residue was purified by silica
gel chromatography (cyclohexane:ethyl acetate 90:10) to
give compound 7 in 86 % yield (1.01 g, 2.3 mmol) as a
colorless oil. 1H NMR (200 MHz, CDCl3): d 0.95 (m,
21H), 1.54 (d, J = 7.4, 3H), 2.78–2.92 (m, 2H), 3.38–3.46
(m, 2H), 3.50–3.61 (m, 2H), 3.79 (s, 3H), 5.49 (q, J = 7.4,
1H), 7.24–7.30 (m, 5ArH). 13C NMR (50 MHz, CDCl3): d
14.7, 15.9, 17.8, 38.1, 42.8, 49.5, 51.2, 52.5, 63.0, 127.0,
127.3, 127.5, 128.5, 139.5, 168.7, 170.3. [a]D -25.0 (c 1,
CHCl3). MS (ESI): m/z 433.3 [M]?, 456.3 [M ? Na]?.
Anal. calcd for C24H39NO4Si: C, 66.47; H, 9.06; N, 3.23.
Found: C, 66.38; H, 9.00; N, 3.18.
(3S,4R)-3-Methyl-2-oxo-1-((S)-1-phenylethyl)-4-
(((triisopropylsilyl)oxy)methyl)pyrrolidine-3-
carboxylic acid, 9
To a solution containing the ester 8 (675 mg, 1.5 mmol) in
MeOH (8 mL) 2 M NaOH (8 mL) was added at rt. The
mixture was heated at 50 °C for 3 h and then, after cooling
to rt, 0.2 M HCl (85 mL) was added. The reaction mixture
was extracted with ethyl acetate (3 9 50 mL) and the
organic layer was dried (Na2SO4). Solvents were removed
under reduced pressure and the title product 9 was recov-
1
ered (620 mg; 95 % yield) as a colorless oil. H NMR
(200 MHz, CDCl3): d 0.95 (m, 21H), 1.53 (s, 3H), 1.56 (d,
J = 7.2, 3H), 2.34–2.36 (m, 1H), 3.05 (dd, J = 4.8,
J = 10.2, 1 H), 3.39 (dd, J = 7.4, J = 10.2, 1H), 3.52 (dd,
J = 8.2, J = 9.8, 1H), 3.79 (dd, J = 5.0, J = 9.8, 1H),
5.44 (q, J = 7.2, 1H), 7.26–7.34 (m, 5 ArH), 9.17 (bs, 1H,
COOH). 13C NMR (50 MHz, CDCl3): d 11.4, 15.9, 17.3,
17.5, 20.6, 43.5, 45.7, 49.6, 53.1, 61.9, 126.6, 126.9, 127.2,
128.1, 128.3, 138.5, 173.4, 173.8. [a]D -40.1 (c 1, CHCl3).
MS (ESI): m/z 433.4 [M]?, 456.4 [M ? Na]?. Anal. calcd
for C24H39NO4Si: C, 66.47; H, 9.06; N, 3.23. Found: C,
66.43; H, 9.11; N, 3.17.
(3S,4R)-Methyl 3-methyl-2-oxo-1-((S)-1-phenylethyl)-
4-(((triisopropylsilyl)oxy)methyl)pyrrolidine-3-
carboxylate, 8
tert-Butyl ((3S,4S)-3-methyl-2-oxo-1-((S)-1-
phenylethyl)-4-(((triisopropylsilyl)oxy)methyl)pyrroli-
din-3-yl)carbamate, 10
To a solution of compound 7 (1.01 g, 2.3 mmol) in dry
THF (10 mL) under inert atmosphere at 0 °C, n-BuLi
(2.5 mmol, 2.5 mL of a 1 M solution in hexane) was added
and the mixture was stirred for 15 min at 0 °C. Then,
methyl iodide (156 lL, 2.5 mmol) was added and the
mixture was stirred for a further 10 min at 0 °C. After
quick sequential addition of H2O (100 mL) and ethyl
acetate (100 mL), the organic phase was separated, and
then the aqueous phase was extracted with additional ethyl
acetate (2 9 100 mL). The organic layers were dried
(Na2SO4) and volatiles were removed under reduced
pressure. The residue was eventually purified by silica gel
chromatography (cyclohexane:ethyl acetate 80:20) to give
the title product 8 (745 mg; 72 % yield) as a colorless oil.
1H NMR (200 MHz, CDCl3): d 0.98 (m, 21H), 1.49 (s,
3H), 1.57 (d, J = 7.2, 3H), 2.35–2.47 (m, 1H), 2.77 (dd,
J = 9.0, J = 9.6, 1H), 3.29 (dd, J = 8.0, J = 9.6, 1H),
3.46 (dd, J = 8.0, J = 10.0, 1H), 3.55 (s, 3H), 3.73 (dd,
J = 6.6, J = 10.0, 1H), 5.55 (q, J = 7.2, 1H), 7.29–7.36
(m, 5 ArH). 13C NMR (50 MHz, CDCl3): d 11.6, 15.7,
17.5, 17.7, 20.5, 43.5, 45.7, 49.6, 53.1, 55.3, 61.8, 126.4,
To a solution containing compound 9 (319 mg, 1.05 mmol)
in t-BuOH (3 mL), DPPA (363 lL, 1.68 mmol) and Et3N
(234 lL, 1.68 mmol) were added and the mixture was
heated at 70 °C for 8 h. After cooling, water (15 mL) was
added, and then the mixture was extracted with ethyl
acetate (2 9 30 mL). The organic layer was dried
(Na2SO4), solvents were removed under reduced pressure,
and the residue was purified by silica gel chromatography
(cyclohexane:ethyl acetate 70:30) to give compound 10
(245 mg, 46 % yield) as colorless oil. 1H NMR (200 MHz,
CDCl3): d 0.90 (m, 21H), 1.51 (s, 3H), 1.53 (d, J = 7.4,
3H), 2.51–2.70 (m, 1H), 3.10 (dd, J = 9.5, J = 9.8, 1H),
3.21–3.50 (m, 2H), 3.58 (dd, J = 4.6, J = 9.8, 1H), 5.39
(q, J = 7.4, 1H), 5.72 (s, 1H, NH), 7.19–7.35 (m, 5 ArH).
13C NMR (50 MHz, CDCl3): d 11.8, 16.1, 17.8, 20.2, 43.6,
46.7, 49.5, 51.8, 54.1, 62.4, 127.3, 127.4, 128.2, 128.5,
139.3, 171.1, 173.0. [a]D 48.4 (c 0.6, CHCl3). MS (ESI): m/
z
504.3 [M]?, 527.3 [M ? Na]?. Anal. calcd for
C28H48N2O4Si: C, 66.62; H, 9.58; N, 5.55. Found: C,
66.53; H, 9.51; N, 5.47.
123

Synthesis of a cyclic isostere of a-methyl homoserine
t-Butyl ((3S,4S)-4-(hydroxymethyl)-3-methyl-2-oxo-1-
((S)-1-phenylethyl)pyrrolidin-3-yl)carbamate, 11
(3aR,6aS)-6a-Methyl-5-((S)-1-phenylethyl)tetrahydro-
1H-furo[3,4-c]pyrrole-1,6(6aH)-dione, 12
To
a
solution containing compound 10 (218 mg,
The pyrrolidin-2-one 8 (100 mg, 0.22 mmol) was dis-
solved in MeOH (1 mL) containing LiOHꢀH2O
(0.28 mmol, 12 mg) and the mixture was refluxed for 5 h.
After removal of the solvent under reduced pressure, 0.1 M
HCl (2.8 mL) was added, and the mixture was extracted
with ethyl acetate (3 9 5 mL). After drying (Na2SO4) and
removal of the solvent, compound 12 (37 mg, 64 % yield)
0.43 mmol) in MeOH (1.0 mL), 3 M HCl (1.0 mL) was
added and the mixture was stirred at 50 °C for 1.5 h and
then at rt for 12 h. After addition of 2 M NaOH (2 mL),
the mixture was extracted with ethyl acetate
(2 9 20 mL), the organic layer was dried (Na2SO4), and
removal of volatiles under reduced pressure gave a res-
idue that after silica gel chromatography (cyclohex-
ane:ethyl acetate 50:50) afforded product 11 (140 mg,
1
was obtained as a yellow oil. H NMR (200 MHz,CDCl3):
d 1.53 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H), 2.76 (dd,
J = 2.1 Hz, J = 10.8 Hz, 1H), 2.92 (m, 1H), 3.53 (dd,
J = 6.6 Hz, J = 10.8 Hz, 1H), 3.60 (dd, J = 6.9 Hz,
J = 9.6 Hz, 1H), 4.38 (dd, J = 8.4 Hz, J = 9.6 Hz, 1H),
5.50 (q, J = 7.2 Hz, 1H), 7.26–7.37 (m, 5H, Ar). [a]D
-16.3 (c 1.0, CHCl3). MS (ESI): m/z: 259.1 [M]?, 282.1
[M ? Na]?. Anal. calcd for C15H17NO3: C, 69.48; H, 6.61;
N, 5.40. Found: C, 69.38; H, 6.55; N, 5.33.
95 %yield) as
a
viscous colorless oil. 1H NMR
(200 MHz, CDCl3): d 1.05 (s, 9H), 1.47 (s, 3H), 1.55 (d,
J = 7.4, 3H), 2.42–2.54 (m, 1H), 2.70 (dd, J = 3.2,
J = 10.6, 1 H), 3.44 (dd, J = 7.2, J = 10.6, 1H), 3.74
(dd, J = 8.6, J = 11.8, 1H), 4.09 (dd, J = 4.8, J = 11.8,
1H), 5.45 (q, J = 7.4, 1H), 5.48 (br s, 1H, NH),
7.18–7.39 (m, 5 ArH). 13C NMR (50 MHz, CDCl3): d
12.1, 15.5, 17.5, 23.6, 34.9, 40.2, 49.2, 59.3, 64.7, 126.7,
127.8, 128.2, 128.3, 138.5, 153.0, 172.4. [a]D -86.7 (c
1.5, CHCl3). MS (ESI): m/z 348.2 [M]?, 371.2
[M ? Na]?. Anal. calcd for C19H28N2O4: C, 65.49; H,
8.10; N, 8.04. Found: C, 65.43; H, 8.01; N, 8.13.
(S)-1-((S)-1-Phenylethyl)-4-
(((triisopropylsilyl)oxy)methyl)pyrrolidin-2-one, 14
Compound 14 (1.83 g, 85 % yield) was obtained according
to the general procedure above reported. 1H NMR
(200 MHz, CDCl3): d 1.06 (m, 21H), 1.46 (d, J = 7.2, 3H),
2.22–2.57 (m, 3H), 3.02 (dd, J = 8.5, J = 9.0, 1H), 3.22
(dd, J = 5.5, J = 9.0, 1H), 3.55–3.66 (m, 2H), 5.53 (q,
J = 7.2, 1H), 7.22–7.78 (m, 5 ArH). 13C NMR (50 MHz,
CDCl3): d 12.0, 16.2, 18.1, 27.0, 30.3, 33.6, 34.3, 44.6,
48.9, 64.9, 127.2, 127.5, 128.6, 140.3, 173.8. [a]D -60.0 (c
1.0, CHCl3). MS (ESI): m/z 375.4 [M]?, 398.4 [M ? Na]?.
Anal. calcd for C22H37NO2Si: C 70.35; H 9.93; N 3.73.
Found: C, 70.27; H, 9.87; N, 3.66.
t-Butyl ((3S,4S)-4-(hydroxymethyl)-3-methyl-2-
oxopyrrolidin-3-yl)carbamate, ent-3
Ammonia (about 4 mL) was condensed in a three-necked
flask at -78 °C, Li shots (14 mg, 2.0 mmol) were added,
and the blue solution was stirred at this temperature for
20 min. Then compound 11 (105 mg, 0.3 mmol) was dis-
solved in a mixture of dry THF (0.9 mL) and t-BuOH
(0.1 mL), and the solution added in one portion. After
3 min, the reaction mixture was quenched by addition of
solid NH4Cl (200 mg) and warmed to room temperature.
Then ammonia was removed, ethyl acetate (10 mL) and
water (3 mL) added, the mixture extracted with ethyl
acetate (2 9 20 mL) and the combined organic layers
dried over Na2SO4. After the solvent was removed in
vacuo, the crude product was purified by silica gel chro-
matography (cyclohexane:ethyl acetate 40:60 as eluent) to
give ent-3 (60 mg, 82 % yield) as a colorless oil. 1H NMR
(200 MHz, CDCl3): d 1.42 (s, 9H), 1.47 (s, 3H), 2.53–2.63
(m, 1H), 3.00 (br s, 1H, OH), 3.42 (d, J = 4.8, 2H), 3.52
(dd, J = 6.7, J = 11.1, 1H), 3.68 (dd, J = 4.9, J = 11.1,
1H), 5.27 (br s, 1H, NH), 6.70 (br s, 1H, NH).13C NMR
(50 MHz, CDCl3): d 22.5, 28.2, 42.1, 46.6, 58.2, 61.2,
79.9, 155.4, 177.8. [a]D 49.6 (c 0.6, CHCl3) [Lit. -50.0 (c
0.6, CHCl3) (Martelli et al. 2010)]. MS (ESI): m/z 244.3
[M]?, 267.3 [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.
(3S,4S,10S)-1-(10-Phenylethyl)-3-methyl-4-
triisopropylsilyloxymethylpyrrolidin-2-one, 15
To a solution of pyrrolidin-2-one 14 (1.02 g, 2.71 mmol) in
dry THF (10 mL) under inert atmosphere at -15 °C,
n-BuLi (3 mmol, 1.87 mL of a 1.6-M solution in hexane)
was added and the mixture was stirred for 15 min at
-15 °C. Then, methyl iodide (181 lL, 2.9 mmol) was
added and the mixture was stirred for a further 10 min at
-15 °C. After addition of H2O (100 mL) and ethyl acetate
(100 mL), the organic phase was separated, and the aque-
ous phase was extracted with additional ethyl acetate
(2 9 100 mL). The organic layers were dried (Na2SO4)
and volatiles were removed under reduced pressure, and
then the residue was purified by silica gel chromatography
(cyclohexane:ethyl acetate 90:10) to give compound 15
(750 mg, 71 % yield) as colorless oil. 1H NMR (200 MHz,
CDCl3): d 1.08 (m, 21H), 1.22 (d, J = 7.2, 3H), 1.51 (d,
123

A. Civitavecchia et al.
J = 7.4, 3H), 1.92–2.03 (m, 1H), 2.43 (dq, J = 7.2,
J = 7.4, 1H), 2.97 (dd, J = 8.2, J = 9.4, 1H), 3.14 (dd,
J = 7.8, J = 9.4, 1H), 3.64–3.78 (m, 2H), 5.55 (q, J = 7.4,
1H), 7.19–7.41 (m, 5 ArH). 13C NMR (50 MHz, CDCl3): d
11.8, 15.4, 15.9, 17.9, 39.2, 42.7, 42.8, 48.7, 63.4, 126.8,
126.9, 127.2, 128.3, 140.3, 176.2. [a]D -94.4 (c 1, CHCl3).
MS (ESI): m/z 389.3 [M]?, 412.3 [M ? Na]?. Anal. calcd
for C23H39NO2Si: C, 70.90; H, 10.09; N, 3.59. Found: C,
70.76; H, 9.97; N, 3.51.
J = 10.5, 1H), 3.31 (dd, J = 2.4, J = 10.5, 1H), 3.68 (dd,
J = 2.7, J = 9.9, 1H), 3.99 (dd, J = 5.1, J = 9.9, 1H),
5.51 (q, J = 7.2, 1H), 7.20–7.43 (m, 5ArH), 7.60–8.20 (br,
1H, OH). 13C NMR (50 MHz, CDCl3): d 12.1, 16.2, 18.0,
21.3, 27.1, 40.6, 44.1, 48.4, 55.1, 65.0, 127.2, 127.6, 128.6,
128.7, 140.2, 170.9, 174.0. [a]D 25.1 (c 1, CHCl3). MS
(ESI): m/z 433.3 [M]?, 456.3 [M ? Na]?. Anal. calcd for
C24H39NO4Si: C, 66.47; H, 9.06; N, 3.23. Found: C, 66.55;
H, 9.18; N, 3.11.
(3S,4S,10S)-1-(10-Phenylethyl)-3-methyl-3-
methoxycarbonyl-4-
`
Acknowledgments Funds from Universita Politecnica delle Marche
(Ancona, Italy) are gratefully acknowledged.
triisopropylsilyloxymethylpyrrolidin-2-one, 16
Conflict of interest The authors declare no conflicts of interest.
To a solution containing pyrrolidin-2-one 15 (700 mg,
1.79 mmol) in dry THF (7 mL) at -15 °C under argon,
n-BuLi (3.94 mmol, 2.46 mL of a 1.6-M solution in hex-
ane) was added, the mixture was stirred for 15 min, and
then methyl chloroformate (152 lL, 1.97 mmol) was
slowly dropped at -15 °C. After 10 min, H2O (50 mL)
and ethyl acetate (100 mL) were quickly added, the
organic phase was separated, then the aqueous phase was
extracted with additional ethyl acetate (2 9 100 mL). The
organic layers were dried (Na2SO4) and volatiles were
removed under reduced pressure: then the residue was
purified by silica gel chromatography (cyclohexane:ethyl
acetate 90:10) to give compound 16 (370 mg, 46 % yield)
as a colorless oil. 1H NMR (200 MHz, CDCl3): d 0.98 (m,
21H), 1.49 (s, 3H), 1.55 (d, J = 7.4, 3H), 2.21–2.42 (m,
1H), 3.00 (dd, J = 8.3, J = 8.9, 1H), 3.19 (dd, J = 8.6,
J = 8.9, 1H), 3.58 (dd, J = 8.0, J = 10.2, 1H), 3.71 (s,
3H), 3.79 (dd, J = 7.0, J = 10.2, 1H), 5.49 (q, J = 7.4,
1H), 7.18–7.41 (m, 5 ArH). 13C NMR (50 MHz, CDCl3): d
12.2, 16.4, 18.0, 21.0, 27.4, 41.0, 44.5, 48.2, 52.5, 55.7,
64.8, 127.3, 127.6, 127.7, 128.7, 140.3, 171.1, 172.1. [a]D
19.8 (c 1, CHCl3). MS (ESI): m/z 447.3 [M]?, 470.3
[M ? Na]?. Anal. calcd for C25H41NO4Si: C 67.07; H
9.23; N 3.13. Found: C 67.16; H 9.27; N 3.01.
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