A novel conformationally restricted analogue of 3-methylaspartic acid via stereoselective methylation of chiral pyrrolidin-2-ones

Article abstract of DOI:10.1016/j.tet.2009.10.004

Conformationally restricted analogues of β-methylaspartic acid were easily prepared starting from chiral N-protected trans-3-amino-4-methoxycarbonyl pyrrolidin-2-ones. The key step of the synthesis was the methylation reaction at C-4, proceeding with high diastereoselection syn to the protected amino group lying at C-3 of the pyrrolidin-2-one ring.

Full text of DOI:10.1016/j.tet.2009.10.004

Tetrahedron 66 (2010) 400–405
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A novel conformationally restricted analogue of 3-methylaspartic acid via
stereoselective methylation of chiral pyrrolidin-2-ones
,
Emanuela Crucianelli a, Roberta Galeazzi a, Gianluca Martelli a, Mario Orena a
*
,
Samuele Rinaldi a, Piera Sabatino b
a
`
Dipartimento I.S.A.C., Universita Politecnica delle Marche, Via Brecce Bianche, 60121 Ancona, Italy
b
`
Dipartimento di Chimica ‘G. Ciamician’, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Conformationally restricted analogues of
b
-methylaspartic acid were easily prepared starting from chiral
Received 14 July 2009
Received in revised form
11 September 2009
Accepted 2 October 2009
Available online 13 October 2009
N-protected trans-3-amino-4-methoxycarbonyl pyrrolidin-2-ones. The key step of the synthesis was the
methylation reaction at C-4, proceeding with high diastereoselection syn to the protected amino group
lying at C-3 of the pyrrolidin-2-one ring.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
this acid in the formation of pyrimidine precursors.6 In addition,
they are involved in metabolic pathways such as the reversible
The binding affinity of bioactive peptides to their receptors and
subsequent biological transduction relies on both the backbone
conformation of the peptides, and the side-chain orientation of key
pharmacophore groups.1 Moreover, topographical considerations are
an important approach for exploring the stereochemical re-
quirements for receptor recognition and for signal transduction,1,2 so
that novel designed amino acids having constrained a side chain are
incorporated into peptide templates. In fact, the use of enantiomeri-
isomerization of (S)-glutamic acid to (2S,3S)-3-methyl aspartic acid
catalysed by glutamate mutase.7 (2S,3R)-3-Methyl aspartic acid was
recently found to be precursor of the unit C of cryptophycin I,
a potent anticancer agent from Nostoc cyanobionts,8 and a compo-
nent of lipodepsipeptides.9
Eventually, a series of side-chain-constrained RGD peptides
containing both (2S,3R)-1 and (2S,3S)-3-methylaspartic acid 2
within the RGD sequence have been assayed for binding to the
integrin receptors aIIbb3 and avb3 and the results demonstrated the
importance of the side-chain orientation of this particular residue
within the RGD sequence.10
cally pure b-substituted amino acids into bioactive peptide ligands at
key pharmacophore residues was proven to be a powerful tool for
understanding ligand–receptor binding interactions and in peptido-
mimetic design.3
2. Results and discussion
In recent years we synthesized a range of novel conformation-
ally constrained amino acids by using asymmetric synthetic strat-
egies with the aim to obtain mimetics of bioactive oligopeptides4
and neurotransmitter analogues.5 Within this topic, (2S,3R)-3-
methyl aspartic acid, 1, and its (2S,3S)-diastereomer, 2, were com-
pounds of particular interest.
Initially, we considered the lactams 3a,b, protected analogues of
b-methylaspartic acid, in which the conformational restriction
arising from the presence of the lactam ring could be derived from
compounds 4a–c, recently prepared in our laboratory in enantio-
merically pure form.11a
NH2
NH2
H
H
COOH
COOH
R1
N
R1
N
COOCH3
HOOC
HOOC
COOCH3
1
O
O
2
N
H
N
3
4
In fact, they display a toxic action on Escherichia coli being an-
R2
timetabolites of aspartic acid, and interfere with the functioning of
a. R1 = CCl3CO, R2 = PMP
b. R1 = t-Boc, R2 = PMP
c. R1 = CCl3CO, R2 = Ph
a. R1 = CCl3CO
b. R1 = t-Boc
* Corresponding author. Tel.: þ39 071 2204720; fax: þ39 071 2204714.
E-mail address: m.orena@univpm.it (M. Orena).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.004

E. Crucianelli et al. / Tetrahedron 66 (2010) 400–405
401
We were delighted to find that treatment of compound 4a with
LiHMDS (3.0 equiv) at 0 ꢀC, followed by alkylation at ꢁ78 ꢀC with
CH3I (2.5 equiv) furnished in an excellent 77% yield a 90:10 di-
astereomeric mixture of 5a and 6a (Table 1). Crystallisation allowed
isolation of the major diastereomer 5a, whose stereochemistry was
first assigned as (3S,4R,10S) bycomparison of chemical shifts of minor
diastereomer.11 The relative stereochemistry was confirmed as syn
for the Cl3CONH and methyl groups by NOE experiments (Fig. 1) and
eventually single crystal X-ray analysis allowed unambiguous as-
signment of the configuration, as reported in Figure 2.12–14
Next, compounds 5a,b were treated with CAN in acetonitrile–
water.15 Under these conditions cleavage of the 4-methoxy-
phenylethylgroupoccurred,togiveingoodyieldtheenantiomerically
pure 3,4,4-trisubstituted pyrrolidin-2-ones 3a,b, both protected
forms of a conformationally restricted analogue of
b-methylaspartic
acid, 1 (Scheme 1).
H
H
R1
N
R1
N
COOCH3
i
COOCH3
Table 1
O
N
O
Alkylation of pyrrolidin-2-ones 4
N
H
H
5a,b
3a,b
PMP
R1
N
COOCH3
Scheme 1. Reagents and conditions: i CAN, CH3CN–H2O; a, R1¼CCl3CO, 83%; b, R1¼t-
C4H9OCO, 82%.
1. LiHDMS
O
N
2. R3CH2X
(X = Br, I)
Havingestablished that the methylation of pyrrolidin-2-ones 4a–c
proceeds with good stereoselection, leading contrary to the expec-
tations16 to products where the methyl group lies syn to the amide
group,17 we envisaged that this method can disclose the access to a lot
of chiral pyrrolidin-2-ones having a quaternary centre at C-4.
However, when halides other than methyl iodide were employed,
the reaction proceeded with decreased stereoselection. In addition,
diastereomeric mixtures were difficult to separate, an efficient sep-
aration being obtained only when (S)-4-methoxyphenylethylamine
was the chiral inducer (Table 1, entries a–c).18 On the other hand it is
worth mentioning that well defined signal patterns were always
observed in the 1H NMR spectra, and the chemical shifts allowed
a straightforward assignment of the configuration of diastereomers.
In fact, for all compounds the shielding effect due to the aryl group of
the chiral inducer was instrumental in the structural assignment
(Table 2).14
4
R2
H
H
R1
N
COOCH3
R3
R1
N
COOCH3
R3
+
O
O
N
N
5
6
R2
R2
Entry
R1
R2
R3
Yielda % (dr)
a
b
c
d
e
f
CCl3CO
t-Boc
PMP
H
H
77 (90:10)
75 (85:15)
60 (60:40)
77 (89:11)
51 (80:20)
94 (60:40)
75 (60:40)
PMP
PMP
Ph
Ph
Ph
CCl3CO
CCl3CO
CCl3CO
CCl3CO
CCl3CO
Ph
H
(CH3)2CH
CH2]CH
Ph
Table 2
g
Ph
Significant chemical shifts for compounds 5, 6 and 8, 9
a
Determined from 1H NMR spectra of reaction mixtures.
Compound
(C-4)–CH2–R
(C-4)–COOCH3
5a
6a
5b
6b
5c
6c
5d
6d
5e
6e
5f
0.93
1.53
2.08 and 3.16
3.27
0.86
1.44
0.92
1.46
0.81–0.99
1.21–1.34
1.68 and 2.44
2.57
2.06 and 3.13
3.30
1.22
1.09
3.20 and 3.31
2.95 and 3.60
2.15–2.67
2.44–2.55
3.78
3.43
3.76
3.46
3.69
3.40
3.78
3.41
3.67
3.49
3.77
3.43
3.78
3.42
3.72
3.76
3.74
3.82
3.70
3.73
OCH3
H
O
N
COCCl3
HA
H
N
CH3
HB
H
H3C
COOCH3
6f
5g
6g
8a
9a
8b
9b
8c
9c
Figure 1. Selected NOE enhancements for compound 5a.
With the aim to ascertain if a matching/mismatching effect
takes place owing to the contemporary presence of the centres at
both C-3 and C-10, we carried out the alkylation reactions starting
from pyrrolidin-2-ones 7a,b, diastereomers of 4a,c.11a Under the
same reaction conditions, however, similar stereoselection levels
were observed. That is, when methyl iodide was the alkylating
reagent, 4a afforded a mixture of compounds 5a and 6a in 90:10 dr
(matched case) whereas starting from 7a compounds 8a and 9a
were obtained in 89:11 dr (mismatched case). Thus, the configu-
ration at C-10 seems to be independent, the asymmetric induction
clearly depending upon the configuration of C-3, which directs the
Figure 2. ORTEP drawing of compound 5a (50% probability).
An analogous trend was observed for methylation of 4b and 4c,
this latter containing (S)-phenylethylamine as the chiral inducer
(Table 1).

402
E. Crucianelli et al. / Tetrahedron 66 (2010) 400–405
alkylation outcome. Thus, the ratio of the diastereomers seems to
be controlled by the inherent bias of the diastereomeric transition
states, not by the position of the phenyl group of the chiral inducer.
There was no effect also for alkylation of compounds 7a and 7b
carried out with benzyl bromide and allyl bromide, respectively,
thus confirming that the C-10 configuration has very low impact on
these reactions (Table 3).
sequences containing
currently in progress in our laboratory, in particular towards mod-
a- and b
-residues.23 Work along this line is
ulation of the secondary structure of amphiphilic
will be reported in due course.
b-foldamers, and
4. Experimental
4.1. General
Table 3
Alkylation of pyrrolidin-2-one 7a,b
Melting points were measured on an Electrothermal IA 9000
apparatus and are uncorrected. IR spectra were recorded in CHCl3 on
a Nicolet Fourier Transform Infrared 20-SX spectrophotometer. Di-
astereomeric purity was determined by GC analysis using an in-
strument equipped with a capillary column (50 mꢂ0.25 mm i.d.;
stationary phase CP-Sil-5 CB). 1H NMR spectra were recorded at 200
and 400 MHz, whereas 13C NMR spectra were recorded at 50 or
100 MHz, using CDCl3 as a solvent, unless otherwise reported.
H
R1
N
COOCH3
1. LiHDMS,
THF, 0 °C
O
N
2. R3CH2X
(X = Br, I)
7
R2
Chemical shifts (d) are reported in parts per million relative to TMS
and coupling constants (J) in hertz. Assignments were aided by
decoupling and homonuclear two-dimensional experiments. Opti-
cal rotations were measured using a 1 dm path length cell. The
samples were analysed with a liquid chromatography Agilent
Technologies HP1100 equipped with a Zorbax Eclipse XDB-C8 Agi-
lent and Technologies column (flow rate 0.5 mL/min) and equipped
with a diode-array UV detector (220 and 254 nm). Acetonitrile and
methanol for HPLC were purchased from a commercial supplier. All
the samples were prepared by diluting 1 mg in 5 mL of a 1:1 mixture
of H2O and acetonitrile in pure acetonitrile or in pure methanol. The
MSD1100 mass detector was utilized under the following condi-
tions: mass range 100–2500 uma, positive scanning, energy of
fragmentor 50 V, drying gas flow (nitrogen) 10.0 mL/min, nebulizer
pressure 45 psig, drying gas temperature 350 ꢀC, capillary voltage
4500 V. Column chromatography was performed with silica gel 60
(230–400 mesh). Compounds 4a–c and 7a,b were prepared as al-
ready reported.11a
H
H
R1
N
COOCH3
R3
R1
N
CO OCH3
R3
+
O
O
N
N
8
9
R2
R2
Entry
R1
R2
R3
Yielda % (dr)
a
b
c
CCl3CO
CCl3CO
CCl3CO
PMP
PMP
Ph
H
Ph
73 (89:11)
77 (60:40)
90 (60:40)
CH2]CH
Determined from 1H NMR spectra of reaction mixtures.
a
The results we obtained could be rationalised as follows. In
4-alkyl substituted pyrrolidin-2-ones the attack of the electrophile
to the enolate anion was previously found to proceed on the less
hindered side, leading to a 3,4-trans-relationship,16 so that the al-
kylation of the anion of 4 would be expected to occur anti to the
bulky trichloroacetylamino group leading to 6. However, the pref-
erential formation of compound 5 could be explained by a chelation
effect between the lithium bonded to nitrogen of the dianion and
the halogen of the halide. In the presence of overwhelming factors
such as bulkiness of the electrophile, control of the chelation was
less effective, and the electrophile was able to attack the enolate on
the less hindered side, opposite to the trichloroacetylamino group.
Eventually, the chiral inducer did not appear to be involved in
diastereoselection, probably due to the distance occurring between
the reacting centre and the phenyl group of the inducer. In fact, no
significant effect was observed when the alkylation was carried out
starting from the pyrrolidin-2-ones 7 having the opposite config-
uration at both C-3 and C-4 with respect to 4.
4.2. General procedure for alkylation of pyrrolidin-2-ones
4a–c and 7
To a solution of pyrrolidin-2-ones 4a–c or 711a (2.0 mmol) in dry
THF (6 mL), LiHDMS (1 M in hexanes; 6 mL; 6.0 mmol) was added
under argon at 0 ꢀC and the mixture was stirred for 1 h at 0 ꢀC. Then
the mixture was cooled to ꢁ78 ꢀC and solution of the appropriate
halide (5 mmol) dissolved in dry THF (5 mL) was added. After 2 h,
H2O (100 mL) was added and the mixture extracted with ethyl
acetate (3ꢂ20 mL). After drying (Na2SO4) the solvent was removed
under reduced pressure and the residue was purified by silica gel
chromatography (cyclohexane–ethyl acetate 1:1) to give 5, 6 or 8, 9
as diastereomeric mixtures.
4.2.1. (3S,4R,10S)-4-Methoxycarbonyl-1-[10-(4-methoxyphenyleth-10-
yl)]-4-methyl-3-trichloroacetylaminopyrrolidin-2-one, 5a, and its
(3S,4S,10S)-isomer, 6a. The title compounds were obtained from 4a
in 77% yield as a diastereomeric mixture (dr 90:10), which was
easily separated by crystallisation. ESI-MS: m/z 450.1 [M]þ, 473.2
[MþNa]þ. Anal. Calcd for C18H21Cl3N2O5: C, 47.86; H, 4.69; N, 6.20.
Found: C, 47.75; H, 4.74; N, 6.14. Isomer-(3S,4R,10S), 5a: white
3. Conclusions
In summary, enantiomerically pure 3,4,4-trisubstituted pyrro-
lidin-2-ones 5a–c were produced in good yield and 5a,b gave 3a
and 3b, conformationally restricted protected analogues of (S)-b-
methylaspartic acid, 1. These resulting unnatural amino acid
derivatives are new and versatile intermediates possessing
orthogonally functionalized substituents with a wide range of ap-
plications in medicinal chemistry where aspartates are involved.19
Moreover, it is worth noting that compounds 5, having a quater-
crystals: mp 151–153 ꢀC; nmax 3342, 1747, 1705, 1652 cmꢁ1
; dH
(200 MHz, CDCl3) 0.93 (3H, s, CH3), 1.54 (3H, d, J 7.2, 10-CH3), 2.77
(1H, d, J 9.9, pro-R H-5), 3.72 (1H, d, J 9.9, pro-S H-5), 3.78 (3H, s,
OCH3), 3.80 (3H, s, OCH3), 4.93 (1H, d, J 4.8, H-3), 5.48 (1H, q, J 7.2,
H-10), 6.88 (2 ArH, d, J 8.5), 7.15 (1H, d, J 4.8, NH), 7.23 (2 ArH, d, J
8.5); dC (50 MHz, CDCl3) 15.3, 16.2, 47.9, 49.5, 50.2, 52.9, 55.2, 60.1,
nary carbon, are suitable for preparing novel
b-foldamers tethered
on a pyrrolidin-2-one ring.20 The constriction due to this centre,
according to the Thorpe–Ingold effect21 observed for
a-amino
91.7, 114.0, 128.3, 130.5, 159.3, 162.5, 167.6, 173.5; [
CHCl3). Isomer-(3S,4S,10S), 6a: colourless oil: nmax 3345, 1744, 1708,
1660 cmꢁ1
dH (200 MHz, CDCl3) 1.53 (3H, s, CH3), 1.54 (3H, d, J 7.2,
a
]
D
ꢁ40.0 (c 1.0,
acids,22 can give rise to a new class of polypeptide helices, allowing
modulation of the helix in analogy with the behaviour of hybrid
;

E. Crucianelli et al. / Tetrahedron 66 (2010) 400–405
403
10-CH3), 3.18 (1H, d, J 10.5, pro-R H-5), 3.21 (1H, d, J 10.5, pro-S H-5),
3.43 (3H, s, COOCH3), 3.75 (3H, s, OCH3), 4.68 (1H, d, J 8.2, H-3), 5.46
(1H, q, J 7.2, H-10), 6.88 (2 ArH, d, J 8.5), 7.23 (2 ArH, d, J 8.5), 7.79
(1H, d, J 8.2, NH); dC (50 MHz, CDCl3) 14.3, 15.9, 48.1, 49.6, 50.1, 50.5,
52.6, 59.8, 91.9, 114.2, 128.0, 128.3, 128.8, 129.0, 139.0, 163.6, 168.6,
7.1, CH3), 3.18 (1H, d, J 12.4, pro-R H-5), 3.23 (1H, d, J 12.4, pro-S H-
5), 3.41 (3H, s, COOCH3), 4.88 (1H, d, J 8.6, H-3), 5.48 (1H, q, J 7.1, H-
10), 7.22–7.42 (5 ArH, m), 7.71 (1H, d, J 7.6, NH); dC (50 MHz, CDCl3)
14.3, 15.9, 48.1, 49.6, 50.1, 52.6, 59.8, 91.8, 127.3, 128.0, 128.3, 128.8,
129.0, 139.0, 163.3, 168.6, 173.6.
179.6; [
a
]
ꢁ21.7 (c 0.5, CHCl3).
D
4.2.5. (3S,4R,10S)-4-Methoxycarbonyl-4-(200-methyl-prop-100-yl)-1-
(10-phenyleth-10-yl)-3-trichloroacetylaminopyrrolidin-2-one, 5e, and
its (3S,4S,10S)-isomer, 6e. The title compounds were obtained in 51%
yield as a diastereomeric inseparable mixture (dr 80:20). nmax 3353,
1740, 1709, 1651 cmꢁ1; ESI-MS: m/z 462.1 [M]þ, 485.2 [MþNa]þ.
Anal. Calcd for C20H25Cl3N2O4: C, 51.80; H, 5.43; N, 6.04. Found: C,
51.72; H, 5.48; N, 6.12. Isomer-(3S,4R,10S), 5e: dH (200 MHz, CDCl3):
0.45 (3H, d, J 7.0, CH3), 0.58 (3H, d, J 7.0, CH3), 0.81–0.99 (2H, m, CH2),
1.49–1.61 (1H, m, CH),1.56 (3H, d, J 7.2, 10-CH3), 3.01 (1H, d, J 13.2, pro-
R H-5), 3.67 (3H, s, COOCH3), 3.74 (1H, d, J 13.2, pro-S H-5), 4.86 (1H,
d, J 7.4, H-3), 5.53 (1H, q, J 7.2, H-10), 7.00 (1H, d, J 7.4, NH), 7.21–7.37 (5
ArH, m); dC (50 MHz, CDCl3) 15.8, 21.9, 24.0, 24.6, 36.0, 43.7, 49.9,
51.4, 52.4, 59.7, 92.3, 127.5, 127.6, 127.9, 128.6, 128.9, 139.0, 162.5,
167.6,173.1. Isomer-(3S,4S,10S), 6e: dH (200 MHz, CDCl3) 0.77 (3H, d, J
7.0, CH3), 0.85 (3H, d, J 7.0, CH3),1.21–1.34 (2H, m, CH2),1.51–1.61 (1H,
m, CH), 1.52 (3H, d, J 7.2, 10-CH3), 3.15 (1H, d, J 12.4, pro-R H-5), 3.27
(1H, d, J 12.4, pro-S H-5), 3.49 (3H, s, COOCH3), 4.73 (1H, d, J 9.4, H-3),
5.51 (1H, q, J 7.2, H-10), 7.21–7.37 (5 ArH, m), 8.22 (1H, d, J 9.4, NH); dC
(50 MHz, CDCl3) 15.4, 22.3, 25.5, 29.8, 36.0, 44.3, 49.7, 51.4, 53.1, 58.8,
92.6, 127.3, 127.6, 127.9, 128.4, 128.9, 139.2, 162.7, 168.6, 174.5.
4.2.2. (3S,4R,10S)-3-t-Butoxycarbonylamino-4-methoxycarbonyl-4-
methyl-1-[10-(4-methoxyphenyleth-10-yl) pyrrolidin-2-one, 5b, and
its (3S,4S,10S)-isomer, 6b. The title compounds were obtained in
75% yield as an easily separable diastereomeric mixture (dr 85:15).
ESI-MS: m/z 406.2 [M]þ, 429.2 [MþNa]þ. Anal. Calcd for
C21H30N2O6: C, 62.05; H, 7.44; N, 6.89. Found: C, 61.94; H, 7.33; N,
6.93. Isomer-(3S,4R,10S), 5b: colourless oil: nmax 3345, 1724, 1710,
1655 cmꢁ1
; dH (200 MHz, CDCl3) 0.86 (s, 3H, CH3), 1.38 (s, 9H,
3ꢂCH3), 1.47 (3H, d, J 7.2, 10-CH3), 2.65 (1H, d, J 9.8, pro-R H-5), 3.65
(1H, d, J 9.8, pro-S H-5), 3.69 (3H, s, COOCH3), 3.76 (3H, s, OCH3),
4.73 (1H, d, J 6.5, H-3), 5.05 (1H, d, J 6.5, NH), 5.43 (1H, q, J 7.2, H-10),
6.82 (2 ArH, d, J 8.8), 7.17 (2 ArH, d, J 8.8); dC (50 MHz, CDCl3) 15.5,
15.9, 26.1, 47.9, 49.0, 49.2, 52.5, 55.1, 59.9, 79.8, 113.8, 128.2, 130.9,
155.3, 159.1, 168.8, 174.2; [
a
]
-56.3 (c 1.6, CHCl3). Isomer-
D
(3S,4S,10S), 6b: colourless oil: nmax 3347, 1728, 1711, 1658 cmꢁ1
;
dH
(200 MHz, CDCl3) 1.38 (3ꢂCH3, s, 9H), 1.44 (3H, s, CH3), 1.48 (3H, d, J
7.2, 10-CH3), 3.18 (1H, d, J 8.8, pro-R H-5), 3.21 (1H, d, J 8.8, pro-S H-
5), 3.40 (3H, s, COOCH3), 3.73 (3H, s, OCH3), 4.68 (1H, d, J 6.4, H-3),
5.15 (1H, d, J 6.4, NH), 5.48 (1H, q, J 7.2, H-10), 6.81 (2 ArH, d, J 8.8),
7.19 (2 ArH, d, J 8.8); dC (50 MHz, CDCl3) 15.6, 16.0, 26.0, 47.5, 48.8,
49.1, 52.4, 55.4, 59.6, 79.8, 113.6, 128.1, 130.7, 155.1, 159.3, 168.5,
4.2.6. (3S,4R,10S)-4-Allyl-4-methoxycarbonyl-1-(10-phenyleth-10-yl)-
3-trichloroacetylaminopyrrolidin-2-one, 5f, and its (3S,4S,10S)-isomer,
6f. The title compounds were obtained in 94% yield as a di-
astereomeric inseparable mixture (dr 60:40). nmax 3349, 1736, 1712,
1674 cmꢁ1; ESI-MS: m/z 446.1 [M]þ, 469.2 [MþNa]þ. Anal. Calcd for
C19H21Cl3N2O4: C, 50.97; H, 4.73; N, 6.26. Found: C, 51.04; H, 4.68;
N, 6.32. Isomer-(3S,4R,10S), 5f: dH (200 MHz, CDCl3) 1.57 (3H, d, J
7.2, 10-CH3), 1.68 (1H, dd, J 9.6, J 13.7, CH2–CH]), 2.44 (1H, dd, J 5.0, J
13.7, CH2–CH]), 3.06 (1H, d, J 10.3, pro-R H-5), 3.75 (1H, d, J 10.3,
pro-S H-5), 3.77 (3H, s, COOCH3), 4.71–4.81 (2H, m, CH]CH2), 4.96
(1H, d, J 6.4, H-3), 5.15–5.35 (1H, m, CH]CH2), 5.53 (1H, q, J 7.2, H-
10), 7.08 (1H, d, J 6.4, NH), 7.21–7.38 (5 ArH, m); dC (50 MHz, CDCl3)
15.8, 33.3, 45.1, 50.1, 50.8, 52.9, 59.8, 91.9, 120.3, 127.0, 127.2, 127.5,
128.3, 128.8, 131.8, 138.6, 162.6, 167.3, 172.5. Isomer-(3S,4S,10S), 6f:
dH (200 MHz, CDCl3) 1.52 (3H, d, J 7.2,10-CH3), 2.57 (2H, d, J 7.3, CH2–
CH]), 3.18 (1H, d, J 10.5, pro-R H-5), 3.26 (1H, d, J 10.5, pro-S H-5),
3.43 (3H, s, COOCH3), 4.77 (1H, d, J 8.8, H-3), 5.04–5.18 (2H, m,
CH]CH2), 5.51 (1H, q, J 7.2, H-10), 5.51–5.81 (1H, m, CH]CH2),
7.21–7.38 (5 ArH, m), 7.85 (1H, d, J 8.8, NH); dC (50 MHz, CDCl3) 15.7,
38.2, 47.3, 49.5, 52.5, 53.6, 57.9, 92.3,120.4,126.9,127.9,128.3,128.5,
128.8, 131.2, 138.9, 162.4, 168.4, 173.0.
174.1; [
a
]
ꢁ47.1 (c 0.5, CHCl3).
D
4.2.3. (3S,4R,10S)-4-Benzyl-4-methoxycarbonyl-1-[10-(4-methoxy-
phenyleth-10-yl)]-3-trichloroacetylaminopyrrolidin-2-one, 5c, and its
(3S,4S,10S)-isomer, 6c. The title compounds were obtained in 60%
yield as an easily separable diastereomeric mixture (dr 60:40). ESI-
MS: m/z 526.1 [M]þ, 549.2 [MþNa]þ. Anal. Calcd for C24H25Cl3N2O5:
C, 54.61; H, 4.77; N, 5.31. Found: C, 54.55; H, 4.71; N, 5.39. Isomer-
(3S,4R,10S), 5c: colourless oil: nmax 3361, 1731, 1712, 1681 cmꢁ1
; dH
(200 MHz, CDCl3) 1.52 (3H, d, J 7.2, 10-CH3), 2.08 (1H, d, J 13.4,
CHPh), 3.00 (1H, d, J 14.7, pro-R H-5), 3.16 (1H, d, J 13.4, CHPh), 3.67
(1H, d, J 14.7, pro-S H-5), 3.76 (s, 3H, COOCH3), 3.86 (s, 3H, OCH3),
5.00 (1H, d, J 7.8, H-3), 5.57 (1H, q, J 7.2, H-10), 6.22 (1H, d, J 7.8, NH),
6.94–7.15 (5 ArH, m), 7.21–7.35 (4 ArH, m); dC (50 MHz, CDCl3) 16.0,
33.9, 42.9, 49.6, 52.7, 52.8, 55.6, 59.9, 92.2, 114.4, 127.1, 128.4, 129.2,
130.0, 131.1, 134.9, 159.9, 162.7, 167.1, 172.0; [
Isomer-(3S,4S,10S), 6c: colourless oil: nmax 3355, 1734, 1711,
1685 cmꢁ1 dH (200 MHz, CDCl3) 1.44 (3H, d, J 7.0, 10-CH3), 3.06 (1H,
d, J 13.8, pro-R H-5), 3.18 (1H, d, J 13.8, pro-S H-5), 3.27 (2H, s,
CH2Ph), 3.46 (3H, s, COOCH3), 3.79 (3H, s, OCH3), 4.84 (1H, d, J 9.2,
H-3), 5.38 (1H, q, J 7.0, H-10), 6.78–6.89 (2 ArH, d, J 8.2), 7.04–7.41 (7
ArH, m), 8.01 (1H, d, J 9.2, NH); dC (50 MHz, CDCl3) 16.0, 39.8, 47.5,
49.1, 52.7, 54.6, 55.5, 57.7, 92.4, 113.9,114.3, 127.6, 128.5, 128.9, 129.7,
a]
D ꢁ14.3 (c 0.7, CHCl3).
;
4.2.7. (3S,4R,10S)-4-Benzyl-4-methoxycarbonyl-1-(10-phenyleth-10-
yl)-3-trichloroacetylaminopyrrolidin-2-o-ne, 5g, and its (3S,4S,10S)-
isomer, 6g. The title compounds were obtained in 75% yield as
a diastereomeric inseparable mixture (dr 60:40). nmax 3347, 1736,
1708, 1668 cmꢁ1; ESI-MS: m/z 496.1 [M]þ, 522.1 [MþNa]þ. Anal.
Calcd for C23H23Cl3N2O4: C, 55.49; H, 4.66; N, 5.63. Found: C, 55.42;
H, 4.59; N, 5.69. Isomer-(3S,4R,10S), 5g: dH (200 MHz, CDCl3) 1.57
(3H, d, J 7.2,10-CH3), 2.06 (1H, d, J 13.4, CHPh), 3.00 (1H, d, J 14.5, pro-
R H-5), 3.13 (1H, d, J 13.4, CHPh), 3.70 (1H, d, J 14.5, pro-S H-5), 3.78
(3H, s, COOCH3), 5.02 (1H, d, J 7.4, H-3), 5.63 (1H, q, J 7.2, H-10), 6.18
(1H, d, J 7.4, NH), 6.94–7.35 (10 ArH, m); dC (50 MHz, CDCl3) 16.0,
33.9, 42.9, 49.6, 52.7, 52.8, 55.6, 59.9, 91.9, 120.3, 127.0, 127.2, 127.5,
128.3, 128.8, 131.8, 138.6, 162.6, 167.3, 172.5. Isomer-(3S,4S,10S), 6g:
dH (200 MHz, CDCl3) 1.48 (3H, d, J 7.0,10-CH3), 3.11 (1H, d, J 13.6, pro-
R H-5), 3.17 (1H, d, J 13.6, pro-S H-5), 3.30 (2H, s, CH2Ph), 3.42 (3H, s,
COOCH3), 4.86 (1H, d, J 9.2, H-3), 5.41 (1H, q, J 7.0, H-10), 6.98–7.41
(10 ArH, m), 8.04 (1H, d, J 9.2, NH); dC (50 MHz, CDCl3) 16.0, 29.8,
131.2, 134.8, 159.3, 162.7, 168.1, 173.5; [
a
]
D ꢁ38.5 (c 0.52, CHCl3).
4.2.4. (3S,4R,10S)-4-Methoxycarbonyl-4-methyl-1-(10-phenyleth-10-
yl)-3-trichloroacetylaminopyrrolidin-2-o-ne, 5d, and its (3S,4S,10S)-
isomer, 6d. The title compounds were obtained in 77% yield as
a diastereomeric inseparable mixture (dr 89:11). nmax 3352, 1734,
1709, 1655 cmꢁ1; ESI-MS: m/z 420.1 [M]þ, 443.1 [MþNa]þ. Anal.
Calcd for C17H19Cl3N2O4: C, 48.42; H, 4.54; N, 6.64. Found: C, 48.35;
H, 4.49; N, 6.71. Isomer-(3S,4R,10S), 5d: dH (200 MHz, CDCl3) 0.92
(3H, s, CH3), 1.56 (3H, d, J 7.2, 10-CH3), 2.76 (1H, d, J 12.5, pro-R H-5),
3.74 (1H, d, J 12.5, pro-S H-5), 3.78 (3H, s, COOCH3), 4.94 (1H, d, J 6.2,
H-3), 5.51 (1H, q, J 7.2, H-10), 7.18 (1H, d, J 6.2, NH), 7.24–7.41 (5 ArH,
m); dC (50 MHz, CDCl3) 15.4, 16.1, 48.1, 50.2, 50.5, 53.1, 60.2, 91.8,
127.3, 128.0, 128.6, 128.8, 128.9, 138.8, 162.6, 167.9, 173.6. Isomer-
(3S,4S,10S), 6d: dH (200 MHz, CDCl3) 1.46 (3H, s, CH3), 1.53 (3H, d, J

404
E. Crucianelli et al. / Tetrahedron 66 (2010) 400–405
39.8, 47.5, 49.1, 52.7, 54.6, 55.5, 57.7, 92.4, 92.3, 120.4, 126.9, 127.9,
128.3, 128.5, 128.8, 131.2, 138.9, 162.4, 168.4, 173.0.
d, J 8.4, H-3), 5.05 (1H, m, CH]CH2), 5.12–5.17 (1H, m, CH]CH2),
5.48 (1H, q, J 7.2, 10-H), 5.53–5.64 (1H, m, CH]CH2), 7.20–7.40 (5
ArH, m), 7.94 (1H, d, J 8.4, NH); dC (100 MHz, CDCl3) 15.5, 30.1, 38.1,
47.3, 50.0, 52.6, 58.3, 92.1, 120.0, 126.9, 127.0, 127.4, 127.8, 128.7,
131.2, 138.7, 162.4, 168.1, 172.5.
4.2.8. (3R,4S,10S)-4-Methoxycarbonyl-1-[10-(4-methoxyphenyleth-
10-yl)]-4-methyl-3-trichloroacetylaminopyrrolidin-2-one, 8a, and its
(3R,4R,10S)-isomer, 9a. The title compounds were obtained in 73%
yield as an easily separable diastereomeric mixture (dr 89:11). ESI-
MS: m/z 450.1 [M]þ, 473.2 [MþNa]þ. Anal. Calcd for C18H21Cl3N2O5:
C, 47.86; H, 4.69; N, 6.20. Found: C, 47.78; H, 4.60; N, 6.16. Isomer-
(3R,4S,10S), 8a: white solid: mp 122–123 ꢀC; nmax 3355, 1735, 1712,
5. General procedure for removal of the 4-
methoxyphenylethyl group from 5a,b
A solution of 5a or 5b (1.0 mmol) in CH3CN (5 mL) was treated at
room temperature with cerium ammonium nitrate (CAN) (1.1 g,
2.0 mmol) dissolved in H2O (5 mL), and the reaction mixture was
stirred for 3 h. The aqueous layer was extracted with ethyl acetate
(3ꢂ25 mL), theorganiclayerswere combined, washedwith brine and
dried (Na2SO4). Removal of the solvent under reduced pressure pro-
vided a crude residue, which was purified by silica gel chromatogra-
phy (cyclohexane–ethyl acetate 30:70) to give compound 3a or 3b.
1661 cmꢁ1
; dH (400 MHz, CDCl3) 1.22 (3H, s, CH3), 1.51 (3H, d, J 7.2,
10-CH3), 3.03 (1H, d, J 10.4, pro-R H-5), 3.35 (1H, d, J 10.4, pro-S H-5),
3.72 (3H, s, COOCH3), 3.79 (3H, s, OCH3), 4.87 (1H, d, J 5.2, H-3), 5.43
(1H, q, J 7.2, H-10), 6.86 (2 ArH, d, J 8.8), 7.18 (2 ArH, d, J 8.8), 7.38 (1H,
d, J 5.2, NH); dC (100 MHz, CDCl3) 15.8, 15.9, 47.7, 49.7, 50.7, 52.9,
55.2, 60.0, 91.7, 114.1, 128.2, 130.4, 159.3, 162.5, 167.7, 173.3. [a]
D
ꢁ27.6 (c 1.0, CHCl3). Isomer-(3R,4R,10S), 9a: colourless oil: nmax
3351, 1737, 1710, 1665 cmꢁ1
; dH (400 MHz, CDCl3) 1.09 (3H, s, CH3),
1.46 (3H, d, J 7.2, 10-CH3), 2.77 (1H, d, J 10.4, pro-R H-5), 3.52 (1H, d, J
10.4, pro-S H-5), 3.69 (3H, s, OCH3), 3.76 (3H, s, COOCH3), 4.56 (1H,
d, J 8.4, H-3), 5.43 (1H, q, J 7.2, H-10), 6.86 (2 ArH, d, J¼8.8), 7.18 (2
ArH, d, J 8.8), 7.68 (1H, d, J 8.4, NH); dC (100 MHz, CDCl3) 14.8, 15.6,
47.7, 49.4, 50.6, 50.7, 52.6, 59.7, 91.9, 114.2, 127.9, 130.6, 159.4, 163.5,
5.1. (3S,4R)-4-Methoxycarbonyl-4-methyl-2-
trichloroacetylaminopyrrolidin-2-one, 3a
Compound 3a (0.26 g, 83%) was obtained as white solid: mp 86–
88 ꢀC. nmax 3351, 1736, 1711, 1664 cmꢁ1
; dH (200 MHz, CDCl3) 1.30
168.7, 173.8. [
a
]
ꢁ22.1 (c 0.5, CHCl3).
(3H, s, CH3), 3.23 (1H, dd, J 10.0, J 1.8, H-5 pro-R), 3.82 (3H, s, OCH3),
3.87 (1H, d, J 10.0, H-5 pro-S), 4.92 (1H, d, J 5.2, H-3), 6.50 (1H, br s,
NH), 7.24 (1H, d, J 5.2, NH); dC (50 MHz, CDCl3) 6.1, 49.8, 50.2, 53.0,
D
4.2.9. (3R,4S,10S)-4-Benzyl-4-methoxycarbonyl-1-[10-(4-methoxy-
phenyleth-10-yl)]-3-trichloroacetylaminopyrrolidin-2-one, 8b, and its
(3R,4R,10S)-isomer, 9b. The title compounds were obtained in 77%
yield as an easily separable diastereomeric mixture (dr 60:40). ESI-
MS: m/z 526.1 [M]þ, 549.2 [MþNa]þ. Anal. Calcd for C24H25Cl3N2O5:
C, 54.61; H, 4.77; N, 5.31. Found: C, 54.53; H, 4.73; N, 5.37. Isomer-
58.8, 91.7, 162.6, 171.8, 173.4; [a]D -75.9 (c 0.4, CHCl3); ESI-MS: m/z
315.9 [M]þ, 338.1 [MþNa]þ. Anal. Calcd for C9H11Cl3N2O4: C, 34.04;
H, 3.49; N, 8.82. Found: C, 33.96; H, 3.44; N, 8.76.
5.2. (3S,4R)-2-t-Butoxycarbonylamino-4-methoxycarbonyl-4-
methylpyrrolidin-2-one, 3b
(3R,4S,10S), 8b: colourless oil: nmax 3348, 1737, 1709, 1681 cmꢁ1
;
dH
(400 MHz, CDCl3) 1.52 (3H, d, J 7.2, 10-CH3), 2.58 (1H, d, J 14.0, pro-R
H-5), 3.20 (1H, d, J 10.8, CHPh), 3.31 (1H, d, J 10.8, CHPh), 3.40 (1H, d, J
14.0, pro-S H-5), 3.74 (3H, s, COOCH3), 3.78 (3H, s, OCH3), 4.92 (1H, d,
J 7.2, H-3), 5.40 (1H, q, J 7.2,10-H), 6.84 (2 ArH, d, J 8.8), 7.15 (2 ArH, d, J
8.8,), 7.20–7.30 (5 ArH, m), 7.47 (1H, d, J 8.8, NH); dC (100 MHz,
CDCl3) 16.5, 26.9, 34.7, 44.5, 50.1, 52.1, 55.2, 60.0, 92.0, 114.1, 128.2,
Compound 3b (0.22 g, 82%) was obtained as white solid: mp 108–
110 ꢀC. nmax 3348, 1741, 1710, 1655 cmꢁ1
; dH (200 MHz, CDCl3) 1.22
(3H, s, CH3), 1.38 (9H, s, 3ꢂCH3), 3.09 (1H, dd, J 10.0, J 1.7, H-5 pro-R),
3.72 (3H, s, COOCH3), 3.78(1H, d, J 10.0, H-5pro-S), 4.71 (1H, d, J 7.0, H-
3), 5.20 (1H, d, J 7.0, NH), 7.16 (1H, br s, NH); dC (50 MHz, CDCl3) 16.4,
128.7, 129.8, 130.8, 135.4, 159.3, 162.7, 167.6, 172.2. [
CHCl3). Isomer-(3R,4R,10S), 9b: colourless oil: nmax (CHCl3) 3350,
1735, 1709, 1678 cmꢁ1 dH (400 MHz, CDCl3) 1.47 (3H, d, J 7.2, 10-
CH3), 2.95 (1H, d, J 10.4, CHPh), 3.05 (1H, d, J 14.0, pro-R H-5), 3.17
(1H, d, J 14.0, pro-S H-5), 3.60 (1H, d, J 10.4, CHPh), 3.75 (3H, s, OCH3),
3.82 (3H, s, COOCH3), 4.73 (1H, d, J 8.4, H-3), 5.40 (1H, q, J 7.2, H-10),
6.86 (2 ArH, d, J 8.8), 7.14 (2 ArH d, J 8.8), 7.20–7.30 (5 ArH, m), 7.83
(1H, d, J 8.8, NH); dC (100 MHz, CDCl3) 15.8, 26.8, 30.1, 43.4, 47.6, 49.5,
57.5, 58.6, 92.8, 113.7, 114.0, 127.4, 128.3, 128.6, 129.3, 129.7, 131.0,
a
]
D ꢁ19.4 (c 0.5,
28.3, 49.5, 49.9, 52.7, 58.9, 80.1, 155.6, 173.5, 174.3; [a]D 46.3 (c 1.08,
CHCl3); ESI-MS: m/z 272.1 [M]þ, 295.2 [MþNa]þ. Anal. Calcd for
C12H20N2O5: C, 52.93; H, 7.40; N, 10.29. Found: C, 52.86; H, 7.33; N,
10.21.
;
6. Single crystal X-ray investigation of 5a
Compound 5a: colourless crystals, C18H21Cl3N2O5, M¼1806.87,
crystal size 0.45ꢂ0.35ꢂ0.25 mm, orthorhombic, P212121 (No. 19):
a¼9.8532(14) Å, b¼11.0667 (15) Å, c¼18.769(3) Å, V¼2046.6(5) Å3,
133.0, 159.0, 162.7, 168.1, 173.7. [
a
]
D ꢁ27.5 (c 0.44, CHCl3).
Z¼4,
r
(calcd)¼1.46 mg mꢁ3, F(000)¼936,
m
¼0.48 mmꢁ1, 23,251
4.2.10. (3R,4S,10S)-4-Allyl-4-methoxycarbonyl-1-(10-phenyleth-10-
yl)-3-trichloroacetylaminopyrrolidin-2-one, 8c, and its (3R,4R,10S)-
isomer, 9c. The title compounds were obtained in 90% yield as
a diastereomeric inseparable mixture (dr 55:45). nmax 3352, 1736,
1711, 1682 cmꢁ1; ESI-MS: m/z 446.1 [M]þ, 469.2 [MþNa]þ. Anal.
Calcd for C19H21Cl3N2O4: C, 50.97; H, 4.73; N, 6.26. Found: C, 50.93;
H, 4.78; N, 6.22. Isomer-(3R,4S,10S), 8c: dH (400 MHz, CDCl3) 1.53
(3H, d, J 7.2,10-CH3), 2.15 (1H, dd, J 9.2, J 14.4, CH2–C]), 2.67 (1H, dd,
J 5.6, J 14.4, CH2–C]), 3.20 (1H, d, J 10.4, pro-R H-5), 3.35 (1H, d, J
10.4, pro-S H-5), 3.70 (3H, s, COOCH3), 4.92 (1H, d, J 6.4, H-3), 5.02–
5.10 (1H, m, CH]CH2), 5.10–5.15 (1H, m, CH]CH2), 5.45 (1H, q, J 7.2,
10-H), 5.63–5.76 (1H, m, CH]CH2), 7.20–7.40 (5 ArH, m), 7.71 (1H, d,
reflections (2qmax¼57ꢀ) measured on a Bruker Apex II CCD detector
diffractometer at 293 K using Mo K
a
radiation (
l¼0.71073 Å), 4822
unique [Rint¼0.018], used for structure solution (Direct Methods,
SHELXS-97)12 and refinement (full-matrix least-squares on F2,
SHELXL-97)13 with 253 parameters, H atoms found in difference
Fourier and refined with a riding model, R1 (I>2
s
(I)¼0.036,
wR2¼0.107, S¼0.93, largest diff. peak and hole 0.39 and ꢁ0.29 e Åꢁ3
in the vicinity of the Cl atoms. The absolute configuration was de-
termined reliably by using the Flack parameter [0.01(5)] for the
correct absolute structure). ORTEP-3 was used for graphics.14,24
The molecular structure of compound 5a is reported in Figure 2
together with the crystallographic labelling. Hydrogen atoms bear
the same labelling as the C or N atom to which they are attached.
Bond lengths and angles fall within the normal range of values and
will not be discussed here. The assignment of chirality to the ster-
eogenic centres at C(1), S, C(3), S, and C(4), R, has been made un-
ambiguously by using the Flack parameter. The pentacyclic ring
J 6.4, NH); dC (100 MHz, CDCl3)
d 15.8, 34.1, 46.0, 50.3, 52.8, 53.4,
59.6, 91.7, 120.1, 126.9, 127.9, 128.3, 128.6, 128.7, 132.6, 138.5, 162.6,
167.6, 172.4. Isomer-(3R,4R,10S), 9c: dH (400 MHz, CDCl3) 1.51 (3H,
d, J 7.2, 10-CH3), 2.44–2.55 (2H, m, CH2–C]), 2.85 (1H, d, J 10.4, pro-
R H-5), 3.58 (1H, d, J 10.4, pro-S H-5), 3.73 (3H, s, COOCH3), 4.67 (1H,

E. Crucianelli et al. / Tetrahedron 66 (2010) 400–405
405
3. (a) Hruby, V. J. Biopolymers 1993, 33, 1073–1082; (b) Martin, S. F.; Dorsey, G. O.;
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N.; Munshi, S.; Gulnik, S. V.; Topol, I. A. J. Med. Chem. 1998, 41, 1581–1597; (c)
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Tetrahedron: Asymmetry 2003, 14, 3353–3358 and references cited herein.
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Chem. 2002, 10, 3331–3337.
Figure 3. Packing of 5a (50% probability) showing the network of N–H/O bonding
(broken lines) along the a axis, which connects the molecules in a infinite chain; the
remaining H atoms are omitted for clarity.
11. (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.
12. Sheldrick, G. M. SHELXS97; University of Gottingen: Germany, 1997.
13. Sheldrick, G. M. SHELXL97; University of Gottingen: Germany, 1997.
14. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
exhibits an envelope conformation with C(4) 0.5 Å out of the plane
comprising the other four atoms. A strong network of inter-mole-
cular H-bonding interactions occurs, which involves N(2)–H(2) and
O(3) [symmetry operation 0.5þx, 0.5ꢁy, 2ꢁz] with a D/A distance of
3.170(2) and a DHA angle of 165ꢀ. A second H-bonding interaction
involves C(13)–H(13)/O(5) [symm. op. ꢁ1þx, y, z] with D/A dis-
tance of 3.131(3) Å and DHA angle of 130ꢀ, while a second CH/O
interaction occurs between C(3)–H(3) and O(5) [symm. op. 1ꢁx,
0.5þy, 1.5ꢁz] with D/A distance of 3.228(3) Å and DHA angle of
130ꢀ. Finally, a further H-bonding interaction is formed between
C(18)–H(18A) and O(1) [symm op ꢁ0.5þx, 0.5ꢁy, 2ꢁz] with D/A
distance of 3.299(4) Å and DHA angle of 145(3)ꢀ.24,25 Interestingly,
the N–H/O interaction connects the molecules related by the binary
screw axis parallel to a, thus forming an infinite chain of hydrogen
bonded molecules wrapped in a helix along the 100 direction (Fig. 3).
15. Hokhura, H.; Handa, M.; Katagiri, T.; Uneyama, K. J. Org. Chem. 2002, 67, 2692–
2695.
16. (a) Micouin, L.; Varea, T.; Riche, C.; Chiaroni, A.; Quirion, J.-C.; Husson, H.-P.
Tetrahedron Lett. 1994, 35, 2529–2532; (b) Varea, T.; Dufour, M.; Micouin, L.;
Riche, C.; Chiaroni, A.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett. 1995, 36,
1035–1038; (c) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.; Panagiotaki, M.
Heterocycles 2003, 60, 2485–2498.
17. For an alkylation proceeding syn to a hydroxy group, see: Donohoe, T. J.; Sintim,
H. O.; Sisangia, L.; Harling, J. D. Angew. Chem., Int. Ed. 2004, 43, 2293–2296; For
stereoselective alkylations of aspartic acid derivatives, see: Hanessian, S.;
Margarita, R.; Hall, A.; Luo, X. Tetrahedron Lett. 1998, 39, 5883–5886.
18. Interestingly, the ratio of isomers did not change when the nature of the cation
was varied from Li to K, although the yields decreased accordingly.
19. (a) Parr, I. B.; Boehlein, S. K.; Dribben, A. B.; Schuster, S. M.; Richards, N. G. J.
J. Med. Chem. 1996, 39, 2367–2378; (b) Karginov, V. A.; Mamaev, S. V.; An, H.;
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Acknowledgements
20. Galeazzi, R.; Mammi, S.; Martelli, G.; Menegazzo, I.; Orena, M.; Rinaldi, S. Chem.
Commun. 2006, 4915–4917.
This work was supported by UNIVPM (Fondi di Ateneo 2006)
and by Nanodream s.r.l. (Iesi, Ancona, Italy).
21. (a) Sagan, S.; Karoyan, P.; Lequin, O.; Chassaing, G.; Lavielle, S. Curr. Med. Chem.
2004, 11, 2799–2822; (b) Yeh, M.-Y.; Luh, T.-Y. Chem. Asian J. 2008, 3, 1620–1624.
22. (a) Toniolo, C.; Crisma, M.; Formaggio, F.; Peggion, C. Biopolymers 2001, 60, 396–
419; (b) Toniolo, C.; Formaggio, F.; Kaptein, B.; Broxtermann, Q. B. Synlett 2006,
1295–1310.
Supplementary data
23. (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219–3232;
(b) Sanford, A. R.; Gong, B. Curr. Org. Chem. 2003, 7, 1649–1659; (c) Baldauf, C.;
Gu¨ nther, R.; Hofmann, H.-J. Angew. Chem., Int. Ed. 2004, 43, 1594–1597; (d)
Ananda, K.; Vasudev, P. G.; Sengupta, A.; Raja, K. M. P.; Shamala, N.; Balaram, P.
J. Am. Chem. Soc. 2005, 127, 16668–16674.
24. Crystallographic data for the structural analysis of compound 5a have been
deposited at the Cambridge Crystallographic Data Centre. The CCDC no. 652268
has been assigned to the compound 5a. Copies of the information may be
obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: þ44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk or www:
http://www.ccdc.cam.ac.uk).
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.10.004.
References and notes
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