A new versatile and diastereoselective synthesis of polysubstituted 2-oxopiperazines from naturally occurring amino acids

Article abstract of DOI:10.1016/j.tetasy.2007.10.027

A highly stereoselective approach to 1,3,4,5- and 1,3,3′,4,5-polysubstituted 2-oxopiperazines is reported. The method is based on the synthetic elaboration of naturally occurring amino acids to obtain enantiomerically enriched C-5 substituted oxopiperazines, which are further functionalized at C-3 via enolate formation and reaction with electrophiles. Notably, the two nitrogens of the ring can be orthogonally protected.

Full text of DOI:10.1016/j.tetasy.2007.10.027

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2680–2688
A new versatile and diastereoselective synthesis of polysubstituted
2-oxopiperazines from naturally occurring amino acids
Gianna Reginato,a,* Barbara Di Credico,a Daniele Andreotti,b Anna Mingardi,b
Alfredo Paiob and Daniele Donatib
aICCOM—CNR, Dipartimento di Chimica Organica ‘U. Schiff’, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
bGlaxoSmithKline, Medicine Research Centre, Via A. Fleming 4, 37135 Verona, Italy
Received 27 September 2007; accepted 19 October 2007
Abstract—A highly stereoselective approach to 1,3,4,5- and 1,3,30,4,5-polysubstituted 2-oxopiperazines is reported. The method is based
on the synthetic elaboration of naturally occurring amino acids to obtain enantiomerically enriched C-5 substituted oxopiperazines,
which are further functionalized at C-3 via enolate formation and reaction with electrophiles. Notably, the two nitrogens of the ring
can be orthogonally protected.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
scaffolds have been found to stabilize inverse c-turns in
small peptides.10 For all these reasons, the synthesis of a
variety of piperazinones with substitution at different ring
positions is of particular significance for medicinal chemists
and many methods have been developed to achieve this
goal.12
Aza-lactams constitute a class of highly interesting mole-
cules and have found widespread use as synthetic inter-
mediates and in medicinal chemistry.1 Substituted
oxo-piperazines are components of a variety of bioactive
compounds that include, amongst the others, constrained
substance P analogues,2 farnesyltransferase (FPTase),
geranylgeranyltransferase-I (GGPTase-I),3,4 elastase5 and
factor Xa inhibitors,6 melanocortin receptors (MCR) ago-
nists7,8 and fibrinogen glycoprotein IIb–IIIa antagonists.9
Thus, substituted oxopiperazines are not only found in
central nervous system (CNS) active drugs but also might
have significant potential as cancer chemotherapeutic
agents,3,4 or be promising candidates for the treatment
and prevention of a range of diseases such as arthritis, asth-
ma, depression,2 obesity, sexual disfunctions,8 emphysema,
cystic fibrosis and rheumatoid arthritis.5 In some cases, the
oxopiperazine core is used as a conformationally con-
strained peptidomimetic3,8–11 wherein the Ni and Niꢀ1 posi-
tions of the peptide backbone fragments are linked by an
ethylene bridge. This results in increasing the structural
rigidity of the original peptide and has been found to
modify the biological properties, occasionally enhancing
affinity, specificity and enzymatic stability. Finally, such
Stemming from our interest in the asymmetric synthesis of
biologically interesting compounds, we have become inter-
ested in finding a general and highly stereoselective ap-
proach to 1,3,4,5-tetra-substituted- and 1,3,30,4,5-penta-
substituted 2-oxo-piperazines.
The method we designed, taking advantage of naturally
occurring amino acids as starting materials, allows us to
prepare some new oxopiperazinones, in which the substitu-
tion and the stereochemistry at C-5 can be pivoted by the
choice of the starting amino acid and substitution at C-3
is accomplished via enolate formation and reaction with
electrophiles (Scheme 1). In addition, we wanted to ortho-
gonally protect the two nitrogens of the ring as it might be
Bn
N
Bn
N 1
NHBoc
OH
O
O
E
Base
E
3
5
4
N
Boc
R
N
Boc
R
R
O
*
Corresponding author. Tel.: +39 0554573558; fax: +39 0554573580;
e-mail: gianna.reginato@unifi.it
Scheme 1.
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.027

G. Reginato et al. / Tetrahedron: Asymmetry 18 (2007) 2680–2688
2681
particularly valuable, allowing the stepwise positioning of
substituents when the oxopiperazine core is used as a
molecular scaffold.
spectrum was repeated at 70 ꢁC. To exclude the presence
of diastereoisomers, the (S,R)-amide was also prepared
and a very similar behaviour was found, although the sig-
nals of the two rotamers showed different chemical shifts.
1
The H NMR spectrum of a mixture of the two diastereo-
2. Results and discussion
meric amides was recorded and an evident splitting of all
the signals, owing to the four different rotamers which
are present at rt, was observed, thus confirming the diaste-
reomeric purity of the two amides. This is shown in Figure
1 where the 1H NMR spectra of the two diastereomers and
of the mixture, in the diagnostic distance d = 5.50–
3.00 ppm, are reported.
The key intermediates of our procedure were vicinal
diamines 3. This class of compounds, particularly in the
chiral series, is commonly encountered as synthetic inter-
mediates13 and several methods have been developed for
their synthesis.14 For instance, a-amino aldehydes 2 are
commonly used to prepare diamines via reductive amina-
tion with a primary amine.15 Following this approach, we
converted three different commercially available Boc
protected L-amino acids into amino aldehydes 2 by LiAlH4
reduction of the corresponding Weinreb amides 1.16,17
Reductive amination18,19 with benzylamine gave orthogo-
nally protected diamines 3, which were purified by flash
chromatography. Bromoacetylation of the diamines gave
bromodiamides 4, which provided 5-substituted 2-oxo
piperazines 5 (Scheme 2) via base-promoted cyclization.
Having fixed the substitution and the stereochemistry at
C-5, we started to study if a stereoselective alkylation of
C-3 could be achieved.
It is well known that glycine derived diketopiperazines
(DKP) can be alkylated at the C-6 atom with high facial
selectivity after enolate formation and the addition of elec-
trophiles. This reaction, in which diastereoselectivity is effi-
ciently controlled via 1,4 asymmetric induction, has been
applied, for instance, to the synthesis of enantiomerically
pure a-amino acids.23–25 Likewise, the enantioselective syn-
thesis of 3-substituted 2-oxo-piperazines has been reported
via the stereoselective alkylation of achiral 2-oxopiper-
azine, by placing a chiral auxiliary at the N-1 atom26
(Scheme 3).
Although a similar approach has recently been reported on
different substrates,15,20,21 to the best of our knowledge the
whole sequence has never been applied to the synthetic
elaboration of naturally occurring amino acids. Thus, by
using this reaction sequence, three new chiral 5-substituted
oxopiperazines 5a,b,c, respectively, derived from Boc pro-
tected L-alanine, L-valine and O-benzyl L-tyrosine, were
obtained in reasonable overall yields and fully character-
ized after purification (Scheme 2).
Following a similar approach, compounds 5a,b,c were
deprotonated using a t-BuLi (2 equiv)/HMPA (4 equiv)
mixture. The reaction was performed in THF at ꢀ78 ꢁC
and the enolate formed was reacted with allylbromide to
quantitatively afford the corresponding 3-allylated 2-oxo-
piperazines 6a,b,c which were purified by flash chromato-
graphy and fully characterized (Scheme 4). Remarkably,
only one diastereoisomer was found in the final reaction
mixture.
NHBoc
N(Me)OMe
NHBoc
b, c
NHBoc
a
R
R
R
O
1a,b,c
O
2a,b,c
HN
3a,b,c
a R = Me (Ala)
b R = CH(CH3)2 (Val)
d
The stereochemistry of the newly formed stereogenic centre
was deduced by NOE difference spectroscopy in CDCl3.
Selected NOE enhancements for 5a are shown in Figure
2. Irradiation of the methyl protons (d = 0.90 ppm) pro-
duced an evident enhancement of the signal of Hd, accord-
ing to a syn relationship; this was accompanied by the
enhancement of the signals due to the Hb and to the benz-
ylic protons. Irradiation at Hc (d = 3.74 ppm) produced an
evident enhancement of the signals of Ha, Hb and of the
methyl but had no effect on the Hd, which is in accordance
with an anti relationship between these two protons.
c R CH2(C6H4)OBn (Tyr)
NHBoc
R
Boc
N
R
e
N
O
N
Br
5a,b,c
4a,b,c
O
overall yield
pure 5: 39-10%
a: LiAlH4. b: BnNH2, NaBH3CN. c: CH3COOH/MeOH.
d: BrCH2COOH, DCC, NMM. e: NaH
Scheme 2.
Finally, irradiation at Hd (d = 4.38 ppm) produced the
expected enhancement of the CH3 signal and of the allylic
CH2 but had no effect on Hc, confirming that these hydro-
gen atoms lie on the opposite face of the oxopiperazine
ring. These experiments were thus consistent with an anti
relative stereochemistry between substituents at C-3 and
C-5, which are in agreement with a conventional 1,3 asym-
metric induction where the N-Boc protecting group plays
no role in controlling the facial selectivity.27 The absolute
(3S,5S)-configuration thus follows from the known C-5
To confirm the enantiomeric purity of the final com-
pounds, oxopiperazine 5a was deprotected in the presence
of TFA. The corresponding Mosher’s amide was prepared
using (S)-a-methoxy-a-trifluoromethyl-phenylacetic acid
chloride.22 Unfortunately, the 1H NMR analysis of the dia-
stereomeric amide was complicated by the presence of two
distinct rotamers in an approximate 2:1 ratio, which were
observed when the spectrum was recorded at rt in C6D6.
The two rotamers collapsed into broad signals when the

2682
G. Reginato et al. / Tetrahedron: Asymmetry 18 (2007) 2680–2688
Bn
N
Bn
N
O
O
E
3
Base
E
3
6
6
O
N
Bn
O
O
N
Bn
OH
O
OH
O
N
N
Base
E
1
1
3
3
N
PG
5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2
(S,S) - (RT)
N
PG
E
Scheme 3.
R
O
R
Boc
Boc
N
t-BuLi/HMPA
N
N
N
5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2
(S,S) - (70 ˚C)
Br
O
5a,b,c
6a,b,c
65-33%
Scheme 4.
δ = 4.38
δ = 0.90
CH3
Hc
Hb
Ha
Boc
N
Boc
N
Hd
Hd
5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2
(S,R) - (RT)
CH3
Hc
δ = 3.74
Hb
N
O
N
O
Ha
H
H
H
H
Figure 2. Selected NOE enhancements for 5a.
conversion of the starting oxopiperazine into the corre-
sponding 3-substituted derivatives 7–11 was obtained. In
most cases only one diastereoisomer was formed, however
reaction with chloroformate afforded compound 7 as a
mixture of diastereoisomers, which could not be separated
by chromatography. This might be due to the acidity of
proton at C-3. Again, when acetaldehyde was used, the
expected alcohol 10 was found but as a complex mixture
of diastereoisomers.
5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2
(S,R) - (70 ˚C)
With the aim of achieving more decorated scaffolds, double
functionalization at the 3-position was also attempted (see
Scheme 5). Therefore, compounds 6a and 9 were deproto-
nated under the same conditions and reacted with allylbro-
mide to afford 3,30-disubstituted oxopiperazines 12 and 13,
respectively. Once again compound 13 was recovered as a
single diastereisomer in which an anti relative stereochem-
istry between the allyl group at C-3 and the methyl at C-5
was deduced by NOE difference spectroscopy in CDCl3.
This seems to show that the presence of a substituent at
C-3 had no influence in directing the anti approach of the
approaching electrophile.
5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2
(S,R)+(S;S) - (RT)
Figure 1. 1H NMR (400 MHz, C6D6, d = 5.50–3.00 ppm) of Mosher’s
amides of compound 5a.
stereogenic centre derived from the naturally occurring
a-amino acid used as starting material.
To exploit the synthetic utility of such a reaction, com-
pound 5a was reacted, under the reported conditions, with
a range of different electrophiles and the results are
reported in Table 1. In almost all the cases, a high yielding
Selected NOE enhancements for 13 are shown in Figure 3.
Irradiation of the methyl protons (d = ꢀ0.19 ppm)

G. Reginato et al. / Tetrahedron: Asymmetry 18 (2007) 2680–2688
Table 1. Synthesis of 3,5-disubstituted oxopiperazines
2683
Substrate
Electrophile
Final compound
Yielda (%)
O
Boc
N
O
5a
70 (30%)
Cl
O
OEt
N
O
Bn
7
Boc
N
O
5a
5a
5a
90 (30%)
90 (43%)
65 (27%)b
Br
Br
O
N
O
O
Bn
8
Boc
N
N
Bn
9
Boc OH
N
O
N
O
Bn
10
Boc
N
COOEt
OEt
Br
5a
85 (40%)
N
O
O
11
a Yield of isolated compound is given in parentheses.
b A complex mixture of diastereoisomers.
Boc
t-BuLi
Boc
Boc
N
N
N
HMPA
N
N
N
AllylBr
He
O
He
Boc
N
Boc
N
δ = - 0.19
O
O
O
12
Hd'
Hd
33%
35%
6a
CH3
Hc
CH3
Hc
Hb
δ = 4.02
Hb
Boc
N
O
N
Ha
Ha
N
t-BuLi
HMPA
H
H
N
H
H
AllylBr
9
O
13
Figure 3. Selected NOE enhancements for 13.
Scheme 5.
The absolute (3S,5S)-configuration was thus inferred.
produced an evident enhancement of the signal of the
benzylic CH2He/He0, which is in accordance with a syn
relationship; this was accompanied by the enhancement
of the signals of Hc. Irradiation at Hc (d = 4.02 ppm)
produced an evident enhancement of the allylic CH2 signals
He/He0 and of the methyl but had no effect on He, accord-
ing to an anti relationship.
3. Conclusions
In conclusion, a stereoselective method for the synthesis of
highly decorated and orthogonally protected 2-oxo-pipera-
zines, from amino acids, has been reported. Further syn-
thetic elaborations of the 2-oxopiperazine scaffold are
currently in progress.

2684
G. Reginato et al. / Tetrahedron: Asymmetry 18 (2007) 2680–2688
4. Experimental
acetate = 1:4] gave 3b as a yellow oil (2.620 g, 81%). Rf: 0.6.
Compound 3b: H NMR (200 MHz) d: 7.40–7.32 [m, 5H];
1
4.1. General methods
4.82 [d, J = 7.6 Hz, 1H]; 3.95–3.85 [m, 2H]; 3.66–3.53 [m,
1H]; 2.98–2.73 [m, 2H]; 1.92–1.71 [m, 1H]; 1.44 [s, 9H];
0.91 [d, J = 6.4 Hz, 6H]. 13C NMR (50.3 MHz) d: 157.05;
Reactions were monitored by TLC on SiO2, detection was
made using a basic KMnO4 solution. Flash column chro-
matography was performed using glass columns (10–
50 mm wide) and SiO2 (230–400 mesh). 1H NMR were
recorded at 200 or 400 MHz. For those compounds which
133.22; 128.78; 128.72; 128.58; 128.52; 127.85; 80.40;
24
60.32; 53.95; 51.81; 30.84; 28.29; 19.03; 18.00. ½aꢁD
¼
þ1:2 (c 0.94, CHCl3). Anal. Calcd for C17H28N2O2: C,
69.83; H, 9.65; N, 9.58. Found: C, 69.87; H, 9.61; N, 9.60.
1
are present as slowly interconverting rotamers, H NMR
experiments were performed at 50 ꢁC and signals of the
averaged spectrum are reported when possible. 13C NMR
spectra were recorded at 50.3 MHz. Chemical shifts were
determined relative to the residual solvent peak (CHCl3,
d 7.26 ppm for 1H NMR; CHCl3, d 77.00 ppm for 13C
NMR). Polarimetric measurements were performed at
k = 589 nm, and the temperature is specified case by case.
All commercial reagents were used without further purifi-
cation. Aldehydes 2a–c were prepared according to the lit-
erature.28,29 THF was dried by distillation over sodium
benzophenone ketyl. CH2Cl2 was dried over CaCl2, and
4.2.3.
(S)-tert-Butyl-1-(benzylamino)-3-(4-(benzyloxy)-
phenyl)propan-2-ylcarbamate 3c. To amide 1c (2.0 g,
4.83 mmol) in THF (45 mL) LiAlH4 (228 mg, 6.0 mmol)
was added. After workup 1706 mg (99%) of crude aldehyde
2c was obtained and reacted with benzylamine (0.6 mL,
5.9 mmol), NaCNBH3 solution (7.08 mL) and acetic acid
(0.6 mL) in dry MeOH (42 mL). After workup and purifi-
cation [petroleum ether/ethyl acetate = 1:4], 1.815 g (83%)
of 3c were obtained. Rf: 0.2. Compound 3c: 1H NMR
(200 MHz) d: d (CDCl3, 200 MHz): 7.42–7.30 [m, 10H];
7.08 [d, J = 8.8 Hz, 2H]; 6.89 [d, J = 8.8 Hz, 2H]; 5.04
[m, 1H]; 4.80 [d, J = 7.8 Hz, 1H]; 3.90–3.72 [m, 2H+1H];
2.99 [br s, 1H]; 2.79–2.68 [m, 2H+2H]; 1.42 [s, 9H]. 13C
NMR (100.6 MHz) d: 157.42; 155.66; 140.14; 137.11;
130.58; 130.29 (·2); 128.53 (·2); 128.36 (·2); 128.11 (·2);
˚
stored over 4 A molecular sieves. DMF was distilled over
˚
CaCl2, and stored over 4 A molecular sieves. Petroleum
ether, unless specified, is the 40–70 ꢁC boiling fraction.
4.2. Synthesis of orthogonally protected diamines 3
127.88; 127.42 (·2); 126.98; 114.77 (·2); 79.18; 70.04;
24
64.18; 53.75; 51.34; 38.11; 28.39. ½aꢁD ¼ ꢀ1:4 (c 1.09,
Aldehydes 2a–c (1 equiv) were dissolved in dry MeOH
(10 mL) and benzylamine (1.5 equiv) was added, followed
by an NaCNBH3 solution in dry THF (1 M, 1.5 equiv)
and acetic acid (2.5 equiv). The mixture was stirred over-
night at room temperature, after which MeOH was evapo-
rated and the crude was dissolved in ethyl acetate (20 mL).
The organic phase was washed with a NaHCO3 saturated
solution (10 mL) and brine (10 mL), dried over Na2SO4
and concentrated to afford diamines 3a–c which were puri-
fied by flash chromatography.
CHCl3). Anal. Calcd for C28H34N2O3: C, 75.31; H, 7.67;
N, 6.27. Found: C, 75.26; H, 7.64; N, 6.23.
4.3. Synthesis of 2-oxopiperazines 5
Synthesis of (2-bromoacetyl)-amides 4a–c: A solution of
bromoacetic acid (4.23 equiv) and DCC (2 equiv) in dry
CH2Cl2 (4 mL) was stirred at rt for 1 h. To this mixture,
after cooling at ꢀ15 ꢁC, a solution of 3a–c (1 equiv) in
dry CH2Cl2 (4 mL) and NMM (2.85 equiv) was added.
The mixture was stirred at room temperature for 2 h and
then diluted with CH2Cl2 (5 mL) and quenched by the
addition of H2O (10 mL). The organic phases were col-
lected and the aqueous phase was extracted with DCM.
The combined organic phases were washed with H2O
(20 mL) and brine (20 mL), dried over Na2SO4 and concen-
trated. The crude was filtered over a silica gel column to
afford compounds 4a–c, which were used without further
purification.
4.2.1. (S)-tert-Butyl-1-(benzylamino)-propan-2-yl-carbamate
3a. To amide 1a (1.0 g, 4.3 mmol) in THF (45 mL)
LiAlH4 (205 mg, 5.4 mmol) was added. After workup alde-
hyde 2a (771 mg, 4.5 mmol) was obtained and reacted with
benzylamine (0.73 mL, 6.7 mmol), NaCNBH3 solution
(7.0 mL) and acetic acid (0.63 mL) in dry MeOH
(45.0 mL). Purification [petroleum ether/ethyl ace-
tate = 1:8] gave 3a as a colourless oil (856 mg, 73%). Rf:
1
0.8. Compound 3a: H NMR (200 MHz) d: 7.37–7.28 [m,
5H]; 4.84 [br s, 1H]; 3.97–3.79 [m, 1H+2H]; 2.77–2.70 [m,
2H]; 1.44 [s, 9H]; 1.16 [d, J = 7.0 Hz, 3H]. 13C NMR
(50.3 MHz) d: 156.15; 137.04; 128.56 (·2); 128.47 (·2);
Cyclization to oxopiperazines 5a–c: Bromides 4a–c (1 equiv)
were dissolved in dry THF/DMF (1/1, 10 mL)) and cooled
at 0 ꢁC. NaH (3 equiv) was added and the mixture was stir-
red at room temperature for 2 h, after which it was
quenched by the careful addition of H2O (50 mL). The
solution was extracted with EtOAc (3 · 20 mL), and the
combined organic phases were washed with H2O
(30 · 20 mL) and brine (20 mL), dried over Na2SO4 and
concentrated to afford oxopiperazines 5a–c which were
purified by flash chromatography.
127.7; 79.96; 53.96; 52.93; 45.77; 28.44; 19.17.
24
½aꢁD ¼ ꢀ1:8 (c 1.05, CHCl3). Anal. Calcd for
C15H24N2O2: C, 68.15; H, 9.15; N, 10.60. Found: C,
68.21; H, 9.16; N, 10.57.
4.2.2.
(S)-tert-Butyl-1-(benzylamino)-3-methylbutan-2-yl-
carbamate 3b. To amide 1b (2.0 g, 7.7 mmol) in THF
(75.0 mL), LiAlH4 (365 mg, 9.6 mmol) was added. After
workup aldehyde 2b (2.223 g, 11.1 mmol) was obtained
and reacted with benzylamine (1.8 mL, 16.6 mmol), NaC-
NBH3 solution (16.6 mL) and acetic acid (1.57 mL) in
dry MeOH (100.0 mL). Purification [petroleum ether/ethyl
4.3.1. (S)-1-Benzyl,4-tert-butoxycarbonyl,5-methyl-2-oxo-
piperazine 5a. To a solution of bromoacetic acid (1.59 g,
11.4 mmol) and DCC (1.11 g, 5.4 mmol) in dry CH2Cl2
(8 mL) a solution of 3a (712 mg, 2.7 mmol) in dry CH2Cl2

G. Reginato et al. / Tetrahedron: Asymmetry 18 (2007) 2680–2688
2685
(8 mL) was added, together with NMM (0.8 mL,
7.7 mmol). Filtration [petroleum ether/ethyl acetate (4:1)]
gave 4a as a yellow oil (894 mg, 86%). Compound 4a
(2.2 mmol) was reacted with NaH (264 mg, 6.6 mmol) in
THF/DMF (1/1) (30 mL). Purification [petroleum ether/
ethyl acetate = 1:4] gave 5a as a yellow solid (509 mg,
76%). Rf: 0.6. Compound 5a: 1H NMR (400 MHz) d:
7.35–7.25 [m, 5H]; 4.83 [d, J = 14.5 Hz, 1H]; 4.41–4.32
[m, 1H+1H+1H]; 3.85 [d, J = 18.4 Hz, 1H]; 3.51 [dd,
J = 12.4, 4.4 Hz, 1H]; 2.92 [dd, J = 12.4, 1.6 Hz, 1H];
1.45 [s, 9H]; 1.07 [d, J = 6.8 Hz, 3H]. 13C NMR
(100.6 MHz) d: 165.54; 153.52; 136.08; 128.67 (·2);
1.00, CHCl3). Anal. Calcd for C30H34N2O4: C, 74.05; H,
7.04; N, 5.76. Found: C, 74.10; H, 7.05; N, 5.71.
4.4. Alkylation of 2-oxopiperazines
Oxopiperazines 5a–c (1 equiv) were dissolved in dry THF
(10 mL) and HMPA (3.3 equiv), then the solution was
cooled at ꢀ78 ꢁC and carefully reacted with a solution of
t-BuLi (1.7 M, pentane, 2 equiv). After 15 min, the suitable
electrophile (3.3 equiv) was added. The reaction mixture
was stirred at ꢀ78 ꢁC for 3–5 h, then treated with a satu-
rated aqueous solution of ammonium chloride (10 mL).
The two phases were separated, extracted with CH2Cl2
(3 · 10 mL), dried and concentrated to afford a crude
which was purified by flash chromatography.
128.42; 127.77 (·2); 80.60; 50.21; 49.92; 44.69; 28.32;
24
15.75. ½aꢁD ¼ þ0:7 (c 0.81, CHCl3). Anal. Calcd for
C17H24N2O3: C, 67.08; H, 7.95; N, 9.20. Found: C, 67.12;
H, 7.92; N, 9.23.
4.4.1.
(3S,5S)-1-Benzyl,3-allyl,4-tert-butoxycarbonyl,5-
4.3.2.
(S)-1-Benzyl,4-tert-butoxycarbonyl,5-isopropyl-2-
methyl-2-oxopiperazine 6a. Oxopiperazine 5a (100 mg,
0.3 mmol) was reacted with HMPA (197 lL, 1.12 mmol),
t-BuLi (400 lL, 0.7 mmol) and allylbromide (93 lL,
1.12 mmol) in dry THF (6 mL) for 3 h. Purification [hex-
ane/ethyl acetate = 2:1] gave 6a as a yellow oil (76 mg,
65%). Rf: 0.8. Compound 6a: 1H NMR (200 MHz) d:
7.26–7.19 [m, 5H]; 5.81–5.62 [m, 1H]; 5.04–4.95 [m,
1H+1H]; 4.64 [d, Jxy = 14.3 Hz, 1H]; 4.42 [d,
Jxy = 14.3 Hz, 1H]; 4.32 [t, J = 6.6 Hz, 1H]; 4.01 [m, 1H];
3.54 [dd, J = 13.3, 3.6 Hz, 1H]; 2.81 [dd, J = 13.3,
1.8 Hz, 1H]; 2.57 [m, 1H+1H]; 1.40 [s, 9H]; 0.90 [d,
J = 6.6 Hz, 3H]. 13C NMR (50.3 MHz) d: 168.10; 153.44;
135.97; 133.12; 128.64 (·2); 128.50 (·2); 127.72; 118.11;
oxopiperazine 5b. To a solution of bromoacetic acid
(2.60 g, 18.7 mmol) and DCC (1.82 g, 8.8 mmol) in dry
CH2Cl2 (12 mL) a solution of 3b (1293 mg, 4.4 mmol) in
dry CH2Cl2 (12 mL) was added together with NMM
(1.38 mL, 12.6 mmol). Filtration [petroleum ether/ethyl
acetate (4:1)] gave 4b as a yellow oil (894 mg, 86%). Com-
pound 4b (700 mg, 1.7 mmol) was reacted with NaH
(72 mg, 5.1 mmol) in dry THF/DMF (1/1) (22 mL). Purifi-
cation [petroleum ether/ethyl acetate = 1:3] gave 5b as a
yellow oil (290 mg, 53%). Rf: 0.4. Compound 5b: 1H
NMR (400 MHz, 50 ꢁC) d: 7.35–7.26 [m, 5H]; 4.95 [d,
J = 14.0 Hz, 1H]; 4.46 [br d, J = 18.6 Hz, 1H]; 4.22 [d,
J = 14.0 Hz, 1H]; 3.89–3.77 [m, 1H]; 3.72 [d, J = 18.6 Hz,
1H]; 3.42 [dd, J = 12.6, 4.6 Hz, 1H]; 3.20 [dd, J = 12.6,
1.4, 1H]; 1.85–1.69 [m, 1H]; 1.46 [s, 9H]; 0.85 [d,
J = 6.6 Hz, 3H]; 0.59 [d, J = 6.6 Hz, 3H]. 13C NMR
(50.3 MHz) d: 165.09; 153.62; 136.05; 128.43 (·2); 128.32
80.42; 57.44, 50.57; 48.99; 46.73; 38.67, 28.44, 17.48.
24
½aꢁD ¼ 11:1 (c 1.26, CHCl3). Anal. Calcd for C20H28-
N2O3: C, 69.74; H, 8.19; N, 8,13. Found: C, 69.70; H,
8.22; N, 8.12.
(·2); 127.56; 80.29; 55.65; 53.84; 49.64; 46.21; 45.06;
4.4.2. (3S,5S)-1-Benzyl,3-allyl,4-tert-butoxycarbonyl,5-iso-
propyl-2-oxopiperazine 6b. Oxopiperazine 5b (541 mg,
1.62 mmol) was reacted with HMPA (776 lL, 4.42 mmol),
t-BuLi (296 lL, 2.68 mmol) and allylbromide (373 lL,
4.42 mmol) in dry THF (23 mL) for 2 h. Purification [hex-
ane/ethyl acetate = 3:1] gave 6b as a white solid (203 mg,
33%). Rf: 0.5. Compound 6b: 1H NMR (200 MHz) d:
7.26–7.21 [m, 5H]; 5.80–5.59 [m, 1H]; 5.02–4.95 [m,
1H+1H]; 4.64 [d, Jxy = 14.2 Hz, 1H]; 4.36–4.26 [m,
1H+1H]; 3.68 [m, 1H]; 3.37 [dd, J = 13.2, 3.8 Hz, 1H];
3.08 [dd, J = 13.2, 2.2 Hz, 1H]; 2.68–2.50 [m, 2H]; 1.79–
1.61 [m, 1H]; 1.40 [s, 9H]; 0.77 [d, J = 6.6 Hz, 3H]; 0.56
[d, J = 6.6 Hz, 6H]. 13C NMR (50.3 MHz) d: 168.49;
154.04; 136.05; 128.69 (·2); 128.52 (·2); 127.72, 132.90;
24
28.27; 26.57; 19.51. ½aꢁD ¼ þ0:9 (c 0.45, CHCl3). Anal.
Calcd for C19H28N2O3: C, 68.65; H, 8.49; N, 8.43. Found:
C, 68.61; H, 8.46; N, 8.47.
4.3.3.
(S)-(1-Benzyl)-4-tert-butoxycarbonyl,5-[(4-benzyl-
oxy)-benzyl]-2-oxopiperazine 5c. To a solution of bromo-
acetic acid (1.320 g, 9.5 mmol) and DCC (910 mg,
4.4 mmol) in dry CH2Cl2 (20 mL) a solution of 3c
(1.00 g, 2.2 mmol) in dry CH2Cl2 (20 mL) was added to-
gether with NMM (6.9 mL, 6.2 mmol). After workup
640 mg (70%) of crude 4c was obtained as a white solid
and used without further purification. Compound 4c
(300 mg, 0.5 mmol) was reacted with NaH (38 mg,
1.59 mmol) in dry THF/DMF (1/1)(7mL). Purification
[petroleum ether/ethyl acetate = 3:1] gave 5c as a yellow
oil (81 mg, 31%). Rf: 0.3. Compound 5c: 1H NMR
(400 MHz, 50 ꢁC) d: 7.32–7.23 [m, 10H]; 6.71 [d, J = 8.4,
2H]; 6.65 [d, J = 8.8, 2H]; 4.95–4.93 [m, 2H]; 4.80 [d,
J = 14.4, 1H]; 4.34–4.21 [m, 1H+1H+1H]; 3. 84 [d,
J = 18.8, 1H]; 3.30 [dd, J = 12.4, 4.4, 1H]; 2.92 [dd,
J = 12.4, 1.6 Hz, 1H]; 2.64 [dd, J = 13.6, 6.0 Hz, 1H];
2.49–2.43 [dd, J = 13.6, 9.2 Hz, 1H]; 1.33 [s, 9H]. 13C
NMR (50.3 MHz) d: 165.04; 157.11; 153.11; 136.62;
136.02; 129.70; 129.25; 128.61 (·2); 128.50 (·2); 128.20
118.23; 80.35; 58.12; 56.03; 50.52; 45.54, 38.00; 29.82;
24
28.41; 19.64; 19.38. ½aꢁD ¼ þ1:0 (c 1.0, CHCl3). Anal.
Calcd for C22H32N2O3: C, 70.94; H, 8.66; N, 7.52. Found:
C, 70.88; H, 8.63; N, 7.55.
4.4.3. (3S,5S)-1-Benzyl,3-allyl,4-tert-butoxycarbonyl,5-[4-
(benzyloxy)-benzyl]-2-oxopiperazine 6c. Oxopiperazine 6c
(162 mg, 0.33 mmol) was reacted with HMPA (195 lL,
1.1 mmol), t-BuLi (65 lL, 0.66 mmol) and allylbromide
(93 lL, 1.1 mmol) in dry THF (5 mL) for 5 h. Purification
[hexane/ethyl acetate = 3:1] gave 6c as a white solid (56 mg,
1
(·2); 127.55 (·2); 127.58; 127.05; 114.60 (·2); 80.41;
69.75; 53.66; 49.76; 46.47; 45.011; 28.15. ½aꢁD ¼ ꢀ62:9 (c
32%). Rf: 0.6. Compound 6c: H NMR (400 MHz, 50 ꢁC)
24
d: 7.34–7.17 [m, 10H]; 6.74 [d, J = 8.6 Hz, 2H]; 6.67 [d,

2686
G. Reginato et al. / Tetrahedron: Asymmetry 18 (2007) 2680–2688
J = 8.6 Hz, 2H]; 5.75–5.65 [m, 1H]; 4.99–4.94 [m,
1H+1H+2H]; 4.68 [d, J = 14.4 Hz, 1H]; 4.38 [t,
J = 5.6 Hz, 1H]; 4.30 [d, J = 14.4 Hz, 1H]; 3.98 [m, 1H];
3.29 [dd, J = 3.6, 1.2 Hz, 1H]; 2.84–2.28 [m,
2H+2H+1H]; 1.44 [s, 9H]. 13C NMR (100.6 MHz) d:
168.61; 157.46; 153.63, 136.96; 136.39; 133.12; 130.10;
128.96 (·2); 128.77 (·2); 128.55 (·2); 127.94; 127.43 (·2);
1.00, CHCl3). Anal. Calcd for C24H30N2O3: C, 73.07; H,
7.66; N, 7.10. Found: C, 73.02; H, 7.62; N, 7.13.
4.4.7. (3S,5S)-1-Benzyl,3-(1-hydroxyethyl)-4-tert-butoxy-
carbonyl,5-methyl-2-oxopiperazine 10. Oxopiperazine 5a
(45 mg, 0.15 mmol) was reacted with HMPA (75 lL,
0.50 mmol), t-BuLi (182 lL, 0.30 mmol) and acetaldehyde
(25 lL, 0.50 mmol) in dry THF (2.0 mL) for 5 h. Purifica-
tion [hexane/ethyl acetate (1:1)] gave 10 as a complex mix-
ture of diastereoisomers which have not been separated
(15 mg, 27%). Rf: 0.2. Compound 10, major diastereoiso-
127.33 (·2); 114.88 (·2); 118.38; 80.75; 69.97; 60.35;
24
57.48; 53.32; 50.51; 44.65; 36.13; 28.40. ½aꢁD ¼ ꢀ31:8 (c
1.31, CHCl3). Anal. Calcd for C33H38N2O4: C, 75.26; H,
7.27; N, 5.32. Found: C, 75.24; H, 7.25; N, 5.30.
1
mer: H NMR (200 MHz) d: 7.32–7.28 [m, 5H]; 4.63 [br
4.4.4. (3S,5S)-1-Benzyl,3-carboxyethyl,4-tert-butoxy-carb-
5a
s, 1H]; 4.41 [d, J = 6.2 Hz, 1H]; 4.19–4.07 [m, 1H+1H];
3.60 [dd, J = 13.4, 3.6 Hz, 1H]; 2.96 [dd, J = 13.4, 2.0 Hz,
1H]; 1.47 [s, 9H]; 1.17 [d, J = 6.8 Hz, 3H]; 0.98 [d,
J = 6.4 Hz, 3H]. 13C NMR (50.3 MHz) d: 167.51; 154.82;
135.77; 128.78 (·2); 128.66 (·2); 128.06; 81.31; 69.78;
62.40; 50.48; 49.19; 47.09; 28.28; 19.86; 17.13.
onyl,5-methyl-2-oxopiperazine
7. Oxopiperazine
(30 mg, 0.1 mmol) was reacted with HMPA (58 lL,
0.33 mmol), t-BuLi (118 lL, 0.2 mmol) and ethyl chloro-
formate (31 lL, 0.33 mmol) in dry THF (1.5 mL) for 3 h.
Purification [hexane/ethyl acetate = 2:1] gave 7 as a diaste-
reomeric mixture (10 mg, 30%). Rf: 0.4. Compound 7,
major diastereoisomer: 1H NMR (400 MHz, 50 ꢁC) d:
7.40–7.25 [m, 5H]; 5.06 [br s, 1H]; 4.74 [d, J = 14.4 Hz,
1H]; 4.50 [d, J = 14.4 Hz, 1H]; 4.35–4.24 [m, 1H+2H];
3.43 [dd, J = 12.6, 4.6 Hz, 1H]; 3.02 [dd, J = 13.0, 4.6 Hz,
1H]; 1.40 [s, 9H]; 1.34 [t, J = 7.2 Hz, 3H]; 0.90 [d,
J = 6.4 Hz, 3H]. 13C NMR (50.3 MHz) d: 170.0; 168.43;
157.61; 135.75; 128.76 (·2); 128.45 (·2); 127.95; 81.39;
61.95; 60.32; 50.46; 50.11, 49.17; 28.22; 17.46; 14.09.
4.4.8.
butoxycarbonyl,5-methyl-2-oxopiperazine
(3S,5S)-1-Benzyl,3-(ethoxycarbonylmethyl)-4-tert-
11. Oxopipe-
razine 5a (45 mg, 0.15 mmol) was reacted with HMPA
(0.75 mL, 0.50 mmol), t-BuLi (0.182 mL, 0.30 mmol) and
ethylbromoacetate (0.55 mL, 0.50 mmol) in dry THF
(2.0 mL) for 3 h. Purification [hexane/ethyl acetate = 2:1]
afforded 21 mg (40%) of compound 11 as an oil. Rf: 0.3.
1
Compound 11: H NMR (400 MHz, 50 ꢁC) d: 7.35–7.27
[m, 5H]; 4.74 [d, 1H, J = 14.4 Hz]; 4.58–4.54 [m, 1H];
4.49 [d, 1H, J = 14.4 Hz]; 4.16–4.09 [m, 2H+1H];
3.68 [dd, J = 13.0 Hz, J = 3.8 Hz, 1H]; 2.98 [d, J = 5.6
Hz, 1H]; 2.91 [dd, J = 12.8 Hz, J = 2.4 Hz, 1H]; 1.47 [s,
9H]; 1.25 [t, J = 7.2 Hz 3H]; 0.98 [d, J = 6.8 Hz, 3H]. 13C
NMR (50.3 MHz) d: 167.41; 153.75; 135.82; 128.66 (·2);
4.4.5.
(3S,5S)-1-Benzyl,3-methoxymethyl,4-tert-butoxy-
carbonyl,5-methyl-2-oxopiperazine 8. Oxopiperazine 5a
(30 mg, 0.1 mmol) was reacted with HMPA (58 lL,
0.33 mmol), t-BuLi (118 lL, 0.2 mmol) and bromomethyl
methyl ether (30 lL, 0.33 mmol) in dry THF (1.5 mL) for
3 h. Purification [hexane/ethyl acetate = 2:1] gave 8 as a
128.52 (·2); 127.70; 80.90; 60.70; 54.47; 50.46; 48.70;
1
24
white oil (10 mg, 30%). Rf: 0.4. Compound 8: H NMR
46.82; 39.05; 28.40; 17.15; 14.30 ½aꢁD ¼ þ9:4 (c 0.93,
(400 MHz, 50 ꢁC) d: 7.40–7.25 [m, 5H]; 4.79 [d,
J = 14.4 Hz, 1H]; 4.50 [d, J = 14.4 Hz, 1H]; 4.39–4.37 [m,
1H]; 4.08–4.05 [m, 1H]; 3.94–3.88 [m, 1H]; 3.85 [dd,
J = 9.4, J = 2.0 Hz, 1H]; 3.80 [dd, J = 9.4, J = 2.4 Hz,
1H]; 3.32 [s, 3H]; 2.79 [dd, J = 12.4, J = 2.0 Hz, 1H]; 1.47
[s, 9H]; 1.02 [d, J = 6.4 Hz, 3H]. 13C NMR (50.3 MHz) d:
167.66; 159.49; 135.92; 128.34 (·2); 128.20 (·2); 127.47;
CHCl3). Anal. Calcd for C21H30N2O5: C, 64.59; H, 7.74;
N, 7.17. Found: C, 64.63; H, 7.71; N, 7.14.
4.4.9.
(S)-1-Benzyl,3,30-diallyl,4-tert-butoxycarbonyl,5-
methyl-2-oxopiperazine 12. Oxo-piperazine 6a (27 mg,
0.07 mmol) was reacted with HMPA (40 lL, 0.23 mmol),
t-BuLi (80 lL, 0.14 mmol) and allylbromide (19 lL,
0.23 mmol) in dry THF (2.5 mL) for 2 h. Purification [hex-
ane/ethyl acetate = 9:1] gave 12 as a colourless oil (10 mg,
80.55; 67.65, 62.00; 59.22; 50.66, 49.26; 46.59; 28.50;
24
17.13. ½aꢁD ¼ þ14:4 (c 0.61, CHCl3). Anal. Calcd for
C19H28N2O4: C, 65.49; H, 8.10; N, 8.04. Found: C, 65.43;
H, 8.13; N, 8.01.
1
33%). Rf: 0.3. Compound 12: H NMR (400 MHz, 50 ꢁC)
d: 7.30–7.26 [m, 5H]; 5.76–5.62 [m, 1H+1H]; 5.11–4.97
[m, 2H+2H]; 4.71 [d, J = 14.0 Hz, 1H]; 4.45 [d,
J = 14.0 Hz, 1H]; 4.35–4.26 [m, 1H]; 3.59 [dd, J = 12.6,
J = 3.8 Hz, 1H]; 3.24–3.18 [m, 1H]; 3.10–3.08 [m,
1H+1H]; 2.77 [dd, J = 12.6, 1.8 Hz, 1H]; 2.64–2.58 [m,
1H]; 1.49 [s, 9H]; 0.94 [d, J = 6.4 Hz, 3H]. 13C NMR
(50.3 MHz) d: 169.66; 154.72; 136.30; 135.30; 133.37;
128.94 (·2); 128.57 (·2); 127.79; 118.80; 118.12; 79.90;
4.4.6. (3S,5S)-1,3-Dibenzyl,4-tert-butoxycarbonyl,5-methyl-
2-oxopiperazine 9. Oxopiperazine 5a (65 mg, 0.22 mmol)
was reacted with HMPA (109 lL, 0.73 mmol), t-BuLi
(259 lL, 0.44 mmol) and benzyl bromide (87 lL,
0.73 mmol) in dry THF (1.5 mL) for 3 h. Purification [hex-
ane/ethyl acetate = 2:1] gave 9 as a white solid (37 mg,
43%). Rf: 0.5. Compound 9: 1H NMR (100.6 MHz,
50 ꢁC) d: 7.30–7.04 [m, 10H]; 4.73 [d, J = 14.2 Hz, 1H];
4.60–4.57 [m, 1H]; 4.09 [d, J = 14.2 Hz, 1H]; 3.86 [m,
1H]; 3.45 [m, 1H]; 3.14 [dd, J = 13.6, 3.2 Hz, 1H]; 2.8 [d,
J = 12.8 Hz, 1H]; 2.08 [dd, J = 12.4, 2.0 Hz, 1H]; 1.62 [s,
9H]; 0.88 [d, J = 6.4 Hz, 3H]. 13C NMR (100.6 MHz) d:
168.12; 153.78; 135.86; 135.78; 130.07 (·2); 129.10 (·2);
67.57; 51.39; 48.96; 46.10; 42.89; 29.69; 28.50; 19.23;
24
14.19. ½aꢁD ¼ ꢀ3:3 (c 0.25, CHCl3). Anal. Calcd for
C23H32N2O3: C, 71.84; H, 8.39; N, 7.29. Found: C, 71.89;
H, 8.42; N, 7.16.
4.4.10.
(3S,5S)-1-Benzyl,3-allyl,30benzyl,4-tert-butoxy-
128.49 (·2); 128.04 (·2); 127.79; 126.85; 78.24; 58.58;
carbonyl,5-methyl-2-oxopiperazine 13. Oxo-piperazine 9
(37 mg, 0.09 mmol) was reacted with HMPA (54 lL,
24
50.17; 47.75; 46.10; 39.36; 28.40; 17.08. ½aꢁD ¼ þ15:1 (c

G. Reginato et al. / Tetrahedron: Asymmetry 18 (2007) 2680–2688
2687
0.31 mmol), t-BuLi (112 lL, 0.19 mmol) and allylbromide
(26 lL, 0.31 mmol) in dry THF (2 mL) for 3 h. Purification
[hexane/ethyl acetate = 7:1] gave 13 as a yellow oil (16 mg,
35%). Rf: 0.5. Compound 13: H NMR (400 MHz, 50 ꢁC)
128.50 (·2), 128.31 (·2); 128.14 (·2); 127.82; 126.32;
83.92; 55.51; 49.87; 49.67; 44.81; 43.20; 21.14; 14.30. 19F
NMR (200 MHz) d: 70.59.
1
d: 7.19–7.17 [m, 10H]; 5.69–5.57 [m, 1H]; 5.05–4.91 [m,
2H]; 4.79 [d, J = 14.2 Hz, 1H]; 4.15 [d, J = 14.2 Hz, 1H];
4.05–3.95 [m, 1H]; 3.69 [d, J = 13.2 Hz, 1H]; 3.56 [m,
1H]; 3.42 [dd, J = 12.4, 4.0 Hz, 1H]; 3.39–3.35 [m, 1H];
2.67–2.61 [m, 1H]; 2.49 [dd, J = 12.4, 0.8 Hz, 1H]; 1.47 [s,
9H]; ꢀ0.19 [d, J = 6.8 Hz, 3H]. 13C NMR (50.3 MHz) d:
169.44; 153.56; 138.72; 136.12; 133.33; 131.19 (·2); 128.78
(·2); 128.36 (·2); 127.89 (·2); 127.65; 126.58; 118.90;
References
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34, 367.
2. Tong, Y.; Fobian, Y. M.; Wu, M.; Boyd, N. D.; Moeller, K.
D. J. Org. Chem. 2000, 65, 2484.
3. Dinsmore, J. C.; Bergman, J. M.; Wei, D. D.; Zartman, C. B.;
Davide, J. P.; Greenberg, I. B.; Liu, D.; O’Neill, T. J.; Gibbs,
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80.17; 69.79; 51.18; 48.87; 46.07; 43.94; 39.82; 28.62;
24
16.37. ½aꢁD ¼ þ0:4 (c 0.65, CHCl3). Anal. Calcd for
C27H34N2O3: C, 74.62; H, 7.89; N, 6.45. Found: C, 74.66;
H, 7.86; N, 6.42.
4. Bergman, J. M.; Abrams, M. T.; Davide, J. P.; Greenberg, I.
B.; Robinson, R. G.; Buser, C. A.; Huber, H. E.; Koblan, K.
S.; Kohl, N. E.; Lobell, R. B.; Graham, S. L.; Hartman, G.
D.; Williams, T. M.; Dinsmore, C. J. Biorg. Med. Chem. Lett.
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P.; Sinha, U.; Scarborough, R. M.; Zhu, B.-Y. Biorg. Med.
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4.5. Synthesis of the Mosher’s amides
Oxopiperazine 5a (100 mg, 0.3 mmol) was dissolved in
CH2Cl2 (10 mL), cooled at 0 ꢁC and reacted with an excess
of TFA (1.00 mL). The mixture was stirred at rt overnight
then hydrolyzed with water (10 mL), extracted with
CH2Cl2 (10 mL) and washed with Na2CO3 saturated solu-
tion (10 mL) and brine (10 mL). Evaporation of the solvent
gave the deprotected oxopiperazine which was used with-
out further purification (70 mg, 98%).
1-Benzyl-5-methyl-2-oxo-piperazine: 1H NMR (200 MHz)
d: 7.38–7.16 [m, 10H]; 4.63 [d, 1H, J = 14.6 Hz]; 4.39 [d,
1H, J = 14.6 Hz]; 3.66–3.48 [m, 2H]; 3.07–2.82 [m,
2H+1H]; 2.21 [br s, 1H]; 1.03 [d, J = 5.8 Hz, 3H]. 13C
NMR (50.3 MHz) d: 167.26; 136.35; 128.47 (·2); 127.97
(·2); 127.35; 53.57; 49.88; 49.77; 48.51; 19.00.
8. Tian, X.; Mishra, R. K.; Switzer, A. G.; Hu, X. E.; Kim, N.;
Mazur, A. W.; Ebetino, F. H.; Wos, J. A.; Crossdoersen, D.;
Pinney, B. B.; Farmer, J. A.; Sheldon, R. J. Biorg. Med.
Chem. Lett. 2006, 16, 4668.
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Z.-I.; Kawamura, M.; Fujisawa, Y.; Kita, S. J. Med. Chem.
1998, 41, 489.
10. Pohlmann, A. R.; Guillaume, D.; Quirion, J.-C.; Husson,
H.-P. J. Pept. Res. 1997, 51, 116.
11. Herrero, S.; Garcia-Lopez, M. T.; Latorre, M.; Cenarruza-
beitia, E.; Rio, J. D.; Herranz, R. J. Org. Chem. 2002, 67,
3866.
Deprotected oxopiperazine (50 mg, 0.2 mmol) was dis-
solved into pyridine (2 mL) and cooled to 0 ꢁC. A solution
of MTPA-Cl (100 mg, 0.4 mmol) in pyridine (1 mL). The
reaction mixture was stirred overnight, then added with
water (5 mL), extracted with diethyl ether and washed with
Na2CO3 solution (5 mL) and brine (5 mL). Evaporation
gave a crude which was filtered on silica gel.
12. Dinsmore, C. J.; Zartman, C. B. Tetrahedron Lett. 2000, 41,
6309, and reference cited therein.
13. Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580.
(S,S)-Mosher’s amide, major rotamer: 1H NMR (400 MHz,
C6D6) d: 7.56 [d, J = 7.4 Hz H]; 7.21–6.82 [m, 8H]; 4.89 [d,
1H, J = 19.1 Hz]; 4.79–4.70 [m, 1H]; 4.09 [d, 1H,
J = 14.4 Hz]; 3.71 [d, 1H, J = 14.4 Hz]; 3.28 [d, 3H,
J = 1.6 Hz]; 2.75 [dd, J = 11.2, 3.6 Hz, 1H]; 2.11 [dd,
J = 12.6, 2.1 Hz, 1H]; 0.65 [d, 3H, J = 6.6]. 13C
NMR (50.3 MHz, CDCl3) d: 164.38; 163.67; 136.66;
132.94; 129.62; 128.71 (·2); 128.45 (·2); 128.25 (·2);
127.89 (·2); 126.33; 120.05; 84.01; 55.15; 49.90; 49.16;
45.06; 43.16; 24.91; 15.50. 19F NMR (200 MHz, CDCl3)
d: 70.44.
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C6D6) d: 7.51 [d, J = 7.4 Hz, 2H]; 7.06–6.87 [m, 8H]; 4.68–
4.58 [m, 1H]; 4.52 [d, 1H, J = 18.0 Hz]; 4.41 [d, 1H,
J = 14.4 Hz]; 3.97 [d, 1H, J = 14.4 Hz]; 3.35 [d, 3H,
J = 1.6 Hz]; 2.82 [d, J = 18.0, 1H]; 2.13 [dd, J = 12.9,
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